Clinical experience with exenatide in obese North Indian patients with type 2 diabetes mellitus

Abstract

Objective:

To share our clinical experience with exenatide in obese North Indian subjects with type 2 diabetes.

Materials and Methods:

We share our experience with use of exenatide in 74 patients treated at Indraprastha Apollo Hospital, a tertiary care centre in New Delhi, India Subjects included obese / overweight subjects (mean weight and BMI; 97.67 ± 5.6 kg and 34.56 kg/m²) with known history of type 2 DM (Mean: 9 ± 5.6 years) and maintaining suboptimal glycemic control (HbA1c >7%) on oral antidiabetic agents, with or without basal insulin. Metformin and sulphonylureas were continued (with dose adjustment if indicated), as was basal insulin (glargine / detemir). TZDs and DPP4 inhibitors were discontinued. The dose of exenatide was increased to 10 mcg twice a day after 4-12 weeks. 56 patients completed minimum 3 month therapy. 42 patients completed 6 months, 32, 9 months and 25 completed 12 months. Data of patients who had completed at-least 3 months of therapy was included for analysis.

Results and Discussion:

69.77, 67.44, and 13.95% of the patients were receiving metformin, secretagogues or thiazolidinediones alone or in combination; 17.76% of the patients were on basal insulin. The change in fasting and post-prandial blood glucose levels were significant at 3, 6, 9 and 12 months with p-value <0.05. The mean weight loss at one, three, and six months and one year was 1.7 ± 1.3, 3.8 ± 2.5, 6.3 ± 3.4, and 8.3 ± 4.3 kg, respectively (P <0.05). The mean HbA1c (baseline: 8.8 ± 1.3%) at 3, 6 months and at one year was 7.8 ± 0.9, 7.7 ± 0.8 and 7.2 ± 0.8 (P <0.05). Thirty-five percent of the patients had a ‘good’ A1c value (< 7%) at the end of 12 months. 13 patients discontinued exenatide (three due to lack of response, six due to cost of therapy and four due to severe nausea). Nausea was the most common side effect, occurring in 95% patients within 1 month, although the incidence declined with passage of time.

Conclusions:

Clinical use of Exenatide is associated with significant improvement in glycemic control and major weight loss (8.3±4.3 kg at 1 year) in obese subjects with type 2 diabetes. Nausea is the most common side effect. In conclusion, exenatide is a effective and useful option for treatment of type 2 diabetes in obese Indian subjects.

INTRODUCTION

The pathogenesis of type 2 diabetes mellitus (T2DM) has traditionally been thought to involve two principal defects, that is, insulin resistance and insulin deficiency, due to pancreatic beta cell dysfunction.[1] However, in addition to these two defects, the role of pancreatic alpha cells and hyperglucagonemia in the genesis of hyperglycemia, in type 2 diabetes, has received increased attention recently. Thus, the concept of islet (beta and alpha) cell dysfunction, comprising insulin deficiency and glucagon excess (rather than just beta cell dysfunction) has gained ground. Traditional therapies for diabetes (besides insulin itself) have focused on stimulating beta cells directly or ameliorating insulin resistance.

The recently introduced incretin-based therapies serve to address these very important pathways in T2DM. Incretin-based therapies include DPP-IV inhibitors (sitagliptin, vildagliptin, saxagliptin, and alogliptin) and GLP-1 analogs (Exenatide and liraglutide).[2] This group of drugs has been shown to improve beta cell function (stimulate insulin secretion), prevent beta cell loss and reduce glucagon secretion.[3] In addition to these anti-hyperglycemic effects GLP 1 analogs also reduce appetite, thereby promoting weight loss, which in itself is a major co-morbidity associated with T2DM. Exenatide is the first GLP-1 receptor agonist approved and commercially marketed as a therapeutic agent in inadequately controlled T2DM subjects.[4] Data from randomized controlled trials have clearly proven the safety and efficacy (blood glucose control and weight loss) of Exenatide in patients with T2DM.[5] However, there is very limited data on the use of Exenatide in Asian Indian subjects with T2DM.[6] We report for the first time the beneficial effects on glycemic control and the weight loss effects of Exenatide, when used as an add-on therapy in adult obese Asian Indian subjects with T2DM, in a tertiary care setting in North India.

MATERIALS AND METHODS

Study design

The current investigation was an open-label, non-randomized, retrospective study carried out at the Indraprastha Apollo Hospital, a tertiary care center in North India, between October 2007 and October 2008.

