|Year : 2022 | Volume
| Issue : 4 | Page : 377-384
Glycemic treatment effect of oral semaglutide plus other antidiabetic medications: An Indian experience
Manoj Chawla1, Debmalya Sanyal2, Supratik C Bhattacharyya3
1 Lina Diabetes Center, Mumbai, Maharashtra, India
2 Department of Endocrinology, KPC Medical College, Kolkata, India
3 Consultant Endocrinologist and Diabetologist, Apollo Sugar Clinics, Kolkata, West Bengal, India
|Date of Submission||10-Jul-2022|
|Date of Decision||19-Aug-2022|
|Date of Acceptance||12-Sep-2022|
|Date of Web Publication||21-Dec-2022|
Dr. Supratik C Bhattacharyya
Consultant Endocrinologist and Diabetologist, Apollo Sugar Clinics, Kolkata 700064, West Bengal
Source of Support: None, Conflict of Interest: None
A long-acting oral glucagon-like peptide-1 (GLP-1) receptor agonist, semaglutide is a new armamentarium to glycemic treatments. The Peptide Innovation for Early Diabetes Treatment (PIONEER) 3, 4, 5, 6, and 10 provided the necessary evidence on the efficacy of semaglutide in type 2 diabetes. The American Diabetes Association considers GLP-1 receptor agonists and insulin a high glycemic efficacy therapy. Further, a GLP-1 receptor agonist is recommended when there is a need for minimizing weight gain or promoting weight loss. There are no reports or clinical trials on oral semaglutide in Indian subjects with type 2 diabetes. We present seven case reports where semaglutide was initiated with other antidiabetic medications to bring the glycated hemoglobin (HbA1c) under target and promote weight loss. Between 45 days and 60 days of treatment with antidiabetic drugs, including semaglutide, resulted in a 1.5% reduction in HbA1c. A reduction in body weight ranged from 1.7 kg to 10 kg. Large-scale randomized trial in Indian patients is warranted to confirm our findings.
Keywords: GLP-1, glucagon-like peptide-1, oral GLP-1 receptor agonist, oral semaglutide, semaglutide, Type 2 diabetes
|How to cite this article:|
Chawla M, Sanyal D, Bhattacharyya SC. Glycemic treatment effect of oral semaglutide plus other antidiabetic medications: An Indian experience. J Diabetol 2022;13:377-84
| Key Messages:|| |
Semaglutide is the only glucagon-like peptide-1 receptor agonist available in injection and oral formulation.
The Peptide Innovation for Early Diabetes Treatment (PIONEER) trials helped establish the efficacy of semaglutide in type 2 diabetes.
Combined with insulin alone or metformin, semaglutide significantly reduced glycated hemoglobin (HbA1c).
Semaglutide is safe for use in patients with cardiovascular disease or chronic kidney diseases.
Semaglutide oral treatment, in addition to other standard treatments for diabetes, has been associated with a bodyweight reduction ranging from 1.7 kg to 10 kg.
| Introduction|| |
The global diabetes statistics pegged the prevalence of diabetes in 2021 as 536.6 million, likely to increase to 783.7 million in 2045. India contributed 74.19 million to the global 2021 statistics and is projected to increase to 124.87 million in 2045. The National Family Health Survey (NFHS) 5 (2019–2021) showed a rising in obesity/overweight in women (20.6% in NHFS-4 [2015–206] to 24% in NFHS-5) and men (18.9% in NHFS-4 [2015–206] to 22.9% in NFHS-5). Overweight or obese individuals have a threefold higher risk of developing diabetes, whereas morbidly obese individuals have a 20-fold risk of developing diabetes. The term diabesity was coined to signify the interlink between the two big epidemics, diabetes and obesity.,, Overweight and obesity in diabetes are associated with suboptimal glycemic control. Hence, diabesity increases the risk of complications. Hence, managing diabesity is challenging. Several medications developed for weight loss have failed to serve the desired effect and were associated with serious adverse effects. Hence, antidiabetic medications with complementary effects on weight loss are desired. Conventional antidiabetic medications such as thiazolidinediones, insulin, sulphonylureas, and meglitinides increase weight, likely increasing insulin resistance and suboptimal glycemic control.
