A New Class of Drugs that Lowers HbA1C and Promotes Weight Loss in Type 2 Diabetes

Abstract & Commentary

Synopsis: Exenatide (Extendin-4) significantly lowered HbA1C and caused weight loss in type 2 diabetes patients.

Source: Buse JB, et al. Diabetes Care. 2004;27:2628-2635.

Exenatide is an incretin mimetic. Incretins are gut peptide hormones which are activated by nutrient ingestion. Some peptide hormones, in particular glucagon-like peptide (GLP-1) have been noted to play a role in beta cell health. GLP-1 acts via GLP-1 receptors on beta cells to enhance proinsulin gene transcription and replenishes beta cell insulin stores.1

The objective of this study was to evaluate the ability of exenatide to improve glycemic control in patients with type 2 diabetes failing maximally effective doses of a sulfonylurea as monotherapy.

This was a blinded, placebo controlled, 30-week study. After a 4-week, single blind, placebo lead in period, 377 subjects were randomized (60% men, age 55 ± 11 years; BMI, mean of 33 kg/m2; HbA1C, 8.6). At 4 weeks they were begun on 5 mcg subcutaneous exenatide twice daily (before breakfast and dinner; arms A + B) or placebo. Subsequently subjects in arm B were escalated to 10 mcg b.i.d. exenatide. All subjects continued sulfonylurea therapy.

At week 30, mean HbA1C changes from baseline were -0.86, -.46, and 0.12 for the 10 mcg, 5 mcg and placebo arms.

Of subjects with baseline HbA1C greater than 7% (n = 237) 41% (10 mcg), 33% (5 mcg), and 9% (placebo) achieved HbA1C less than 7%. Fasting plasma glucose concentrations decreased in the 10 mcg arm compared with placebo. Subjects in the exenatide arms had a dose-dependent progressive weight loss with an end of study loss in the 10 mcg arm of -1.6 kg. from baseline. The most frequent adverse events were generally mild or moderate and gastrointestinal in nature. No severe hypoglycemia was observed.

Buse and colleagues concluded that exenatide significantly reduced HbA1C in patients with type 2 diabetes failing maximal doses of a sulfonylurea. It was generally well tolerated and associated with weight loss.4

Comment by Ralph R. Hall, MD, FACP

One of the important aspects of this study was a favorable decrease in the proinsulin to insulin ratio toward more physiological proportions. This is consistent with the findings that exenatide may favorably effect beta cell regeneration.

Xu et al achieved enhanced replication and neogenesis of beta cells in rats using extendin-4.2 Bonner-Weir noted in a presentation that Xu found that in partially pancreatectomized rats, after removal of 90% of the pancreas, extendin-4 ameliorated hyperglycemia. A 40% increase in beta cell mass was observed as well as increased replication and neogensis.3

DeFronzo et al, in a study similar to that of Busse et al, using patients who were on metformin and given exenatide found similar improvements in HbA1C and weight loss.4

Nausea occurred in a number of patients early in these studies but decreased with time and was not associated with a large number of patient withdrawals from the study. Nausea did not appear to be the reason for weight loss since patients who did not experience nausea experienced similar weight loss.

The exenatide glucose lowering effect appears to be attributed to an effect on daytime postprandial glycemia because the glucose lowering effect on fasting plasma glucose was modest compared to the reduction in HbA1C.

Incretin hormones enhance insulin secretion, reduce glucagon secretion, inhibit gastric emptying, and improve satiety. They also appear to stimulate beta cell replication and neogenesis resulting in increasing beta cell mass.

Incretin memetic hormones such as exenatide are promising additions to our current treatment of type 2 diabetes.

Dr. Hall, Emeritus Professor of Medicine University of Missouri- Kansas City School of Medicine, is Associate Editor of Internal Medicine Alert.

References

1. Stoffers DA, et al. Diabetes. 2000;49:741-748.

2. Xu G, et al. Diabetes. 1999;48:2270-2276.

3. Bonner-Weir S. (Symposium): Resurrecting Beta Cell Function, Amer Assoc Clin Endo 13th Annual Meeting 2004.

4. DeFronzo R, et al. (Abstract) American Diabetes Assoc. 64th Annual session, 2004 (6-LB, late breaking abstracts).