A Multidisciplinary Perspective on Semaglutide Treatment and Medical Nutrition Therapy in Obesity Management

Abstract

Purpose of Review

This review 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. Semaglutide promotes significant weight loss and metabolic improvement, but optimal outcomes often require combining this pharmacological treatment with tailored nutritional interventions. This review focuses on two prominent dietary strategies whose nutritional profiles may complement semaglutide’s mechanisms of action: the Mediterranean diet (MD) and very-low-energy ketogenic therapy (VLEKT).

Recent Findings

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. Both dietary approaches, when integrated with semaglutide therapy, have the potential to preserve lean body mass, reduce gastrointestinal adverse events, and enhance adherence through improved satiety and tolerability.

Summary

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. Ultimately, we emphasise that shifting the clinical focus from weight reduction alone to a targeted approach integrating semaglutide with evidence-based nutritional strategies may represent the most promising pathway towards sustainable obesity management.

Introduction

Obesity is a major global health concern; the newly introduced term ‘globesity’ highlights the scale of this growing pandemic [1, 2]. The World Health Organization (WHO) recognises obesity as one of the most significant chronic health challenges affecting the adult population [3]. As of 2022, an estimated 2.5 billion adults worldwide were classified as overweight, including 890 million with obesity, a number projected to rise substantially in the coming decades [3–5].

The European Association for the Study of Obesity has described obesity as ‘the gateway to ill health’, reflecting its strong association with a wide range of chronic conditions [2]. Excess body weight (BW) is a well-established risk factor for type 2 diabetes (T2D), cancer, cardiovascular diseases (CVD), asthma, gallbladder disease, osteoarthritis, and chronic back pain, underscoring its profound impact on both individual and public health [6].

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 [7]. Beyond the clinical implications, the economic burden of obesity and its comorbidities are equally alarming [5, 8].

Given the rising prevalence and impact of obesity, timely, comprehensive, and effective management strategies are more critical than ever. Since the late 1990s, several pharmacological agents have received regulatory approval for chronic weight management in both Europe and the United States. These include orlistat, phentermine-topiramate (FDA-approved only), naltrexone-bupropion, liraglutide, setmelanotide, semaglutide, and tirzepatide [9, 10].

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 [11–13]. Its clinical effectiveness, combined with a favourable safety profile, has positioned it as a cornerstone of modern obesity pharmacotherapy [12]. 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 [14, 15]. Although semaglutide marks a significant breakthrough, its optimal impact is achieved when embedded within a comprehensive, multidisciplinary care framework [15]. Medical nutritional therapy (MNT) plays a pivotal and complementary role, enhancing weight loss outcomes, mitigating common side effects, and supporting long-term adherence [14, 16]. 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 [14, 17]. Structured approaches such as higher-protein, lower-carbohydrate, Mediterranean, or ketogenic regimens have shown potential to improve weight loss, body composition (BC), and metabolic health and may offer synergistic benefits when paired with semaglutide [18–21].

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 [8, 22–25]. In this perspective, the qualitative goal of maintaining LBM is increasingly recognised as being as important as quantitative weight loss [23].

Lifestyle-based interventions remain fundamental to obesity care and should form the foundation of any comprehensive weight loss programme [14]. 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 [15, 26]. 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 [27]. Tailored approaches may help alleviate these side effects, support healthy BC, and improve long-term treatment engagement [15, 27].

This review examines the intersection of semaglutide therapy and MNT, aiming to collate and summarise the available evidence to support practical, evidence-based dietary recommendations for patients receiving semaglutide. Special attention is given to how dietary interventions may help mitigate common adverse events (AEs) associated with semaglutide, such as GI discomfort, and how specific macronutrient distributions, caloric targets, and meal patterns may enhance adherence, optimise therapeutic outcomes, and support favourable change in BC.

Semaglutide as a Pharmacological Strategy for Weight Management

Semaglutide, approved for the treatment of obesity in 2021, is a GLP-1RA—a class of peptide-based drugs that mimic the effects of the endogenous incretin hormone glucagon-like peptide-1 (GLP-1) [9, 28].

Endogenous GLP-1 is secreted by L-cells in the small intestine in response to food intake. Upon release, it binds selectively to GLP-1 receptors, which are widely distributed throughout the body, including the GI tract, pancreas, brainstem, hypothalamus, and vagal afferent nerves [27–30]. By binding to these receptors, GLP-1 enhances insulin secretion from pancreatic β-cells and suppresses glucagon secretion in a glucose-dependent manner, slows gastric emptying, and regulates appetite by increasing satiety and promoting a sense of fullness through its action on the hypothalamus [27, 28, 31–33].

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. Table 1 provides a detailed comparison of the different forms of semaglutide, outlining their intended uses, approved patient groups, dosage instructions, notable features, and supporting clinical trials [34].

Table 1.

Overview of FDA-approved semaglutide formulations

Indications	Pharmaceutical form	Dosage and administration	Supporting evidence	References
Indicated as an adjunct to diet and exercise for glycaemic control in adults with T2D; also approved for reducing major cardiovascular AEs in adults with T2D and established cardiovascular disease.	Subcutaneous injection	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. Administer subcutaneously once weekly, on the same day each week, with or without food, into the abdomen, thigh, or upper arm.	Significant glycated haemoglobin reduction demonstrated in SUSTAIN 1–5 trials compared with placebo and active comparators. SUSTAIN 6 showed 26% relative risk reduction in major adverse cardiovascular events (HR 0.74; 95% CI: 0.58–0.95) over 2 years versus placebo, supporting cardiovascular benefit.	Kommu S, Whitfield P. Semaglutide. StatPearls Publishing; 2024. (StatPearls);
Approved 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). Also approved for adolescents ≥ 12 years with BMI at or above the 95th percentile for age and sex.	Subcutaneous injection	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. Administer subcutaneously once weekly, on the same day each week, with or without food, into the abdomen, thigh, or upper arm. In patients with T2D, monitor blood glucose before and during treatment.	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. STEP TEENS showed greater BMI reductions in adolescents aged 12–17 with semaglutide 2.4 mg weekly plus lifestyle intervention versus placebo.	Kommu S, Whitfield P. Semaglutide. StatPearls Publishing; 2024. (StatPearls);
Indicated as an adjunct to diet and exercise for glycaemic control in adults with T2D.	Oral tablets	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. Taking two 7 mg tablets to achieve the 14 mg is not recommended, as this has not been studied.	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). PIONEER 6 showed non-inferiority to placebo for cardiovascular outcomes, confirming safety but no reduction in major cardiovascular events.	Kommu S, Whitfield P. Semaglutide. StatPearls Publishing; 2024. (StatPearls);

AE adverse event, BMI body mass index, CI confidence interval, FDA Food and Drug Administration, HR hazard ratio, T2D type 2 diabetes

Mechanism of Action, Safety, and Efficacy

Semaglutide exerts its effects through both central and peripheral pathways, replicating and enhancing the physiological actions of endogenous GLP-1 [35]. 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 [36]. These modifications significantly prolong its half-life, enabling convenient once-weekly subcutaneous administration [27, 36]. 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 (Fig. 1) [9, 28, 29, 35–37].

Fig. 1.

Effects of semaglutide. 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. Abbreviations: GLP-1, glucagon-like peptide-1

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 [13, 38–46]. In addition, the STEP trials examined the impact of semaglutide on weight-related complications and potential benefits beyond weight loss.

Table 2 summarises the first 10 STEP trials.

Table 2.

