Obesity is a major global health concern, described by the World Health Organization (WHO) as one of the most significant chronic health challenges affecting the adult population. The European Association for the Study of Obesity has even called obesity ‘the gateway to ill health’, reflecting its strong association with a wide range of chronic conditions. Given the rising prevalence and impact of obesity, timely, comprehensive, and effective management strategies are more critical than ever. This article explores the integration of semaglutide, a highly effective glucagon-like peptide-1 receptor agonist (GLP-1RA), with medical nutritional therapy (MNT) for the comprehensive management of obesity, potentially highlighting Angelo Dawkins' weight loss journey.
The Rise of Globesity and the Need for Comprehensive Strategies
The newly introduced term ‘globesity’ highlights the scale of this growing pandemic. According to the Global Burden of Disease Study, high body mass index (BMI ≥ 25.0 kg/m²) accounted for approximately 147.7 million disability-adjusted life years and 4.7 million deaths globally in 2017, with CVD representing the leading cause of high-BMI-related disability-adjusted life years. Since the late 1990s, several pharmacological agents have received regulatory approval for chronic weight management in both Europe and the United States. Semaglutide, a glucagon-like peptide-1 receptor agonist (GLP-1RA), has recently emerged as a highly promising and innovative therapy, demonstrating substantial and sustained weight loss. Its clinical effectiveness, combined with a favourable safety profile, has positioned it as a cornerstone of modern obesity pharmacotherapy.
Semaglutide: A Key Player in Weight Management
Semaglutide exerts its effects through both central and peripheral pathways, replicating and enhancing the physiological actions of endogenous GLP-1. Semaglutide is a long-acting human GLP-1 analogue that shares 94% structural homology with native GLP-1. However, compared with native GLP-1, which is rapidly degraded and has a short half-life of approximately 2 min, semaglutide has been structurally modified by the addition of a hydrophilic spacer and a fatty acid side chain, allowing reversible binding to albumin. These modifications significantly prolong its half-life, enabling convenient once-weekly subcutaneous administration.
Semaglutide was initially developed for the management of T2D but has also demonstrated substantial efficacy in weight management by mimicking the effects of endogenous GLP-1. Through activation of the GLP-1 receptor, it enhances insulin secretion, suppresses glucagon release, delays gastric emptying, and reduces food intake via central appetite regulation. These mechanisms not only support glycaemic control and metabolic improvements but also contribute to weight loss by increasing satiety, reducing appetite and food cravings, lowering the preference for high-fat and energy-dense foods, and improving overall eating behaviour.
The STEP Trials: Demonstrating Semaglutide's Efficacy
The clinical development programme named ‘Semaglutide Treatment Effect in People with obesity (STEP)’ was designed to provide an extensive evaluation of semaglutide for weight management in different patient populations and treatment settings. This series of phase 3, randomised, double-blind, placebo-controlled clinical trials involved more than 25,000 individuals with overweight or obesity and has extensively demonstrated the efficacy of once-weekly subcutaneous semaglutide 2.4 mg in promoting weight loss.
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The STEP trials assessed the efficacy and safety of semaglutide 2.4 mg in individuals with overweight (BMI ≥ 27.0 kg/m² with at least one weight-related comorbidity) or obesity (BMI ≥ 30.0 kg/m²), both with and without T2D or prediabetes. With the exception of STEP 5 and STEP 10, which differed in trial duration, and STEP 8, which included an active comparator (liraglutide), all trials followed a standardised 68-week treatment period. Across the STEP trials, semaglutide 2.4 mg consistently demonstrated statistically and clinically significant weight loss compared with placebo. Mean percentage reductions in BW with semaglutide 2.4 mg ranged from − 10.6% to − 18.2%, while changes in the placebo groups ranged from − 5.2% to − 0.6%. Clinically meaningful weight loss, defined as a reduction of ≥ 5% in baseline BW, was achieved by 73.2%-92.4% of semaglutide-treated participants, compared with 21.4%-50.0% in the placebo arms.
