GLP-1 receptor agonists in cardiovascular disease: a guide for cardiologists

Obesity is a global epidemic, which, directly and indirectly, contributes to almost all cardiovascular diseases, including atherosclerotic cardiovascular disease, heart failure and atrial fibrillation. Reduction of weight is associated with substantial improvements in cardiometabolic risk factors, including blood pressure and glycaemic control, with over 10% weight loss required to see improvement in rates of major adverse cardiovascular events. Glucagon-like peptide-1 (GLP-1) receptor agonists have changed the landscape of type 2 diabetes and obesity management, showing significant benefit in glycaemic control and weight loss. Their potential for cardiovascular benefits means that they will likely have a central role in the management of patients with obesity-related cardiovascular diseases. This review summarises currently available GLP-1-based pharmacotherapies and highlights recent trials demonstrating cardiovascular benefits, and also provides practical guidance for patient selection, available agents, their initiation and patient monitoring. This will serve as an aid for cardiovascular clinicians, who will inevitably encounter patients suitable for, or already using, these drugs in their daily practice.

Introduction

Obesity and cardiovascular disease

In England, two thirds of adults are now living with overweight or obesity.^1,2 About 40% of deaths attributable to a high body mass index (BMI) are due to cardiovascular disease.³ Coupled with being intimately linked to prevalent cardiovascular risk factors, such as hypertension, dyslipidaemia and type 2 diabetes (T2D), obesity, directly and indirectly, contributes to almost all cardiovascular diseases, including atherosclerotic cardiovascular disease, heart failure and atrial fibrillation (AF).⁴ All clinicians involved in the care of patients with cardiovascular disease will inevitably encounter people with co-existing obesity, and will be required to address this important risk factor. However, despite the clear links between obesity and the spectrum of cardiovascular diseases, obesity management is often overlooked by cardiologists.^5,6

Established and emerging weight loss strategies

Lifestyle interventions, incorporating changes to dietary behaviours and increasing physical activity, have been shown to be effective in reducing weight by about 5–10%.⁷ Although, this amount of weight loss can improve multiple cardiometabolic risk factors, including blood pressure and glycaemic control,⁸ at least 10% weight loss is required in people with obesity and T2D to see improvement in cardiovascular events and mortality.^9,10 Even with the most intensive lifestyle interventions, weight loss tends to plateau around 10% and long-term weight loss maintenance remains difficult – likely due to compensatory mechanisms, such as increased appetite and reduced energy expenditure.¹¹

Bariatric surgery has been shown to be very effective in weight reduction, with Roux-en-Y gastric bypass being associated with around 25% weight loss in the long term,¹² and has been shown to reduce the incidence of major adverse cardiovascular events (MACE) in observational studies.¹³ Although recommended in the UK obesity guidelines, bariatric surgery is not easily scalable at the population level. Patients with multiple comorbidities are often considered unsuitable for this intervention due to perceived surgical risks, and many are reluctant to pursue this option.¹⁴

Historically, anti-obesity drugs have been poorly tolerated, and many have been discontinued due to safety concerns, including cardiotoxicity.^15,16 However, over the last decade, glucagon-like peptide-1 (GLP-1) receptor agonists (RAs) have changed the landscape of T2D and obesity management. GLP-1 is a gut-derived hormone produced in response to eating, with receptors present in various tissues in the body, including the pancreas, kidneys, gastrointestinal tract, brain and heart.^17,18 In the pancreas, it increases the release of insulin and reduces glucagon secretion. Moreover, it slows gastric emptying and acts on the brain to reduce appetite, leading to fewer food cravings and a reduction in the anticipated pleasure of eating,¹⁹ consequently reducing calorie intake and leading to weight loss.

