Comparative Effects of Randomized Second-Line Therapy for Type 2 Diabetes on a Composite Outcome Incorporating Glycemic Control, Body Weight, and Hypoglycemia: an Analysis of the Glycemia Reduction Approaches in Type 2 Diabetes - A Comparative Effectiveness (GRADE) Study

Background: The GRADE Study (5047 participants, mean follow-up 5.0 years) demonstrated differences in glycemic control over time among four randomized therapies added to metformin. Weight gain and hypoglycemia are also important outcomes for people with type 2 diabetes. We compared the effects of the four randomized GRADE medications on a composite outcome incorporating glycemic deterioration, weight gain, and hypoglycemia. Methods: The composite outcome was time to first occurrence of any of: HbA1c >7.5%, confirmed; ≥5% weight gain; or severe or recurrent non-severe hypoglycemia. Secondary analyses examined individual components of the composite outcome, subgroup effects and potential mediators, and treatment satisfaction. Cumulative incidence was estimated using the Kaplan-Meier estimator. Cox proportional hazards models assessed pairwise group differences in risk of an outcome. Results: Risk of reaching the composite outcome (events per 100 participant-treatment years, PTYs) was lowest with liraglutide (19/100 PTYs) followed by sitagliptin (26/100 PTYs), glargine (29/100 PTYs), and glimepiride (40/100 PTYs); all pairwise comparisons were statistically significant. Risk of weight gain and hypoglycemia had the same order, but risk of glycemic deterioration was lowest with glargine, followed by liraglutide, glimepiride, and sitagliptin. No significant heterogeneity in risk of composite outcome was detected across pre-specified covariates. Participants who reached the composite outcome had modestly but significantly lower treatment satisfaction. Conclusions: Among common second-line drug classes for type 2 diabetes, liraglutide had the lowest and glimepiride the highest risk of reaching a composite outcome encompassing glycemic deterioration, weight gain, and hypoglycemia. These findings may inform decision-making regarding type 2 diabetes therapy.