Cardiovascular Disease and Type 2 Diabetes: Has the Dawn of a New Era Arrived?

Abstract

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.

What now on the CANVAS of diabetes medications with cardiovascular protection? Could metformin, pioglitazone, SGLT2 inhibitors and liraglutide complement each other to save lives?

“…Now that the results of CANVAS have been added to those of PROactive, EMPA-REG OUTCOME, LEADER and SUSTAIN-6, we can perhaps speculate, from the points made above and in our previous editorials, [3][4][5] that the combination of metformin, pioglitazone, an SGLT2 inhibitor (in particular, empaglifozin and canaglifozin) and liraglutide appears to be the optimum cocktail of medications for improving both glycaemic control and cardiovascular outcomes for people with type 2 diabetes at high cardiovascular risk. Further, the evidence we have today suggests that the agents in this combination may complement each other to prevent cardiovascular events and save lives, although this remains to be proven by randomised, prospective cardiovascular outcome trials.…”

“…7 We also noted that the SUSTAIN 6 trial provided further evidence of cardiovascular benefit from long-acting GLP-1 receptor agonists. 5 Of note, the GLP-1 receptor agonist used in SUSTAIN 6 was similar to that used in LEADER and closely resembles native GLP-1. In contrast, exenatide, which was employed in the EXSCEL trial, 8 differs significantly in structure from native GLP-1 and seems to have failed to demonstrate the same level of cardiovascular protection.…”

“…4,5 We noted emerging evidence that sodium glucose transporter 2 (SGLT2) inhibitors might mitigate the fluid retention associated with pioglitazone, 6 raising the possibility that pioglitazone and empagliflozin might complement each other, not only in reducing cardiovascular risk, but also in reducing side effects related to fluid retention. 4,5 We pointed to the evidence that the early use of triple therapy combination of metformin, pioglitazone and a GLP-1 receptor agonist achieved lower HbA1c, weight loss and much less hypoglycaemia compared with the traditional approach of sequential escalation through metformin, sulphonylurea and insulin, which was associated with significant weight gain. 7 We also noted that the SUSTAIN 6 trial provided further evidence of cardiovascular benefit from long-acting GLP-1 receptor agonists.…”

“…3,4 We proposed that the accumulated evidence from multiple studies suggested that pioglitazone probably exerts its beneficial effects by slowing down, or even reversing, the atherosclerotic process, whereas empagliflozin seemed to reduce cardiovascular deaths and heart failure by an entirely different, more haemodynamic, mechanism as well as perhaps by increasing circulating ketone bodies, providing the failing myocardium with a more efficient fuel source. [3][4][5] We proposed that liraglutide, by reducing cardiovascular outcomes but, in contrast to empaglifozin, not heart failure, seemed to exert its effect through mechanisms different from those of both pioglitazone and empagliflozin. 4,5 We noted emerging evidence that sodium glucose transporter 2 (SGLT2) inhibitors might mitigate the fluid retention associated with pioglitazone, 6 raising the possibility that pioglitazone and empagliflozin might complement each other, not only in reducing cardiovascular risk, but also in reducing side effects related to fluid retention.…”

“…[3][4][5] We proposed that liraglutide, by reducing cardiovascular outcomes but, in contrast to empaglifozin, not heart failure, seemed to exert its effect through mechanisms different from those of both pioglitazone and empagliflozin. 4,5 We noted emerging evidence that sodium glucose transporter 2 (SGLT2) inhibitors might mitigate the fluid retention associated with pioglitazone, 6 raising the possibility that pioglitazone and empagliflozin might complement each other, not only in reducing cardiovascular risk, but also in reducing side effects related to fluid retention. 4,5 We pointed to the evidence that the early use of triple therapy combination of metformin, pioglitazone and a GLP-1 receptor agonist achieved lower HbA1c, weight loss and much less hypoglycaemia compared with the traditional approach of sequential escalation through metformin, sulphonylurea and insulin, which was associated with significant weight gain.…”