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Twice-daily exenatide trumped glimepiride as add-on to metformin

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PHILADELPHIA — Twice-daily exenatide appeared more beneficial than usual care with glimepiride in preventing the deterioration of glycemic control in patients with type 2 diabetes, according to data presented at the American Diabetes Association’s 72nd Scientific Sessions.

“Metformin is widely used as first-line therapy for patients with type 2 diabetes but eventually fails to control glycemia in many patients,” Guntram Schernthaner, MD, of the Department of Medicine I, Rudolfstiftung Hospital in Vienna, Austria said during a presentation. “In many countries worldwide, the most frequently used second-line antidiabetes therapy is a sulfonylurea. Diabetes progression involves beta-cell failure and exenatide BID might be at least as good if not better than a sulfonylurea in maintaining long term glycemic control.”

EUREXA trial

“Metformin is only efficient for a limited time period. At the moment, it is still unclear which drug should be added after metformin,” Schernthaner told Endocrine Today.

Schernthaner and colleagues conducted the European Exenatide (EUREXA) trial in 128 centers in 14 countries to evaluate the duration of glycemic control achieved with twice-daily exenatide (Byetta, Amylin) vs. once-daily glimepiride (Amaryl, Sanofi-Aventis) in patients whose type 2 diabetes is inadequately controlled with metformin.

They randomly assigned 515 patients to exenatide and 514 to glimepiride, of whom 490 and 487, respectively, were included in the intention-to-treat analysis. Primary outcome was time to inadequate glycemic control or need for alternative treatment, defined as an HbA1c of greater than 9% after the first 3 months of treatment or more than 7% at two consecutive visits after 6 months.

The study results, which were simultaneously published in The Lancet, showed that 41% of patients assigned exenatide vs. 54% assigned glimepiride experienced treatment failure (HR=0.748; 95% CI, 0.63-0.899). Forty-four percent vs. 31% achieved an HbA1c of less than 7%, and 29% vs. 18% achieved concentrations of 6.5% or less (P=.0001). Additionally, significantly greater reductions in body weight were noted in the exenatide group when compared with the glimepiride group (P<.0001).

The researchers observed less documented symptomatic (P<.0001), nocturnal (P=.007) and non-nocturnal (P<.0001) hypoglycemia among patients in the exenatide vs. the glimepiride study arms. Discontinuation due to treatment-related adverse events was significantly higher among those receiving exenatide vs. glimepiride during the first 6 months, but not after.

“This is also very relevant for clinical decision-making. If you have a low HbA1c, you can use any drug. If you have a higher HbA1c, which is usually the situation, then you need a drug with more durability in reducing weight and with low risk for hypoglycemia. So, I believe it’s the relatively best drug at the moment. No one drug is optimal,” Schernthaner said.

Considerations

In an accompanying editorial, Sten Madsbad, MD, of Hvidore Hospital and University of Copenhagen, acknowledged the benefits of using a GLP-1 receptor agonist such as exenatide rather than a sulfonylurea such as glimepiride, but highlighted certain issues. For instance, although data suggest exenatide has cardioprotective effects, it has been associated with an increase in heart rates.

“After the lesson learned from rosiglitazone, the US Food and Drug Administration now requires the assessment of cardiovascular risks of new diabetic drugs both before and after approval, and results of cardiovascular outcome studies for the different GLP-1 receptor agonists are expected after 2015.”

For more information:

Gallwitz B. Lancet. 2012;doi:10.1016/S0140-6736(12)60479-6.

Madsbad S. Lancet. 2012;doi:10.1016/S0140-6736(12)60769-7.

Schernthaner G. Joint ADA/The Lancet Symposium. Presented at: the American Diabetes Association’s 72nd Scientific Sessions; June 8-12, 2012; Philadelphia.

Disclosure: This study was funded by Eli Lilly and Amylin Pharmaceuticals Dr. Schernthaner is on the advisory panel for AstraZeneca, Bristol-Myers Squibb, Boehringer Ingelheim, Eli Lilly and Company, GlaxoSmithKline, Novartis, Novo Nordisk A/S, Poxel SA, Roche, Sanofi-Aventis, Servier, Takeda, Amgen and is on the speaker’s bureau for Boehringer Ingelheim, Eli Lilly and Company, GlaxoSmithKline, Novartis, Novo Nordisk A/S, Poxel SA, Roche, Sanofi-Aventis, Servier and Takeda. Dr. Madsbad has been a consultant or adviser to Novartis, Novo Nordisk, Merck Sharp and Dohme, Sanofi-Aventis, AstraZeneca, Johnson and Johnson, Roche, Mannkind, Boehringer-Ingelheim, Zeeland, Lilly and Intarcia Therapeutics, nd has received fees for speaking from Novo Nordisk, Merck Sharp and Dohme, Johnson and Johnson, Roche, Schering-Plough, Sanofi-Aventis, Novartis, Lilly, Bristol-Myers Squibb and AstraZeneca.