Abstract Body (Do not enter title and authors here): Background: The potential benefits and risks of combination sodium-glucose co-transporter-2 inhibitors (SGLT-2i) and glucagon-like peptide-1 receptor agonists (GLP-1RA) therapy versus (vs.) monotherapy, remain a subject of debate to reduce metabolic and cardiovascular outcomes in patients with diabetes mellitus. This study aims to systematically review and meta-analyze the available evidence from randomized controlled trials (RCTs).
Methods: A comprehensive search identified relevant RCTs comparing combination therapy with SGLT-2i and GLP-1RA to monotherapy or placebo. The primary outcome was the incidence of major adverse cardiovascular events (MACE) (all-cause mortality, cardiovascular mortality, stroke, myocardial infarction, and hospitalization for heart failure (hHF)). Secondary outcomes included changes in metabolic parameters and adverse events. Random-effects meta-analysis estimated risk ratios, mean difference, and 95% confidence intervals (CI).
Results: The meta-analysis included 11 RCTs with 42,851 participants, of which 2,870 on combination therapy, and the rest on SGLT-2i (37.1%), GLP-1RA (20.1%) monotherapies or placebo (42.8%). Combination therapy had a significantly lower risk of MACE vs. GLP-1RA monotherapy (RR=0.81, 95% CI 0.65;1.00) and placebo (RR=0.73, 95% CI 0.61;0.88). Combination therapy also had a lower risk of hHF vs. GLP-1RA, SGLT-2, and placebo monotherapies (RR=0.37, 95% CI 0.22;0.65), (RR=0.37, 95% CI 0.19;0.75), and (RR=0.43, 95% CI 0.24;0.75), respectively. Combination therapy was showed greater weight loss and HbA1c reduction vs. SGLT-2i monotherapy (MD=-2.03, 95% CI -2.85;-1.21 and MD=-0.74, 95% CI -1.21;-0.27), respectively, while no difference vs. GLP-1RA monotherapy. Incidence of nausea and diarrhea was higher with combination therapy vs. SGLT-2i monotherapy (MD=3.34, 95% CI 1.74;6.43 and MD=1.75, 95% CI 1.10;2.77), respectively.
Conclusion: Combination SGLT-2i and GLP-1RA therapy may provide superior cardiovascular, weight, and HbA1c outcomes vs. monotherapy, despite higher gastrointestinal adverse events. These results impact the management of patients with metabolic and cardiovascular diseases, and highlighting the need for further research to optimize combination therapy.