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 Table of Contents  
Year : 2022  |  Volume : 13  |  Issue : 2  |  Page : 145-153

Expert consensus on triple combination of glimepiride, metformin, and voglibose usage in patients with type 2 diabetes mellitus in Indian settings

1 Department of Endocrinology, Pondicherry Institute of Medical Sciences, Pondicherry, India
2 Indraprastha Apollo Hospitals, New Delhi, India
3 Department of Diabetology, North Delhi Diabetes Centre, 180, Jai Apartments, Sec 9, Rohini 110085, New Delhi, India
4 Endocrinology, Diabetology, and Metabolic Physician, Mumbai, Maharashtra, India
5 Department of Endocrinology, St John’s Medical College, Bangalore, Karnataka, India
6 Department of Endocrinology and Metabolism, MS Ramaiah Medical College, Bangalore, Karnataka, India
7 North Delhi Diabetes Centre, New Delhi, India
8 Scientific Services, USV Private Limited, Mumbai, Maharashtra, India

Date of Submission13-Oct-2021
Date of Decision02-Feb-2022
Date of Acceptance03-Feb-2022
Date of Web Publication21-Jul-2022

Correspondence Address:
Dr. Mahesh V Abhyankar
Scientific Services, USV Pvt Ltd, Mumbai, Maharashtra
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/jod.jod_118_21

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Background: Type 2 diabetes mellitus (T2DM) is a progressive disease affecting a huge chunk of the population globally. Aim: This study aimed to address the existing gaps in knowledge about the triple-drug combination and to provide guidance to the clinicians on the triple-drug combination in Indian settings. Materials and Methods: Doctors’ opinions (n = 2262) were recorded based on surveys and round table meetings. The National Expert Group approved a standard questionnaire that included 13 questions pertaining to T2DM management using a triple combination of glimepiride, metformin, and voglibose, which were prepared, discussed, and evaluated by the experts. After due discussions, the expert group analyzed the result and further recommendations were made and a consensus statement was derived. Results: Out of 2262, 1498 were consulting physicians, 358 were diabetologists, 93 were endocrinologists, 104 were cardiologists, and 209 were family physicians with focus on diabetes practice or had more than 10 years of experience from different regions from India. A strong consensus was observed for targeting postprandial hyperglycemia in the management of T2DM, which may reduce cardiovascular (CV) disease risk. The experts opined that meal pattern was the major factor affecting glycemic variability. The experts recommended early use of triple combination as it improves glycemic control (early aggressive control, beyond three oral drugs are on no benefit, ingrained). More than 90.0% of clinicians believed that this combination is cost-effective. Most agreed (32.0%) that this combination moderately reduces body weight. Additionally, it was felt that triple combination in patients with T2DM is also beneficial during Ramadan. Conclusion: In the present expert opinion-based consensus, most of the healthcare providers believed that triple-drug combination can potentially improve glycemic control and can delay/postpone the microvascular and CV complications. However, more multicentric studies are needed to support these recommendations.

Keywords: Cardiovascular disease, cost-effective, postprandial hyperglycemia, Ramadan, triple combination

How to cite this article:
Das AK, Wangnoo SK, Chawla R, Shaikh A, Bantwal G, Kalra P, Jaggi S, Abhyankar MV, Prasad A, Sarda P. Expert consensus on triple combination of glimepiride, metformin, and voglibose usage in patients with type 2 diabetes mellitus in Indian settings. J Diabetol 2022;13:145-53

How to cite this URL:
Das AK, Wangnoo SK, Chawla R, Shaikh A, Bantwal G, Kalra P, Jaggi S, Abhyankar MV, Prasad A, Sarda P. Expert consensus on triple combination of glimepiride, metformin, and voglibose usage in patients with type 2 diabetes mellitus in Indian settings. J Diabetol [serial online] 2022 [cited 2022 Aug 12];13:145-53. Available from: https://www.journalofdiabetology.org/text.asp?2022/13/2/145/351752

  Introduction Top

Type 2 diabetes mellitus (T2DM) is a major chronic disorder affecting a huge chunk of the population globally, and 1.6 million deaths occur every year. According to the International Diabetes Federation (IDF), 1 in 10 adults have diabetes, and over 3 in 4 adults with diabetes live in low- and middle-income countries.[1] Nearly 537 million people have diabetes, which is estimated to rise to 643 million by 2030 and further up to 783 million by 2045.[1] India ranks at the top with 77 million people with T2DM among the Southeast Asian countries.

