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 Table of Contents  
REVIEW ARTICLE
Year : 2020  |  Volume : 11  |  Issue : 3  |  Page : 148-157

Indian reality of managing type 2 diabetes: an expert review of global and national guidelines for optimum insulin use


1 Diabetes Care and Research Centre, Patna, Bihar, India
2 Galaxy Speciality Centre, Jaipur, Rajasthan, India
3 Jaipur Diabetes Research Centre, Jaipur, Rajasthan, India
4 Rudraksh Super Speciality Care, Siliguri, West Bengal, India
5 Arthur Asirvatham Hospital, Madurai, Tamil Nadu, India
6 S L Raheja Hospital, Mumbai, Maharashtra, India
7 Pondicherry Institute of Medical Sciences, Pondicherry, India
8 Dr. Mohan’s Diabetes Specialities Centre, Chennai, Tamil Nadu, India

Date of Submission04-Jul-2020
Date of Decision02-Aug-2020
Date of Acceptance09-Jul-2020
Date of Web Publication1-Sep-2020

Correspondence Address:
Dr. Ajay Kumar
Consultant Physician and Diabetologist and Director, Diabetes Care & Research Centre, Patna, Bihar.
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/JOD.JOD_59_20

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  Abstract 

Several guidelines provide recommendations on insulin therapy in people with type 2 diabetes mellitus (T2DM). Major global guidelines have been adapted in multiple countries, and local consensus recommendations have been published giving guidance on insulin therapy considering local realities. This expert review focuses on the recommendations from global and Indian guidelines on insulin therapy in people with T2DM. It emphasizes on a patient-centric approach, including the glycemic parameters, psychosocial aspects, phase of life, and the Indian realities of T2DM management in guiding optimum insulin therapy for initiation and intensification. Therapeutic inertia towards timely insulin initiation needs to be bridged. Owing to the high carbohydrate diet and high postprandial glucose (PPG) excursions, insulin co-formulation and premix insulins offering total glycemic control can be preferred for a timely insulin initiation in Indians with T2DM that is uncontrolled despite multiple oral antidiabetic drugs. They also provide simplicity and convenience for insulin initiation and intensification. Among basal insulins, insulin degludec and glargine U300 are found to be safer, and offer more dosing flexibility than the first-generation basal insulin analogs. Faster-acting insulin aspart has been shown to provide better PPG control and dosing flexibility compared to a rapid-acting insulin analog with a lower risk of hypoglycemia. Thus, based on available evidences, a preferred use of insulin analog over conventional human insulins is suggested, keeping cost considerations in mind. The review also discusses optimum use of concomitant medications with insulin therapy for T2DM management.

Keywords: Antidiabetic therapy, expert review, Indian population, insulin therapy, T2DM


How to cite this article:
Kumar A, Sharma SK, Gupta A, Dasgupta A, Asirvatham AJ, Talwalkar PG, Das AK, Mohan V. Indian reality of managing type 2 diabetes: an expert review of global and national guidelines for optimum insulin use. J Diabetol 2020;11:148-57

How to cite this URL:
Kumar A, Sharma SK, Gupta A, Dasgupta A, Asirvatham AJ, Talwalkar PG, Das AK, Mohan V. Indian reality of managing type 2 diabetes: an expert review of global and national guidelines for optimum insulin use. J Diabetol [serial online] 2020 [cited 2020 Nov 26];11:148-57. Available from: https://www.journalofdiabetology.org/text.asp?2020/11/3/148/294051




  Introduction Top


Diabetes is a growing public health concern worldwide. Globally, 463 million people are living with diabetes. The current prevalence of 9.3% is expected to increase to 10.2% by 2030.[1] People living with uncontrolled diabetes are at a high risk of developing micro- and macro-vascular complications. If left untreated, it could lead to frequent hospitalization and ultimately death. National and international professional diabetes bodies have thus evolved recommendations for good glycemic control and optimum management of type 2 diabetes mellitus (T2DM).[2],[3]

