Glucagon-like Peptide-1 Receptor Analogues for the Treatment of Obesity

There is an increasing prevalence of obesity worldwide, associated with significant morbidity and mortality, which frequently reduces quality of life and life expectancy. Consequently, there is a substantial and growing personal and economic burden necessitating the development of more effective therapies for obesity. Glucagon-like peptide-1 receptor analogues (GLP-1RAs) are licensed for the treatment of type 2 diabetes (T2D), and there is substantial evidence that these drugs not only improve cardiovascular outcomes but also promote weight loss. More recent evidence supports the use of the GLP-1RAs liraglutide and semaglutide in people with obesity without T2D. This article discusses the results of the major cardiovascular outcome trials for GLP-1RAs in people with T2D, the SCALE Obesity and Prediabetes study (Effect of liraglutide on body weight in non-diabetic obese subjects or overweight subjects with co-morbidities: SCALE™ - Obesity and Pre-diabetes; ClinicalTrials.gov identifier: NCT01272219; investigating liraglutide) and the STEP studies (Semaglutide treatment effect in people with obesity; assorted studies; investigating subcutaneous semaglutide). We also highlight the importance of a cost-effective approach to obesity pharmacotherapy. Clinicians should consider the use of GLP-1RAs in people with obesity, especially those with T2D or other obesity-related diseases, such as hypertension and dyslipidaemia. Ongoing trials, as well as clinical and cost-effectiveness appraisals, are anticipated over the next 12 months, and their findings may change the current landscape of obesity pharmacotherapy.

Obesity is a growing problem worldwide with extensive health and economic consequences, rendering interventions that encourage weight loss of great interest. Obesity is usually defined as a body mass index (BMI) of 30 kg/m 2 or above, or 27.5 kg/m 2 or above in Asian populations.
Based on the health survey for England 2019, 28% of adults in England are obese. 1 This is not unique to the UK, as the prevalence of obesity has increased in every country worldwide over the past 50 years, driven mainly by changes in the global food system and more sedentary lifestyles. 2,3 From 1999-2000 to 2017-2018, the prevalence of obesity in the USA increased from 30.5% to 42.4%. 4 In 2016, the World Health Organization (WHO) found that 1.9 billion adults aged over 18 were overweight, which equates to 39% of the population. 5 Of these adults, 650 million were obese, which equates to 13% of the population. 5 The disparity between the UK, USA and WHO obesity prevalence could be explained by the low prevalence of obesity in low-income countries. 6 Despite obesity being preventable and the known economic and health implications, obesity will also be a problem for future generations, as 38 million children under the age of 5 were overweight or obese in 2019. 5 Treatment, as well as prevention, will therefore continue to be an important intervention.
A raised BMI is associated with an increase in all-cause mortality, largely driven by excess cardiovascular disease. 7 Obesity is also associated with significant morbidity and mortality from a wide range of health conditions, including various cancers, cerebrovascular disease, hypertension, type 2 diabetes mellitus (T2D), chronic kidney disease, osteoarthritis and back pain. As a result, obesity is associated with long-term physical impairment and reduced quality of life for many people around the world, including those of working age. 8 In addition, obesity has been identified as an independent risk factor for COVID-19 mortality in hospitalized patients. 9 The economic impact of obesity is substantial, and the amount spent on the treatment of obesity and T2D in the UK is more than the combined cost of the police, fire service and judicial system. 10 In 2014/15, obesity-related illness cost the UK National Health Service £6.1 billion. 10 The estimated medical cost of obesity in the USA ranged from US$147 billion to nearly US$210 billion per year. 4 The medical cost for people with obesity was US$1,429 higher than medical costs for people with a healthy weight. 4 Therefore, weight loss interventions have the potential to significantly improve the cost-effectiveness of health services. Bupropion/naltrexone is a combination of a dopamine and norepinephrine reuptake inhibitor (bupropion) and an opioid receptor antagonist (naltrexone). These both work centrally to increase satiety and were originally used for nicotine, alcohol and opiate addictions.
Bupropion/naltrexone produces weight loss of a mean of 4.4 kg, and side effects include nausea, headaches and dizziness. 16  shown a significant effect on weight loss and other metabolic outcomes related to obesity, including major adverse cardiovascular events and renal outcomes. 20,21 In this article, we present the evidence supporting the use of GLP-1RAs in the treatment of obesity in people with or without T2D and discuss ongoing clinical trials of drugs within this class.