The hormone glucagon-like peptide-1 (GLP-1) is produced by the enteroendocrine L cells of the gut and released into the blood following food intake. The circulating GLP-1 stimulates insulin secretion, inhibits the release of glucagon, and augments the number of glucose-responsive β cells.,, Recent research points out that the GLP1 generated by the pancreas might stimulate insulin secretion. In addition, GLP-1 also inhibits gastric emptying and food intake, thereby limiting weight gain. A basic understanding of the action of GLP-1 leads to the therapeutic strategies that activate GLP-1 or GLP-1 receptors. Until the introduction of oral semaglutide, all GLP-1 receptor agonist therapies marketed to date are administered by injection.
Semaglutide is a long-acting GLP-1 receptor agonist approved by the American Diabetes Association (ADA). It is a GLP-1 receptor agonist that can be administered as once a weekly subcutaneous dose or a once-daily oral dose.,, Semaglutide is the only GLP-1 agonist available as an injectable and oral formulation. The once-daily oral formulation of semaglutide is available in 3, 7, and 14 mg tablets. Treatment is initiated with 3 mg, and within a month, the dose can be titrated to 7 mg. If the glycemic target is not reached after a month with 7 mg semaglutide, the dose is titrated to 14 mg. Clinical trials have shown that it is superior to placebo and sitagliptin, exenatide extended-release, dulaglutide, and insulin glargine in achieving tight glycemic control and reducing body weight. We present a series of case reports wherein switching to semaglutide lead to good glycemic control and weight reduction.
| Case 1|| |
A 48-year-old woman with type 2 diabetes visited the clinic with complaints of uncontrolled diabetes. She had an 8-year history of diabetes. She weighed 110 kg, and her body mass index (BMI) was 40.9 kg/m2. [Table 1] gives the current treatment that she was prescribed for 3–6 months. Laboratory reports [Table 2] showed fasting blood glucose (FBG) of 212 mg/dL, postprandial blood glucose (PPBG) of 256 mg/dL, glycated hemoglobin (HbA1c) of 10.3%, and serum creatinine of 0.6 mg/dL. The patient took dulaglutide for 3 months and was compliant but did not want to continue it. Dulaglutide was replaced with semaglutide (3 mg in the morning). In addition, the patient was also prescribed canagliflozin 100 mg (once daily at lunchtime), IDegAsp (30 U each in the morning and night), insulin aspart (20 U in the afternoon), and glimepiride/metformin (1/1000 mg, twice daily, morning and evening). The patient was followed up after 2 weeks. The FBS was 140 mg/dL, and the PPBG was 160 mg/dL. The treatment was effective, but the patient complained of hunger pangs. The dose of semaglutide was increased to 7 mg, and the insulin dose was adjusted. The change in treatment is shown in [Table 1]. One month after the first follow-up, the HbA1c decreased to 8.8% (HbA1c decreased by 1.5%), and weight had reduced by 10 kg and BMI was 37.31 kg/m2. The patient was comfortable and did not report any gastrointestinal discomfort except for severe acidity. Insulin aspart (15 U in the afternoon) was stopped. The dose of semaglutide and canagliflozin was titrated to 14 mg and 300 mg, respectively. There was no change in the dose of IDegAsp or glimepiride/metformin.
|Table 2: Clinical and laboratory parameters before and after the initiation of semaglutide in each case report|
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| Case 2|| |
A 55-year-old man with long-standing diabetes (17.5 years) presented to the clinic with complaints of uncontrolled diabetes. Despite receiving multiple oral antidiabetic medications and insulin, HbA1c was 8.1%; PPBS, 181 mg/dL; FBS, 150 mg/dL total cholesterol, 172 mg/dL; triglycerides, 234 mg/dL; HDL cholesterol, 18 mg/dL; LDL cholesterol, 118 mg/dL; very LDL cholesterol, 47 mg/dL; cholesterol-to-HDL ratio, 9.6; serum creatinine, 1.11 mg/dL; uric acid, 5.2 mg/dL; blood urea nitrogen, 16 mg/dL; total bilirubin, 0.39 mg/dL; serum glutamic-oxaloacetic transaminase (SGOT), 30 IU/L; and serum glutamic pyruvic transaminase (SGPT), 29 IU/L. The patient weighed 83.5 kg, and his BMI was 26.96 kg/m2. [Table 1] provides the details of his current treatment and the change in treatment. Before initiating semaglutide, he received insulin therapy for 4 months and other oral medications for 8 years. After 4 weeks, the semaglutide dose was titrated to 7 mg. The patient came for a follow-up after 2 months. The patient was feeling better. The HbA1c was 7.7%, FBG was 158 mg/dL and PPBG was 179 mg.dL. There was a 1.7 kg reduction in weight and BMI was 26.38 kg/m2. The semaglutide dose was titrated to 14 mg and asked to continue the same medications. The patient reported gastrointestinal upset and loss of appetite when the dose of semaglutide was titrated from 7 mg to 14 mg for 1–2 weeks and the side effects subsided after 2 weeks.
