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Linagliptin Noninferior to Glimepiride in Diabetes Patients Failing Metformin

Two-year results suggest that the use of the DPP-4 inhibitor linagliptin is as effective as glimepiride in treating diabetic patients who are inadequately controlled with metformin…. 

In addition to achieving similar reductions in hemoglobin A1c, treatment with linagliptin resulted in less weight gain, less hypoglycemia, and a significantly lower risk of cardiovascular events compared with the commonly used sulfonylurea.

Lead author, Dr. Baptist Gallwitz (Eberhard-Karls-University Tübingen, Germany) stated that, "I think these are very interesting findings, even if the study wasn’t powered for cardiovascular end points.""It shows that there might be an advantage with the DPP-4 inhibitors vs the sulfonylureas. There are prospective studies powered for these cardiovascular events ongoing, and we will have the results in a few years’ time. But with the results of these smaller trials, like ours, I’m already quite positive that the larger studies will go in the same direction."

Gallwitz explained that while metformin is the first-line treatment for patients with diabetes, over time HbA1c levels tend to increase simply as a result of disease progression. This often requires the addition of another agent, which is frequently a sulfonylurea. Linagliptin was approvedto be used along with diet and exercise to lower blood sugar in adults with type 2 diabetes, and one of the advantages of this drug class is that it works in a blood glucose-dependent manner, meaning it releases insulin from the pancreas when the blood sugar is high and insulin is needed. In contrast, sulfonylureas release insulin from the pancreas independent of blood sugar, and this is why the drug class exposes patients to risks of hypoglycemia.

The noninferiority study included 777 patients with type 2 diabetes randomly assigned to treatment with 5 mg of linagliptin and 775 patients assigned to 1 mg to 4 mg of glimepiride. All patients included in the study were receiving at least 1500 mg/day of metformin alone or with another oral antidiabetic agent and had HbA1c concentrations ranging from 6.5% to 10.0% (or 6.0% to 9.0% for patients treated with metformin and another oral antidiabetic agent).

After two years of follow-up, HbA1c concentrations decreased to a similar extent with both treatments: 0.16% for linagliptin vs 0.36% for glimepiride. The average difference between groups was 0.20%, a result that met the predefined criteria for noninferiority (p=0.0004 for noninferiority). In addition, treatment with linagliptin resulted in fewer reported cases of hypoglycemia (7% in the linagliptin arm vs 36% in the glimepiride arm; p<0.0001). Overall, the incidence of any adverse event and drug-related adverse events was lower in patients treated with linagliptin. Patients treated with the DPP-4 inhibitor also lost weight compared with glimepiride-treated patients, who gained weight (linagliptin -1.4 kg vs glimepiride 1.3 kg; p<0.0001).

In terms of clinical outcomes, major cardiovascular events occurred in 2% of the 776 patients treated with linagliptin and 3% of the 775 patients treated with glimepiride. This translated into a relative risk reduction of 54% (relative risk [RR] 0.46; p=0.02). The researchers report that the reduction in major events was driven primarily by a significant reduction in the risk of nonfatal strokes (RR 0.27; p=0.03).

"We would like to see the DPP-4 inhibitors more and more the preferred class of drug for add-on treatment to metformin," said Gallwitz. "They have the same efficacy as sulfonylureas at lowering blood glucose but do so with less danger of hypoglycemia and less weight gain and probably fewer cardiovascular events."

Gallwitz B, Rosenstock J, Rauch J, et al. Two-year efficacy and safety of linagliptin compared with glimepiride in patients with type 2 diabetes inadequately controlled on metformin: a randomized, double-blind, noninferiority trial. Lancet 2012; DOI:10.1016/S0140.6736(12)60691-6. Scheen AJ, Paquot N. Gliptin versus a sulphonylurea as add-on to metformin. Lancet 2012; DOI:10.1016/S0140.6736(12)60859-9. Published online June 27, 2012 in the Lancet, the study was first presented at the American Diabetes Association 2011 Scientific Sessions in San Diego, CA.