Once-weekly 2.4 mg Semaglutide for Weight Management in Obesity: A Game Changer?

The treatment of obesity can no longer be reduced to a simplistic view of weight loss. Metabolic adaptation leads to systematic weight regain following weight-loss efforts, and new obesity treatments should therefore aim to induce long-standing double-digit weight loss, and thus improve and even reverse obesity-associated comorbidities such as type 2 diabetes. Until now, only metabolic surgery has been able to achieve such a goal, but this invasive procedure cannot be offered on a large scale. Among the alternatives, lifestyle interventions and drug therapies have often been disappointing. The recent availability of once-weekly subcutaneous 2.4 mg semaglutide (a glucagon-like peptide-1 receptor agonist; Wegovy™ Novo Nordisk A/S, Bagsværd, Denmark) has changed the scene, and semaglutide is considered a ‘game changer’ in the treatment of obesity. The results from the phase III STEP (Semaglutide treatment effect in people with obesity) clinical programme have shown that semaglutide provides clinically meaningful and sustained weight loss in ranges much higher than those achieved with previously available pharmacotherapies. These results led to the approval of semaglutide by regulatory authorities as an adjunct to a reduced-calorie diet and increased physical activity in people with obesity or overweight, with at least one weight-related comorbidity. With data from phase II and III clinical trials showing that newer drugs (i.e. the glucagon-like peptide-1 and gastric inhibitory polypeptide dual receptor agonist tirzepatide and the amylin agonist cagrilintide, either alone or combined) produce a greater sustained weight loss than semaglutide, an upstream ‘weight-centric’ strategy has emerged as a new standard for the treatment of type 2 diabetes.

≥27.5 kg/m 2 in Asian populations and ≥30.0 kg/m 2 in all other populations -is an epidemic that has spread across the world. 1 Recent data from the World Health Organization (WHO) indicate that 59% of adults and almost one in three children (29% of boys and 27% of girls) in Europe are overweight or living with obesity. 2 According to the WHO, the prevalence of obesity in the Europe is higher than in any other WHO region except for America, and is among the leading causes of death and disability in this region. Of note, while obesity has been a health issue in high-income countries for many years, the greatest rise in its incidence is now seen in low-and middle-income countries. 3 Obesity should not be reduced to a simplistic view of 'too much weight', but rather be viewed as a driving force behind many health problems. Obesity should be defined as 'abnormal or excessive fat accumulation that presents a risk to health'. 4 More than 200 complications are linked to obesity, thereby explaining the increased morbidity and mortality related to the condition and the 4 million obesity-related deaths worldwide in 2015. 5,6 Obesity (even moderate when the visceral adipose tissue is involved) is associated with an increased risk of developing metabolic syndrome, type 2 diabetes (T2D), cardiovascular disease (CVD) (including hypertension, hyper-or dyslipidaemia, ischaemic heart disease, heart failure, ischaemic stroke), mechanical dysfunction (osteoarthritis), obstructive sleep apnoea syndrome (OSAS), malignancies (e.g. breast cancer, prostate cancer) and mental health issues, including depression, anxiety and eating disorders. [7][8][9][10][11] Lately, we have even learned that people with obesity are at higher risk of developing more severe disease and complications from COVID- 19. 12 The quality of life (QoL) of people with obesity or overweight is often impaired and their lifespan significantly reduced. 13 A high BMI is associated with decreased life expectancy of up to 10 years compared with those with healthy BMI and, for every 5 kg/m 2 BMI increment above the range of 22.5-25.0 kg/m 2 , overall mortality is increased by 30%. 14 CVD is the leading cause of death in people with obesity, followed by T2D. 6 In addition to the individual burden, the economic cost associated with obesity should also be noted. The estimated total cost of high BMI to health services worldwide is US$990 billion per year, which represents 13.2% of total healthcare expenditure. 3

