Diabetes from Research to Clinical Practice Volume 4, 1st

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Dedicated to the living memory of Muhammad Ibrahim
(c. 1911 1989)
Disclaimer

While every effort has been made to ensure that the contents of the book are
up to date and correct, the authors, editors and the publisher assume no
responsibility for eventual mistakes in the book, or eventual damages that
might occur to the patients because of their treatment according to the
information contained in the book. Clinicians are advised to follow approved
local, national or international guidelines, and use their professional judgment
to ensure correct and optimal treatment of their patients.

vii
Contents

Diabetes: From Research to Clinical Practice . . . . . . . . . . . . . . . . 1

Md. Shahidul Islam
Glucose Lowering Treatment Modalities of Type 2 Diabetes
Mellitus . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7
Asena Gökçay Canpolat and Mustafa Şahin
Latent Autoimmune Diabetes in Adults: A Review
of Clinically Relevant Issues . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 29
Marta Hernández and Dídac Mauricio
Hypoglycaemia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 43
Muhammad Muneer
Hypoglycemia, Malnutrition and Body Composition . . . . . . . . . . . 71
I. Khanimov, M. Shimonov, J. Wainstein, and Eyal Leibovitz
Acute Metabolic Emergencies in Diabetes: DKA, HHS
and EDKA . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 85
Muhammad Muneer and Ijaz Akbar
The Role of the Mediterranean Dietary Pattern on Metabolic
Control of Patients with Diabetes Mellitus: A Narrative
Review . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 115
Jéssica Abdo Gonçalves Tosatti, Michelle Teodoro Alves,
and Karina Braga Gomes
Glycaemic Control and Vascular Complications in Diabetes
Mellitus Type 2 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 129
Francesco Maranta, Lorenzo Cianfanelli, and Domenico Cianflone
Diabetes Mellitus and Acute Myocardial Infarction:
Impact on Short and Long-Term Mortality . . . . . . . . . . . . . . . . . . 153
Valentina Milazzo, Nicola Cosentino, Stefano Genovese,
Jeness Campodonico, Mario Mazza, Monica De Metrio,
and Giancarlo Marenzi
Effects of GLP-1 and Its Analogs on Gastric Physiology
in Diabetes Mellitus and Obesity . . . . . . . . . . . . . . . . . . . . . . . . . . 171
Daniel B. Maselli and Michael Camilleri

ix
x Contents

GLP-1 Receptor Agonists and SGLT2 Inhibitors

for the Treatment of Type 2 Diabetes: New Insights
and Opportunities for Cardiovascular Protection . . . . . . . . . . . . . 193
Laura Bertoccini and Marco Giorgio Baroni
Glucose Lowering Efficacy and Pleiotropic Effects
of Sodium-Glucose Cotransporter 2 Inhibitors . . . . . . . . . . . . . . . 213
Mohammad Shafi Kuchay, Khalid Jamal Farooqui,
Sunil Kumar Mishra, and Ambrish Mithal
Gestational Diabetes Mellitus Screening and Diagnosis . . . . . . . . . 231
U. Yasemin Sert and A. Seval Ozgu-Erdinc
Management of Gestational Diabetes Mellitus . . . . . . . . . . . . . . . . 257
Z. Asli Oskovi-Kaplan and A. Seval Ozgu-Erdinc
From Entero-Endocrine Cell Biology to Surgical Interventional
Therapies for Type 2 Diabetes . . . . . . . . . . . . . . . . . . . . . . . . . . . . 273
Marta Guimarães, Sofia S. Pereira, and Mariana P. Monteiro
Laparoscopic Vertical Sleeve Gastrectomy as a Treatment
Option for Adults with Diabetes Mellitus . . . . . . . . . . . . . . . . . . . . 299
Timothy R. Koch and Timothy R. Shope
Surgical Treatment of Type 2 Diabetes Mellitus in Youth . . . . . . . 321
Anna Zenno and Evan P. Nadler
Insulin Recommender Systems for T1DM: A Review . . . . . . . . . . 331
Joaquim Massana, Ferran Torrent-Fontbona, and Beatriz López
Algorithms for Diagnosis of Diabetic Retinopathy and Diabetic
Macula Edema- A Review . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 357
Karkuzhali Suriyasekeran, Senthilkumar Santhanamahalingam,
and Manimegalai Duraisamy
Diabetic Macular Edema: State of Art and Intraocular
Pharmacological Approaches . . . . . . . . . . . . . . . . . . . . . . . . . . . . 375
Annalisa Gurreri and Alberto Pazzaglia
New Concepts in the Management of Charcot Neuroarthropathy
in Diabetes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 391
Karakkattu Vijayan Kavitha, Vrishali Swanand Patil,
Carani Balarman Sanjeevi, and Ambika Gopalakrishnan
Unnikrishnan
Non-alcoholic Fatty Liver Disease and Diabetes Mellitus . . . . . . . . 417
Gebran Khneizer, Syed Rizvi, and Samer Gawrieh
Global Experience of Diabetes Registries: A Systematic
Review . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 441
Roya Naemi and Leila Shahmoradi
Diabetes and Genetics: A Relationship Between Genetic Risk
Alleles, Clinical Phenotypes and Therapeutic Approaches . . . . . . . 457
Shomoita Sayed and A. H. M. Nurun Nabi
Contents xi