Since the approval of the first GLP-1 RA for T2D 20 years ago,²⁰ more selective GLP-1 RAs have been developed, offering improved efficacy, better tolerability, and potential cardiovascular benefits. Their substantial impact on weight loss has led to trials of higher-dose formulations for obesity treatment. Figure 1 provides a summary of the weight loss seen in T2D and obesity, and table 1 provides information on the formulations available. Furthermore, combinations of GLP-1 with other entero-pancreatic hormones, such as glucose-dependent insulinotropic polypeptide (GIP), amylin and glucagon, have been developed as dual or triple agonists. Tirzepatide, which targets both GLP-1 and GIP receptors, is the first dual agonist to receive approval both for T2D and obesity management indications, and has greater weight loss efficacy compared with selective GLP-1 RAs.^21,22

The potential of GLP-1-based therapies as durable, safe and effective weight loss drugs with associated cardiovascular benefits mean that they will likely have a central role in the management of patients with obesity-related cardiovascular diseases. Weight loss with GLP-1-based therapies is associated with significant improvements in multiple cardiovascular risk factors, including blood pressure, lipid levels, albuminuria and glycaemia.^23–28 Beyond risk factor control, recent trials have demonstrated marked benefits on hard cardiovascular outcomes, with exciting therapeutic potential in atherosclerotic cardiovascular disease²⁹ and heart failure with preserved ejection fraction (HFpEF),^30,31 with potential benefit in other conditions including AF.^32,33 A recent meta-analysis of 21 trials, including almost 100,000 patients at high-risk of cardiovascular events, demonstrated that GLP-1 RAs reduce both mortality and MACE.³⁴ This review aims to summarise available GLP-1-based pharmacotherapies and highlight recent trials demonstrating cardiovascular benefits (figure 1 and table 2). We provide practical guidance for patient selection, drug initiation and patient monitoring (figure 2). This will serve as an aid for cardiovascular clinicians, who will inevitably encounter patients suitable for, or already using, these drugs in their daily practice.

The effect of GLP-1 RAs on cardiovascular outcomes

GLP-1 mono-agonists and cardiovascular outcome trials in T2D

Most cardiovascular outcome trials undertaken with GLP-1 RAs have been in people with T2D and cardio–renal–metabolic (CaReMe) diseases. These were initially driven by a mandate from the US Food and Drug Administration (FDA) necessitating long-term cardiovascular outcome trials for safety of therapies for T2D.³⁵

Summaries of the key cardiovascular outcome trials in T2D of GLP-1 RAs have previously been published.^36,37 While some of these trials found that GLP-1 RAs were non-inferior compared with placebo for MACE in people with T2D, several, primarily the long-acting GLP-1 RAs, showed superiority compared with placebo: REWIND (dulaglutide),³⁸ LEADER (liraglutide),³⁹ SUSTAIN-6⁴⁰ and SOUL⁴¹ (subcutaneous and oral semaglutide), and Harmony Outcomes (albiglutide)⁴² trials.

Initial results of these trials indicated that improved outcomes with GLP-1 RAs in T2D were mainly driven by reduced atherosclerotic cardiovascular events, demonstrated by a significant reduction in nonfatal stroke in the REWIND and SUSTAIN-6 trials, and cardiovascular death in the LEADER trial, with no reduction in the exploratory outcome of heart failure hospitalisations across trials.^38–40 This is in contrast to trials of sodium-glucose cotransporter-2 (SGLT2) inhibitors, which did show a reduction in the rate of heart failure hospitalisations.^43–45 However, a recent meta-analysis of clinical trials that compared GLP-1 RAs with placebo in people with T2D demonstrated both a 13% reduction in the rate of MACE and a significant reduction in heart failure hospitalisations, with 3.7% participants experiencing the outcome in the placebo arm and 3.2% in those randomised to a GLP-1 RA.⁴⁶

GLP-1 mono-agonists and cardiovascular outcome trials in people with obesity without diabetes