Summary of key efficacy and safety outcomes in the STEP programme based on the trial product estimand

RCT (N and follow-up period)	Variable	Semaglutide 2.4 mg	Placebo	Active comparator	P value	Note
STEP 1 (12) (N = 1961, 68 weeks)	Change in body weight (%)	−16.9	−2.4	NA	< 0.001
	Patients achieving significant (≥ 5%) weight loss (%)	92.4	33.1	NA	< 0.001
	AE rate (%)	89.7	86.4	NA
	Serious AE rate (%)	9.8	6.4	NA
	Discontinuation rate due AEs (%)	7.0	3.1	NA
STEP 2 (37) (N = 1210, 68 weeks)	Change in body weight (%)	−10.6	−3.1	−7.6% (Sema 1.0 mg)	< 0.0001a	Including patients with concomitant T2D
	Patients achieving significant (≥ 5%) weight loss (%)	73.2	27.6	59.2%	< 0.0001a
	AE rate (%)	87.6	76.9	81.8%
	Serious AE rate (%)	9.9	9.2	7.7%
	Discontinuation rate due AEs (%)	6.2	3.5	5.0%
STEP 3 (43) (N = 611, 68 weeks)	Change in body weight (%)	−17.6	−5.0	NA	< 0.001	Concomitant intensive behavioural therapyb
	Patients achieving significant (≥ 5%) weight loss (%)	89.8	50.0	NA	< 0.001
	AE rate (%)	95.8	96.1	NA
	Serious AE rate (%)	9.1	2.9	NA
	Discontinuation rate due AEs (%)	5.9	2.9	NA
STEP 4 (42) (N = 902, 68 weeks)	Change in body weight (%)	−18.2	−5.2	NA	< 0.001	Run-in period before randomisationc
	Patients achieving significant (≥ 5%) weight loss (%)	90.5	50.0	NA	NA
	AE rate (%)	81.3	75.0	NA
	Serious AE rate (%)	7.7	5.6	NA
	Discontinuation rate due AEs (%)	2.4	2.2	NA
STEP 5 (38) (N = 304, 104 weeks)	Change in body weight (%)	−16.7	−0.6	NA	< 0.0001	Longer follow-up period
	Patients achieving significant (≥ 5%) weight loss (%)	83.3	34.9	NA	< 0.0001
	AE rate (%)	96.1	89.5	NA
	Serious AE rate (%)	7.9	11.8	NA
	Discontinuation rate due AEs (%)	5.9	4.6	NA
STEP 6 (39) (N = 401, 68 weeks)	Change in body weight (%)	−13.5	−2.2	−10.1 (Sema 1.7 mg)	< 0.0001d	Conducted in east Asian population (Japan and South Korea), with or without T2D
	Patients achieving significant (≥ 5%) weight loss (%)	83.3	21.4	72	< 0.0001d
	AE rate (%)	86.0	79.0	82
	Serious AE rate (%)	5.0	7.0	7
	Discontinuation rate due AEs (%)	3.0	1.0	3
STEP 7 (41) (N = 375, 44 weeks)	Change in body weight (%)	−12.8	−3.0	NA	< 0.0001	Conducted in a predominantly East Asian population (China, Hong Kong, Brazil, and South Korea) with or without T2D
	Patients achieving significant (≥ 5%) weight loss (%)	88.7	28.6	NA	< 0.0001
	AE rate (%)	93.0	86.0	NA
	Serious AE rate (%)	5.0	6.0	NA
	Discontinuation rate due AEs (%)	3.0	2.0	NA
STEP 8 (44) N = 338, 68 weeks)	Change in body weight (%)	−17.1	−1.8	−6.6 (lira 3.0 mg)	< 0.001	Liraglutide was administered once daily via subcutaneous injection
	Patients achieving ≥ 10% weight loss (%)	73.6	NA	28.3	< 0.001
	AE rate (%)	95.2	95.3	96.1
	Serious AE rate (%)	7.9	7.1	11
	Discontinuation rate due AEs (%)	3.2	3.5	12.6
STEP 9 (36) (N = 407, 68 weeks)	Change in body weight (%)	−14.5	−2.3	NA	< 0.001	Conducted in patient with concomitant painful knee osteoarthritis
	Patients achieving significant (≥ 5%) weight loss (%)	87.0	29.2	NA	< 0.001
	AE rate (%)	NA	NA	NA
	Serious AE rate (%)	10.0	8.1	NA
	Discontinuation rate due AEs (%)	6.7	3.0	NA
STEP 10 (40) N = 138 52 weeks)	Change in body weight (%)	−15.5	−2.2	NA	< 0.0001	Including patients with concomitant T2D and prediabetes
	Patients achieving significant (≥ 5%) weight loss (%)	90.6	26.7	NA	< 0.0001
	AE rate (%)	NA	NA	NA
	Serious AE rate (%)	9.0	9.0	NA
	Discontinuation rate due AEs (%)	6.0	1.0	NA

All values are calculated using the trial product estimand, representing the effects observed under the assumption that the drug or placebo was taken as intended

^aComparisons were made between semaglutide 2.4 mg and both placebo and the active comparator (semaglutide 1.0 mg). Statistical significance was p < 0.0001 for both comparisons. ^bThis intervention included an initial 8-week low-calorie meal replacement diet (1000–1200 kcal/day), followed by a transition to a conventional hypocaloric diet (1200–1800 kcal/day), along with progressive physical activity goals and regular behavioural counselling over a 68-week period

^cAll patients began treatment with open-label semaglutide, starting at 0.25 mg and gradually escalating to 2.4 mg once weekly by week 16, continuing through week 20. At week 20, patients (N = 803) were randomised to either continue semaglutide 2.4 mg or switch to placebo for an additional 48 weeks. The results refer to the entire trial period (weeks 0–68). After the randomised period (weeks 20–68), changes in body weight were − 7.9% with semaglutide 2.4 mg and + 6.9% with placebo. According to the trial product estimand, the respective changes were − 8.8% in the treatment group and + 6.5% in the placebo group

^dComparisons were made between semaglutide 2.4 mg versus placebo and semaglutide 1.7 mg versus placebo. Statistical significance was p < 0.0001 for both comparisons. Abbreviations: AE, adverse event; Lira, liraglutide; NA, not applicable; RCT, randomised controlled trial; Sema, semaglutide; STEP, Semaglutide Treatment Effect in People with Obesity Program; T2D, type 2 diabetes

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 [40] and STEP 10 [42], which differed in trial duration, and STEP 8 [46], which included an active comparator (liraglutide), all trials followed a standardised 68-week treatment period. Participants in all studies received semaglutide or placebo in conjunction with structured lifestyle interventions, including caloric restriction and increased physical activity.

Across the STEP trials, semaglutide 2.4 mg consistently demonstrated statistically and clinically significant weight loss compared with placebo [13, 38–46]. 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 [13, 38–46]. Notably, the STEP TEENS trial showed that semaglutide 2.4 mg, administered once weekly via subcutaneous injection, can be used in individuals aged 12 years and older, as adolescents with obesity treated with semaglutide experienced a significant reduction in BMI compared with placebo, along with improvements in several cardiometabolic risk factors [47].

Overall, the efficacy of semaglutide in weight reduction was demonstrated in patients both with concomitant T2D—specifically in STEP 2 [39], which included only patients with T2D, as well as in STEP 6, 7, and 10, which included both patients with and without T2D [41–43]—and without diabetes (STEP 1, 3, 4, 5, 8, and 9) [13, 38, 40, 44–46].

STEP 10 [42] was the first phase 3 trial designed to assess the efficacy of semaglutide 2.4 mg specifically in individuals with obesity and prediabetes. The trial included reversion to normoglycaemia as its primary endpoint and demonstrated that semaglutide significantly increased the rate of glycaemic normalisation compared with placebo, alongside substantial reductions in BW.