Dietary SCFAs Immunotherapy: Reshaping the Gut

Microbiota in Diabetes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 499
Yu Anne Yap and Eliana Mariño
Animal Models and Renal Biomarkers of Diabetic
Nephropathy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 521
Laura Pérez-López, Mauro Boronat, Carlos Melián,
Yeray Brito-Casillas, and Ana M. Wägner
In Vivo and In Vitro Models of Diabetes: A Focus
on Pregnancy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 553
Joaquín Lilao-Garzón, Carmen Valverde-Tercedor,
Silvia Muñoz-Descalzo, Yeray Brito-Casillas, and Ana M. Wägner
Correction to: Hypoglycemia, Malnutrition and Body
Composition . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 577
I. Khanimov, M. Shimonov, J. Wainstein, and Eyal Leibovitz

Index . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 579
Adv Exp Med Biol - Advances in Internal Medicine (2020) 4: 1–5
https://doi.org/10.1007/5584_2020_553
# Springer Nature Switzerland AG 2020
Published online: 25 June 2020

Diabetes: From Research to Clinical

Practice

Md. Shahidul Islam

Abstract several anti-VEGF agents are being used.

Numerous people living in the middle- and
The number of people living with diabetes, the
low-income countries cannot afford the costs
number of deaths attributable to it, and the cost
of care of diabetes. Institutions like the World
of treating the disease and its complications are
Health Organization, the World Bank and the
increasing exponentially. Centuries of research
International Monetary Fund should roll out
led to the discovery of insulin and other drugs
plans to convince the politicians to invest
based on pathophysiology from “the triumvi-
more in improving the diabetes care facilities.
rate to ominous octet”. The agonists of the
glucagon-like peptide-1 (GLP-1) receptor,
Keywords
and the inhibitors of the sodium-glucose trans-
port protein 2 (SGLT2) are the new drugs that Anti-VEGF · Cardiovascular outcomes ·
improve cardiovascular outcomes and provide Diabetes and GLP-1 receptor agonists ·
renal protection, and they are being used Diabetes and SGLT2 inhibitors · Diabetic
increasingly for evidence-based treatment of keto-acidosis · Diabetic macular edema ·
type 2 diabetes. Bariatric surgery, when Euglycemic diabetic keto-acidosis ·
indicated, results in excellent weight- and Gestational diabetes · Hyperglycemic
metabolic-control, and in many instances hyperosmolar comma · Hypoglycemia ·
even remission of diabetes. Technological Renal protection · Type 1 diabetes ·
advances like Flash glucose monitoring, con- Type 2 diabetes
tinuous subcutaneous insulin infusion (CSII),
and continuous glucose monitoring (CGM) In 2019, 463 million adults in the world were
have improved glycemic control, reduced living with diabetes, and about half of them
episodes of severe hypoglycemia, and were unaware of their condition (Saeedi et al.
improved quality of life. For the treatment of 2019). About 80% of them were living in the
diabetic macular edema intravitreal injection of middle- and low-income countries. Number of
children and adolescents living with type 1 diabe-
M. S. Islam (*) tes was 1.1 million (Patterson et al. 2019). The
Department of Clinical Science and Education, estimated global healthcare expenditure for dia-
Södersjukhuset, Karolinska Institutet, Research Center,
Stockholm, Sweden betes in the world was 760 billion USD (Williams
et al. 2020). In 2019, 2.4 million of deaths among
Department of Emergency Care and Internal Medicine,
Uppsala University Hospital, Uppsala, Sweden adults (20–79 year) were attributed to diabetes
e-mail: [email protected] (Saeedi et al. 2020).