| Case 3|| |
A 66-year-old man visited the clinic for a routine follow-up. He weighed 85 kg and BMI was 29.41 kg/m2. He had a long-standing history of diabetes (15 years) and dyslipidemia and a recent history (2 years) of ischemic heart disease. His treatment history reflected oral anti-diabetes drug failure with sulphonylurea, metformin, and DPP4 inhibitor. He was taking IDegAsp and insulin aspart for the past 5 years. His FBS was 156 mg/dL; postprandial blood sugar (PPBS) 195 mg/dL; HbA1c, 8.7; urine albumin to creatinine ratio (ACR), 200 mg/g; serum creatinine, 1.27 mg/dL; serum uric acid, 7.4 mg/dL; and serum fructosamine L, 319 mmol/L. C-peptide levels were within normal limits. Liver enzymes were within normal limits. His new treatment is shown in [Table 1]. He was asked to take semaglutide 3 mg for 10 days. After 10 days, his FBS was 118 mg/dL; PPBS, 145 mg/dL; and predinner, 94 mg/dL. Semaglutide dose was titrated to 7 mg for 2 weeks and thereafter, he was asked to take 14 mg. The dose of insulin glargine was increased to 62 U at bedtime. No changes were made to the rest of his medications. After 3 months, HbA1c was 7.2%; FBS was 108 mg/dL; PPBS, 138 mg/dL; and ACR, 90 mg/g. He had lost 2 kg and BMI was 28.71 kg/m2. The patient did not report any side effects and tolerated the medications well.
| Case 4|| |
A 61-year-old man with diabetes, dyslipidemia, and hypertension (10 years) visited the clinic with complaints of pain and inflammation of the foreskin and glans. He weighed 84.5 kg and BMI was 29.24 kg/m2. On examination, his blood pressure was 140/90 mm Hg. His current medications are shown in [Table 1]. The dose of sulphonylureas was progressively increased from 2 mg to 6 mg over 4 years. He was diagnosed with balanoposthitis. Clotrimazole ointment was prescribed for local application. After a week, he was asked to follow-up with HbA1c and serum fructosamine results. His FBS was 156 mg/dL; PPBS, 187 mg/dL; HbA1c 7.7; LDL-cholesterol, 68 mg/dL; HDL, 32 mg/dL; and serum fructosamine was 378 mmol/L. His liver and kidney function tests were not performed. [Table 1] shows the change in the treatment regimen. Semaglutide 3 mg was prescribed for 10 days and then the dose was increased to 7 mg. After 10 more days, the dose of semglutide was increased to 14 mg. After 2 months, he had lost 2 kg and his BMI was 28.5 kg/m2. His blood pressure was 150/70 mm Hg. His FBS was 91 mg/dL; PPBS, 101 mg/dL; and serum fructosamine, 268 mmol/L. Patient reported mild fulness and satiety with no other tolerability issues. The dose of insulin glargine was reduced to 10 U, and sulphonylureas was reduced to 2 mg other medications were continued.
| Case 5|| |
A 51-year-old woman with a longstanding history of diabetes (16 years), hypertension, and dyslipidemia visited the clinic for regular follow-up. She also had a diagnosis of chronic kidney disease (stage 1) 6 months ago. She weighed 66 kg, and her BMI was 27 kg/m2. [Table 1] shows the medications that she was taking for 4 months. Her blood pressure was 146/92 mm Hg. Her fasting blood sugar was 203 mg/dL; PPBS, 231 mg/dL; serum creatinine 0.7 mg/dL; HbA1c 9.6%; and estimated glomerular filtration rate, 93. Her blood glucose levels were not under control (HbA1c increased from 8.6 to 9.6 within 2 months). She had gained 3 kg weight since her previous visit. She was advised to take insulin but refused. She was taking dulaglutide 1.5 mg for 6 months. The patient was adherent to the GLP-1 receptor agonist but was reluctant to continue with dulaglutide. Hence dulaglutide 1.5 mg was replaced with semaglutide. Semaglutide was initiated at 3 mg for 10 days, and then the dose was titrated to 7 mg. After 2 weeks, semaglutide dose was increased to 14 mg. After 2 months, there was a weight loss of 3.7 kg and BMI was 25.53 kg/m2. FBS was 136 mg/dL and HbA1c was 8.1% (a 1.5% decrease in 2 months) [Table 2]. There were no gastrointestinal side effects except for abdominal fullness and reduced appetite. She was advised a 1500 kcal/day diet and a daily 30-min physical activity. Stage 1 chronic kidney disease was managed with lifestyle changes and appropriate antihypertensive medications.
