Endocrine and Metabolic Science 4 (2021) 100103

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Endocrine and Metabolic Science

journal homepage: www.elsevier.com/locate/endmts

Narrative review

Initiation and intensification of insulin therapy in type 2 diabetes mellitus:

Physician barriers and solutions – An Indian perspective
Viswanathan Mohan a,∗, Jagat J Mukherjee b, Ashok K Das c, Krishna Seshadri d,
Arundhati Dasgupta e
a
M.D., FRCP (London, Edinburgh, Glasgow, Ireland), Chairman & Chief Diabetologist, Dr. Mohan’s Diabetes Specialities Centre & Madras Diabetes Research
Foundation, Conran Smith Road, Gopalapuram, Chennai 600 086, India
b
MBBS, MD (Medicine), DNB (Medicine), MRCP, FAMS, FRCP, Senior Consultant, Div. of Diabetes & Endocrinology, Dept of Medicine, Apollo Gleneagles Hospital, 58
Canal Circular Road, Kolkata
c
MBBS, MD, PhD, DNB, FAMS, FICP, FACP, FRCP, Professor and Head of Medicine, JIPMER, Puducherry
d
Senior Consultant, Chennai Diabetes and Endocrine Center, Chennai, Tamil Nadu, India
e
MBBS, MD, DM (Endo), Consultant Endocrinologist, Rudraksh Superspeciality Care, Siliguri

a b s t r a c t

The prevalence of type 2 diabetes mellitus (T2DM) is increasing worldwide, and its complications are highly contributing to mortality. Compared to oral hypoglycemic
agents, reduction in HbA1c is maximum with insulin therapy. Evidence suggests the potential benefits of achieving normoglycemia with early intensive insulin therapy.
Despite the high levels of uncontrolled T2DM in Indian patients, the use of insulin remains suboptimal. Initiation of insulin therapy in patients with T2DM is often
inappropriately delayed due to physician’s barriers. These include physicians’ inadequacy of skill and time required for insulin therapy, perceived complications
of insulin therapy and perceived lack of treatment benefit. These barriers can be overcome by physician education and training, using effective patient education
methods and tools, and bridging gaps to improve adherence by the patients. Pharmaceutical industry, government health authorities, medical institutions, healthcare
professionals and patients can help to overcome the clinical inertia for the initiation and titration of insulin in patients with type 2 diabetes.

Achieving glycemic goal is important in a person with type 2 attending smoking cessation classes, and regular exercise, resulted in
diabetes mellitus an absolute risk reduction of death from any cause and death from car-
diovascular causes by 20% and 13% respectively (Gaede et al., 2008).
The global estimate of prevalence of diabetes in adults between the Evidence from the United Kingdom Prospective Diabetes Study provides
age group of 20 to 79 years has tripled from 151 million in the year 2000 evidence that better glycemic control results in reductions in the long-
to 463 million in the year 2019 (IDF Diabetes Atlas Eighth, 2017). This term diabetic complications (Stratton et al., 2000).
figure is projected to reach 700 million by the year 2045. The preva- This manuscript will identify the role of early initiation of insulin
lence of diabetes in adults (20-79 years) in India is estimated to almost therapy, that is, after three months of diagnosis of patients with T2DM
double from 77 million in the year 2019 to 134 million in 2045. Every (Owens, 2013, Weng et al., 2008 May 24, Harrison and Adams-Huet,
sixth person with diabetes in the world is an Indian (IDF Diabetes Atlas 2012). It will state the subgroup of patients in whom early therapy can
Eighth, 2017). There are also exist regional and geographical differences be initiated. Along with this, it will identify potential physician and
with the prevalence of diabetes being the highest in Tamil Nadu, Kerala patient-related barriers to insulin initiation and intensification and will
and Delhi followed by Punjab, Goa and Karnataka as per statistics from provide possible solutions to bridge these gaps.
the year 2016 (Tandon et al., 2018).
The objective of treating a person with type 2 diabetes mellitus
(T2DM) is not only avoiding acute complications related to hyper- Role of early initiation of insulin therapy in type 2 diabetes
glycemia (including hyperglycemic hyperosmolar state) but also pre- mellitus
venting the long-term micro and macro-vascular complications. The
STENO 2 study evaluating the multifactorial intervention on mortality Progressive deterioration in beta-cell function is the hallmark of the
in persons with T2DM with microalbuminuria demonstrated that inten- natural history of T2DM. The aetiology of gradual but persistent de-
sive therapy with multiple drug combinations to treat T2DM, hyperten- cline in beta-cell function and/or mass is multifactorial implicating in-
sion and hyperlipidemia, dietary and behavior modification including sulin resistance, glucotoxicity, lipotoxicity, and inflammation. Evidence
has shown that by reducing glucotoxicity, exogenously administered in-

∗
Corresponding author.
E-mail addresses: [email protected] (V. Mohan), [email protected] (J.J. Mukherjee), [email protected] (A.K. Das), [email protected]
(K. Seshadri), [email protected] (A. Dasgupta).

