Antidiabetic combination therapy and cardiovascular outcomes: An evidence-based approach

Type 2 diabetes mellitus is associated with a 2-4 times increased risk of cardiovascular (CV) disease. Glucagon-like polypeptide-1 receptor agonists (GLP1RA) and sodium-glucose cotransporter-2 inhibitors (SGLT2i) are two important classes of drugs with CV benefits independent of their antihyperglycemic efficacy. The CV outcome trials of both GLP1RA and SGLT2i have demonstrated CV superiority/neutrality concerning major adverse CV events (MACE). While GLP1RAs have exhibited a significant reduction in ischemic stroke and myocardial infarction (MI), SGLT2i have demonstrated a uniformly significant reduction in hospitalization for heart failure (HF) as a class effect. The unique clinical benefits and the distinct but complementary mechanisms of action make the combination of these drugs a mechanistically sound one. Recent meta-analyses suggest an independent and additive benefit of combination therapy of GLP1RA/SGLT2i vs monotherapy. Zhu et al, in a recent issue of the World Journal of Diabetes, demonstrates a numerically lower hazard ratio (HR) for CV outcomes with combination therapy vs monotherapy with either agent, with a reduction in MACE compared to GLP1RA alone [HR = 0.51, 95% confidence interval (CI): 0.16-1.65], or SGLT2i alone (HR = 0.48, 95%CI: 0.15-1.54). The CV death rate was also lower with combination therapy compared to GLP1RA alone (HR = 0.58, 95%CI: 0.08-3.39), or SGLT2i alone (HR = 0.55, 95%CI: 0.07-3.25). Fatal and non-fatal MI and fatal and non-fatal stroke were reduced with combination therapy compared to GLP1RA alone (HR = 0.45, 95%CI: 0.10-2.18 and HR = 0.86, 95%CI: 0.12-6.23, respectively), or SGLT2i alone (HR = 0.44, 95%CI: 0.09-2.10 and HR = 0.74, 95%CI: 0.10-5.47, respectively). Hospitalization for HF was prevented with combination therapy compared to GLP1RA alone (HR = 0.26, 95%CI: 0.03-1.88), or SGLT2i alone (HR = 0.33, 95%CI: 0.04-2.53). They also demonstrated that GLP1RA or SGLT2i monotherapy may not provide significant improvement in CV death and recurrent MI in patients with prior MI or HF, proposing a role for combination therapy in this subgroup. Appropriate patient selection is vital to optimize CV risk reduction as well as the cost-effectiveness of this combination therapy.