| Case 6|| |
A 41-year-old obese man with type 2 diabetes and dyslipidemia was treated with medications listed in [Table 1] for a year. He had an 8-year history of diabetes and dyslipidemia. After 9 months of initiating liraglutide, he had lost 5 kg weight. Still, no further weight loss was observed during the last 6 months. He weighed 88 kg and BMI was 34.5 kg/m2. His FBS was 200 mg/dL; PPBS, 214 mg/dL; and HbA1c, 8.1%; and serum creatinine was 0.8 mg/dL. The patient was adherent to the GLP-1 receptor agonist but did not want to continue with liraglutide. Therefore, liraglutide was replaced with oral semaglutide. Initially, 3 mg of semaglutide was prescribed for 2 weeks and the 7 mg was given for another 10 days before increasing the dose to 14 mg [Table 1]. After 45 days, he lost 2.5 kgs, and his blood sugar improved (FBS: 137 mg/dL, PPBS: 125 mg/dL, HbA1c: 6.9%) [Table 2]. There was no change in serum creatinine after initiating semaglutide. The patient reported abdominal fullness and reduced appetite after initiating semaglutide.
| Case 7|| |
A 67-year-old woman visited the clinic with complaints of pain and inability to articulate her middle finger. On examination, she was diagnosed with a trigger finger. She had a longstanding history of diabetes, hypertension, and dyslipidemia for 15 years. She weighed 53 kg and BMI was 22.3 kg/m2. Her lab results showed that her diabetes was not under control, with HbA1c being 9%, FBS, 139 mg/dL, and PPBS, 209 mg/dL. Her liver function tests were normal, low-density lipoprotein was 88 mg/dL, and serum creatinine was 0.75 mg/dL. To manage the trigger finger, she was advised physiotherapy for 10 days, an ice pack, and diclofenac 50 mg twice daily for five days. She was on the current medications [Table 1] for 7 months. She was advised to take insulin but refused. Despite adequate treatment, her HbA1c was above target. Her new treatment regimen is shown in [Table 1]. Semaglutide 3 mg was changed to 7 mg after 2 weeks. After 2 weeks, semaglutide was titrated to 14 mg. She was followed up after 2 months. Her finger was improving. There was a significant improvement in HbA1c (7.5%). Her FBS was 114 mg/dL, and PPBS, 179 mg/dL [Table 2]. Her blood pressure was 120/80 mm Hg. She had lost 3 kg bodyweight and BMI was 21.08 kg/m2. Patient reported mild fulness and satiety but did not warrant discontinuation of semaglutide. She was asked to continue the same medications for another 3 months.
| Discussion|| |
In our clinical experience, between 45 days and 60 days of treatment with antidiabetic drugs, including semaglutide, resulted in up to a 1.5% reduction in HbA1c [Table 1]. A reduction in body weight ranged from 1.7 kg to 10 kg [Table 1]. The ADA 2022 recommends a GLP-1 receptor agonist before insulin. The GLP-1 receptor agonist is considered a higher glycemic efficacy therapy than insulin and other combination therapies per the ADA treatment algorithm. If target HbA1c is not reached, GLP-1 receptor agonists, DPP-4 inhibitors, sodium-glucose cotransporter-2 (SGLT2) inhibitors, and thiazolidinediones are recommended as agents with no or low risk of hypoglycemia. If weight reduction is warranted, GLP-1 receptor agonists are the agents of choice. In all the cases discussed, the clinical goal was to achieve weight loss and good glycemic control. Hence, initiation of semaglutide was apt in these patients. The ADA recommends GLP-1 receptor agonists in patients with HbA1c above target while on therapy with SGLT2 inhibitors. The HbA1c of patients (Cases 4 and 5) were above the desired HbA1c despite receiving empagliflozin as a part of their therapy. Hence, they were switched over to semaglutide. Two months of treatment with semaglutide resulted in good glycemic control and weight loss. Insulin therapy and the GLP-1 receptor agonist are initiated if the target HbA1c is not achieved. In our patients (Cases 1 and 2), the HbA1c was above target; hence we started aggressive therapy with canagliflozin, semaglutide, insulin degludec/aspart, insulin aspart, glimepiride/metformin. Suppose patients on insulin therapy fail to achieve the target HbA1c, then ADA recommends the addition of a GLP-1 receptor agonist and combination therapy for higher glycemic efficacy. One of our patients (Case 3) failed to achieve the target HbA1c despite insulin therapy. Hence oral semaglutide, glimepiride/metformin/ pioglitazone, and insulin glargine were initiated. As ADA recommends the addition of a GLP-1 receptor agonist to insulin therapy and combination therapy for higher glycemic efficacy, treatment was intensified in a patient (Case 4) on insulin therapy. The ADA also recommends the initiation of GLP-1 receptor agonist before insulin or with insulin in patients with Hb1c above target. One of the patients (Case 7) who refused to take insulin was treated with oral antidiabetics, including semaglutide.