Pathophysiology
The pathophysiology of obesity is multifactorial and involves social determinants, genetic predisposition and metabolic, behavioural, psychological and environmental factors. 15 Together, these factors alter the energy balance by modifying satiety and feeding signalling in the brain.
touchREVIEWS in Endocrinology Obesity occurs when the energy intake exceeds the total body energy expenditure. 16 Three areas of the brain, namely the hypothalamus, the mesolimbic area and the prefrontal cortex (executive functioning areas), are directly involved in the control of energy balance. [17][18][19] Homeostatic mechanisms include peripheral signals from the gastrointestinal (GI) tract (for food intake information) and from the adipose tissue (for energy use) that are transmitted via the vagus nerve through the central nervous system, where they are processed in the brain stem and hypothalamus.
Neural pathways specialized in satiety, hunger and energy expenditure are permanently activated. [17][18][19] These pathways have been programmed through millennia of human phylogenetic development so that homeostasis maintains a person's weight at the highest possible level. 19,20 This explains why any weight loss immediately triggers compensatory neurohormonal pathways (e.g. involving leptin, ghrelin, peptide YY, gastric inhibitory peptide, slowing of resting metabolism) that increase hunger and decrease energy expenditure -as metabolic adaptation -until a new set-point of energy balance is reached. 19,20 Thus, even if people with obesity temporarily succeed in losing weight, they immediately face millennia of adaptation leading to weight regain, often to an even greater level from where they started. Given the complex pathophysiology of obesity and the potent counterregulatory neuroendocrine pathways activated to counter weight loss, obesity can no longer be attributed to a lack of willpower. Rather, it should be treated like other chronic cardiometabolic conditions such as T2D, hypertension and hyper-or dyslipidaemia, with treatment aiming to disrupt long-term acquired biochemical circuits. 21,22 Losing weight and maintaining weight loss over the long term will always be a challenge. Meeting this challenge, both medically and at a societal level, has become unavoidable as the consequences of obesity in terms of health and economic costs become ever clearer.
Reducing obesity improves not just QoL and wellbeing, but also obesityrelated comorbidities. Weight loss of 5% is associated with improved blood pressure and glycosylated haemoglobin (HbA1c) levels. Weight loss of 5-10% is associated with reduced intrahepatocellular lipids in non-alcoholic fatty liver disease, reduced triglyceride and non-high-density lipoprotein cholesterol levels, increased high-density lipoprotein cholesterol levels, improved ovulation and prevention of T2D. Weight loss of 10-15% improves physical function in people with osteoarthritis, gastro-oesophageal reflux disease, OSAS, inflammation and fibrosis in non-alcoholic steatohepatitis, and incontinence. More than 15% weight loss may be associated with remission of T2D (which does not mean cure), improvement in heart failure and reduced cardiovascular mortality ( Table 1). 23

Treating obesity: lifestyle measures and metabolic surgery
Although lifestyle interventions, including calorie reduction, daily exercise and behavioural therapy, are considered the cornerstone of treating obesity, it must be recognized that weight loss achieved through these measures is rarely clinically meaningful and often not sustainable over the long term. Clearly, other means, including drug therapies and metabolic surgery (also known as bariatric or metabolic surgery), must be used to promote weight loss. Metabolic surgery is a powerful tool for treating obesity. [24][25][26][27] It can induce weight loss of up to 15-30% of baseline body weight, along with reduced long-term mortality and remission of T2D. One of the major lessons we have learned from metabolic surgery, through double-digit weight loss, is its ability to disrupt the pathophysiological evolution of T2D. The term 'metabolic' arose from the findings that Roux-en-Y gastric bypass and sleeve gastrectomy induce deep changes in gut hormone and insulin secretion and sensitivity, independent of weight. 28,29 A more anorectic hormonal profile helps patients to lose weight and counters increased appetite over the long term. However, metabolic surgery is not a trivial procedure. Several complications can arise in both the short-and long-term postoperative periods. Without long-term medical control, patients may suffer from micronutrient deficiencies, and the risk of weight regain and recurrence of T2D is real. 30,31 The association between the benefits of metabolic surgery and increased secretion of gut hormones such as glucagon-like peptide (GLP)-1 has led to the development of a class of drugs active in both obesity and T2D.
GLP-1 is an incretin hormone (a 30-amino acid peptide hormone) that is continuously released by enteroendocrine cells in the small intestine, but in greater amounts in response to food intake. Its main physiological actions include enhancing glucose-dependent insulin secretion, suppressing postprandial glucagon secretion, slowing gastric emptying and inducing satiety through hypothalamic stimulation. 32 Long-acting GLP-1 receptor agonists (GLP-1 RAs) have therefore been engineered for the treatment of T2D and obesity. [33][34][35] Treating obesity: drug therapy to date Until recently, the development of new drugs in the field of obesity has been marked by resounding failures. Some drugs have been withdrawn from the market due to serious side effects, including increased morbidity and mortality. 36 The therapeutic performance of these drugs is somewhat disappointing, with 3-5% weight loss in patients treated with orlistat and 5-10% in those receiving naltrexone, liraglutide or phentermine. 36 in Europe in January 2020 for the treatment of T2D. 48,49 Due to the need for these approvals to be achieved, this drug has only recently become available on the market.