The major concern associated with diabetes is the consequential macrovascular and microvascular complications and poor quality of life. Clinical studies have revealed that rigorous glycemic control prevents diabetic complications.[2] Several factors including unhealthy eating habits, history of cardiovascular (CV) diseases, non-adherence to treatment and exercise, abnormal lipid profile, treatment type, obesity, irregular follow-up, and rural residence are associated with poor glycemic controls.[3],[4],[5] Therefore, achieving glycemic control is a herculean task in the management of T2DM. It has also been demonstrated that diabetes control during the first year after diagnosis is strongly associated with future risk for diabetes complications and mortality. This underlines the need for achieving early glycemic control for improving outcomes for people with diabetes.[6]

In addition to fasting plasma glucose (FPG), postprandial glucose (PPG) control is also of paramount importance. PPG is an important factor in the control of diabetes. Excess carbohydrate consumed by Indians leads to poor control of diabetes and resultant complications in them. The STARCH study conducted in the Indian population with and without T2DM demonstrated that carbohydrates constitute 64.1% of total energy from the diet in T2DM patients.[7] It also showed similarity in dietary habits of both participants, those with and without T2DM and in diverse regions. In UKPDS 83, it was found that Asian Indians were at greater risk for any diabetes-related endpoint vs. White Caucasians. Postprandial hyperglycemia contributes to glycemic control and most importantly to the development of CV complications in T2DM.[8] The untoward effect of a high carbohydrate diet on lipid profile and CV risk can be alleviated by consuming low glycemic index diets with the inclusion of fiber-rich foods.[9] Long-term glycemic control depends chiefly on PPG that is often overlooked. A meta-analysis has demonstrated that PPG is more closely associated with HbA1c than FPG, hence superior in predicting the overall glycemic control.[10] Treatment guidelines for T2DM from American Diabetes Association, IDF, and European Association recommend PPG targets along with A1c and FPG targets. However, current treatment strategies are more effective in controlling FPG. PPG has been given less attention in maintaining long-term glycemic control.[11] A terminology “PGA1c” (both PPG and HbA1c) has been suggested by the authors to bring the focus on achieving good control of PPG along with HbA1c for optimum management of people with T2DM. Considering the importance of controlling PPG in overall treatment goals, it may be prudent to target PGA1c (PPG and HbA1c) more effectively which may improve disease outcomes.

Glycemic variability (GV) is another important measure when evaluating glycemic control and is more reliable than glycated hemoglobin (HbA1c) values. Similar to glycemic control, GV is associated with macrovascular and microvascular complications of diabetes, hypoglycemia, and mortality rates.[12],[13] A meta-analysis including a series of 1143 patients demonstrated that curtailing GV could improve insulin resistance, decrease carotid intima-media thickness, and lower the risk of CV diseases.[14]

The standard stepwise approach in the management of T2DM is limited by drawbacks such as frequent delays in achieving glycemic goals and long-term exposure to hyperglycemia. However, combination therapy has potential benefits such as addressing multiple pathophysiological defects, mitigating clinical inertia, achieving glycemic targets early, and delaying associated complications. Moreover, fixed-dose drug combinations help to address treatment-related issues and patient burden due to combination therapy comprising individual drugs.[15]

There is an inverse relationship between adherence to oral antidiabetic drugs and HbA1c. Fixed-dose combinations (FDCs) help in reducing pill burden and dosing frequency and thereby improve adherence.

Subsequent to widespread acceptance of dual therapy for oral antidiabetic drugs (OADs), triple combination of glimepiride, metformin, and voglibose was introduced, considering their individual clinical benefits as well as their synergistic action. In management of patients with T2DM who consume a high carbohydrate diet, glimepiride/metformin/voglibose could be an effective treatment option to inhibit the absorption of starch by impeding the terminal step of carbohydrate digestion at the brush border of the intestinal epithelium. Studies have shown the glycemic efficacy and safety profile of triple OAD combinations.[16],[17]

Guidelines recommend a triple combination of OADs as an effective alternative prior to initiation of insulin for the management of T2DM.[18] India is one of the countries where the triple combination is implemented but several questions remain unanswered regarding the use of this triple combination.

To address these issues and provide guidance to the clinicians, deliberations by experts on different aspects of the triple combination of glimepiride, metformin, and voglibose in Indian settings were done. Based on these deliberations, an expert consensus was developed.

