This article won first prize in the recent British Junior Cardiologists’ Association (BJCA) essay competition.
Introduction
In 1736, Benjamin Franklin declared that ‘an ounce of prevention is worth a pound of cure’. With an ever-growing incidence of obesity, diabetes and cardiovascular disease, compounded by overwhelmed health services, this principle remains central to healthcare policies today. Diabetes has long been known to be associated with cardiovascular disease, principally heart failure, and the two are interlinked through mechanisms including increased oxidative stress, which leads to myocardial inflammation and fibrosis. There is now increasing focus on the concept of the ‘metabolic syndrome’ as an umbrella term that links obesity with comorbidities including type two diabetes (T2DM) and cardiovascular disease.1 Increasingly, with the development of novel antidiabetic medications, there is recognition that such drugs have benefits in cardiovascular medicine, notably in preventing further cardiac events in select populations.
Sodium-glucose cotransporter type 2 (SGLT2) inhibitors have been approved for use in diabetes since 2012, but more recent research has identified their positive impacts on heart failure. As such, this class of medications has become well established in cardiovascular medicine as one of the ‘pillars’ of medical therapy for heart failure with significant prognostic benefit across the spectrum of ejection fractions.2 SGLT2 inhibitors have, therefore, provided a blueprint, showing that novel diabetes drugs have already changed the management of cardiovascular disease, and this has stimulated research into how other classes of antidiabetic medications might be used in cardiovascular medicine in the future.
GLP-1 agonists target T2DM and obesity to counteract metabolic syndrome effects on the cardiovascular system
With an ever-increasing incidence of obesity underpinning a growing burden of diabetes and cardiovascular disease, drugs targeting the metabolic syndrome and reversal of obesity causing it, have been a focus of ongoing research. One such example is glucagon-like peptide 1 (GLP-1) agonists. GLP-1 is an incretin hormone that enhances insulin release, and GLP-1 agonists are now common as antidiabetic therapies. GLP-1 agonists were initially noted to cause weight loss, to the extent that they have become licensed for management of obesity, independent of type 2 diabetes.
The cardiovascular benefits of GLP-1 agonists in the treatment of patients with type 2 diabetes are now well established too. A meta-analysis by Kristensen et al.3 comprising seven placebo-controlled randomised trials for GLP-1 agonists in over 56,000 diabetic patients showed that GLP-1 therapies reduce major adverse cardiovascular events by 12%, with statistically significant reductions in cardiovascular mortality, myocardial infarction and hospital admission for heart failure. Given the close links between diabetes and cardiovascular disease, as already outlined, this is unsurprising. However, ongoing research into GLP-1 agonists has sought to expand their indication, with the SELECT (Semaglutide Effects on Cardiovascular Outcomes in People with Overweight or Obesity) trial4 in 2023 demonstrating that patients with pre-existing cardiovascular disease and obesity, but without diabetes, showed a reduced incidence of cardiovascular death and non-fatal myocardial infarction with the administration of weekly semaglutide. Therefore, novel antidiabetic drugs are now being considered for indications outside of diabetes, and purely for their cardiovascular benefits. Given the significance of this trial in a non-diabetic population, this supports the idea that GLP-1 agonists have wider effects, targeting obesity and the metabolic syndrome, rather than just diabetes per se, to derive cardiovascular benefit. There does, however, remain a significant research gap in proving the benefit of these drugs in patients without established cardiovascular disease, and this should be an area of ongoing research in the coming years.
The metabolic syndrome is closely associated with HFpEF
Heart failure is now classified along a spectrum of left ventricular ejection fractions, with distinct differences in management options for heart failure with reduced ejection fraction (HFrEF) and preserved ejection fraction (HFpEF). Notably, the incidence of HFpEF, with fewer treatment options, is increasing,5 and there are strong associations between the metabolic syndrome and HFpEF. Obesity is now believed to drive the development of HFpEF due to cytokine release from adipose tissue and induction of diastolic dysfunction.6 Savji et al. (2018)7 studied 22,681 participants and observed for incident heart failure. Over 12 years of follow-up, raised body mass index (BMI), waist circumference and raised fasting glucose were associated with a greater risk of development of HFpEF than HFrEF.