https://doi.org/10.1016/j.endmts.2021.100103
Received 4 December 2020; Received in revised form 1 April 2021; Accepted 11 May 2021
2666-3961/© 2021 The Authors. Published by Elsevier Ltd. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/)
V. Mohan, J.J. Mukherjee, A.K. Das et al. Endocrine and Metabolic Science 4 (2021) 100103

Table 1 sectional, multi-centre (330 centres) survey of 6168 diabetes patients

The average HbA1c reduction expected with available class of drugs. treated at general hospitals, diabetes clinics and referral clinics across
Drug class Average % HbA1c reduction India. Most of the participants of the study (93.2%) were using oral
anti-diabetic drugs (OADs) and 35.2% were on insulin (±OADs). Mean
Glucagon-like peptide-1 receptor agonists 1.12
HbA1c was 8.9 ± 2.1% and the mean fasting (FPG), post prandial (PPG)
Sodium-glucose transport protein 2 inhibitors 0.74
Dipeptidyl peptidase-4 inhibitors 0.74 and random (RBG) plasma glucose levels were 148 ± 50 mg/dl 205 ± 66
Alpha-glucosidase inhibitors 0.72 mg/dl and 193 ± 68mg/dl respectively. Although glycaemic control was
Thiazolidinediones 0.96 sub-optimal in these patients, insulin therapy was not initiated. Dose op-
Sulfonylureas 0.77
timization was also not performed; neither the regimen was intensified
Glinides 0.64
Metformin 1.21
to maintain glycaemic control in them (Mohan et al., 2014).
Basal insulin 1.28 Another cross-sectional registry-based retrospective study analyzed
Biphasic insulin 1.91 data of 748 diabetes outpatients. Mean duration of diabetes among these
Prandial insulin 1.08 patients was 12.24 ± 7.60 years with mean duration of insulin therapy
Basal bolus insulin 1.22
being 3.42 ± 4.18 years. Insulin was initiated after a mean duration of
8.80 ± 6.42 years. Mean HbA1c% was 9.12 ± 2.12, and only 15.2% of
participants achieved a target of HbA1c <7%. Yet, mean insulin dose per
sulin can improve beta-cell function by allowing ‘beta-cell rest’ (Owens, kilogram of body weight/day (0.51 ± 0.27 units) and total daily dose
2013). of insulin (33.36 ± 18.44 units) was low.(Baruah et al., 2017) These
Compared to other hypoglycemic agents, reduction in HbA1c is max- data indicate the lag in initiating insulin therapy in patients with T2DM
imum with insulin therapy (Table 1). (Esposito et al., 2012 Mar, US FDA, in India as well as barriers in dose optimization. (Mohan et al., 2014,
US FDA 2013). Baruah et al., 2017)
Several studies have established the potential benefits of achieving
normoglycemia with early intensive insulin therapy. Weng et al., found
that intensive insulin therapy not only restored partial beta-cell function Reasons for the inertia in the initiation and intensification of
but also significantly improved insulin resistance (Weng et al., 2008). insulin therapy
However, the participants of their study had relatively lower glucose
levels (11.2 mmol/L) and a shorter duration of T2DM at baseline, which Initiation and intensification of insulin therapy in people with T2DM
helped to facilitate higher glycemic control with early insulin therapy in India is delayed (Kumar et al., 2013). In the IMPACT (Improving
(Weng et al., 2008 May 24). Management Practices And Clinical Outcomes in Type 2 diabetes) trial,
Harrison et al., showed that beta-cell function could be preserved for 20,653 patients treated with premixed insulin therapy from 885 cen-
at least 3.5 years following early initiation of intensive insulin therapy. ters across India were enrolled. Forty percent physicians said that only
They also found that the effect could be sustained even if patients were 10 to 25% of the patients agreed to start insulin therapy following the
not continued on intensive insulin therapy after the initial three months first counseling. Mean duration of diabetes before initiating insulin in
(Harrison and Adams-Huet, 2012). In their study, triple oral therapy patients using OADs was 7 years, indicating a delay in the initiation of
with oral hypoglycemic agents, metformin, glyburide, and pioglitazone, insulin therapy. (Pantalone et al., 2018 Jul) In another study, the mean
was found to be equally effective in terms of preserving beta cell func- duration of diabetes was 12.24 ± 7.60 years and insulin was initiated
tion and aiding glycemic control in patients with T2DM when initiated after a mean diabetes duration of 8.80 ± 6.42 years, also indicating a
during the first three months of their diagnosis (Harrison and Adams- significant delay in initiating insulin treatment. (Baruah et al., 2017)
Huet, 2012). In the DiabCare India study, majority of physicians felt a combina-
Intensive insulin therapy in new-onset T2DM will alleviate glucotox- tion of two OADs (92.7%) or three OADs (74.2%) was justified com-
icity thereby reducing insulin resistance and improving beta-cell func- pared to insulin therapy. (Mohan et al., 2014) Barriers for initiating
tion through the induction of beta-cell rest (Owens, 2013). Although insulin therapy include patient and physician‐related factors. Patient-
from the above evidence, it would seem that treating persons with T2DM related factors include fear of injections, anticipation of pain and cost.
with an initial period of intensive insulin therapy at diagnosis to max- Physician-related factors include lack of awareness, complex regimens
imize beta-cell recovery rather than following the stepwise treatment and risk of adverse effects associated with insulin therapy such as weight
intensification in response to therapy failure would be ideal, there are gain and hypoglycaemia as well as the high treatment cost. (Mohan
still a number issues that need further research and clarification (Owens, et al., 2014) Majority of physicians expressed burden related to ex-
2013, Harrison and Adams-Huet, 2012). However, early insulin therapy plaining insulin therapy to the patients and selection of insulin and its
initiated after 3 months of diagnosis can be beneficial in T2DM patients dose. (Pantalone et al., 2018 Jul) The Diabetes Attitudes, Wishes and
with near mildly elevated blood glucose levels (close to 11.2 mmol/L). Needs (DAWN) survey indicated that insulin initiation is delayed much
longer by Indian physicians compared to physicians from other coun-
tries. (Peyrot et al., 2005 Nov) Physicians’ clinical inertia could be one
Current position of insulin use in the management of type 2
of the major causes for the delay in the initiation and intensification of
diabetes mellitus in India
insulin therapy in India. (Pantalone et al., 2018 Jul)

