Introducing an important therapy for obesity to primary care: once-weekly subcutaneous semaglutide 2.4 mg

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KEYWORDS:

• Semaglutide 2.4 mg
• obesity
• weight management
• primary care
• cardiometabolic
• quality of life
• best-practices

Video 1

Introducing an Important Therapy for Obesity to Primary Care Once-Weekly Subcutaneous Semaglutide 2.4mg

Obesity is a complex, chronic disease that represents a global public health challenge [1]. Worldwide, the prevalence of obesity has increased substantially in recent decades, with estimates from the World Health Organization indicating that more than 1.9 billion adults were overweight in 2016, including over 650 million adults with obesity [2]. In the United States in particular, more than 40% of adults are estimated to live with obesity [3]. It is well recognized that obesity is associated with an increased risk of adverse health outcomes, such as type 2 diabetes (T2D), cardiovascular disease, dyslipidemia, obstructive sleep apnea, osteoarthritis, and impaired quality of life (QoL) [1,2,4–6]. Weight loss represents a central component of obesity management, with the overall goal of addressing weight-related complications and improving the patient’s health and wellbeing [1,4,6].

Primary care practitioners (PCPs) are at the frontline of care for people with overweight and obesity [4,6,7]. Obesity management should be a routine part of primary care, supported by access to effective long-term treatment options [8]. Since obesity is multifactorial in nature, its management can benefit from the input of various disciplines. However, we believe that PCPs are well positioned to have a positive impact on obesity outcomes by managing people with obesity in their usual clinical practice [4,8,9]. The practical aspects of treating obesity in primary care can be complicated by challenges such as lack of time, and limitations with insurance coverage and reimbursement for counseling and medications [10,11]. It is hoped that obesity management will be enhanced in future through increasing efforts to address the bias, stigma, and discrimination surrounding obesity, and through the introduction of effective, easy to use treatment [4,9,12,13].

Successful management of obesity requires recognition of the fact that the disease has a complex multifactorial pathophysiology, including genetic, metabolic, neuroendocrine, behavioral, sociocultural, and environmental contributors, and is not simply a product of poor lifestyle [1,4,14]. Treatment guidelines for obesity management in primary care are available from various organizations and advocate a multimodal approach that we believe can be achieved in the PCP’s office [1,4–7]. Care should be compassionate, patient-centric, and avoid stigmatization [4,12]. Given the heterogenous nature of obesity, it is unlikely that a single intervention will help to manage all cases of obesity, and as such treatment plans should be multimodal and individualized to the patient. While lifestyle modification in the form of healthy eating and physical activity are cornerstones of weight management, tailored treatment for obesity can also include interventions such as medical nutrition therapy, psychological and behavioral counseling, and pharmacotherapy and/or bariatric surgery [1,4].

Pharmacotherapy is typically recommended as an adjunct to lifestyle intervention to help achieve and maintain weight loss for those with obesity (body mass index [BMI] of ≥30 kg/m²) or with overweight (BMI of ≥27 kg/m²) and weight-related complications [1,4,7]. Studies have shown that adding pharmacotherapy to lifestyle interventions in the primary care setting improves the likelihood of achieving clinically meaningful weight loss [15,16]. Pharmacotherapies therefore have the potential to empower PCPs in the weight management of their patients by providing an additional strategy beyond lifestyle interventions alone. However, historically, few approved drugs have been available [5], and those that have been available typically induce weight losses less than the 10% threshold recommended for addressing many weight-related complications [1,5]. The new era of effective anti-obesity medications, which generate much greater sustained weight loss, will likely change this entire field [5].

Traditionally, obesity has been simply explained as an energy imbalance between caloric intake and expenditure; however, it is now understood that this imbalance can result from a number of factors, including a complex neuro-hormonal system regulating appetite, food intake, metabolism, and energy balance [4,14,17]. Several pharmacotherapies aim to induce weight loss through modulation of this system, including glucagon-like peptide-1 receptor agonists (GLP-1RAs) [5]. GLP-1 is an incretin hormone responsible for a range of physiological effects, including glucose-dependent induction of insulin secretion and suppression of glucagon secretion [18–20], and the central actions of decreased appetite and the promotion of satiety [19]. GLP-1RAs mimic the actions of endogenous GLP-1 and have effects in the pancreas and brain, leading to both improved glycemic control and weight loss [21–23]. The weight loss seen with GLP-1RAs is believed to arise from a reduction in energy intake, mediated by effects on neural pathways that lead to reduced appetite, increased satiety, and improved control of eating [21,22,24,25].