Approximately 40% of people with coronary artery disease are living with obesity, making it a major addressable risk factor in many with established atherosclerotic heart disease.^47,48 In people without diabetes, the SELECT (Semaglutide Effects on Cardiovascular Outcomes in People with Overweight or Obesity) trial recruited participants with a BMI ≥27 kg/m² and established cardiovascular disease (previous myocardial infarction [MI], stroke or symptomatic peripheral vascular disease) and randomised them to semaglutide 2.4 mg weekly or placebo.²⁹ The trial is summarised in table 2. More than 75% of participants had a history of previous MI, and one quarter had chronic heart failure. The mean reduction in body weight in participants randomised to semaglutide was 10.2% over 208 weeks.⁴⁹ The primary composite end point of death from cardiovascular causes, nonfatal MI, and nonfatal stroke was significantly lower in the semaglutide, versus placebo, arm by 20%, with an absolute risk reduction of 1.5%. Lower rates of nonfatal MI and coronary revascularisation were demonstrated, showing a reduction in atherosclerotic cardiovascular events similar to trials in people with T2D. The trial also showed lower occurrence of heart failure end points (hazard ratio [HR] 0.82, 95% confidence interval [CI] 0.71 to 0.96) and death from any cause (HR 0.81, 95%CI 0.71 to 0.93) in the semaglutide group. A subgroup analysis also revealed patients with previous coronary artery bypass graft (CABG), who are at elevated risk of atherosclerotic events, had an absolute risk reduction of 2.3% of the composite primary outcome with semaglutide compared with placebo.⁵⁰

Tirzepatide (dual agonist) and cardiovascular outcome trials in T2D and obesity

A prespecified cardiovascular meta-analysis of seven clinical trials (each with a minimum follow-up of 26 weeks) evaluated time to first MACE in 4,887 tirzepatide-treated participants with T2D versus 2,328 controls.⁵¹ Approximately one-third of the study population had pre-existing cardiovascular disease. This showed a trend towards a reduction in MACE and cardiovascular death during an average of one year of treatment. Furthermore, the results of the SURPASS-CVOT trial, a randomised-controlled trial including over 13,000 participants with T2D, a BMI >25kg/m² and established cardiovascular disease, have recently been published. This showed tirzepatide was non-inferior to dulaglutide for the composite end point of death from cardiovascular causes, myocardial infarction and stroke over a median follow-up of four years.⁵²

Regarding the impact of tirzepatide on cardiovascular events in people with obesity without diabetes and established cardiovascular disease or high cardiovascular risk profile, the SURMOUNT-MMO trial (NCT05556512) is a large, ongoing trial focused on adults with obesity, and either established cardiovascular disease or risk factors. It aims to enrol over 15,000 participants to evaluate whether tirzepatide can reduce major health outcomes compared with placebo. The primary end point is a composite of all-cause mortality, nonfatal MI, nonfatal stroke, coronary revascularisation, or heart failure events. Results from the trial are expected by October 2027.

Several other dual therapies are currently being assessed for weight loss and cardiovascular disease, including the combination of cagrilintide, a long-acting amylin analogue, with semaglutide (NCT05669755) and survodutide, a dual glucagon and GLP-1 RA (NCT06077864). Retatrutide, a triple agonist targeting GIP, GLP-1, and glucagon receptors, is also under evaluation in the TRIUMPH-OUTCOMES cardiovascular and renal outcomes trial (NCT06138056).

Heart failure

HFpEF

Obesity is present in over half of those with HFpEF,⁵³ and it is widely recognised that HFpEF is frequently associated with other comorbidities, such as hypertension, T2D and chronic kidney disease (CKD). Obesity-related HFpEF may, itself, also form a distinct phenotype warranting specific treatments.^54,55 Unsurprisingly, targeting HFpEF treatment with weight loss has been the subject of intense research interest, and the results of trials with GLP-1-based RAs in this cohort of patients (table 2 and figure 1) were eagerly awaited.

