Endocrine Reviews, 2024, 45, 379–413

https://doi.org/10.1210/endrev/bnad037
Advance access publication 16 January 2024
Review

The Basis for Weekly Insulin Therapy: Evolving Evidence

With Insulin Icodec and Insulin Efsitora Alfa
Julio Rosenstock,1,* Rattan Juneja,2 John M. Beals,2 Julie S. Moyers,2 Liza Ilag,2
and Rory J. McCrimmon3
1
Velocity Clinical Research at Medical City, Dallas, TX 75230, USA
2
Lilly Diabetes and Obesity, Eli Lilly and Company, Indianapolis, IN 46225, USA
3

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School of Medicine, University of Dundee, Dundee DD1 9SY, Scotland, UK
Correspondence: Julio Rosenstock, MD, Velocity Clinical Research at Medical City, 7777 Forest Ln, C-685, Dallas, TX 75230, USA.
Email: [email protected].

Abstract
Basal insulin continues to be a vital part of therapy for many people with diabetes. First attempts to prolong the duration of insulin formulations
were through the development of suspensions that required homogenization prior to injection. These insulins, which required once- or twice-daily
injections, introduced wide variations in insulin exposure contributing to unpredictable effects on glycemia. Advances over the last 2 decades
have resulted in long-acting, soluble basal insulin analogues with prolonged and less variable pharmacokinetic exposure, improving their
efficacy and safety, notably by reducing nocturnal hypoglycemia. However, adherence and persistence with once-daily basal insulin treatment
remains low for many reasons including hypoglycemia concerns and treatment burden. A soluble basal insulin with a longer and flatter
exposure profile could reduce pharmacodynamic variability, potentially reducing hypoglycemia, have similar efficacy to once-daily basal
insulins, simplify dosing regimens, and improve treatment adherence. Insulin icodec (Novo Nordisk) and insulin efsitora alfa (basal insulin Fc
[BIF], Eli Lilly and Company) are 2 such insulins designed for once-weekly administration, which have the potential to provide a further
advance in basal insulin replacement. Icodec and efsitora phase 2 clinical trials, as well as data from the phase 3 icodec program indicate that
once-weekly insulins provide comparable glycemic control to once-daily analogues, with a similar risk of hypoglycemia. This manuscript
details the technology used in the development of once-weekly basal insulins. It highlights the clinical rationale and potential benefits of
these weekly insulins while also discussing the limitations and challenges these molecules could pose in clinical practice.

Graphical Abstract

Once daily basal insulins* Once weekly basal insulins*

Longer duration of action

Relative plasma insulin levels

NPH
IDet • Flatter pharmacokinetic profiles
IGlar U100 • Reduced variability
IGlar U300 • Reduced injection burden
IDeg

Basal glucose
excursions

Glucose levels
Weekly insulin

2100 0300 0900 1500 2100 Day 2 Week 2 Week 4

Time after injection

*Schematic representation of single doses © 2023 Endocrine Society

Key Words: basal insulin, once-weekly insulin, insulin icodec, insulin efsitora, peak-to-trough ratio, hypoglycemia
Abbreviations: ADA, American Diabetes Association; CGM, continuous glucose monitoring; CKD, chronic kidney disease; DKA, diabetic ketoacidosis; DTSQ,
Diabetes Treatment Satisfaction Questionnaire; ERR, estimated rate ratio; ETD, estimated treatment difference; ETR, estimated treatment ratio; FcRn, neonatal
Fc receptor; FDA, US Food and Drug Administration; FPG, fasting plasma glucose; GLP-1, glucagon-like peptide-1; HbA1c, glycated hemoglobin A1c; HGP,

Received: 5 May 2023. Editorial Decision: 13 December 2023. Corrected and Typeset: 16 January 2024
© The Author(s) 2024. Published by Oxford University Press on behalf of the Endocrine Society.
This is an Open Access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/), which
permits unrestricted reuse, distribution, and reproduction in any medium, provided the original work is properly cited.
380 Endocrine Reviews, 2024, Vol. 45, No. 3

hepatic glucose production; HSA, human serum albumin; IDet, insulin detemir; IGF-1, insulin-like growth factor-1; IGF-1R, insulin-like growth factor-1 receptor;
IgG, immunoglobulin G; IGlar, insulin glargine; IR, insulin receptor; IV, intravenous; MAD, multiple ascending dose; MAPK, mitogen-activated protein kinase;
NPH, neutral protamine Hagedorn; PD, pharmacodynamic; PK, pharmacokinetic; P/T, peak-to-trough; PYE, patient-year of exposure; QWINT, Once-Weekly
(QW) Insulin Treatment; RA, receptor agonist; SAD, single ascending dose; SC, subcutaneous; SCI, single-chain variant of insulin; t1/2, half-life; T1D, type 1
diabetes; T2D, type 2 diabetes; TAR, time above range; TBR, time below range; TIR, time in range.

development of long-acting, soluble basal insulin therapies

ESSENTIAL POINTS that prolong pharmacokinetic (PK) exposure, flatten the insu­
lin exposure profile, and lessen variability over a 24-hour pe­
• Over the last 25 years, long-acting soluble once-daily
riod to help mimic endogenous insulin action. These strategies
basal insulin analogues have improved the efficacy
produced the first generation of basal insulin analogues, insu­
and safety of treatment compared to earlier insulin
lin glargine (IGlar U100; Sanofi S/A) and insulin detemir (IDet
formulations
U100; Novo Nordisk A/S). These molecules, while seen as an
• Despite availability of once-daily insulins, adherence
advance as compared to NPH in time-action (IGlar) or vari­
and persistence on therapy are lower than desired

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ability (IDet), did not achieve all the properties desired of a
• A once-weekly insulin with a flat pharmacokinetic basal insulin (1). IGlar U100 offered a significant development
profile could reduce the injection burden and glycem­
in basal insulin therapy by demonstrating a solution formula­
ic variability, which may translate to better adher­
tion with reduced nocturnal hypoglycemia compared to NPH
ence and persistence to insulin treatment
due to its flatter metabolic activity profile and by introducing
• Insulin icodec, an acylated insulin analogue, and in­
the concept of a simple treat-to-target dosing regimen for
sulin efsitora alfa, an Fc-fused insulin receptor agon­
weekly titration based on daily fasting glucose levels that
ist, are in late-stage clinical development as
changed the standards of care for insulin management in
once-weekly insulins
type 2 diabetes (T2D) (3-5). However, despite these advances,
• Available clinical data from insulin icodec and insulin
some patients still require twice-daily dosing of IGlar U100 or
efsitora show comparable glycemic control to
IDet (1). Subsequent iterations of these first-generation basal
once-daily analogues with a generally similar risk of
insulin analogues, by formulation and/or chemical modifica­
hypoglycemia
tions, yielded a longer acting second generation of analogues:
• Education around the new dosing regimens for once-
IGlar U300 (Sanofi) and insulin degludec (IDeg U100, IDeg
weekly insulins will be needed to facilitate safe and
U200; Novo Nordisk). These second-generation basal insulins
effective use of these molecules deliver a true once-daily basal profile for nearly all patients.
Despite the availability of these improved once-daily options,
effective basal insulin therapy can be challenging due to dose ad­
Over the past century, since the discovery of insulin, tremen­ ministration timing, frequent dose adjustments, and a high
dous advances have been made to create insulin molecules number of injections (∼365/year) (1). Collectively, these affect
that can more closely match physiologic insulin secretion pro­ adherence and result in only approximately 5% to 45% of pa­
files. Therapies have evolved from the initial crude pancreatic tients achieving desired glycemic goals in the real world (6-8).
extracts with beef or pork sources to biosynthetic molecules In the past decade, protein engineers have harvested learn­
allowing for amino acid changes and chemical modification. ings from these first- and second-generation basal insulin ana­
The quest has been, and continues to be, the achievement of logues, as well as other clinically tested basal insulins (eg,
exogenous insulins that mimic endogenous secretion of both insulin peglispro; Eli Lilly and Company), to design molecules
bolus and basal time-action. that integrate novel strategies to create a third generation of
The first attempts to prolong the duration of time-action fo­ basal insulin therapies. The goal of these third-generation in­
cused on altering the formulations of short-acting insulin. sulins is to extend the time-action profile to allow for once-
Beginning in the 1930s, intermediate- to long-acting formula­ weekly administration and to more closely mimic endogenous
tions were developed by the addition of excess zinc (lente and ul­ basal insulin distribution profiles. The development of a once-
tralente) and/or protamine (neutral protamine Hagedorn [NPH] weekly basal insulin with a longer, flatter exposure profile,
insulin and protamine zinc insulin) (1). These amorphous and/or coupled with controlled tissue distribution properties and at­
crystalline formulations were designed to slow the absorption of tenuated potency at the insulin receptor (IR) could reduce
insulin from the subcutaneous (SC) depot but required the pa­ variability by controlling fluctuations in glucose levels during
tient to resuspend prior to twice-daily or once-daily administra­ the week, while maintaining an acceptable and manageable
tion. These formulations were associated with unpredictable hypoglycemia profile. However, an important limitation
glucose control and higher than desired rates of hypoglycemia, with these insulins is the inability to rapidly adapt to changes
which were attributed to (a) insufficient time-action that re­ in insulin requirements, which the body achieves with con­
quired multiple daily injections; (b) challenges calculating dose trolled endogenous insulin secretion.
requirements due to high glucose control variability; (c) higher An additional premise to consider is that patients’ prefer­
than desired variability in dissolution of the suspension in the ence for fewer injections may facilitate improved insulin ac­
heterogeneous SC space; and (d) inconsistent homogenization ceptance, adherence, and treatment persistence as patients
of the suspension (2). These limitations were magnified further would likely prefer 52 instead of 365 injections per year. In pa­
in a basal/bolus dosing regimen. tients with type 1 diabetes (T1D), weekly insulins could bene­
Over the last 25 years, major advances in insulin engineer­ fit, not only with the reduction in injection number, but
ing, coupled with creative formulation designs that enhanced potentially from a reduction in the frequency of recurrent dia­
insulin self-association properties, have resulted in the betes ketoacidosis in those at highest risk, for example,
Endocrine Reviews, 2024, Vol. 45, No. 3 381

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Figure 1. Insulin pharmacokinetics. Schematic PK/PD profile for basal insulin after administration of a single dose after maintenance phase (steady state)
has been achieved highlighting key PK/PD parameters. P/T ratio: difference between the highest and lowest concentration of injected insulin at steady
state; and t1/2: the time it takes for 50% of the drug to be eliminated relative to the Cmax. AUC, area under the curve; Cmax, peak insulin concentration
reached; GIR, glucose infusion rate; GIRmax, time of maximum glucose infusion rate; INS, insulin (analogue) concentration; PD, pharmacodynamic; PK,
pharmacokinetic; Tmax, time when peak insulin concentration is reached. Reproduced with permission from Heise and Meneghini (9).

adolescents whose compliance with insulin therapy can be in­ used, wherein, circulating insulin levels build on the remaining
consistent. However, to use these insulins safely, health care insulin from previous injections prior to elimination. The
providers and patients will be required to learn new dosing amount of accumulation is dependent on the half-life (t1/2) of
regimens that are unfamiliar today. These include (a) the po­ the basal insulin, the insulin dose, and the frequency of dosing.
tential need for an initial one-time loading dose, (b) the need With consistent dosing, a steady state is eventually achieved.
to learn how to transition between once-daily and once- Typically, a time period equivalent to 3 to 5 half-lives is required
weekly insulins, (c) patient management for missed doses or to reach steady state. Depending on the rigor of the definition,
accidental dosing errors, and (d) patient management during PK levels reach approximately 90% of the steady-state concen­
hospitalizations, surgery, fasting, and exercise. tration after 3×t1/2 and approximately 99% after 5×t1/2 (9). A
This review is intended to provide in-depth information level of 90% (∼3×t1/2) is considered by many to be the threshold
that describes the technology supporting the development of for clinically relevant steady state. Once at steady state, insulin
once-weekly basal insulins, and address the strategies ex­ levels will not increase further, as long as similar doses are ad­
plored to safely create a circulating “pool” or “reservoir” of ministered at appropriately spaced intervals relative to the half-
insulin capable of engaging the IR over a weekly time frame life of the insulin (9). Conversely, increasing insulin dose before
and mimicking the effects of endogenous insulin action. It steady state is reached could result in overinsulinization and in­
highlights the clinical rationale and potential benefits of week­ duce hypoglycemia.
ly insulins while also and importantly, discusses the challenges Peak-to-trough (P/T) ratio refers to the difference between the
these molecules could pose for clinical practice. peak and nadir concentrations of the injected insulin. P/T ratio is
commonly used only in the context of therapeutic insulins since
endogenously secreted insulin in individuals without diabetes
Terminology With Exogenously Administered
closely and constantly matches glucose excursions. Notably, a
Insulins high P/T ratio is desirable for a given dose of rapid-acting, pran­
Exogenously administered basal insulins have been designed to dial insulin and a low P/T ratio is desirable for a basal insulin (see
mimic the prolonged time-action of secreted endogenous insulin, Fig. 1 and 2A). One of the consequences of prolonging insulin
that is, create a PK profile (serum insulin concentration) for in­ time-action is enabling therapeutic accumulation and the subse­
sulin that concomitantly drives intermeal pharmacodynamic quent flattening of the PK profile, resulting in a lower P/T ratio
(PD) effects on glucose. In this context, key terms will be used (9). The P/T ratio reflects variability, which is affected by the
to describe therapeutic basal insulin properties (Fig. 1). rate of absorption, the molecule’s half-life, and the dosing interval
With the development of ultra long-acting basal insulins, clini­ of the insulin. A low P/T ratio indicates the insulin has a consistent
cians can be concerned with insulin doses overlapping or accu­ plasma exposure profile and thus, a more predictable concentra­
mulating; consequently, it is important to understand the tion of insulin available between dosing intervals (9). If appropri­
concept of insulin “steady state.” This concept refers to a state ately generated, a flatter PK profile can decrease within- and
where a dynamic equilibrium in insulin concentration exists between-day glucose variability, potentially reducing the risk of
within therapeutic limits between doses. To reach steady-state hypoglycemia, as well as enhancing patient satisfaction because
conditions with basal insulins, controlled accumulation is the PD effect will be more predictable.
382 Endocrine Reviews, 2024, Vol. 45, No. 3

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Figure 2. PK profiles of rapid-acting insulin and basal insulins. A, PK profile of a rapid-acting insulin analogue with a t1/2 of 1.3 hours (left) and basal insulins
(right) with a t1/2 of 6 hours (NPH insulin), 12.5 hours (insulin glargine U100), or 25 hours (insulin degludec). B, Effect of missed dosing and double dosing on PK
profiles of rapid-acting insulin and basal insulins at steady state. As shown in the figure, the effects of missed or double dosing are greatest with basal insulin
having a shorter half-life. NPH, neutral protamine Hagedorn; PK, pharmacokinetic. Reproduced with permission from Heise and Meneghini (9).

With current basal insulins, this attribute was manifested in signaling, distribution, clearance, and time-action. It is, how­
the second-generation once-daily basal insulin analogues, ever, important to note that even the best therapeutic basal insu­
IDeg and IGlar U300, which demonstrated longer time-action lins fail to truly mimic pancreatic-secreted insulin (19).
profiles and lower hypoglycemia risk compared to IGlar U100
(10-16). Iterations in basal insulin have led to both a reduction Endogenous Insulin
in nocturnal and daytime hypoglycemia (1), resulting in dia­ Structure
betes treatment guidelines recommending IDeg and IGlar
Mature endogenous insulin is a 2-chain hormone, composed of
U300 as preferred basal insulin therapies (17).
51 amino acids, that is enzymatically derived from a single-chain
Loading dose/one-time starting dose refers to an initial one-
proinsulin in the β cell of the pancreas (2). The self-association
time dose used to shorten the time to reach steady state. For
and zinc-binding properties of mature insulin facilitate storage
an insulin with a very long half-life, such as weekly insulins, a
in the secretory granules as stable hexamers. On secretion
loading dose may be useful in rapidly achieving efficacious insu­
from the pancreas into the portal vein, hexameric insulin disso­
lin concentrations to safely enable patient-tailored insulin titra­
ciates into the active monomeric conformation (20).
tions to reach glucose targets. Loading doses are not used with
current basal insulins; however, loading doses were used for Receptor signaling
beef ultralente insulin, an early long-acting basal insulin in cer­ Monomeric insulin signals through the IR, a transmembrane
tain circumstances to shorten time to steady state (18). tyrosine kinase receptor, with an extracellular α-subunit and
an intracellular β-subunit (21). Insulin binding to the
α-subunits elicits a series of phosphorylation events, which
Physiological Basis for Basal Insulin
have been extensively reviewed previously (21, 22). These
Replacement phosphorylation events mediate pleiotropic intracellular ac­
To help understand why therapeutic once-weekly basal insulins tivities including, but not limited to, induction of glycogenesis
could be an advantage in clinical practice, it is useful to identify and stimulation of glucose uptake through translocation of
the similarities and differences between endogenously released glucose transporter type 4 (GLUT4) to the cell membrane,
and SC administered therapeutic insulin with regard to which is responsible for glucose uptake in muscle and fat (21).
Endocrine Reviews, 2024, Vol. 45, No. 3 383

Insulin distribution Insulin receptor uptake and degradation

Biosynthesis Insulin

Clatherin-dependent Caveolar
IR endocytosis endocytosis
p p
p p
Pancreas pH~7 pH~7
Rapid IR
Portal vein recycling

~50% first-pass clearance

Late endosome Enzyme

Insulin
Secondary hepatic

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extraction pH<7
(~30% clearance)
Liver pH<7 Early endosome

Periphery
Lysosome
Glucose uptake ≤25% clearance degradation
Endosome IR
recycling compartment

Adipose Skeletal
tissue muscle Kidney

Figure 3. Metabolic pathway for endogenous insulin. Left, The distribution of endogenous insulin through the body. Endogenous insulin is produced in
the pancreas. It is then transported to the liver through portal circulation. The majority of insulin (40%-80%) is cleared by the liver by hepatocytes with
approximately 50% cleared through first-pass extraction from the portal vein. The insulin exiting the liver is distributed to the adipose tissue muscle and
kidney, where it controls the utilization of glucose and free fatty acids for energy. Any insulin that is not distributed to the parenchyma is either filtered by
the kidney (∼25%) or recycled back to the liver by the arterial blood flow, where an additional approximately 30% is cleared. Right, Generalized mech­
anism for insulin intracellular degradation via IR-mediated endocytosis in the liver. Insulin binds to the IR and forms a complex inducing internalization into
the cell via 2 routes, clatherin-dependent or caveolar endocytosis. Receptor-bound insulin is released in the acidic early endosome and is degraded by
enzymes that include protein disulfide isomers, insulin-degrading enzyme, and cathepsin D. The IR is recycled back to the cell surface by the rapid IR
recycling and endosome IR recycling compartment pathways. Any degraded IR and insulin fragments are routed to the lysosome for further degradation.
IR, insulin receptor.

Broadly speaking, endogenous insulin mediates metabolic ac­ Biology

tivities via the AKT/protein kinase B (PKB) metabolic pathway The biology of insulin has been extensively reviewed (29).
(23). Additionally, sustained IR stimulation can induce a mito­ The energy demands of the human body (ie, adenosine tri­
genic response via the mitogen-activated protein kinase phosphate [ATP] production) throughout the day uses a var­
(MAPK) pathway (23). This pathway plays a minor role, if iety of substrate sources (glucose, glycogen, fatty acids,
any, with endogenously secreted insulin since serum concentra­ ketones, and more rarely amino acids) depending on the
tions are generally low and highly regulated; however, thera­ presence of insulin and glucagon, hormones that facilitate
peutic insulin, specifically insulin analogues, require greater
energy-source storage and utilization (30). Insulin mediates
consideration of the MAPK pathway and the related insulin-like
numerous cellular effects on tissues including, but not lim­
growth factor-1 (IGF-1) receptor signaling pathway. Thus, it is
ited to, muscle, adipose, liver, and kidney tissues. Notably,
important that any new insulin be characterized to ensure the
metabolic and mitogenic signaling properties are appropriate, insulin controls the use and storage of (a) carbohydrates by
relative to native insulin (24). increasing glucose uptake, enhancing glycolysis, driving
On binding to the receptor, phosphorylation of the β-subunit glycogen synthesis, and attenuating glycogen breakdown;
controls IR internalization and trafficking through receptor- (b) lipids by attenuating lipolysis to regulate availability of
mediated endocytosis (22, 23). In acidified intracellular endo­ free fatty acids, increasing triacylglycerol synthesis for trigly­
somes, insulin is released from the IR, allowing various enzymes ceride formation, increasing uptake of triglycerides from the
to degrade the hormone, most notably, insulin-degrading en­ blood, and attenuating fatty acid oxidation; and (c) proteins
zyme (IDE) (25), cathepsin D (26, 27), and protein disulfide by enhancing uptake of some amino acids, accelerating pro­
isomerase (Fig. 3) (28). This postinternalization degradation in tein synthesis in muscle, and downregulating protein degrad­
cells is the major pathway for insulin elimination. As discussed ation (31).
later, the reduced affinity of IR binding with once-weekly insu­ Consequently, in healthy individuals, insulin is continuous­
lins and subsequent reduced postreceptor clearance is one mech­ ly released from pancreatic β cells to maintain euglycemia by
anism by which the duration of action of these once-weekly controlling both endogenous glucose production in the liver,
insulins is prolonged. and to a lesser extent from the kidneys, as well as exogenous
384 Endocrine Reviews, 2024, Vol. 45, No. 3

Subcutis
Transcytosis Vesiculo-vacuolar
organelle transport

Endothelium JAM A VE cadherin

Occludin JAM
Claudin 5 PECAM-1
Blood

Tight junction Adherens junction Large pore

(≤ 1 nm) (≤ 3 nm) (25-30 nm)
~0.2% total surface area ~0.002-0.02% total

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Insulin analog hydrodynamic size ≤3 nm
Insulin analog hydrodynamic size ≥3 nm
B
Muscle

Transcytosis Vesiculo-vacuolar
organelle transport
Endothelium

JAM A VE cadherin
Occludin JAM
Claudin 5 PECAM-1
Blood

Tight junction Adherens junction Large pore

(≤ 1 nm) (≤ 3 nm) (25-30 nm)
~0.2% total surface area ~0.002-0.02% total

Human Unbound HSA-bound

Efsitora
insulin icodec icodec
Increasing hydrodynamic size

Figure 4. Pore theory of insulin transport pathways. Insulin molecules, based on their hydrodynamic size, can use multiple paths to reach circulation from
A, the subcutaneous space and B, the parenchymal tissue from the circulation. Insulins may use vesicular-vacuolar organelle transport, or transcytosis
through binding to insulin receptors for transcellular transport. Insulin molecules with a hydrodynamic size less than 3 nm such as human insulin and
unbound icodec can also use adherens junctions for paracellular transport. Very large insulin molecules such as efsitora (molecular weight 64.1 kDa) and
HSA-bound icodec (molecular weight ∼73 kDa) are thought to predominantly use the large pores (25-30 nm). Both are likely absorbed from the sub­
cutaneous depot via the slow-flowing lymphatic system due to their large hydrodynamic size, which slows the release into the circulation and limits
parenchymal exposure. HSA, human serum albumin.