GLP-1RAs were first developed for the treatment of T2D and multiple long-acting GLP-1RAs are approved for this indication [26,27]. With regards to obesity, the first US Food and Drug Administration (FDA)-approved GLP-1RA for weight management was once-daily subcutaneous liraglutide 3 mg, which has been available since 2015 [28–30]. In June 2021, once-weekly subcutaneous semaglutide 2.4 mg was approved by the FDA for the treatment of people with overweight or obesity [31]. Based on the substantial weight loss seen in clinical trials with semaglutide 2.4 mg as an adjunct to lifestyle intervention, it has been proposed to be the first ‘second-generation’ medication for weight management [5,32,33]. Semaglutide lowers energy intake and body weight via multiple mechanisms, including reduction of appetite and food cravings, better control of eating and lower relative preference for fatty foods [25,34]. Semaglutide 2.4 mg has the potential to help more than half of treated patients to achieve ≥15% weight loss, and more than one-third to achieve ≥20% weight loss [5,32,33]. This represents a substantial improvement in effectiveness over that reported for previously approved obesity medications, which lead to <10% weight loss in the majority of patients [5]. As an adjunct to lifestyle intervention, semaglutide may therefore help practitioners and patients in achieving the weight loss targets recommended for amelioration of the complications associated with obesity [5].

Across a series of four articles, this supplement aims to provide a summary of the evidence for semaglutide 2.4 mg in weight management, as an adjunct to lifestyle intervention, based on the results of the phase 3 Semaglutide Treatment Effect in People with obesity (STEP) 1–5 clinical trials [32,35–38], together with recommendations for integrating once-weekly subcutaneous semaglutide 2.4 mg into weight management in primary care. The STEP 1–5 clinical trials, summarized in Table 1, were conducted in people with overweight or obesity, with or without T2D [32,35–38]. In the first article in this supplement, Dr Amaro, Dr Sugimoto, and Dr Wharton appraise the efficacy and safety of semaglutide 2.4 mg for weight management, drawing on the published evidence from these trials [32,35–38].

Table 1 The phase 3 Semaglutide Treatment Effect In People with obesity (STEP) 1–5 clinical trials [32,33,35–38].

	STEP 1 Weight management, without T2D^a (N=1,961)	STEP 2 Weight management in T2D^b (N=1,210)	STEP 3 Weight management with IBT^c (US only), without T2D^a (N=611)	STEP 4 Sustained weight management without T2D^a (Run-in period: N=902; Randomized: N=803)	STEP 5 Long-term weight management without T2D^a (N=304)
Trial length (weeks)	68	68	68	68	104
Interventions	Lifestyle intervention^d plus: Semaglutide 2.4 mg OW or Placebo (randomized 2:1)	Lifestyle intervention^d plus: Semaglutide 2.4 mg OW or Semaglutide 1.0 mg OW or Placebo (randomized 1:1:1)	IBT^c plus: Semaglutide 2.4 mg OW or Placebo (randomized 2:1)	Lifestyle intervention^d plus: Run-in period (weeks 0–20) Semaglutide OW (target dose of 2.4 mg) From week 20 Semaglutide 2.4 mg OW or Placebo (randomized 2:1)	Lifestyle intervention^d plus: Semaglutide 2.4 mg OW or Placebo (randomized 1:1)

^aAdults with overweight or obesity (BMI ≥27.0 kg/m² or ≥30.0 kg/m², respectively) with at least one comorbidity, and without diabetes. ^bAdults with overweight or obesity and T2D, with HbA_1c levels of 7.0–10.0%. ^cIBT, including initial 8-week low-calorie diet followed by a hypocaloric diet for 60 weeks, 30 counseling sessions, and 100 minutes/week of physical activity increased by 25 minutes/week every 4 weeks until 200 minutes/week. ^dParticipants received treatment as an adjunct to lifestyle intervention (monthly counseling on a –500-kcal/day diet relative to estimated energy expenditure at week 0, and a recommended 150 minutes/week of physical activity).