Semaglutide in HFpEF

Once-weekly subcutaneous semaglutide 2.4 mg was investigated in the STEP HFpEF DM³¹ and STEP HFpEF³⁰ trials, which were multi-centre placebo-controlled randomised trials in patients with HFpEF and a BMI >30 kg/m², with and without diabetes, respectively. The co-primary end points were change in the Kansas City Cardiomyopathy Questionnaire (KCCQ) clinical summary score, which quantifies heart failure-related symptoms and physical function, and percentage change in body weight after receiving the intervention for 52 weeks.

In the STEP HFpEF DM trial, participants had a mean BMI of 36.9 kg/m², 29% of patients had New York Heart Association (NYHA) class III or IV heart failure and median N-terminal pro-B-type natriuretic protein (NT-proBNP) was 493 pg/ml. Median glycated haemoglobin (HbA1c) was 6.8%, indicating very good diabetic control for most participants. Semaglutide caused a 6.4% greater reduction in body weight than placebo, and the KCCQ clinical summary score showed a mean improvement of 13.7 points in the semaglutide group versus 6.4 points in the placebo group (p<0.001 for both end points).

In the STEP HFpEF trial, the median age and BMI were similar to the STEP HFpEF DM trial, but a larger proportion (56.1%) were female. One third of participants had NYHA class III or IV heart failure with a median NT-proBNP level of 450.8 pg/ml. Only 3.6% of participants were receiving SGLT-2 inhibitors compared with 32.8% in the STEP HFpEF DM trial. Mean percentage change in body weight was –13.3% in the semaglutide group versus –2.6% in the placebo group (p<0.001) with a mean change in KCCQ clinical summary score of 16.6 points in the semaglutide group compared with 8.7 points in the placebo group (p<0.001).

Additionally, both trials reported a modest improvement in participant’s six-minute walk distance, along with a reduction in NT-proBNP of 23% in the STEP-HFpEF DM trial and 21% in the STEP HFpEF trial. Although not sufficiently powered to assess clinical events, in the STEP HFpEF trial one participant receiving semaglutide was hospitalised for heart failure during the trial period versus 12 participants in the placebo arm, and in the STEP HFpEF DM trial, seven participants receiving semaglutide versus 18 participants in the placebo group were hospitalised due to heart failure. A participant-level pooled analysis of four randomised-controlled trials, including the STEP HFpEF and STEP HFpEF DM trials, comprising 3,743 individuals with HFpEF, demonstrated that semaglutide significantly reduced the risk of the composite outcome of cardiovascular death or first worsening heart failure event compared with placebo.⁵⁶

Importantly, the improvements in KCCQ clinical summary score with semaglutide, compared with placebo in these trials, were larger compared with other drugs in HFpEF, including SGLT2 inhibitors and the non-steroidal mineralocorticoid receptor antagonist finerenone.^57–59 However, it is unclear whether symptom relief – such as reduced shortness of breath – is only due to weight loss, or whether there are direct effects of semaglutide on heart failure. In STEP HFpEF, clinical benefits with semaglutide were closely tied to the degree of weight loss, underscoring weight reduction as a key therapeutic mechanism in obesity-related HFpEF.⁶⁰ Weight reduction caused by GLP-1 RAs likely contributes to the benefit seen, through reduced plasma volume, decreased ectopic fat and lowering of blood pressure.⁶¹ Patients with T2D treated with GLP-1 RAs have improved diastolic function^62,63 (although this has not been consistent across studies⁶⁴), as well as improvements in myocardial strain⁶⁵ and perfusion.⁶⁶

