A Proposed India-Specific Algorithm for Management of Type 2 Diabetes

Abstract

Several algorithms and guidelines have been proposed by countries and international professional bodies; however, no recent updated management algorithm is available for Asian Indians. Specifically, algorithms developed and validated in developed nations may not be relevant or applicable to patients in India because of several factors: early age of onset of diabetes, occurrence of diabetes in nonobese and sometimes lean people, differences in the relative contributions of insulin resistance and β-cell dysfunction, marked postprandial glycemia, frequent infections including tuberculosis, low access to healthcare and medications in people of low socioeconomic stratum, ethnic dietary practices (e.g., ingestion of high-carbohydrate diets), and inadequate education regarding hypoglycemia. All these factors should be considered to choose appropriate therapeutic option in this population. The proposed algorithm is simple, suggests less expensive drugs, and tries to provide an effective and comprehensive framework for delivery of diabetes therapy in primary care in India. The proposed guidelines agree with international recommendations in favoring individualization of therapeutic targets as well as modalities of treatment in a flexible manner suitable to the Indian population.

Introduction

India has nearly 66.8 million cases of diabetes, and these numbers are expected to rise to 120.9 million in 2035.¹ So as to help clinicians choose the best option for their patients from the impressive array of available therapeutic options, various professional bodies such as the International Diabetes Federation, World Health Organization, American Diabetes Association, European Association for the Study of Diabetes, American Association of Clinical Endocrinologists, Canadian Diabetes Association, and Australian Diabetes Association have proposed algorithms and guidelines. Some previous attempts have been made in this direction in India (by the Indian Council of Medical Research, Association of Physicians of India, Research Society for Study of Diabetes in India, and other associations); however, no recent indexed publication on India-specific management guidelines is available.

Need for an India-Specific Algorithm: Type 2 Diabetes in Asian Indians Is Different and Distinctive

For various reasons, algorithms developed and validated in developed nations may not be relevant or applicable to patients in India. It has long been recognized that type 2 diabetes (T2D) in Asian Indians differs significantly from that found in white Caucasians. Any treatment decision in Indians should take into account not only these differences, but also socioeconomic and cultural factors (such as dietary practices), which may render some therapeutic options less suitable in this population.

The following points summarize some of the key issues that should be taken into consideration while prioritizing treatment options in Asian Indians:

1. Heterogeneity of prevalence: Urban versus rural; socioeconomic strata; place of residence (e.g., remote and hilly areas)^2
–4

2. Body composition: Risk of diabetes is present at lower levels of body mass index than in white Caucasians and sometimes even in lean individuals. Prevalent abdominal adiposity and nonalcoholic fatty liver disease add to the risk.^5,6

3. Presentation of T2D:

a. Early age of onset: nearly a decade earlier than for white Caucasians⁷

b. Presentation late, sometimes with complications^8

–11

c. Lean patients with diabetes: Such patients have been reported to have more hyperglycemia and higher risk of complications.

4. Ketosis: Although ketosis as a presenting feature of T2D is unusual, studies from Pakistan have shown that up to 14% of patients with T2D have ketosis at the time of first diagnosis. Precipitating factors for ketosis include infection, major surgery, severe trauma, use of steroids, interruption of treatment, and high intake of sugar-sweetened beverages.^12

–15

5. Infections: (e.g., co-existence of tuberculosis): Patients with T2D in India often present with infections. In particular, coexistence of tuberculosis and diabetes may be more in Asian Indians than in white Caucasians.¹⁶

6. Metabolism:

a. Higher magnitude of insulin resistance than other races: Asian Indians have a comparatively lower insulin sensitivity index and lower rate of glucose disposal than European-origin whites in the United States, even after adjustment for both total body fat and truncal skinfold thickness. Thus, Asian Indians are more insulin resistant than Caucasians independent of generalized or truncal adiposity.^7,17 On account of this, insulin sensitizers would be useful in Indians.

b. Higher postprandial glycemia than other races: Asian Indians show higher postprandial glycemia for the same dietary carbohydrate load compared with Caucasians and other races.^18,19 Hence postprandial blood glucose regulators such as α-glucosidase inhibitors may be of greater value in Asian Indians.

c. Early-onset β-cell dysfunction: Asian Indians with even mild dysglycemia have reduced β-cell function, regardless of age, adiposity, insulin sensitivity, or family history of diabetes,²⁰ and some data suggest that β-cell dysfunction appears to be more strongly associated with T2D than insulin resistance.²¹

7. Dietary factors (e.g., high carbohydrate load in diets): South Asian diets are predominantly based on starchy foods, typically consisting of high amounts of carbohydrates in the form of refined cereals.^22,23

8. High risk of complications: Asian Indians have high risk of complications including diabetic nephropathy and cardiovascular disease.^8,11 These complications of diabetes have implications for development of hypoglycemia (more in nephropathy, impacts cardiovascular disease) and may influence treatment decisions (with particular reference to sulfonylureas).