Numerous aspects such as genetic makeup, social system, financial apparatus, civic infrastructure, clinical practice environment, and patient-related factors are considered while drafting a guideline.[4] Many popular global guidelines have originated from North America and the European regions that account for one-fourth of the world’s diabetes population. Whereas, nearly more than half of the remaining population resides in the other parts of the world, particularly Southeast Asia.[1] Thus, understanding local realities in such areas, in addition to the consideration of different global guidelines, is vital. Therefore, the Research Society for Study of Diabetes in India (RSSDI), the Indian National Consensus Group (INCG), and the Indian Council of Medical Research (ICMR) have shared guidelines and consensus statements specific to the treatment of Indian population with diabetes.[5],[6],[7],[8] This review will discuss about the recommendations from the western and Indian guidelines/consensus on insulin therapy. It will also discuss the key aspects of insulin therapy, such as when to initiate, the patient-centric approach, factors that determine the choice of insulin, and the use of concomitant oral antidiabetic drugs (OADs) or glucagon-like peptide-1 receptor agonists (GLP-1RAs).


  Initiating Insulin Therapy in T2DM: When? Top


To achieve good glycemic control, patients with diabetes require anti-hyperglycemic agents along with maintaining a healthy lifestyle. Metformin, unless contraindicated, is the firstline treatment for T2DM. However, other OADs can also be used as appropriate.[5],[9],[10] To reduce cardiovascular (CV) events in patients with T2DM, the use of GLP-1 RAs or sodium-glucose cotransporter 2 inhibitors (SGLT2i) can be considered as the firstline therapy based on the presence of atherosclerotic CV disease (ASCVD) or high/very high CV risk (target organ damage or multiple risk factors).[11] Though insulin is initiated sometimes at diagnosis, it generally enters the regimen only after insufficiency of multiple OADs.[12],[13]

Insulin after OAD insufficiency

By the time diabetes is diagnosed, the function of β-cell is already reduced to its half.[14] Due to the progressive nature of T2DM, the function of β-cell continues to decline even after treatment, resulting in the worsening of glycemic control. Intensive treatment with OADs over a certain period has shown control, but eventually glucose levels continue to rise steadily.[15],[16] Large epidemiological studies conducted in India have shown suboptimal glycosylated hemoglobin (HbA1c) control in Indians with diabetes. In the DiabCare study with 5272 patients, the mean HbA1c reported was 8.9±2.1%.[17] Similarly, at baseline, the A1Chieve study with 20,554 participants, the PRESENT study with 3559 patients, and the IMPROVE study with 17,491 patients have shown a mean HbA1c of 9.2%, 9.23%, and 9.3%, respectively.[18],[19],[20] Despite the recommendations and documented benefits of timely insulin initiation, therapeutic inertia for the initiation of insulin therapy still exists.[21] This delay may result in an increased risk of diabetes-related complications. Evidence demonstrating the benefits of multiple OADs for better HbA1c control has been unsuccessful.[22] Moreover, the addition of a fourth OAD failed to provide the desired control of HbA1c.[23] Hence, a timely initiation of insulin becomes imperative for reducing the future risk of diabetes-related complications.

Insulin at diagnosis

The objective of early intensified treatment of T2DM is to achieve and maintain a strict glycemic control and further reduce the risk of diabetes-related complications. In usual clinical practice, insulin is considered only when dual- or triple-OAD therapy is not adequate to achieve the required glycemic goal. Studies have shown that short-term insulin therapy at diagnosis could help change the course of diabetes. In a prospective study, the approach of early premix insulin treatment for 2 months followed by OADs was analyzed in 122 newly diagnosed, treatment-naive cases. Within 2 months from the initiation of insulin therapy, the target glucose and HbA1c levels, as recommended by many guidelines, were achieved and sustained up to 3 years even after insulin was discontinued, and the patients were switched over to OADs.[13] Another study with 426 newly diagnosed cases of T2DM showed that a short course of insulin therapy for 4–6 weeks achieved good long-term glycemic control that sustained for 2 years and improved the pancreatic function.[24] A short-term intensive insulin therapy in newly diagnosed cases has been tried in multiple studies to induce glucose remission, which is secondary to improved β-cell function.[25],[26] A systematic review by Kramer et al. suggested that a short-term insulin therapy could improve the pathophysiological defects underlying T2DM, which can often last more than a year.[26] It has been shown that insulin also has anti-inflammatory, antioxidant, antiapoptotic, antilipolytic, cardioprotective, and neuroprotective properties.[27],[28],[29] These evidences suggest a definite benefit with early insulin therapy even in Indians with T2DM.