1
2 M. S. Islam

Research in the past decades have increased people, especially in the middle- and low-income
our understanding of the different types of diabe- countries, metformin and sulfonylurea still remain
tes and their treatment. In addition to the type the first-line drugs because of their low prices
1 diabetes, type 2 diabetes, and gestational diabe- (Mohan et al. 2020).
tes, there are other forms of diabetes that include The history of discovery and clinical applica-
diabetes of cystic fibrosis, fibro-calculous tion of GLP-1 through decades of basic- and
pancreatopathy, drug-induced diabetes, and dif- translational-researches is fascinating (Drucker
ferent monogenic diabetes syndromes. Some peo- et al. 2017). The list of beneficial effects of
ple with “type 1 diabetes” have no evidence of GLP-1 receptor agonists is long. These include
autoimmune β-cell damage. Some people with stimulation of glucose-dependent insulin secre-
apparent “type 2 diabetes” have autoimmune dia- tion, inhibition of glucagon secretion, delay of
betes (Latent Autoimmune Diabetes in Adults, gastric emptying, activation of the “ileal brake”,
LADA). They have an intermediate phenotype improvement of satiety, reduction of food intake,
between type 1 diabetes and type 2 diabetes. reduction of body weight, increase of natriuresis,
These people can be identified by demonstrating reduction of blood pressure, and promotion of
anti-glutamic acid decarboxylase (GAD) anti- β-cell growth (Buteau 2008). The blood-pressure
body. Treatment of these people must be lowering effect of the GLP-1 receptor agonists is
individualized, and in this respect measurement mediated partly by GLP-1 mediated increase in
of C-peptide may help the clinicians in choosing the secretion of the atrial natriuretic peptide and
the appropriate treatment. by the positive effects of GLP-1 on the endothe-
When it comes to the drug treatment of diabe- lial cells (Helmstadter et al. 2020). The delaying
tes, we are witnessing an era of more effect on the gastric emptying is successively
“personalized approach”. Glucose-lowering reduced when the short-acting GLP-1 receptor
drugs that are safe and that clearly improve car- agonists are used for long time, or when the
diovascular outcomes are now available. long-acting GLP-1 receptor agonists are used
Inhibitors of dipeptidyl peptidase-4 (DPP-4), (Umapathysivam et al. 2014). Bariatric surgery,
agonists of the glucagon-like peptide-1 (GLP-1) apart from causing anatomical changes, increases
receptor, and the inhibitors of the sodium-glucose GLP-1-secreting L cells in the small intestine and
transport protein 2 (SGLT2) represent major increases secretion of the gastrointestinal satiety
advances in the treatment of type 2 diabetes. hormone peptide YY. These changes result in
GLP-1 receptor agonists and SGLT2 inhibitors improvement of glycemia, remission of type 2 dia-
reduce cardiovascular events and mortality by betes, and reduction of diabetes-associated mor-
glycemic- and extra-glycemic effects. The use of bidity and mortality.
these drugs is increasing, especially in the high- In people with type 2 diabetes, GLP-1 receptor
income countries. Metformin is no longer the first agonists reduce cardiovascular deaths, major
line drug, but it should be considered for over- adverse cardiac events, and hospitalization for
weight patients with type 2 diabetes who does not heart failure. These drugs should be used when-
have cardiovascular disease or who have only ever possible for the treatment of people with
moderate risk of cardiovascular disease. For diabetes who have atherosclerotic cardiovascular
patients with cardiovascular disease, an SGLT2 diseases. These drugs should also be considered
inhibitor, or a GLP-1 receptor agonist that offers in people with type 2 diabetes who does not have
cardiovascular protection, is recommended as the established cardiovascular diseases, but have high
first line drug. GLP-1 receptor agonists are partic- risk factors for developing cardiovascular
ularly suitable for overweight or obese people diseases (Buse et al. 2020).
with type 2 diabetes. DPP-4 inhibitors, GLP-1 It has taken about 178 years from the discov-
receptor agonists, and SGLT2 inhibitors are usu- ery of phlorizin in 1835 to the clinical use of a
ally not associated with hypoglycemia. For many stable derivative of phlorizin as a specific
Diabetes: From Research to Clinical Practice 3

