Injectable Diabetes Drug May Improve Poor Glycemic Control in Uncontrolled Diabetes

Laurie Barclay, MD

December 29, 2010

December 29, 2010 — Adding the twice-daily injectable drug exenatide to the treatment regimen improves poor glycemic control in patients with uncontrolled diabetes, according to the results of a parallel, randomized, placebo-controlled trial reported online December 6 in the Annals of Internal Medicine.

"The study adds to the rationale of using insulin in combination with a GLP-1 [glucagon-like peptide] analogue in type 2 patients — it is not surprising that efficacy is greater, given that their actions to lower glucose are highly complementary," Michael Horowitz, MBBS, PhD, FRACP, professor of medicine at the University of Adelaide and director of the Endocrine and Metabolic Unit at the Royal Adelaide Hospital in Australia, told Medscape Medical News when asked for independent comment. "The critical issue is what should be used first, but if fiscal issues are ignored, a case could be made for the GLP-1 analogue to be used before insulin, particularly in older type 2 patients who are already taking metformin, given that there is no real risk of hypoglycemia. The high prevalence of gastrointestinal adverse effects is a concern, which may potentially be less of an issue with other compounds."

The goal of this study, by John B. Buse, MD, PhD, from the University of North Carolina School of Medicine at Chapel Hill, and colleagues, was to determine whether twice-daily exenatide injections would reduce hemoglobin A1c (HbA1c) levels to a greater extent than placebo in persons receiving insulin glargine. Inclusion criteria were adults with type 2 diabetes and an HbA1c level of 7.1% to 10.5% who were receiving insulin glargine alone or combined with metformin, pioglitazone, or both.

This trial took place from October 2008 to January 2010 at 59 centers in 5 countries and was blocked and stratified by HbA1c level at site, with participants, investigators, and study personnel blinded to treatment allocation. By use of a central, computer-generated, random-sequence interactive voice response system, participants were randomly assigned to receive exenatide, 10 μg twice daily, or placebo for 30 weeks.

The main study endpoint was change in HbA1c level, and secondary endpoints were the percentage of participants with HbA1c values of 7.0% or less and 6.5% or less, 7-point self-monitored glucose profiles, body weight, waist circumference, insulin dose, hypoglycemia, and adverse events.

"This study has assessed whether the use of the GLP1-1 analogue, exenatide, has the capacity to improve glycemic control in type 2 patients who have failed to achieve acceptable glycated hemoglobin levels despite the use of glargine insulin," Dr. Horowitz said. "This is an important issue given the increasing number of type 2 patients who require insulin with its concomitant complications of hypoglycemia and weight gain."

The study was completed by 112 of 138 participants randomly assigned to exenatide and by 101 of 123 randomly assigned to placebo. In the exenatide group, the HbA1c level decreased by 1.74% vs 1.04% in the placebo group (between-group difference, −0.69%; 95% confidence interval [CI], −0.93% to −0.46%; P < .001). Weight change was a 1.8-kg loss in the exenatide group and a 1.0-kg gain in the placebo group (between-group difference, −2.7 kg; 95% CI, −3.7 to −1.7). Average increases in insulin dosage were 13 U/day with exenatide and 20 U/day with placebo. Both groups had similar estimated rates of minor hypoglycemia.

"The outcome of the study indicates that the addition of exenatide to glargine results in a meaningful reduction in glycated hemoglobin of 0.69% which is attributable to a decrease in postprandial glucose excursions, rather than a reduction in preprandial glucose," Dr. Horowitz said. "The latter is to be expected given that exenatide has been shown to slow the rate of gastric emptying.... As has been reported in other studies using GLP-1 analogues, blood pressure decreased modestly."

Adverse events led to study discontinuation by 13 participants in the exenatide group and by 1 in the placebo group (P < .01). Compared with the placebo group, the exenatide group had higher rates of nausea (41% vs 8%), diarrhea (18% vs 8%), vomiting (18% vs 4%), headache (14% vs 4%), and constipation (10% vs 2%).

"Limitations of the study are its multicenter nature — 55 sites in 5 countries were required to recruit 261 subjects," Dr. Horowitz said. "Follow-up was for 30 weeks, which is reasonable, but not ideal. Importantly, there was a very high prevalence of gastrointestinal adverse effects in the exenatide group, despite initial titration of the dose, so that 18% withdrew from the study for this reason."

Other study limitations acknowledged by the investigators were slight imbalances between groups at baseline in terms of sex, use of concomitant glucose-lowering medications, and HbA1c value.

"The high prevalence of adverse effects, e.g. 41% of exenatide patients reported nausea, compared to 8% of those on placebo, may have also potentially compromised the blinding of the study," Dr. Horowitz explained. "Patients with a propensity for hypoglycemia were excluded from participating in this study, but there seems little reason to suspect that exenatide would increase this risk given that the stimulation of insulin and suppression of glucagon are known to be glucose-dependent."

"The outcomes of the study require confirmation with longer periods of
 observation and particular focus on the issue of hypoglycemia," Dr. Horowitz concluded. "There was substantial heterogeneity in the response, and it would be of interest to investigate potential mechanisms for this. For example, I suspect that the effect of exenatide to lower postprandial glucose will be greater in those patients in whom the rate of gastric emptying is relatively faster, and that in patients with gastroparesis (which occurs in up to 50% of patients with longstanding diabetes) glucose lowering will occur primarily as a result of the suppression of glucagon and stimulation of insulin."

Alliance of Eli Lilly and Co and Amylin Pharmaceuticals funded this study and employs some of the authors. The financial disclosures of the study authors can be viewed online at the Annals of Internal Medicine Web site . In the last 18 months, Dr. Horowitz has acted as a consultant and/or received research support from Novartis, GlaxoSmithKline, AstraZeneca, Bristol-Myers Squibb, and Sanofi-Aventis.

Ann Intern Med. Published online December 6, 2010. Abstract


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