Recommendations from global and Indian guidelines on insulin initiation

  • American Diabetes Association (ADA)/European Association for the Study of Diabetes (EASD), ADA, American Association of Clinical Endocrinologists (AACE), and American College of Endocrinology (ACE):
  • As an injectable, GLP-1RAs are the preferred choice compared to insulin.[9],[10],[30]


  • If injectable therapy is needed to reduce HbA1c and if the person is already on GLP-1RA or if GLP-1 RA is not appropriate, insulin should be added.[9],[10],[30]


  • Fixed combination of GLP-1RA and basal insulin, or prandial and basal insulin combination is recommended when HbA1c is >10% and/or >2% above the target.[30]


  • Insulin therapy can be initiated early if there is evidence of ongoing catabolism (weight loss), if symptoms of hyperglycemia are present, or when HbA1c levels >10% or blood glucose levels ≥300mg/dL.[9]


  • RSSDI:

  • Insulin should be considered in cases where a person fails to achieve or maintain HbA1c levels after the administration of three OADs, out of which one should be a newer agent, or if the person is intolerant to any individual agent or a combination of agents.[5]


  • When there is evidence of glucotoxicity or lipotoxicity, and if HbA1c is >10% at the time of diagnosis, a short course of insulin for about a month can be considered.[5]




  • Key messages on when to start insulin in T2DM are mentioned in [Table 1].
    Table 1: When to start insulin in T2DM?: Key messages

    Click here to view



      Choosing a Patient-centric Insulin Regimen Top


    The selection of an appropriate insulin regimen depends on patient characteristics, including glycemic status, dietary patterns, psychosocial needs, financial situation, and comorbid conditions.[31] Fasting plasma glucose (FPG) levels, postprandial plasma glucose (PPG) levels, and HbA1c values are critical parameters for guiding the choice of insulin regimen. Although ADA/EASD and AACE consensus recommend the initiation of basal insulin, if the postprandial increment is >54 mg/dL, a premix insulin initiation should be preferred; and if the increment is <18mg/dL, then basal insulin can be considered.[32] Insulin regimen can also be recommended based on HbA1c values. However, the relative contribution of FPG and PPG differs at different levels of HbA1c. Evidence suggests a larger contribution of FPG when HbA1c is high, and a larger contribution of PPG when HbA1c is low.[33] However, this is true for the Caucasian population. It has been shown that the contribution of PPG to hyperglycemia is much higher in the Asian population and on par with the contribution from FPG even at higher quartiles of HbA1c.[34] PPG is a crucial component and ignoring it would lead to a failure in achieving treatment goals. Vahatalo et al. studied the ratio of FPG (mg/dL) to HbA1c (%) in deciding the relative contribution of fasting glycemia wherein a cutoff of 20 was taken. A lower ratio (<20) means postprandial type of hyperglycemia, which will need to be controlled through prandial or premix insulins.[35],[36] Zisman et al. adopted the BeAM value (difference between bedtime and morning blood glucose values) as an indicator of target PPG. It was reported that a BeAM value >55mg/dL demands control through prandial or premix insulins.[37]

    Among the other patient-related factors affecting the choice of insulin regimen are psychosocial factors (awareness, education about diabetes and its related complications, self-motivation and cost of therapy), patients’ ability to handle number of injections, delivery devices, and openness to switch to different insulin regimens.[31],[38],[39] Patient’s age and general condition is also a crucial factor. In a survey, it was noticed that doctors prefer basal-bolus insulin regimen in children and pregnant women, while they prefer premix insulins over basal/basal-plus or basal-bolus regimen for adults and elderly patients.[31] Based on these multiple factors, the treating physician should spend time on each patient and take into consideration the individual requirements. However, in reality, the mean duration of consultation by a primary care physician in India is only 1.5–2.3 minutes.[40]