inhibitor of sodium-glucose transport protein surgical procedure can result in sustained loss of
2 (SGLT2) (Vick et al. 1973). This group of excess bodyweight, and improvement or even
drugs should be used for the treatment of people resolution of diabetes (Gill et al. 2010). The deci-
with type 2 diabetes who have heart failure, spe- sion to treat type 2 diabetes by bariatric surgery
cially heart failure with reduced ejection fraction, must be taken after serious consideration of
and in people with type 2 diabetes who have patients’ psychological and social situations,
chronic kidney disease (Buse et al. 2020). They since these people will need long-term lifestyle
reduce major adverse cardiac events, cardiovas- support, monitoring of micronutrients, and some
cular deaths, hospitalization for heart failure, the may need psychiatric support for adjustment to
rate of progression of the chronic kidney disease, the changes after surgery.
and liver fats in people with nonalcoholic fatty Diabetic retinopathy affects about 80% of the
liver disease (NAFLD) (Buse et al. 2020). Despite people who have diabetes for >20 years. The main
the risks of some side effects like urinary tract cause of blindness in diabetic retinopathy is dia-
infections and euglycemic diabetic ketoacidosis, betic macular edema. Imaging techniques includ-
this group of drugs are being increasingly used, ing optical coherence tomography (OCT), OCT
especially in the high-income countries. angiography, fluorescence angiography, ultra-
In 2019, more than 20 million babies were born widefield fluorescence angiography, are used for
to mothers with diabetes during pregnancy (Yuen diagnosis, classification and follow up of diabetic
et al. 2019). Women must be screened for gesta- macular edema. OCT, which is rapid,
tional diabetes but there is no consensus about the non-invasive, and accurate is the most widely
optimal evidence-based screening strategy, diag- used imaging technique in the clinical practice.
nostic methods and diagnostic thresholds. The new Extensive research has increased our understand-
diagnostic criteria for gestational diabetes are ing about the role of angiogenesis and inflamma-
based on the HAPO study that focused on the tion in the pathogenesis of diabetic macular edema.
perinatal outcomes (Group HSCR 2009). Use of Intravitreal injection of anti-VEGF agents
these criteria have increased the prevalence of e.g. Bevacizumab, Ranibizumab and Aflibercept
gestational diabetes 6–11-fold (Behboudi- are recommended as first line treatment in diabetic
Gandevani et al. 2019). The benefits, and possible macular edema (Schmidt-Erfurth et al. 2017).
harms of reducing the threshold of the diagnostic Diabetes is the most common cause of chronic
criteria need careful evaluation. Gestational diabe- kidney disease and end-stage kidney disease in the
tes mellitus is treated by dietary modifications and world. The benefits of angiotensin converting
exercise. For pharmacological treatment, insulin is enzyme inhibitors or angiotensin receptor blockers
the first choice. As an alternative to insulin, some in patients who have diabetes and severely
women can be treated by metformin, but it is an increased albuminuria is well established. In addi-
off-label use. The sulfonylurea drug glyburide can tion, the SGLT2 inhibitors should be used in people
also be used as second line drug in some selected with type 2 diabetes who have eGFR >30 ml/min/
patients. Both metformin and glyburide cross the 1.73m2. These drugs reduce the risks of death due
placenta and their long-term safety remains to kidney disease, dialysis and kidney transplanta-
unclear (American Diabetes Association 2020a). tion in people with type 2 diabetes (Neuen et al.
Reduction of weight in people with type 2 dia- 2019).
betes who are obese, by lifestyle modification and Diabetes increases the risk of non-alcoholic
optimal medical treatment is often difficult and fatty liver disease (NAFLD), and its progressive
sometimes impossible. Some of these people, phenotype nonalcoholic steatohepatitis (NASH).
when carefully selected, will benefit from bariat- People with type 2 diabetes, especially those who
ric surgical procedures (American Diabetes Asso- are obese may be screened for NAFLD, and those
ciation 2020b). Laparoscopic vertical sleeve at high risk of developing NASH should be
gastrectomy, a newer low morbidity bariatric refereed to hepatologists. Clinical prediction
4 M. S. Islam