Sustained weight loss was maintained over extended treatment durations of up to 104 weeks in STEP 5 [40], while efficacy was also consistent across ethnically diverse populations, as demonstrated in STEP 6 [41] and STEP 7 [43]. Moreover, in STEP 8 [46], semaglutide 2.4 mg exhibited superior efficacy compared with liraglutide 3.0 mg, achieving a mean reduction in BW of more than 10%. In trials with secondary endpoints, such as STEP 9 [38], semaglutide also resulted in significant improvements in obesity-related comorbidities, including osteoarthritis-related pain and rates of reversion to normoglycaemia, further underscoring its broad clinical utility.

Beyond weight reduction and glycaemic control, semaglutide 2.4 mg has demonstrated significant cardiovascular benefits. The SELECT trial (Semaglutide Effects on Heart Disease and Stroke in Patients With Overweight or Obesity), a phase 3 study involving 17,604 adults with overweight or obesity and pre-existing CVD but no diabetes, revealed that once-weekly subcutaneous semaglutide 2.4 mg reduced the risk of major adverse cardiovascular events by 20% compared with placebo over a mean follow-up of 39.8 months, including cardiovascular death, nonfatal myocardial infarction, and nonfatal stroke [48].

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. In a prespecified pooled analysis, semaglutide was superior to placebo in improving heart failure-related symptoms and physical limitations, enhancing exercise tolerance, and promoting significant weight loss, underscoring its potential to address both metabolic and functional deficits in obesity-related HFpEF [49].

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). After 72 weeks of treatment, participants reported higher rates of histological resolution of steatohepatitis and improvement in liver fibrosis those who received placebo, alongside substantial weight reduction [50, 51].

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 [13, 38–46]. 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 [52]. 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 [52] and SUSTAIN [53, 54] 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. This supports the conclusion that semaglutide-induced weight loss is predominantly mediated by mechanisms unrelated to GI side effects [52].

Sex-related Response Patterns To Semaglutide

Understanding the impact of patient sex on treatment response is critical to optimising obesity therapies [55]. Emerging evidence suggests that sex may significantly influence weight loss outcomes with GLP-1 RAs, highlighting the need to consider sex-specific factors when evaluating the efficacy and tailoring the use of semaglutide [55].

A recent meta-analysis highlighted that females generally achieve greater weight loss than males when treated with GLP-1 RAs [55]. Notably, sex-related differences in weight reduction became more pronounced with increasing degrees of weight loss and in trials with longer treatment durations [55]. Although evidence on sex differences in semaglutide’s weight loss efficacy remains controversial, several hypotheses have been proposed to explain why females may experience greater weight reduction than males:

1. Pharmacokinetic differences: females often exhibit higher plasma levels of GLP-1 RAs due to lower BW and slower drug clearance compared with males, resulting in increased exposure to the medication and potentially greater weight loss [55–57].

2. Hormonal interactions: oestrogen may synergise with GLP-1 RAs to enhance appetite regulation by activating brain regions involved in controlling food intake and modifying reward pathways [55, 56]. This interaction may also help reduce leptin resistance, further promoting weight loss in females [58].

3. Metabolic and inflammatory markers: females treated with GLP-1 RAs tend to show more pronounced improvements in biomarkers linked to obesity and inflammation, such as reductions in C-reactive protein and tumor necrosis factor (TNF)-α, which may contribute to better weight loss outcomes [55, 59].

4. GI side effects and adherence: females appear more prone to GI AEs like nausea or vomiting during GLP-1 RA therapy, which can reduce caloric intake [57]. Additionally, stricter adherence to treatment protocols among females could partly explain their greater weight reduction [55].

Gastrointestinal Adverse Events

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 [13, 27, 38, 40–46, 52]. This highlights the importance of proactive management in clinical practice, as these events, while generally not severe, carry significant clinical relevance.

The most commonly reported GI AEs include nausea, diarrhoea, vomiting, and constipation, which are typically mild to moderate in intensity and transient in duration [13, 38, 40–46, 52].

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 [60]. 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 [60–62]. In summary, semaglutide-induced nausea and vomiting are thought to result from a combination of delayed gastric emptying and direct activation of central emetic pathways [60, 62, 63].

Beyond GI AEs, semaglutide was found to associate with a higher incidence of gallbladder-related disorders, primarily cholelithiasis [13, 40, 42, 44–46], and acute pancreatitis [13, 39, 42, 44] compared with placebo; however, these events remained relatively uncommon, affecting fewer than 5% [13, 40, 42, 44–46] and 1% [13, 39, 42, 44] of semaglutide-treated participants, respectively. As observed in the STEP trials, treatment discontinuations due to AEs occurred in 2.4%–7.0% of participants receiving semaglutide, compared with 1.0%–4.6% of those receiving placebo [13, 38–46].

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 [64–66]. 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 [64]. If side effects persist and remain intolerable despite extended up-titration, a lower maintenance dose may be considered to support adherence and reduce the risk of treatment discontinuation [66].

Equally, comprehensive education at therapy initiation shall be provided to patients to inform them about the potential onset of GI AEs and provide with appropriate strategies for their management [15, 64]. It is particularly important to emphasise that these symptoms are usually transient and mild to moderate in severity [15, 64, 65]. In addition, patients should receive clear guidance on eating behaviours, food choices, and lifestyle modifications that can help prevent or reduce the severity of GI symptoms [15, 52]. Recommended practices include eating slowly and in small portions, eating only when truly hungry, and stopping at the onset of satiety. Patients should avoid eating close to bedtime, refrain from lying down immediately after meals, and avoid intense physical activity following meals [15, 52]. Concerning food choices, a low-fat diet with meals prepared by boiling, baking, or grilling is crucial for a better management of GI AEs [15]. Patients should avoid sweet, spicy, heavily seasoned, canned, or highly processed foods and instead opt for foods with a high water content—such as soups, liquid yogurt, gelatine, and similar items [15].

Impact of Semaglutide on BC

The potential impact of semaglutide on BC emerges as another important issue besides the most commonly discussed GI AEs [67]. In general, BC refers to the relative proportions of FM and LBM in the body, where LBM indicates all components of the body excluding fat tissue, thus including skeletal muscle, organs, bones, body fluids, and water contained within adipose tissue [25]. Evidence suggests that, while promoting weight loss, semaglutide can also determine LBM reduction [68, 69]. These changes, though not classically classified as AEs, can have important implications for metabolic health and physical function, and their magnitude appears to vary depending on factors such as baseline nutritional status, physical activity, and adherence to dietary interventions. Accurate assessment of BC in patients with severe obesity is particularly critical, as it provides essential insights into physiological alterations that are not evident through conventional anthropometric measures. Despite the challenges posed by physical size and changes in fat-free mass composition [70], BC analysis remains a key tool for guiding clinical decisions in obesity management and monitoring treatment effects [24, 71]. Gold-standard techniques such as magnetic resonance imaging and computed tomography (CT) provide precise assessments of skeletal muscle mass (MM) but are costly, time-consuming, and impractical for routine outpatient use. Dual-energy X-ray absorptiometry offers a more accessible and reproducible option, with high precision for measuring lean mass, despite lower resolution than magnetic resonance imaging and CT [71]. Among field techniques, bioelectrical impedance analysis (BIA) and non-diagnostic ultrasound evaluation are widely used in clinical practice due to their non-invasive nature, ease of use, and low cost [72, 73]. While less precise than imaging-based methods, BIA can provide valuable insights into hydration status and body cell mass [74]. The technique is based on the measurement of the body’s resistance (R) to the flow of a low-intensity electrical current and the reactance (Xc), which reflects the capacitive properties of cell membranes. These raw parameters are used to derive phase angle, an indicator of cell integrity and overall nutritional and functional status [75, 76]. For instance, excess adiposity is typically associated with increased R and decreased Xc, resulting in a lower phase angle. In contrast, lean body mass—characterised by a high content of water and electrolytes, which enhance conductivity—is linked to reduced R and elevated Xc [73]. These parameters are particularly useful for tracking longitudinal changes in patients undergoing lifestyle or pharmacological interventions [74]. Therefore, BIA represents a valuable tool for monitoring the effects of dietary strategies and therapies with GLP-1 receptor agonists, supporting personalised nutritional and therapeutic decision-making over time. Muscle function tests can complement BC assessments and help identify sarcopenic obesity; however, many existing diagnostic cut-offs were developed in older adults and may not apply to younger populations, highlighting the need for updated studies to validate these tools during treatment with obesity medications [24].