    In addition, Indians generally show an inclination towards a high-carbohydrate and a high-calorie diet. Such a dietary habit is said to be responsible for the high insulin resistance and PPG levels.[41],[42] Unlike in the western population, the contribution of PPG to hyperglycemia is much higher in the Asian population.[33],[34] Studies have shown that both PPG and FPG levels are deranged and well above the recommended levels in Indians with diabetes.[18],[19],[20] The majority of these patients have HbA1c >9% despite being on treatment with multiple OADs.[43],[44] Therefore, there is a need for a timely initiation of an insulin regimen that can maintain total (PPG+FPG) glycemic control with safety. Insulin co-formulation and premix insulins are a combination of basal and bolus components that can provide desired control over PPG and FPG levels in Indians with diabetes.[8],[45]

    Recommendations from global and Indian guidelines on the choice of insulin regimen

    ADA and AACE/ACE recommend using basal insulin alone for insulin initiation.[9],[10],[30] Whereas, the guidelines of the National Institute for Health and Care Excellence (NICE), the Canadian Diabetes Association, and the International Diabetes Federation (IDF) consider the use of premix insulin apart from basal insulin for insulin initiation.[46],[47],[48] In addition, regional guidelines designed after considering local realities and patient demographics, including those from RSSDI, Diabetes Australia, Clinical Practice Guidelines (Malaysia) and East African Diabetes Study Group (EADSG), recommend basal insulin, premix insulin, or insulin co-formulation for initiating insulin therapy and thus are more relevant.[5],[49-51]

    Key messages on choosing a patient-centric insulin regimen are mentioned in [Table 2].
    Table 2: Choosing a patient-centric insulin regimen: Key messages

    Click here to view



      Switching to Other Insulin/Insulin Regimen Top


    An internet survey of 1250 physicians across eight countries (China, France, Japan, Germany, Spain, Turkey, the UK, and the USA) reported that their patients omit insulin therapy for at least one day in a month. More than 70% of them reported that patients do not take insulin as prescribed. They stated fear of hypoglycemia, fixed meal timing, number of injections, stress, and public embarrassment as reasons to avoid insulin. Hence, there is a need for a simple and convenient regimen to intensify the therapy.[52] The available options to intensify therapy with insulin are basal-plus, basal-bolus, premix insulin, and insulin co-formulation. In a meta-analysis of 5255 patients, Giugliano et al. compared glycemic control with basal-bolus vs. premixed insulin regimen in people with T2DM. No significant difference was reported with regard to changes in HbA1c levels, overall hypoglycemia, weight change, and daily insulin dose requirement.[53] So, the factors that affect the choice of an intensified insulin regimen are the number of injections, which are certainly fewer with premix insulin; self-monitoring of blood glucose, which will be less frequent with premix insulin; or patients’ ability to inject insulin, which will be convenient in case of premix insulins.[32]

    Insulin co-formulation is a combination of basal and bolus insulin analogs. When compared with basal-plus or basal-bolus therapy, insulin degludec/insulin aspart co-formulation has been shown to be a convenient option with similar glycemic control requiring fewer number of injections and with significantly lower risk of nocturnal hypoglycemia and total insulin dose requirement.[54] Another available co-formulation is a combination of basal insulin with GLP-1RA. This co-formulation is a good option to intensify therapy after basal insulin alone failed to achieve glycemic control. In comparison to basal-bolus therapy, the co-formulation of degludec with liraglutide showed non-inferior HbA1c reduction (with treat-to-target designs) in addition to showing a significant improvement in severe and confirmed hypoglycemia, total insulin dose requirement, and weight gain.[55]

