Exanatide: The New Shot for Diabetes
Exanatide: The New Shot for Diabetes
Abstract & Commentary
By Eileen C. West, MD, Director of Primary Care Women's Health, Clinical Assistant Professor of Internal Medicine; University of Oklahoma School of Medicine, Oklahoma City. Dr. West reports no financial relationships to this field of study.
Synopsis: A new injectable diabetes medication in the family of incretin mimetic drugs has been shown to be as effective as insulin in controlling average blood sugars in Type 2 diabetics who are difficult to control on oral medications, without as much associated weight gain.
Source: Heine RJ, et al. Exenatide versus insulin glargine in patients with suboptimally controlled type 2 diabetes: a randomized trial. Ann Intern Med. 2005;143:559-569.
Incretins, or so-called gut hormones, are produced in the gastrointestinal tract in response to eating and help to maintain healthy blood sugar levels. Two novel classes of investigational therapiesthe incretin mimetics and incretin enhancersrepresent a new wave of diabetes research. They aim to improve high blood sugar associated with meals, which is often the cause for inability to achieve desired glucose control. Their arrival on the market has been much anticipated. In April 2005 exanatide (Byetta) became the first incretin mimetic to receive FDA approval. It is an injectable drug which mimics the effects of glucagonlike peptide 1 (GLP-1), an incretin hormone. The actions of GLP-1 include enhancement of glucose-dependent insulin secretion and regulation of glucagon release and the rate of gastric emptying which helps to lower high blood sugar.1 It also enhances β-cell function and promotes satiety, leading to reduced calorie intake and weight loss. Unfortunately, GLP-1, when administered, has a circulating half-life of only 1 to 2 minutes. Agents that mimic or enhance the activities of GLP-1 and are not broken down so quickly are of great interest.
A recent advance in insulin therapy has been the introduction of insulin glargine (Lantus), an analogue of human insulin which is designed for once daily dosing. Insulin glargine is more convenient and is associated with fewer hypoglycemic episodes than NPH insulin, but requires titration, causes weight gain, and does not address postprandial glucose elevation.2
A recent paper by Heine and colleagues3 explores the use of exanatide in patients with type 2 diabetes who are not optimally controlled on oral medications. It compares the effects of exanatide and insulin glargine on glycemic control in patients who are already taking combination metformin and sulfonylurea therapy. In their open-label Phase III clinical trial, 551 patients from 13 countries were given exanatide, 10 µ twice daily subcutaneously or insulin glargine 1 daily dose titrated to keep fasting blood glucose levels below 5.6 mmoL/L (< 100 mg/dL). HbA1c levels were measured at baseline, 12 weeks, and 26 weeks. Patients monitored their own blood sugars several times per day. The typical patient in the study was in his or her late fifties, Caucasian or Hispanic, had been diabetic for 10 years, weighed 88 kg, and had an HbA1c of 8.2% at the start of the study.
After 26 weeks of using exanatide or glargine, both groups of patients reduced HbA1c levels by 1.11% to an average of 7.1%. Exanatide lowered postprandial glucose more effectively while insulin glargine lowered fasting blood glucose more effectively. Of particular interest is that body weight decreased 2.3 kg in the exanatide group but increased 1.8 kg in the insulin group. Episodes of low blood sugar were comparable, but nighttime hypoglycemia was less common with exanatide. The biggest side effects were gastrointestinal and were much more common with exanatide than insulin glargine. They included nausea (57.1% of patients vs 8.6%), vomiting (17.4% vs 3.7%) and diarrhea (8.5% vs 3.0%). These side effects caused 19.4% of patients in the exanatide arm to drop out of the study.
Commentary
We have a growing range of medications which act in different ways to control high blood sugar in type 2 diabetes. Exanatide appears to be a promising new alternative to daily insulin glargine injection when target blood sugars are not reached with oral medications. It mimics the effects of the gut hormone GLP-1. Based on the above study, it appears to be as effective as insulin glargine in lowering average blood sugar levels. It is the only medication besides metformin which is not associated with weight gain in type 2 diabetics, and appears, in fact, to promote weight loss. It is associated with fewer nocturnal hypoglycemia episodes than insulin glargine. The twice daily injections may be inconvenient for some patients, and the prevalence of GI side effects may limit its usefulness. The study described above is a Phase 3 clinical trial, and more data is forthcoming to understand how useful the new medication will be. Like many Phase 3 trials, it was sponsored by the makers of the new drug. The patients were randomly assigned to one of the medication arms, but were aware of which drug they were taking. This can lead to bias in reporting results and side effects.
Until now, diabetes research has targeted insulin resistance, but we are beginning to understand the importance of pancreatic islet cell health. It is hoped that new information about incretin hormones will lead to improved insulin secretion by the beta-cells and glucagon secretion by the alpha-cells. There are several drugs currently under development in the family of incretin mimetics and incretin enhancers. The mimetics mimic the effects of glucagon-like peptide 1, and the enhancers are oral agents that increase the amount of incretin hormones produced by the body. Novel treatments are on the horizon and their future looks bright.
References
1. Drucker, DJ. Enhancing incretin action for the treatment of type 2 diabetes. Diabetes Care. 2003;26: 2929-2940.
2. Janka HU, et al. Comparison of basal insulin added to oral agents versus twice-daily premixed insulin as initial insulin therapy for type 2 diabetes. Diabetes Care. 2005;28:254-259.
3. Heine, LF et al. Exanatide versus Insulin Glargine in Patients with Suboptimally Controlled Type 2 Diabetes. A Randomized Trial. Ann Intern Med. 2005;143: 559-569.
A new injectable diabetes medication in the family of incretin mimetic drugs has been shown to be as effective as insulin in controlling average blood sugars in Type 2 diabetics who are difficult to control on oral medications, without as much associated weight gain.Subscribe Now for Access
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