glucose uptake from dietary sources during intermeal and Whole-Body distribution
mealtime periods (32). This insulin secretion is pulsatile In healthy individuals, 40% to 80% of the pancreatic-secreted
with a frequency of these secretions occurring every 5 to 15 insulin is used and cleared through the IR in hepatic tissues
minutes (33-35). In the fasted state, insulin release is reduced (see Fig. 3) (37-40). This level of insulin extraction by hepatic
and referred to as a basal profile. In the fed-state, insulin secre­ tissues is attributed to both first-pass extraction from the por­
tion is increased (bolus secretion) to attenuate hepatic glucose tal vein (∼50%) and secondary extraction from hepatic arter­
production (HGP) and increase glucose utilization. In healthy ial blood supplies (∼30%) (41, 42). Specifically with first-pass
individuals, the pancreatic insulin demands to maintain eugly­ extraction, the locally high insulin concentration, coupled
cemia are parsed to approximately 50% for the basal periods with the high affinity of native insulin for the IR, ensures ef­
and approximately 50% for postprandial periods (32). The fective suppression of HGP by limiting glycogenolysis (43)
pulsatile secretion of endogenous insulin is layered onto a cir­ and gluconeogenesis (44). The creation of this hepatic/periph­
cadian rhythm with the rate of insulin secretion rising during eral insulin concentration gradient by hepatic uptake and
the morning hours, peaking in the afternoon, and then de­ clearance modulates insulin exposure to peripheral tissue rela­
creasing during the evening and when sleeping (34, 36). This tive to the liver (41, 42), thus controlling glucose uptake from
circadian periodicity helps control endogenous insulin release the blood.
to compensate for the effects of insulin counterregulatory Insulin exposure to parenchymal tissues (eg, adipose and
hormone surges in the morning (eg, growth hormone and cor­ muscle tissue) is controlled by paracellular junctions in the
tisol), while facilitating increased nocturnal HGP to compen­ capillary endothelium (Fig. 4). The perfusion of these tissues
sate for reduced intermeal glucose levels. is adequately described by “pore theory,” wherein the
Endocrine Reviews, 2024, Vol. 45, No. 3 385

hydrodynamic size of insulin enables transport across the ca­ for insulin precipitation at neutral pH in the SC depot
pillary endothelium. Transport across the capillary endothe­ (Fig. 5), slowing the release of insulin into the circulation for
lium takes advantage of the high rate of filtration and durations of time up to 18 to 24 hours in most patients and
reabsorption of fluid across adherens junctions, which are producing a therapeutic half-life of 12 to 15 hours (1, 19, 55).
less than or equal to 3 nm in diameter and account for ap­ Being a solution, IGlar U100 did not require resuspension,
proximately 0.2% of the total surface area of the capillary unlike NPH and ultralente. This, together with its long half-
endothelium and, to a lesser extent, large paracellular gaps, life, provided extended glycemic control with less variability.
which are estimated to be 25 to 30 nm in diameter and In addition, the reduced P/T ratio of IGlar U100, when com­
account for 0.002% to 0.02% of the total surface area of pared to NPH, lowered the risk of nocturnal hypoglycemia,
the capillary endothelium (19, 29, 45). These latter large para­ providing a tangible benefit and clinical advance in basal
cellular gaps should not be confused with the fenestrated insulin replacement (1).
sinusoidal endothelial of the liver and kidneys, which are A different strategy to extend the time-action profile and re­
gaps greater than 100 nm in diameter. duce variability of action was employed with IDet U100 ap­
Lastly, insulin perfuses the kidney where approximately proved in 2004 (Europe)/2005 (United States) and IDeg
25% of the extrahepatic insulin is cleared (46-48), making U100 and U200 approved in 2015 (1). Both products, which

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this organ the second most important organ for insulin clear­ are also solution formulations, used a modified insulin (ie,
ance (Fig. 3). In the kidney, insulin filtration occurs in the des-B30), which was conjugated to an acyl chain at a lysine
proximal tubule by diffusion across the glomerular capillaries site (ie, Lys-B29) (56, 57). The acyl chains introduced 2 im­
and is taken up by the IR in the peritubular capillaries. Insulin portant time-action properties: specifically, higher-order hex­
engagement of the IR in the kidney also produces a pleiotropic amer association in the SC depot and reversible binding to
array of activities, including glucose uptake by podocytes, human serum albumin (HSA) in the SC, serum, and interstitial
maintenance of barrier permeability, stimulation of glucose fluids. IDet used a 14-carbon fatty acid chain while the
reabsorption, control of kidney gluconeogenesis, and insulin second-generation IDeg incorporated a 16-carbon acyl diacid,
degradation (49). Notably, the clearance of insulin can be which further extended the duration of action (56, 57). These
slowed in patients with diabetic nephropathy/chronic kidney modifications introduced higher level association in the SC de­
disease (CKD), necessitating dose adjustment of some insulin pot, that is, dihexamerization of IDet hexamers (56) and mul­
therapies, such as human insulin and IGlar, if renal function tihexamerization of IDeg hexamers (57), which protracted
deteriorates, as discussed later (50-52). release of monomeric insulin into the circulation (see Fig. 5).
The reversible binding to HSA also creates a bound “reser­
Clearance voir” of nearly inactive insulin, which can reversibly dissoci­
Endogenous insulin has a biological half-life of 3 to 10 mi­ ate from HSA to yield an acylated insulin derivative capable
nutes (29, 53) or absolute clearance rate from the blood of of engaging the IR.
32 to 84 L/h (19), which is rapid and akin to glucagon-like The soluble nature of these acylated insulins, in both the
peptide-1 (GLP-1), a small peptide with a clearance rate of formulation and in the SC depot, reduced variability relative
145 L/h (54). This rapid clearance and elimination of insulin to the first-generation basal insulins NPH and ultralente,
from the circulation is directly linked to the distribution to tis­ which require resuspension prior to use. However, the short
sues (liver, kidney, and parenchyma) where IR-induced endo­ duration of action of IDet, ie, t1/2 = 5-7 hours, and clearance
cytosis leads to rapid plasma clearance followed by of 8.4 L/h, which is only approximately 10 times slower
intracellular enzymatic degradation (19, 25) (see Fig. 3). than endogenous insulin, necessitated twice-daily dosing in
many patients to provide adequate daily basal insulin cover­
Exogenously Administered Once-Daily Basal age, especially in those with T1D (1, 19, 58). The iteration
Insulins to IDeg increased the duration of action beyond 1 day, that
is, t1/2 = 25 hours and clearance of 2.1 L/h, which is up to
Structures and structural properties 40 times slower than endogenous insulin and attributable, in
While endogenous secretion and utilization of insulin is highly part, to stronger binding to HSA (1, 19). Collectively, these at­
regulated in healthy individuals, people with T1D with marked tributes allowed IDeg the flexibility of injection any time in an
insulin deficiency, and some people with T2D during later stages 8- to 40-hour window at steady state without losing efficacy
of the disease, are unable to meet all the insulin demands of or accumulating insulin (59). In addition, IDeg showed lower
the body, and specifically to this review, basal insulin demands. glucose variability compared to IGlar U100 and consequently
Consequently, this deficiency requires therapeutic insulin lowered the risk of hypoglycemia.
supplementation to maintain euglycemia. In this section, the IGlar U300 was introduced in 2018, by creating a more
characteristics, attributes, and limitations of currently available concentrated formulation of insulin glargine, which altered
once-daily basal insulins are discussed. precipitation properties in the SC depot and slowed insulin ab­
The creation of a desirable therapeutic basal insulin needs to sorption thereby prolonging the half-life of IGlar U300 to
address, at least, 3 primary challenges: (a) duration of action, (b) 19 hours (see Fig. 5) (19). This advance was considered a clin­
day-to-day and/or within-day SC absorption variability, and (c) ically significant improvement over IGlar U100, again by
hypoglycemia risk, especially during the overnight hours. contributing to lower glycemic variability and lower hypogly­
The first real breakthrough in addressing these challenges cemia risk compared to IGlar U100 (15, 16).
was the development of IGlar U100, an insulin analogue,
which was approved in 2000 (1). This elegantly designed basal Signaling and biology
insulin used amino acid changes to shift the isoelectric point of Exogenous basal insulin molecules, by design, were developed
insulin nearer to neutral pH. This shift allowed the prepar­ to mimic the insulin signaling and cellular biology observed
ation of IGlar in an acidic unbuffered solution that allowed with endogenous insulin, that is, to bind to the IR causing a
386 Endocrine Reviews, 2024, Vol. 45, No. 3

A Glargine U100 B Glargine U300

Dilution in SC space Dilution in SC space

pH-induced Slow dilution pH-induced Slow dilution

precipitate upon injection to monomers precipitate
precip
pre cipita upon injection
njection
nje to monomers

Blood flow Blood flow

Capillary Capillary

200
Serum insulin (μU/mL)

150 Insulin glargine

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NPH insulin

Serum insulin (pmol/L)

100 150
Glargine U100
125 Glargine U300
100
50 75
50
LLOQ
25
0 0
0 6 12 18 24 0 6 12 18 24 30 36
Time (hr) Time (hr)

C Detemir D Degludec
Dilution in SC space Dilution in SC space

Hexamer Dihexamer Dimer Monomer

Mon Dihexamer Multi-hexamer
Multi-hexame Dimer
Dim er Monomer

Albumin Albumin
binding binding

Bloodd flo
Bloo floww Blood flo
Blood floww
Capillary Capillary

800 200
3000 300

2500 Insulin detemir 250 600 150

Serum degludec (pmol/L)

Degludec 0.4U/kg
Serum glargine (pmol/L)

Serum glargine (pmol/L)

Serum detemir (pmol/L)

Insulin glargine U100 Glargine U300 0.4U/kg

2000 200
4000 100
1500 150

1000 100
2000 50
500 50

0 0 0 0
0 6 12 18 24 0 6 12 18 24
Time (hr) Time (hr)

Figure 5. Daily basal insulin analogues. Adapted with permission from Hirsch et al (1). A, Left: Mechanism of protraction of IGlar U100 through
pH-induced precipitation at the SC space. Right: PK profiles of IGlar U100 compared to NPH (each 0.3 U/kg) from a euglycemic clamp study in 20 indi­
viduals with T1D. Data from Lepore et al (55). B, Left: Mechanism of protraction of IGlar U300 through pH-induced precipitation at the SC space. Me­
chanism is the same as for IGlar U100 but with a more sustained release due to the more concentrated formulation resulting in slower release of insulin
glargine from the precipitate. Right: PK profile of IGlar U300 compared to IGlar U100 (each 0.4 U/kg) from a euglycemic clamp study in 18 individuals with
T1D. Data from Becker et al (13). C, Left: Mechanism of protraction of IDet through di-hexamer formation in the SC space and binding to albumin. Right:
PK profile of IDet compared to IGlar U100 (both 0.35 U/kg) from a euglycemic clamp study in 12 patients with T1D. Data from Porcellati et al (58). D, Left:
Mechanism of protraction of IDeg through sustained release from multihexamer formation and binding to albumin. Right: PK profile of IDeg compared to
IGlar U100 (both 0.4 U/kg) in 22 patients with T1D. Data from Heise et al (11). NPH, neutral protamine Hagedorn; PK, pharmacokinetic; SC, subcutaneous;
T1D, type 1 diabetes.
Endocrine Reviews, 2024, Vol. 45, No. 3 387

series of phosphorylation events that mediate pleiotropic in contrast to endogenous insulin, in which the majority of in­
intracellular activities as discussed earlier. The first- and sulin clearance occurs in the liver (40), exogenous unmodified
second-generation long-acting soluble basal insulins demon­ insulin and human NPH insulin are cleared primarily by the
strate binding affinities for the IR of approximately 50% of kidney (30%-80%) (72). With regard to acylated basal insu­
human insulin for IGlar (60) and approximately 15% of hu­ lins, IDet and IDeg, renal clearance is minimized by reversible
man insulin for IDet (61) and IDeg (62). Although weaker binding to HSA, which is not readily filtered by the kidney due
binding agonists, relative to human insulin, these basal insu­ to the size and negative charge; consequently, these acylated
lins generate the same insulin signaling and cellular biology insulins increase their plasma concentration. However, as dis­
pathway activation observed with endogenous insulin (63). cussed earlier, acylated insulin distribution to the parenchyma
The engineering/acylation of these exogenous insulins ne­ is restricted to transport of the limited amount of unbound
cessitate greater scrutiny of mitogenicity mediated by the acylated insulin across the adherens junctions, or hypothetic­
MAPK pathway. Of particular importance is the mitogenic ally, HSA-bound acylated insulin across the less prevalent
potential of nonnative basal insulin analogues, where the rela­ large paracellular gaps. This begins to shift the hepatic/periph­
tive mitogenic-to-metabolic activity needed to be similar to eral gradient back toward that observed with endogenous in­
native human insulin to prevent risk of cell proliferation sulin (67-69, 73). When studied in patients with renal failure

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(oncogenic risk) greater than native insulin (64). This was (including end-stage renal disease) no PK differences were
an unwarranted concern raised for IGlar U100 that was dissi­ seen for IDeg (74) or IDet (75). In contrast, the time-action
pated with the better understanding of the actions of IGlar me­ and clearance of IGlar is completely dependent on controlling
tabolites M1 and M2 (65). The main consideration, however, absorption from the SC and tissue distribution, which is simi­
remains, that the mitogenic potential of all insulin analogues is lar to exogenous human insulin. Although the PK of IGlar has
something that must be considered. not been evaluated in renal failure, some studies with human
insulin have shown increased plasma insulin levels in the set­
Whole-Body distribution ting of compromised renal function necessitating dose reduc­
tion, which may therefore also be necessary in patients on
As with endogenous insulin, parenchymal tissues can be exposed
IGlar (76, 77).
to therapeutic basal insulins through paracellular junctions in
the capillary endothelium as described by the pore theory out­
lined previously. Depending on their hydrodynamic size, some Limitations With Once-Daily Basal Insulins
basal insulins (ie, human insulin, IGlar, unbound IDet, and un­ Distribution challenges
bound IDeg) can use adherens junctions less than or equal to
The goal of basal insulin replacement therapy is to attempt to
3 nm to cross the capillary endothelium, whereas larger mole­
mimic endogenous basal insulin activity. As discussed, unlike
cules (ie, HSA-bound IDet, HSA-bound IDeg) are hypothetically
endogenous human insulin, all currently available once-daily
limited to the less prevalent 25- to 30-nm large paracellular gaps
basal insulin analogues are administered in the SC space; con­
(see Fig. 4) (19). Consequently, the basal insulin therapy em­
sequently, the hepatic/peripheral concentration gradient gen­
ployed dictates which paracellular junctions can be used and
erated with endogenous insulin secretion is lost (2, 41). This
thus control peripheral exposure. However, it should be noted,
can lead to underinsulinization of the liver and challenges
that all of these insulin analogues can access tissues with fenes­
with effectively controlling HGP. Moreover, attempts to in­
trated sinusoidal endothelia.
crease hepatic insulinization with human insulins and insulin
Administration of insulin by SC injection not only alters the
analogues can be fraught with challenges of overinsulinization
plasma concentration and time-action, but also distribution of
of the peripheral tissues, which can result in increased risk of
the hormone to hepatic and parenchymal tissues. Notably,
hypoglycemia and weight gain (41). These limitations are par­
most therapeutic insulins will distribute equally across hepatic
ticularly applicable to human insulin formulations (eg, NPH)
and extrahepatic tissues; therefore, with therapeutic insulin,
and IGlar, whereas evidence suggests that acylated insulin
the periphery can experience relative overinsulinization and
molecules (eg, IDet and IDeg) may possess better hepatopre­
the liver underinsulinization (19). Consequently, patients
ferential profiles (41, 67, 73, 78, 79).
can experience inadequate suppression of HGP with thera­
Preclinical and clinical research over the past decade has high­
peutically administered insulins (66-71) This is in contrast
lighted the value of insulin analogues with enhanced hepatic in­
to endogenous insulin in mammals, where insulin secretion
sulinization (67, 69-71). Insulin analogues that exhibit a more
is directly into the portal vein to initially perfuse the liver
hepatoselective profile with controlled peripheral exposure
where approximately 50% is used to control HPG, thus min­
have the potential to mimic the hepatic/peripheral insulin con­
imizing systemic insulin concentrations through hepatic util­
centration gradient seen with endogenous insulin (41). Insulin
ization coupled with intracellular degradation (41, 42). To
peglispro, a 25.8-kDa molecule consisting of a 20-kDa poly­
achieve sufficient insulin activity at the liver without raising
ethylene glycol (PEG) chain covalently bound to lysine-B28
peripheral insulin levels excessively (with resulting risk of
of insulin lispro, was developed to try to provide a more
hypoglycemia), the next generation of once-weekly basal insu­
“physiological” insulin profile (80). The distribution properties
lins need to control peripheral exposure to mimic the hepatic
of insulin peglispro mimic, to a degree, the hepatic/peripheral
to peripheral gradient of endogenous insulin.
distribution gradient observed in normal physiology (80). The
large hydrodynamic size of insulin peglispro slowed exposure
Clearance to the parenchyma by limiting access to only large paracellular
As with endogenous insulin, the plasma concentration junctions (25-30 nm), while still allowing facile passage into
of exogenous basal insulins is highly linked to tissue distribu­ the liver tissue via fenestrations (100-200 nm) in the hepatic si­
tion (liver, kidney, and parenchyma) and the associated nusoidal endothelium. Insulin peglispro demonstrated a longer
IR-induced endocytosis and enzymatic degradation. However, half-life (24-46 hours) and slower clearance (1.3 L/h), which
388 Endocrine Reviews, 2024, Vol. 45, No. 3

was approximately 65 times slower than native insulin (19). peglispro, have guided engineering strategies that have pro­
Moreover, insulin peglispro demonstrated promising results by duced 2 once-weekly insulin therapies in late-stage clinical de­
attenuating peripheral glucose uptake at comparable HGP sup­ velopment; insulin icodec (icodec or IDec; Novo Nordisk) and
pression levels to IGlar U100 in healthy individuals (69), and pa­ insulin efsitora alfa (efsitora or basal insulin Fc or BIF; Eli
tients with T1D (70, 80, 81). A pooled analysis of 5 clinical trials Lilly and Company) (86, 87). These molecules use similar strat­
demonstrated reduced nocturnal hypoglycemia with insulin pe­ egies, but with some key differences, to extend basal activity.
glispro compared to IGlar (82). However, because of hepatic Most notably the attributes include (a) significantly attenuated
side effects, notably, increases in alanine transaminase (ALT), IR binding affinity that appropriately modulates activation as a
possibly related to hepatobiliary clearance of PEG, and an al­ function of concentration and (b) secondary binding strategies
tered hepatic fat distribution profile relative to IGlar, the devel­ to either HSA (icodec) or the neonatal Fc receptor (FcRn) (efsi­
opment of insulin peglispro was discontinued in 2015 (80). tora) to extend the time-action profile, slow clearance, and con­
trol tissue exposure. These characteristics appear to provide,
Pharmacokinetic variability ultra-long-acting basal insulins that could simplify patient usage
The PK and PD variability of the once-daily basal insulins are, and may contribute to improved adherence for patients.
in part, affected by absorption differences from disparate SC Icodec recently completed an extensive phase 3 program

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depot sites, physical state of the insulin (ie, crystalline, (ONWARDS trials) (88) and has been submitted for regula­
amorphous precipitate, or solution), and frequency of dosing tory review with first decisions anticipated in 2024 (89).
as a function of the half-life/clearance of the insulin. As de­ Efsitora completed a phase 2 program and has commenced
scribed earlier, the current twice daily/once-daily basal insulin phase 3 trials (QWINT trials). Both insulins are designed for
analogues have altered their rates of absorption either through once-weekly administration and may use one-time loading-
precipitation and redissolution (IGlar) or via higher-order dose strategies; consequently, the molecules have the potential
hexameric and HSA-association imparted by the addition of to introduce an advancement in basal insulin replacement,
acyl chains (IDet and IDeg). Notably, IGlar U100 demon­ which was established over the past 20 years with the
strated more variability compared to IDet and IDeg (83, 84), treat-to-target approach (4). The development principles
due, in part, to redissolution of the precipitated/insoluble underpinning these insulins are discussed next and then subse­
state of insulin in the SC. Furthermore, as the half-life of the quently, emerging clinical data with once-weekly insulins are
basal insulin is prolonged, the P/T ratio can be reduced by en­ discussed.
abling therapeutic accumulation (9, 85). These longer-half lives
and reduced P/T ratios can lessen the effect of missed dosing
and double dosing on PK profiles as described in Fig. 2B.
Prolonging Time-Action
With once-daily basal therapies with exposure profile of less Icodec and efsitora use multiple novel mechanisms to extend
than 1 day, each injection presents the patient with variation time-action.
that is independent from previous injections; however, therap­
ies that have longer half-lives than dosing frequency, such as
Circulating “reservoir” of insulin for prolonging
IDeg, can average variability from prior injections allowing
glucose-lowering activity
the patient to buffer the stochastic nature of an individual
absorption process (Fig. 5D). To date, a primary tool used for extending time-action is con­
trolled SC release from the injection depot. As noted earlier
with the once-daily acylated insulins, IDet and IDeg, hexame­
Attributes of an Ideal Basal Insulin ric and HSA association control the distribution of active
Theoretically, an ideal basal insulin therapy may (a) possess a monomeric insulin species that can cross the capillary endo­
PK profile that continuously controls basal glucose produc­ thelium to access peripheral tissues (90, 91). Moreover, bind­
tion (more physiological); (b) possess a PK and PD profile ing to HSA minimizes both insulin activity and first-pass
that minimizes day-to-day variability (more predictable); (c) clearance by the kidneys.
mimic the hepatic/peripheral insulin gradient seen with en­ Interestingly, although once-weekly icodec is also an acylated
dogenous insulin (more physiological), thus minimizing over­ insulin and forms hexamers, it deviates from its precursors (ie,
insulinization of the extrahepatic tissue and attenuating the IDet and IDeg) in that it does not form higher-order dihexamers
risk of hypoglycemia (safer); (d) reduce the frequency of injec­ or multihexamers (Fig. 6). Icodec protracts time-action through
tions (greater acceptance, adherence, and persistence); (e) sim­ reversible, higher-affinity binding to HSA resulting in a large
plify dosing (greater adherence and persistence); and (f) be hydrodynamic size insulin/HSA complex that circulates system­
responsive to changes in glucose (more physiological). In the ically, creating a longer-lived reservoir in the blood for con­
next section we will describe the technology used to develop trolled active insulin generation for basal glucose control (see
once-weekly basal insulins to address some of the challenges Fig. 6) (86, 92). The molecular weight of unbound (free) icodec
observed with once-daily basal insulin analogues and assess is 6.4 kDa (93). The hydrodynamic size of free icodec is likely
which of the attributes of an idealized basal insulin these mol­ capable of using adherens junctions for absorption across the
ecules can achieve. capillary endothelium from the SC space to the blood
(Fig. 4A), and subsequent distribution to the parenchyma
(Fig. 4B), whereas larger HSA-bound icodec (molecular weight
Development Principles for Once-Weekly
∼73 kDa) is unable to use these junctions. HSA-bound icodec,
Basal Insulin therefore, likely limits absorption and distribution through
The insights afforded to scientists from the development use of the less prevalent large paracellular junctions to cross
of chemically modified insulins, that is, IGlar, IDet, IDeg, the capillary endothelium, use of the lymphatic system (94),
insulin-327 and insulin-406 (Novo Nordisk), and insulin and/or by controlling the generation of unbound icodec.
Endocrine Reviews, 2024, Vol. 45, No. 3 389

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Figure 6. Insulin icodec. A, Icodec is an acylated insulin analogue with 3 amino acid changes (TyrA14Glu, TyrB16His, and PheB25His; orange) relative to
human insulin to facilitate stability and reduce IR affinity. The reduced IR affinity tempers receptor-mediated clearance. A C20 icosane diacid is added with
a spacer and enables strong and reversible HSA-binding to prolong plasma half-life. B, Delayed icodec absorption from the subcutaneous is achieved by
diffusion controlled hexameric dissociation and binding of monomers to HSA. C, Icodec circulates primarily in an HSA-bound state with limited con­
centration of unbound icodec. The reduced insulin receptor affinity of icodec regulates binding to the IR by requiring higher local concentration for IR
engagement; thus, providing more control of glucose uptake in the parenchyma. HSA, human serum albumin; IR, insulin receptor.

Figure 7. Insulin efsitora alfa. A, Efsitora is an insulin receptor agonist that is composed of a novel single-chain variant of insulin fused to a human IgG2 Fc
domain. The insulin molecule has amino acid changes as shown in the figure to modulate IR affinity and reduce postreceptor clearance, as well as fa­
cilitate chemical stability and manufacturability. The reduced insulin IR affinity of efsitora regulates binding to the IR by requiring higher local concentration
for IR engagement; thus, providing more control of glucose uptake in the parenchyma. B, Once injected, circulating efsitora binds to FcRn within the
endothelial cells (insert). As seen in the insert, FcRn-bound efsitora is protected from degradation and is recycled back to the cell surface and into the
blood. This creates a reservoir of insulin and prolongs circulating exposure. This protection/recycling system is controlled by pH switching where in the
acidic endosome (∼pH 5.8) the Fc domain/FcRn binding is favored. However, at extracellular neutral pH environment such as in the blood (pH ∼7.2),
efsitora release from the FcRn is favored. The reduced IR affinity of efsitora regulates binding to the IR by requiring higher local concentration for IR
engagement; thus, providing more control of glucose uptake in the parenchyma. FcRn, Fc receptor; IR, insulin receptor.