Preserving LBM during pharmacological weight loss is essential, as muscles and internal organs possess a much higher metabolic rate than fat tissue. Maintaining lean mass helps sustain resting energy expenditure, thereby facilitating weight loss and supporting long-term weight maintenance [25]. Conversely, MM loss contributes to homeostatic adaptations that reduce energy expenditure during weight loss, potentially accelerating weight regain. Each kilogram of MM lost decreases resting metabolic rate by approximately 13 kcal/day, substantially more than the ~ 4 kcal/day reduction per kilogram of fat lost. This highlights the necessity of preserving or increasing MM during weight loss to limit metabolic slowdown, prevent plateaus, and reduce the risk of weight regain. Ultimately, the loss of skeletal MM and function can impair metabolic health, increase the likelihood of weight cycling, diminish quality of life, and lead to other complications [25].

Assessing the true impact of pharmacological treatments such as GLP-1RAs on BC remains challenging due to variability in study populations, treatment durations, concurrent lifestyle interventions, and the lack of standardised methods for evaluating LBM and FM. Many trials report only aggregate ‘lean mass changes’ without distinguishing between muscle, organ, or fluid components, limiting insights into the functional and metabolic consequences of weight loss [69, 77].

Although GLP-1RAs exert beneficial effects by delaying gastric emptying, enhancing satiety, and reducing caloric intake—mechanisms that predominantly promote FM reduction—they are also associated with a loss of lean mass, particularly in the context of substantial weight loss where muscle preservation is critical for metabolic health [77].

However, current evidence is still inconclusive to demonstrate a direct negative effect of GLP-1 RAs on LBM loss, largely due to heterogeneity in study designs and the limited number of trials specifically evaluating this endpoint [77]. A recent meta-analysis demonstrated that GLP-1 RAs lead to significant absolute reductions in lean mass (mean difference ≈ −0.86 kg vs. placebo), FM (−2.95 kg), and total BW (−3.55 kg), with lean mass accounting for approximately 25% of total weight loss [77]. However, the relative proportion of lean mass compared with total BW did not significantly change, suggesting that lean mass loss tends to parallel overall weight reduction rather than indicating selective fat loss [77]. Supporting these findings, a subgroup analysis from the STEP 1 trial showed that participants treated with once-weekly subcutaneous semaglutide 2.4 mg for 68 weeks experienced significant improvements in BC. Total FM decreased by 19.3%, and visceral FM by 27.4%, while LBM declined by ~ 10%. Despite this reduction, the proportion of LBM relative to total BW increased by 3% points, and the lean-to-FM ratio improved significantly—particularly among individuals who achieved ≥ 15% weight loss [13, 78].

Taken together, these observations indicate that although semaglutide may induce favourable changes in BC by preferentially reducing FM, substantial lean mass loss can still occur, especially with greater overall weight loss. This underscores the need for integrated strategies combining pharmacotherapy with personalised dietary interventions and resistance exercise [24, 71], not only to preserve MM and support metabolic health but also to minimise the risk of nutritional deficiencies and sarcopenia [79–81].

Effect of Semaglutide on Gut Microbiota

As a dynamic interface between diet, host metabolism, and drug response, the intestinal microbiota represents a critical, yet often overlooked, factor in the personalisation of obesity treatment. Understanding how nutritional strategies and GLP-1 RAs interact with the gut microbial ecosystem may offer novel insights into optimising therapeutic outcomes and mitigating AEs. In this context, the effect of semaglutide on gut microbiota is discussed here, exploring the implications for appetite regulation, inflammation, and metabolic health [78].

Emerging evidence highlights a complex, bidirectional relationship between the gut microbiota and GLP-1 RAs, including semaglutide [82]. On THE one hand, microbial metabolites such as short-chain fatty acids (SCFAs) stimulate endogenous GLP-1 secretion by activating G-protein-coupled receptors GPR43 (FFAR2) and GPR41 (FFAR3) on enteroendocrine L cells. This activation increases intracellular calcium, promoting the release of GLP-1 and peptide YY, both of which regulate appetite and glucose metabolism [82]. On the other hand, GLP-1-based therapies can alter gut microbiota composition and diversity, potentially exerting anti-inflammatory effects that influence host metabolism and overall health. These interactions suggest that the gut microbiota not only mediates the metabolic benefits of GLP-1 RAs but also may modulate individual responses to treatment [83].

Research indicates that GLP-1 RAs influence the gut microbiota and intestinal environment through both central and peripheral mechanisms [84]. These agents can affect the intestinal immune system and alter microbial composition via activation of the sympathetic nervous system, through mechanisms such as norepinephrine release, which has been associated with increased levels of bacteria like Escherichia coli [84].

Animal model studies consistently demonstrated that semaglutide can significantly alter gut microbiota, suggesting that part of semaglutide’s metabolic benefit may derive from its capacity to modulate inflammation via gut-immune-microbiota interactions and to correct dysbiosis induced by high-fat diets [82, 84]. Ingestion of semaglutide has been associated with increases in bacterial groups such as Alistipes, Alloprevotella, and Akkermansia (usually linked to healthier metabolic profiles) and reductions in Romboutsia, Dubosiella, and Enterorhabdus [84]. These changes suggest a potential role for semaglutide in correcting dysbiosis induced by high-fat diets [84]. Notably, Akkermansia muciniphila, often linked to improved insulin sensitivity and reduced inflammation, has shown increased abundance following semaglutide administration, supporting its potential therapeutic relevance [83].

In addition to compositional changes, GLP-1 appears to influence the inflammatory state of the gut. In diabetic models, dysbiosis promotes low-grade inflammation through increased intestinal permeability and systemic circulation of lipopolysaccharides, which activate Toll-like receptor 4 and impair barrier integrity. In response, enteroendocrine cells upregulate GLP-1 secretion, and GLP-1 receptor activation has been shown to suppress pro-inflammatory cytokines and macrophage infiltration. The metabolic advantages of semaglutide appear to originate partly from its ability to adjust inflammatory responses through interactions between the gut immune system and microbiota [82].

However, the impact of semaglutide on the microbiota is not uniform. Some studies reported reduced microbial diversity, suggesting that its effects may vary depending on host metabolic status, dietary patterns, and comorbidities [84]. Moreover, GLP-1 resistance, a condition in which patients fail to respond adequately to GLP-1 RAs, may be linked to gut microbiota dysbiosis, further emphasising the importance of microbiota composition in treatment efficacy [84].

