Mortality Risk of Noninsulin Glucose-Lowering Drugs in Type 2 Diabetes—A Network Meta-analysis of Observational Trials

Given the short-comings of randomized controlled trials, such as low numbers of patients and events, we aimed to perform a network meta-analysis of observational trials on the effects of non-insulin glucose-lowering drugs on all-cause and cardiovascular mortality in type 2 diabetes. We searched MEDLINE and EMBASE through August 2017. From the 38 eligible studies, we extracted patient characteristics, exposure, outcome, confounder-adjusted effect measures, and risk of bias. All-cause and cardiovascular mortality risk were assessed with random-effects network meta-analysis. In 32 studies reporting on all-cause mortality (1,661,945 persons) and in 11 studies on cardiovascular mortality (358,784 persons), 119,591 (7.2%) and 9,221 (2.6%) persons, respectively, died during follow-up. Compared to metformin, sulfonylurea drugs (SU) increased all-cause mortality risk (HR: 1.42 (95% CI: 1.29-1.56)). Dipeptidyl peptidase-4 inhibitors (DDP4i) added to metformin significantly decreased all-cause mortality risk compared to metformin monotherapy (HR: 0.76 (0.63-0.93)), any other drug class as monotherapy, and SU + metformin dual therapy (HR: 0.69 (0.60-0.79)). DPP-4i + metformin dual therapy was associated with even larger reductions in risk of cardiovascular mortality; HR: 0.40 (0.21-0.79) when compared to metformin monotherapy, and HR: 0.41 (0.23-0.74) when compared to SU + metformin dual therapy. Glucagon-like-peptide-1 receptor agonists + metformin dual therapy tended to, but did not significantly, decrease mortality risk when compared to metformin monotherapy (all-cause mortality, HR: 0.88 (0.53-1.47); cardiovascular mortality, HR: 0.74 (0.30-1.82)). In conclusion, this large network meta-analysis evidently confirmed that SU, compared to metformin, increased all-cause mortality risk. DPP-4i + metformin dual therapy, compared to other treatments, resulted in a consistent risk reduction of both all-cause and cardiovascular mortality. Disclosure B. Bongaerts: None. L.M. Lindner: None. A. Hoyer: None. O. Kuss: None. C. Herder: Other Relationship; Self; Sanofi, Eli Lilly and Company. H. Al-Hasani: None. K. Mussig: None. M. Roden: Speaker9s Bureau; Self; Boehringer Ingelheim GmbH. Research Support; Self; Boehringer Ingelheim GmbH. Consultant; Self; Poxel SA. Research Support; Self; Danone Nutricia Early Life Nutrition, GlaxoSmithKline plc., Nutricia Advanced Medical Nutrition, Sanofi. W. Rathmann: Advisory Panel; Self; AstraZeneca. Research Support; Self; Novo Nordisk A/S.