9. Awareness: Many patients with diabetes in India, particularly in rural areas, lack awareness and knowledge regarding the disease and its management. This renders them at risk of hyperglycemia and its attendant complications, but more importantly of hypoglycemia.^24,25

10. Socioeconomic factors: Diabetes in India is still a disease of the relatively more affluent strata of society. However, there is some evidence that the epidemic is now moving into the lower socioeconomic strata as well.²⁵ The latter category of patients will likely experience difficulty in affording treatment with the newer therapeutic agents, especially those that are still under patent protection, as most medical expenses in India are borne out of pocket by the patient.²⁴

It is evident from the discussion above that guidelines and algorithms developed for use in western countries may not be applicable in Asian Indians. Thus, there is a clear need for developing specific guidelines for the pharmacotherapy of T2D in this population, taking into account the characteristic phenotype of Indian patients with T2D, as well as their dietary, socioeconomic and cultural patterns.^18,19

Proposed Therapeutic Algorithm for T2D in Asian Indians

Aim

The proposed algorithm aims to provide a simple and easy-to-implement framework for the management of T2D in Asian Indians in primary care.

Scope of the algorithm

The proposed algorithm deals specifically with the management of T2D in nonpregnant Asian Indian adults. As the majority of the population in India resides in rural areas with limited access to secondary and tertiary care facilities, the algorithm has been designed to be practical for use in the primary care setting.

Preamble

Decisions on selection of drug therapy in Asian Indians with T2D are to be made based on blood glucose profile, presence of comorbidities, age, socioeconomic and educational status, probability of developing hypoglycemia and wherewithal to tackle it, location of residence (e.g., remote areas without access to medical facilities), and overall likelihood of compliance with therapy.

Search Strategy

A literature search was conducted in electronic databases (PubMed, Embase, and Google Scholar) up to December 2015 and was limited to articles published in English. The search terms were “type 2 diabetes,” “management algorithm,” “glycosylated hemoglobin,” “oral anti-diabetic agents,” “insulin,” “India,” and “Asian Indians.” Although all articles were studied, those on management of T2D (74 articles [available upon request from the corresponding author]) were reviewed in detail.

Results

A summary of the proposed algorithm is given in Table 1.

Table 1.

Proposed Algorithm for Initiation and Intensification of Antihyperglycemic Pharmacotherapy in Adult Non-pregnant Asian Indians with Type 2 Diabetes

	Stratification 1 (HbA1c <9% and according to BMI levels) ^a	Stratification 2 (HbA1c ≥9% or plasma blood glucose ≥240 mg/dL) ^a	Stratification 3 (severe morbidity) ^a
First-line therapy	Monotherapy with: • Met^b • SU • DPP 4i	• Combination of two OADs (SU + Met,^b DPP 4i + Met) • Consider triple OAD therapy/insulin in selected cases	• Insulin (with or without OADs)
Second-line therapy	• Add insulin • Add second oral agent (SU,^b DPP 4i, AGI, GLP-1RA, SGLT2i)	• Add insulin • Add third oral agent (SGLT2i, GLP-1RA, AGI, TZD)	• Intensify insulin
Third-line therapy	• Insulin + multiple OADs • Intensify insulin (if already initiated)	• Add insulin • Intensify insulin therapy (if already initiated)	• Intensify insulin therapy • Consider adding GLP-1RA to insulin^c

See text for details on stratification groups.

See text for details.

Agent/regimen of first choice. ^cIf not contra-indicated.

AGI, α-glucosidase inhibitor; BMI, body mass index; DPP 4i, dipeptidyl peptidase-4 inhibitor; GLP-1RA, glucagon-like peptide-1 receptor agonist; HbA1c, glycosylated hemoglobin; Met, metformin; OAD, oral antihyperglycemic drug; SGLT2i, sodium–glucose cotransporter-2 inhibitor; SU, sulfonylureas; TZD, thiazolidinedione (pioglitazone).

First-line therapy

Stratification is done according to:

a. Body mass index: three categories—less than 18 kg/m² (underweight), 18–22.9 kg/m² (normal), and greater than or equal to 23 kg/m² (overweight/obese)

b. Initial glycosylated hemoglobin (%) level: less than 9% and greater than or equal to 9%

c. Severe morbidity (severe infections, myocardial infarction, markedly high blood glucose levels with ketonuria/ketoacidosis, marked liver or renal dysfunction, significant physical trauma)

Stratification 1

Glycosylated hemoglobin less than 9% (plasma blood glucose levels less than 240 mg/dL) and according to body mass index values as indicated above:

1. Metformin is the agent of choice for all patients, except those with substantial weight loss, underweight patients, and those who are intolerant to metformin. Metformin is to be started at a low dose and escalated to the maximum tolerable dose in those with body mass index ≥23 kg/m² or abdominal obesity (waist circumference ≥90 cm in men and ≥80 cm in women).