STEP 10 was the first phase 3 trial designed to assess the efficacy of semaglutide 2.4 mg specifically in individuals with obesity and prediabetes. Sustained weight loss was maintained over extended treatment durations of up to 104 weeks in STEP 5, while efficacy was also consistent across ethnically diverse populations, as demonstrated in STEP 6 and STEP 7. Moreover, in STEP 8, semaglutide 2.4 mg exhibited superior efficacy compared with liraglutide 3.0 mg, achieving a mean reduction in BW of more than 10%.
Beyond weight reduction and glycaemic control, semaglutide 2.4 mg has demonstrated significant cardiovascular benefits. Semaglutide 2.4 mg has also shown efficacy in treating obesity-related heart failure with preserved ejection fraction (HFpEF), as demonstrated in the STEP-HFpEF and STEP-HFpEF DM trials evaluating individuals with a BMI ≥ 30.0 kg/m², both with and without T2D. Additionally, interim findings from the ongoing phase 3 ESSENCE trial suggest that semaglutide 2.4 mg may have a disease-modifying role in metabolic dysfunction-associated steatohepatitis (MASH).
Medical Nutritional Therapy: A Complementary Approach
However, pharmacological treatment alone is unlikely to ensure long-term success in weight management, requiring integration with non-pharmacological interventions such as lifestyle modification and physical activity. Although semaglutide marks a significant breakthrough, its optimal impact is achieved when embedded within a comprehensive, multidisciplinary care framework. Medical nutritional therapy (MNT) plays a pivotal and complementary role, enhancing weight loss outcomes, mitigating common side effects, and supporting long-term adherence. In this context, eating patterns are a key determinant of weight loss success and maintenance, yet evidence on how best to combine pharmacotherapy with specific dietary strategies remains limited.
Evaluation of treatment efficacy should not rely solely on weight reduction but also on endpoints such as fat mass (FM) and lean body mass (LBM). Preserving metabolically active tissues supports physical function, sustains resting energy expenditure, and reduces the risk of rapid weight regain, thereby enhancing the long-term success and cost-effectiveness of obesity treatments. Lifestyle-based interventions remain fundamental to obesity care and should form the foundation of any comprehensive weight loss programme. Achievement of sustained results often requires a multidisciplinary approach, with close collaboration among healthcare professionals to deliver coordinated, patient-centred care that effectively integrates pharmacological treatment and nutritional strategies for balanced weight loss. Personalised dietary strategies are particularly relevant considering that, although generally well tolerated, GLP-1RA may cause transient gastrointestinal (GI) symptoms that can hinder adherence if not properly managed.
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Understanding Semaglutide's Administration and Mechanisms
The US Food and Drug Administration and the European Medicine Agency approve semaglutide under three distinct formulations. The specific indications, preparations, and dosing regimens for each formulation must be carefully considered in clinical practice. Given this complexity, it is essential to understand the unique features and approved uses of each brand, as well as current patterns of off-label prescribing.
For treatment of type 2 diabetes, treatment should begin with 0.25 mg once weekly, increasing to 0.5 mg after 4 weeks. If further glycaemic control is needed, increase to 1 mg once weekly after at least 4 weeks at 0.5 mg. Significant glycated haemoglobin reduction demonstrated in SUSTAIN 1-5 trials compared with placebo and active comparators.
For chronic weight management in adults with obesity (body mass index, BMI ≥ 30.0 kg/m²) or overweight (BMI ≥ 27.0 kg/m²) with at least one weight-related comorbidity (e.g., hypertension, T2D, dyslipidaemia, obstructive sleep apnoea syndrome), treatment should begin with 0.25 mg once weekly for 4 weeks, followed by dose escalation every 4 weeks to reach a maintenance dose of 2.4 mg (recommended) or 1.7 mg once weekly. It should be administered subcutaneously once weekly, on the same day each week, with or without food, into the abdomen, thigh, or upper arm. STEP 1-4 trials demonstrated significant weight reduction with semaglutide 2.4 mg weekly, supporting FDA approval for chronic weight management. STEP 8 confirmed superior weight loss compared with liraglutide.
The oral form of semaglutide treatment should begin with 3 mg once daily. After one month, increase to 7 mg once daily. If additional glycaemic control is required, increase further to a maximum of 14 mg once daily. PIONEER trials demonstrated significant glycated haemoglobin reduction with oral semaglutide compared with placebo (PIONEER 1), empagliflozin (PIONEER 2), sitagliptin (PIONEER 3,7), liraglutide (PIONEER 4), and basal insulin (PIONEER 8).