Tirzepatide in HFpEF

Due to the greater weight reduction expected, and its engagement with GIP receptors, which are expressed widely in ventricular cardiomyocytes, tirzepatide may result in even greater improvement in HFpEF outcomes compared with semaglutide.^22,67 The SUMMIT trial randomised patients with obesity and HFpEF (>50%) – nearly half of whom had pre-existing T2D – to receive subcutaneous tirzepatide or placebo for at least 52 weeks, with a median follow-up of 104 weeks.⁶⁸ The population was similar to the STEP HFpEF trials. Median NT-proBNP was, however, lower and about only one quarter of participants had NYHA class III or IV heart failure. Despite the lower-risk population than STEP HFpEF, cardiovascular death or worsening heart failure was reduced (9.9% with tirzepatide group vs. 15.3% in the placebo group, p=0.026), an outcome driven by a lower rate of heart failure events. Tirzepatide also showed greater improvement in KCCQ clinical summary scores at 52 weeks compared with placebo (19.5 vs. 12.7 points), which was a co-primary end point. It also met all key secondary end points, including improved exercise capacity – patients on tirzepatide walked about 18 metres farther in the six-minute walk test than those on placebo. Additionally, in a cardiac magnetic resonance (CMR) substudy of the SUMMIT trial, tirzepatide reduced left ventricular mass in patients with HFpEF by 8%.⁶⁹

Heart failure with reduced ejection fraction (HFrEF)

There have been no specific trials of semaglutide or tirzepatide in HFrEF to date, with trials focusing on patients with HFpEF due to its greater association with obesity and metabolic disease, and current limited therapies available.

In patients with established heart failure with impaired left ventricular function (left ventricular ejection fraction [LVEF] <40%) with a recent acute heart failure admission, liraglutide was shown to have no significant effect on time to death, time to rehospitalisation for heart failure or proportional change in NT-proBNP over 180 days.⁷⁰ A meta-analysis of this trial, and a subgroup with a LVEF <40% of the EXSCEL trial, which investigated exenatide in T2D, found that GLP-1 RAs may increase the risk of heart failure hospitalisations in this cohort of patients.⁷¹ In the LIVE trial, patients with chronic heart failure and an ejection fraction <45%, liraglutide did not improve LVEF or volumes from baseline to 24 weeks compared with placebo, and more serious adverse cardiac events occurred in the liraglutide group compared with placebo (19% vs. 3%, p=0.04).⁷² These results, therefore, led to caution in the use of GLP-1 RAs in patients with an ejection fraction of <40%. Notably, the weight loss in these trials was less compared with those in HFpEF trials with semaglutide and tirzepatide.

In the SELECT trial, 4,286 participants had a history of heart failure at enrolment, with just over half of these participants having HFpEF, one-third HFrEF and the rest had unclassified heart failure. Semaglutide 2.4 mg weekly improved the composite outcome of MACE, all-cause mortality, and hospitalisation or urgent hospital visit for heart failure compared with placebo, and these benefits were consistent across heart failure subtypes and independent of age, sex, BMI, or NYHA class.⁷³ There was also no increase in adverse events in either heart failure subgroup. These findings reinforce semaglutide’s cardioprotective role and provides some reassurance around the use of GLP-1 RA in patients with impaired LV function. Future studies will clarify this.

Atrial fibrillation

Obesity has been shown to be an independent risk factor for AF,^74,75 and up to 20% of AF cases may be directly attributable to individuals living with overweight or obesity. Additionally, obesity reduces the success rate of pharmacological rhythm control and catheter ablation.^76,77 Several studies have suggested that weight reduction by lifestyle change is an effective strategy in reducing AF symptom burden, and ≥10% weight loss, achieved by 38% of participants in the LEGACY study, was associated with reversal of persistent AF to paroxysmal or no AF over 48 months, as well as a six-fold greater probability of being free from AF.^78,79 GLP-1 RAs are, therefore, an attractive potential treatment for patients with AF.