The large hydrodynamic size of once-weekly insulin efsitora endogenous FcRn to extend exposure and protect the efsitora
is achieved by fusion to an Fc domain (molecular weight of ef­ from elimination due to pinocytosis (96); which enables the
sitora is 64.1 kDa) (Fig. 7) (87), which shifts absorption from creation of a systemic reservoir of available insulin for basal
the SC site to the slower flowing lymphatic system (95), and glucose control (see Fig. 7). Proteins in the blood, eg,
limits efsitora to the less prevalent large paracellular junctions immunoglobulin G (IgG), are susceptible to cellular uptake
to cross the capillary endothelium (see Fig. 4A and 4B). via pinocytosis, which is the process by which extracellular
Additionally, efsitora makes use of the FcRn recycling system solutes are taken up into a cell via small vesicles. The FcRn sys­
to prolong action. The Fc domain of efsitora binds to tem protects IgG, which contains an Fc domain, from
390 Endocrine Reviews, 2024, Vol. 45, No. 3

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Figure 8. Icodec dosing and build-up to efficacious exposure. A, Schematic depiction of the distribution of insulin icodec (red hexagons) bound to albumin
(gray) in the different biological compartments over time from initiation of once-weekly dosing (injection 1) through injection 5, showing the accumulation
of insulin icodec in the intercellular space. B, Modeling of insulin icodec concentration when dosed without a loading dose (black dashed) and with a
loading dose (black solid) compared to once-daily insulin glargine U100 (gray).

degradation in the acidic vesicles created on pinocytosis and hydrodynamically large and polar proteins in tissues is substan­
extends exposure by using pH-dependent recycling of the tially reduced relative to plasma concentrations due to this
IgG back to the blood. This protection/recycling system is con­ slow convective uptake and rapid target-mediated elimination.
trolled by pH switching; that is, in the acidic vesicles Biodistribution studies with nonbinding IgG established the
(∼pH 5.8) the Fc domain/FcRn binding is favored and protec­ range of tissue-to-blood ratio at 0.004 to 0.68 (100, 101). In or­
tion is afforded; however, dissociation is favored in the extra­ gans and tissues relevant to glucose control, antibody concen­
cellular neutral pH environment (pH ∼7.2) allowing for trations relative to plasma, were 14% and 12%, respectively
recycling (see Fig. 7) (96). Fusion proteins, such as efsitora in the kidney and liver, and 5% and 4%, respectively in adipose
(87) and dulaglutide (97), incorporate this Fc domain to create and muscle tissue (100, 101). In addition, studies with antibody
a circulating reservoir of the therapeutic agent with long and fragments of varying molecular size show that molecules of ap­
continuous action by using the FcRn recycling system. proximately 60 kDa (eg, a single-chain biospecific antibody
(scFv)2), akin to efsitora, have similar biodistribution to gluco­
Clearance neogenic organs, that is, the liver and kidney (102). Although
no studies have yet definitely shown the tissue action profile
As noted, therapeutic insulin is cleared from the blood by tis­
for efsitora, the prospects of using a systemic depot system act­
sue distribution to the liver, kidney, and parenchyma, where
ing as a reservoir for efsitora, exploiting large paracellular junc­
IR-mediated endocytosis leads to insulin degradation.
tions to regulate distribution to tissues, and attenuating IR
Consequently, slowing clearance from the body requires con­
engagement, may provide the desired control of peripheral in­
trolling tissue distribution, attenuating IR-mediated endo­
sulinization to enable once-weekly administration.
cytosis, and limiting first-pass renal filtration.
Attenuating insulin receptor–mediated endocytosis
Controlling tissue distribution Weakening IR affinity, through appropriate protein engineer­
Although no formal insulin distribution studies have been re­ ing and acylation, can attenuate receptor-mediated clearance
ported to date for these 2 once-weekly insulins, much can be in insulin-sensitive tissue by increasing the local concentration
inferred from the literature. requirement for IR engagement. This attenuated binding affin­
Preclinical insights from insulin-327 and insulin-406, 2 acy­ ity, coupled with control of available active basal insulin dis­
lated insulins with tight affinity for HSA that demonstrate tributed to extrahepatic tissue, governs IR activity and
hepatoselectivity in dogs (67, 98), coupled with clinical in­ receptor-mediated endocytosis, and, by extension, insulin
sights from IDet (73), suggest that the increased binding affin­ clearance and degradation.
ity of icodec to HSA could attenuate peripheral exposure and With icodec, reduced receptor-mediated clearance is
increase hepatic exposure. achieved by using 3 amino acid substitutions (TyrA14Glu,
Based on the evidence generated by research on antibodies TyrB16His, and PheB25His) to weaken IR affinity as well as
(99-101) and antibody fragments of varying molecular weight improve stability (see Fig. 6). Affinity modulation, coupled
(102), molecules akin to efsitora transit slowly across the with stronger albumin binding, using an icosane C20 fatty di­
vascular endothelium by convection through different sized acid, ensures the formation of a large reservoir of HSA-bound
pores in the vascular wall. Moreover, the concentration of insulin in the blood and periphery that is available for the
Endocrine Reviews, 2024, Vol. 45, No. 3 391

sustained release of active insulin, albeit with attenuated affin­ potency. However, since the tissue levels of both these insulins
ity (Fig. 8) (86, 92). are not known, these assumptions remain speculative.
At the level of the receptor, icodec is more selective for the IR It is important to note that no mitogenicity concerns have
vs the IGF-1 receptor (IGF-1R) and once bound to the IR, ico­ been found in animal or in vitro preclinical studies for either
dec shows similar affinity for both IR isoforms A and B (86). icodec or efsitora, but, as for with any novel insulin, careful
The binding affinity of icodec for IR isoform A is 0.5% that surveillance in real-world use will be required to develop full
of human insulin in the absence of serum albumin and confidence in their safety.
0.03% that of insulin when assessed in the presence of 1.5%
HSA (86). In cell-based assays, icodec was a full agonist for Limiting first-pass renal filtration
the IR with a balanced mitogenic-to-metabolic potency ratio First-pass renal clearance, via fenestrated endothelium, is a
comparable to insulin as monitored by signaling (phosphoryl­ significant route of clearance for therapeutic-unmodified insu­
ation of IR, AKT/PKB, extracellular signal-regulated kinase), lin, that is, human insulin or IGlar, which have molecular
metabolic activity (lipogenesis and glycogen synthesis), and weights of ∼6 kDa. As noted earlier, the clearance of insulin
mitogenic activity (DNA synthesis). In addition to IGF-1R af­ can be adversely altered in patients with diabetic nephrop­
finity, the IR (particularly IR isoform A) residence time has athy/CKD. Thus, renal impairment necessitates dose adjust­

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been implicated as a factor in the mitogenic potential of ments with human insulin and IGlar as kidney function
some insulin analogues (23). While the IR binding kinetics deteriorates (50-52). However, increasing the hydrodynamic
and residence time have not been reported for icodec, com­ size of the insulin, such as insulin peglispro (103), or binding
pared to human insulin, the in vitro mitogenic effects of icodec acylated insulins to HSA, such as IDeg (104), can eliminate the
with respect to mitogenic activity in cells were categorized as need for insulin dose adjustments in diabetes patients with
low (86). Thus, icodec signaling properties are similar to na­ CKD. These findings are relevant to weekly basal insulins
tive insulin; however, with reduced binding affinity. Despite too and have been taken into consideration in their develop­
reduced IR binding and weaker potency, icodec is a full agonist ment (105). With icodec acylation, the linker (2xOEG-gGlu)
of the IR and elicits robust glucose-lowering capability (92). and fatty acid moiety (C20 fatty diacid) were selected for
Efsitora exists as a covalent homodimer with each monomer stronger, yet reversible, HSA binding to attenuate the extent
composed of a single-chain variant of insulin (SCI), wherein the of renal clearance (92). With efsitora, the conjugation to an
B-chain is linked to the A-chain by a short linker and the SCI is Fc domain creates a large molecule (64.1 kDa), akin to the
linked to the Fc domain by an interdomain linker that connects size of HSA, that can also limit filtration through the renal
the C-terminus of the SCI to the N-terminus of an IgG2 Fc do­ glomeruli (87).
main (see Fig. 7) (87). Efsitora uses amino acid changes at
TyrB16Glu, PheB25His, ThrB27Gly, ProB28Gly, LysB29Gly, Effect of prolonging time-action
ThrB30Gly, IleA10Thr, TyrA14Asp, and AsnA21Gly, coupled
Collectively, the effect of controlling distribution, IR affinity,
with the SCI format, to modulate IR affinity as well as contribute
and renal clearance can prolong PK and glucose-lowering.
to manufacturability properties (eg, expression, chemical stabil­
With icodec, the time-action profile is extended in diabetic
ity, and physical stability) (see Fig. 7) (87).
rats with a concomitant reduction in glycated hemoglobin
Preclinical data demonstrated that efsitora is a selective
A1c (HbA1c) (92). Efsitora has also demonstrated an extended
agonist for the IR vs IGF-1R (87). In IR binding assays, efsi­
time-action and prolonged glucose-lowering profile in
tora showed an approximately 100-fold reduced binding af­
streptozotocin-treated diabetic rats (87). These long duration
finity compared to native insulin. In cell-based assays
exposure profiles warranted study in humans with these mol­
evaluating the functional activation of IR tyrosine autophos­
ecules, which are discussed later.
phorylation, efsitora had reduced potency for activation of
IR, consistent with the binding data, and exhibits some degree
of selectivity for activation of IR-B phosphorylation compared Minimizing Hypoglycemia Risk
to IR-A, relative to native insulin. While the biological rele­ While the extension of the time-action profile is necessary for a
vance of this is not clear, these data indicate that efsitora once-weekly basal insulin, the expectation of possible pro­
may have signaling selectivity for IR-B, the isoform associated longed and/or recurrent hypoglycemia are concerns. Ideally,
with metabolic signaling, as opposed to IR-A, which is more a glucose-sensing basal insulin, in which insulin activity is con­
associated with mitogenic signaling (87). Following activation trolled by levels of circulating glucose, could alleviate or pre­
of IR by efsitora, a more rapid dephosphorylation of the IR vent hypoglycemia concerns. However, such insulins are not
was observed compared to native insulin, suggesting that efsi­ currently available. As such, any new insulin needs to be stud­
tora had a faster off rate from the IR and a favorable dephos­ ied carefully to ascertain hypoglycemia risk.
phorylation profile relative to a mitogenic insulin analogue Novo Nordisk has historically appeared to embrace a strat­
(AspB10) (87). In cell-based functional assays for metabolic egy designed to closely match insulin half-life to the desired
(lipogenesis) and mitogenic potential, efsitora exhibits full dosing profile, for example, IDeg with a half-life of 25 hours,
IR agonism, however, with reduced potency compared to in­ which is designed for once-daily dosing and icodec with a half-
sulin, which is consistent with reduced IR binding affinity. life of 196 hours (∼8 days) to support once-weekly therapy
Despite attenuated IR binding potency of efsitora, robust (19). This strategy enables faster attainment of steady state
glucose-lowering efficacy with long duration of action is ob­ and faster reduction in plasma concentration post dosing,
served in vivo (87). however, with an apparently slightly high P/T ratio. As illus­
The attenuated IR binding and clearance in insulin-sensitive trated in Fig. 8, steady-state concentrations can be achieved
tissues allow accumulation to increase insulin concentrations following 5 weekly doses of the same dose level. The time to
of both icodec and efsitora explaining their robust glucose- steady state can be further accelerated by giving a one-time
lowering efficacy despite highly attenuated IR binding loading or starting dose (see Fig. 8). Although no P/T ratio
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Figure 9. Pharmacokinetic and pharmacodynamic profiles of icodec in people with type 2 diabetes. A, Mean (SE) total serum icodec concentrations for
12, 20, 24 nmol/kg doses during week 5 of once-weekly dosing. PK results showed that icodec reached tmax at 16 hours after dosing, with a mean t1/2 of
196 hours. B: The PD effect of insulin icodec over a weekly dosing interval as derived from the observed data using a PK/PD model. The highest activity
occurs at day 3 (∼16%), while on day 7 it is approximately 12%. An equal distribution across the 7 days of 14.3% per day is showed by the solid line.
AUCGIR, area under curve for glucose infusion rate; HSA, human serum albumin; PD, pharmacodynamic; PK, pharmacokinetic; t1/2, half-life; tmax, time to
peak insulin concentration. Data from Nishimura et al (86).

Figure 10. Efsitora dosing and build-up to efficacious exposure. A, Schematic depiction of the distribution of efsitora in the different biological com­
partments over time from initiation of once-weekly dosing (injection 1) through injection 8, showing the gradual movement of insulin efsitora from the
subcutis through the blood to the intercellular space where build-up occurs. B, Model of insulin efsitora concentration when dosed without a loading dose
(black dashed) and with a loading dose (black solid) compared to once-daily insulin glargine U100 (gray).

has been reported for insulin icodec, based on the half-life, a low P/T ratio when administered weekly. Notably, the
Heise (106) estimated the P/T ratio of icodec to be 1.81. PD long half-life of efsitora could enable dosing intervals longer
modeling of icodec data shows that at steady state, over the than 1 week; however, this would increase the required dose
course of 7 days, the highest activity occurs at day 3 at each delivery, thus increasing the peak concentration and
(∼16%) while on day 7 it is approximately 12% (Fig. 9) leading to a higher P/T ratio and may not necessarily simplify
(86). An estimate by Home (107) suggests the interday efficacy treatment as it is easier for patients to remember a weekly dose
variability of icodec to be 1.36 on day 3 relative to day 7. than a dose every other week.
The approach taken by Eli Lilly and Company with efsitora Although ultimately hypoglycemia is caused by the mis­
appears to embrace generation of the lowest P/T ratio. match between glucose levels and insulin availability, the PK
Efsitora has a relatively flat PK profile with an approximately data show that both icodec and efsitora have flatter insulin ex­
17 day half-life to support once-weekly dosing (Fig. 10). At posure profiles compared to once-daily basal insulins, which
steady state, efsitora has a P/T ratio of 1.14 (108) (Fig. 11). may translate to a day-to-day hypoglycemia risk that could
Time to steady state can be shortened by giving a one-time be similar to or perhaps even potentially lower than once-daily
starting/loading dose (see Fig. 10). The long half-life of efsi­ basal insulins. Additionally, as discussed earlier, because of
tora enables therapeutic accumulation and the generation of the large hydrodynamic size of HSA-bound icodec or efsitora,
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Figure 11. Pharmacokinetic properties of efsitora in people with type 2 diabetes. A, Mean plasma efsitora concentrations following a single subcuta­
neous dose (10, 20, and 35 mg doses) in people with T2D. PK results showed that efsitora reached tmax at 4 days after dosing, with a mean t1/2 of ap­
proximately 17 days. B, Mean plasma efsitora concentrations following dosing for 1, 2, 5, and 10 mg doses from a 6-week ascending dose study in people
with T2D. The peak-to-trough ratio was determined to be 1.14. t1/2, half-life; tmax, time to peak insulin concentration. Data from Heise et al (108).

peripheral exposure and activity could be attenuated. It is im­ The estimated difference suggests an equivalent of an approxi­
portant to note, however, that the effects of icodec or efsitora mately 36% higher effect seen on day 3 than day 7 as inter­
on hepatic glucose output relative to peripheral glucose up­ preted by Home (107). No serious or severe adverse events,
take have not yet been studied and these theoretical attributes severe hypoglycemic episodes, or injection site reactions
for hypoglycemia risk reduction with these molecules will were reported in this phase 1 study (86).
need to be affirmed by robust clinical trial and real-world A second study investigated whether injection region af­
use data. fected exposure and glucose-lowering with icodec (110).
Twenty-five participants with T2D received single SC icodec
Other Once-Weekly Basal Insulins in Development injections (5.6 U/kg) in the thigh, abdomen, or upper arm.
Total icodec exposure, as measured by area under the curve
Other than icodec and efsitora, there are several other mole­
from zero to infinity after a single dose, was similar between
cules that have or are being studied as once-weekly basal insu­
all 3 injection sites and the glucose-lowering effect coefficient
lins, all of which are either very early in development or have
of variation was also comparable at all injection sites (110).
been discontinued. These have been described in a previous re­
view (109).
Phase 2 studies
Emerging Clinical Data With Once-Weekly Dosing and titration strategies for icodec were tested to help
Insulins inform phase 3 studies through a series of phase 2 studies,
Insulin Icodec all in patients with T2D: 2 in insulin-naive patients (111,
112) and 1 in those already on once-daily basal insulin (113).
Phase 1 studies The first phase 2 icodec study was a 26-week study in 247
In a phase 1 clinical study in patients with T2D (n = 50), the insulin-naive patients with T2D (111). Once-weekly icodec ad­
median tmax of icodec was 16 hours and the mean half-life ministered initially at 70 units (10 units × 7) was compared to
was 196 hours (∼8 days) (86). In this double-blind, double- once-daily IGlar U100 starting at 10 units. Both insulins were
dummy, randomized clinical trial, participants who were administered SC and titrated in a traditional treat-to-target ap­
insulin-treated ± metformin received 5-week treatments of proach to a fasting blood glucose target of 70 to 108 mg/dL.
once-weekly icodec (12, 20, or 23 nmol/kg) plus once-daily The primary end point was change in HbA1c from baseline to
placebo (n = 13, 13, 12) or once-daily IDeg (0.4 U/kg) plus week 26. Rosenstock et al (111) found that a baseline of
once-weekly placebo (n = 12). At baseline, randomly assigned HbA1c of 8.1% and 8.0% with once-weekly icodec and IGlar
participants to receive icodec had a mean ± SD HbA1c of 7.4 U100 were reduced to 6.7% and 6.9% respectively, with an es­
± 0.6% and age 57.8 ± 4.3 years (86). On days 2 and 7 follow­ timated between-group difference in HbA1c change from base­
ing the last insulin dose, PD properties at close to steady state line to week 26 of −0.18 percentage points favoring icodec
were assessed in 24-hour glucose clamp procedures and the (95% CI, −0.38 to 0.02; P = .080). There was a higher rate of
glucose-lowering effect over a once-weekly dosing interval level 1 (<70 mg/dL to ≥54 mg/dL) hypoglycemic events in the
was derived from the observed data using a PK/PD model. icodec group (5.09 events per patient-year of exposure [PYE])
While the glucose-lowering effect (measured as a percentage compared with IGlar U100 (2.11 events per PYE; estimated
of area under curve for glucose infusion rate [AUC GIR]) rate ratio [ERR] 2.42; 95% CI, 1.50-3.88). However, the inci­
showed a close to even distribution over 7 days, there is a dence of combined level 2 (<54 mg/dL) or severe (level 3) hypo­
small increase from day 1 (13.0%) to day 3 (16.3%) and slight glycemia was not statistically significantly different; 16.0% for
decrease on day 7 (12.0%) compared to day 3 (see Fig. 9) (86). icodec vs 9.8% for IGlar U100, with low rates of 0.53 and
394 Endocrine Reviews, 2024, Vol. 45, No. 3

0.46 events per PYE for icodec and IGlar U100, respectively 7 × 2 [ie, 100% increase in the weekly insulin dose adminis­
(ERR 1.09; 95% CI, 0.45-2.65). There was only one participant tered once at the beginning of the study]) followed by the par­
that had an episode of severe hypoglycemia (defined as requiring ticipants going back 1 week later to their previously calculated
assistance) in the icodec arm. total weekly dose (previous dose ×7) administered once a
This study was followed by another, shorter study lasting 16 week as icodec. This loading-dose strategy was compared to
weeks, again in insulin-naive patients with T2D. In this study, 50 participants to whom no one-time loading dose was ad­
icodec was dosed to 2 different fasting glucose targets: the ministered. The control group (also 50 individuals) received
American Diabetes Association (ADA)-recommended 80 to once-daily IGlar U100. All 3 groups were titrated to a fasting
130 mg/dL, and a more aggressive 70 to 108 mg/dL (112). glucose target of 80 to 130 mg/dL with a ±28-unit weekly ti­
Three titration algorithms with different once-weekly dosing tration for icodec and ±4 units for IGlar U100. The primary
were investigated. In the group with the ADA-recommended tar­ outcome measure was percentage TIR (70-180 mg/dL) during
get (80-130 mg/dL), one protocol incorporated a weekly icodec the last 2 weeks of treatment (weeks 15 and 16) as measured
increase or decrease (±) of 21 units (titration arm A) while the by blinded CGM (Dexcom G6). The study showed a statistic­
other used a ±28 unit change (titration arm B). The icodec arm ally significant difference in TIR favoring icodec when a load­
with the more aggressive fasting glucose goal (70-108 mg/dL) ing dose was used (7.9 percentage points; 95% CI, 1.8-13.9)

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was titrated once weekly with a ±28-unit change (titration and no significant difference between icodec and IGlar U100
arm C). The comparator was IGlar U100 titrated to a fasting when there was no loading dose of icodec. Incidences and
glucose goal of 80 to 130 mg/dL with a weekly increase/decrease rates of level 1 hypoglycemic episodes were comparable be­
of 4 units. The investigators used percentage time in range tween treatment arms and, while the rate and pattern of com­
(70-180 mg/dL) (TIR) during the last 2 weeks of treatment bined level 2 and level 3 hypoglycemic events appeared lower
(weeks 15 and 16) as their primary outcome measure using a in the icodec treatment group with no loading dose than for
blinded Dexcom G6 real-time continuous glucose monitoring the IGlar U100 group, these were similar between the icodec
(rt-CGM). The results of the study showed that titration arm with loading dose and IGlar U100 groups. Time below range
A (target 80-130 mg/dL and ±21-unit weekly icodec dose (TBR) (<70 mg/dL) was slightly higher for icodec with a load­
change) afforded the best balance between glycemic control ing dose (1.6%) compared to icodec with no loading dose
while not increasing the risk of hypoglycemia compared to (0.6%) or IGlar U100 (0.5%). Since the results of the study
IGlar U100. Titration Arm B (target 80-130 mg/dL and showed that the one-time starting-dose strategy was the
±28-unit weekly icodec dose change) showed a significantly most effective in increasing TIR and avoiding transient hyper­
greater TIR compared to IGlar U100 (estimated treatment dif­ glycemia, a loading-dose strategy, albeit with a lower loading
ference [ETD] 7.08 percentage points; 95% CI, 2.12-12.04; dose of an additional 50% instead of 100%, was employed in
P = .005) corresponding to an extra 102 minutes longer TIR. the phase 3 icodec program for patients switching from a
No severe hypoglycemic episodes occurred in any treatment once-daily to a once-weekly basal insulin (88).
group, and the rates of combined level 2 and level 3 hypogly­ Overall, across the phase 2 studies, icodec achieved similar
cemia episodes were low for all insulin icodec titrations. glycemic control to IGlarU100 (111-113). The rates of com­
Although overall hypoglycemia rates were low, rates of com­ bined level 2 and level 3 hypoglycemic episodes were low
bined level 2 and level 3 hypoglycemia with icodec in titration for all treatment groups. In addition, a post hoc analysis of
arm B were higher compared to IGlar U100 (0.15 vs 0 events data from 2 of the phase 2 studies also found that hypogly­
per PYE, respectively). Titration to attain a more stringent glu­ cemia duration was similar with icodec compared to IGlar
cose target of 70 to 108 mg/dL (titration arm C) was also asso­ U100 in insulin-naive and insulin-treated patients with T2D,
ciated with a higher rate of hypoglycemia for icodec in regardless of titration algorithm or use of a loading dose
comparison with IGlar U100, while TIR was not statistically sig­ (114).
nificantly different. There was no clustering of level 1 hypogly­
cemic events in the days following the day of injection for
icodec titrations A and B (glucose target 80-130 mg/dL), sug­ Phase 3 studies
gesting no noticeable “peak effect” with these approaches. Icodec's phase 3 program, entitled ONWARDS, consisted of 6
The results of this study appear to support the titration algo­ clinical trials. Key design features of the ONWARDS trials are
rithm used in the phase 3 trials where a fasting glucose target outlined in Table 1 and described in detail by Philis-Tsimikas
of 80 to 130 mg/dL was used with a ±20-unit weekly icodec et al (88). ONWARDS 1 to 5 were treat-to-target studies in
titration (88). people with T2D, which assessed efficacy and safety of icodec
As discussed earlier, a key difference between currently compared to a once-daily comparator (IGlar U100 or IDeg)
available once-daily basal insulins and once-weekly basal in­ and/or placebo in combination with noninsulin glucose-
sulins is to determine if a one-time starting dose, or loading lowering medications. ONWARDS 1, 3, and 5 were in insulin-
dose, is necessary to achieve an efficacious insulin steady-state naive patients. ONWARDS 2 and 4 were in insulin-treated
level more quickly. This is particularly important for patients populations, the former in patients on basal insulin and the
switching from once-daily basal insulins to once-weekly insu­ latter in the setting of basal-bolus therapy. ONWARDS 6
lins to prevent transient hyperglycemia during the transition was a treat-to-target study conducted in people with T1D in
period. To test this hypothesis, a 16-week study investigated which the comparator insulin was IDeg.
2 approaches for switching to once-weekly icodec in 154 pa­ In ONWARDS 1 to 4, and 6, insulin doses were titrated to a
tients with T2D previously on basal insulin (113). Fifty-four prebreakfast glucose target of 80 to 130 mg/dL with a weekly
patients were randomly assigned to a one-time starting dose adjustment of ±20 U for icodec and ±3 U for the once-daily
of icodec calculated based on the previous basal insulin dose comparator (88). In ONWARDS 5, titration of icodec was
multiplied by 7 and then doubling this calculated dose as a guided by a digital app based on the titration algorithms
one-time starting loading dose (total daily basal insulin dose × used in the other ONWARDS studies while the once-daily
Table 1. Icodec phase 3 trial design (ONWARDS 1-6)