A network meta-analysis of oral semaglutide (once-daily) vs. injectable GLP-1 receptor agonists in subjects with type 2 diabetes suggests that oral semaglutide 14 mg, as an add-on to basal insulin is effective in reducing HbA1c and weight. Glycemic targets could be met within 26 ± 4 weeks. The efficacy of oral semaglutide 14 mg as an add-on to basal insulin was similar to or better than most injectable GLP-1 receptor agonists. There was no difference in tolerability profile.
The PIONEER 3 study by Rosenstock et al. showed that in adults with type 2 diabetes uncontrolled with metformin with or without sulfonylurea, oral semaglutide (7 mg and 14 mg) significantly reduced HbA1c and body weight compared to sitagliptin.
The Peptide Innovation for Early Diabetes Treatment (PIONEER) 4 study by Prately et al. established that the efficacy (reduction in HbA1c) of oral semaglutide was similar to that of subcutaneous liraglutide and superior to placebo at 26 weeks. Weight loss was superior with semaglutide (–4.4 kg) than with subcutaneous liraglutide (–3.1 kg) or placebo (–0.5 kg). There was no difference in the safety and tolerability profile of semaglutide and subcutaneous liraglutide. Given the PIONEER 4 results, replacing liraglutide with semaglutide in patients (cases 1 and 6) is justified.
The PIONEER 6 study was a pre-approval cardiovascular outcomes trial, which ruled out the excess cardiovascular risk vs. placebo in people with type 2 diabetes. This evidence facilitated the initiation of semaglutide in patients with comorbid cardiovascular disease (Case 3) or cardiovascular risk factors (dyslipidemia and hypertension [Cases 4, 5, and 7]).
The PIONEER 10 study by Yabe et al. showed that HbA1c reduction with oral semaglutide (3 mg, 7 mg, and 14 mg) was comparable to a weekly subcutaneous dulaglutide 0·75 mg after 52 weeks. In addition, there was a significant weight reduction with semaglutide (7 mg and 14 mg). Hence, the PIONEER 10 study supports the replacement of dulaglutide with oral semaglutide (Case 5) without compromising efficacy. The pharmacokinetics of semaglutide is not affected by renal impairment. Semglutide is well-tolerated by subjects with varying degrees of renal impairment, and therefore no change in dose is warranted. The PIONEER 5 study found that oral semaglutide was potentially a new treatment option for patients with type 2 diabetes and moderate renal impairment. Given the outcome of the PIONEER 5 study, the use of semaglutide in a patient with stage I chronic renal failure (Case 5) is justified.
In the first patient (Case 1), after 6 weeks, there was a 10 kg reduction in weight. It is evident that different patients respond differently to the semaglutide. The weight loss could be attributed to both SGLT2 inhibitor and oral semaglutide. Further, weight loss also could be attributed to reduction in insulin dose (the afternoon insulin aspart was reduced to 15 U from 25 U). After 6 weeks, the afternoon insulin aspart was stopped.
In the second patient (case 2), the patient wanted to reduce the number of injections and without compromising on the glycemic control. Hence, semaglutide was added and the evening dose of insulin dose was stopped.
