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After the LEADER trial and SUSTAIN-6, how do we explain the cardiovascular benefits of some GLP-1 receptor agonists?
1Department of Endocrinology-Diabetology, University Hospital, 2 bd Maréchal de Lattre de Tassigny, F-21000 Dijon, France; INSERM CRI 866, Dijon, France.
Insights
Glucagon-like peptide (GLP)-1 receptor agonists like liraglutide and semaglutide significantly reduce cardiovascular events. Their antiatherogenic effects may stem from improved lipid profiles, weight loss, and direct cardiac benefits, not just glucose control.
Area of Science:
- Cardiology
- Endocrinology
- Pharmacology
Background:
- Recent cardiovascular outcome trials (CVOTs) demonstrated significant reductions in major cardiovascular (CV) events with glucagon-like peptide (GLP)-1 receptor agonists.
- The LEADER (liraglutide) and SUSTAIN-6 (semaglutide) trials showed progressive separation of treatment and placebo curves, indicating potential antiatherogenic effects.
Purpose of the Study:
- To explore the underlying mechanisms for the observed beneficial cardiovascular effects of GLP-1 receptor agonists.
- To evaluate potential contributions of lipid modulation, weight reduction, anti-inflammatory actions, and direct myocardial effects.
Main Methods:
- Analysis of data from cardiovascular outcome trials, specifically the LEADER and SUSTAIN-6 trials.
- Review of in-vitro and human studies investigating the effects of GLP-1 receptor agonists on various cardiovascular risk factors and pathways.
Main Results:
- Modest reductions in glycated haemoglobin and systolic blood pressure are unlikely to fully explain the CV benefits.
- Significant improvements in lipid profiles, particularly reduced postprandial hypertriglyceridemia, are implicated.
- Weight reduction, decreased visceral fat, direct anti-inflammatory effects, and potential direct myocardial benefits were also highlighted.
Conclusions:
- The antiatherogenic effects of GLP-1 receptor agonists are likely multifactorial, involving lipid improvements, weight management, and direct cardiovascular actions.
- While glucose and blood pressure reductions play a role, other mechanisms appear more critical for the observed CV risk reduction.
Abstract:
Recent cardiovascular outcome trials - the LEADER with liragutide and SUSTAIN-6 with semaglutide - have shown significant reductions of major cardiovascular (CV) events with these glucagon-like peptide (GLP)-1 receptor agonists. Progressive separation of the treatment and placebo curves, starting clearly between 12 and 18 months of the trial period, and significant reductions in the risk of myocardial infarction and stroke, indicate that the beneficial CV effects observed with GLP-1 receptor agonists could be due to an antiatherogenic effect. So far, the reasons for such an effect of GLP-1 receptor agonists have not been entirely clear, although several hypotheses may be proposed. As the reductions in glycated haemoglobin and systolic blood pressure (SBP) in these trials were modest, and both trials lasted only a short period of time, reductions in hyperglycaemia and SBP are unlikely to be involved in the beneficial CV effects of GLP-1 receptor agonists. On the other hand, their effect on lipids and, in particular, the dramatic decrease in postprandial hypertriglyceridaemia may explain their beneficial CV actions. Reduction of body weight, including a significant decrease in visceral fat in patients using GLP-1 receptor agonists, may also have beneficial CV effects by reducing chronic proatherogenic inflammation. In addition, there are in-vitro data showing a direct anti-inflammatory effect with these agents that could also be involved in their beneficial CV effects. Moreover, studies in humans have shown significant beneficial effects on ischaemic myocardium after a very short treatment period, suggesting a direct effect of GLP-1 receptor agonists on myocardium, although the precise mechanism remains unclear. Finally, as a reduction in insulin resistance has been associated with a decrease in CV risk, it cannot be ruled out that the lowering of insulin resistance induced by GLP-1 receptor agonists might also be involved in their beneficial CV actions.
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