ONWARDS 1 ONWARDS 3 ONWARDS 5 ONWARDS 2 ONWARDS 4 ONWARDS 6

Clinicaltrials.gov NCT04460885 NCT04795531 NCT04760626 NCT04770532 NCT04880850 NCT04848480

No.
Population T2D, insulin naive T2D, previously insulin-treated T1D
Study status Complete
Key trial details
Endocrine Reviews, 2024, Vol. 45, No. 3

Primary objective Noninferiority in HbA1c change from baseline compared to once-daily comparator
Key secondary Superiority in TIR (70-180 mg/ Superiority in HbA1c PRO measures; rate and Superiority in HbA1c change; Superiority in HbA1c change; TIR (70-180 mg/dL);
assessments dL); superiority in HbA1c change; rate and incidence of level 2 TIR (70-180 mg/dL); PRO TIR (70-180 mg/dL); rate rate and incidence of
change; rate and incidence of incidence of level 2 and and 3 hypoglycemia measures; rate and incidence and incidence of level 2 level 2 and 3
level 2 and 3 hypoglycemia 3 hypoglycemia events events of level 2 and 3 hypoglycemia and 3 hypoglycemia events hypoglycemia events
events events
Randomized trial Open-label Double-blind Open-label with Open-label Open-label Open-label
design real-world elements
No. 984 588 1085 526 582 583
Trial duration, wk 78 26 52 26 26 52
Main phase 52 26 52 26 26 26
Extension phase 26 — — — — 26
Once-daily Glargine U100 Degludec Degludec, Glargine Degludec Glargine U100 Degludec
comparator U100, or Glargine
U300
Bolus insulin — — — — Aspart 2-4× daily Aspart ≥2× daily
during study
Background Noninsulin glucose-lowering agents ± noninsulin glucose-lowering agents −
medications
Technology CGM — Digital dose titration CGM CGM CGM
employed in app
study
Key inclusion criteria
Demographics Adults aged ≥ 18 y
HbA1c at screening, 7.0-11.0 (53.0-96.7) 7.0-11.0 (53.0-96.7) >7.0 (>53.0) 7.0-10.0 (53.0-85.8) 7.0-10.0 (53.08-85.8) <10.0 (<85.8)
% (mmol)
BMI ≤40.0 ≤40.0 — ≤40.0 ≤40.0 —

Abbreviations: aspart, insulin aspart; BMI, body mass index; MDI, multiple daily injections; PRO, patient-reported outcome; T1D, type 1 diabetes; T2D, type 2 diabetes; TIR, time in range.
395

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396 Endocrine Reviews, 2024, Vol. 45, No. 3

basal insulin comparator (IDeg, IGlar U100, or IGlar U300) IDeg, again with similar FPG changes from baseline in the 2
was chosen and titrated to standard of care at the discretion treatment groups (ETD 0; 95% CI, −6 to 5 mg/dL) (117).
of the investigator (88, 115). ONWARDS 5 compared icodec titrated with a cloud-based
In the insulin-naive studies (ONWARDS 1, 3, 5), the start­ dosing app with investigator-chosen daily basal insulin ana­
ing insulin dose was 70 U per week for icodec (115-117). In logues (IDeg, IGlar U100 or IGlar U300) titrated at the inves­
ONWARDS 1 and 3, the starting dose for the once-daily com­ tigator's discretion according to standard practice. In this
parator was 10 U per day and in ONWARDS 5, the compara­ study with some real-world elements, mean HbA1c was re­
tor was initiated in accordance with local product labels. In duced from 9.0% or 8.9% at baseline to 7.2% and 7.6% at
the basal switch studies (ONWARDS 2 and 4), icodec starting week 52 for icodec with the app and once-daily analogues, re­
doses were calculated as the pretrial total daily insulin dose spectively. An ETD for HbA1c change of −0.38 percentage
multiplied by 7 (118, 119). For the first injection only, an add­ points (95% CI, −0.66 to −0.09) confirmed noninferiority
itional 50% of this calculated once-weekly dose was given as a (P < .001) and superiority of icodec with the app (P = .009)
one-time loading dose before reverting to the standard weekly (115).
dose on week 2 with titration beginning the subsequent week Overall level 2 (<54 mg/dL) hypoglycemia rates were low
(week 3). In the T1D study (ONWARDS 6), the weekly dose (<1 event per PYE) in all of these studies in insulin-naive pa­

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was calculated in the same way (daily basal dose times 7) and a tients. No episodes of severe hypoglycemia were reported
one-time loading dose was given (88). This loading dose was for icodec in ONWARDS 3 and 5, and 1 episode was reported
either an additional 50% or 100% of the calculated starting in ONWARDS 1 vs 7 with IGlar U100 (115-117).
dose depending on screening HbA1c level (< 8.0% or ≥ In ONWARDS 1, at week 52 rates of combined clinically
8.0%, respectively) or prestudy insulin treatment (ie, 50% significant or severe hypoglycemia with icodec were 0.30
one-time additional dose for participants previously receiving events per PYE compared with IGlar U100 at 0.16 events
twice-daily basal insulin or IGlar U300, regardless of screen­ per PYE (ERR 1.64; 95% CI, 0.98-2.75) (116). When the
ing A1c). CGM data were collected using the Dexcom G6 sys­ 26-week extension phase and 5-week follow-up period were
tem worn intermittently in blinded mode for ONWARDS 1, 2, included, that is, at week 83, combined clinically significant
4 and throughout the study unblinded for ONWARDS 6 (88). or severe hypoglycemia rates were significantly higher with
All studies achieved their primary end points of noninferior­ icodec (0.30 events per PYE) compared with IGlar U100
ity to the once-daily comparator for HbA1c change from base­ (0.16 events per PYE; ERR 1.63; 95% CI, 1.02-2.61) but still
line (noninferiority margin: 0.3%) (115-120). ONWARDS 1, less than 1 event per PYE. The increased frequency of com­
2, 3, 5 also achieved statistically significant superiority in bined level 2 and level 3 hypoglycemia translated to 1 extra
HbA1c reduction (115-118). hypoglycemic event every 3 years. There was no significant
difference in TBR (<54 mg/dL) at weeks 48 to 52 with icodec,
(0.3%) compared with IGlar U100 (0.2%; estimated treat­
Studies in insulin-naive patients with type 2 diabetes ment ratio [ETR] 1.27; 95% CI, 0.94-1.71); both groups
All 3 studies in insulin-naive patients (ONWARDS 1, 3, and 5) were below the guideline-recommended threshold of less
demonstrated statistical superiority of once-weekly icodec vs than 1%. Significantly more icodec-treated individuals were
once-daily basal insulin comparators in HbA1c reduction able to achieve guideline target HbA1c of less than 7% without
(115-117). In ONWARDS 1, mean HbA1c was reduced level 2 or 3 hypoglycemia compared to IGlar (53% vs 43% at
from 8.5% or 8.4% at baseline to 6.9% and 7.1% at week week 52; odds ratio [OR] 1.49; 95% CI, 1.15-1.94).
52 for icodec and IGlar U100, respectively, with an ETD for In ONWARDS 3, while a greater proportion of participants
HbA1c change of −0.19 percentage points (95% CI, −0.36 on icodec achieved a guideline HbA1c target of less than 7%
to −0.03), which confirmed noninferiority and superiority of without level 2 or 3 hypoglycemia compared to IDeg (52%
icodec to IGlar U100 (116). TIR (70-180 mg/dL) at weeks vs 40%), in contrast to ONWARDS 1 where the comparator
48 to 52 was significantly higher with icodec (71.9%) com­ was IGlar U100, there were almost 3 times more events of
pared to IGlar U100 (66.9%; ETD 4.27 percentage points; combined level 2 or 3 hypoglycemia with icodec compared
95% CI, 1.92-6.62). These statistically significant TIR differ­ to IDeg (50 events vs 17 events, respectively). Combined level
ences were maintained through the extension phase (weeks 2 or 3 hypoglycemic rates were also statistically significantly
74-78) of the trial (116). Time above range (TAR; > higher from week 0 to week 26 in the icodec group (0.35 vs
180 mg/dL) was statistically significantly lower with icodec 0.12 events per PYE; 95% CI, 1.30-7.51; P = .01), all events
(27%) compared with IGlar U100 (32%; ETD −4.58 percent­ being driven by level 2 hypoglycemia with no episode of severe
age points; 95% CI, −6.99 to −2.17) at weeks 48 to 52. hypoglycemia reported (117). These differences might be re­
Notably, the superior HbA1c and TIRs with icodec compared lated to the considerably lower rate of hypoglycemia with
with IGlar U100 were demonstrated despite similar fasting IDeg in this study. As discussed earlier, IDeg has shown lower
plasma glucose (FPG) values in the 2 groups in this hypoglycemia risk compared to IGlar U100 (10).
treat-to-target trial. These results raise the possibility that al­ In ONWARDS 5, in the setting of a significant HbA1c differ­
though FPG may still be appropriate to use for titrating week­ ence in favor of icodec with the app, rates of combined level 2
ly insulins, CGM metrics might be more informative in or 3 hypoglycemia were not statistically significantly different
monitoring response to therapy with weekly insulins, a con­ (0.19 vs 0.14 events per PYE; ERR 1.17; 95% CI, 0.73 to
cept discussed further in the Clinical Implications Section. 1.86) but numerically slightly higher with icodec with the
Similar findings were observed in the double-blind app compared with once-daily analogues (115). A greater pro­
ONWARDS 3 study, which compared icodec to IDeg over portion of individuals on icodec with the app in ONWARDS 5
26 weeks. In ONWARDS 3, icodec demonstrated a statistical­ achieved a guideline HbA1c target of less than 7% without lev­
ly superior HbA1c change from baseline to week 26 (ETD el 2 or 3 hypoglycemia compared to once-daily insulins (41%
−0.2 percentage points; 95% CI, −0.3 to −0.1) compared to vs 32%). It is noteworthy that in this study, patients were on
Endocrine Reviews, 2024, Vol. 45, No. 3 397

significantly higher doses for icodec with the app vs once-daily At week 26 the rates of combined level 2 and level 3 hypo­
analogues (227 vs 185 U/week; ETR 1.22; 95% CI, glycemia were 0.73 events per PYE for icodec and 0.27 for
1.12-1.33). The authors also note that no plateau was ob­ IDeg (118). Overall rates of level 2 or level 3 hypoglycemia
served in icodec dose over the 52 week study period, whereas were numerically but not statistically significantly higher
when dose adjustments were made by investigators according with icodec vs IDeg (ERR 1.93 events per PYE; 95% CI,
to standards of care in the once-daily analogues group, a plat­ 0.93-4.02) and more patients on icodec achieved a
eau in insulin dose was observed around week 22. These re­ guideline-recommended HbA1c target of less than 7% without
sults indicate that a supporting titration app could address experiencing level 2 or level 3 hypoglycemia (37% vs 27%).
the lack of titration often seen in clinical practice. When assessed by CGM metrics at week 22 to 26, TBR
Although these hypoglycemia data in insulin-naive people (<54 mg/dL) was similar for both treatment arms and within
with T2D are reassuring with a low frequency of events, par­ guideline recommendation of less than 1%: 0.3% for icodec
ticularly given that all 3 studies showed statistical superiority and 0.2% for IDeg (ETR 1.37; 95% CI, 0.92-2.04; P = .12).
with regard to HbA1c reduction, icodec-treated patients gen­ There was a modest increase in body weight from baseline
erally had higher event rates of hypoglycemia, especially to week 26 associated with icodec, with an estimated mean
when compared to IDeg, and caution would be appropriate change of +1.4 kg for icodec and −0.3 kg for IDeg (ETD

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in the less meticulously monitored real-world use until health 1.70; 95% CI, 0.76-2.63) in the setting of a higher total
care providers and patients accrue more experience with this dose of icodec compared to IDeg at study end (268 vs
therapy. 244 U/wk) (118).
Another concern with the initiation of insulin therapy is Similar to that observed in the insulin-naive ONWARDS 5
weight gain. In ONWARDS 1, 3, and 5, modest increases in study, the patients in ONWARDS 2, who were already on
body weight were observed with icodec (2.2-2.8 kg); however, basal insulin at study entry, also appeared to show a prefer­
there were no significant differences between icodec and the ence for icodec vs IDeg based on significantly higher DTSQ
once-daily insulin comparators (115-117). The weight gain total treatment satisfaction scores (ETD 1.25; 95% CI,
in these studies was similar to that observed in the earliest 0.41-2.10; P = .0035) (118). These results could again suggest
studies with IGlar (4) as well as in a large observational study the potential for greater patient acceptance of weekly insulin
(121), and occurred in the setting of superior HbA1c reduction therapy. However, these DTSQ data are from open-label stud­
and with similar, or in ONWARDS 5, higher, total insulin ies and there may be a bias given the unblinded treatments.
dose of icodec vs once-daily insulin comparators. Additionally, the clinical trial setting may not fully reflect
Since weekly insulins may help improve adherence to treat­ the preferences of individuals in the real world.
ment, it is important to gauge patient preference. In ONWARDS 4 was a 26-week study that investigated icodec
ONWARDS 5, patient-related outcome measures were stud­ compared with once-daily IGlar U100 in participants with
ied (115). The change from baseline to week 52 in the T2D inadequately controlled on a basal-bolus insulin regimen
Diabetes Treatment Satisfaction Questionnaire (DTSQ) total (119). Mean HbA1c was reduced from 8.3% at baseline to
treatment satisfaction score (ETD 0.78; 95% CI, 0.10-1.47) 7.1% at week 26 in both insulin arms. There was an ETD
and the Treatment Related Impact Measure for Diabetes for HbA1c change of 0.02 percentage points (95% CI, −0.11
(TRIM-D) compliance domain score at week 52 (ETD 3.04; to 0.15; P < .0001), which demonstrated noninferiority of ico­
95% CI, 1.28-4.81) statistically significantly favored icodec dec to IGlar U100. For weeks 22 to 26, TIR (70-180 mg/dL)
with the app compared with once-daily analogues. These find­ was similar between icodec and IGlar U100 (67% vs 66%)
ings could indicate greater patient acceptance of icodec with and the TAR (>180 mg/dL) was also similar (30.5% vs
the app compared with once-daily basal insulins and its poten­ 31.3%). These metrics did not reach guideline recommenda­
tial to address the challenges of inadequate titration and poor tions of more than 70% TIR (70-180 mg/dL) and less than
treatment adherence. 25% TAR (>180 mg/dL). FPG change from baseline to
week 26 was similar between the 2 treatments (ETD
−2.48 mg/dL; 95% CI, −10.59 to 5.63; P = .55).
Basal insulin-switch studies in patients with type 2 diabetes There were significantly higher rates of level 1 hypogly­
ONWARDS 2 was a 26-week study that investigated icodec cemia with icodec compared with IGlar U100 (31.5 vs 24.9
compared with once-daily IDeg in patients with T2D, inad­ events per PYE; ERR 1.25; 95% CI, 1.03-1.52; P = .025)
equately controlled on once-daily or twice-daily basal insulin (119). Rates of combined level 2 or 3 hypoglycemia, however,
(118). Mean HbA1c was reduced from 8.2% or 8.1% at base­ were similar between icodec and IGlar U100 (5.6 vs 5.6 events
line to 7.2% and 7.4% at week 26 with icodec and IDeg, re­ per PYE; ERR 0.99; 95% CI, 0.73-1.33; P = .93). Across the
spectively, with an ETD of −0.22 percentage points (95% trial period, there was no apparent clustering for combined
CI, −0.37 to −0.08), confirming noninferiority (P < .0001) level 2 or level 3 hypoglycemic events at any time point in
and superiority (P = .0028) of icodec to IDeg. There were no the icodec or IGlar U100 groups nor was there any difference
statistically significant differences in TIR (70-180 mg/dL) or in nocturnal hypoglycemic events. There were 7 severe hypo­
TAR (>180 mg/dL) for icodec vs IDeg assessed from week glycemic events with icodec compared to 3 in the IGlar U100
22 to 26, with neither group achieving guideline recom­ arm. There were no significant differences between icodec and
mended targets of more than 70% TIR (70-180 mg/dL) or IGlar U100 for TBR (<54 mg/dL), which were within guide­
less than 25% TAR (>180 mg/dL). The superior HbA1c re­ line recommended targets of less than 1%.
sults for icodec were shown despite both TIR (70-180 mg/dL) The authors found that although total dose increased for
(ETD 2.41 percentage points; 95% CI, −0.84 to 5.65; both groups, as would be expected in a treat-to-target trial,
P = .15) and FPG change (ETD 0.71 mg/dL; 95% CI, −5.12 the total dose for the icodec group was significantly lower
to 6.54; P = .81) being similar at study end for both treatment compared to the IGlar U100 group from week 24 to 26
arms. (514 vs 559 U/week [∼73 vs ∼80 U/day]; ETR 0.92; 95%
398 Endocrine Reviews, 2024, Vol. 45, No. 3

CI, 0.85-0.99; P = .034) (119). The authors further deter­ The mean weekly total insulin dose, adjusted for screening
mined that this lower total dose was driven by a lower meal­ dose, was not statistically significantly different between ico­
time dose of aspart (not by the frequency of mealtime dec and IDeg from week 24 to 26 (311 U/wk [∼44 U/d] vs
injection) and, interestingly, with the basal icodec dose being 323 U/wk [∼46 U/d]; ETR: 0.96; 95% CI, 0.90-1.03;
higher compared to IGlar U100 (305 vs 279 U/wk [∼44 vs P = .27) (120). The mean basal insulin dose was statistically
∼40 U/day]; ETR 1.09; 95% CI, 1.01-1.18; P = .029). significantly higher for the icodec group compared to the
Despite the differences in total dose of insulin between the IDeg group from week 24 to 26 (170 U/week [∼24 U/d] vs
groups, mean increases in body weight change from baseline 151 U/wk [∼22 U/d]; ETR 1.12 [95% CI 1.07 to 1.18];
were similar between icodec (2.7 kg) and IGlar U100 P < .0001), whereas the mean bolus dose was statistically
(2.2 kg; ETD 0.57 kg; 95% CI, −0.39 to 1.54; P = .34). significantly lower with icodec (132 U/wk [∼19 U/d] vs
A post hoc analysis of TIR metrics from ONWARDS 2 and 161 U/wk [∼23 U/d]; ETR 0.82; 95% CI, 0.74-0.90;
4 (both studies conducted in patients previously on insulin) P < .0001). Mean increases in body weight change from base­
compared TIR metrics at the time of the switch to icodec line to week 26 were similar between icodec (1.3 kg) and IDeg
(0-4 weeks) and again at steady state (22-26 weeks) (122). (1.0 kg; ETD 0.28 kg; 95% CI, −0.37 to 0.92; P = .41).
There was no difference in TIR metrics between the groups Findings were similar at week 52.

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at the time of the switch. At steady state, again, both the icodec The mean change in DTSQ total treatment satisfaction
and comparator insulin groups showed similar improvement score from baseline to week 26 was statistically significantly
in TIR and TAR with no statistically significant differences be­ lower for icodec (1.97) than for IDeg (3.06; ETD −1.09;
tween treatment arms. The TBR results were also similar ex­ 95% CI, −1.85 to −0.34; P = .0044) (120). Similar findings
cept for ONWARDS 2 where there was a statistically higher were observed at week 52. The authors suggest that this differ­
TBR (<70 mg/dL) for icodec compared to IDeg (ERR 1.59; ence favoring IDeg may reflect this population of individuals
95% CI, 1.21-2.08; P = .001) but not for TBR (<54 mg/dL) with experience of once-daily basal insulins initially struggling
(122). Further analysis of these data found that duration of with once-weekly insulin use.
hypoglycemic episodes of less than 70 mg/dL were also similar Clearly, more studies in T1D are needed to complete the
with icodec vs IDeg or IGlar U100 during switch and at steady learning curve on how to better titrate icodec, ideally based
state (123). When these findings are viewed in conjunction on CGM profiles and not guided by the same titration regi­
with other published data from these studies that showed no mens used for T2D that could well explain the differences in
clustering of hypoglycemic events at any time during the dur­ hypoglycemia seen in ONWARDS 6. Hopefully, the use of
ation of the trials, the data are reassuring since they do not in­ CGM for icodec adjustments may mitigate hypoglycemia
dicate that hypoglycemia risk is increased when a loading dose risk in selected T1D populations.
is administered.