    Based on evidence, most of the international guidelines recommend that patients who were initiated on basal insulin and needing intensification can add bolus insulin to the regimen as basal-plus and basal-bolus therapy.[9],[30],[46-48] Patients who were initiated on premix insulin once or twice daily and needing intensification can increase one more injection of premix insulin a day or add bolus insulin as per meals or can even be shifted to basal-bolus therapy.[9],[10],[30],[46],[47],[48] Even GLP-1RAs are recommended for intensifying the therapy with basal insulin.[9],[10],[30] National guidelines consider the scope of convenience and simplicity. They recommend basal-plus, basal-bolus regimen, and insulin co-formulation or premix insulin for insulin intensification.[5],[49],[50],[51] Key messages on switching to other insulin and insulin regimens are mentioned in [Table 3].
    Table 3: Switching to other insulin/insulin regimen: Key messages

    Click here to view



      Choosing the Right Insulin Top


    Insulins have undergone significant changes from the era of Banting and Best to today. Insulin analogs have shown better safety and efficacy due to their improved pharmacological profile.

    Pharmacological and clinical profile of human and analog insulins

    NPH insulin was developed to control FPG but had a higher risk of hypoglycemia. With a more predictable glucose-lowering effect, insulin glargine U100 and insulin detemir showed better efficacy and a lower risk of hypoglycemia compared to NPH insulin.[56],[57] Insulin glargine U300 is a concentrated form of glargine U100, which has shown lesser glycemic variability, lower risk of hypoglycemia, and better flexibility compared to glargine U100.[58],[59],[60] On the other hand, the ultra-long-acting insulin degludec has a fourfold lower glycemic variability compared to insulin glargine U100 and glargine U300 with a significantly lower risk of hypoglycemia (severe and nocturnal) and better flexibility.[61],[62],[63]

    In case of bolus insulins, the objective has been to match the after-meal physiological insulin profile. RHI controls postprandial hyperglycemia, but has a delayed onset of action and a slightly longer duration of action after meals, leading to a lack of mealtime flexibility and risk of hypoglycemia. Rapid-acting insulins attain a peak in less time and have a faster onset of action compared to regular human insulin. They also provide better PPG control with a lower risk of hypoglycemia and mealtime flexibility.[64] The ultra-rapid-acting, faster-acting insulin aspart closely mimics the physiological mealtime insulin secretion.[65] It provides postmeal dosing flexibility (up to 20min after start of the meal), improved 1-hour and 2-hour PPG control, better HbA1c reduction, and lower risk of hypoglycemia compared to insulin aspart.[66]

    Human premix insulin can control both FPG and PPG through titration based on the value of premeal blood glucose and can be used once or twice daily.[50] However, it lacks mealtime flexibility, and there was still an opportunity for better PPG control with further lowering of hypoglycemia risk. This led to the development of biphasic analog insulins that can be administered once, twice, or even thrice daily with a benefit of lower risk of hypoglycemia, better PPG control, and mealtime flexibility compared to biphasic human insulin.[67],[68],[69],[70] Further innovation with premix insulin led to the development of co-formulation of insulin degludec and insulin aspart (IDegAsp). It has the advantage of once- or twice-daily dosing with the largest meal(s) of the day. It also provides a better control of FPG, lower risk of hypoglycemia, lower insulin dose requirement, and lesser weight gain compared to biphasic analog insulin.[71],[72]


      Cost-effectiveness of Analog Insulins Top


    The dose of anti-hyperglycemic agents is adjusted based on glucose levels. Some medications need to be up-titrated, which may increase the short-term medication cost. This is necessary to achieve the target glucose goals and reduce long-term costs associated with diabetes-related complications.[73] Hypoglycemia with insulin therapy is a serious complication that can affect diabetes treatment. Hence, the prevention of hypoglycemia is an important part of diabetes management.[74],[75] It thus becomes necessary to understand the cost of insulin therapy and differentiate it from the price of insulin in the background of risk of hypoglycemia.

