• Suetonia C Palmer, Britta Tendal, Reem A Mustafa, Per Olav Vandvik, Sheyu Li, Qiukui Hao, David Tunnicliffe, Marinella Ruospo, Patrizia Natale, Valeria Saglimbene, Antonio Nicolucci, David W Johnson, Marcello Tonelli, Maria Chiara Rossi, Sunil V Badve, Yeoungjee Cho, Annie-Claire Nadeau-Fredette, Michael Burke, Labib I Faruque, Anita Lloyd, Nasreen Ahmad, Yuanchen Liu, Sophanny Tiv, Tanya Millard, Lucia Gagliardi, Nithin Kolanu, Rahul D Barmanray, Rita McMorrow, Ana Karina Raygoza Cortez, Heath White, Xiangyang Chen, Xu Zhou, Jiali Liu, Andrea Flores Rodríguez, Alejandro Díaz González-Colmenero, Yang Wang, Ling Li, Surya Sutanto, Ricardo Cesar Solis, Fernando Díaz González-Colmenero, René Rodriguez-Gutierrez, Michael Walsh, Gordon Guyatt, and Strippoli Giovanni F M GFM 0000-0002-6936-0616 Sydney School of Public Health, University of Sydney, Sydney, NSW, Australia gfmstrippoli@gmail.com. .
• Department of Medicine, University of Otago, Christchurch, New Zealand.
• BMJ. 2021 Jan 13; 372: m4573.

ObjectiveTo evaluate sodium-glucose cotransporter-2 (SGLT-2) inhibitors and glucagon-like peptide-1 (GLP-1) receptor agonists in patients with type 2 diabetes at varying cardiovascular and renal risk.DesignNetwork meta-analysis.Data SourcesMedline, Embase, and Cochrane CENTRAL up to 11 August 2020.Eligibility Criteria For Selecting StudiesRandomised controlled trials comparing SGLT-2 inhibitors or GLP-1 receptor agonists with placebo, standard care, or other glucose lowering treatment in adults with type 2 diabetes with follow up of 24 weeks or longer. Studies were screened independently by two reviewers for eligibility, extracted data, and assessed risk of bias.Main Outcome MeasuresFrequentist random effects network meta-analysis was carried out and GRADE (grading of recommendations assessment, development, and evaluation) used to assess evidence certainty. Results included estimated absolute effects of treatment per 1000 patients treated for five years for patients at very low risk (no cardiovascular risk factors), low risk (three or more cardiovascular risk factors), moderate risk (cardiovascular disease), high risk (chronic kidney disease), and very high risk (cardiovascular disease and kidney disease). A guideline panel provided oversight of the systematic review.Results764 trials including 421 346 patients proved eligible. All results refer to the addition of SGLT-2 inhibitors and GLP-1 receptor agonists to existing diabetes treatment. Both classes of drugs lowered all cause mortality, cardiovascular mortality, non-fatal myocardial infarction, and kidney failure (high certainty evidence). Notable differences were found between the two agents: SGLT-2 inhibitors reduced mortality and admission to hospital for heart failure more than GLP-1 receptor agonists, and GLP-1 receptor agonists reduced non-fatal stroke more than SGLT-2 inhibitors (which appeared to have no effect). SGLT-2 inhibitors caused genital infection (high certainty), whereas GLP-1 receptor agonists might cause severe gastrointestinal events (low certainty). Low certainty evidence suggested that SGLT-2 inhibitors and GLP-1 receptor agonists might lower body weight. Little or no evidence was found for the effect of SGLT-2 inhibitors or GLP-1 receptor agonists on limb amputation, blindness, eye disease, neuropathic pain, or health related quality of life. The absolute benefits of these drugs vary substantially across patients from low to very high risk of cardiovascular and renal outcomes (eg, SGLT-2 inhibitors resulted in 5 to 48 fewer deaths in 1000 patients over five years; see interactive decision support tool (https://magicevidence.org/match-it/200820dist/#!/) for all outcomes.ConclusionsIn patients with type 2 diabetes, SGLT-2 inhibitors and GLP-1 receptor agonists reduced cardiovascular and renal outcomes, with notable differences in benefits and harms. Absolute benefits are determined by individual risk profiles of patients, with clear implications for clinical practice, as reflected in the BMJ Rapid Recommendations directly informed by this systematic review.Systematic Review RegistrationPROSPERO CRD42019153180.© Author(s) (or their employer(s)) 2019. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.

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