Clinical pharmacology studies

Study in patients with type 1 diabetes One of the key preconceived concerns with once-weekly insu­
ONWARDS 6 was a 52-week study comparing icodec and IDeg lins is their potential for hypoglycemia compared to
in participants with T1D (main phase 26 weeks) (88, 120). In once-daily basal insulins. The 2 key questions that come up
ONWARDS 6, mean HbA1c was reduced from 7.59% at base­ are 1) How long would an episode of hypoglycemia last? 2)
line to 7.15% at week 26 with icodec and from 7.63% to 7.10% Would the episode recur?
with IDeg (120). The ETD for HbA1c change was 0.05 percent­ To investigate this risk, Pieber et al conducted a study com­
age points with 95% CI, −0.13 to 0.23, which demonstrated paring clinical, physiological, and counterregulatory hormone
noninferiority of icodec to IDeg (P = .0065). The change in responses to double and triple doses of icodec with IGlar U100
mean HbA1c from baseline to week 52 was statistically signifi­ in a 2-period crossover study in participants with T2D who
cantly lower with icodec than IDeg (−0.37 vs −0.54 percentage were already on insulin ± oral glucose-lowering medication
points; ETD 0.17 percentage points; 95% CI, 0.02-0.31; (124). Participants received either once-weekly icodec for 6
P = .021). For weeks 22 to 26, TIR (70-180 mg/dL) and TAR weeks or once-daily IGlar U100 for 11 days at equimolar total
(>180 mg/dL) were similar between treatment groups with weekly doses based on the individual's run-in IGlar dose
neither group achieving guideline-recommended targets of (mean 30 ± 14 units) and titrated to a target FPG of 80 to
greater than 70% TIR (70-180 mg/dL) or less than 25% TAR 130 mg/dL. Once at steady state, during each treatment peri­
(>180 mg/dL). Mean change in FPG from baseline to week 26 od, a double dose and triple dose of icodec or IGlar U100 were
was lower with icodec (−15.1 mg/dL) vs IDeg (−33.7 mg/dL; administered followed by hypoglycemia induction at expected
ETD 18.6 mg/dL; 95% CI, 8.6-28.6], P = .0003). time of maximum glucose-lowering effect post dose (44 hours
The overall rates of combined level 2 or 3 hypoglycemia or 7 hours post dose for icodec or IGlar U100, respectively).
from baseline to week 26 were statistically significantly higher Plasma glucose levels were initially maintained at euglycemia
with icodec vs IDeg (19.93 vs 10.37 events per PYE; ERR (100 mg/dL) by variable intravenous (IV) glucose/insulin and
1.89; 95% CI, 1.54-2.33; P < .0001) (120). This significantly then allowed to decrease to a nadir of no less than 45 mg/dL
higher rate of combined level 2 or 3 hypoglycemia with icodec with the discontinuation of the IV glucose infusion. Once na­
was maintained when the 26-week extension phase and dir glucose was achieved, it was maintained for 15 minutes,
5-week follow-up period were included (ie, evaluation over following which the IV glucose was used to restore euglyce­
57 weeks). Rates of nocturnal combined clinically significant mia. Validated hypoglycemia symptoms scores as well as cog­
or severe hypoglycemia were also statistically significantly nitive tests were performed during hypoglycemia, and
higher with icodec vs IDeg. For weeks 22 to 26, TBR counterregulatory hormones were measured at nadir glucose.
(<54 mg/dL) was statistically significantly higher with icodec All patients also had real-time CGM performed through the
vs IDeg (1.0% vs 0.7%; P = .0014). treatment periods.
Endocrine Reviews, 2024, Vol. 45, No. 3 399

Clinically significant hypoglycemia (<54 mg/dL) occurred hepatic impairment) received a single SC icodec dose (1.5 U/
in a similar proportion of patients receiving overdoses of ico­ kg) and were monitored for PK (126). The authors found
dec or IGlar U100 (double dose: 40% vs 36%, respectively; that compared to participants with normal hepatic function,
OR 1.28; P = .63; triple dose: 53% vs 70%, respectively; there was a slightly greater total icodec exposure with mild
OR 0.48; P = .14). Following a triple dose, the mean nadirs and moderate hepatic impairment, while no difference was
were 56 mg/dL for icodec vs 52 mg/dL for IGlar U100 (treat­ observed for severe hepatic impairment (126). Again, the au­
ment ratio 1.07; P < .001). With each dose of icodec, the time thors concluded that no specific dose adjustment of icodec is
it took to restore euglycemia was less than 30 minutes. The required in people with hepatic impairment.
time to recovery with icodec vs IGlar U100 was similar follow­
ing a triple dose but longer following a double dose. Insulin Efsitora
Counterregulatory hormone levels increased to a similar ex­
tent during hypoglycemia induction for both icodec and Phase 1 studies
IGlar U100 with the exception of a slightly greater increase The PK profile of efsitora was evaluated using single ascending
in adrenaline and cortisol in response to hypoglycemia follow­ doses (SADs) and multiple ascending doses (MADs) (108). In
ing a triple dose of icodec. Symptoms related to hypoglycemia a 6-week SAD study conducted in healthy participants (n = 6

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were also comparable between the icodec and IGlar U100 at each dose, 5 and 10 mg) and individuals with T2D (n = 6 at
groups. Since both the hypoglycemia symptom scores and each dose; 10, 20 and 35 mg), efsitora administration resulted
counterregulatory responses evoked by icodec was similar to in glucose-lowering within 3 days of administration and led to
IGlar U100, it appears likely that practices around hypogly­ a decrease in FPG that was dose-responsive and sustained for
cemia recognition and acute treatment that are currently in at least 5 days post dose (Fig. 11A). PK results showed that ef­
place for once-daily insulin analogues could also be applicable sitora reached tmax at 4 days after dosing, with a mean half-life
to once-weekly insulin treatment. of approximately 17 days (range, 14.8-18.5 days) in individu­
However, because of the long duration of action of icodec als with T2D. Efsitora mean 7-point glucose profiles measured
there is a risk of hypoglycemia recurrence. CGM data from on days 4 and 43 (1 week after the final dose) remained con­
this study showed time spent in hypoglycemia in the weeks fol­ stant and were similar to IGlar U100 (1 U/kg; n = 8). The rates
lowing the double/triple doses was low even in those who had and duration of hypoglycemic events with efsitora were simi­
experienced clinically significant hypoglycemia (mean ± SD lar to IGlar U100 (108).
TBR [<54 mg/dL]: double dose 0.21 ± .45%; triple dose In the MAD study, 33 individuals with T2D were randomly
0.56 ± 1.70%). The number of level 2 hypoglycemia events assigned to once-daily IGlar U100 or once-weekly efsitora.
was also low from the end of the hypoglycemia induction ex­ Based on the results of the SAD data and PK modeling, a
periments until 2 weeks after the icodec double dose (4 epi­ loading-dose strategy was implemented to reduce the time to
sodes in 3 participants) and until 1 week after the triple dose steady-state concentration. Individuals randomly assigned to
(6 episodes in 5 participants). Although these findings are re­ efsitora received a one-time loading dose of 3 times their
assuring, the study has a number of limitations: 1) patients at weekly dose. They then received a fixed dose (1, 2, 5, and
greater risk for hypoglycemia, those with renal failure, and in­ 10 mg) once-weekly for the following 5 weeks. Individuals
dividuals older than 72 years were excluded; 2) recovery from randomly assigned to IGlar U100 continued their usual dosing
hypoglycemia was with a continuous infusion of IV glucose, regimen throughout the study. The P/T ratio of efsitora con­
not with traditional clinical measures such as administration centrations over a 1-week period at steady state was deter­
of oral carbohydrate or glucagon; and 3) hypoglycemia recur­ mined to be 1.14. This indicates an approximately 14%
rence risk was reduced by skipping the next scheduled dose of increase in PK levels during the week from the time of injec­
icodec (and IGlar U100) after hypoglycemia induction. tion. This P/T was calculated as the ratio of maximum concen­
Nonetheless, these data offer guidance on what to expect tration on day 4 after dosing to the concentration at 168 hours
with inadvertent overdoses and also, skipping the next dose (7 days) post dose. Efsitora concentrations were flat across all
of the once-weekly insulin in the event of a significant hypo­ dose levels (Fig. 11B). Unlike in the icodec PK study (86), it
glycemic episode could reduce the risk of recurrence. should be noted that with efsitora, a loading dose was used
Several other studies in people at higher risk for hypogly­ in this study to shorten time to steady state (Fig. 10B).
cemia have been completed; people with renal impairment
(NCT identifier NCT03723785) (125), or hepatic impairment Phase 2 studies
(NCT identifier NCT04597697) (126). In the renal study, 58 Efsitora's phase 2 program included 3 treat-to-target studies:
participants with varying levels from renal function (normal 1 study in patients with T2D previously treated with
renal function [n = 12], mild [n = 12], moderate [n = 12], once-daily basal insulin (127), 1 in insulin-naive patients
and severe [n = 12] renal impairment, and end-stage renal dis­ with T2D, and 1 in patients with T1D (128). In these phase
ease [n = 10]) received a single SC icodec dose (1.5 U/kg) and 2 studies, efsitora was dosed in milligram increments from a
were monitored for PK (125). The authors found that icodec reconstituted lyophilized powder since at the time of phase 2
exposure trended numerically slightly higher for patients studies the soluble insulin formulation was not yet available.
with renal impairment compared to those with normal renal The first phase 2 study was conducted in patients with T2D
function (125). As discussed earlier, since this molecule is already on basal insulin. The aim of this 32-week study was to
not renally excreted, these data do not suggest that doses of assess not only efficacy but also frequency of titration as well
icodec will need to be modified based on its PK in renal failure as determine the optimal loading dose (127). A total of 399
but more so on the clinical characteristics of the patient. In participants were randomly assigned (1:1:1) to either of 2
patients with hepatic dysfunction, 25 participants with vary­ once-weekly efsitora treatment groups with different fasting
ing levels from hepatic function (normal hepatic function glucose targets and titration frequency or to a control group
[n = 6], mild [n = 6], moderate [n = 6], and severe [n = 7] receiving once-daily IDeg. One efsitora group had a fasting
400 Endocrine Reviews, 2024, Vol. 45, No. 3

glucose target less than or equal to 140 mg/dL with the insulin The first dose was a one-time loading dose equal to 3 times
injected every week and titrated every 2 weeks, while the other the estimated weekly dose and ranged from 3 mg for some­
had a fasting glucose target less than or equal to 120 mg/dL, one with median fasting glucose of 140 mg/dL or less and
again injected once a week but titrated every 4 weeks, that body weight of 80 kg or less to 16.5 mg for someone with
is, in the 2 efsitora groups, the dose could be changed every a median fasting glucose of more than 220 mg/dL and weight
2 or 4 weeks. Both efsitora treatment groups received a one- of 120.1 kg or more. From week 2, the participants received
time loading dose ranging from 1.5 to 3 times their calculated their calculated weekly dose, which was then titrated every
weekly dose (127). The control group received IDeg U100 in­ week up to week 12, and then every 4 weeks thereafter to a
jected once a day and titrated every week to a fasting glucose fasting glucose goal of 80 to 100 mg/dL. IDeg was initiated at
target of 100 mg/dL or less. Participants used an unblinded 10 units and titrated weekly to the same goal. Participants
Dexcom G6 for CGM. The primary objective of the study used a blinded Abbott Libre Pro for CGM during 14-day periods
was to assess the change in HbA1c from baseline. prior to weeks 0, 12, and 26. The primary end point was HbA1c
Following 32 weeks of treatment, from a mean HbA1c of change from baseline to week 26.
8.1%, there was a −0.6% reduction for both efsitora treat­ From a baseline of 8.0%, efsitora (−1.20%) demonstrated
ment groups and a −0.7% reduction for the IDeg group. noninferiority in HbA1c reduction to IDeg (−1.26%; ETD

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Pooled analysis of the efsitora groups showed noninferiority .06 [90% CI −0.11-0.24]; P = .56) (129). The rates of level
in HbA1c change vs IDeg. Level 1 hypoglycemia event rates 1 and level 2 patient-reported hypoglycemia were similar be­
were approximately 25% lower for the efsitora groups than tween efsitora and IDeg (3.29 vs 2.77 and 0.22 vs 0.15
the IDeg group. Level 2 hypoglycemia event rates were numer­ events/patient/year, respectively) with no severe hypoglycemia
ically lower for the efsitora groups compared to IDeg, but reported in either group. TIR (70-180 mg/dL) over a 24-hour
these differences did not reach statistical significance. period increased with both treatments for the 12- and
However, fasting glucose levels were higher with both efsitora 26-week assessments compared with baseline measures,
arms than with IDeg, which presumably could have amelio­ with participants on both efsitora and IDeg having on average
rated the hypoglycemia risk with efsitora (127). The data TIR 75% or greater over the 24-hour period by the
did demonstrate that irrespective of the higher fasting glucose end-of-study assessment. Efsitora demonstrated lower TBR
levels in both efsitora arms, HbA1c reduction was similar to (54- < 70 mg/dL) compared with IDeg (4.60% vs 7.06%;
IDeg, which had a lower fasting glucose. This could suggest P < .1). There was no statistically significant difference in the
better glucose control during the rest of the daytime with body weight gain from baseline to week 26 between efsitora
the longer-acting efsitora. These results were further sup­ (2.9 kg) and IDeg (2.5 kg). Although no statistical analysis
ported by the study's CGM findings, in which during the for change in insulin doses have been presented for this study,
32-week treatment period, both efsitora groups and IDeg efsitora dose was numerically higher at study end, increasing
had similar TIR (70-180 mg/dL), TAR (>180 mg/dL), and from approximately 14 units/day at the beginning of the study
TBR (≤70 mg/dL) over 24 hours. During the nighttime, partic­ to 51 units/day at week 26 compared to IDeg, which increased
ipants in the efsitora group with a fasting glucose target of from approximately 10 units/day to 45 units/day at study end.
140 mg/dL or less had significantly lower TBR (≤70 mg/dL) The significance of this dose difference is not apparent at
compared to IDeg probably driven by a higher glucose target this time, and data from the ongoing phase 3 studies in similar
(127). Additionally, at week 32 the duration of TBR was low populations will hopefully provide some answers.
and similar across the 7 days after injection of efsitora, showing In another phase 2 study in patients with T1D, the efficacy of
that duration of hypoglycemia was not affected by the day post efsitora vs IDeg was assessed in 265 patients over a 26-week
injection. However, these hypoglycemia data with efsitora will treatment period (128). Participants in the efsitora arm received
need to be confirmed in phase 3 trials, where more stringent fast­ one dose of efsitora once-weekly with titration once-weekly for
ing blood glucose targets of 80 to 120 mg/dL are being studied weeks 1 to 12 and every 4 weeks thereafter. Efsitora was initi­
and what will actually be achieved in the trials. ated in a similar way as in the T2D insulin-naive population de­
These data on the discordance between fasting glucose and scribed earlier with a one-time loading dose. Since these patients
HbA1c are similar to results from the icodec phase 3 studies were already on basal insulin, the one-time loading dose took
discussed earlier, in which superior HbA1c reductions were into account the previous basal insulin dose, adjusted for fasting
seen with icodec despite similar FPG levels as the comparator glucose, and then multiplied by a factor of 3. After this one-time
insulin, again suggesting that continuous weekly insulin ex­ dose, participants took their weekly dose based on their prior
posure may be affecting glycemic parameters other than just (prestudy dose) and titrated weekly to a fasting glucose target
fasting glucose. of 80 to 100 mg/dL. IDeg was self-administered once daily
People treated with efsitora had significantly smaller in­ and titrated to the same target. Mealtime insulin adjustment
creases in body weight from baseline to week 32 (1.0 kg) com­ was left at the discretion of the study investigators with guidance
pared with those treated with IDeg (2.0 kg) (127). Since exact to follow standard of care. Participants used an unblinded
unit dose conversion from mg to international units (IU) was Dexcom G6 for CGM. HbA1c change from baseline to week
not available for efsitora in this study, one cannot make an in­ 26 was the primary end point.
sulin dose comparison between efsitora and IDeg. The lower From a baseline of HbA1c of 7.5%, efsitora demonstrated
hypoglycemia rates, however, with efsitora could have con­ noninferiority to IDeg in HbA1c change (0.04% and
tributed to the less gain in weight. −0.13%, respectively; ETD 0.17%; 90% CI, 0.01-0.32;
Additional phase 2 data comes from a 26-week, open-label P = .07). Percentages of TIR (70-180 mg/dL) during the
study in insulin-naive patients with T2D, in which 278 patients 24-hour period at week 26 were similar between treatment
were randomly assigned to 1:1 to efsitora once-weekly or IDeg groups at week 26. The event rates for level 1 (efsitora:
once-daily (129). In the efsitora arm, weekly dose was determined 207.6 and IDeg: 206.7 events/patient/year) and level 2 (efsi­
based on median baseline fasting glucose and weight (129). tora: 40.7 and IDeg: 45.5 events/patient/year) hypoglycemia
Endocrine Reviews, 2024, Vol. 45, No. 3 401

captured from CGM were similar for efsitora and IDeg. formulated in solution and dosed in international units ad­
Similar durations of time in the hypoglycemic range were ob­ ministered using prefilled insulin delivery devices.
served between efsitora and IDeg groups for both level 1 (28.4 Key design features of the QWINT trials are outlined in
vs 32.0 minutes; P = .371) and level 2 (7.46 vs 7.89 minutes; Table 2. QWINT 1 to 4 are treat-to-target studies in people
P = .82) hypoglycemia, with no prolonged or repeated hypo­ with T2D that will assess efficacy and safety of efsitora com­
glycemia observed (128). People treated with efsitora had sig­ pared to a once-daily comparator (IDeg or IGlar U100) in
nificantly smaller increases in body weight from baseline to combination with noninsulin glucose-lowering medications.
week 26 (0.1 kg) compared with those treated with IDeg QWINT 1 compares a fixed dosing-escalation approach for
(0.6 kg; P = .028). There was no significant change in the once-weekly efsitora, with once-daily IGlar U100 as the com­
basal insulin doses over the course of the study, and mealtime parator in insulin-naive patients. QWINT 2 is also studying an
insulin doses were similar in both treatment groups, which insulin-naive population, whereas QWINT 3 and 4 are in
might explain the minimal change in weight especially when insulin-treated patients, the former in patients on basal insulin
coupled with small change in HbA1c. alone and the latter for those on basal-bolus therapy. QWINT
It is noteworthy that in the phase 2 program efsitora was 5 is studying people with T1D.
dosed in milligrams rather than in international units with

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the rationale that using phase 1 data to determine internation­ Clinical pharmacology
al units from insulin might not be the most accurate in all pop­
A 2-period, open-label clinical trial to evaluate the effect of ef­
ulations (130), and data from the phase 2 program would
sitora compared to IGlar U100 in participants with T2D
allow for a more appropriate calculation of the conversion
under conditions of increased hypoglycemic risk is reported
to international units. As discussed earlier, in all 3 phase 2
in ClinicalTrials.gov as having completed data collection for
studies, based on the PK needs to accelerate time to steady
primary outcome measure (NCT identifier NCT04957914),
state, a one-time loading dose was administered (127-129).
but no results have been posted or disclosed at the time of
Overall, in patients with T2D, in its phase 2 studies, efsitora
this writing.
achieved similar glycemic control to IDeg with no clinically
significant differences in the rates of hypoglycemia. In the
basal switch study, total and nocturnal level 1 hypoglycemia Potential Benefits and Concerns With
were significantly lower in efsitora titrated to a fasting glucose
Once-Weekly Basal Insulin
target of 140 mg/dL compared to IDeg, which had an fasting
glucose target of less than 100 mg/dL, which may have con­ Adherence and Persistence With Once-Daily Basal
tributed to this lower risk as discussed earlier (127). In this Insulins
study, the duration of TBR with efsitora was similar irrespect­ Despite the availability of at least 4 different basal insulin ana­
ive of the day since the last injection (127). These hypogly­ logues, there are still challenges both in the initiation of basal
cemia data with efsitora will need to be confirmed in phase3 insulin (“clinical or insulin initiation inertia”) and, when ini­
trials, in which more stringent fasting blood glucose targets tiated, achieving glycemic goals (“treatment or titration
of 80 to 120 mg/dL are being studied. In both of the T2D stud­ inertia”).
ies, TIR metrics showed an improvement in TIR similar to Multiple studies have shown that many patients and health
IDeg and importantly periods of TBR especially at night care providers are reluctant to initiate insulin (initiation iner­
were less than those seen with IDeg. These lower hypogly­ tia) (131-135). A number of reasons for this clinical inertia
cemia findings with efsitora compared to icodec could be the have been proposed, with key factors including fear of needles
result of differences in study design, glycemic control, and/ and pain; concerns about side effects, especially hypoglycemia
or insulin titrations or perhaps influenced by efsitora's flat and weight gain; complexity of insulin dosing and glucose
PK profile. Results from the ongoing Phase 3 studies will monitoring; and even potential effect on employment (135).
show if these initial observations continue to hold. Even after insulin is initiated, only a minority of individuals
In patients with T1D, even with a tight fasting glucose target reach recommended glycemic targets (6-8). Health care pro­
of less than 100 mg/dL, efsitora did not show a higher rate of viders highlight multiple challenges with insulin titration
hypoglycemia compared to IDeg. These findings were supported (treatment inertia) with again concerns about side effects, es­
by TIR metrics, which did not show an increase in hypoglycemia, pecially hypoglycemia and weight gain, as well as a lack of re­
or its duration compared to IDeg. Retrospectively, when using sources to train patients, and concerns about patients’
all the data from the phase 2 program, the investigators indicated potential for nonadherence (133, 136-138). Patients them­
that efsitora was underdosed by approximately 30% in patients selves also cite hypoglycemia and weight gain as concerns
with T1D (128). This resulted in an initial period of hypergly­ along with the perception that being on insulin means having
cemia and led to a compensatory increase in the mealtime insulin a more severe disease. Complexity of dosing, and cost of insu­
to manage glycemia during the first couple of weeks. These ob­ lin and the associated injection and monitoring supplies also
servations highlight the importance of using a loading dose play a substantial role in treatment inertia (131, 139-143).
with the correct conversion factor and also suggest that there Combined, these barriers with insulin treatment result in not
will be a learning curve for management of weekly basal dosing only the underachievement of glycemic targets, but also can
in patients with T1D. entail long-term economic costs (144).
Multiple approaches have been tried to overcome initiation
Phase 3 and treatment inertia with insulins, including diabetes self-
Based on the phase 2 study results, efsitora has now initiated a management training, nurse- and pharmacist-led insulin
phase 3 program, entitled QWINT (Once-Weekly [QW] management, increased psychological support, as well as ad­
Insulin Treatment), which consists of 5 clinical trials. All stud­ vancements to simplify injection devices (131). Despite these
ies are currently ongoing. In the phase 3 studies, efsitora is interventions, however, challenges with once-daily basal insulin
 402

Table 2. Efsitora phase 3 trial design (QWINT 1-5)

QWINT 1 QWINT 2 QWINT 3 QWINT 4 QWINT 5

Clinicaltrials.gov NCT05662332 NCT05362058 NCT05275400 NCT05462756 NCT05463744

No.
Population T2D, insulin naive T2D, previously insulin-treated T1D
Key trial details
Primary objective Noninferiority in HbA1c change from baseline compared to once-daily comparator
Key secondary Superiority in HbA1c change; rate Superiority in HbA1c change, TIR Superiority in HbA1c change, Superiority in HbA1c and rate Superiority in HbA1c, TIR
assessments and incidence of level 2 and 3 (70-180 mg/dL), and rate of TIR, and rate of nocturnal of nocturnal level 2 (70-180 mg/dL), and rate of
hypoglycemia; PRO measures nocturnal hypoglycemia; PRO level 2 hypoglycemia hypoglycemia nocturnal level 2 hypoglycemia
measures
Randomized trial Open-label Open-label Open-label Open-label Open-label
design
No. 670a 912a 986 670a 692
Study start date January 2023 June 2022 March 2022 August 2022 August 2022
Trial duration, wk 52 52 78 26 52
Main phase 52 52 26 26 26
Extension phase — — 52 — 26
Once-daily Glargine U100 Degludec Degludec Glargine U100 Degludec
comparator
Bolus insulin during — — — Lispro Lispro
study
Background ≥1 noninsulin glucose-lowering agent 0-3 noninsulin glucose-lowering 0-3 noninsulin —
medication agents glucose-lowering agents
Technology — CGM
employed in study
Key inclusion criteria
Demographics Adults aged ≥ 18 y
HbA1c at screening 7-10 (53.0-85.8) 7-10.5 (53.0-91.3) 6.5-10 (47.5-85.8) 7-10 (53.0-85.8) 7-10 (53.0-85.8)
BMI — ≤45 ≤45 ≤45 ≤35

Abbreviations: BMI, body mass index; CGM, continuous glucose monitoring; HbA1c, glycated hemoglobin A1c; MDI, multiple daily injections; PRO, patient-reported outcome; T1D, type 1 diabetes; T2D, type 2
diabetes; TIR, time in range.
a
Estimated enrollment.
Endocrine Reviews, 2024, Vol. 45, No. 3

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Endocrine Reviews, 2024, Vol. 45, No. 3 403

persist. Data from a large US database show that within the testing blood glucose may also be reduced, lowering the treat­
first year of initiation of basal insulin, almost half interrupted ment burden associated with insulin treatment.
therapy in the first 3 months, with 15% of patients discontinu­ In addition, digital health tools such as dosing guide apps
ing insulin completely during these 3 months (145). Another may reduce barriers in insulin therapy and some such tech­
study of electronic medical records of more than 40 000 nologies available today have been shown to be associated
individuals, this time from the United States and multiple with better glycemic control in people with T2D (157, 158).
European countries, showed that after insulin initiation there In the ONWARDS 5 study with icodec in insulin-naive T2D
was an initial reduction of HbA1c at 6 months after which patients, real-world elements of once-weekly insulin using a
HbA1c plateaued, with less than a third of patients achieving dosing guide app were assessed. As discussed earlier, data in­
an HbA1c target of 7% or less at 24 months (146). What is, dicate that this approach was successful, with superior HbA1c
however, difficult to ascertain from these data is whether pa­ reduction, higher insulin doses from continued titration, and
tients were actually taking the insulin as prescribed. In other similarly low rates of hypoglycemia with icodec used with a
words, assessing adherence to treatment in the real world is dosing app compared to standard of care using once-daily
challenging and it may take more technological advances basal insulins. In addition, patient-reported outcomes from
such as smart insulin pens to truly assess patient adherence. this study also indicate improved treatment satisfaction and

