• Apostolos Tsapas, Ioannis Avgerinos, Thomas Karagiannis, Konstantinos Malandris, Apostolos Manolopoulos, Panagiotis Andreadis, Aris Liakos, David R Matthews, and Eleni Bekiari.
• Clinical Research and Evidence-Based Medicine Unit and Diabetes Centre, Aristotle University of Thessaloniki, Thessaloniki, Greece, and Harris Manchester College, University of Oxford, Oxford, United Kingdom (A.T.).
• Ann. Intern. Med. 2020 Aug 18; 173 (4): 278-286.

BackgroundSeveral pharmacologic options for type 2 diabetes are available.PurposeTo compare benefits and harms of glucose-lowering drugs in adults with type 2 diabetes.Data SourcesSeveral databases from inception through 18 December 2019 and ClinicalTrials.gov on 10 April 2020.Study SelectionEnglish-language randomized trials that had at least 24 weeks of intervention and assessed the effects of glucose-lowering drugs on mortality, glycemic, and vascular outcomes.Data ExtractionPairs of reviewers extracted data and appraised risk of bias.Data Synthesis453 trials assessing 21 antidiabetic interventions from 9 drug classes were included. Interventions included monotherapies (134 trials), add-on to metformin-based therapies (296 trials), and monotherapies versus add-on to metformin therapies (23 trials). There were no differences between treatments in drug-naive patients at low cardiovascular risk. Insulin regimens and specific glucagon-like peptide-1 receptor agonists (GLP-1 RAs) added to metformin-based background therapy produced the greatest reductions in hemoglobin A1c level. In patients at low cardiovascular risk receiving metformin-based background treatment (298 trials), there were no clinically meaningful differences between treatments for mortality and vascular outcomes. In patients at increased cardiovascular risk receiving metformin-based background treatment (21 trials), oral semaglutide, empagliflozin, liraglutide, extended-release exenatide, and dapagliflozin reduced all-cause mortality. Oral semaglutide, empagliflozin, and liraglutide also reduced cardiovascular death. Odds of stroke were lower with subcutaneous semaglutide and dulaglutide. Sodium-glucose cotransporter-2 (SGLT-2) inhibitors reduced heart failure hospitalization and end-stage renal disease. Subcutaneous semaglutide and canagliflozin increased diabetic retinopathy and amputation, respectively.LimitationInconsistent definitions of cardiovascular risk and low-level confidence in some estimates for patients at low cardiovascular risk.ConclusionIn diabetic patients at low cardiovascular risk, no treatment differs from placebo for vascular outcomes. In patients at increased cardiovascular risk receiving metformin-based background therapy, specific GLP-1 RAs and SGLT-2 inhibitors have a favorable effect on certain cardiovascular outcomes.Primary Funding SourceEuropean Foundation for the Study of Diabetes, supported by an unrestricted educational grant from AstraZeneca. (PROSPERO: CRD42019122043).

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