Conference Coverage

Exenatide Bests Glimepiride as a Metformin Add-On

Publish date: June 11, 2012
By
Miriam E. Tucker

View on the News

Drug Has Lower Risk of Hypoglycemia

The stepwise approach to the management of type 2 diabetes starts with lifestyle interventions with the addition of one or more antidiabetic drugs. Most clinical guidelines indicate that metformin should be the first-line drug, but no consensus exists about additional use of other glucose-lowering drugs or insulin when glucose control deteriorates over time, wrote Dr. Sten Madsbad in an accompanying editorial.

Therefore, physicians typically chose the second drug based on factors such as effectiveness in HbA1c reduction, safety, cost, and patient-specific factors such as effect on weight and tolerability.

With a follow-up of 3 years, the current study is so far the longest randomized trial to compare a GLP-1 receptor agonist with a commonly used treatment in type 2 diabetes. Overall, it indicates that exenatide twice daily is more effective than glimepiride in terms of several clinical parameters related to treatment of patients with type 2 diabetes.

Strengths of the study are the long-term follow-up and the comparison between the frequently used glimepiride and a GLP-1 receptor agonist. Physicians are divided in their opinions about the safety and effectiveness of sulphonylureas, which potentiate insulin secretion and lead to a rapid improvement in glycemic control, but result in faster deterioration of glycemic control than do metformin or a glitazone. The adverse effects of sulphonylureas are predictable, with most patients gaining weight, and risk of hypoglycemia is higher than with metformin. Studies linking sulphonylureas with cardiovascular adverse effects are based on databases rather than on randomized trials.

As a drug class, GLP-1 receptor agonists improve glycemia by stimulating insulin secretion and the inhibition of glucagon release, but only when glucose concentrations are raised, thus conferring a lower risk of hypoglycemia than that noted with sulphonylureas. Moreover, exenatide twice daily reduces postprandial glucose excursions, and the GLP-1 receptor agonist class of agents induce weight loss in most patients; however, they are associated with gastrointestinal side effects and have been linked to pancreatitis, although those data conflict.

Analyses of phase II and phase III trials with exenatide twice daily vs. placebo or insulin showed no evidence of cardiovascular harm with exenatide, and some data suggest they may be associated with a reduction in cardiovascular events. The Food and Drug Administration now requires the assessment of cardiovascular risks of new glucose-lowering drugs both before and after approval, and results of cardiovascular outcome studies for the different GLP-1 receptor agonists are expected after 2015.

Dr. Madsbad is with the department of endocrinology at the University of Copenhagen and its Hvidovre University Hospital. Dr. Madsbad has been a consultant for, adviser to, and/or speaker for Novartis Pharma, Novo Nordisk, Merck Sharp & Dohme, Sanofi-Aventis, AstraZeneca, Johnson & Johnson, Roche, Mannkind, Boehringer-Ingelheim, Zeeland, Lilly, Intarcia Therapeutics, Schering-Plough, and Bristol-Myers Squibb.


 

FROM THE ANNUAL SCIENTIFIC SESSIONS OF THE AMERICAN DIABETES ASSOCIATION

PHILADELPHIA – Exenatide twice daily prevented glycemic deterioration better than did glimepiride in type 2 diabetes patients who had metformin failure in an open label, randomized, controlled trial.

Common practice for patients with type 2 diabetes who are inadequately controlled by metformin has been to add a sulphonylurea to the treatment regimen. Although these agents have a rapid short-term effect and are low cost, they are associated with hypoglycemia and worsening glycemic control over time. Glucagonlike peptide–1 (GLP-1) receptor agonists, on the other hand, improve glycemic control with no increased risk of hypoglycemia, and are associated with weight loss and improvements in cardiovascular risk factors and can be used as alternative add-ons to metformin treatment, said Dr. Guntram Schernthaner at the annual scientific sessions of the American Diabetes Association.

"Up to now, EUREXA is the longest study undertaken with a GLP-1 receptor agonist, and could contribute substantially to decisions in clinical practice," said Dr. Schernthaner of Rudolfstiftung Hospital in Vienna.