A review of the major epidemiological studies divulged that glycemic

control is sub-optimal in people with T2DM in India (Table 2) (India Physicians’ barriers to insulin therapy
Diabetes Care Index 2019, Mohan et al., 2014, Mohan et al., 2017,
Shestakova et al., 2007 Dec, Valensi et al., 2008 Nov). Poor access to Perceived lack of knowledge and time
medical care, lower treatment compliance of the patients and clinical in-
ertia of the physicians (‘recognition of the problem, but failure to act’) General physicians and family doctors in India have sub-optimal
are the principal causes of poor glycemic control in the country (Baruah knowledge of guidelines, time constraints, and attitudinal issues. (Elliott
et al., 2017). et al., 2011 Jul-Aug) An observational study was conducted in Chennai
Insulin use is suboptimal among people with T2DM in India. The two using a questionnaire for primary care physicians to assess the knowl-
studies, DiabCare India and the India Insulin Usage Audit evidence the edge and approach towards insulin use. About 30% of the physicians
state of under-utilization of insulin in India in the face of high HbA1c stated that they think that insulin may not be required in initial stage
(Mohan et al., 2014, Baruah et al., 2017). DiabCare India was a cross- of management of T2DM patients irrespective of their glycemic status.

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V. Mohan, J.J. Mukherjee, A.K. Das et al. Endocrine and Metabolic Science 4 (2021) 100103

Table 2
Data from epidemiological studies: Glycosylated hemoglobin (HbA1c) control in Indian patients is sub-optimal.