GLP-1 RAs in AF

Initial studies of GLP-1 RAs identified an increased heart rate with their use, which led to concerns about increased arrhythmic risk,^80,81 however, it has since been shown that GLP-1 RAs may be associated with a lower occurrence of AF in patients with T2D.⁸² Although there are no randomised trials of GLP-1 agonists in AF, observational data suggest they may have benefit. The use of GLP-1 RAs prior to catheter ablation for AF reduced the recurrence of AF over 12 months compared with those not receiving a GLP-1 RA.⁸³ A meta-analysis of eight studies in people with T2D treated with GLP-1 RAs did not show a difference in the occurrence of AF in treated patients versus placebo, although these studies were not designed to assess the occurrence or burden of AF, and this was reported as part of the safety outcomes.³³

Interestingly, in the STEP HFpEF and STEP HFpEF DM trials the improvement in KCCQ clinical summary score was larger in patients with AF compared with those without AF (change in KCCQ clinical summary score 11.7 vs. 4.1, respectively, p<0.01), despite similar changes in body weight.³² Of the participants with AF, 40% had paroxysmal AF, 24% persistent AF, and 35% permanent AF, with similar results seen across each group. A small single-centre randomised trial has just started recruitment to investigate whether tirzepatide will impact the severity and burden of symptoms of AF versus placebo (NCT06802081). Further larger studies of the use of GLP-1-based therapies in AF are required to demonstrate effectiveness at reducing AF symptom burden, however, these results provide promise that the weight loss that can be achieved with GLP-1 RAs will show benefit in this cohort of patients.

Current indications for chronic weight management in the UK

The GLP-1 RAs currently available in the UK for weight management are outlined in table 1.⁸⁴ Following a recent update in the National Institute for Health and Care Excellence (NICE) guidance on the management of overweight and obesity, three subcutaneous GLP-1-based therapies are now recommended, alongside a reduced-calorie diet and physical activity: semaglutide 2.4 mg once weekly, liraglutide 3 mg once daily and tirzepatide 5, 10 and 15 mg once weekly.¹⁴ A summary of the patients eligible for each drug, and who can prescribe them, is presented in figure 2.

Current NICE guidelines recommend that semaglutide 2.4 mg for overweight and obesity be prescribed and managed through specialist weight management services, with treatment limited to a maximum of two years. Its use for cardiovascular risk reduction is currently undergoing NICE consultation.⁸⁵

On the other hand, the recent NICE approval for tirzepatide recommends its availability in primary care, guided by a phased-implementation plan that aims to prioritise 220,000 people with greatest clinical need and multiple obesity-related complications over the next three years.⁸⁶ This prioritised group includes individuals with established atherosclerotic cardiovascular disease (defined as ischaemic heart disease, cerebrovascular disease, peripheral artery disease or heart failure), although long-term outcome trials with tirzepatide are ongoing, including the SURPASS-CVOT (a dedicated cardiovascular outcome trial in people with T2D) and SURMOUNT-MMO (a major morbidity and mortality trial in people with obesity without diabetes). Going forward, and as evidence for the benefits of GLP-1-based therapies on multiple obesity-related complications expands, it may be beneficial for other secondary-care specialties – such as cardiology – to play a more active role in identifying eligible patients and recommending initiation, particularly for those with established cardiovascular disease. In some cases, enabling initiation within these clinics, in collaboration with lifestyle support services in the community, could also help improve timely access to treatment.

Practical prescribing of GLP-1-based therapies

A summary of practical prescribing advice is presented in figure 2.

Initiation, uptitration and other considerations

GLP-1-based therapies for weight management (liraglutide 3 mg, semaglutide 2.4 mg and tirzepatide), should be initiated at a low dose and gradually uptitrated according to the individual Summary of Product Characteristics (SpC), following a ‘start low, go slow’ strategy, particularly in the presence of gastrointestinal side effects.⁸⁷ Specialist nurses can often help with this, particularly in the context of diabetes where there is concern around hypoglycaemia due to concomitant medication. Patients should be advised of common side effects, as well as the expected effects on appetite and weight, and to keep well hydrated.⁸⁴ Patients should be guided on mitigation of side effects, including reducing meal sizes, avoiding high fat and spicy food, and reducing alcohol and fizzy drink intake.⁸⁷ Additional patient education should be provided for injectable GLP-1 RAs on the storage and technique for administration to ensure safe and effective use.