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Clearly, multiple barriers exist that affect success with compliance for icodec using the dosing app (115) Studies
once-daily insulin therapy and the availability of once-weekly such as this provide useful insights about the possibilities of
basal insulins, and the associated significant reduction in the empowering patients to self-titrate their insulin.
number of injections, may offer one promising option.
Reduced glycemic variability
Potential Advantages of Once-Weekly Insulins Fear of hypoglycemia and its potential consequences for pa­
Flexibility in time of administration tients, including cognitive dysfunction, can add to the stress
of an insulin regimen (159, 160). If the flatter PK profile of
The stable and predictable PK profile of a once-weekly basal in­
once-weekly insulins could translate into a decrease in
sulin has the potential to minimize patient burden and the micro­
day-to-day (interday/between-day) glycemic variability, then
management of insulin therapy that is currently required to
there is a potential to reduce the emotional and physical bur­
maintain desirable glycemic control. These ultra-long-acting
den of unpredictability with insulin therapy. Early data from
insulins would provide more flexibility in the timing of the
an efsitora phase 2 study demonstrated lower within-day gly­
dosing and may be more forgiving to dosing errors or skipped
cemic variability compared to IDeg. Between-day glycemic
doses. Compared to once-daily basal insulins discussed earlier
variability was also lower but only during the nighttime hours
(Fig. 2B), once a once-weekly insulin reaches steady state it
(127). However, these data should be interpreted with caution
can be more forgiving and offer more flexibility than once-daily
since fasting blood glucose targets were 20 to 40 mg/dL higher
insulins, since skipping a dose may not result in an immediate or
for efsitora compared to IDeg. These preliminary observations
irremediable loss of efficacy given the long half-life of these
will need to be confirmed, and more data from the phase 3 tri­
drugs. Icodec dosing guidelines from their protocol offer guid­
als are needed. The challenge with hypoglycemia assessment
ance that for a missed dose it should be taken “as soon as pos­
in these studies is that, at least in the patients with T2D
sible” but if 3 days or fewer remain before the next dose, that
when on basal insulin alone, overall hypoglycemia rates are
week's dose should be skipped (116). There is precedence for
extremely low making it hard to tease out differences between
this approach of skipping a dose with other weekly agents
the once-weekly and once-daily insulins. When more CGM
used in diabetes management, for example, dulaglutide and sem­
metrics are available from the phase 3 studies, there will be
aglutide (147, 148). As discussed earlier, IDeg, the once-daily in­
an opportunity to study differences not only in the within-day
sulin with the longest half-life, has also been studied for
glycemic variability as is traditionally examined with
administration within an 8- to 40-hour window without show­
once-daily insulins but also between-day variability, which
ing loss of efficacy (59). With weekly insulins having a much lon­
may be a more important metric to assess with once-weekly
ger half-life, similar principles of flexibility could apply.
insulins.
Similarly, the flat PK profile of once-weekly insulins may
also enable more consistent and perhaps less bolus dosing in
patients on mealtime insulin since a steady basal insulin cover­ Patients that may benefit from once-weekly insulin
age over days, particularly during the night or between meals, One could argue that any patient with T2D inadequately con­
is likely to reduce bolus needs. On the other hand, one could trolled on multiple glucose-lowering agents requiring basal in­
also argue that the increase in flexibility with dosing could sulin therapy, is a good candidate for a once-weekly insulin.
lead to more complacency and worsening of glycemic control. Weekly insulins may well have greater acceptance simply
Although real-world evidence would be the ultimate arbitra­ based on the reduction in injection burden compared to
tor for this concern, experience with long-acting GLP-1 recep­ once-daily insulins. Flexibility in dose timing may also be ap­
tor agonists (RAs) so far has shown that decreased frequency pealing to many. More specifically, patients with T2D who
of injection does not decrease persistence to treatment (149). have difficulty with medication compliance may see significant
When surveyed, both patients and health care providers in­ benefits from the reduced injection burden, flexibility of dos­
dicate a preference for fewer injections both with insulin and ing, and “forgiveness” when missing a dose.
GLP-1 RAs (137, 150-156). A reduction therefore in patient A once-weekly basal insulin, particularly if combined with
burden with a simplified, weekly dosing regimen, reducing less aggressive glucose targets (161), may prove safer and pro­
the injection burden by 313 injections every year may lead vide a financial benefit for those patients that require a health
to an improvement in adherence and persistence to insulin care provider such as a caregiver to deliver and administer in­
therapy. In addition, once at steady state, the frequency of sulin since the total cost of insulin therapy includes these care
404 Endocrine Reviews, 2024, Vol. 45, No. 3

visits in addition to the unit price of insulin. Such patients in­ dosing principles. It is informative that these one-time loading
clude older individuals and those in nursing homes and other doses have not induced any increased hypoglycemia risk over
extended care facilities. There is even the potential for these the initial weeks of the initiation of once-weekly insulins in
challenging populations to become more self-sufficient due studies so far.
to the stability of the glucose profiles over weeks instead of
days because of the long duration of action of these insulins Patients in whom once-weekly insulin may be challenging
that can limit the need for multiple titrations. The same may
In the views of the authors, because of the lack of endogenous
be true for some people with T1D who have difficulty with
insulin production and obtunded counterregulatory re­
medication compliance and who experience recurrent diabetic
sponses, patients with long-standing T1D represent a more
ketoacidosis (DKA) because of inconsistent insulin adminis­
challenging population for using once-weekly insulins.
tration. In these patients, once-weekly insulins may provide
Given their slow onset of action, once-weekly insulins may
benefit because of their stable and predictable profile consider­
not always be the best initial basal insulin in those with newly
ing that a common precipitating factor for DKA is insulin non­
diagnosed T1D but may still be a good option since early T1D
adherence, especially in teenagers (162). Furthermore, the
with some residual β-cell function may be easier to manage.
long duration of action of these insulins could, in theory, re­
However, as discussed earlier, increased hypoglycemia was

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strain ketogenic hormone production.
seen in the icodec phase 3 T1D study compared to IDeg
Additionally, once-weekly insulins may enable clinicians to
(ONWARDS 6) (120). In ONWARDS 6, rates of combined
think differently about approaches to management of diabetes
clinically significant or severe hypoglycemia were higher
in ways that have not traditionally been apparent, which
with icodec vs IDeg, although the authors note that rates
could lead to exploration of new treatment regimens. For
were lower than those reported in previously published
example, could patients using insulin pumps who experience
treat-to-target studies investigating IDeg in people with
recurrent DKA potentially benefit from a low dose of once-
T1D. Additionally, the statistically significant treatment dif­
weekly basal insulin in the background?
ference favoring IDeg vs icodec in DTSQ total treatment sat­
isfaction score might suggest that the trial participants, who
Preconceived Concerns With Once-Weekly Insulins had experience with once-daily basal insulins, initially
Dose calculations struggled with once-weekly insulin use. Although efsitora
did not appear to increase hypoglycemia compared to IDeg
Despite the potential benefits of a once-weekly basal insulin
in patients with T1D (128), this was in a phase 2 trial and
regimen, there are several theoretical concerns with dosing.
one must wait for results from the ongoing phase 3 study
These insulins would represent a substantial transformation
(QWINT 5) before drawing any conclusions. Real-world ex­
in current dosing regimens, which rely on once-daily basal in­
perience on how to best titrate both the once-weekly basal
sulin administration. Whereas the doses of once-daily basal
and mealtime insulins in people with T1D will also help in de­
insulins in use today are comparable between different insulin
termining the best way to dose in this population. Overall, the
analogues, it will require effort from patients and health care
currently available data with once-weekly insulins in T1D in
providers alike to understand the new, weekly regimens. To
adults should be regarded only as preliminary and more
initiate these insulins, weekly dose equivalents will need to
data especially with CGM based metrics might be required
be calculated, not only for insulin-naive patients, but also
to learn how to minimize hypoglycemia risk with these insu­
for those switching from a once-daily to a once-weekly
lins in people with T1D. In addition, if an indication is sought
treatment.
for a pediatric population with T1D, a careful assessment of
Several major differences in dosing between once-daily and
data specific to this population would be needed.
once-weekly regimens are anticipated. First, since an entire
Similarly, these insulins are not appropriate to initiate in pa­
week's basal insulin dose will need to be administered at one
tients hospitalized with acute illnesses, since they can take
time, there will be a perception of risk that the dose is too
weeks to achieve glycemic control, and basal insulin with a
large. These apparent large doses could in themselves add
more rapid onset of action and shorter half-life is preferred
stress both for the patient and health care provider if it is
in this circumstance.
not properly explained that these doses represent a standard
daily dose that is now being added up for 7 days. Such explan­
ations may help in alleviating concerns about the magnitude Clinical Implications
of these doses. For example, an insulin dose of 0.4 U/kg/day Implications of Dosing Differences Compared to
for a 70-kg individual will be approximately 196 units every Once-Daily Basal Insulins
week, which in daily equivalents is 28 units/day. Both health
care providers and patients may, therefore, benefit from think­ Switching between once-weekly and once-daily basal insulins
ing in daily dose equivalents. Second, to shorten the time to The ability to switch from a once-daily basal insulin to a once-
reach a steady-state concentration, as discussed earlier, both weekly insulin and vice versa has been investigated, in part, in
icodec and efsitora have used a one-time loading (or starting) the clinical trials as patients initiated and terminated the study
dose in clinical trials, which enables patients to achieve effica­ drugs. In phase 2 studies that have been reported so far, the
cious exposure more quickly compared to when no loading transition to a once-weekly basal insulin at the start of the re­
dose is given (see Figs. 8 and 10). This loading dose will likely ported trials and the transition back to a once-daily basal in­
be unique for each once-weekly basal insulin analogue based sulin did not appear to result in adverse consequences. In
on differences in PK. Nonetheless, just the concept of a load­ addition, as previously discussed, TIR data from 2 icodec
ing dose, although pharmacokinetically accurate and re­ phase 3 studies at the time of the switch from once-daily basal
quired, will no doubt cause angst both for patients and insulin to icodec showed that such switches did not lead to a
providers, highlighting the need for retraining on insulin- loss of glycemic control or more hypoglycemia when a loading
Endocrine Reviews, 2024, Vol. 45, No. 3 405

dose was administered (122, 123). In the ONWARDS 1 study it will provide data over not only the course of 1 day but the
in insulin-naive patients, at study end, according to the study whole week, allowing for monitoring for recovery as well as
protocol, the first dose of the once-daily insulin post trial recurrence of hypoglycemia (163). In addition, CGM glycemic
was administered after a 2-week gap from the last icodec trends may allow for proactive dose changes to try to preempt
dose accompanied by recommendations for more frequent hypoglycemia (or hyperglycemia) since any dose change with
monitoring of glucose (116). We should learn more as glucose a weekly insulin might not manifest itself for a few weeks, un­
data at the time of switch back to once-daily insulins from the like with a daily basal insulin when the change is manifest
completed studies become available. These data will be par­ within the next 24 hours. In the ongoing and completed stud­
ticularly valuable if there is CGM information overlapping ies with icodec and efsitora in T2D, CGM was used, for the
the time of the switch and a few weeks beyond. most part, in a blinded fashion to collect data and not for
therapeutic intervention. More recently, icodec has initiated
Monitoring glucose responses with once-weekly basal insulins a study in adults with T2D where a flash CGM is being used
Given the long duration of action of these insulins and with in­ for titration of the insulin (NCT identifier NCT05823948).
creasing access to CGM technology, monitoring the response Once these data are available, they may help further inform
to therapy with once-weekly insulins may be facilitated by the utility of CGM for clinical practice with once-weekly insu­

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TIR measures (163). As discussed earlier, data from the icodec lins. The major downside of this approach, however, is that
phase 3 studies show a lack of concordance between FBG re­ not every patient will have access to CGM technology.
duction and HbA1c; for similar FBG reductions to comparator
daily insulin, icodec achieved a superior HbA1c change (115- Management in Common Clinical Scenarios
119). In a phase 2 study, efsitora also achieved a similar As the half-lives of once-daily basal insulins have been pro­
HbA1c reduction with lower hypoglycemia compared to longed, health care providers have learned both through clin­
IDeg when FBG targets were set to be 20 to 40 mg/dL higher ical practice and real-world and clinical pharmacology studies
than IDeg (127). These findings generate 2 clinical questions: how to manage dosing in common clinical scenarios such as
1) Is FBG the ideal way to monitor response to therapy with hypoglycemia, hospitalization, fasting (due to medical proce­
weekly insulins? 2) Are FBG targets that are standardized dures, religious reasons, weight management) as well as exer­
for once-daily basal insulins appropriate for weekly insulins? cise. Some of these learnings may be extrapolated to
Although clinical trials are still using fasting glucose and once-weekly insulins.
treat-to-target methodologies with narrow fasting glucose tar­
gets as mandated by regulators, in clinical practice, even Hypoglycemia management with once-weekly insulins
though FBG may still be the parameter to titrate the dose of
weekly insulin, the actual response to therapy might be better A number of factors may affect recovery from hypoglycemia
assessed with CGM since it would provide more details on gly­ or lead to prolonged or recurrent hypoglycemia in people
cemic trends than a unitary FBG measure. Second, widening with diabetes. Prolonged hypoglycemia can result from (a)
of the FBG targets beyond the treat-to-target goals of 80 to failure to generate an appropriate glucagon and other coun­
130 mg/dL used in regulatory studies may be an approach terregulatory hormone response, which is mainly applicable
that could be considered with once-weekly insulins even in in T1D but can also occur in long-standing T2D; (b) failure
the absence of CGM. These widened targets, such as those of insulin to dissipate; and (c) failure to recognize the precipi­
used in one arm of the efsitora phase 2 study (FBG target tating factors responsible for the episode and take corrective
≤140 mg/dL) (127), could potentially reduce the risk of hypo­ action to prevent recurrence. Given the long half-life of once-
glycemia compared to once-daily insulins. Although such a weekly insulins, it is important to consider not only how to
change in target range may compromise achieving stringent manage an acute episode but how to best monitor for recur­
HbA1c goals, these targets may be appropriate especially in rence or persistence of hypoglycemia were an episode to
some high-risk populations such as older individuals or people occur.
with advanced cardiovascular risk or CKD. Additional ana­ As discussed earlier, at least with the T2D population, ico­
lysis of CGM data from ongoing and completed clinical trials dec has a similar counterregulatory hormone response and re­
with these molecules could help inform some of these clinical covery compared to IGlar U100 during an acute episode of
implications. hypoglycemia (124). This is reassuring and suggests that
from the perspective of management of an acute episode, the
fundamental principles should be no different to those with
Hypoglycemia Evaluation once-daily basal insulins: administer calculated amounts of
To assess hypoglycemia, one will still need to use traditional carbohydrates, monitor response, and repeat as necessary.
monitoring measures in clinical trials to determine nocturnal, These principles appear to be working in the phase 2 and
total, and severe hypoglycemia rates to provide reassurance to phase 3 programs with these once-weekly insulins as there
clinicians and patients as they transition to once-weekly was no evidence presented of a delay or resistance to recover
insulins. from level 2 hypoglycemia or even from the small number of
In phase 2 and 3 trials in patients with T2D, self-monitored severe hypoglycemic episodes.
blood glucose has been used for titration and hypoglycemia Post hoc analysis of icodec CGM data showed that irre­
evaluation; study design protocols are clear and easily adopt­ spective of the titration algorithms used or the presence of a
able for clinical practice (88, 116). In clinical practice, during loading dose, the duration of a hypoglycemic episode was
the titration phase when these insulins are initiated, at a min­ similar with both icodec and IGlar U100 (114, 123). With
imum, more frequent monitoring will be needed not only to efsitora, the duration of time spent in hypoglycemia (both
gauge glycemic response but also for hypoglycemia detection. level 1 and 2) as measured by CGM was similar across all
One can argue that CGM would be useful in this regard since 7 days post injection in a phase 2 basal switch study (127).
406 Endocrine Reviews, 2024, Vol. 45, No. 3

It is, however, important to note that randomized clinical tri­ supplement with a rapid-acting insulin in case of unwanted
als are generally conducted in low-risk populations and risk of hyperglycemia.
hypoglycemia may be higher in the real world and that recur­ Using PK schematics, one can create scenarios comparing
rence may not necessarily be directly due to the insulin itself once-weekly insulins and the most commonly used basal insu­
but rather to other underlying medical conditions, errors lin IGlar as depicted in Fig. 12 that might help clinicians
with dosing, dietary noncompliance, or not following hypo­ understand and develop protocols for management with once-
glycemia management instructions. Until more data from weekly insulins in common clinical situations such a fasting
the clinical trials becomes available and clinical experience ac­ and exercise.
crues with these insulins, at the very least, more frequent mon­
itoring over a few days following a hypoglycemic event would
be prudent. Such monitoring might be especially important Implications of Once-Weekly Insulins as
during the nighttime hours when endogenous glucose produc­ Combination Therapy With Glucagon-like Peptide-1
tion is the only source of carbohydrates. In addition, since the Receptor Agonists
once-weekly insulin would take longer to dissipate compared Since approval of the first incretin for treatment of T2D in
to once-daily insulins, one could argue that if frequent level 1 2005, GLP-1 RAs are now widely and successfully used

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hypoglycemia occurs (which is considered an alert level) this (165). This increased use is driven not only by the availability
could be a trigger to widen the glucose targets and/or initiate of newer and more potent GLP-1 RAs and glucose-dependent
a proactive reduction in the dose of the once-weekly insulin, insulinotropic polypeptide (GIP)/GLP-1 RA formulations (tir­
bearing in mind that the effect of the reduced dose might zepatide), but also by their cardiovascular benefits and re­
not manifest immediately. On the other hand, a level 2 episode duced frequency of injections compared to the daily
or even frequent level 1 episodes might bring up the consider­ injection of the first-generation compounds. These benefits
ation of not only reducing the next dose but perhaps even skip­ have resulted in changes in guidelines to recommend
ping a dose entirely as was done in the icodec clinical GLP-1RAs as first-line agents (17). Guidelines also recom­
pharmacology study when hypoglycemia was precipitated in mend that if insulin is to be used, it should be used in combin­
a controlled setting (124). These cautions would be particular­ ation with GLP-RAs both for greater efficacy and as well as
ly important in people with very tightly controlled HbA1c, old­ durability of its effects (17). These recommendations are
er individuals, those who are eating less or who are losing based on data showing that GLP-1RAs when combined with
weight, and patients with renal dysfunction (CKD). basal insulin either as separate agents or in fixed-ratio combi­
nations offered both improved HbA1c efficacy and favorable
effects on weight and hypoglycemia risk (166).
Management during hospitalization, fasting, and exercise However, considerable delay in intensification of treatment
During hospitalization and for surgeries, patients and health with addition of insulin has been reported in patients with
care providers would need to consider the implications of T2D despite being inadequately controlled with GLP-1 RAs
being on an ultra-long-acting basal insulin. These scenarios (167). Given the similar frequency of injections, once-weekly
were of concern when ultralente was first introduced (18), basal insulins may facilitate a simplified integration with once-
and then again during the development of IDeg, which is cur­ weekly incretin therapies. Both drugs could be administered as
rently the once-daily basal insulin with the longest half-life separate injections or as one combined fixed-dose preparation.
(164). Although not realized in clinical practice, these con­ One such fixed-dose combination of icodec and GLP-1 RA, sem­
cerns are real and need to be considered with every new long- aglutide (IcoSema), is currently in 3 phase 3 studies (COMBINE
acting basal insulin including once-weekly insulins. To the 1 (NCT05352815), COMBINE 2 (NCT05259033), and
best of our knowledge, there have been no specific reports COMBINE 3 (NCT05013229) to evaluate the efficacy and
on study participants who have been admitted to hospital safety of this combination therapy approach.
while using these once-weekly insulins in the phase 2 or 3 stud­
ies. Protocols from the phase 3 program on how these com­
mon clinical situations were managed in the studies should Future Considerations
offer some clues, but dedicated hospital studies and real-world With efsitora in late-phase development and icodec already
experience will truly inform clinical practice. As discussed submitted for regulatory approval, it is reasonable to think
earlier, research is currently evaluating the effects of efsitora through future considerations that could come into play
as compared to IGlar on frequency and severity of hypogly­ were these insulins to be approved.
cemia in situations where such risk increases (exercise and For patients with T2D, ADA/European Association for the
fasting) (NCT identifier NCT04957914), but no data are Study of Diabetes guidelines recommend the use of basal insu­
available at the time of this writing. lins with the lowest propensity to cause hypoglycemia (17,
In the opinion of the authors, patients in the hospital for 168). Although CGM metrics for hypoglycemia (TBR) are in­
protracted illness and those requiring a steady source of enter­ creasingly used in clinical practice and collected in most phase
al or parenteral nutrition might theoretically benefit from con­ 3 once-weekly insulin studies, they are currently not accepted
tinuing once-weekly basal insulin if they were already on it by regulators or guidelines as a means to compare hypogly­
and were at steady state prior to being admitted since they cemia rates. However, recent draft guidance from the
would have a steady source of insulin to meet basal metabolic US Food and Drug Administration (FDA), if approved, may
needs. Similarly, short overnight or less than 24-hour hospital affect these limitations (169).
stays might not require any change in once-weekly insulin that The FDA and other regulatory agencies recommend a
was already being administered as an outpatient when the pa­ treat-to-target approach when studying insulin in a clinical tri­
tient is on stable doses. However, these patients will still re­ al (170). The critical step in this approach is to set a fixed (and
quire close glucose monitoring to detect hypoglycemia or to narrow) fasting glucose range, most commonly 80 to 120 or
Endocrine Reviews, 2024, Vol. 45, No. 3 407

Sleep

Relative plasma insulin levels

IGlar U100 Basal glucose
excursions
Glucose levels
Weekly insulin

2100 0300 0900 1500 2100 Day 2 Day 3 Day 4

Time of day Days after injection
B

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Exercise
Relative plasma insulin levels

IGlar U100 Basal glucose

excursions
Glucose levels
Weekly insulin

2100 0300 0900 1500 2100 Day 2 Day 3 Day 4

Time of day Days after injection
C

Overnight fast
Relative plasma insulin levels

IGlar U100 Basal glucose

excursions
Glucose levels
Weekly insulin

2100 0300 0900 1500 2100 Day 2 Day 3 Day 4

Time of day Days after injection
D

Prolonged fast
Relative plasma insulin levels

IGlar U100 Basal glucose

excursions
Glucose levels
Weekly insulin

2100 0300 0900 1500 2100 Day 2 Day 3 Day 4

Time of day Days after injection

Figure 12. Schematic representation of the potential effect of sleep, exercise, and overnight and extended fasting (red boxes) on icodec and efsitora
dosed once-weekly compared to IGlar U100 dosed at 2100 hours daily. A, Following dosing at 2100 hours, peak IGlar U100 concentration would be
expected in the early morning hours, whereas with weekly icodec or efsitora, there would be minimal difference in insulin exposure. B, A 30-minute
period of exercise at around 0700 hours is depicted. In this example, exercise would occur either at the peak action or shortly thereafter of an IGlar U100
dose administered at 2100 hours. With icodec or efsitora given the constant exposure of insulin concentrations without a peak, the effect of the exercise
on glucose levels would be more predictable. C, With overnight fasting, IGlar U100 could have a peak in the early morning hours that could increase the
risk of hypoglycemia and a dose reduction of the IGlar on the night of the fast may be prudent. With icodec and efsitora no change in dose will be needed.
D, With a prolonged fast, for example, following major abdominal surgery or similar event, where the person is dependent on endogenous glucose or an
exogenous glucose source, based on target range of glucose for the patient, with weekly insulins no intervention may be acceptable. With IGlar, multiple
dose adjustments may be required.
408 Endocrine Reviews, 2024, Vol. 45, No. 3