  Materials and Methods Top

Doctors’ opinions (n = 2262) were recorded based on survey and round table meetings (RTMs). A standard questionnaire pertaining to T2DM management using a triple combination of glimepiride, metformin, and voglibose was prepared, discussed, and evaluated by the experts. The questionnaire was validated by the National Expert Group. A multidisciplinary expert panel of endocrinologists and diabetologists, with clinical and research expertise in the diagnosis and treatment of T2DM, was convened and recommendations were formulated.

The questionnaire was discussed and deliberations by the experts were recorded for further reference. All the insights were captured and comprehensively reviewed and discussed to derive the final expert recommendations. The doctors included were 1498 consulting physicians, 358 diabetologists, 93 endocrinologists, 104 cardiologists, and 209 family physicians. The clinicians were enrolled across all four zones of the country. The surveys and RTMs were conducted throughout the country between June 2020 and January 2021. The questionnaire included in total 13 questions mainly emphasizing four aspects of diabetes management, such as postprandial glucose and HbA1c (PGA1c), early treatment intensification in patients with T2DM, the synergy of glimepiride, metformin, and voglibose combination with other OADs, and insulin and diabetes management in subgroups and special populations. Furthermore, the questionnaire also focussed on different aspects of using a triple combination of glimepiride, metformin, and voglibose in patients with T2DM. [Figure 1] displays the consensus process flow chart.
Figure 1: Consensus flow chart

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The obtained recommendations were graded as very strong (greater than 75% of respondents supportive with a statement), strong (50–75% of respondents supportive with a statement), and moderate (<50% of respondents supportive with a statement).

  Results Top

In total, 2262 clinicians participated in RTMs and online survey, of which majority were consultant physicians (n = 1498) followed by diabetologists (n = 358), and the remaining clinicians belonged to other specialties, such as cardiologists, endocrinologists, chest physicians, nephrologists, dermatologists, etc. The following four sections related to diabetes care and implementing a triple combination of glimepiride, metformin, and voglibose in patients with T2DM was discussed and data collected. [Figure 2] displays the responses of clinicians regarding the use of a triple combination of glimepiride/metformin/voglibose for early intensification, in CV-risk patients and in combination with newer OADs.
Figure 2: Triple combination of glimepiride/metformin/voglibose use in T2DM

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Postprandial glucose + HbA1c (PGA1c)

The experts strongly agreed (consensus level: very strong; 91.3%) that controlling PPG can provide good control on long-term GV. All the experts agreed that primarily targeting postprandial hyperglycemia in the management of T2DM can provide a delay in CV complications (consensus level: very strong; 94.7%). The clinicians believed that targeting PPG also prevents renal impairment (69.6%), followed by retinopathy (62.1%) and diabetic foot ulcer (53.3%).

More than 90.0% of clinicians reported that meal pattern and variability (consensus level: very strong; 89.5%) are the major factors affecting GV, followed by lifestyle and compliance (consensus level: strong; 72.3%). Duration of diabetes (52.1%), metabolic variability (46.6%), body mass index (BMI) (34.5%), glomerular filtration rate (GFR) between 30 and 45 mL/min (25.2%), and visit-to-visit FPG variability (21.8%) were other factors responsible for GV.

Early treatment intensification in patients with T2DM

The clinicians majorly (consensus level: very strong; 80.7%) believe that early intensification to triple combination of glimepiride/metformin/voglibose can delay the requirement of insulin. Most clinicians also believed (consensus level: strong; 72.7%) that the glimepiride/metformin/voglibose combination is CV-neutral. Majority of the clinicians (consensus level: very strong; 86.8%) believed that early intensification treatment with a triple combination of glimepiride/metformin/voglibose helps in the achievement of target HbA1c in case of high HbA1c at baseline (1.5–2.0% above target). Many clinicians also considered that this combination may delay the risk of macrovascular and microvascular complications (consensus level: strong; 70.2%) and preserve beta-cell mass and function for longer duration (consensus level: strong; 51.1%) [Figure 3].
Figure 3: Advantage of early intensification with glimepiride/metformin/voglibose combination and effect of this combination on BMI. CV = cardiovascular, OADs = oral antidiabetic drugs, T2DM = type 2 diabetes mellitus

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Synergy of glimepiride/metformin/voglibose combination with other drugs

The clinicians suggested that triple FDC of glimepiride/metformin/voglibose synergizes with other OADs (57.3%). More than 90.0% of the clinicians believed (consensus level: very strong; 94.2%) that this combination is cost-effective in the Indian scenario.