Another 37.6 % relied on prescribing maximum doses of oral hypogly- al., 2008) Besides weight gain and hypoglycemia, adverse cutaneous re-
caemic agents than beginning insulin therapy for diabetes patients. Only actions have been cited as an additional barrier for both physicians and
38.4% of physicians expressed their ability to manage T2DM during patients for the initiation and intensification of insulin therapy. (Miles et
surgeries and 48.6% physicians had confidence and skill to manage ges- al., 2007) Thus, local injection site reactions, hypoglycemia and weight
tational diabetes. (Polinski et al., 2013 Jan-Feb) In a survey conducted gain are perceived as key complications of insulin therapy that prevent
in Delaware, USA, nearly 62 % of the physicians reported that were physicians from intensifying treatment.
not able to provide adequate self-management education. (Elliott et al.,
2011 Jul-Aug) As per another survey in the USA, nearly 50% of the Addressing physician barriers for optimum insulin use
physicians reported that they lacked experience with insulin therapy.
(Polinski et al., 2013 Jan-Feb) Irrespective of the country, insulinopho- The barriers related to physician to use insulin therapy effectively
bia among physicians is common. discussed earlier can be alleviated by:
However, in India, awareness about diabetes and its complications • Physician education and training
among patients is very low which results in poor glycemic control • Effective patient education methods and tools
(HbA1c >7% [>53 mmol/mol]). (Pantalone et al., 2018 Jul) Educating
patients about diabetes is important to achieve treatment goals. Due to Physician education and training
lack of trained diabetes educators in India, the burden of educating the
patients falls on to physicians. (Valensi et al., 2008 Nov) A systematic re- Most of the physicians do not have adequate information on the types
view analyzed the average primary care physician consultation length in of insulin, insulin regimen to the followed, and knowledge on the ini-
economically developed and low-income/middle-income countries. The tiation and intensification of insulin therapy. (Miles et al., 2007) Case-
study included 179 studies from 111 publications covering 2,85,70,712 based continuous medical education (CME) programs on insulin therapy
consultations in 67 countries. The average consultation length varied will help the physician to identify the right patient for insulin therapy
from 48 Seconds in Bangladesh to 22.5 min in Sweden. The average pa- and initiate insulin therapy. Hands-on workshops for physicians on how
tient consultation time in India ranged from 1.5 to 2.3 minutes while to administer insulin safely and effectively will empower them to teach
it is 15 to 20 minutes in US and Sweden. It is thereby evident that In- the right technique to their patients. Such CMEs and workshops will re-
dian physicians are not only over-stressed but are overburdened at work, duce clinical inertia and strengthen the confidence of the physicians.
hence, not able to sufficiently educate patients about the use of insulin (American Diabetes Association 2019 2019, Funnell, 2007) Knowledge
and its role in aiding in their glycemic control. However, this study in- about types of insulin (Table 3) and devices (Table 4) available is useful
cluded primary care physicians treating all types of patients and not to quickly choose the insulin suitable for the patients. (Glasgow et al.,
diabetes patients alone. (Irving et al., 2017) 2006 Sep, Kalra and Kalra, 2010, Rubin, 2005 May)
The following guidelines have been developed to improve insulin
Perceived complications of insulin therapy
initiation and intensification:
The Global Attitudes of Patients and Physicians (GAPP) study was • Evidence-based guidelines for insulin initiation, optimization and
conducted to assess the patient and physician beliefs regarding insulin continuation in type 2 diabetes mellitus provide specific recommen-
therapy. Internet survey of 1250 physicians (600 specialists, 650 pri- dations on initiation and intensification of insulin therapy in man-
mary care physicians) who treat patients with diabetes and telephone agement of T2DM using basal, premixed and basal-bolus insulin reg-
survey of 1530 insulin-treated patients in China, France, Japan, Ger- imens in Indian clinical practice. (Ellis et al., 2018) It indicates that
many, Spain, Turkey, the UK or the USA was conducted. The results insulin therapy must be initiated at the diagnosis of T2DM of HbA1c
suggested that insulin-related hypoglycemia is the main obstacle that levels are above 9% or the fasting blood glucose level exceeds 250
prevents physicians from initiating effective treatment with insulin in mg/dL (refer to Figure 1 for detailed guideline).
patients with T2DM. Physicians and endocrinologists opined that hy- • Indian national consensus group national guidelines on initiation
poglycaemia limits treatment aggressiveness, and they find it difficult and intensification of insulin therapy with premixed insulin analogs
to manage the efficacy (hyperglycaemia) and safety (hypoglycaemia) of help to optimize premixed insulin analog therapy. (Zolnierek and
the treatment simultaneously. (Peyrot et al., 2012) An internet survey Dimatteo, 2009)
was conducted in the USA among physicians seeing 10 or more patients • Consensus on insulin dose and titration algorithms in ambulatory
with T2DM per week. About 88% of the physicians strongly agreed that care of type 2 diabetes in india is a useful reference tool for health
the benefits of insulin therapy outweigh the risks of weight gain; an- care practitioners, to initiate, optimise and intensify insulin therapy
other 44% stated that the risk of hypoglycaemia made them reluctant and to successfully achieve optimal glucose control. (Rubin, 2005
to prescribe insulin to most patients who were ≥ 85 years old. (Hayes et May)

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V. Mohan, J.J. Mukherjee, A.K. Das et al. Endocrine and Metabolic Science 4 (2021) 100103

Table 3
Types of insulin

Insulin Onset (Min) Peak (Hrs) Duration (Hrs) Standard costs (MRP) in Website link
India