Interventions such as prebiotics, probiotics, antidiabetic drugs, and bariatric surgery have also been shown to modulate the gut microbiota, reinforcing the idea that targeting the microbiota may enhance the outcomes of GLP-1-based therapies [82]. However, the precise mechanisms linking gut microbiota, GLP-1 secretion, and host metabolic regulation remain incompletely understood and warrant further investigation. Given the intricate crosstalk between the gut microbiota and pharmacological interventions, personalised approaches that consider individual microbiome profiles and dietary habits could help optimise metabolic benefits and reduce the risk of AEs. This is particularly relevant in the context of semaglutide, where variability in treatment response may be influenced by baseline microbial composition and host-specific factors [82]. Tailored nutritional and therapeutic strategies may enhance efficacy and minimise AEs, highlighting the need for a personalised, integrative approach. Future research employing multiomics technologies will be essential to unravel the mechanisms underlying these interactions and to guide the development of individualised therapeutic strategies for obesity and T2D [82].

Importance of Medical Nutrition Therapy during Pharmacological Treatment

The use of GLP-1 RAs, such as semaglutide, has emerged as a highly effective strategy for promoting weight loss and improving metabolic outcomes, primarily through appetite suppression and reduced caloric intake. However, these pharmacological effects may exacerbate pre-existing nutritional deficiencies, particularly in protein and essential micronutrients, thereby increasing the risk of muscle loss and sarcopenia [24]. In this context, a focus on weight loss alone is not enough: MNT becomes essential to support treatment outcomes, ensuring nutritional adequacy fundamental to support metabolic health and preserve MM during semaglutide treatment [85]. Recent evidence highlights the critical importance of preserving MM through targeted nutritional strategies [86, 87]. Furthermore, synergistic combination of dietary protein and resistance training (RT) is recognised as a potent stimulus for muscle protein synthesis (MPS) and may effectively counteract the muscle loss commonly associated with weight reduction in individuals with obesity [86, 87]. Skeletal muscle, in particular, plays a pivotal role not only in mechanical functions such as movement and posture but also in whole-body protein metabolism and energy expenditure [86]. A well-structured nutritional plan is essential not only to facilitate fat loss while preserving LBM but also to manage GI AEs and other complications, ensure adequate nutrient intake, and ultimately, prevent weight regain. However, specific nutritional guidelines tailored to patients undergoing treatment with GLP-1RAs, such as semaglutide, are still lacking.

In response to these challenges, the Muscle maintenance, Energy balance, Avoid side effects, Liquid intake (MEAL) plan has recently been proposed as a structured nutritional framework specifically designed to support patients undergoing GLP-1 RA therapy, such as semaglutide [88, 89]. This approach aims to preserve MM, maintain energy balance despite reduced appetite, manage GI Aes, and ensure adequate hydration. To preserve MM, the plan recommends initiating meals with a protein intake of approximately 20–30 g, ideally from lean sources with high biological value, aiming for a daily protein target of 1–1.5 g per kilogram of BW. For patients with reduced appetite, protein shakes containing at least 20 g of protein can serve as a useful alternative [88, 89]. Given the appetite-suppressing effects of GLP-1 RAs, the MEAL approach emphasises maintaining energy balance through frequent small meals and nutrient-dense snacks such as fruit, yogurt, or nuts. It also encourages the inclusion of complex carbohydrates and healthy fats while avoiding simple sugars. To mitigate GI AEs, discussed in detail in the following sections, the plan advocates for light cooking methods, small portion sizes, upright posture after eating, and controlled fibre intake [88, 89]. Finally, proper hydration is considered essential. A daily fluid intake of approximately 2–3 L is advised, prioritising water and hydrating foods while limiting alcohol, caffeinated beverages, and sugary drinks [88, 89].

Synergy between Medical Nutrition Therapy and Semaglutide: Dietary Insights

One major concern during therapy is inadequate protein intake, which can impair muscle strength and function, thereby increasing the risk of weight regain through repeated cycles of weight loss and regain (yo-yo effect) [26]. This risk is particularly elevated in individuals with a history of weight cycling or those undergoing weight loss without adequate physical activity [26]. Although sarcopenia is commonly associated with aging, sarcopenic obesity can also affect younger adults undergoing weight management, underscoring the importance of sufficient protein intake [26].

Variations in dietary fat as well as quality and intake of proteins can significantly influence appetite regulation during semaglutide therapy [90]. Short-term studies have shown that diets rich in polyunsaturated fatty acids (PUFAs) reduce hunger and ghrelin levels more effectively than monounsaturated fat-rich diets, despite similar energy content [90]. Moreover, protein is generally more satiating than other macronutrients, as it promotes the release of satiety hormones like cholecystokinin, peptide YY, and GLP-1 [90]. High-protein meals have been associated with increased feelings of fullness and reduced hunger, supporting better adherence to calorie restriction [90]. Early evidence suggests plant-based and animal-based proteins may have comparable effects on appetite, although further research is needed to confirm these findings [90].

Beyond nutrient adequacy, the physical and compositional properties of food significantly influence GI tolerance during semaglutide therapy. Factors like energy density, viscosity, and moisture content significantly influence gastric emptying, which in turn affects digestion, satiety, and the severity of GI symptoms [60]. Liquids typically leave the stomach faster than solid foods; however, calorie-dense liquids can slow gastric emptying due to interactions between nutrients and intestinal receptors. The pressure gradient between the stomach and duodenum also influences the rate at which liquids empty. Additionally, the energy content of a meal plays a significant role: low-energy foods tend to exit the stomach more quickly than high-energy options. For example, water passes rapidly, whereas nutrient-rich solid meals remain in the stomach longer [60]. Viscosity is another important factor. High-viscosity foods slow gastric emptying and prolong GI transit, thereby influencing digestion, nutrient absorption, glycaemic control, and satiety. However, the exact role of viscosity remains debated, as many foods exhibit complex, non-newtonian behaviour that complicates predictions of their digestive effects [60].

A number of macronutrients have also been shown to have an impact on gastric motility: high-protein meals can shorten the initial latency of gastric emptying, while fibre, particularly indigestible components, can significantly slow it [4, 5]. These findings underscore the importance of strategic meal planning during semaglutide therapy. Small, lower-fat meals with moderate viscosity and adequate protein and fibre content may help reduce GI discomfort and improve treatment adherence [60].

Gentinetta et al. proposed an updated version of the Harvard Healthy Eating Plate, adapted for patients on GLP-1 RAs, which emphasises personalised dietary strategies, guided by healthcare professionals [60]. For cereal-based foods, the inclusion of complex carbohydrates such as pasta, bread, and crackers is encouraged, while limiting whole grains and foods rich in simple sugars may help moderate fibre intake and support gastric emptying. Protein intake should focus on lean sources, including white meats and blue fish, whereas red meats and processed cold cuts are best avoided. Legumes are also highly nutritious, but are best consumed peeled, preferably at lunch rather than dinner, to enhance digestibility and reduce GI discomfort [60]. Fresh cheeses may be consumed in moderation and at appropriate temperatures, while aged cheeses, due to their higher fat content, should be limited. Although dietary fats can delay gastric emptying, moderate intake remains essential. Extra virgin olive oil is recommended for its content of unsaturated fatty acids and beneficial polyphenols [60, 91]. Vegetables contribute to fibre intake and satiety; however, to maintain digestive comfort, low-fibre varieties without peels or seeds are preferable, and portion control should be emphasised [60].

Management of GI AEs

Tailored dietary strategies, combined with structured dose-escalation protocols and patient education on meal timing, portion sizes, and food choices, can mitigate GI symptoms and support long-term therapeutic success. In the presence of GI AEs, one of the first precautions recommended is to extend the titration period or delay dose escalation until symptoms subside. If side effects emerge during dose increases, clinicians may consider reverting to the previously well-tolerated dose and then gradually reintroducing titration, or alternatively, establishing a maximum tolerated dose for continued therapy. These symptoms are often more pronounced in individuals with suboptimal dietary habits; thus, optimising nutritional intake alongside pharmacological adjustments can be an effective strategy for symptom control [60, 92].