Patients

Available medical records of the patients who had poor glycemic control on oral anti-diabetic medications (OAD) including metformin, sulfonylurea, thiazolidinediones, or basal insulin, in various combinations, and were prescribed exenatide for glycemic control as a part of standard of care at the center, were included in the study. Patients with chronic kidney or liver disease or history of pancreatitis were not started on Exenatide. All patients gave an informed consent for data use in the study. We have analyzed data for patients, who were able to complete at least three months of therapy (n = 56).

Medications

All patients in the current investigation were prescribed Exenatide using a multi-dose disposable pen (Byetta^®, 250 μg/ml, Eli Lily Co).[7] The drug was started at a dose of 5 μg given subcutaneously twice a day, within 60 minutes of breakfast and dinner. If tolerated well, the drug dose was increased to 10 μg twice a day. DPP-IV inhibitors were discontinued when the patients were started on Exenatide. The dose of OAD's was kept constant, unless the patient had hypoglycemia episodes, in which case the sulfonylurea dose was reduced.

Anthropometric and biochemical analysis

Weight was assessed using standard methods and equipments. Weight was assessed first at one month, and thereafter, every three months, for one year. Fasting and postprandialblood glucose levels were estimated after the patient had fasted for eight to ten hours. The blood glucose was analyzed using an autoanalyzer. Glycosylated hemoglobin (HbA1c) was analyzed using the high performance liquid chromatographic method.

Endpoint assessment

The efficacy of the drug was assessed by seeing documented changes in the HbA1c and body weight change from baseline. The glycemic endpoint was considered good if values of HbA1c fell below 7% at 12 months. The glycemic endpoint was also evaluated by fasting and postprandialblood glucose values.

Safety

At each visit patients were questioned about the occurrence of hypoglycemia, either by the presence of symptoms or on self-monitoring of blood glucose, using a glucometer. Hypoglycemia was defined as severe if the event required assistance of another person to actively administer carbohydrate, glucagon, or other resuscitative actions. Plasma glucose measurements may not have been available during such an event, but neurological recovery attributable to the restoration of plasma glucose to normal is considered sufficient evidence that the event was induced by a low blood glucose concentration.[8] At each visit patients were asked about specific symptoms such as pain in abdomen, nausea, and vomiting. Serum amylase and lipase were assessed in those with a clinical suspicion of pancreatitis. The study was approved by the independent institutional ethical review board.

Data analysis

Data have been presented as mean ± standard deviation, a p value was considered significant if it was < 0.05. Standard descriptive analysis and students t-test were used for analysis. The Stata/SE version 9 for windows was used for the analysis.

RESULTS

In the period between 2007 and 2008, a total of 74 patients were initiated on Exenatide. Complete baseline data was available for a total of 56 patients and complete data was available for 25 patients at one year; 69.77, 67.44, and 13.95% of the patients were receiving metformin, secretagogues or thiazolidinediones alone or in combination; 17.76% of the patients were on basal insulin for glycemic control. Exenatide was discontinued in three patients due to lack of response (glycemic or weight loss) and six patients discontinued it due to cost factor. At the time of analysis, 56 patients had completed the minimum three-month therapy, 42 patients had completed six months, 32 had completed nine months, and 25 had completed 12 months.

The mean initial weight was 97.7 ± 5.6 kg and the mean BMI was 34.56 kg/m². The median duration of diabetes was 9 ± 5.6 years. For evaluating the effect of the duration of diabetes on the glycemic efficacy of Exenatide, we divided the patients into two categories based on the number of years after diagnosis of diabetes, < 10 years (71%) and > 10 years (29%). Exenatide was effective irrespective of the duration of diabetes.

The benefits on glycemic and weight reduction effects of Exenatide are depicted in Table 1. The mean weight loss at one, three, and six months and one year were 1.7 ± 1.3, 3.8 ± 2.5, 6.3 ± 3.4, and 8.3±4.3 kg, respectively. All these values were statistically significant (P value < 0.05) when compared to the values at baseline. Thirty-five percent of the patients had a ‘good’ A1c value (< 7%) at the end of 12 months.

Table 1.

Comparison of glycemic control and weight loss over a period of one year

Nausea was the most common side effect reported in 95% of our patients and was severe enough for us to stop the treatment in only six patients. None of the patients had clinical or laboratory evidence of acute pancreatitis.

