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2-Year Efficacy and Safety of Linagliptin Compared With Glimepiride in Patients With Type 2 Diabetes Inadequately Controlled on Metformin: A Randomized, Double-Blind, Non-Inferiority Trial
Study Questions:
What is the long-term efficacy and safety of linagliptin compared with a commonly used sulphonylurea (glimepiride) as second-line treatment in participants with type 2 diabetes inadequately controlled on metformin?
Methods:
In this 2-year, parallel-group, noninferiority, double-blind trial, outpatients with type 2 diabetes and glycated hemoglobin (HbA1c) 6.5–10.0% on stable metformin alone or with one additional oral antidiabetic drug (washed out during screening) were randomly assigned (1:1) by computer-generated random sequence via a voice or web response system to linagliptin (5 mg) or glimepiride (1–4 mg) orally once daily. Study investigators and participants were masked to treatment assignment. The primary endpoint was change in HbA1c from baseline to week 104. Analyses included all patients randomly assigned to treatment groups who received at least one dose of treatment, had a baseline HbA1c measurement, and had at least one on-treatment HbA1c measurement.
Results:
A total of 777 patients were randomly assigned to linagliptin and 775 to glimepiride; 764 and 755 were included in analysis of the primary endpoint. Reductions in adjusted mean HbA1c (baseline 7.69% [standard error 0.03] in both groups) were similar in the linagliptin (−0.16% [0.03]) and glimepiride groups (−0.36% [0.03]; difference, 0.20%; 97.5% confidence interval [CI], 0.09–0.30), meeting the predefined noninferiority criterion of 0.35%. Fewer participants had hypoglycemia (58 [7%] of 776 vs. 280 [36%] of 775 patients; p < 0.0001) or severe hypoglycemia (1 [<1%] vs. 12 [2%]) with linagliptin compared with glimepiride. Linagliptin was associated with significantly fewer cardiovascular events (12 vs. 26 patients; relative risk, 0.46; 95% CI, 0.23–0.91; p = 0.0213).
Conclusions:
The authors concluded that linagliptin was noninferior to glimepiride in lowering HbA1c, but was associated with significantly less hypoglycemia and weight loss.
Perspective:
The study reports that in patients with type 2 diabetes inadequately controlled on metformin, linagliptin was noninferior to glimepiride in lowering HbA1c, but was associated with significantly less hypoglycemia and weight loss. Furthermore, linagliptin was associated with significantly fewer cardiovascular events compared with glimepiride. These findings support the use of linagliptin in combination with metformin as a therapeutic option for treatment of type 2 diabetes. This study also adds to the evidence base for evaluation of recommendations for second-line treatment after metformin. However, only long-term trials with incretin-based treatments would provide enough data for both efficacy (i.e., effects on diabetic complications) and safety (i.e., concerns about pancreatitis and pancreatic cancer) to decide on optimal second-line treatment after metformin therapy.
Keywords: Hemoglobin A, Risk, Quinazolines, Pancreatitis, Weight Loss, Purines, Transcription Factors, Dipeptidyl-Peptidase IV Inhibitors, Hypoglycemia, Pancreatic Neoplasms, Incretins, Sulfonylurea Compounds, Diabetes Complications, Outpatients, Metformin, Cardiovascular Diseases, Hypoglycemic Agents, Confidence Intervals, Diabetes Mellitus
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