Patient-specific factors, including comorbidities and concomitant medications, need to be considered, as with the initiation of any new medication. The British National Formulary should be consulted for a full list of drug interactions.⁸⁴ Of note, GLP-1-based treatments, and in particular tirzepatide, transiently delay gastric emptying, which may affect the rate of absorption of other oral medications, especially during the early phase of treatment. Most cardiovascular drugs are considered safe to be co-prescribed with GLP-1 RAs, although closer monitoring of warfarin and digoxin may be required with co-administration of tirzepatide. Additionally, female patients on oral contraceptives should switch to non-oral methods or use an add-on barrier method for four weeks after starting tirzepatide, and after each dose increase. The delay in gastric emptying associated with tirzepatide is transient, owing to the development of tachyphylaxis with repeated dosing; however, the effect may transiently recur following dose escalation.⁸⁸

Adverse effects and cautions

The most commonly reported adverse effects with GLP-1 RAs are gastrointestinal, including nausea, vomiting, diarrhoea and constipation.^22,89–91 These symptoms are the most common reason for discontinuation of the drug, although symptoms are largely mild-to-moderate in severity. Slow uptitration and patient education may help with these symptoms. Real-world data suggest that discontinuation at 12 months may approach 50%, which is higher than that seen in randomised trials;⁹² however, other factors, including the cost of the medication, rather than adverse events, may contribute to this observation.⁹³

There have been concerns about the loss of lean body mass, particularly skeletal muscle, with the use of GLP-1 RAs. However, despite a range in the proportion of weight loss attributable to lean body mass seen across clinical trials of GLP-1 RAs (between 20% and 50%), this is similar to that seen with lifestyle interventions and bariatric surgery.^94,95 Physical function and mobility improves with GLP-1 RAs,⁹⁶ and imaging studies have suggested improvement in muscle composition with reduction in muscle fat infiltration.⁹⁷ However, rebound weight gain with cessation of GLP-1 RAs, and weight cycling, may lead to an overall reduction in percentage of lean body mass, as weight increase is predominantly due to increases in adipose tissue, with a lesser increase in muscle mass.^98,99 This, therefore, may be of concern if these medications are stopped, but further studies are needed.

Gallbladder-related disease, including cholecystitis, is more common in those randomised to a GLP-1-based therapy in trials, and this appears to be associated with greater weight loss, although the incidence was low with an occurrence of up to 3.8% with tirzepatide over three years compared with 0.7% with placebo.^90,100 Previous concerns of acute pancreatitis have been alleviated by a meta-analysis of clinical trials of GLP-1 RAs in T2D,¹⁰¹ however, current guidance is to discontinue the drug if pancreatitis develops.⁸⁴ Furthermore, concerns regarding increased risk of pancreatic and thyroid cancer have not been confirmed in studies,^101–103 and the European Medicines Agency have concluded that there is no evidence of a causal link between GLP-1 RAs and thyroid cancer.¹⁰⁴

Additional clinical considerations for people with T2D

Most studies have shown no increased risk of hypoglycaemia in people with T2D receiving GLP-1 RAs, except if these therapies are used concomitantly with insulin or sulfonylureas.⁹¹ People on insulin or sulfonylureas are advised to reduce their insulin doses, or cut down sulfonylurea doses, as appropriate, as they uptitrate GLP-1 doses, and may require additional input from diabetes teams to mitigate this risk of hypoglycaemia. Dipeptidyl peptidase-4 (DPP-4) inhibitors should be stopped on the initiation of a GLP-1 RA.

The rapid reductions in HbA1c with GLP-1-based therapies may increase the risk of diabetic retinopathy. In the SUSTAIN-6 trial, semaglutide 1 mg was associated with a higher rate of retinopathy-related complications (3% vs. 1.8% with placebo). Risk was greatest in individuals with pre-existing retinopathy, higher baseline HbA1c, and longer diabetes duration.¹⁰⁵ Patients with active retinopathy – such as those requiring urgent treatment, or with macular oedema – were not included in the SURPASS programme with tirzepatide. Caution is needed when starting treatment in these high-risk groups, especially if glycaemia is poorly controlled.