DISCUSSION

Incretins, such as GLP-1, enhance glucose-dependent insulin secretion, and exhibit other glucose lowering actions following their release into the circulation from the gut. Exenatide is a GLP-1 receptor agonist that enhances glucose-dependent insulin secretion by the pancreatic beta-cell. It suppresses inappropriately elevated glucagon secretion and slows gastric emptying. The amino acid sequence of Exenatide partially overlaps that of human GLP-1. Exenatide has been shown to bind and activate the human GLP-1 receptor in vitro. This leads to an increase in both glucose-dependent synthesis of insulin, and secretion of insulin from pancreatic beta cells. Exenatide promotes insulin release from pancreatic beta cells only in the presence of elevated glucose concentrations. The glucose-dependent insulin secreting effect of Exenatide releases insulin predominantly in the presence of elevated blood glucose levels. This insulin secretion subsides as blood glucose concentrations decrease and approach euglycemic levels. Finally, Exenatide does not impair the normal glucagon response to hypoglycemia.

In the present study we report the beneficial effects (weight reduction and glycemic control) of the addition of a GLP-1 analog (Exenatide) in obese, poorly controlled, T2DM patients in a tertiary care hospital in north India. The ongoing therapy for diabetes was kept unchanged (secretagogues, Metformin, and basal insulin) except in those patients who were on thiazolidinediones or DPP-IV inhibitors, where these drugs were withdrawn. The results of our study indicate a significant improvement in the indices of glycemic control (fasting/postprandial blood glucose and HbA1c) and weight reduction in the study population. Not only were these effects significant, but they were also sustained for over a period of up to one year. The weight reduction and glycemic improvement were maximal in the first three months of therapy, but were sustained for a period of one year. Our results are in tune with the results of several randomized controlled trials of Exenatide, which have reported beneficial effects of GLP-1 analogs when used in combination with oral agents and/or basal insulin.[5] Clinical data indicate that glycemic control and complications of diabetes correlate not only with fasting flood glucose, but are also largely contributed to by postprandial blood glucose levels.[9] The results of our study also confirm the overall effectiveness of Exenatide in glycemic control, with equitable reduction in fasting and postprandial blood glucose levels and HbA1c (35% of the patients achieved an HbA1c of < 7%). This unique characteristic of Exenatide may in the long term culminate into better glycemic control and greater future cardiovascular risk reduction, as compared to other therapies for diabetes. However, more and longer studies are needed to prove this hypothesis.

Weight loss is an important part of therapy for T2DM, as almost all (80−90%) T2DM patients are obese or overweight. Clinical trials have demonstrated the major benefits of modest weight reduction (5−10%) on both glycemic control and future cardiovascular disease risk.[10] Meta-analyses have demonstrated that glinides, sulfonylureas, and thiazolidinediones are associated with weight gain ranging from 1.77 kg to 2.08 kg, when compared with the placebo.[11] Potential increases in body weight due to these anti-diabetic drugs may negatively influence patient health by increasing the risk of cardiovascular disease and should be a consideration when selecting drug therapy. Glinides and sulfonylureas likely promote weight gain by increasing insulin secretion. Thiazolidinediones probably promote weight gain by increasing fluid retention. Compared with sulfonylureas and thiazolidinediones, GLP-1 analogs are associated with an approximately 4 kg difference in weight, which in some patients may be close to the clinically relevant weight reduction value of 5%, typically associated with decreased insulin resistance and improvements in serum lipids and blood pressure.[12] Similar to this data weight reduction in our study has been significant and sustained over a period of 12 months. Glucagon-like peptide-1 analogs may promote weight loss by increasing satiety and prolonging gastric emptying time.[13]

As compared to randomized controlled trials where the study subjects’ characteristics were homogenous, the present study provides evidence of the safety and efficacy (glycemic control and weight reduction) of Exenatide when used in a heterogeneous population, in a ‘real- world′ setting. GLP-1 analogs have a definite role to play in the management of diabetes, the American Diabetes Association (ADA)/International Diabetes Federation (IDF) have endorsed this in the latest position statements, wherein GLP-1 has been placed as an early therapeutic option for management of T2DM.[14] The other aspect for the use of GLP-1 in the Indian scenarios is strengthened by the increasing prevalence of obesity and overweight in the diabetic population. GLP-1 analogs are the only drugs presently available that address these important issues. The factors for using GLP-1 (Exenatide) include, cost of therapy, side effects, and injectable therapy (twice a day). Reduced frequency of injections (once a day / once a week) and lesser side effects are being addressed in the newer GLP 1–based therapies.