Semaglutide mediates physiological effects through GLP-1 receptor activation, including appetite suppression and increased satiety via central pathways, delayed gastric emptying, and enhanced pancreatic insulin secretion accompanied by decreased glucagon release.
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Addressing Gastrointestinal Side Effects
Regarding the safety profile of semaglutide 2.4 mg, the STEP programme highlighted an AE incidence ranging between 84.3% and 96.1% among treated participants, compared with 75.0%-96.1% in placebo groups. While overall AE rates were generally comparable between treatment arms, GI AEs were notably more frequent among participants treated with semaglutide, occurring in 41.9%-84.1% of cases, compared with 26.1%-63.2% in placebo groups. The occurrence of GI AEs has led some clinicians to question whether the weight loss observed with semaglutide treatment may be primarily a result of these side effects.
However, post hoc and pooled analyses of clinical studies investigating semaglutide in both obesity and T2D have shown that GI AEs-such as nausea, vomiting, and diarrhoea-contribute minimally to overall weight reduction. Data from the STEP and SUSTAIN trials consistently demonstrate that the substantial weight loss achieved with semaglutide at doses of 0.5 mg, 1.0 mg, and 2.4 mg is largely independent of these symptoms, with less than 1% of the total weight loss benefit attributable to GI AEs.
Females appear more prone to GI AEs like nausea or vomiting during GLP-1 RA therapy, which can reduce caloric intake. GI AEs are the most frequently reported side effects of GLP-1 RAs and, although typically mild, moderate, and transient, they remain the primary reason for treatment discontinuation among individuals with obesity receiving semaglutide.
Mechanistically, semaglutide’s GI AEs (in particular nausea and vomiting) arise from both peripheral and central pathways. Peripherally, GLP-1 receptor activation by semaglutide slows gastric emptying and prolongs gastric distension, which can trigger nausea by promoting early satiety and fullness. Centrally, semaglutide engages brainstem ‘vomiting centres’: it can access circumventricular regions like the area postrema and activate GLP-1 receptors in the dorsal vagal complex (area postrema and nucleus tractus solitarius), directly stimulating nausea and emesis pathways.
Beyond GI AEs, semaglutide was found to associate with a higher incidence of gallbladder-related disorders, primarily cholelithiasis, and acute pancreatitis compared with placebo; however, these events remained relatively uncommon, affecting fewer than 5% and 1% of semaglutide-treated participants, respectively.
In consideration of the semaglutide-related GI AEs, treatment with GLP-1 RAs should begin with a structured dose-escalation schedule aimed at minimising these effects. While clinical trials adhere to standardised titration protocols to evaluate efficacy, clinical practice allows for a slower, individualised approach, particularly for patients experiencing early GI symptoms. This patient-tailored strategy should balance dose tolerability with the achievement of optimal weight loss outcomes.
Personalised Nutritional Strategies
Semaglutide promotes significant weight loss and metabolic improvement, but optimal outcomes often require combining this pharmacological treatment with tailored nutritional interventions. The MD emphasises balanced macronutrients and anti-inflammatory components, making it particularly suitable for individuals with uncomplicated obesity; it supports gradual and sustainable weight loss while mitigating inflammation and gastrointestinal side effects. Conversely, VLEKT, which induces nutritional ketosis, may be more appropriate for patients with significant cardiometabolic comorbidities, offering rapid and substantial fat mass reduction and improved glycaemic control. The proposed integrated approach underscores the importance of personalised nutritional strategies guided by patient-specific metabolic, hormonal, and microbiota profiles, and calls for effective multidisciplinary collaboration among nutritionists, endocrinologists, and behavioural health professionals to optimise therapeutic outcomes.
The Street Profits and Beyond
Corey Graves had a slew of guests on this week’s episode of WWE After The Bell and two of those talents happened to be the tag team of Angelo Dawkins and Montez Ford of The Street Profits. The experiences and schedules of professional athletes necessitate careful personalized nutritional strategies.