130 mg/dL. The test insulin and the comparator are both then but more deliberations among clinicians, researchers, and
titrated to reach this glycemic target so other outcome meas­ regulators are needed.
ures such as hypoglycemia or weight gain can be properly There is ongoing concern about the cost of insulin, particular­
evaluated. The reason for this approach is to set a level playing ly in the United States, the reasons for which have been extensive­
field that allows for the comparison of secondary effects when ly covered elsewhere (171, 172). If approved, once-weekly
both the test insulin and comparator standard-of-care insulin insulins can potentially offer substantial advantages, especially
have the same degree of glycemic control. This methodology in delivering insulin to the frail in the community where assist­
has worked well so far when one was comparing a once-daily ance may be required for dosing and so any reduction in the fre­
insulin with another once-daily insulin. However, comparing quency of these can be particularly beneficial (173). In addition
an insulin with a half-life of approximately 8 days (icodec) or to the reduced injection burden compared to once-daily insulins,
approximately 17 days (efsitora) with either IGlar U100 (t1/2 once at steady state, the frequency of self-glucose testing may
12-15 hours) or IDeg (t1/2 ∼25 hours) may not create a level also be reduced. With efsitora, for example, titrating every 2
playing field for testing secondary outcome measures given or 4 weeks produced similar reductions in HbA1c compared to
such different pharmacokinetics. The longer duration of ac­ titrating every week with once-daily IDeg (127). Having an insu­
tion could give a once-weekly insulin an advantage in efficacy lin with a very long half-life many also allow glycemic control to

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since it would be available for glucose metabolism even when be maintained in the event of an inadvertent missing of a dose,
the comparator once-daily insulin has reached a PK nadir, a which could be a considerable advantage to those people who
nadir it will hit almost every day or in some cases before the skip doses.
day is done. This advantage for once-weekly insulins mani­
fested itself in the results from the icodec phase 3 program,
which demonstrated superior HbA1c reduction compared to Conclusion
both IGlar U100 and IDeg at primary end point in 4 of the Since its discovery more than 100 years ago, insulin therapy
5 studies in T2D patients (115-119). Moreover, as discussed has advanced significantly with safer and more efficacious
earlier, despite similar FBG reduction to the comparator iterations of the hormone in a quest to mimic endogenous ac­
once-daily insulin, icodec was able to demonstrate better tion. Once-weekly insulins are the latest advance with poten­
HbA1c. The improved HbA1c must therefore be the result of tial to provide a significant transformation in basal insulin
the effect of the weekly insulin at other times of the day, an ef­ therapy. Two molecules, icodec and efsitora, have reached ad­
fect that may be measurable with CGM. At this time, how­ vanced stages of clinical development with the possibility of
ever, there is no regulatory path to either study insulins reaching patients within the next few years.
using CGM metrics or to promote the data from CGM Both molecules create a circulating reservoir of insulin with
metrics. the sustained release of active insulin that can engage the IR.
This landscape, however, may be changing. Recently, the Icodec achieves this by conjugating with HSA while efsitora is
FDA has released draft guidance addressing 2 issues: 1) the composed of a novel single-chain variant of insulin fused to a hu­
use of CGM in clinical trials and 2) hypoglycemia assessment man IgG2 Fc domain. Both molecules have large hydrodynamic
as an efficacy end point in clinical trials. According to this sizes and have reduced IR affinity compared to native insulin,
guidance, the use of CGM to assess TIR may be acceptable limiting internalization and IR-mediated clearance. These mo­
but only as an additional efficacy end point. The primary lecular properties attenuate transport across capillary endothe­
end point will still need to be HbA1c. The FDA also acknowl­ lium, limit activity, and prolong time-action and thus facilitate
edges that CGM may carry advantages over self-monitored once-weekly administration. The main differences between the
blood glucose in the assessment of hypoglycemia given its abil­ 2 molecules lie in their half-lives, which are approximately 8
ity to detect hypoglycemic episodes that could be missed by days for icodec and approximately 17 days for efsitora. These
self-monitored blood glucose testing. However, to use hypo­ differences likely translate into a more rapid time to steady state
glycemia as a safety/efficacy end point, the FDA considers a re­ for icodec but a flatter PK profile for efsitora.
duction in level 3 hypoglycemia to be the preferred measure From the data we have so far, both once-weekly insulins appear
for a claim of safety/efficacy, provided both the test and con­ as efficacious as once-daily basal insulins. Overall frequency of
trol group achieved equipoise or similar HbA1c reduction. In hypoglycemia is low, and level 2 and 3 hypoglycemia rates so
situations where hypoglycemia risk was expected to be low, far are not clinically significantly different from once-daily basal
a composite of level 2 and 3 may be acceptable. In addition, insulins in people with T2D. In people with T1D, however, there
any CGM technology that is used needs to have been appro­ is reason for caution until additional data are available but overall
priately validated and assessed by the FDA. A full discussion we are just at the beginning of the learning curve how to use once-
of the guidance is beyond the scope of this review, and the weekly insulins in these patients. More research, including data
reader is directed to the FDA draft for details (169). from CGM metrics on both hypoglycemia and hyperglycemia
The challenge, however, still remains that even with the from both phase 3 programs, will be informative but to fully es­
new guidance, there does not seem to be a clear path on tablish the hypoglycemia and safety profile of these insulins, lon­
how to compare the effect of once-weekly insulins with those ger evaluation in clinical practice will be required.
from once-daily insulins to have clinically relevant interpre­ These insulins, however, do offer the enticing possibility of
tations of both efficacy and safety. Standardized CGM met­ a major change in how we administer basal insulin. While the
rics of TIR, TBR, and within-day glycemic variability have uniqueness of their dosing compared to daily basal insulins
been developed for once-daily and mealtime insulins and will require substantial investment in time and effort on the
pump therapy. New metrics that take into account the ex­ part of the health care community, these molecules have the
tended PK profiles of weekly insulins may need to be devel­ potential to become “game changers” to improve acceptance,
oped to accurately assess glycemic changes with these adherence, and persistence on insulin therapy because of the
molecules. There are no clear and easy answers at this time significant reduction in injection burden. If approved for
Endocrine Reviews, 2024, Vol. 45, No. 3 409

use, real-world experience with these weekly insulins will be diabetes. HOE 901/3002 Study Group. Diabetes Care.
the ultimate arbitrator of their success. 2000;23(8):1130-1136
6. Blonde L, Brunton SA, Chava P, et al. Achievement of target A1C
<7.0% (<53 mmol/mol) by U.S. type 2 diabetes patients treated
Acknowledgments with basal insulin in both randomized controlled trials and clinical
Writing and editorial support was provided by Alastair practice. Diabetes Spectr. 2019;32(2):93-103.
Knights, PhD (Eli Lilly and Company). 7. Blonde L, Meneghini L, Peng XV, et al. Probability of achieving
glycemic control with basal insulin in patients with type 2 diabetes
John M. Beals, PhD, retired from Eli Lilly and Company
in real-world practice in the USA. Diabetes Ther. 2018;9(3):
Jan. 14, 2022. 1347-1358.
8. Raccah D, Chou E, Colagiuri S, et al. A global study of the unmet
Funding need for glycemic control and predictor factors among patients
with type 2 diabetes mellitus who have achieved optimal fasting
This work was supported by Eli Lilly and Company. plasma glucose control on basal insulin. Diabetes Metab Res
Rev. 2017;33(3):e2858.
Author Contributions 9. Heise T, Meneghini LF. Insulin stacking versus therapeutic accu­

Downloaded from https://academic.oup.com/edrv/article/45/3/379/7550051 by guest on 17 July 2024

mulation: understanding the differences. Endocr Pract.
All authors contributed to the drafting and revision of the 2014;20(1):75-83.
manuscript and provided permission for the final version to 10. Ratner RE, Gough SCL, Mathieu C, et al. Hypoglycaemia risk
be published. with insulin degludec compared with insulin glargine in type 2
and type 1 diabetes: a pre-planned meta-analysis of phase 3 trials.
Diabetes Obes Metab. 2013;15(2):175-184.
Disclosures 11. Heise T, Hövelmann U, Nosek L, Hermanski L, Bøttcher SG,
J.R. reports grants/research support from Applied Therapeutics, Haahr H. Comparison of the pharmacokinetic and pharmacody­
AstraZeneca, Boehringer Ingelheim, Eli Lilly and Company, namic profiles of insulin degludec and insulin glargine. Exp Opin
Hanmi, Merck, Oramed, Novartis, Novo Nordisk, Pfizer, and Drug Metab Toxicol. 2015;11(8):1193-1201.
Sanofi; honorarium or consulting fees from Applied 12. Wysham C, Bhargava A, Chaykin L, et al. Effect of insulin deglu­
dec vs insulin glargine U100 on hypoglycemia in patients with type
Therapeutics, Boehringer Ingelheim, Eli Lilly and Company,
2 diabetes: the SWITCH 2 randomized clinical trial. JAMA.
Hanmi, Novo Nordisk, Oramed, Sanofi, Structure 2017;318(1):45-56.
Therapeutics, Terns Pharma, and Zealand; honorarium for lec­ 13. Becker RHA, Dahmen R, Bergmann K, Lehmann A, Jax T, Heise
tures and/or educational events from Boehringer Ingelheim, Eli T. New insulin glargine 300 units·mL−1 provides a more even ac­
Lilly and Company, Novo Nordisk, and Sanofi; support for at­ tivity profile and prolonged glycemic control at steady state com­
tending meetings and/or travel from Boehringer Ingelheim, Eli pared with insulin glargine 100 units·mL−1. Diabetes Care.
Lilly and Company, Novo Nordisk, and Sanofi; and has served 2014;38(4):637-643.
on scientific advisory boards and received honorarium from 14. Becker RHA, Nowotny I, Teichert L, Bergmann K, Kapitza C.
Applied Therapeutics, Boehringer Ingelheim, Eli Lilly and Low within- and between-day variability in exposure to new insu­
Company, Hanmi, Novo Nordisk, Oramed, Sanofi, Structure lin glargine 300 U/mL. Diabetes Obes Metab. 2015;17(3):
261-267.
Therapeutics, Terns Pharma, and Zealand. R.J., J.S.M., and
15. Goldman J, White JR. New insulin glargine 300 U/mL for the
L.I. are employees and shareholders of Eli Lilly and Company.
treatment of type 1 and type 2 diabetes Mellitus. Ann
J.M.B. is a former employee of Eli Lilly and Company; he retired Pharmacother. 2015;49(10):1153-1161.
January 2022. R.J.M. has served on advisory boards for Novo 16. Pasquel FJ, Lansang MC, Khowaja A, et al. A randomized con­
Nordisk and Sanofi; and has received lecture fees from Novo trolled trial comparing glargine U300 and glargine U100 for the
Nordisk and Sanofi and has received institutional research sup­ inpatient management of medicine and surgery patients with
port from Sanofi, Eli Lilly and Company, Novo Nordisk, MSD, type 2 diabetes: glargine U300 hospital trial. Diabetes Care.
Astra Zeneca, Abbott, Amgen, and Accunostics. 2020;43(6):1242-1248.
17. ElSayed NA, Aleppo G, Aroda VR, et al. 9. Pharmacologic ap­
proaches to glycemic treatment: standards of care in diabetes—
References 2023. Diabetes Care. 2022;46(Supplement_1):S140-S157.
1. Hirsch IB, Juneja R, Beals JM, Antalis CJ, Wright EE Jr. The evo­ 18. Turner RC, Phillip MA, Ward EA. Ultralente based insulin regi­
lution of insulin and how it informs therapy and treatment mens—clinical applications, advantages and disadvantages. Acta
choices. Endocr Rev. 2020;41(5):733-755. Med Scand. 1983;671(S671):75-86.
2. Beals JM, DeFelippis MR, Paavola CD, Allen DP, Garg A. Bruce 19. Paavola CD, Allen DP, Shekhawat D, Hansen RJ, Beals JM.
Baldwin D. Insulin. In: Crommelin DJA Sindelar RD and ADME Properties of Insulins. the ADME Encyclopedia: A
Meibohm B (eds.), Pharmaceutical Biotechnology: Fundamentals Comprehensive Guide on Biopharmacy and Pharmacokinetics.
and Applications. Springer International Publishing; 2019:403-427. Springer International Publishing; 2021: 1-13.
3. Heinemann L, Linkeschova R, Rave K, Hompesch B, Sedlak M, 20. Pertusa JAG, León-Quinto T, Berná G, et al. Zn2+ chelation by se­
Heise T. Time-action profile of the long-acting insulin analog in­ rum albumin improves hexameric Zn2+-insulin dissociation into
sulin glargine (HOE901) in comparison with those of NPH insulin monomers after exocytosis. PLoS One. 2017;12(11):e0187547.
and placebo. Diabetes Care. 2000;23(5):644-649. 21. De Meyts P. The insulin receptor and its signal transduction net­
4. Riddle MC, Rosenstock J, Gerich J; Insulin Glargine 4002 Study work. [updated 2016 Apr 27]. In: Feingold KR Anawalt B and
Investigators. The treat-to-target trial: randomized addition of Blackman MR, et al. (eds.), Endotext. MDText.com, Inc.; 2000.
glargine or human NPH insulin to oral therapy of type 2 diabetic 22. Liao Z, Zhang C, Ding L, Moyers JS, Tang JX, Beals JM.
patients. Diabetes Care. 2003;26(11):3080-3086 Comprehensive insulin receptor phosphorylation dynamics pro­
5. Yki-Järvinen H, Dressler A, Ziemen M; HOE 901/3002 Study filed by mass spectrometry. FEBS J. 2022;289(9):2657-2671.
Group. Less nocturnal hypoglycemia and better post-dinner glu­ 23. Belfiore A, Malaguarnera R, Vella V, et al. Insulin receptor iso­
cose control with bedtime insulin glargine compared with bedtime forms in physiology and disease: an updated view. Endocr Rev.
NPH insulin during insulin combination therapy in type 2 2017;38(5):379-431.
410 Endocrine Reviews, 2024, Vol. 45, No. 3

24. Hansen BF, Kurtzhals P, Jensen AB, Dejgaard A, Russell-Jones D. subjects: a dose-response study. Am J Physiol-Endocrinol
Insulin X10 revisited: a super-mitogenic insulin analogue. Metab. 1983;244(6):E517-E527.
Diabetologia. 2011;54(9):2226-2231. 48. Rabkin R, Simon NM, Steiner S, Colwell JA. Effect of renal dis­
25. Duckworth WC. Insulin degradation: mechanisms, products, and ease on renal uptake and excretion of insulin in man. N Engl J
significance. Endocr Rev. 1988;9(3):319-345. Med. 1970;282(4):182-187.
26. Authier F, Métioui M, Fabrega S, Kouach M, Briand G. 49. Pina AF, Borges DO, Meneses MJ, et al. Insulin: trigger and target
Endosomal proteolysis of internalized insulin at the C-terminal re­ of renal functions. Front Cell Dev Biol. 2020;8:519.
gion of the B chain by cathepsin D. J Biol Chem. 2002;277(11): 50. Rabkin R, Ryan MP, Duckworth WC. The renal metabolism of in­
9437-9446. sulin. Diabetologia. 1984;27(3):351-357.
27. Posner BI. Insulin signalling: the inside story. Can J Diabetes. 51. Rave K, Heise T, Pfü tzner A, Heinemann L, Sawicki PT. Impact of
2017;41(1):108-113. diabetic nephropathy on pharmacodynamic and pharmacokinetic
28. Wroblewski VJ, Masnyk M, Khambatta SS, Becker GW. properties of insulin in type 1 diabetic patients. Diabetes Care.
Mechanisms involved in degradation of human insulin by cytosol­ 2001;24(5):886-890.
ic fractions of human, monkey, and rat liver. Diabetes. 52. Cavanaugh KL. Diabetes management issues for patients with
1992;41(4):539-547. chronic kidney disease. Clin Diabetes. 2007;25(3):90-97.
29. Tokarz VL, MacDonald PE, Klip A. The cell biology of systemic 53. Arnolds S, Kuglin B, Kapitza C, Heise T. How pharmacokinetic

Downloaded from https://academic.oup.com/edrv/article/45/3/379/7550051 by guest on 17 July 2024

insulin function. J Cell Biol. 2018;217(7):2273-2289.
and pharmacodynamic principles pave the way for optimal basal
30. Da Poian A, El Bacha T, Luz M. Nutrient utilization in humans:
insulin therapy in type 2 diabetes. Int J Clin Pract. 2010;64(10):
metabolism pathways. Nat Educ. 2010;3:11.
1415-1424.
31. Dimitriadis G, Mitrou P, Lambadiari V, Maratou E, Raptis SA.
54. Meier JJ, Nauck MA, Kranz D, et al. Secretion, degradation, and
Insulin effects in muscle and adipose tissue. Diabetes Res Clin
elimination of glucagon-like peptide 1 and gastric inhibitory poly­
Pract. 2011;93:S52-S59.
peptide in patients with chronic renal insufficiency and healthy
32. Polonsky KS, Given BD, Van Cauter E. Twenty-four-hour profiles
and pulsatile patterns of insulin secretion in normal and obese sub­ control subjects. Diabetes. 2004;53(3):654-662.
jects. J Clin Invest. 1988;81(2):442-448. 55. Lepore M, Pampanelli S, Fanelli C, et al. Pharmacokinetics and
33. Lang DA, Matthews DR, Peto J, Turner RC. Cyclic oscillations of pharmacodynamics of subcutaneous injection of long-acting hu­
basal plasma glucose and insulin concentrations in human beings. man insulin analog glargine, NPH insulin, and ultralente human
N Engl J Med. 1979;301(19):1023-1027. insulin and continuous subcutaneous infusion of insulin lispro.
34. Boden G, Ruiz J, Urbain JL, Chen X. Evidence for a circadian Diabetes. 2000;49(12):2142-2148. Doi:10.2337/diabetes.49.12.
rhythm of insulin secretion. Am J Physiol-Endocrinol Metab. 2142
1996;271(2):E246-E252. 56. Havelund S, Plum A, Ribel U, et al. The mechanism of protraction
35. Goodner CJ, Walike BC, Koerker DJ, et al. Insulin, glucagon, and of insulin detemir, a long-acting, acylated analog of human insu­
glucose exhibit synchronous, sustained oscillations in fasting lin. Pharm Res. 2004;21(8):1498-1504.
monkeys. Science. 1977;195(4274):177-179. 57. Steensgaard DB, Schluckebier G, Strauss HM, et al.
36. Stenvers DJ, Scheer FAJL, Schrauwen P, la Fleur SE, Kalsbeek A. Ligand-controlled assembly of hexamers, dihexamers, and linear
Circadian clocks and insulin resistance. Nat Rev Endocrinol. multihexamer structures by the engineered acylated insulin deglu­
2019;15(2):75-89. dec. Biochemistry. 2013;52(2):295-309.
37. Campioni M, Toffolo G, Basu R, Rizza RA, Cobelli C. Minimal 58. Porcellati F, Rossetti P, Busciantella NR, et al. Comparison of
model assessment of hepatic insulin extraction during an oral pharmacokinetics and dynamics of the long-acting insulin analogs
test from standard insulin kinetic parameters. Am J glargine and detemir at steady state in type 1 diabetes. Diabetes
Physiol-Endocrinol Metabol. 2009;297(4):E941-E948. Care. 2007;30(10):2447-2452. Doi:10.2337/dc07-0002
38. Eaton RP, Allen RC, Schade DS. Hepatic removal of insulin in 59. Meneghini L, Atkin SL, Gough SCL, et al. The efficacy and safety
normal man: dose response to endogenous insulin secretion. J of insulin degludec given in Variable once-daily dosing intervals
Clin Endocrinol Metab. 1983;56(6):1294-1300. compared with insulin glargine and insulin degludec dosed at
39. Polonsky KS, Rubenstein AH. C-Peptide as a measure of the secre­ the same time daily: a 26-week, randomized, open-label,
tion and hepatic extraction of insulin: pitfalls and limitations. parallel-group, treat-to-target trial in individuals with type 2 dia­
Diabetes. 1984;33(5):486-494.
betes. Diabetes Care. 2013;36(4):858-864.
40. Meier JJ, Veldhuis JD, Butler PC. Pulsatile insulin secretion dic­
60. Sommerfeld MR, Müller G, Tschank G, et al. In vitro metabolic
tates systemic insulin delivery by regulating hepatic insulin extrac­
and mitogenic signaling of insulin glargine and its metabolites.
tion in humans. Diabetes. 2005;54(6):1649-1656.
PLoS One. 2010;5(3):e9540.
41. Herring R, Jones RH, Russell-Jones DL. Hepatoselectivity and the
61. Owens RA, Hansen RJ, Kahl SD, et al. In vivo and in vitro char­
evolution of insulin. Diabetes Obes Metab. 2014;16(1):1-8.
acterization of basal insulin peglispro: a novel insulin analog. J
42. Bergman RN. Non-esterified fatty acids and the liver: why is insu­
Pharmacol Exp Ther. 2016;357(3):459-465.
lin secreted into the portal vein? Diabetologia. 2000;43(7):
62. Nishimura E, Sorensen A, Hansen B, et al. Insulin degludec: a new
946-952.
43. Marks JS, Botelho LH. Synergistic inhibition of hepatic glycoge­ ultra-long, basal insulin designed to maintain full metabolic effect
nolysis in the presence of insulin and a cAMP antagonist. J Biol while minimizing mitogenic potential. Diabetologia.
Chem. 1986;261(6):2781-2785. 2010;53(Suppl 1):S388-S389.
44. Claus TH, Pilkis SJ. Regulation by insulin of gluconeogenesis in 63. Varewijck AJ, Janssen JAMJL. Insulin and its analogues and their
isolated rat hepatocytes. Biochim Biophys Acta. 1976;421(2): affinities for the IGF1 receptor. Endocr-Related Cancer.
246-262. 2012;19(5):F63-F75.
45. Yuan SY, Rigor RR. Regulation of Endothelial Barrier Function. 64. Tennagels N, Werner U. The metabolic and mitogenic properties
Morgan & Claypool Life Sciences; 2010. Chapter 2, Structure and of basal insulin analogues. Arch Physiol Biochem. 2013;119(1):
Function of Exchange Microvessels. 1-14.
46. Henriksen JH, Tronier B, Bülow JB. Kinetics of circulating en­ 65. Owens DR. Glargine and cancer: can we now suggest closure?
dogenous insulin, C-peptide, and proinsulin in fasting nondiabetic Diabetes Care. 2012;35(12):2426-2428.
man. Metabolism. 1987;36(5):463-468. 66. DeFronzo RA, Eldor R, Abdul-Ghani M. Pathophysiologic ap­
47. Ferrannini E, Wahren J, Faber OK, Felig P, Binder C, DeFronzo proach to therapy in patients with newly diagnosed type 2 dia­
RA. Splanchnic and renal metabolism of insulin in human betes. Diabetes Care. 2013;36(Supplement_2):S127-S138.
Endocrine Reviews, 2024, Vol. 45, No. 3 411

67. Edgerton DS, Moore MC, Winnick JJ, et al. Changes in glucose analog designed for once-weekly dosing. BMJ Open Diabetes
and fat metabolism in response to the administration of a hepato- Res Care. 2021;9(1):e002301.
preferential insulin analog. Diabetes. 2014;63(11):3946-3954. 87. Moyers JS, Hansen RJ, Day JW, et al. Preclinical characterization
68. Edgerton DS, Kraft G, Smith M, et al. Insulin's direct hepatic effect of LY3209590, a novel weekly basal insulin fc-fusion protein. J
explains the inhibition of glucose production caused by insulin se­ Pharmacol Exp Ther. 2022;382(3):346-355.
cretion. JCI Insight. 2017;2(6):e91863. 88. Philis-Tsimikas A, Bajaj HS, Begtrup K, et al. Rationale and design
69. Henry RR, Mudaliar S, Ciaraldi TP, et al. Basal insulin peglispro of the phase 3a development programme (ONWARDS 1–6 trials)
demonstrates preferential hepatic versus peripheral action relative investigating once-weekly insulin icodec in diabetes. Diabetes
to insulin glargine in healthy subjects. Diabetes Care. 2014;37(9): Obes Metab. 2023;25(2):331-341.
2609-2615. 89. Nordisk Novo. Novo Nordisk A/S: New data show once-weekly in­
70. Mudaliar S, Henry RR, Ciaraldi TP, et al. Reduced peripheral ac­ sulin icodec met additional endpoints in adults with type 2 diabetes
tivity leading to hepato-preferential action of basal insulin peglis­ in phase 3a trials [press release]. 2023, June 25. Available from:
pro compared with insulin glargine in patients with type 1 https://www.prnewswire.com/news-releases/new-data-show-once-we
diabetes. Diabetes Obes Metab. 2016;18(S2):17-24. ekly-insulin-icodec-met-additional-endpoints-in-adults-with-type-2-d
71. Moore MC, Smith MS, Sinha VP, et al. Novel PEGylated basal in­ iabetes-in-phase-3a-trials-301862521.html#:∼:text=SAN%20DIEG
sulin LY2605541 has a preferential hepatic effect on glucose me­ O%2C%20June%2024%2C%202023, the%20studies%20met%