Diabetes and obesity: The role of incretin hormones
The incretin effect was first identified by Nauck et al. 35 years ago. 22 The incretin effect describes augmented insulin secretion from the pancreas following an oral intake containing carbohydrate. A blunted incretin response was observed in people with T2D. 23 Subsequently, GLP-1 was recognized as a major player in the incretin system, raising the possibility of manipulating this system to treat people with T2D. 24 Enteroendocrine L-cells of the small intestine secrete incretin hormones, The influence of GLP-1RAs on weight is secondary to the combined impact of chemically mediated satiety within the hypothalamus and mechanical satiety by reducing gastric emptying to engender satiation. 27 Whilst some authors speculate that GLP-1RAs increase energy expenditure through brown fat activation and reduced peripheral lipid storage, this has not been demonstrated in human subjects. 28,29 The commonest side effects associated with GLP-1RAs include nausea, vomiting and gastrointestinal disturbance, which reduce food intake and support weight loss. 30

Obesity without diabetes: A role for GLP-1RAs?
There is evidence that the incretin response is blunted in people with obesity in the absence of underlying T2D, implying therapeutic potential in this often difficult-to-treat group. 39     The observed weight loss with semaglutide in the STEP studies was greater than that seen with liraglutide in the SCALE Obesity and Prediabetes study, or any other pharmacotherapy. 40 In addition, semaglutide in the STEP studies maintained the weight loss at 68 weeks, supporting its use in the long-term management of obesity. Nevertheless, differences in study populations, trial duration and prevalence of prediabetes between the studies preclude direct comparison. We eagerly await the results of the STEP-8 study, which is a head-to-head trial of semaglutide 2.4 mg once weekly versus liraglutide 3 mg once daily. 52 Available evidence from the STEP studies suggests that semaglutide may have the potential to bridge the gap between pharmacotherapy and bariatric surgery. The degree of weight loss observed in the STEP studies is comparable to that with some bariatric procedures. 54 In the Swedish Obese Subjects study, maximal weight loss observed after 1-2 years of vertical banded gastroplasty and laparoscopic adjustable gastric banding was 25% and 20%, respectively. 54 In the STEP-4 trial, 40% of participants who were on semaglutide for 68 weeks lost 20% or more of their initial body weight. 48

Cost-effectiveness of GLP-1RAs in obesity
With the ever-increasing financial pressures faced by health systems worldwide, the cost-effectiveness of pharmacotherapy for obesity is important. In the UK, NICE generally accepts an incremental cost-effectiveness ratio of up to £20,000 per QALY gained. Recently, NICE supported the use of liraglutide for weight loss, though only in people with a BMI ≥35 kg/m 2 with prediabetes and high cardiovascular risk and when prescribed by a tier 3 weight management service. 18 This was following a confidential price reduction for purchases from such weight management services, which brought the cost per QALY to £11,293. 18 Semaglutide is not currently recommended by NICE for the treatment of obesity without T2D in the UK, though an appraisal of the clinical and cost-effectiveness of this GLP-1RA recently started, and publication is expected within the next 12 months. 57 One study based on the Research study comparing a new medicine semaglutide to liraglutide in people with type 2 diabetes (SUSTAIN 10) trial found that the use of injectable semaglutide 1 mg weekly rather than liraglutide 1.2 mg daily for people with T2D resulted in a lifetime cost saving of £140 per patient. 58 This cost saving was driven by a reduction in diabetes-related complications associated with the greater reductions in HbA1c and body weight. 58 However, for the treatment of obesity, semaglutide was found to be not as cost-effective as other obesity pharmacotherapy due to its relatively higher costs, despite its more significant clinical impact than other drug therapies for obesity. 59 Of note, the abovementioned studies do not include evidence from recently published STEP studies. Further cost-effectiveness studies of semaglutide in people with obesity will be supported by the ongoing SELECT (Semaglutide effects on heart disease and stroke in patients with overweight or obesity; ClinicalTrials.gov identifier: NCT03574597) study investigating major adverse cardiovascular outcomes in people who were overweight or obese without T2D. 53 The SELECT study aims to recruit 17,500 participants, and the estimated study duration for an individual participant is from 31 to 59 months. The primary outcome measure is time-to-first-occurrence of a composite endpoint consisting of cardiovascular death, non-fatal myocardial infarction or non-fatal stroke. It is estimated to be completed by September 2023. We await the outcome of the ongoing NICE appraisal with great interest.

Conclusions
Over the past two decades, GLP-1RAs have shown great promise in the treatment of people with T2D. Benefits beyond improved glycaemic control, including weight loss, improved cardiovascular risk factors, markers of fatty liver and renal disease and, most importantly, cardiovascular morbidity and mortality, make them a particularly attractive therapeutic option. The impact of GLP-1RAs, particularly liraglutide and semaglutide, on weight loss should guide clinicians to choosing these drugs when considering pharmacotherapy for people with T2D and obesity. However, recent trial data indicate that even in people without T2D, there is high-quality evidence to support their use for weight loss. With the promising results from the STEP 1-4 trials, semaglutide has been added to the pharmacotherapy of weight management. Additionally, given the promise of the dual GIP/GLP-1 agonist tirzepatide for the treatment of obesity in people with T2D, further trials exploring cardiovascular outcomes with this drug would be welcome to support its use in routine clinical practice.
Ongoing cost-effectiveness analyses of these drugs in various populations and subpopulations are essential to validate the health economic impact of these drugs. The SELECT study may further justify the use of semaglutide in people with obesity to improve cardiovascular morbidity and mortality and thereby influence its incremental cost-effectiveness ratio. Clinicians should be aware of these findings and consider the use of these drugs when appropriate to improve health outcomes and reduce the prevalence of obesity-related disability, which is frequently observed in people with T2D. q