Abstract
Metformin and GLP-1 receptor agonists (GLP-1RAs) are both widely used in the treatment of type 2 diabetes (T2DM) in part because of their potential for cardiovascular risk reduction. However, both have unfortunate gastrointestinal (GI) side effects (SEs) - chiefly diarrhea with metformin, occurring in 30% or more of patients - and nausea with GLP-1RAs, with a prevalence of 10-20%. Although these agents are frequently used in combination, the possibility of SE synergism has not been previously explored. We report 6 patients (4M and 2F, 70±2 years old, BMI 34±3 kg/m2, hemoglobin A1c 7.5±0.8%) with T2DM who developed GI SEs when taking metformin and a GLP-1RA in combination. At baseline, all were taking metformin 2000-2500 mg/day in divided doses before meals or otherwise on an empty stomach, with no GI SEs. When a GLP-1RA was added to metformin, all began having SEs, either nausea (n=1) diarrhea (n=3) or both (n=2). In all 6 patients, GI SEs resolved within 48-72 hours of stopping metformin and did not recur when metformin was resumed but taken immediately after eating (PC). In 3 patients, the GLP-1RA was eventually increased to the maximum approved dosage without recurrence of SEs. Conclusions: These 6 cases demonstrate side effect synergism between GLP-1RAs and metformin that resolved when metformin was taken PC. Thus, treatment with a GLP-1RA can unmask the SEs of metformin. PC administration of metformin allows some patients to tolerate a full dose of both medications, with potential for greater benefit in the treatment of T2DM.
Published Version
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