    Pollock et al. compared the cost-effectiveness of insulin detemir (detemir) vs. NPH insulin in the United Kingdom. In patients with T2DM, insulin therapy with detemir led to an increase in treatment costs by 171 British pounds (GBP) over a 1-year time. However, the reduced rate of hypoglycemia resulted in an incremental gain of 0.120 quality-adjusted life-years (QALY), yielding an incremental cost-effectiveness ratio (ICER) of 1422 GBP per QALY gained.[76] Similarly, in Asian patients, Lau et al. reported glargine to be cost-effective compared to NPH insulin. Insulin glargine U100 resulted in an incremental gain of 0.217 QALY, yielding an ICER of 98,663 Hong Kong dollars per QALY gained.[77]

    The relative higher prices of rapid-acting insulin analogs compared to RHI were more than offset by the reduced costs associated with CV complications and hypoglycemia.[78] Premixed insulin analogs are not far different. In Indian patients, switching from insulin glargine U100 (IGlar) to biphasic insulin aspart (BIAsp 30) resulted in a decline in the yearly incremental cost by INR 14,447. Additionally, BIAsp 30 resulted in an incremental QALY of 0.24 with a risk reduction in end-stage renal disease by 53%, severe vision loss by 25%, and myocardial infarction by 14%.[79] All the above evidences suggest that better care and reduced risk of hypoglycemic events will reduce the cost of treatment for diabetes. In line with the evidence, the ADA recommends the following order in terms of lower hypoglycemia risk with basal insulin: degludec/glargine U300, glargine U100/detemir, NPH insulin. However, while initiating insulin therapy, one must consider the financial situation of patients. As a result, the WHO recommends human insulin in low-resource setting. Also, in patients with severe hypoglycemia with human insulin, the WHO recommends using long-acting insulin analogs.[80] In Indian settings too, the RSSDI consensus recommends that insulin analogs may be preferred over human insulins, keeping drug acquisition price considerations in mind.[5] Key messages on choosing the right insulin are mentioned in [Table 4].
    Table 4: Choosing the right insulin: Key messages

    Click here to view



      Concomitant Use of OADs and GLP-1 RAs with Insulin Therapy Top


    In the current clinical practice, insulin therapy is commonly used along with OADs. A combination therapy with metformin leads to an increase in insulin sensitivity and reduction of daily insulin doses.[81] Bedtime insulin–daytime sulphonyl urea (BIDS) strategy has achieved significant HbA1c reduction. However, HbA1c reduction was less compared to insulin monotherapy.[82] Likewise, insulin when used along with other anti-hyperglycemic agents produced substantial HbA1c reduction.[83],[84],[85]

    So, when combining insulin therapy with OADs and GLP-1 analogs, guidelines such as ADA and RSSDI consensus recommend continuing the use of metformin. If basal insulin has been titrated to an acceptable FPG level (or if the dose is >0.5 unit/kg per day) and HbA1c remains above the target, changing to a combination injectable therapy by adding GLP-1RA is recommended. It has also been recommended to discontinue sulphonylureas and DPP4i when using combination injectable therapy.[9] Other OADs apart from metformin may be continued or discontinued on an individual basis.[5] Key messages on concomitant use of insulin with OADs and GLP-1RA are mentioned in [Table 5].
    Table 5: Concomitant use of OADs and GLP-1RA: Key messages

    Click here to view



      Summary Top


    Despite being on dual- or triple-OADs, only a small proportion of patients achieve their desired HbA1c target. Often insulin therapy is delayed due to lack of time, training, team, and the necessary tools (4Ts). Timely insulin therapy should be strengthened with due consideration to local realities so as to reduce the risk of diabetes-related complications. The choice of regimen for insulin initiation should be done with a patient-centric approach after considering the clinical practice settings, available consultation time, dietary patterns, glycemic parameters, phase of life, psychosocial factors, presence of complications, and comorbidities so that insulin therapy can fit into the lives of patients. As T2DM is progressive in nature, insulin intensification should be timely, simple, and convenient, and appropriate patient-friendly regimens should be preferred. In general, after due consideration of the cost, analog insulins should be preferred over conventional human insulins, and concomitant use of other anti-hyperglycemic agents should be judicious with appropriate dose adjustments in order to improve the safety and effectiveness of insulin therapy.

    Acknowledgements

    The authors acknowledge Sagar Wagh and Sandeep Subramaniam of APCER Life Sciences, Ahmedabad, India, for providing medical writing/editorial support in accordance with Good Publication Practice (GPP3) guidelines.

    Financial support and sponsorship

    Nil.

    Conflicts of interest

    There are no conflicts of interest.



     
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