Patients having high HbA1c values (>8%) would be benefited most by modern sulfonylurea present in the triple combination along with metformin and voglibose (consensus level: strong; 67.5%), followed by obese patients (consensus level: moderate; 24.6%) [Figure 4].
Figure 4: Advantage of sulfonylurea present in metformin/glimepiride/voglibose combination. CV = cardiovascular; HbA1c = glycated hemoglobin; T2DM = type 2 diabetes mellitus

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Diabetes subgroups and special populations

Most agreed that this combination moderately reduces body weight (32.0%), whereas others believed that it has weight-neutral effects (consensus level: moderate; 28.9%). Some clinicians (consensus level: moderate; 35.4%) opined that the majority of the elderly population can be recommended with voglibose-based triple combination for better control and safety [Figure 5]. Clinicians somewhat agree (consensus level: moderate; 43.0%) that the triple combination of glimepiride, metformin, and voglibose in patients with T2DM is beneficial during Ramadan, and others strongly agree to this (consensus level: moderate; 42.6%).
Figure 5: Use of metformin/glimepiride/voglibose combination in special population

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  Discussion Top

The primary objective of this survey was to understand the opinion of clinicians about different aspects of triple FDC of glimepiride/metformin/voglibose in the management of T2DM and present collective data in the form of consensus report. Limited clinical studies, real-world data, and guidelines with regard to the use of this triple FDC are the major attributes of conducting this survey. This expert opinion aimed to create awareness, guide in clinical decision-making, and identify future research areas to attain critical scientific data about the glimepiride/metformin/voglibose combination in patients with T2DM and special circumstances.

Achieving target HbA1c goal by early and aggressive treatment approach helps reduce associated microvascular complications, CV complications, and mortality risk.[19] Hence, PPG should be primarily focussed to achieve optimal glycemic control. Controlling PPG helps better control long-term GV and delays CV complications that are agreed strongly by all the clinicians. In addition to FPG, PPG is also one of the most important factors in the management of T2DM and its complications, believed by a majority of experts in this study. A meta-analysis showed that PPG has a closer association with HbA1c than FPG. PPG was found to be better in predicting overall glycemic control in the absence of HbA1c.[10] The contribution of PPG to hyperglycemia has been shown to be much higher in the Asian population and at par with the contribution from FPG even at higher quartiles of HbA1c.[20]

The long-term hyperglycemia is associated with damage and dysfunction of various organs through inflammatory reactions and oxidative stress, which is evidenced in several clinical trials and observational studies.[21],[22] A comparative study in 529 patients with T2DM showed that it is an independent risk factor for CV events in T2DM, with a stronger predictive power in women.[23] The present survey showed a strong consensus among the experts believing the fact that targeting postprandial hyperglycemia delays CV complications and other complications of the kidneys and eyes. The guidelines for the management of postmeal glucose in patients with T2DM from the IDF state the importance of PPG control in alleviating CV risks and include therapeutic strategies for reducing CV.[24] Evidence also suggests higher PPG be an independent risk factor for retinopathy, renal impairment along with neurological problems, and stroke. The pharmacologic therapies that target to lower PPG are observed to reduce CV morbidity and mortality.[25]

There was a strong consensus that meal pattern (contents and quantity) and lifestyle measures play an important role in controlling GV. The meal pattern should have an adequate amount of fiber, fruits, vegetables, low-fat dairy products, whole grains, nuts, fish, and lean meats along with lifestyle changes, regular physical activity, weight, and stress management. Cutting down carbohydrate intake from 65–75% to 50–55% and adding 20–25% proteins probably would be a beneficial approach.[26]

The present survey responders showed mixed opinions about using the triple FDC during fasting. Metformin, glimepiride, and voglibose are deemed safe during fasting due to their lower risk of hypoglycemia.[27],[28] Voglibose can be used safely without any dose adjustment.[28]