model based on routinely available clinical Diabetes care is much more than prescribing
variables can be used for assessing the likelihood new drugs or recommending new technologies.
of NASH in people with diabetes and NAFLD. Delivering optimal diabetes care needs a dedicated
The degree of steatosis and fibrosis of the liver can team consisting of general practitioners, consultant
be estimated by transient elastography. NAFLD diabetologists, diabetes specialist nurses, practice
and NASH in people with diabetes are treated by nurses, dietitians, diabetes educators, pharmacists,
weight loss through lifestyle modification, and social workers, podiatrists, ophthalmologists,
optimization of blood glucose control initially psychologists and other specialist consultants. Peo-
with metformin. The GLP-1 receptor agonist ple with diabetes must live their lives with meticu-
liraglutide leads to resolution of NASH and lous attention to numerous details including what
slows progression to fibrosis and it should be they eat, when they eat, how much they exercise,
used in people who have diabetes and NAFLD or frequent glucose-monitoring, and multiple insulin
NASH (Armstrong et al. 2016). The insulin sensi- injections every day. Attention to all these details
tizer pioglitazone also improves steatosis, inflam- and the fear of hypoglycemic episodes can make
mation and fibrosis but, it is not used so often life stressful. It is essential to treat people with
because of the risk of weight gain and heart failure. diabetes with warmth and empathy and provide
Hypoglycemia in people with or without diabe- emotional supports whenever they need it.
tes is associated with increased morbidity and mor- About 80% of the people with diabetes live in
tality. Fear of severe hypoglycemia limits the the middle- and low-income countries. The sad-
optimal control of glycemia and the quality of life. dest reality is that many people living in these
Prevention of hypoglycemia is an essential objective countries do not have access to diabetes care
of diabetes management. Patient education, selec- facilities of acceptable quality, and they cannot
tion of appropriate insulin regime, dietary afford the costs of even the essential medicines
modifications, frequent monitoring of glucose, and for their treatment (Mohan et al. 2020; Manne-
use of automated insulin dose advisors, particularly Goehler et al. 2019). The total healthcare expen-
for people with type 1 diabetes, can reduce the diture for diabetes in the high-income countries is
frequency of severe hypoglycemic episodes. Use about 300 times more than in the low-income
of Flash glucose monitoring, continuous subcutane- countries (Williams et al. 2020). While, mean
ous insulin infusion (CSII), continuous glucose annual health expenditure per person with diabe-
monitoring (CGM) systems, and bionic pancreas tes in the USA is 11,915 USD, it is only about
can prevent severe hypoglycemic episodes, improve 64 USD in Bangladesh. This tragic inequality
glycemic control and improve quality of life. needs an innovative solution. International
Diabetic ketoacidosis, hyperglycemic institutions like the World Health Organization,
hyperosmolar state, and euglycemic diabetic the World Bank and the International Monetary
ketoacidosis are life-threatening conditions. Pre- Fund should roll out plans to convince the
vention, immediate hospitalization, and guideline- politicians of these countries to invest in improve-
based management of these conditions are essential ment of their diabetes care facilities so that people
to reduce mortality. Not surprisingly, the death rates with diabetes can get improved care within the
from these acute conditions are higher in some of framework of universal health coverage
the middle- and low-income countries, where some (Moucheraud et al. 2019).
people cannot obtain insulin or cannot afford the
cost of insulin. It is essential that insulin is made Acknowledgement Financial support was obtained from
available in all countries at affordable costs (Greene the Karolinska Institutet and the Uppsala County
Council.
and Riggs 2015; The Lancet Diabetes E 2020).
Diabetes: From Research to Clinical Practice 5