Management strategies should be tailored to the specific GI symptoms experienced [15, 64]. Patients with nausea can achieve symptom relief by consuming bland, easily digestible foods, such as crackers, apples, mint, or ginger-based drinks, approximately 30 min after taking semaglutide, while avoiding heavy meals [15]. In cases of vomiting, it is important to maintain adequate hydration and adopt a pattern of small, frequent meals [15]. If nausea or vomiting persists despite these measures, and after considering dose reduction, the use of antiemetic and/or prokinetic medications may be appropriate [15].

For diarrhoea, patients should prioritise hydration and consume well-tolerated foods such as chicken, rice, and carrots, while avoiding high-fibre foods, coffee, alcohol, sports drinks, and meals that are extremely hot or cold. In contrast, constipation can often be alleviated by increasing dietary fibre and fluid intake, with the possible use of stool softeners and encouragement of regular physical activity [15]. In this context, the practical guidance provided by the American Gastroenterological Association and the American College of Gastroenterology for the management of chronic idiopathic constipation (CIC) [93] could also inform supportive strategies in patients experiencing constipation as a side effect of semaglutide.

Table 3 provides an overview of all the strategies discussed.

Table 3.

Nutrition-based management of semaglutide-associated GI symptoms GI, Gastrointestinal

Clinical condition	Recommended food	Foods to avoid	Additional dietary strategies	References
Nausea and vomiting	Crackers, apples, mint, ginger-based drinks consumed about 30 min after taking a GLP-1 RA.	Heavy, greasy, or spicy meals; large portion Solid foods during acute vomiting; dairy if poorly tolerated.	Stay well hydrated; eat small, frequent meals; consume food ~ 30 min after semaglutide; remain upright after eating.	Gorgojo-Martínez et al. 2023 Almandoz et al. 2023 Lacy et al. 2018
Diarrhoea	Water, lemon water, bicarbonate solution; chicken broth, rice, carrots, ripe peeled fruits, baked fruits.	High-fibre foods; dairy products; laxatives; coffee; alcohol; soft drinks; very hot or cold foods; products with ‘-ol’ sweeteners (sorbitol, mannitol, xylitol, maltitol); sports drinks. Avoid or limit foods high in fibre, including whole grains (cereals, nuts, seeds, whole grain bread), legumes (beans, lentils), fibrous vegetables (artichokes, asparagus, cabbage, cauliflower, mushrooms, onions), and fruits with skins or high fibre content (apples, apricots, blackberries, cherries, mango, nectarines, pears, plums).	Ensure generous hydration.	Gorgojo-Martínez et al. 2023 Almandoz et al. 2023
Constipation	Water, sugar-free liquids; whole grains, vegetables, beans, peas, lentils, fruits, nuts, and seeds.	Low-fibre processed foods; excessive dairy products.	Include enough fibre in the diet; maintain good hydration; consider fibre supplements if whole food intake is insufficient.	Gorgojo-Martínez et al. 2023 Almandoz et al. 2023 Chang et al. 2023

If these symptom-specific strategies are insufficient, clinicians may consider changing the semaglutide administration protocol by reducing the dose [15, 64].

Importantly, any patient presenting with abdominal pain should be evaluated according to standard clinical protocols. Treatment should be discontinued if acute pancreatitis is suspected and not resumed if confirmed. Additionally, gallbladder imaging and appropriate follow-up should be considered in cases suggestive of cholelithiasis, particularly in the context of rapid weight loss [12, 64, 94].

Ultimately, the synergistic integration of pharmacological therapy and nutritional strategies—through adequate macronutrient and micronutrient intake, effective management of GI AEs, and preservation of MM—has the potential to significantly enhance clinical outcomes [67, 95]. However, further research is warranted to develop comprehensive, evidence-based guidelines that fully harness this synergy, maximising therapeutic benefits while minimising associated risks.

MNT To Support Weight Loss: Optimising Semaglutide Therapy

Growing scientific evidence supports the use of MNT to improve both the tolerability and the efficacy of semaglutide, thereby optimising clinical outcomes in obesity management [96–107]. In the STEP trials, semaglutide was administered as part of a comprehensive lifestyle intervention that included a reduced-calorie diet (approximately 500 kcal/day deficit based on baseline energy requirements) and a minimum of 150 min of physical activity per week [38–46, 78, 97]. These findings highlight that semaglutide’s weight-loss and metabolic effects are maximised when combined with structured nutritional and behavioural interventions.

Among the most commonly adopted dietary approaches, the mediterranean diet (MD) and ketogenic diet (KD) represent two distinct yet promising options. Both have demonstrated benefits for weight reduction, glycaemic control, and cardiometabolic health [21, 91, 108, 109]. When appropriately tailored to the individual, these diets may complement semaglutide therapy by supporting treatment adherence, enhancing metabolic outcomes, and potentially mitigating GI AEs.

Mediterranean Diet

The MD is a traditional dietary pattern characterised by high consumption of plant-based foods such as vegetables, fruits, legumes, whole grains, nuts, and olive oil, moderate intake of fish and poultry, low intake of red and processed meats, and moderate consumption of red wine during meals [110]. Originally rooted in the culinary habits of Mediterranean countries, it has been extensively studied for its cardiovascular and metabolic benefits [110]. In obesity management, the MD supports weight loss and BC improvements, while reducing inflammation and enhancing metabolic health [91, 111]. Its rich content in monounsaturated fatty acids and PUFAs, as well as antioxidants, polyphenols, and dietary fibre, underlies its multi-targeted benefits, many of which may synergise with pharmacotherapies such as semaglutide to optimise clinical outcomes [112].

Epidemiological evidence consistently supports an inverse association between adherence to the MD and both BMI and weight gain [113, 114], with stronger adherence linked to long-term weight loss maintenance [115]. Importantly, even when calorie restriction is not enforced, the MD does not promote weight gain, suggesting a natural satiety-enhancing and metabolically favourable composition [116].

From this perspective, the MD represents a particularly suitable strategy for patients undergoing pharmacological therapy with GLP-1 RAs such as semaglutide. The diet’s inherent balance and satiety-promoting properties may support the drug’s appetite-suppressing effects while contributing to better compliance and sustained weight management (Fig. 2).

Fig. 2.

Synergistic effects of semaglutide in combination with the MD or VLEKT. Integrated comparison of semaglutide, MD, and VLEKT, emphasising their distinct mechanisms of action and combined potential in addressing obesity, metabolic dysfunction, sarcopenic risk, managing GI AEs, and improving patient adherence. Abbreviations: AE, adverse event; CVD, cardiovascular disease; GI, gastrointestinal; MASH, metabolic dysfunction-associated steatotic liver disease; MD, Mediterranean diet; PCOS, polycystic ovary syndrome; T2D, type 2 diabetes; VLEKT, very-low–energy ketogenic therapy

In clinical practice, the MD could be recommended especially for patients who initiate semaglutide with a relatively uncomplicated metabolic profile, promoting gradual, sustainable weight loss without strict restriction. It also appears protective against central adiposity: even when associated with a high fat content (~ 42% of energy), participants following an ad libitum MD supplemented with olive oil or nuts experienced slight reductions in BW and less gain in waist circumference (WC) over a median follow-up of 4.8 years, compared with a low-fat diet group [117].

