Jan de Leijer, UMC Utrecht
Introduction: Sodium-glucose cotransporter-2 (SGLT-2) inhibitors and glucagon-like peptide-1 receptor agonists (GLP-1 RAs) reduce cardiorenal risk in type 2 diabetes. However, the effects of combining these drugs remains uncertain. This systematic review aimed to evaluate the potential effectiveness and safety of combination therapy compared to monotherapy in individuals with type 2 diabetes.
Methods: We systematically searched PubMed and Embase from inception to July 2024 for cohort studies comparing combination therapy with monotherapy in type 2 diabetes. The primary outcome was a composite of major adverse cardiovascular events (MACE). Secondary outcomes included all-cause mortality, cardiovascular mortality, hospitalisation for heart failure, a kidney composite endpoint, and serious adverse events. Risk of bias was assessed with ROBINS-I. Risk ratios (RR) and 95% confidence intervals (95%CIs) were pooled in random effects meta-analyses. Certainty of evidence was assessed using GRADE.
Results: We included 18 cohort studies (1,164,774 participants). In cohort studies, combination therapy was associated with a lower risk of MACE (RR:0.56; 95%CI:0.43-0.71; low certainty of evidence) and the kidney composite endpoint (RR:0.48; 95%CI:0.32-0.73; very low certainty of evidence) relative to SGLT-2 inhibitor or GLP-1 RA monotherapy. Combination therapy was also associated with a lower risk of all-cause mortality, cardiovascular mortality, and hospitalisation for heart failure (RR:0.50; 95%CI:0.40-0.63; low certainty of evidence; RR:0.26; 95%CI:0.16 – 0.43; low certainty of evidence; and RR:0.67; 95%CI:0.64-0.71; moderate certainty of evidence). Although safety data could not be pooled due to lack of events, no differences were observed in the risk of severe hypoglycaemia, diabetic keto-acidosis, genito-urinary infections, and gastro-intestinal side effects. No data were reported on the risk of serious adverse events or major adverse limb events.
Conclusion: Observational studies suggest that combining a SGLT-2 inhibitor and a GLP-1 RA in type 2 diabetes may lower the risk of MACE, all-cause and cardiovascular mortality, hospitalisation for heart failure, and kidney composite endpoints compared to monotherapy with either drug. Of course, residual confounding cannot be overcome but results support the need for future randomised trials of combined versus monotherapy.
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