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Adv Exp Med Biol - Advances in Internal Medicine (2020) 4: 7–27
https://doi.org/10.1007/5584_2020_516
# Springer Nature Switzerland AG 2020
Published online: 22 March 2020

Glucose Lowering Treatment Modalities

of Type 2 Diabetes Mellitus

Asena Gökçay Canpolat and Mustafa Şahin

Abstract Keywords

This chapter gives an overview of present Acarbose · Dipeptidyl peptidase 4 inhibitors ·

knowledge and clinical aspects of antidiabetic Glucagon-like peptide 1 receptor agonists ·
drugs according to the recently available Glucose-lowering therapies · Meglitinides ·
research evidence and clinical expertise. Metformin · Sodium-glucose transporter two
Many agents are acting on eight groups of inhibitors · Sulphonylurea ·
pathophysiological mechanisms, which is com- Thiazolidinediones
monly called as “Ominous Octet” by DeFronzo.
The muscle, liver and β-cell, the fat cell, gastro-
intestinal tract, α-cell, kidney, and brain play
1 Introduction
essential roles in the development of glucose
intolerance in type 2 diabetic individuals
Diabetes mellitus (DM) is a chronic metabolic
(Defronzo, Diabetes 58:773–795, 2009).
disease associated with the metabolism of
A treatment paradigm shift is seen in the
carbohydrates, fats, and proteins due to insulin
initiation of anti-hyperglycemic agents from
deficiency or insulin resistance. The treatment
old friends (meglitinides or sulphonylürea) to
strategy of DM has to be based on the knowledge
newer agents effecting on GLP-1 RA or
of its pathophysiology. The general goals of the
SGLT-2 inhibitors. It is mostly about the
treatment of DM are to provide glycemic control,
other protective positive effects of these agents
avoid acute complications, prevent or delay the
for kidney, heart, etc. Although there are
appearance of chronic complications of the dis-
concerns for the long term safety profiles;
ease, and thus to improve the quality of life. The
they are used widely around the World. The
management of type 2 DM also includes manag-
delivery of patient-centered care, facilitating
ing conditions associated with T2DM, such as
medication adherence, the importance of
obesity, hypertension, dyslipidemia, and cardio-
weight loss in obese patients, the importance
vascular disease.
of co-morbid conditions are the mainstays of
Obesity, hypertension, and diabetes are
selecting the optimal agent.
increasingly common epidemics worldwide.
What can be the reason for this incredible
A. Gökçay Canpolat and M. Şahin (*) increase? Since a change in our genes can not
Department of Endocrinology and Metabolism, Ankara
explain this increase in such a short time, we
University School of Medicine, Ankara, Turkey
e-mail: [email protected]; Mustafa. can say that the cause is environmental and epi-
[email protected]; [email protected] genetic. Western diet, endocrine disrupters,

7
 8

Table 1 General features of major anti-hyperglycemic agents

Hba1c % Cardiac Major side
Hypo Weight reduction Renal Hepatic GIS benefits/risks Bone effects
Metformin N N 1.5 Contraindicated Safe in mild to Moderate N N Gis
GFR <30 ml/min moderate CLD
SU/Glinid Moderate- Increase 1–2/1 Contraindicated Avoided N N N Hypo
Severe/Mild GFR <30 ml/min
Agi N N 0.5–0.7 Contraindicated Safe (except Child C) Moderate N N Gis
GFR <15 ml/min
TZD N Increase 0.5–1.4 Contraindicated Safe in Child A N Moderate risk Moderate Bone, heart,
GFR <30 ml/min risk edema
DPP4 inh N N 0.5–1 Dose reduction Safe in Child A N Agent N Skin,
(except lina) dependent nasopharyngitis
SGLT- N Decrease 0.5–1 Dose reduction Safe in Child A N Benefit N/Minor Genital
2 inh Contraindicated risk infection
GFR <45 ml/min
GLP-1RA N Decrease 1–1.5 Exenetide Safe Moderate Benefit N Gis
contraindicated
GFR <30 ml/min
AGI alpha-glucosidase inhibitors, CLD Chronic Liver Disease, DPP4 inh Dipeptidyl peptidase 4 inhibitors, GFR Glomerular filtration rate, GIS Gastrointestinal, GLP-1RA
Glucagon-like peptide 1 receptor agonists, N Neutral, SGLT-2 inh Sodium-glucose transporter 2 inhibitor, SU sulphonylurea, TZD Thiazolidinedione
A. Gökçay Canpolat and M. Şahin
Glucose Lowering Treatment Modalities of Type 2 Diabetes Mellitus 9