Human Insulin
Regular Soluble ∼60 min 2-4 hours 6 – 8 hours INR 319 (100IU/ml Penfill https://www.1mg.com/drugs/actrapid-hm-100iu-
– 3 ml in 1 penfill) ml-penfill-248417
Donner T, Sarkar S. Insulin – Pharmacology,
Therapeutic Regimens, and Principles of Intensive
Insulin Therapy. [Updated 2019 Feb 23]. In:
Feingold KR, Anawalt B, Boyce A, et al., editors.
Endotext [Internet]. South Dartmouth (MA):
MDText.com, Inc.; 2000-. Available from:
https://www.ncbi.nlm.nih.gov/books/NBK278938/
Neutral Protamine 60-180 min 4 – 8 hours 14-24 hrs INR 319 (100IU/ml Penfill https://www.1mg.com/drugs/insulatard-hm-
Hagedorn insulin – 3 ml in 1 penfill) 100iu-ml-penfill-372998
Saleem F, Sharma A. NPH Insulin. [Updated 2020
Jun 23]. In: StatPearls [Internet]. Treasure Island
(FL): StatPearls Publishing; 2021 Jan-. Available
from:
https://www.ncbi.nlm.nih.gov/books/NBK549860
Biphasic human 30 min 1.5-3.5 hours 7-8 hours INR 319 (100IU/ml Penfill https://www.1mg.com/drugs/actrapid-hm-100iu-
insulin – 3 ml in 1 penfill) ml-penfill-248417
https://www.ema.europa.eu/en/documents/product-
information/actrapid-epar-product-
information_en.pdf
Rapid-acting analogs
Insulin aspart within 15 1-3 hour 3-5 hours INR 704 (100IU/ml Penfill https://www.1mg.com/drugs/novorapid-100iu-ml-
minutes – 3 ml in 1 penfill) solution-for-injection-372477
Donner T, Sarkar S. Insulin – Pharmacology,
Therapeutic Regimens, and Principles of Intensive
Insulin Therapy. [Updated 2019 Feb 23]. In:
Feingold KR, Anawalt B, Boyce A, et al., editors.
Endotext [Internet]. South Dartmouth (MA):
MDText.com, Inc.; 2000-. Available from:
https://www.ncbi.nlm.nih.gov/books/NBK278938/
Insulin lispro within 15 ∼1 hour 3-5 hours INR 819 (100IU/ml - 3 ml https://www.1mg.com/drugs/humalog-100iu-ml-
minutes in 1 cartridge) solution-for-injection-341834
Donner T, Sarkar S. Insulin – Pharmacology,
Therapeutic Regimens, and Principles of Intensive
Insulin Therapy. [Updated 2019 Feb 23]. In:
Feingold KR, Anawalt B, Boyce A, et al., editors.
Endotext [Internet]. South Dartmouth (MA):
MDText.com, Inc.; 2000-. Available from:
https://www.ncbi.nlm.nih.gov/books/NBK278938/
Insulin faster aspart within 5 min ‘∼1 hour 3-4 hours INR 612 (100IU/ml Penfill https://www.1mg.com/drugs/fiasp-100iu-ml-
- 3 ml in 1 cartridge) solution-for-injection-506095
https://www.ema.europa.eu/en/documents/product-
information/fiasp-epar-product-
information_en.pdf
Insulin glulisine 15-30 minutes 0.5-1 hr 4 hrs INR 629.49 (100IU https://www.1mg.com/drugs/apidra-100iu-
Cartridge - 3 ml in 1 cartridge-155177
cartridge) Donner T, Sarkar S. Insulin – Pharmacology,
Therapeutic Regimens, and Principles of Intensive
Insulin Therapy. [Updated 2019 Feb 23]. In:
Feingold KR, Anawalt B, Boyce A, et al., editors.
Endotext [Internet]. South Dartmouth (MA):
MDText.com, Inc.; 2000-. Available from:
https://www.ncbi.nlm.nih.gov/books/NBK278938/
Basal insulin
Insulin degludec 30-90 min Peakless >42 hours INR 1440 (100 Units/ml https://www.1mg.com/drugs/tresiba-100-units-
Penfill - 3 ml in 1 penfill) ml-penfill-394685
Nasrallah SN, Reynolds LR. Insulin Degludec, The
New Generation Basal Insulin or Just another
Basal Insulin?. Clin Med Insights Endocrinol
Diabetes. 2012;5:31-37. doi:10.4137/CMED.S9494
Insulin glargine U100 30-60 min No peak 16-24 hours INR 722.54 (100IU/ml https://www.1mg.com/drugs/lantus-100iu-ml-
Solution 3 ml in 1 solution-for-injection-113528
cartridge) Nasrallah SN, Reynolds LR. Insulin Degludec, The
New Generation Basal Insulin or Just another
Basal Insulin?. Clin Med Insights Endocrinol
Diabetes. 2012;5:31-37. doi:10.4137/CMED.S9494
(continued on next page)

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V. Mohan, J.J. Mukherjee, A.K. Das et al. Endocrine and Metabolic Science 4 (2021) 100103

Table 3 (continued)

Insulin Onset (Min) Peak (Hrs) Duration (Hrs) Standard costs (MRP) in Website link
India