The STEP phase III clinical programme
The decision of regulatory authorities to approve once-weekly subcutaneous 2.4 mg semaglutide as an anti-obesity medication was based on data from four trials of the STEP (Semaglutide treatment effect in people with obesity) phase IIIa clinical programme, which involved >4,500 people. 42 were also greatly improved, which is of particular note considering the impact of obesity on physical and mental health-related QoL. 57,58 In the DXA subpopulation, total fat mass and regional visceral fat mass were reduced from baseline with semaglutide.
Adverse effects were in line with those expected with GLP-1 RAs, with mild-to-moderate GI events. There were also more gallbladder disorders, mostly cholelithiasis, in the semaglutide group (2.6% versus 1.2% in the placebo group), likely associated with pronounced weight loss.
More participants in the semaglutide group than in the placebo group discontinued treatment owing to GI events (4.5% versus 0.8%). 51 were reported by 64% of participants in the 2.4 mg semaglutide group, 58% in the 1.0 mg semaglutide group and 34% in the placebo group. 52

STEP 3
The STEP 3 clinical trial was conducted at 41 sites in the USA only, and recruited 611 adults (mean age 46 years; 81% women; 76% White and 19% Black/African American) with obesity or overweight, but without T2D. 53 Participants were randomly assigned in a 2:1 manner to receive either 2.4 mg semaglutide (n=407) or placebo (n=204) for 68 weeks.
The treatment was administered as an adjunct to a low-calorie diet for the first 8 weeks, followed by 60 weeks of intensive behavioural therapy including a hypocaloric diet and increased physical activity. The

Incretin-based and poly-agonist therapies
Visceral adiposty T2D T2D-related complications Based on these results, it clearly appears that 2.4 mg semaglutide produces greater long-term weight loss than once-daily injected 3.0 mg liraglutide in adults with overweight or obesity, but without diabetes.
Other STEP trials in the placebo group (p<0.0001), with 77% and 34% of participants, respectively, losing ≥5% of their body weight (p<0.0001). 60 STEP 6 (STEP 6: Research study investigating how well semaglutide works in people living with overweight or obesity; ClinicalTrials.gov identifier: NCT03811574) was a randomized, double-blind, double-dummy, placebocontrolled, phase IIIa superiority trial. 61 The trial was similar to STEP 1, but was performed at 28 outpatient clinics in Japan and South Korea.
The results of STEP 6 were published in February 2022. 61 65 The results are expected next year.