processed food, changes in microbiota, technol- according to diabetes guidelines for approxi-
ogy itself, increased sugar consumption, inactiv- mately 60 years.
ity, and stress are the leading causes of this The mechanism of action of metformin is
outbreak. According to the 9th edition of new through activating AMP-activated Protein Kinase
IDF atlas, 463 million adults are currently living (AMPK), which is a nutrient sensor activated in
with diabetes, and there will be 578 million adults states of low energy balance, activates uncoupling
with diabetes by 2030 and 700 million by 2045 mitochondrial oxidative phosphorylation and
(Saeedi et al. 2019). increases cellular AMP levels. The resultant
The main elements of treatment are lifestyle effect is inhibiting gluconeogenesis. Metformin
modification and nutrition therapy, exercise, and also decreases intestinal glucose absorption,
medical therapies. Oral antidiabetic agents, insu- improves peripheral glucose uptake, lowers
lin, and non-insulin injectable anti-hyperglycemic fasting plasma insulin levels, and increases insu-
agents are mainstays for medical therapies lin sensitivity (Wang et al. 2017). Another new
(Table 1). Regarding the treatment approaches hypothesis is to reduce intestinal bile acid resorp-
in recent years, national and international tion and lead to increase GLP-1 secretion, modu-
authorities published current treatment guidelines late the composition of the gut microbiota
one after another (American Diabetes A 2019; (Sansome et al. 2019).
Davies et al. 2018). Lifestyle intervention and metformin treat-
ment may be useful in high-risk prediabetic
patients (Moin 2019). Metformin also improves
metabolic and cardiovascular risk factors, includ-
2 Pharmacotherapy for Type
ing osteoprotegerin and receptor activator of the
2 Diabetes
nuclear factor–B ligand (RANKL) levels in pre-
diabetes (Arslan et al. 2017).
The glucose-lowering agents target different
The initial starting dose is generally 500 mg
pathophysiological pathways like insulin secre-
once or twice a day; then, the dosage is increased
tion, hepatic glucose production and utilization,
to 2000 mg/day. The reason for this increment is
insulin resistance, gastric emptying, satiety, and
based on its gastrointestinal side effects with an
GLP-1 action (Fig. 1).
incidence rate of 20–30%, such as nausea,
Many agents are acting on eight groups of
vomiting, anorexia, diarrhea, and metallic taste.
pathophysiological mechanisms, which is com-
The scariest and serious adverse effect is lactic
monly called as “Ominous Octet” by DeFronzo.
acidosis with an incidence rate of 1/30,000 and
The muscle, liver, and β-cell, the fat cell, gastro-
occurs in high-risk patients for this condition.
intestinal tract, α-cell, kidney, and brain play
Metformin is contraindicated in patients with
essential roles in the development of glucose
renal insufficiency (prominently Glomerular Fil-
intolerance in type 2 diabetic individuals on the
tration Rate (GFR) <30 ml/min) (Lee and Halter
mechanisms mentioned above.
2017). It is used precautiously in patients with a
GFR <60 ml/min, and the dose is escalated. It is
also contraindicated in clinical settings of hepatic
2.1 Biguanides insufficiency (liver cirrhosis), any form of acido-
sis, chronic heart failure, chronic lung diseases
2.1.1 Metformin with severe hypoxemia, and alcohol abuse.
Since Phenformin was removed from markets due Another general precaution to avoid lactic acido-
to deaths because of lactic acidosis in the ’70s, sis is to discontinue metformin 24–48 h before
metformin (1,1- dimethyl biguanide hydrochlo- administration of high dose radiographic contrast
ride) is the only available biguanide in the material or general anesthesia. Elderly patients
world. It had been derived from Galega officinalis should be handled with care for metformin
(French lilac) and used as the first-line agent usage. B12 deficiency can be seen during