2. Sulfonylureas are to be considered as the first line of therapy in patients who are underweight or who cannot tolerate metformin. The preferred sulfonylureas are glimepiride, gliclazide, and glipizide. Sulfonylureas are an attractive therapeutic option on account of their low cost and the predominant role of β-cell dysfunction in the pathogenesis of T2D in this population.²⁰

3. Alternatively, dipeptidyl peptidase-4 inhibitors may also be considered if cost is not of major concern.

Stratification 2

Glycosylated hemoglobin ≥9% (plasma blood glucose levels greater than or equal to 240 mg/dL):

1. Combination therapy with two oral antidiabetic drugs should be offered to those without other major comorbidity. Sulfonylurea–metformin combination is suggested as the preferred combination for dual therapy in this setting. Dipeptidyl peptidase-4 inhibitor–metformin combination may be used if affordability is not an issue.

2. Use of triple oral therapy (by adding a dipeptidyl peptidase-4 inhibitor, thiazolidinedione, or α-glucosidase inhibitor) might be considered occasionally on an individual basis, taking into account levels of blood glucose, comorbidities, and overall patient's medical and economic profiles.

3. Insulin may be considered initially with or without oral antidiabetic drugs if blood glucose levels are very high even in the absence of ketosis.

Stratification 3

Severe morbidity:

1. Insulin should be offered as initial treatment of choice. Regular, NPH, or premix insulin can be used to initiate therapy. In severely ill patients who require hospitalization, consideration should be given to use of multiple daily insulin injections (regular–NPH combination or basal–bolus regimen). Insulin analogs can be used with benefit if cost considerations permit.

Second-line therapy

The options available to the clinician after failure of first-choice medication include the following:

1. Addition of insulin. Insulin therapy may be initiated with premix human insulin or with NPH insulin. Basal insulin analogs (e.g., glargine) may be used if cost considerations permit the same.

2. Addition of second oral agent. The choice of a second oral agent depends on patient profile and previously introduced drug(s).

a. If the patient is not at target with metformin or sulfonylurea monotherapy, consider giving a combination of the two drugs.

b. Dipeptidyl peptidase-4 inhibitors can be added to the first-line agent if cost is not a major concern. These agents are likely to be helpful in addressing the early loss of β-cell function that characterizes T2D in this population.²⁰

c. α-Glucosidase inhibitors are attractive therapeutic options as add-on drugs in Asian Indians as their mechanism of action helps in blunting the postprandial glucose spikes caused by large amounts of refined cereals in the diet.^22,23

d. In obese patients, sodium–glucose cotransporter-2 inhibitors and glucagon-like peptide-1 receptor analogs are preferred agents for adding on to metformin because of their weight loss benefits. However, the cost of these agents should be considered while planning therapy.

e. Thiazolidinedione. Pioglitazone should be offered in the low dose (7.5–15 mg/day), wherever possible.^26,27 Furthermore, this drug improves insulin sensitivity, cardiovascular and inflammatory risk markers, and vascular response more in Asian Indians than in white Caucasians.²⁴

f. Patients with severe infections or other comorbidities as defined above should be treated with insulin.

Third-line therapy

In case of failure of second-line therapy, the options include:

1. Use of multiple oral antidiabetic drugs with insulin therapy

2. In case the patient is already on insulin, intensification of the insulin regimen as follows:

a. Basal insulin (NPH, basal analogue) with variable mealtime bolus (regular or rapid-acting analog). The high cost of insulin analogs must be considered while planning therapy.

b. Twice daily premixed insulin

c. Split-mix regimen (morning and evening combinations of regular and NPH insulin)

d. Adding glucagon-like peptide-1 agonist to insulin

In every case, therapeutic lifestyle change should be recommended and encouraged to the maximum extent possible. Regular monitoring of glycemic control and frequent follow-up with the healthcare team are essential. Physicians should guard against therapeutic inertia, which can increase the “avoidable glycemic burden” and predispose to the development of complications.

The guidelines proposed above differ from the American Diabetes Association/European Association for the Study of Diabetes guidelines, in that they provide the clinician with multiple options for first-line therapy, based on patient characteristics (body mass index, morbidities), severity of hyperglycemia, and use of second-line drugs in line with metabolic and dietary profiles of Asian Indians. Similarly, while initiating insulin, the proposed guidelines provide the flexibility of using NPH insulin, premix insulin, or insulin analogs, in contrast to the American Diabetes Association/European Association for the Study of Diabetes guidelines, where analog insulin is specifically recommended.

The guidelines proposed above have certain limitations. They are based on expert consensus and not on the results of large-scale randomized controlled trials. Second, the heterogeneity of the Asian Indian population may alter the clinical applicability of these guidelines to the entire population. There is a need for further studies to address these issues. We hope that these guidelines will stimulate further discussions and generate ideas for well-planned studies to test the usefulness and cost-effectiveness of these guidelines.

Conclusions

The proposed algorithm is a simple-to-use and comprehensive framework for delivery of diabetes therapy in low-cost primary care settings in India. It is nevertheless imperative that clinicians discuss all aspects of the available therapies with the patient in order to arrive at a joint decision on the best possible yet individualized therapy.

Footnotes

Author Disclosure Statement

This review has not been financed by any pharmaceutical company, and the members of the India Diabetes Management Algorithm Proposal Group declare no conflict of interest.

Appendix

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