Abstract
The objective of this paper is to obtain an overview of the safety and tolerance of glimepiride by presenting results from the clinical trials in patients with non-insulin-dependent diabetes mellitus that were conducted during the development of this new product. A total of 21 clinical studies with a minimum duration of two weeks were conducted during the clinical development of glimepiride in the United States and Europe. This included four placebo-controlled, four active-controlled (with glyburide and glipizide), and three noncomparative trials conducted in the United States and 10 European studies (eight active controlled and two non-comparative). All of the patients provided an extensive medial history which included information on concomitant medications, underlying diseases, and ongoing adverse events. During the clinical studies, the patients were monitored for treatment-emergent signs and symptoms (TESS), clinical laboratory abnormalities, discontinuations, deaths, and serious adverse events. Over 6,500 patients were included in the worldwide clinical trials with more than 4,200 of these patients treated with glimepiride; 1,500 of these patients were treated for at least 1 year. In controlled clinical trials in the United States, 2,013 subjects received glimepiride, 294 placebo, 322 glyburide, and 258 glipizide. In European studies, the duration of therapy ranged from 14 days to 2.8 years in the 1,489 patients who received glimepiride and the 1,247 control patients who were treated with either glyburide or gliclazide. In the japanese studies, a total of 983 patients were treated, 718 on glimepiride.
In the US trials, similar types of adverse events were reported in subjects who received glimepiride, glyburide, or glipizide. The most commonly reported TESS were upper respiratory infection, headache, accidental injury, flu-like syndrome, and sinusitis. None of the TESS that were considered possibly or probably treatment related occurred in more than 2% of the patients. Those which occurred in ≥1% of glimepiride patients include dizziness, headache, asthenia, and nausea. The incidence of laboratory-confirmed hypoglycemia (blood glucose <60 mg/dl) ranged from 0.9% to 1.7% for glimepiride recipients in the US studies. Discontinuation from the study was most commonly a result of hyperglycemia in placebo recipients. Among the more than 6,500 patients in the clinical program, 52 deaths occurred, the majority of which were attributable to cardiovascular events. Glimepiride did not interact with any disease condition, concomitantly used medication, or concomitant disease in a medically meaningful manner. European data supported the findings of the US trials as did the Japanese data. A number of placebo-controlled, active-controlled, and non-comparative studies involving more than 6,500 patients (>4,200 patients treated with glimepiride) who were treated for up to three years have demonstrated that glimepiride has a superior safety profile. The incidence of laboratory confirmed hypoglycemia was consistently < 1.7%. The risk of cardiovascular events during treatment with glimepiride was equivalent to that seen with other sulfonylureas. No medically important interactions were found between glimepiride and any demographic variable, disease, or concomitant drug use. No pattern of laboratory abnormalities could be attributed to the use of glimepiride. The safety profile of glimepiride in controlled clinical trials was excellent and was as good as, or better than, that of the marketed sulfonylureas (glyburide, glipizide, and gliclazide) that were used as comparative agents in this clinical development program.
Key words
Safety - Treatment Emergent Signs and Symptoms (TESS) - Deaths, Discontinuations, and Serious Events (DDOS)
