Effectiveness of GLP-1 RAs and SGLT2 inhibitors in preventing T2DM in high-risk patients: an updated systematic review and meta-analysis.

INTRODUCTION: There are conflicting results and limited data regarding the individual effectiveness of glucagon-like peptide 1 receptor agonists (GLP-1 RAs) and sodium-glucose cotransporter 2 (SGLT2) inhibitors and their combined action in preventing type 2 diabetes mellitus (T2DM) in high-risk adults. An updated investigation is warranted. We aimed to explore their effectiveness in preventing T2DM in high-risk patients and assess changes in body weight/body mass index (BMI), glycemic parameters, and safety. MATERIALS AND METHODS: PubMed, Cochrane Library Central Register of Controlled Trials, and Scopus were searched for eligible randomized controlled trials (RCTs), and a systematic review (SR) and meta-analysis (MA) were conducted. GRADE assessment was conducted for rating the overall certainty of evidence. RESULTS: All 24,157 participants in 10 GLP-1 RA RCTs were overweight/obese. Compared to placebo, GLP-1 RAs reduced T2DM incidence (OR 0.51; 95% CI 0.28, 0.94;-value 0.03), and 2.4 mg of semaglutide was overall effective (OR 0.38; 95% CI 0.16, 0.94;-value < 0.0001). Subgroup analysis indicated effectiveness in patients more than 50 years across the world, in cardiovascular disease, after 100 weeks, and during the post-intervention period. Liraglutide was not overall effective. However, subgroup analyses demonstrated effectiveness for studies that were performed worldwide, for women more than 40 years, at 3.0 mg daily, after 55 weeks of administration, and only during intervention. Exenatide was not effective. Heterogeneity was large (Q 54.56,-value < 0.0001;² 84%, 95% CI 74%, 89%), and MA was performed using the random-effects model. Heterogeneity was explained by countries' performance in semaglutide- and liraglutide-based RCTs and participants' mean age, dosage, duration, and post-intervention evaluation in liraglutide-based RCTs. Sensitivity analyses considering studies with post-intervention assessment and studies with the largest sample size and dropout rate more than 5% in semaglutide-based RCTs explain further heterogeneity. The quality of evidence was low. Compared to placebo, GLP-1 RAs reduced weight (kg) and BMI (kg/m²) (mean difference -6.35,-value < 0.00001 and -2.46,-value < 0.00001, respectively). Finally, GLP-1 RAs were safe (OR for adverse events 1.01;-value 0.95). CONCLUSIONS: GLP-1 RAs may prevent diabetes in high-risk adults and ameliorate body and glycemic factors. Their effectiveness should be considered carefully due to the low quality of evidence. No safety issues were identified. Future investigation is necessary to provide consistency of estimations. SYSTEMATIC REVIEW REGISTRATION: OSF Registration, identifier DOI 10.17605/OSF.IO/8XH4.