In this open-label, randomized, controlled European trial, 1,029 patients from 128 centers in 14 countries were randomized to exenatide twice daily (starting at 5 mcg twice daily for 4 weeks, followed by 10 mcg twice daily for the remaining study period) or glimepiride per physician dosing practice. The intention-to-treat population comprised 490 patients in the exenatide group and 487 in the glimepiride group.

The study was simultaneously published in the Lancet (2012 June 9 [doi:10.1016/S0140-6736[12]60479-6]).

Patients were taking a median metformin dose of 2,000 mg/day. The mean exenatide dose was 17.4 mcg/day and the mean glimepiride dose was 2.0 mg/day. Average treatment time was about 2 years in both groups. Mean baseline hemoglobin A1c was 7.5% in the exenatide group and 7.4% in those randomized to glimepiride.

The primary outcome was time to inadequate glycemic control (defined as an HbA1c level greater than 9% after the first 3 months of treatment, or greater than 7% at two consecutive visits 3 months apart after the first 6 months). That end point was reached by 203 (41%) patients in the exenatide group, compared with 262 (54%) in the glimepiride group, a significant difference. These included 5 in the exenatide group and 7 in the glimepiride group who had an HbA1c of more than 9%, and 198 vs. 255 with HbA1c levels greater than 7% at two visits. The hazard ratio for inadequate glycemic control with exenatide, compared with glimepiride, was 0.75.

Median time to inadequate HbA1c control was 180 weeks with exenatide vs. 142 weeks with glimepiride. The risk of treatment failure was greater with higher baseline HbA1c, as was the reduction in risk with exenatide compared with glimepiride, Dr. Schernthaner reported.

Compared with those in the glimepiride group, significantly more patients in the exenatide group achieved HbA1c values lower than 7% (31% vs. 45%, respectively) and 6.5% or less (18% vs. 29%). Fasting glucose levels were also significantly lower in the exenatide group after year 1, year 2, and year 3 of treatment. There was an overall treatment effect in favor of the exenatide group, with significant differences between groups in mean HbA1c levels at years 2 and 3. Self-monitored postmeal excursions of blood glucose after meals were significantly lower in the exenatide group than in the glimepiride group.

Five patients in each treatment group died, but all deaths were from causes regarded as unrelated to the study treatment. Significantly more patients discontinued in the exenatide group than in the glimepiride group because of adverse events (49 vs. 17). However, discontinuations due to adverse events mostly gastrointestinal were significantly different between treatments only in the first 6 months of study, Dr. Schernthaner said.

Systolic blood pressure decreased in patients in the exenatide group but not in the glimepiride group, resulting in a significant, 3.1-mm Hg difference between groups from year 1 to year 3. Body weight fell from baseline to end point in the exenatide group by 3.32 kg, while it rose by 1.15 kg in the glimepiride group, also a significant difference.

The proportion of patients reporting hypoglycemia was lower in patients in the exenatide group than in those in the glimepiride group. For hypoglycemia of any type during the study, the estimated mean rate was 1.52 episodes per year in the exenatide group, compared with 5.32 episodes per year in the glimepiride group, he reported.

EUREXA was funded by Eli Lilly and Amylin Pharmaceuticals. Dr. Schernthaner disclosed that he has been a consultant for and received honoraria from Amgen, AstraZeneca, Bristol-Myers Squibb, Boehringer-Ingelheim, Eli Lilly, Merck, Novartis, Poxel, Roche, Sanofi-Aventis, Novo Nordisk, Servier, and Takeda. Dr. Madsbad has been a consultant for, adviser to, and/or speaker for Novartis Pharma, Novo Nordisk, Merck Sharp & Dohme, Sanofi-Aventis, AstraZeneca, Johnson & Johnson, Roche, Mannkind, Boehringer-Ingelheim, Zeeland, Lilly, Intarcia Therapeutics, Schering-Plough, and Bristol-Myers Squibb.

Next Article:

Gastric Bypass Induces Diabetes Remission in Mildly Obese