Recent randomized clinical trials have shows that liraglutide and empagliflozin reduce CVD outcomes while semaglutide is cardiovascularly safe in adults with type 2 diabetes. Should these medications be first line therapy? Should they replace metformin? I believe the answer would depend on patient-physician discussion on cost, convenience, preference, likelihood of adherence, contraindications, side effects and added benefits (weight loss, blood pressure, lipids, renal preservation).
Hyperglycemia is the major risk factor for microvascular complications in patients with type 2 diabetes (T2D). However, cardiovascular disease (CVD) is the principal cause of death, and lowering HbA1c has only a modest effect on reducing CVD risk and mortality.
The recently published LEADER and SUSTAIN-6 trials demonstrate that, in T2D patients with high CVD risk, the glucagon-like peptide 1 receptor agonists liraglutide and semaglutide reduce the primary major adverse cardiac events (MACE) end point (cardiovascular death, nonfatal myocardial infarction, nonfatal stroke) by 13% and 24%, respectively.
The EMPA-REG OUTCOME, IRIS (subjects without diabetes), and PROactive (second principal end point) studies also demonstrated a significant reduction in cardiovascular events in T2D patients treated with empagliflozin and pioglitazone.
However, the benefit of these four antidiabetes agents (liraglutide, semaglutide, empagliflozin, and pioglitazone) on the three individual MACE end points differed, suggesting that different underlying mechanisms were responsible for the reduction in cardiovascular events.
Since liraglutide, semaglutide, pioglitazone, and empagliflozin similarly lower the plasma glucose concentration but appear to reduce CVD risk by different mechanisms, there emerges the intriguing possibility that, if used in combination, the effects of these antidiabetes agents may be additive or even multiplicative with regard to cardiovascular benefit.