Beyond weight loss itself, it is important to understand the wider potential benefits of treatments for patients with obesity. Given the increased risk of developing cardiovascular and metabolic diseases associated with obesity [6], considering the effect of weight-management medications like semaglutide on cardiometabolic parameters and comorbidities is critical. In the second article in this supplement, Dr Amaro, Dr Skolnik, and Dr Sugimoto examine evidence from the STEP 1–5 trials for the effect of semaglutide on cardiometabolic risk factors and obesity-related comorbidities. These trials assessed a broad spectrum of cardiometabolic parameters, ranging from waist circumference, glycated hemoglobin, lipids, blood pressure, and heart rate, to markers of inflammation (C-reactive protein) and liver function (aspartate aminotransferase and alanine aminotransferase) [32,35–38]. Furthermore, as obesity and weight-related complications can have multifactorial impacts on both physical functioning and mental health [39,40], it is also important to consider the effect of treatment on patients’ QoL. In the third article in this supplement, Dr O’Neil and Dr Rubino discuss the effects of semaglutide on weight- and health- related QoL, control of eating, and body composition. The broader effects of semaglutide discussed in these two articles complement the reductions in body weight associated with semaglutide treatment, inform understanding of the overall effectiveness of treatment, and may help guide decision making in primary care.

In the final article in this supplement, Dr Kyrillos, Dr Skolnik, Dr Mukhopadhyay, and Dr Pennings provide guidance on contemporary weight management best-practices for primary care, such as patient-centricity and motivational interviewing, and review the roles of nutritional therapy, behavioral therapy, and pharmacotherapy. Through this discussion, the authors highlight the need for PCPs to become comfortable with actively and routinely diagnosing and treating obesity, just as they would any other chronic diseases, such as hypertension and hyperlipidemia. In addition, the importance of avoiding weight-related bias is explored, given its deleterious effect on patient motivation, participation in care, weight loss, and other health outcomes [12,13,41–43]. With this context given, the authors discuss a variety of practical considerations for the integration of once-weekly semaglutide 2.4 mg into weight management in primary care. Topics include which patient populations would be most suitable for treatment with semaglutide, advice on pre-treatment counseling to set realistic patient expectations of treatment [44], and recommendations for follow-up, monitoring, and maintenance treatment after initiation of semaglutide.

The availability of once-weekly semaglutide 2.4 mg for weight management, as an adjunct to increased physical activity and a reduced-calorie diet that is individualized, scientifically supported, and relevant to the patient, represents an important advance in therapeutic options for patients with overweight or obesity. This primary care-focused series of articles reviews key facets of the clinical profile of semaglutide and explores its potential role in improving outcomes for people living with overweight or obesity. By complementing this information with a synopsis of the latest guidelines and treatment approaches for multimodal obesity management, we hope readers will gain a clear and usable understanding of the key considerations for integrating once-weekly semaglutide 2.4 mg into routine treatment in primary care.

Abbreviations

BMI, body mass index

FDA, US Food and Drug Administration

GLP-1, glucagon-like peptide-1

GLP-1RA, glucagon-like peptide-1 receptor agonist

HbA_1c, glycated hemoglobin

IBT, intensive behavioral therapy

OW, once weekly

PCP, primary care practitioner

QoL, quality of life

STEP, Semaglutide Treatment Effect in People with obesity

T2D, type 2 diabetes

Declaration of financial/other relationships

Janine V. Kyrillos: honoraria for non-promotional talks – Novo Nordisk, and fees from Eli Lilly for participation in a US Medical Education Obesity Advisory Board.

Patrick M. O’Neil: research grants to his university – Eli Lilly, Epitomee Medical, Novo Nordisk, and WW International; fees for consulting or advisory board participation – Gedeon Richter and Pfizer; and honoraria for non-promotional talks – Novo Nordisk and Robard.

Sean Wharton: research funding, advisory/consulting fees, and/or other support – AstraZeneca, Bausch Health Inc., Boehringer Ingelheim, CIHR, Janssen, Lilly, and Novo Nordisk.

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Acknowledgments

Medical writing and editorial support were provided by Nicole Cash, PhD, of Axis, a division of Spirit Medical Communications Group Limited, and Peter Birch, MA, CMPP, a contract writer working on behalf of Axis (and were funded by Novo Nordisk Inc.), under the direction of the authors. Novo Nordisk Inc. also performed a medical accuracy review.

Additional information

Funding

This peer-reviewed article was supported by Novo Nordisk Inc.; the company was provided with the opportunity to perform a medical accuracy review.