Discussion
Treating obesity is not just about weight loss, but also about improving or reversing obesity-related risk factors and health issues. With the publication of several clinical trials on metabolic surgery, obesity began to appear as a clinically manageable and even reversible disease. [25][26][27] We also learned that double-digit weight loss (of around 15%) after metabolic surgery could even result in T2D remission. [25][26][27] After the results of the first trials from the STEP clinical programme were published, it appeared that such magnitude of weight loss can also be achieved by pharmacological means. [51][52][53][54] Once-weekly 2.4 mg semaglutide has been reported to induce 10-18% weight loss and to significantly improve health, prevent T2D and bring about disease remission (although this last claim has still to be definitively proved).
The magnitude of weight loss is much higher (actually, double the weight-loss efficacy) than the 5-10% weight loss achieved with previous behavioural and pharmacological approaches. Therefore, once-weekly 2.4 mg semaglutide is narrowing the gap between pharmacotherapy and metabolic surgery ( Figure 1). It should be kept in mind that the effects of once-weekly 2.4 mg semaglutide have been evaluated over a period of up to 2 years (STEP 5), compared with metabolic surgery, which has been evaluated over periods sometimes exceeding a decade.
Nonetheless, this drug may be considered a less invasive alternative to metabolic surgery in people who do not meet the eligibility criteria for metabolic surgery, do not want to undergo surgery or do not succeed in maintaining long-term weight loss with surgery. 42,50 With such an impact on weight, the neurohormonal mechanisms driving metabolic adaptation in response to weight loss should be activated with semaglutide treatment. However, 2.4 mg semaglutide is able to disrupt this pathway, as shown by the long-term durability of weight loss. 60 By doing so, semaglutide solves the second biggest concern associated with weight loss (besides the magnitude of effect) -namely, weight regain.
By reversing metabolic abnormalities, semaglutide treatment improves metabolic health function. This has been consistently observed across the STEP clinical programme, with participants experiencing improved QoL in terms of energy gain, less pain, increased movement and feeling better in everyday life. 54,60 Obesity is a chronic lifelong disease, and the sustained weight loss observed over 2 years in STEP 5 is encouraging. However, further clinical trials and clinical practice with 2.4 mg semaglutide over the long term are needed to verify whether semaglutide can maintain its benefits over the very long term. STEP 4 showed that the weight-loss effect is maintained touchREVIEWS in Endocrinology as long as semaglutide is administered, and stops immediately after discontinuation. 54 As a chronic disease, it can be argued that obesity should be treated as any other chronic metabolic disorder, with life-long therapy required. 21,22 Semaglutide is expensive and unaffordable for many people. Economic issues will be raised when its reimbursement is discussed by health authorities. However, as far as economic issues are concerned, metabolic surgery and its long-term follow-up are also very expensive.
A cost-effectiveness analysis should therefore be carried out. Any economic discussion should take into account the substantial cost savings that will result from the improvement, prevention and potential remission of obesity-associated diseases, such as T2D, other cardiometabolic disorders and mental health-related problems. Based on the example of statins over the last 30 years, and with the proviso that the evidence regarding the benefits of semaglutide continues to accumulate in the years to come, one may hope that this agent will be used and reimbursed in both primary and secondary prevention and intervention. The development of generic versions of the molecule will make the discussion much easier, but this is far in the future.
One important piece of evidence will be provided by the ongoing SELECT trial, which will study cardiovascular outcome data (e.g. three-point major adverse cardiovascular events) after 2.5-5 years. 65 These results will be of crucial importance for the future of semaglutide. Following on from the theory that molecules acting on two or more different receptors would be expected to generate more weight loss than a single receptor agonist, new molecules have been engineered.
Among them, tirzepatide (formerly LY3298176) is a novel, once-weekly, injectable, dual glucose-dependent insulinotropic polypeptide (GIP) and GLP-1 RA that integrates GIP and GLP-1 actions into a single molecule. 67 In a recent open-label phase III clinical trial, three doses of once-weekly tirzepatide induced additional weight loss from baseline to 40 weeks versus once-weekly 1 mg semaglutide in people with T2D. 68 After 40 weeks of treatment, weight loss of ≥15% was observed in 15-40% of participants receiving tirzepatide versus 9% of those receiving semaglutide. 68 Of note, doses of semaglutide higher than 1 mg were not compared with tirzepatide.
Another weight-loss drug in the pipeline is the long-acting amylin agonist cagrilintide (AM833). Amylin is a peptide that is co-secreted with insulin and C-peptide from pancreatic β-cells and has important appetite-regulatory effects via central effects on satiety pathways. 69 A randomized, placebo-controlled, multiple-ascending dose, phase Ib trial (A research study of how NNC0174-0833 taken with semaglutide works in people who are overweight or obese; ClinicalTrials.gov identifier: NCT03600480) recently showed that the combination of once-weekly 2.4 mg semaglutide plus once-weekly 2.4 mg cagrilintide resulted in a 17.1% mean weight loss at week 20 of treatment, compared with 9.8% with semaglutide alone. 70 Based on these very encouraging preliminary results, we can expect to see weight loss in the range of 20-30%similar to that seen with metabolic surgery -in the next phase III clinical trial programme.

Conclusion
The phase III STEP clinical programme has shown that 2.4 mg semaglutide provides clinically meaningful and durable weight loss beyond that achieved with other currently available agents for obesity.
It also improves the health and QoL of people with obesity or overweight (with or without T2D).
Double-digit weight loss can be accompanied by T2D remission.
As the goal of double-digit weight loss is now achievable with new anti-obesity drugs, the time has come to update how T2D should be treated and to shift the strategy from a glucose-centric approach to a more weight-oriented view, as recently suggested by Lingvay et al. 21 More than 90% of people with T2D are overweight or have obesity, and >20% of people with obesity have T2D. There is a clear continuous pathophysiological pathway between central adiposity and T2D ( Figure 2). It therefore makes sense to treat T2D upstream in the pathophysiological continuum. By doing so, a unique treatment (i.e. GLP-1 RAs) will be active from early-onset obesity, to T2D, and to late-onset T2D-related comorbidities. Once-weekly 2.4 mg semaglutide may become essential in the treatment of people with obesity or overweight with or without T2D, because it directly addresses the pathophysiological link between obesity and T2D. It can improve (or prevent) T2D-associated complications, as well as the many physical and mental health problems that are associated with obesity.
To answer the question raised in the title of this review: yes, onceweekly 2.4 mg semaglutide is a 'game changer' in the treatment of obesity. However, in view of the newest anti-obesity drugs currently under investigation with even greater potency than once-weekly 2.4 mg semaglutide, it may be that, in the field of obesity, the best is yet to come -and the first 'STEPS' will surely be followed by others…❑