Insulin detemir 30-60 min No peak Up to 24 hours INR 1318 100IU/ml https://www.1mg.com/drugs/levemir-100iu-ml-
Flexpen - 3 ml in 1 flexpen-207005
flexpen Nasrallah SN, Reynolds LR. Insulin Degludec, The
New Generation Basal Insulin or Just another
Basal Insulin?. Clin Med Insights Endocrinol
Diabetes. 2012;5:31-37. doi:10.4137/CMED.S9494
Insulin glargine U300 6 hrs No peak 36 hours INR 1831.33 (300 U/mL - 1 https://www.1mg.com/drugs/toujeo-300-u-ml-
Solution for Injection in 1 solostar-388884
pre-filled pen) RosselliJL et al, U300 Insulin Glargine, J pharm
Technol, 2015, 31(5), 234-242.
Premix insulin
Biphasic IAsp 70% 10-20 min 0.5-3 hours 14- 24 hours Biphasic Aspart 30- INR https://www.1mg.com/drugs/novomix-30-100iu-
aspart protamine, 30% 704 (100 Units/ml Penfill - ml-penfill-289278
aspart 50% aspart 3 ml in 1 penfill) https://www.1mg.com/drugs/novomix-50-100iu-
protamine, 50% aspart Biphasic Aspart 50- INR ml-penfill-372999
730 (100 Units/ml Penfill - Donner T, Sarkar S. Insulin – Pharmacology,
3 ml in 1 penfill) Therapeutic Regimens, and Principles of Intensive
Insulin Therapy. [Updated 2019 Feb 23]. In:
Feingold KR, Anawalt B, Boyce A, et al., editors.
Endotext [Internet]. South Dartmouth (MA):
MDText.com, Inc.; 2000-. Available from:
https://www.ncbi.nlm.nih.gov/books/NBK278938/
Biphasic Lispro 75% 15-20 minutes 0.5-2.5 hours 14-24 hours Lispromix 25 - INR 745 https://www.1mg.com/drugs/humalog-mix-25-
lispro protamine, 25% (100 Units/ml Penfill - 3 100iu-ml-cartridge-341582
lispro 50% lispro ml in 1 penfill) https://www.1mg.com/drugs/humalog-mix-50-
protamine, 50% lispro Lispromix 50 - INR 745 100iu-ml-cartridge-341579
(100 Units/ml Penfill - 3 Donner T, Sarkar S. Insulin – Pharmacology,
ml in 1 penfill) Therapeutic Regimens, and Principles of Intensive
Insulin Therapy. [Updated 2019 Feb 23]. In:
Feingold KR, Anawalt B, Boyce A, et al., editors.
Endotext [Internet]. South Dartmouth (MA):
MDText.com, Inc.; 2000-. Available from:
https://www.ncbi.nlm.nih.gov/books/NBK278938/
IDegAsp coformulation 9-14min 1.2 hours >24 hours INR 1024 (100 Units/ml https://www.indiamart.com/proddetail/ryzodeg-
70% degludec, 30% Penfill - 3 ml in 1 penfill) penfill-5-x-3ml-21513443473.html
aspart Haahr H, Fita EG, Heise T. A Review of Insulin
Degludec/Insulin Aspart: Pharmacokinetic and
Pharmacodynamic Properties and Their
Implications in Clinical Use. Clin Pharmacokinet.
2017 Apr;56(4):339-354.

Fig. 1. Recommendations for initiation of insulin therapy.

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V. Mohan, J.J. Mukherjee, A.K. Das et al. Endocrine and Metabolic Science 4 (2021) 100103