The experts were of the opinion that glimepiride/metformin/voglibose FDC produces weight-neutral effects in patients with high BMI. Metformin is effective in controlling the levels of total cholesterol, low-density lipoprotein, and triglycerides.[29] Individuals treated with metformin lost 2.5% of their basal body weight when compared with a 7.5% loss in the lifestyle group.[30] A Japanese study showed a decrease in visceral adipose tissue area and subcutaneous adipose tissue ratio by voglibose along with improvement in glycemic control, serum lipid profiles, insulin sensitivity, and acute insulin response in the voglibose groups.[31] Modern sulfonylureas like glimepiride are considered to be weight-neutral. Metformin and voglibose may provide benefits of weight loss.[32],[33]

Metformin and glimepiride can be used safely in patients with estimated GFR (eGFR) >60 mL/min along with frequent monitoring and dose reduction in advanced stages. Metformin is also known to slow down renal fibrosis by promoting AMP-activated protein kinase phosphorylation.[34],[35] Voglibose is absorbed to some extent and renally excreted. It is administered without dose adjustments in dialysis patients, but contraindicated in patients with eGFR <30 mL/min.[36]

Literature suggests that the renoprotective, cardioprotective, and hepatoprotective effects of metformin improve clinical outcomes and reduce all-cause mortality in patients. Life expectancy is increased in obese and cancer patients, implying its geroprotective effect.[37] The majority of the clinicians believe that this triple combination can be recommended in 30–50% of elderly patients for better control.

The major reason for treatment failure in T2DM is the glycemic burden due to secondary failure to anti-hyperglycemic treatment, decreased insulin release from beta-cells, higher GV, and poor patient adherence.[38] The TIGHT study conducted in Indian population with T2DM demonstrated that the odds of having any microvascular complications increased with the duration of diabetes [past 1–2 years, odds ratio (OR): 1.67; 2–5 years, OR: 2.53; >5 years, OR: 4.01; P < 0.0001], hypertension (stage I, OR: 1.18 and stage II, OR: 1.34; P < 0.05), and uncontrolled HbA1c (OR: 1.28; P < 0.0001).[39]

The patients with prolonged periods of poor glycemic control before treatment if intensified have lower chances of attaining glycemic control after intensification. A study from the USA showed that newly diagnosed patients with T2DM in whom metformin monotherapy failed, early intensification (<6 months) was associated with a significantly shorter time to subsequent HbA1c control.[40] Another large cohort study (n = 11525) in a real-world setting showed that 37% of the patients had their treatment intensified in <6 months and 11% had their treatment intensified 6–12 months after the index date. In this study, fewer than half of the patients with T2D and poor glycemic control received intensification within 12 months after treatment failure.[41]

Adding a third therapy to existing dual therapy results in further reduction in the HbA1c level. Gross et al.[42] reported a 0.70–1.08% additional absolute HbA1c reduction with a third therapy added to metformin and sulfonylurea than without a third agent. The findings of the ADVANCE trial showed that a difference of 0.8% in HbA1c led to 14% reduction in the risk of major microvascular events.[43] A meta-analysis reported that a difference of 0.88% in HbA1c was associated with a 9% reduction in the risk of a major CV event.[44]

The clinical guidelines for diabetes management recommend early and continued adequate glucose control in order to avoid prolonged exposure to hyperglycemia and prevent CV adverse events.[45] Another study showed that the early and intensive glucose control resulted in relative reductions in risk, which persisted for 10 years for any diabetes-related endpoint (9%, P = 0.04), microvascular disease (24%, P = 0.001), risk reductions for myocardial infarction (15%, P = 0.01), and death from any cause (13%, P = 0.007).[46] Majority of the clinicians believed that the early intensification to FDC of glimepiride/metformin/voglibose can delay the insulin requirement, is CV-neutral and delays the risk of associated complications. Insulin is the most important therapy for the management of T2DM and cannot be replaced by OADs, but in terms of quality of life and patient-oriented problems, OADs rank at the top. Availability of OADs, particularly the triple FDCs, helps in achieving the glycemic pentad by acting through various modes of action. Furthermore, the insulin dose is reduced, and its requirement is delayed resulting in an improved patient’s quality of life.[47] A preliminary report by Nakamura et al.[48] showed a significant decrease in the levels of CV system-related biomarkers after the administration of glimepiride, suggesting its anti-oxidative, anti-inflammatory, and angiogenic properties.