Special populations

Use in CKD

In the FLOW trial, which was a dedicated trial in T2D and CKD, patients who received semaglutide 1 mg weekly (the dose approved for T2D) had a 24% lower risk of the composite renal outcome (onset of kidney failure, substantial reduction in estimated glomerular filtration rate [eGFR], or death from kidney or cardiovascular causes) compared with placebo over a median follow-up of 3.4 years.¹⁰⁶ However, depending on the specific drug, discontinuation of a GLP-1 RA may need to be considered in end-stage renal disease.^37,84 Liraglutide 3 mg should not be initiated if creatinine clearance is <30 ml/min/m² and semaglutide should be avoided in end-stage renal disease. However, tirzepatide can be started in those with renal failure and can be continued with dialysis, although there is limited experience of its use in this circumstance.¹⁰⁷

Type 1 diabetes

GLP-1 RAs are not currently indicated for use in type 1 diabetes, however, in a selective group of patients they may have some benefit. In people with type 1 diabetes, two clinical trials found that liraglutide 1.8 mg (dose approved for T2D) reduced HbA1c and insulin requirements, as well as body weight,^108,107 and similar results were found with exenatide in the short term.¹¹⁰ Further research is needed to establish their exact role in this population with a randomised-controlled trial underway (NCT06914895).

Conclusion

GLP-1-based therapies, which have shown significant benefits in patients with T2D and obesity, have also shown promising results in patients with cardiovascular disease. Semaglutide improves cardiovascular outcomes in patients with obesity, with and without diabetes, and both semaglutide and tirzepatide have shown benefit in patients with HFpEF. They will, no doubt, be medications cardiologists will utilise increasingly frequently in the future, although currently largely restricted to weight management clinics, and will form a significant aid in managing patients with obesity. Engaging with patient preference and offering the most appropriate options will be key to targeting this population. Additional trials of GLP-1-based therapies are ongoing, and further advancements will likely revolutionise the management of obesity, and become foundational treatments for the primary and secondary prevention of cardiovascular disease.

Key messages

• Obesity contributes to almost all forms of cardiovascular disease – including atherosclerotic cardiovascular disease, heart failure and atrial fibrillation – and in people with type 2 diabetes and obesity, over 10% weight loss is required to see improvement in rates of major adverse cardiovascular events
• Glucagon-like peptide-1 (GLP-1) receptor agonists show significant benefits in glycaemic control and weight loss
• GLP-1 receptor agonists’ potential for cardiovascular benefits means that they will likely have a central role in the management of patients with obesity-related cardiovascular diseases

Conflicts of interest

DP has acted as a speaker for Novo Nordisk, Eli Lilly, Boehringer Ingelheim and Johnson and Johnson and has received grants from Novo Nordisk, Novo Nordisk UK Research Foundation, Academy of Medical Sciences/Diabetes UK, Health Education East Midlands and the National Institute for Health and Care Research (NIHR). MJD has acted as a consultant/advisor and speaker for Eli Lilly, Novo Nordisk and Sanofi, has attended advisory boards for AbbVie, Amgen, AstraZeneca, Biomea Fusion, Carmot/Roche, Sanofi, Zealand Pharma, Regeneron, GSK and EktaH and as a speaker for AstraZeneca and Boehringer Ingelheim. SA, GPM, GSG: none declared.

Funding

SA is funded through a Clinical Research Training Fellowship from the British Heart Foundation. MJD and DP are funded by the NIHR Leicester Biomedical Research Centre, Leicester, UK. GPM is funded by an NIHR Research Professorship award and GSG by an NIHR Academic Clinical Lectureship.

Acknowledgements

Figures 1 and 2 were created in BioRender (https://BioRender.com/nwvkptm and https://BioRender.com/hba4iwl).

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