Understanding of the differing pathophysiological mechanisms of heart failure phenotypes and the association of the metabolic syndrome with HFpEF has translated to clinical trials for antidiabetic and anti-obesity medications in this population. The STEP-HFpEF (Effect of Semaglutide 2.4 mg Once Weekly on Function and Symptoms in Subjects with Obesity-related Heart Failure with Preserved Ejection Fraction) trial (2023)8 is the first placebo-controlled randomised trial to assess the effect of semaglutide, a GLP-1 agonist, in patients with HFpEF and raised BMI without diabetes. Patients in the treatment arm of this trial showed improvements in the Kansas City Cardiomyopathy Questionnaire clinical summary score (KCCQ-CSS) and six-minute walk distances. In this sense, the STEP-HFpEF trial provides another example for the expanding indication of GLP-1 agonists in cardiovascular medicine for non-diabetic patients. However, this trial was not adequately powered to explore cardiovascular mortality or heart failure hospitalisation as outcomes, and this will require further research in the future.
There are numerous combination GLP-1 therapies in the drug pipeline
With the commercial success and increasingly widening indications for GLP-1 agonists becoming apparent, future pharmaceutical development has shifted to combination GLP-1 agonist drugs, which additionally target the glucose-dependent insulinotropic polypeptide (GIP) and glucagon receptors.
Tirzepatide is a GLP-1 and GIP agonist already shown to provide substantial and prolonged weight loss,9 and a recent meta-analysis suggested tirzepatide causes a greater reduction in HbA1c and weight loss compared with semaglutide.10 It is currently enrolled in a range of trials to establish a potential benefit in cardiovascular disease, including the SUMMIT trial (NCT04847557),11 which explores the role of tirzepatide in patients with obesity and HFpEF.
Survodutide is a combination GLP-1 and glucagon agonist shown to be more efficacious than the GLP-1 agonist semaglutide in inducing weight loss.12 The SYNCHRONIZE-CVOT trial (NCT06077864)13 is currently exploring its effect on cardiovascular outcomes in patients with obesity.
Retatrutide is a triple combination drug targeting GLP-1, GIP and glucagon receptors, which has been shown to be effective in causing weight loss in early clinical trials.14 The TRIUMPH-3 trial (NCT05882045)15 aims to explore the efficacy and safety of retatrutide in patients with obesity and established cardiovascular disease, it aims to complete in February 2026.
These three drugs, therefore, provide evidence that combination GLP-1 therapies can be more effective in reducing weight than GLP-1 agonism with semaglutide alone and, therefore, have potential for greater cardiovascular benefit.
Conclusion
Novel diabetes drugs have already revolutionised cardiovascular medicine, with SGLT2 inhibitors a key component of guideline-directed medical therapy for heart failure. Antidiabetic drugs targeting GLP-1 affect key processes underpinning the metabolic syndrome, with effective and sustained weight loss. This has now been shown to translate to cardiovascular benefit in populations with pre-existing cardiovascular disease, notably HFpEF. Future trials should explore the role of these drugs in non-diabetic, obese populations without established cardiovascular disease. GLP-1 agonists, therefore, provide exciting possibilities for preventative medicine and, thus, represent a paradigm shift, increasing the focus of cardiovascular medicine on disease prevention, rather than reversal of established disease.
Key messages
- Glucagon-like peptide 1 (GLP-1) agonists provide an example of drugs which can target the metabolic syndrome to prevent effects on the cardiovascular system
- Drugs targeting a combination of glucose-dependent insulinotropic polypeptide (GIP), GLP-1 and glucagon receptors may have greater effects than those that target GLP-1 alone
- Future research is likely to focus on the role of these drugs in cardiovascular disease prevention, in particular in patients with obesity and metabolic syndrome without established cardiovascular disease
Conflicts of interest
None declared.
Funding
None.
References
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