Patient adherence to therapy is of utmost importance for therapeutic success in diabetes management that is agreed upon in the present survey (53.7%). Studies show that FDC resulted in a 26% decrease in the risk of non-compliance compared with the free-drug component regimen. A cross-sectional study in the Spanish population demonstrated that one-quarter of patients with T2DM have difficulties attaining the HbA1c goal, despite adequate FPG levels. Therefore, PPG should be focussed to identify and intensify treatment.[49] Likewise, glycemic control is poor among Indians, despite the availability of major classes of OADs.[50] Thus, targeting both PPG and FPG is an important strategy for achieving optimal glycemic control.[51]

More than 90% of clinicians believed that this combination is cost-effective, particularly in the Indian scenario. Evidence suggests that metformin, glimepiride, and voglibose are cost-effective drugs that can prolong life expectancy compared with standard care alone[52]; hence, they can be used in Indian settings.[53]

Multiple strengths of glimepiride and metformin FDCs are beneficial in T2DM, irrespective of age, duration of diabetes, BMI, diabetes complications including neuropathy, retinopathy, nephropathy, peripheral vascular disease, diabetic foot and CV disease, and use of concomitant medications. Hypoglycemic episodes were reported in only a minority of patients, even with higher doses of glimepiride and metformin FDC.[54]

The participating clinicians agreed that this triple therapy can be combined with newer OADs such as SGLT2i or gliptins. The apt choice of patients for prescribing FDC of glimepiride, metformin, and voglibose is an important aspect. The majority of the clinicians suggested that this FDC is optimal in patients having a high HbA1c value (>8%) followed by obese or overweight patients with T2DM.

This survey shows a strong consensus about the safety, efficacy, and cost-effectiveness of this triple FDC and sheds light on various aspects of its use in the Indian population, with other OADs and early intensification.

We also acknowledge few limitations of GMV FDC ,which may include challenges in finer titration of individual ingredients; however, availability of different FDC formulations (stock-keeping unit) may help to ease the struggle. It may be difficult to identify the causative drug when the patient experiences adverse effects; however, glimepiride, metformin, and voglibose are established molecules with several decades of clinical experience and clinicians are well versed with side effects of each of these molecules. Additionally, this survey-based expert opinion included views of HCPs managing diabetes patients and who have experience of using triple combination of GMV, but not based on randomized controlled trial which may limit the validity of the conclusion. The authors suggest readers to carefully generalize the results. More multicentric studies are warranted to support the benefits of GMV combination in patients with T2DM including its CV-neutral effect.

  Conclusion Top

Along with FPG, physicians should also consider PPG to attain the target HbA1c levels. This cost-effective triple combination of GMV can potentially help PPG control, which further reduces the microvascular and CV complications and delays the insulin requirement. Judicious use of this drug can provide a safe and effective alternative to patients with T2DM during fasting and in elderly population. Considering lack of recommendations for the use of triple combination, this “Expert Opinion” may fulfill the need for authoritative guidance on use of this combination for management of T2DM in different patient populations in Indian scenario [Box 1] and [Box 2]. However, multicentric studies are required to corroborate the benefits and side effects of the GMV triple combination.
Box 1: Key properties of glimepiride, metformin, and voglibose

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Box 2: Expert opinion pertaining to triple combination

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We acknowledge Farida Hussain, Thamburaj, Gopal Jani, and Gajanan Mohite for their assistance in carrying out the project. The medical writing support was provided by Hansa Medcell, and from Sapna Patil and Ruchika Thale of Sqarona Medical Communications LLP (Mumbai).

Financial support and sponsorship

This study was funded by USV Private Limited.

Conflicts of interest

Mahesh V. Abhyankar, Ashish Prasad, and Prashant Sarda are employees of USV Pvt Ltd. All other authors have no conflicts of interest to declare.

Authors’ contribution

AKD, SKW, RC, GB, PK, AS, SJ, MVA, AP, and PS: study design, data acquisition, analysis of data, drafting of the manuscript. AKD, SKW, RC, GB, PK, AS, SJ, MVA, AP, and PS: study design, interpretation of data, drafting of the manuscript, critical revision. AKD, SKW, RC, GB, PK, AS, SJ, MVA, AP, and PS: acquisition, analysis, and interpretation of data. AKD, SKW, RC, GB, PK, AS, SJ, MVA, AP, and PS: study concept and design, critical revision, study supervision. AKD, SKW, RC, GB, PK, AS, SJ, MVA, AP, PS: study concept and design, critical revision, mobilization of funding. All authors read and approved the final manuscript.

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  [Figure 1], [Figure 2], [Figure 3], [Figure 4], [Figure 5]

  [Table 1], [Table 2]


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