Meta-analyses of randomised controlled trials (RCTs) also confirm that energy-restricted MD interventions yield greater weight loss than control or low-fat diets, particularly when combined with increased physical activity [116]. Benefits also extends to BC, with reduction in visceral fat and preservation of fat-free mass (FFM), a critical factor in sustaining long-term weight loss and metabolic rate [91, 118].

The ability of the MD to reduce visceral adiposity while preserving LBM may have important implications in the context of semaglutide therapy, which is known to reduce overall fat but, in some rare cases, also to associate with a LBM loss [68, 69]. The literature is conflicting on this topic, and although in vitro studies in obese mice have shown a positive effect of semaglutide in promoting muscle protein synthesis, increasing the relative proportion of skeletal muscle, and improving muscle function [119, 120], a synergistic dietary strategy such as the MD may help mitigate this concern and optimise the quality of weight loss. This integrated approach is particularly recommended in sedentary elderly individuals, who are at increased risk of sarcopenic obesity, with the goal of ensuring a more balanced BC and FFM.

When combining semaglutide and the MD diet, the evaluation of sex-specific responses to the MD should be considered. Indeed, sex-specific responses to dietary patterns may be influenced by biological differences, such as differences in hormonal regulation and body fat distribution. Research shows that females are potentially more susceptible to T2D with chronic refined carbohydrate intake, whereas males may be more susceptible to chronic disease when chronically consuming high-fat diets, particularly those high in animal products [121, 122]. These differences support the need for gender-specific nutritional guidelines, especially in combination with pharmacological therapies.

A recent review showed that the MD reduces the risk of CVD in both genders, though the effects may be more pronounced in males [108]. Similarly, the MD was consistently associated with a reduced risk of T2D across genders, with females showing improvements in insulin resistance and glucose metabolism, while males more often benefited from reductions in BW and BMI. Moreover, the MD may confer targeted advantages for women with female-specific conditions such as polycystic ovary syndrome, pregnancy-related complications, and autoimmune diseases like rheumatoid arthritis and systemic lupus erythematosus [108].

Another salient advantage of the MD is its anti-inflammatory potential [123, 124]. Chronic low-grade inflammation contributes to obesity-related comorbidities [123, 124], and the MD has consistently demonstrated immunomodulatory effects, even in the absence of weight loss [123, 124]. This is particularly relevant for patients on semaglutide, since GI AEs, such as nausea and bloating, might be aggravated by low-grade systemic inflammation [125]. By lowering the inflammation burden, the MD may help improve tolerability and enhance semaglutide’s efficacy in improving glycaemic and metabolic outcomes, especially in patients with high inflammatory burden, metabolic syndrome, or comorbid inflammatory conditions [125, 126].

Finally, adherence to the MD has been associated with increased microbial diversity and enrichment of short-chain fatty acid-producing bacteria [127]. Key components of the MD such as dietary fibre and polyphenols from olive oil act as prebiotics, stimulating the growth of beneficial microbes and improving mucosal integrity [127]. These changes are particularly relevant in obesity, where microbial diversity is typically reduced [127]. Improved microbiota composition may further enhance semaglutide’s efficacy and tolerability by lowering gut-derived inflammation, thus potentially optimising GLP-1 analogue action (Fig. 2).

Ketogenic Diet

Another dietary strategy of growing interest in the management of overweight and obesity is the KD [128–131]. This nutritional approach aims to induce a state of physiological ketosis through a marked restriction of carbohydrate intake, typically below 30–50 g per day [128–132]. During the initial 3–4 days of carbohydrate deprivation, the body relies on glycogenolysis and gluconeogenesis to maintain blood glucose levels [128–132]. As these sources decline, reduced glucose and insulin levels stimulates free fatty acids mobilisation from adipose tissue. These are subsequently converted in the liver into ketone bodies, which serve as an alternative energy source for extrahepatic tissues, including the brain, skeletal muscle, heart, and kidneys [104, 128–132].

Although the KD is primarily defined as a nutritional intervention aimed at inducing ketosis, the term has been applied to a wide range of dietary patterns differing in macronutrient and energy composition, including the Atkins diet, the classic KD, the high-fat KD and the VLCKD [106]. However, standardising carbohydrate intake alone does not fully capture the complexity of these interventions, as protein intake must also be carefully regulated to ensure effective nutritional ketosis. To reflect the therapeutic intent and the need for standardised macronutrient targets, the term ‘very-low–calorie ketogenic diet’ has been recently revised and replaced with ‘very-low–energy ketogenic therapy (VLEKT)’, as proposed by the ‘KetoNut’ expert panel of the Italian Society of Nutraceuticals (SINut) and the Italian Association of Dietetics and Clinical Nutrition (ADI) [106].

VLEKT refers to a structured protocol providing less than 800 kcal per day, aimed at promoting rapid weight loss in individuals with overweight or obesity. The use of the letter ‘E’ (Energy) is preferred over ‘C’ (Calorie) to avoid potential confusion with carbohydrates rather than caloric intake. The inclusion of the letter ‘T’ for Therapy emphasises the therapeutic nature of this dietary approach. VLEKT should be considered as a medical-nutritional intervention requiring a thorough clinical assessment and formal prescription by a trained healthcare professional. A qualified nutritionist must implement and tailor the plan, while educating patients about hidden carbohydrates sources that may hinder ketosis. Like pharmacological therapies, VLEKT has specific indications, contraindications, and requires regular monitoring. It is typically structured into progressive phases to support long-term weight maintenance: starting with protein preparations and low-carbohydrate vegetables, followed by gradual reintroduction of natural foods and carbohydrates across six stages [129, 132].

While carbohydrate restriction is central to ketogenic therapy, it is a misconception to consider it a high-protein diet. Excessive protein intake, especially in the context of energy restriction, can increase gluconeogenesis, thereby impair ketone body production. According to the Ketogenic Nutritional Therapy (KeNuT) consensus by the Italian Society of Endocrinology (SIE), protein intake should be carefully calibrated, generally ranging from 0.8 to 1.5 g/kg ideal BW [106, 129].

Regarding fat intake, the goal is not to promote the consumption of saturated fats but rather to emphasise high-quality unsaturated fat sources such as extra virgin olive oil, rice bran oil, wheat germ oil, and sunflower oil, which support both metabolic health and ketosis [106, 129].

VLEKT may be particularly suitable for individuals with obesity (BMI ≥ 30.0 kg/m²) or overweight (BMI 25.0–29.9 kg/m²) with abdominal obesity. Individuals with higher levels of insulin resistance may benefit more from VLEKT due to reduced insulin demand [133]. It is especially recommended when excess weight is associated T2D, polycystic ovary syndrome, MASH, CVD, hypogonadism, musculoskeletal limitations, or as a preoperative intervention before bariatric surgery, and for weight regain after surgery [129].

Ketogenic nutritional therapy has gained increasing recognition not only for its efficacy in facilitating weight loss but also for its broader impact on BC, often outperforming low-fat diets [133]. For this reason, patients under semaglutide could benefit from this nutritional therapy, specifically those with more complicated metabolic profiles and who seek for substantial weight loss in the initial phase. The initial VLEKT phase often results in pronounced weight loss due to reduced glycogen stores and accompanying water loss, which may serve as a psychological motivator, encouraging continued adherence to the dietary regimen [134]. However, this can be difficult to manage in the long term and therefore need proper management.

A recent meta-analysis [109] of 18 randomised controlled trials examined the effects of ketogenic therapy on anthropometric and BC parameters in adults. Compared with low-fat diets, ketogenic therapy was associated with significant reductions in BW, BMI, WC, visceral adipose tissue, FM, and percentage body fat, while also favouring LBM preservation. However, high dropout rates and heterogeneity across protocols limit long-term conclusion, highlighting the need for standardised definitions and structured clinical use [109].