Downloaded from https://academic.oup.com/edrv/article/45/3/379/7550051 by guest on 17 July 2024

tabolism. Diabetes. 2014;63(2):494-504. 20their%20primary
72. Iglesias P, Díez JJ. Insulin therapy in renal disease. Diabetes Obes 90. Søeborg T, Rasmussen CH, Mosekilde E, Colding-Jørgensen M.
Metab. 2008;10(10):811-823. Absorption kinetics of insulin after subcutaneous administration.
73. Hordern SVM, Wright JE, Umpleby AM, Shojaee-Moradie F, Eur J Pharm Sci. 2009;36(1):78-90.
Amiss J, Russell-Jones DL. Comparison of the effects on glucose 91. Gradel AKJ, Porsgaard T, Lykkesfeldt J, et al. Factors affecting the
and lipid metabolism of equipotent doses of insulin detemir and absorption of subcutaneously administered insulin: effect on vari­
NPH insulin with a 16-h euglycaemic clamp. Diabetologia. ability. J Diabetes Res. 2018;2018:1205121.
2005;48(3):420-426. 92. Kjeldsen TB, Hubálek F, Hjørringgaard CU, et al. Molecular en­
74. Novo Nordisk. Tresiba® [Prescribing Information]. 2022; https:// gineering of insulin icodec, the first acylated insulin analog for
www.novo-pi.com/tresiba.pdf. Accessed February 13, 2023. once-weekly administration in humans. J Med Chem.
75. Novo Nordisk A/S. Levemir® [Prescribing Information}. 2022; 2021;64(13):8942-8950.
https://www.novo-pi.com/levemir.pdf. Accessed February 13, 93. Med Chem Express. Insulin icodec. https://www.medchemexpress.
com/insulin-icodec.html. Accessed April 19, 2023.
2023.
94. Charman SA, McLennan DN, Edwards GA, Porter CJ. Lymphatic
76. Sanofi-aventis. Lantus® [Prescribing Information]. 2022; http://
absorption is a significant contributor to the subcutaneous bio­
products.sanofi.us/lantus/lantus.pdf. Accessed February 13,
availability of insulin in a sheep model. Pharm Res.
2023.
2001;18(11):1620-1626.
77. Sanofi-aventis. Toujeo® [Prescribing Information]. 2022; https://
95. Liu L. Pharmacokinetics of monoclonal antibodies and Fc-fusion
www.campus.sanofi/dam/jcr:52ab94b2-83e1-4493-9cd8-01d3b03
proteins. Protein Cell. 2018;9(1):15-32.
3c4aa/toujeo-lantus-combined-pi.pdf. Accessed February 17, 2023.
96. Cavaco M, Castanho MARB, Neves V. Peptibodies: an elegant so­
78. Edgerton DS, Scott M, Farmer B, et al. Targeting insulin to the liv­
lution for a long-standing problem. Peptide Science. 2018;110(1):
er corrects defects in glucose metabolism caused by peripheral in­
e23095.
sulin delivery. JCI Insight. 2019;4(7):e126974.
97. Glaesner W, Mark Vick A, Millican R, et al. Engineering and char­
79. Tiffner K, Boulgaropoulos B, Höfferer C, et al. Quantification of
acterization of the long-acting glucagon-like peptide-1 analogue
basal insulin peglispro and human insulin in adipose tissue inter­
LY2189265, an Fc fusion protein. Diabetes Metab Res Rev.
stitial fluid by open-flow microperfusion. Diabetes Technol
2010;26(4):287-296.
Ther. 2017;19(5):305-314.
98. Gregory JM, Kraft G, Scott MF, et al. Peripherally delivered hep­
80. Jacober SJ, Prince MJ, Beals JM, et al. Basal insulin peglispro:
atopreferential insulin analog insulin-406 mimics the
overview of a novel long-acting insulin with reduced peripheral ef­ hypoglycaemia-sparing effect of portal vein human insulin infu­
fect resulting in a hepato-preferential action. Diabetes Obes sion in dogs. Diabetes Obes Metab. 2019;21(10):2294-2304.
Metab. 2016;18(S2):3-16. 99. Richter WF, Jacobsen B. Subcutaneous absorption of biothera­
81. Bergenstal RM, Lunt H, Franek E, et al. Randomized, double- peutics: knowns and unknowns. Drug Metab Dispos.
blind clinical trial comparing basal insulin peglispro and insulin 2014;42(11):1881-1889.
glargine, in combination with prandial insulin lispro, in patients 100. Lobo ED, Hansen RJ, Balthasar JP. Antibody pharmacokinetics
with type 1 diabetes: IMAGINE 3. Diabetes Obes Metab. and pharmacodynamics. J Pharm Sci. 2004;93(11):2645-2668.
2016;18(11):1081-1088. 101. Shah DK, Betts AM. Antibody biodistribution coefficients. mAbs.
82. Rosenstock J, Marre M, Qu Y, et al. Reduced nocturnal hypogly­ 2013;5(2):297-305.
caemia with basal insulin peglispro compared with insulin glar­ 102. Li Z, Krippendorff B-F, Sharma S, Walz AC, Lavé T, Shah DK.
gine: pooled analyses of five randomized controlled trials. Influence of molecular size on tissue distribution of antibody frag­
Diabetes Obes Metab. 2016;18(11):1093-1097. ments. mAbs. 2016;8(1):113-119.
83. Heise T, Nosek L, Rønn BB, et al. Lower within-subject variability 103. Linnebjerg H, Choi SL, Lam ECQ, Mace KF, Hodgson TS, Sinha
of insulin detemir in comparison to NPH insulin and insulin glar­ VP. Pharmacokinetics of the long-acting basal insulin LY2605541
gine in people with type 1 diabetes. Diabetes. 2004;53(6): in subjects with varying degrees of renal function. Clin Pharmacol
1614-1620. Drug Dev. 2016;5(3):216-224.
84. Heise T, Hermanski L, Nosek L, Feldman A, Rasmussen S, Haahr 104. Kiss I, Arold G, Roepstorff C, Bøttcher SG, Klim S, Haahr H.
H. Insulin degludec: four times lower pharmacodynamic variabil­ Insulin degludec: pharmacokinetics in patients with renal impair­
ity than insulin glargine under steady-state conditions in type 1 ment. Clin Pharmacokinet. 2014;53(2):175-183.
diabetes. Diabetes Obes Metab. 2012;14(9):859-864. 105. Tencer J, Frick I-M, Öquist BW, Alm P, Rippe B. Size-selectivity of
85. Haahr H, Heise T. A review of the pharmacological properties of the glomerular barrier to high molecular weight proteins: upper
insulin degludec and their clinical relevance. Clin Pharmacokinet. size limitations of shunt pathways. Kidney Int. 1998;53(3):
2014;53(9):787-800. 709-715.
86. Nishimura E, Pridal L, Glendorf T, et al. Molecular and pharma­ 106. Heise T. The future of insulin therapy. Diabetes Res Clin Pract.
cological characterization of insulin icodec: a new basal insulin 2021;175:108820.
412 Endocrine Reviews, 2024, Vol. 45, No. 3

107. Home P. Making sense of weekly insulins. Lancet Diabetes from ONWARDS 2 and 4. Diabetes. 2023;72(Supplement_1):
Endocrinol. 2023;11(3):140-141. 804-P.
108. Heise T, Chien J, Beals JM, et al. Pharmacokinetic and pharmaco­ 124. Pieber TR, Arfelt KN, Cailleteau R, et al. Hypoglycaemia fre­
dynamic properties of the novel basal insulin Fc (insulin efsitora quency and physiological response after double or triple doses
alfa), an insulin fusion protein in development for once-weekly of once-weekly insulin icodec vs once-daily insulin glargine
dosing for the treatment of patients with diabetes. Diabetes U100 in type 2 diabetes: a randomised crossover trial.
Obes Metab. 2023;25(4):1080-1090. Diabetologia. 2023;66(8):1413-1430.
109. Rosenstock J, Del Prato S. Basal weekly insulins: the way of the fu­ 125. Haahr H, Kristensen NR, Larsen JH, Wagner F-DH, Ignatenko S.
ture!. Metabolism. 2022;126:154924. 808-P: pharmacokinetic properties of once-weekly insulin icodec
110. Plum-Mörschel L, Andersen LR, Hansen S, et al. Pharmacokinetic in individuals with renal impairment vs. Normal renal function.
and pharmacodynamic characteristics of insulin icodec after sub­ Diabetes. 2023;72(Supplement_1):808-P.
cutaneous administration in the thigh, abdomen or upper arm in 126. Haahr H, Cieslarova B, Donatsky AM, et al. 809-P: the effect of
individuals with type 2 diabetes Mellitus. Clin Drug Investig. various degrees of hepatic impairment on the pharmacokinetic
2023;43(2):119-127. characteristics of once-weekly insulin icodec. Diabetes.
111. Rosenstock J, Bajaj HS, Janež A, et al. Once-weekly insulin for 2023;72(Supplement_1):809-P.
type 2 diabetes without previous insulin treatment. N Engl J 127. Frias J, Chien J, Zhang Q, et al. Safety and efficacy of once-weekly

Downloaded from https://academic.oup.com/edrv/article/45/3/379/7550051 by guest on 17 July 2024

Med. 2020;383(22):2107-2116. basal insulin Fc in people with type 2 diabetes previously treated
112. Lingvay I, Buse JB, Franek E, et al. A randomized, open-label com­ with basal insulin: a multicentre, open-label, randomised, phase
parison of once-weekly insulin icodec titration strategies versus 2 study. Lancet Diabetes Endocrinol. 2023;11(3):158-168.
once-daily insulin glargine U100. Diabetes Care. 2021;44(7): 128. Kazda CM, Bue-Valleskey JM, Chien J, et al. Novel once-weekly
1595-1603. basal insulin Fc achieved similar glycemic control with a safety
113. Bajaj HS, Bergenstal RM, Christoffersen A, et al. Switching to profile comparable to insulin degludec in patients with type 1 dia­
once-weekly insulin icodec versus once-daily insulin glargine betes. Diabetes Care. 2023;46(5):1052-1059.
U100 in type 2 diabetes inadequately controlled on daily basal in­ 129. Bue-Valleskey JM, Kazda CM, Ma C, et al. Once-Weekly basal in­
sulin: a phase 2 randomized controlled trial. Diabetes Care. sulin fc demonstrated similar glycemic control to once-daily insu­
2021;44(7):1586-1594. lin degludec in insulin-naive patients with type 2 diabetes: a phase
114. Silver RJ, Asong M, Begtrup K, Koefoed MM, Heller SR, 2 randomized control trial. Diabetes Care. 2023;46(5):
Rosenstock J. 191-OR: similar hypoglycemia duration with 1060-1067.
once-weekly insulin icodec vs. Insulin glargine U100 in insulin 130. Qu Y, Luo J, Garhyan P, Antalis CJ, Chang AM, Jacober SJ. Dose
naïve or experienced patients with T2D. Diabetes. unit establishment for a new basal insulin using joint modeling of
2021;70(Supplement_1):191-OR. insulin dose and glycemic response. J Diabetes Sci Technol.
115. Bajaj HS, Aberle J, Davies M, et al. Once-Weekly insulin icodec 2018;12(1):155-162.
with dosing guide app versus once-daily basal insulin analogues 131. Russell-Jones D, Pouwer F, Khunti K. Identification of barriers to
in insulin-naive type 2 diabetes (ONWARDS 5) : a randomized tri­ insulin therapy and approaches to overcoming them. Diabetes
al. Ann Intern Med. 2023;176(11):1476-1485. Obes Metab. 2018;20(3):488-496.
116. Rosenstock J, Bain SC, Gowda A, et al. Weekly icodec versus daily 132. Khunti K, Wolden ML, Thorsted BL, Andersen M, Davies MJ.
glargine U100 in type 2 diabetes without previous insulin. N Engl Clinical inertia in people with type 2 diabetes: a retrospective co­
J Med. 2023;389(4):297-308. hort study of more than 80,000 people. Diabetes Care.
117. Lingvay I, Asong M, Desouza C, et al. Once-weekly insulin icodec 2013;36(11):3411-3417.
vs once-daily insulin degludec in adults with insulin-naive type 2 133. Peyrot M, Rubin RR, Lauritzen T, et al. Resistance to insulin ther­
diabetes: the ONWARDS 3 randomized clinical trial. JAMA. apy among patients and providers: results of the cross-national
2023;330(3):228-237. diabetes attitudes, wishes, and needs (DAWN) study. Diabetes
118. Philis-Tsimikas A, Asong M, Franek E, et al. Switching to once- Care. 2005;28(11):2673-2679.
weekly insulin icodec versus once-daily insulin degludec in indi­ 134. Reach G, Consoli SM, Halimi S, et al. The multinational second
viduals with basal insulin-treated type 2 diabetes (ONWARDS diabetes, attitudes, wishes and needs study: results of the French
2): a phase 3a, randomised, open label, multicentre, treat-to-target survey. Patient Prefer Adherence. 2015;9:289-297.
trial. Lancet Diabetes Endocrinol. 2023;11(6):414-425. 135. Ng CJ, Lai PSM, Lee YK, Azmi SA, Teo CH. Barriers and facilita­
119. Mathieu C, Asbjornsdottir B, Bajaj HS, et al. Switching to once- tors to starting insulin in patients with type 2 diabetes: a systemat­
weekly insulin icodec versus once-daily insulin glargine U100 in ic review. Int J Clin Pract. 2015;69(10):1050-1070.
individuals with basal-bolus insulin-treated type 2 diabetes 136. Sorli C, Heile MK. Identifying and meeting the challenges of insu­
(ONWARDS 4): a phase 3a, randomised, open-label, multicentre, lin therapy in type 2 diabetes. J Multidiscip Healthc. 2014;7:
treat-to-target, non-inferiority trial. Lancet. 2023;401(10392): 267-282.
1929-1940. 137. Peyrot M, Barnett AH, Meneghini LF, Schumm-Draeger PM.
120. Russell-Jones D, Babazono T, Cailleteau R, et al. Once-weekly in­ Insulin adherence behaviours and barriers in the multinational
sulin icodec versus once-daily insulin degludec as part of a basal- global attitudes of patients and physicians in insulin therapy study.
bolus regimen in individuals with type 1 diabetes (ONWARDS 6): Diabet Med. 2012;29(5):682-689.
a phase 3a, randomised, open-label, treat-to-target trial. Lancet. 138. Khunti S, Khunti K, Seidu S. Therapeutic inertia in type 2 diabetes:
2023;402(10413):1636-1647. prevalence, causes, consequences and methods to overcome iner­
121. Balkau B, Home PD, Vincent M, Marre M, Freemantle N. Factors tia. Ther Adv Endocrinol Metab. 2019. 10:10.1177/
associated with weight gain in people with type 2 diabetes starting 2042018819844694
on insulin. Diabetes Care. 2014;37(8):2108-2113. 139. Hancu N, Janez A, Lalic N, et al. Expert opinion: a call for basal
122. Bajaj H, Ásbjörnsdóttir B, Lehrskov LL, et al. Continuous glucose insulin titration in patients with type 2 diabetes in daily practice:
monitoring in insulin-experienced individuals with type 2 diabetes southeast European perspective. Diabetes Ther. 2021;12(5):
switched to once-weekly insulin icodec versus once-daily compa­ 1575-1589.
rators in onwards 2 and 4: post-hoc analysis. OP032. Diabetes 140. Alvarenga MA, Komatsu WR, de Sa JR, Chacra AR, Dib SA.
Technol Ther. 2023;25:A-1-A-269. Clinical inertia on insulin treatment intensification in type 2 dia­
123. Bajaj HS, Ásbjörnsdóttir B, Carstensen L, et al. 804-P: similar betes mellitus patients of a tertiary public diabetes center with lim­
hypoglycemia duration with once-weekly icodec vs. degludec or ited pharmacologic armamentarium from an upper-middle
glargine U100 in insulin-treated T2D—a post hoc CGM analysis income country. Diabetol Metab Syndrome. 2018;10(1):77.
Endocrine Reviews, 2024, Vol. 45, No. 3 413

141. Kunt T, Snoek FJ. Barriers to insulin initiation and intensification 158. Moschonis G, Siopis G, Jung J, et al. Effectiveness, reach, uptake,
and how to overcome them. Int J Clin Pract. 2009;63:6-10. and feasibility of digital health interventions for adults with type 2
142. Perreault L, Vincent L, Neumiller JJ, Santos-Cavaiola T. Initiation diabetes: a systematic review and meta-analysis of randomised
and titration of basal insulin in primary care: barriers and prac­ controlled trials. Lancet Digital Health. 2023;5(3):e125-e143.
tical solutions. J Am Board Fam Med. 2019;32(3):431-447. 159. Wredling RAM, Theorell PGT, Roll HM, Lins PES, Adamson
143. Mocarski M, Yeaw J, Divino V, et al. Slow titration and delayed UKC. Psychosocial slate of patients with IDDM prone to recurrent
intensification of basal insulin among patients with type 2 dia­ episodes of severe hypoglycemia. Diabetes Care. 1992;15(4):
betes. J Manag Care Spec Pharm. 2018;24(4):390-400. 518-521.
144. Wei W, Pan C, Xie L, Baser O. Real-World insulin treatment per­ 160. Przezak A, Bielka W, Molę da P. Fear of hypoglycemia—an under­
sistence among patients with type 2 diabetes. Endocr Pract. estimated problem. Brain Behav. 2022;12(7):e2633.
2014;20(1):52-61. 161. ElSayed NA, Aleppo G, Aroda VR, et al. 13. Older adults: stand­
145. Perez-Nieves M, Kabul S, Desai U, et al. Basal insulin persistence, ards of care in diabetes—2023. Diabetes Care.
associated factors, and outcomes after treatment initiation among
2022;46(Supplement_1):S216-S229.
people with type 2 diabetes mellitus in the US. Curr Med Res
162. Flores M, Amir M, Ahmed R, et al. Causes of diabetic ketoacidosis
Opin. 2016;32(4):669-680.
among adults with type 1 diabetes mellitus: insulin pump users
146. Mauricio D, Meneghini L, Seufert J, et al. Glycaemic control and
and non-users. BMJ Open Diabetes Res Care. 2020;8(2):

Downloaded from https://academic.oup.com/edrv/article/45/3/379/7550051 by guest on 17 July 2024

hypoglycaemia burden in patients with type 2 diabetes initiating
e001329.
basal insulin in Europe and the USA. Diabetes Obes Metab.
163. Skyler JS. Weekly insulin becoming a reality. Diabetes Care.
2017;19(8):1155-1164.
2021;44(7):1459-1461.
147. Eli Lilly and Company. Trulicity US prescribing information.
164. Hirsch IB, Draznin B. Transition of patients to and from insulin
2022; http://pi.lilly.com/us/trulicity-uspi.pdf. Accessed July 27,
2023. degludec: a clinical challenge. J Clin Endocrinol Metab.
148. Novo Nordisk. Ozempic US prescribing information. 2017; 2020;105(6):e2294-e2298.
https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/209 165. Crunkhorn S. Illuminating the incretin effect. Nature Milestones,
637lbl.pdf. Accessed July 27, 2023. Diabetes. June 2021; S11; https://www.nature.com/articles/
149. Jung H, Tittel SR, Schloot NC, et al. Clinical characteristics, treat­ d42859-021-00012-3. Accessed March 23, 2023.
ment patterns, and persistence in individuals with type 2 diabetes 166. Maiorino MI, Chiodini P, Bellastella G, Capuano A, Esposito K,
initiating a glucagon-like peptide-1 receptor agonist: a retrospect­ Giugliano D. Insulin and glucagon-like peptide 1 receptor agonist
ive analysis of the diabetes prospective follow-up registry. combination therapy in type 2 diabetes: a systematic review and
Diabetes Obes Metab. 2023;25(7):1813-1822. meta-analysis of randomized controlled trials. Diabetes Care.
150. Polonsky WH, Fisher L, Hessler D, Bruhn D, Best JH. Patient per­ 2017;40(4):614-624.
spectives on once-weekly medications for diabetes. Diabetes Obes 167. Montvida O, Klein K, Kumar S, Khunti K, Paul SK. Addition of or
Metab. 2011;13(2):144-149. switch to insulin therapy in people treated with glucagon-like
151. Qiao Q, Ouwens MJ, Grandy S, Johnsson K, Kostev K. Adherence peptide-1 receptor agonists: a real-world study in 66 583 patients.
to GLP-1 receptor agonist therapy administered by once-daily or Diabetes Obes Metab. 2017;19(1):108-117.
once-weekly injection in patients with type 2 diabetes in 168. Davies MJ, Aroda VR, Collins BS, et al. Management of hypergly­
Germany. Diabetes Metab Syndr Obes. 2016;9:201-205. cemia in type 2 diabetes, 2022. A consensus report by the
152. Qin L, Chen S, Flood E, et al. Glucagon-like peptide-1 receptor American Diabetes Association (ADA) and the European
agonist treatment attributes important to injection-experienced Association for the Study of Diabetes (EASD). Diabetes Care.
patients with type 2 diabetes Mellitus: a preference study in 2022;45(11):2753-2786.
Germany and the United Kingdom. Diabetes Ther. 2017;8(2): 169. U.S. Food and Drug Administration (FDA). Diabetes Mellitus: ef­
335-353. ficacy endpoints for clinical trials investigating antidiabetic drugs
153. Nguyen H, Dufour R, Caldwell-Tarr A. Glucagon-like peptide-1 and biological products guidance for industry; DRAFT
receptor agonist (GLP-1RA) therapy adherence for patients with
GUIDANCE. May 26, 2023; https://www.regulations.gov/
type 2 diabetes in a medicare population. Adv Ther. 2017;34(3):
document/FDA-2023-D-0625-0002. Accessed July 14, 2023.
658-673.
170. US Food and Drug Administration. Center for drug evaluation
154. Weeda ER, Muraoka AK, Brock MD, Cannon JM. Medication
and research. Guidance for industry. Diabetes mellitus: develop­
adherence to injectable glucagon-like peptide-1 (GLP-1) receptor
ing drugs and therapeutic biologics for treatment and prevention.
agonists dosed once weekly vs once daily in patients with type 2
2008; https://www.federalregister.gov/documents/2008/03/03/
diabetes: a meta-analysis. Int J Clin Pract. 2021;75(9):e14060.
155. Morieri ML, Rigato M, Frison V, et al. Effectiveness of dulaglu­ E8-3974/draft-guidance-for-industry-on-diabetes-mellitus-develo
tide vs liraglutide and exenatide once-weekly. A real-world study ping-drugs-and-therapeutic-biologics-for. Accessed February 16,
and meta-analysis of observational studies. Metabolism. 2023.
2020;106:154190. 171. Cefalu WT, Dawes DE, Gavlak G, et al. Insulin access and afford­
156. Polonsky WH, Arora R, Faurby M, Fernandes J, Liebl A. Higher ability working group: conclusions and recommendations.
rates of persistence and adherence in patients with type 2 diabetes Diabetes Care. 2018;41(6):1299-1311.
initiating once-weekly vs daily injectable glucagon-like peptide-1 172. Herman WH, Kuo S. 100 years of insulin: why is insulin so expen­
receptor agonists in US clinical practice (STAY study). Diabetes sive and what can be done to control its cost? Endocrinol Metab
Ther. 2022;13(1):175-187. Clin North Am. 2021;50(3):e21-e34.
157. Kerr D, Edelman S, Vespasiani G, Khunti K. New digital health 173. Abdelhafiz A, Bisht S, Kovacevic I, Pennells D, Sinclair A. Insulin
technologies for insulin initiation and optimization for people in frail, older people with type 2 diabetes—low threshold for ther­
with type 2 diabetes. Endocr Pract. 2022;28(8):811-821. apy. Diabetology. 2022;3(2):369-383.