Evaluating the benefits of the early use of GLP-1 receptor agonists

Originally developed to improve glycaemic control in patients with type 2 diabetes, GLP-1 receptor agonists have emerged as promising agents for weight management and cardiovascular protection, expanding their therapeutic potential beyond diabetes care.¹ Since 2016, clinical trials such as LEADER,² SELECT,³ and SURPASS⁴ have demonstrated the cardiovascular benefits of GLP-1 receptor agonists, consistently showing a reduction in major adverse cardiovascular events (MACE) across virtually all formulations.^5,6 These findings have expanded the therapeutic potential of GLP-1 receptor agonists beyond diabetes management, positioning them as promising agents in the treatment of cardiovascular disease (CVD). Additionally, these new data point to the utility of introducing GLP-1 receptor agonists earlier in the progression of obesity to treat patients who may be at risk of future CVD complications, similar to current statin use as a primary prevention therapeutic, particularly given GLP-1 receptor agonists’ potential to slow disease progression by addressing obesity as the underlying cause of the plethora of other diseases. The effect of this class of medications (table) on weight loss, coupled with their demonstrated cardiovascular benefits, make GLP-1 receptor agonists possible breakthrough solutions in the treatment of obesity and its associated comorbidities. This primary prevention approach would substantially reduce the lifetime burden of chronic diseases on the health-care system and improve patients’ overall health span.

Table:

List of selected currently available and future GLP-1 receptor agonists and their targets

	On the market	Clinical trial status	Route of administration	Receptor target
Exenatide	Yes	Finished	Injection	GLP-1
Liraglutide	Yes	Finished	Injection	GLP-1
Semaglutide	Yes	Finished	Injection or oral	GLP-1
Tirzepatide	Yes	Finished	Injection	GLP-1, GIP
Dulaglutide	Yes	Finished	Injection	GLP-1
Albiglutide	Yes	Finished	Injection	GLP-1
Lixisenatide	Yes	Finished	Injection	GLP-1
Cagrisema	No	Phase 3	Injection	GLP1, amylin
Survodutide	No	Phase 3	Injection	GLP-1, glucagon
Retatrutide	No	Phase 2	Injection	GLP-1, GIP, and glucagon
NNC0165–1875 + semaglutide	No	Phase 2	Injection	GLP-1, PPY
Efinopegdutide	No	Phase 2	Injection	GLP-1, glucagon
Danuglipron	No	Phase 2b	Oral	GLP-1
Orforglipron	No	Phase 1b	Oral	GLP-1
Amycretin	No	Phase 1	Oral	GLP-1, amylin

GIP=glucose-dependent insulinotropic polypeptide. PPY=pancreatic polypeptide.

Obesity, marked by a chronic state of low-grade inflammation resulting from caloric overconsumption, stems initially from dysfunctional adipose tissue.^7,8 Lifestyle modifications including diet and exercise are always recommended for weight management; however, it is challenging for many individuals to adhere to these changes without substantial outside help,⁹ as these modifications are predicated on ready access to nutritious foods¹⁰ and time committed to a healthier lifestyle.¹¹ Additionally, bodyweight is physiologically regulated through many integrated inputs, with adjustments in energy intake and expenditure working together to maintain a specific set point. In cases when a high body weight persists for a long period of time, weight loss can be challenging as the body tends to maintain the current set-point despite efforts at losing weight. Large-scale GLP-1 receptor agonists trials, have not always explicitly targeted obesity reduction as a primary endpoint. However, several recent trials such as STEP 1 published in 2021, focused on weight loss in individuals who are overweight (with one other CVD risk factor) or obese, and have described significant clinical reductions in body weight and waist circumference, along with improvements in cardiovascular risk biomarkers.¹² The growing evidence base suggests a useful role of GLP-1 receptor agonists in primary prevention of obesity; however, more research is needed to assess these medication’s therapeutic potential in individuals at risk for a lifetime of obesity-induced diseases.

The efficacy of GLP-1 receptor agonists in combating obesity and its associated health risks presents a unique opportunity to improve the health of millions of individuals. Therefore, there is a compelling case for considering the early, primary prevention use of GLP-1 receptor agonists in individuals with obesity (BMI >30 kg/m²), or overweight (BMI >25 kg/m²) with indicators of future CVD risks including dyslipidaemia or hypertension, regardless of their current insulin resistance and diabetic status. This type of treatment regimen is feasible due to GLP-1 receptor agonists’ long-term safety, as shown by participants in the SELECT trial who experienced no substantial side-effects for up to 40 months.¹³ Currently there is no limit on the treatment period duration, with drug administration generally stopping once a lower BMI is reached. However, there remain questions on the possible side-effects such as decreased lean mass. It remains unclear whether this loss is a direct effect of GLP-1 receptor agonists on the muscle or a result of improved body weight leading to the need for less mass in general.¹⁴ Taking a primary prevention approach to the use of GLP-1 receptor agonists might reduce the incidence and severity of obesity-initiated diseases including CVD, metabolic dysfunction-associated steatohepatitis, and type 2 diabetes, but if this is at the cost of large scale muscle loss, long-term health might be negatively affected. Another possible important consideration for GLP-1 receptor agonists primary prevention use is the reduced need for other therapies that are typically introduced as chronic weight gain leads to disease presentation, such as statins for cholesterol management or metformin and SGLT2 inhibitors for glycaemic control. Going forward, a cost modelling study should be employed to compare the relative cost of early weight management with the use of GLP-1 receptor agonists versus the treatment cost of obesity-related diseases that tend to appear later in life for patients who did not undergo effective weight management regimens.

The effects of weight management through GLP-1 receptor agonists extend beyond weight loss. Patients with obesity are at an increased risk for cardiovascular morbidity and mortality, and the prevalence of heart failure in this population has been underestimated.¹⁵ The use of GLP-1 receptor agonists might also help improve cardiac function through various systemic mechanisms including lipid profile modification, glycaemic control, and insulin sensitivity.¹⁶ A 2024 prespecified analysis¹⁷ of individuals at risk for ischaemic and heart failure outcomes in the SELECT trial showed improvements across measures, such as hazard ratio, MACE, cardiovascular death, and all-cause death. Additionally, semaglutide treatment improved MACE and all outcomes for people with heart failure with reduced ejection fraction and heart failure with preserved ejection fraction. These results illustrate the effectiveness of treating these populations with GLP-1 receptor agonists.

Although GLP-1 receptor agonists hold immense promise as primary prevention therapeutics, several challenges must be addressed before widespread implementation. In 2022, a study by Wilding and colleagues¹⁸ found that two-thirds of the weight loss with semaglutide was regained 1 year after treatment discontinuation. This result highlights the importance of implementing treatment in combination with lifestyle modifications to maintain long-term weight loss. These results indicate that GLP-1 receptor agonism alone is not enough to reset a metabolic set-point of a person with overweight, as evidenced by the common weight-gain recidivism described.¹⁹ Another hurdle to implementing GLP-1 receptor agonists for the primary prevention of obesity-related diseases including diabetes and CVD is the current cost of these compounds. A monthly prescription without insurance approval in the USA costs more than US$1000, pushing these treatments out of reach for socioeconomic groups that are most affected by the obesity epidemic. Lastly, the long-term effect of GLP-1 receptor agonist use in adolescents, particularly on their growth and development, needs further investigation.¹³ Despite these challenges, the potential of GLP-1 receptor agonists to reshape cardiometabolic disease management and improve the health span of individuals struggling with health issues stemming from chronic obesity remains promising, and it is important to continue efforts to address the barriers to widespread access to these medications.