Table 4 short to address all of the questions that a patient has about self-care.
Pooled prevalence of patients reaching HbA1c goal of <7% on different Setting up a peer advisor and patient support groups (Figure 2) helps to
classes of anti-diabetic drugs. (Peyrot et al., 2012) improve patient behaviours and disease outcome by providing contin-
Drugs HbAlc <7% Pooled prevalence (%) and 95% CI) uous support and encouraging patients to self-manage diabetes. (Lee et
al., 2006 Oct) In patient support group, people with a common illness
Basal insulin 38.9 (35.7-42.2)
can share knowledge and experience following a less hierarchical and
Biphasic insulin 34.4 (31.1-37.9) more reciprocal relationship than what is developed between patients
Prandial insulin 36.3 (26.3-47.7) and health care professionals. To achieve this, physicians must identify
Basal bolus insulin 50.2 (43.0-57.4) a person with diabetes to educate other patients with diabetes in order
GLP-1RA 45.7 (42.2-49.2)
to build a supportive group. The peer supporter should assist in day-
Exenatide LAR (GLP-1RA) 63.2 (54.1-71.5)
DPP-4i 39.0 (35.7-42.3) to-day disease management, provide emotional and social support and
AGI 25.9 (18.5-34.9) assist in linkages to clinical care. The peer supporter should be proactive
Thiazolidinediones 33.2 (28.5-38.2) and should have flexible attitude towards fellow patients. (Wangnoo et
Sulfonylureas 48.2 (43.0-53.5)
al., 2013)
Glinides 39.1 (29.3-49.9)
Metformin 42.0 (35.5-48.9)
Lack of time by the physicians can be overcome by employing
"Diabetic Nurse Educators". The National Diabetes Educator Program
Abbreviations: AGI, alpha-glucosidase inhibitors; DPP-4i, dipeptidyl (NDEP) conducted to educate and train diabetes educators in India. The
peptidase-4 inhibitors; GLP-1RA, glucagon like peptide-1 receptor agonist first cycle of NDEP was conducted during the period June 2011 to March
2012 in 96 training centers in India and trained 1032 diabetes educa-
•
tors from various diabetes clinics across the country. Cristian Medical
Forum for Injection Technique (FIT), India: The Indian recommenda-
College, Vellore and Madras Medical College, Chennai are conducting
tions 2.0, for best practice in Insulin Injection Technique, 2015 helps
short course for nurses to become counselors in diabetes mellitus. Sev-
to improve correct injection technique vital for the achievement of
eral private medical colleges, diabetes hospitals and research institutes
glycemic control. (Lee et al., 2011)
are conducting a course for nurses and other paramedical staff to be-
come diabetes educators. The Diabetes Nurse Educators are essential in
Effective patient education methods and tools diabetes care, particularly in hospital settings. They can help to improve
patient experience and outcomes, and save time of the physicians.
Several patient education methods and approaches are available for
healthcare professionals to improve communication with the patients.
The International Diabetes federation (IDF) has published a curricu- Barriers related to medical profession
lum to educate diabetes health care professionals. This curriculum pro-
vides simple recommendations to strengthen doctor-patient conversa- In India, medical training is focused on acute care and physicians
tions. (International Curriculum for Diabetes Health Professional Educa- find treatment of acute diseases more rewarding. Most of the workload
tion 2018) Physicians can adopt following techniques to improve com- of physicians is due to acute illnesses and infection. In addition, there
munication about self-care management of diabetes: (Lee et al., 2006 is a lack of trained paramedical staff to perform the counseling of pa-
Oct, Heisler, 2007) tients and cost of a team for diabetes management is high. Addressing
these barriers helps to improve optimal use of insulin therapy. (Kalra
• Discuss the most important self-care management tips first. and Kalra, 2010)
• While discussing, use the phrase “This is very important…” for the
key points. Physician communication and patient education can improve adherence
• Provide simple and clear instructions. For example, “Check your
blood glucose every morning within five minutes of waking up and Good communication with patients is associated with better patient
before you eat breakfast”. adherence. A meta-analysis found that the patients of physicians who
• Ask open-ended questions to allow patients to verbalize feelings or communicate effectively reported 19% higher treatment adherence. Fur-
concerns about their diabetes self-care. ther, training physicians in communication skills improved the patient
• Express empathy by listening and asking patients for permission be- adherence by 12%. (Zolnierek and Dimatteo, 2009) Physicians should
fore offering information or advice about diabetes self-care. ask question to check treatment compliance and verify the patient recall
• Engage the patient by helping to solve the problem rather than op- and comprehension of treatment regimen. They should explain the ben-
posing a patient’s resistance to change behaviors. efit of medications to the patients so that patients realise the importance
• Summarize the patient’s statements. It helps to show that you have of adherence. (Rubin, 2005 May)
been listening to their concerns and understand what the patient is
speaking. It also helps to overcome miscommunications.
• Write down the instructions or provide written handouts to the pa- Minimizing costs to improve adherence
tient to help reinforce learning and information retention.
• Ask patients to write a list of questions a few days prior to the med- Cost of insulin therapy is another factor, which determines the level
ical appointment and bring it along with them during the consul- of adherence. Physicians should ask patients if they are having problem
tation. This way, patients are more likely to remember information with adherence due to cost of insulin. They should know the cost of
about issues they have previously considered that directly relate to medications and prescribe the most cost-effective insulin regimen for
them. the patients (refer to table 3). Physicians should be aware of sources
• Establish a team of health workers, patient navigators, and peer men- of financial assistance programs and suggest them to patients, required.
tors to improve health care communication and patient satisfaction. (Rubin, 2005 May)
Prefilled insulin pens have many advantages such as discretion, ease
Educating the patients once about their insulin therapy before its ini- of use, ease of reading the dose, improved accuracy for delivering small
tiation is not adequate. Hence, physicians must offer continuous patient doses, and ease of accurate dosing compared to vial-and-syringe injec-
support. In many cases, education and support alone by healthcare pro- tions. A physician should consider an insulin pen device when prescrib-
fessionals is also not enough to adequately meet several patient needs. ing insulin but should be sensitive regarding the cost issues. Pertaining
The time available for patient support during outpatient visit is often too to this, insulin shall need to be prescribed in a vial and syringe dosage,

6
V. Mohan, J.J. Mukherjee, A.K. Das et al. Endocrine and Metabolic Science 4 (2021) 100103

Fig. 2. Diabetes Peer support intervention.

at times, and the physician should educate the patient regarding match- attending CMEs and workshops, sharing responsibilities with patients,
ing the 40 or 100 IU syringe appropriately with the concentration in the creating short videos to teach insulin injections, and collaborating with
vial. (Heisler, 2007) medical institutions. (Kalra and Kumar, 2019)

