Sodium-glucose cotransporter protein-2 (SGLT-2) inhibitors and glucagon-like peptide-1 (GLP-1) receptor agonists for type 2 diabetes: systematic review and network meta-analysis of randomised controlled trials
Authors: Palmer Suetonia C , Tendal Britta , Mustafa Reem A , Vandvik Per Olav , Li Sheyu , Hao Qiukui , Tunnicliffe David , Ruospo Marinella , Natale Patrizia , Saglimbene Valeria , Nicolucci Antonio , Johnson David W , Tonelli Marcello , Rossi Maria Chiara , Badve Sunil V , Cho Yeoungjee , Nadeau-Fredette Annie-Claire , Burke Michael , Faruque Labib I , Lloyd Anita , Ahmad Nasreen , Liu Yuanchen , Tiv Sophanny , Millard Tanya , Gagliardi Lucia , Kolanu Nithin , Barmanray Rahul D , McMorrow Rita , Raygoza Cortez Ana Karina , White Heath , Chen Xiangyang , Zhou Xu , Liu Jiali , Rodríguez Andrea Flores , González-Colmenero Alejandro Díaz , Wang Yang , Li Ling , Sutanto Surya , Solis Ricardo Cesar , Díaz González-Colmenero Fernando , Rodriguez-Gutierrez René , Walsh Michael , Guyatt Gordon , Strippoli Giovanni F M 
Published: January 2021

Abstract

Objective
To 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.

Design
Network meta-analysis.

Data sources
Medline, Embase, and Cochrane CENTRAL up to 11 August 2020.

Eligibility criteria for selecting studies
Randomised 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 measures
Frequentist 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.

Results

764 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 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 3 to 40 fewer deaths in 1000 patients over five years; see interactive decision support tool (
https://magicevidence.org/match-it/200820dist/#!/
) for all outcomes.

Conclusions

In patients with type 2 diabetes, SGLT-2 inhibitors and GLP-1 receptor agonists reduced cardiovascular and renal outcomes, with some 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 registration
PROSPERO CRD42019153180.