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

Abstract

results of the CANagliflozin cardioVascular Assessment Study (CANVAS) were presented 1 and were also published at the same time in the New England Journal of Medicine. 2 All of us working to treat type 2 diabetes have been waiting with great interest for these results to see to what extent they would match those of the cardiovascular outcome study with empagliflozin (EMPA-REG OUTCOME).In previous editorials we proposed that metformin, pioglitazone, empagliflozin and liraglutide in combination could complement each other to prevent cardiovascular events and save lives in patients with type 2 diabetes at high cardiovascular risk. 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. 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. 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. 8 This raises questions about whether GLP-1 receptor agonists will vary in the extent to which they reduce cardiovascular events in high risk diabetic patients.In line with previous cardiovascular outcome studies, CAN-VAS studied patients at high cardiovascular risk and assessed, as its primary outcome, three-point Major Adverse Cardiovascular Events (3-point MACE: cardiovascular death, non-fatal myocardial infarction and non-fatal stroke). 1,2 Similar to the presentation of EMPA-REG OUTCOME in 2015 3 and LEADER in 2016, 4 the CANVAS findings shown in Figu...

Diabetes medications with cardiovascular protection as we enter a new decade: can SGLT2 inhibitors, long-acting GLP-1 receptor agonists, pioglitazone and metformin complement each other to save lives?

“…In previous editorials we proposed that SGLT2 inhibitors, longacting GLP-1RAs, pioglitazone and metformin in combination could complement each other to prevent cardiovascular events and save lives in patients with type 2 diabetes at high cardiovascular risk. [8][9][10][11][12] We came to this conclusion because of the accumulated evidence from multiple studies suggesting that pioglitazone exerts cardiovascular benefit by slowing down, or even reversing, the atherosclerotic process, [8][9][10][12][13][14][15] whereas SGLT2 inhibitors seem to exert their cardiovascular benefits by improving cardiac haemodynamics and reducing heart failure, [8][9][10]12 and possibly by switching myocardial fuel metabolism to ketones. 16 By contrast, GLP-1RAs appear to exert their cardiovascular benefit by mechanisms different from those of both pioglitazone and SGLT2 inhibitors.…”

“…• Pioglitazone improves cardiovascular outcomes by slowing down or even reversing the atherosclerotic process, independent of its glucose-lowering action. [8][9][10][12][13][14][15] This is not a class effect for thiazolidinediones and does not apply to rosiglitazone. 8 The ADA/EASD consensus statement 22 accepts that pioglitazone has been shown to reduce cardiovascular endpoints, but "without conclusive evidence for benefit".…”

“…13 Pioglitazone is contraindicated in patients with heart failure and thus appropriate care needs to be exercised in its use, but in this context it is of interest that SGLT2 inhibitors may mitigate the fluid retention associated with pioglitazone. 17 • SGLT2 inhibitors as a class seem to exert cardiovascular benefit by improving cardiac haemodynamics and reducing heart failure, [8][9][10]12 and possibly by shifting myocardial substrate utilisation. 16 • SGLT2 inhibitors and pioglitazone in combination may improve cardiovascular outcomes even more by working synergistically to produce benefit in different ways.…”

“…16 • SGLT2 inhibitors and pioglitazone in combination may improve cardiovascular outcomes even more by working synergistically to produce benefit in different ways. [8][9][10]12,13 As SGLT2 inhibitors seem to mitigate the fluid retention associated with pioglitazone, this further increases their possible complementary actions. 17 • With regard to dapagliflozin, it is now established that the cardiac benefits are the same for both people with and without diabetes.…”

Diabetes medications with cardiovascular protection in the wake of EXSCEL: is there a class effect for long-acting GLP-1 receptor agonists?

“…8 Further, the use of all classes of antiglycaemic medications, including those known to improve cardiovascular outcomes (metformin, pioglitazone, SGLT2 inhibitors and GLP-1 receptor agonists) was higher in the placebo arm, 8 and this may have improved cardiovascular outcomes in the placebo arm. [1][2][3] In Figure 1, the major LEADER and EXSCEL outcomes are compared side by side. The similarity in the pattern of the point estimates is noteworthy.…”