Pharmaceutical industry Summary

Pharmaceutical industry can take various initiatives to overcome in- Insulin therapy is an important component of treatment of diabetes.
ertia for insulin therapy such as conducting medical education activities Evidence indicates that early initiation of insulin therapy improves beta-
to create awareness among physicians regarding insulin and devices, ini- cell function and mass by inducing ‘beta-cell rest’. It is therefore prudent
tiating a public-private-partnership program such as Changing Diabetes to consider intensive insulin therapy in the early stages rather than opt-
Barometer and promoting insulin therapy through mass media aware- ing for stepwise standard of care. Despite the benefits of early initiation
ness campaign. (Kalra and Kumar, 2019) of insulin therapy, there is big practical gap in initiating insulin therapy
among the physicians. The acceptance level of the insulin therapy is low
Health authorities among physicians for several reasons. Increase in patient load, lack of
skills and knowledge, fear of hypoglycaemia, weight gain and injection
Government health agencies may increase awareness about insulin site reactions are a few barriers for insulin initiation. Thus, it is impor-
therapy by involving well-known personalities, by conducting CME and tant to consider few initiatives that help physicians to overcome their
certificate courses, conducting training to medical and para medical staff clinical inertia. These could include creating awareness, supporting with
on hypoglycaemia and by arranging patient helpline services. The inau- patient-education materials and providing continued medical education
guration of a program called “Changing Diabetes in Children” by for- activities on insulin and insulin related devises.
mer President APJ Abdul Kalam attracted huge media coverage and in-
creased awareness among public from all the states of India about the Funding
needs of children with type 1 diabetes. (Kalra and Kumar, 2019)
None.
Medical institutions
Declaration of Competing Interest
Medical institutions can build centers for insulin training, train res-
idents doctors on modern insulin types, and train practicing physicians The authors declare that they have no known competing financial
on dose initiation, titration and intensification of insulin. (Kalra and Ku- interests or personal relationships that could have appeared to influence
mar, 2019) the work reported in this paper.
The authors declare the following financial interests/personal rela-
Healthcare professionals tionships which may be considered as potential competing interests:
Medical writing and editorial support in the preparation of this arti-
Healthcare professionals can overcome inertia for insulin therapy cle was provided by Dr. Anusuya D and Dr. Punit Srivastava. Support
by rregularly updating knowledge about insulin therapy, proactively for this assistance was funded by Novo Nordisk, India.

7
V. Mohan, J.J. Mukherjee, A.K. Das et al. Endocrine and Metabolic Science 4 (2021) 100103

CRediT authorship contribution statement Irving, G, Neves, AL, Dambha-Miller, H, et al., 2017. International variations in primary
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Viswanathan Mohan: Conceptualization, Writing – review & edit- Kalra, S, Kalra, B., 2010. A good diabetes Counsellor ’Cares’: Soft skills in diabetes coun-
ing, Supervision. Jagat J Mukherjee: Data curation, Formal analysis, selling. Internet J Health 11, 1.
Funding acquisition. Ashok K Das: Methodology, Validation, Visualiza- Kalra, S, Kumar, A., 2019. Quinary prevention: Defined and conceptualized. J Pak Med
Assoc 69 (12), 1765–1766.
tion. Krishna Seshadri: Writing – original draft, Project administration. Kumar, A, Goel, MK, Jain, RB, Khanna, P, Chaudhary, V., 2013. India towards diabetes
Arundhati Dasgupta: Supervision, Writing – review & editing. control: Key issues. Australas Med J 6 (10), 524–531.
Lee, LJ, Li, Q, Reynolds, MW, et al., 2011. Comparison of utilization, cost, adherence, and
hypoglycemia in patients with type 2 diabetes initiating rapid-acting insulin analog
Acknowledgement
with prefilled pen versus vial/syringe. J Med Econ 14 (1), 75–86.
Lee, WC, Balu, S, Cobden, D, Joshi, AV, Pashos, CL., 2006 Oct. Medication adherence and
All named authors meet the International Committee of Medical the associated health-economic impact among patients with type 2 diabetes mellitus
converting to insulin pen therapy: an analysis of third-party managed care claims
Journal Editors (ICMJE) criteria for authorship for this manuscript, take
data. Clin Ther 28 (10), 1712–1725.
responsibility for the integrity of the work, and have given final approval Miles P, Kerr D, Richardson T. Expert opinion: Cutaneous problems in insulin ther-
for the version to be published. apy. [Internet]. 2007 [2019 cited 22 October] Available from https://www.mims.
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ticle was provided by Dr. Punit Srivastava of Mediception Science Pvt cations among type 2 diabetes patients in India: Data from the A1 chieve Study. JAPI
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Novo Nordisk, India. Novo Nordisk neither influenced the content of Mohan, V, Shah, SN, Joshi, SR, et al., 2014. On Behalf of the DiabCare India 2011 Study
Group. Current status of management, control, complications and psychosocial as-
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diabetes management: Evidence from a large, real-world data set. Diabetes Care 41
Peer Review Summary associated with this article can be found in (7), e113–e114.
Peyrot, M, Barnett, AH, Meneghini, LF, et al., 2012. Insulin adherence behaviours and
the online version, at doi:10.1016/j.endmts.2021.100103.
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