The patient (case 3) visited the physician for the first time. The patient (case 3) presented as a case of oral anti-diabetes drug failure. He was taking insulin for 5 years. Initially he was given basal insulin (once-daily) and then slowly titrated to basal-bolus insulin twice daily. The patient was already on 115 U of insulin and hence semaglutide was initiated at higher dose (14 mg) and insulin was reduced to 50% of his prior dose. The semaglutide dose of 14 mg was continued as there was no tolerability issue. Semaglutide was considered keeping in view its cardiovascular safety profile. As his glycemia was within normal limits, a high urine albumin to creatinine ratio was not considered significant.
The patient (case 4) was also seen by the physician for the first time. He was earlier being treated by another doctor. He presented as oral anti-diabetes drug failure. He had maximized on the dose of sulphonylureas, SGLT2 inhibitor, and DPP-4 inhibitor, and yet did not achieve the target glycemic control. The 21-day glycemic control as measured by fructosamine also reflected oral anti-diabetes drug failure. Balanoposthitis was caused by empagliflozin. Hence the regimen was changed. Insulin was added. Empagliflozin/linagliptin was replaced with semaglutide and lower dose of sulphonylurea. After 2 months, the FBS and PPBS were under control and fructosamine also reduced. The dose of insulin was reduced from 14 U to 10 U. The dose of sulphonylureas was further reduced to 2 mg. In patients with multiple oral anti-diabetes drug failure, insulin is required. In addition, if the patient is obese then a GLP-1 receptor agonist with good efficacy for weight loss or SGLT2 inhibitor is warranted. Before switching to the current regime, there was no change in the dose of medications prescribed during the previous 6 months.
In the case of the fifth patient (case 5), there was no change in the dose and the medications had no confounding effect on weight loss and glycemic control.
In the sixth patient (case 6), although the FBS was above target, the nighttime IdegAsp was stopped because the patient’s target FBS and PPBS was set at 130 mg/dL and 180 mg/d. The patient showed significant improvement in FBS and PPBS and was near target glycemic control along with weight loss. As the patient was leading a sedentary life, he was advised on lifestyle changes (increasing physical activity [45 min brisk walking daily]).
The patient (case 7) presented with oral anti-diabetes drug failure. She was on maximum doses of DPP4 inhibitor, SGLT2 inhibitor, sulphonylureas, and thiazolidinediones yet her HbA1c was very high at 9. She was refused to take insulin injection. Despite counseling for insulin, she did not want to injections. Hence, DPP4 inhibitor (vildagliptin) was replaced with semaglutide. After 2 months, her HbA1c reduced significantly to 7.5%. Trigger finger, one of the complications of diabetes abated with better glycemic control.
We reported a series of cases where semaglutide, a novel oral GLP-1A receptor agonist was initiated. In all cases, the duration of treatment was very short (ranging from 45 to 60 days). Although, the glycemic response and weight loss was satisfactory on a case-to-case basis, the overall impact of semaglutide cannot be quantified. This paper fails to provide the long-term treatment and efficacy of semaglutide. Keeping in view the cost of oral semaglutide, there is a need for cost-benefit analysis to justify the use of semaglutide. The outcome of this case series must be interpreted with caution. Moreover, the confounding effects of other medications on glycemic control and weight loss needs to be established. Large-scale data on the efficacy and safety of oral semaglutide in Indian patients is warranted.
| Conclusion|| |
We present a series of case reports where all patients received semaglutide, an oral GLP-1 receptor agonist. The objective of initiating semaglutide was to bring the HbA1c below target and, at the same time, promote weight loss. Semaglutide was one of the suitable options for our patients with cardiovascular disease, cardiovascular risk factors, and chronic renal disease. Large-scale randomized trial in Indian patients is warranted to confirm our findings.
All named authors meet the International Committee of Medical Journal Editors (ICMJE) criteria for authorship for this manuscript, take responsibility for the integrity of the work, and have given final approval for the version to be published. Medical writing and editorial assistance were provided by Dr. Punit Srivastava of Mediception Science Pvt Ltd agency (www.mediception.com) and financially funded by Novo Nordisk. The authors take full responsibility for the content and conclusions stated in this manuscript. Novo Nordisk neither influenced the content of this publication nor was it involved in the study design, data collection, analysis, interpretation, or review.
Financial support and sponsorship
Medical writing and editorial assistance were provided by Dr. Punit Srivastava of Mediception Science Pvt Ltd agency (www.mediception.com) and financially funded by Novo Nordisk.
Conflicts of interest
There are no conflicts of interest.
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[Table 1], [Table 2]