In the last few years, several placebo-controlled cardiovascular outcome trials (CVOTs) of glucose-lowering pharmacotherapies for type 2 diabetes have been published, as mandated by the US Food and Drug Administration. While dipeptidyl peptidase-4 inhibitors generally proved to be safe (saxagliptin and alogliptin are associated with an increased risk of heart failure hospitalisation, particularly in patients with cardiovascular disease), drugs within the sodium–glucose cotransporter-2 inhibitor and the glucagon-like peptide (GLP)-1 receptor agonist classes not only provided safety, but showed cardiovascular benefits. Positive effects on related cardiorenal disorders have included a slower decline in glomerular filtration rate, reduced hospitalisations for heart failure and benefits for metabolic dysfunction-associated steatohepatitis and moderate-to-advanced fibrotic liver disease.
Analyses of these trials indicated that for patients living with type 2 diabetes, improvements in glycaemia only partly explain these clinical benefits [1]. Another potential explanation is an improvement of cardiorenal risk factors by weight reduction, that is, reduced adiposity with GLP-1 receptor agonists. Indeed, there seems to be a widespread belief that the greater the weight loss with these drugs, the better the reduction in major adverse cardiovascular events (MACE) and other outcomes.
However, among CVOTs investigating the effects of GLP-1 receptor agonists on cardiovascular events no clear association between the amount of placebo-corrected weight loss and MACE is apparent. This is illustrated by the GLP-1 receptor agonist CVOTs that demonstrated minimal and maximal weight loss, respectively. In HARMONY, there was just a 0.8 kg placebo-subtracted weight difference, whereas FREEDOM CVO reported −4.24 kg more weight lost; however, no association of MACE reduction to greater weight loss was observed (Table 1). Indeed, the larger reduction in MACE was for HARMONY, in the context of minimal weight loss. Four GLP-1 receptor agonist CVOTs demonstrated greater than 20% reduction in MACE, that is, HARMONY, AMPLITUDE-O, PIONEER, and SUSTAIN 6. Placebo-controlled weight loss in these trials ranged between −0.8 and −3.4 kg (Table 1). Here again, no association between weight loss and MACE reduction is evident (Table 2). A meta-analysis showed that GLP-1 receptor agonists in people with type 2 diabetes that induce minimal weight loss can reduce MACE [2].
Table 1.
Effects of minimal or maximal weight change induced by glucagon-like peptide-1 receptor agonists on 3-point MACE
| Study | Weight difference in kilograms | Reduction of MACE (in %) |
|---|---|---|
| HARMONY | −0.8 | −22 |
| FREEDOM CVO | −4.24 | +21 |
MACE, major adverse cardiovascular events.
Table 2.
Body weight change in studies with >20% MACE reductions ranked by weight loss
| Study | Reduction of MACE (in %) | Weight difference (in kilograms) | |
|---|---|---|---|
| HARMONY | −22 | −0.8 | |
| AMPLITUDE-O | −27 | −2.6 | |
| SUSTAIN 6 | −26 | −3.2 | |
| PIONEER | −21 | −3.4 | |
MACE, major adverse cardiovascular events.
Furthermore, a post-hoc analysis of the LEADER and SUSTAIN 6 trials found that the cardiovascular benefits of liraglutide or semaglutide were not related to weight loss [3]. Similarly, the SELECT study in patients without diabetes found that semaglutide reduced the risk of MACE also in those who did not achieve clinically relevant weight loss [4]. Of note, in SELECT a reduction in MACE preceded changes in body weight that are considered clinically meaningful [5]. These observations should stimulate a search for other – weight-independent – mechanisms (Table 3).
Table 3.
Postulated mechanisms of glucagon-like peptide-1 receptor agonist-mediated cardioprotection
| Anti-inflammatory effects: GLP-1 receptor agonists have been shown to have anti-inflammatory properties, which may reduce atherogenesis and hence the risk of cardiovascular events |
| • Endothelial function: GLP-1 receptor agonists improve endothelial function, reduce blood pressure and improve tissue blood flow |
| • Direct renal effects: GLP-1-based therapies provide renoprotection with reduced albuminuria and improved renal function; these benefits are associated with a reduced risk of cardiovascular disease |
GLP-1: glucagon-like peptide-1.
As newer compounds, such as the twincretins and others, are generating more marked degrees of weight loss than GLP-1 receptor monoagonists, expectations are high that these agents might improve cardiorenal outcomes even further. The preliminary announcement of the results of SURPASS CVOT – the first active comparator incretin CVOT, in which tirzepatide was compared with dulaglutide – demonstrated noninferiority of tirzepatide to the cardioprotective GLP-1 receptor agonist dulaglutide in time to occurrence of 3-point MACE (hazard ratio = 0.92, 95.3% confidence interval: 0.83–1.0, P = 0.086) (https://investor.lilly.com/news-releases/news-release-details/lillys-mounjaro-tirzepatide-gipglp-1-dual-agonist-demonstrated). Thus, tirzepatide reduced MACE, but despite greater weight loss (12 vs. 4.95%) and reductions in haemoglobin (Hb)A1c (−1.73 vs. −0.9%), no superiority in MACE outcomes was observed compared with dulaglutide. The full results of SURPASS CVOT are awaited.
How should the current scientific literature be most appropriately translated into clinical practice? We offer the following suggestions:
GLP-1 receptor agonist therapy should not be routinely discontinued when goals for weight reduction (or glycaemic control) have been attained. Even in subjects without diabetes, SELECT demonstrated that clinical benefits were independent of weight loss.
Incretin-based injectables should not automatically be discontinued if weight loss goals have not been achieved or weight reduction has reached a plateau.
GLP-1 receptor agonists should be considered for high-risk individuals for whom weight loss may not be the primary therapeutic objective. As noted, in addition to reductions in MACE, GLP-1 receptor agonist CVOTs have consistently demonstrated end-organ protection across the range of weight change. Thus, beyond reducing the risk of cardiovascular events, incretin-based therapies can also provide protection against renal and metabolic hepatic disease.
In conclusion, the degree of weight loss (and reduction of HbA1c in patients living with type 2 diabetes) does not fully explain improved cardiovascular outcomes with incretin-based therapies. Recent analyses indicate that cardiovascular events are already reduced before relevant weight loss is observed [5]. We suggest that the current literature supports the contention that in people with high levels of cardiorenal risk the principal medical indication for these drugs should be protection against cardiorenal-metabolic disease rather than a myopic focus on weight management.
Acknowledgements
Conflicts of interest
The authors report advisory board and speaker engagements for Novo Nordisk and Eli Lilly.
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