These findings are supported by a prospective study on VLCKD intervention [135] showing an average weight loss of approximately 20 kg over 4 months, primarily due to reductions in total and visceral FM (~ 85% of total loss), while LMB and muscle strength were preserved. This preservation is largely attributed to the effects of ketone bodies, particularly β-hydroxybutyrate (BHB), which serve as an alternative energy source during periods of carbohydrate restriction. BHB has been shown to reduce muscle protein breakdown and may even promote muscle protein synthesis, thereby exerting an anticatabolic effect [136, 137]. Such properties possibly make ketogenic therapy valuable for optimising BC in obesity treatment [135].

Moreover, the pronounced effect of ketogenic therapy on appetite regulation may further supports its effectiveness as a nutritional strategy for obesity management. Unlike traditional calorie-restricted diets, nutritional ketosis suppresses appetite, facilitating long-term adherence [134]. This effect is mediated by BHB, which influences hunger-related neurocircuits and interacts with key hormonal signals transmitted via the vagus nerve from the GI tract to the brain [23, 25, 26]. Clinically, patients report greater satiety and reduced hunger, even during significant weight loss. This contrasts with the compensatory increase in appetite typically observed with other dietary approaches [134].

Ketogenic therapy demonstrates notable anti-inflammatory properties that extend beyond its effects on weight loss and metabolic control. BHB acts as a signalling molecule that can modulate inflammation at a cellular level [134, 138]. Given the role of low grade inflammation in obesity, this approach may counter insulin resistance and metabolic dysfunction, and could be useful in T2D, autoimmune disorders, or neurodegenerative diseases [10, 12, 27–29].

Beyond its metabolic and anti-inflammatory effects, recent evidence highlights the importance of sex as a biological variable in determining the response to VLEKT. In a 45-day intervention involving individuals with grade I and II obesity, both sexes achieved significant weight loss, BC improvements, and reduced inflammation, however males experienced greater overall benefits. These findings are supported by additional studies showing that men tend to respond more favourably to VLEKT than premenopausal women, particularly in terms of fat loss and improvements in liver health (e.g., MASH). However, such differences appear to lessen after menopause, with postmenopausal women showing the least metabolic benefit, likely due to hormonal and BC changes [139, 140]. Taken together, these findings highlight the need to consider sex-specific hormonal profiles when designing and implementing VLEKT protocols, in order to enhance efficacy and support personalised obesity management strategies.

Combining ketogenic nutritional therapy (particularly VLEKT) with GLP-1 RAs (such as semaglutide) may represent a synergistic strategy for obesity management, enhancing both clinical efficacy and patient adherence. Ketogenic nutritional therapies alone have shown promise in promoting significant weight loss and improving BC. Their anti-obesity effects are primarily driven by the appetite suppression associated with nutritional ketosis and increased dietary protein intake, both of which contribute to reduce energy intake. Additional mechanisms such as enhanced lipolysis, increased diuresis, greater energy expenditure may further support preferential FM reduction while preserving lean tissue, a particularly valuable outcome for minimising sarcopenia risk during weight loss. When combined with GLP-1 RAs, these effects may be amplified, potentially enhancing compliance and sustainability (Fig. 2). This dual approach may also improve glycaemic control and insulin sensitivity by combining the advantages of carbohydrate restriction with GLP-1–mediated glucose regulation. However, clinical implementation should be personalised, recognising interindividual variability and sex-specific differences in response.

Multidisciplinary Management of Weight Loss

As previously discussed, obesity is a chronic, multifactorial disease shaped by the complex interplay of biological, behavioural, psychological, and social determinants. More than ever, its management demands a multidisciplinary approach, not only to ensure effective treatment but also to prevent long-term complications and support overall quality of life [16]. While scientific and policy responses have traditionally focused on isolated strategies, there is an increasing need to adopt a holistic model that integrates knowledge from physiology, endocrinology, nutrition, immunology, genetics, epigenetics, and microbiome research, alongside socio-economic and environmental factors [141]. Without a paradigm shift in how obesity is conceptualised and addressed, structural barriers to effective prevention and care will likely persist [141]. This need is becoming increasingly urgent as GLP-1 and GIP/GLP-1 RAs are being adopted more widely in clinical practice. Integrating them into obesity management requires ongoing education and training to ensure that clinicians are prepared to prescribe and monitor these therapies and align them with nutritional counselling and behavioural support within an evidence-based framework [26, 67, 95].

Excess BW is only one dimension of obesity. Individuals with obesity face a markedly increased risk of comorbidities such as dyslipidaemia, T2D, hypertension, coronary heart disease, stroke, gallbladder disease, respiratory disorders, sleep apnoea, osteoarthritis, and certain types of cancer [142]. T2D is reported to be 8–14 times more prevalent in individuals with obesity compared with those with normal weight [143]. Beyond metabolic disease, excess BW affects almost all of the body’s major organ systems—including the endocrine, GI, cardiovascular, renal, and central nervous systems.

Endocrine disturbances are particularly common, with insulin resistance representing a hallmark feature. This condition is characterised by impaired glucose disposal and increased hepatic glucose production, as well as disruptions in sex hormone regulation. Male patients often experience hypogonadism and low testosterone levels, while female patients frequently present with polycystic ovary syndrome, characterised by hyperandrogenism and menstrual irregularities [16]. A recent meta-analysis also reported increased prevalence of hypothyroidism and hypogonadism in individuals with obesity, although it remains unclear whether these endocrine alterations are causes or consequences [144].

Given the multifactorial complexity, obesity management cannot be restricted to any single specialty. Instead, it calls for coordinated involvement from a broad spectrum of healthcare professionals, including internists, endocrinologists, nutritionists, psychologists, physical activity specialists, and behavioural health experts. Each professional brings a unique perspective and expertise, contributing to a comprehensive, patient-centred care model in which interdisciplinary collaboration is essential to address the diverse clinical, metabolic, and psychosocial challenges posed by obesity [16, 145]. This perspective is consistent with a recent joint advisory from the American College of Lifestyle Medicine, the American Society for Nutrition, the Obesity Medicine Association, and The Obesity Society, which identified nutritional and lifestyle priorities as essential components of effective and durable GLP-1–based obesity care [146].

While current healthcare systems have made progress in promoting more integrated and sustainable models of obesity care, there remains a pressing need to facilitate collaboration across settings and ensure equitable access to resources. Long-term success depends not only on individual motivation but also on the responsiveness of the surrounding social environment, which plays a critical role in supporting sustained dietary and lifestyle changes [16]. In this context, endocrinologists and nutritionists play a pivotal role in the coordinated care of patients treated with semaglutide [145] (Figs. 3 and 4).

Fig. 3.

Multidisciplinary care pathway for semaglutide in obesity and metabolic disorders. Central roles of the endocrinologist and nutritionist in the multidisciplinary management of obesity and metabolic disorders with semaglutide: from patient selection, metabolic assessment, and dose titration to individualised nutritional planning, symptom management, and long-term adherence monitoring. Abbreviations: CKD, chronic kidney disease; CVD, cardiovascular disease; GI, gastrointestinal

Fig. 4.

Integrated nutritional-pharmacological strategy for obesity management with semaglutide. Conceptual framework highlighting the synergistic interaction between semaglutide therapy and personalised nutritional interventions (MD and VLEKT). Nutritional strategies target both optimisation of clinical outcomes (weight loss, inflammation, and microbiota) and proactive management of GI AEs (nausea, vomiting, diarrhoea, and constipation). The approach is embedded within a multidisciplinary model led by endocrinologists and nutritionists to support individualised care, adherence, and preservation of lean body mass. Abbreviations: AE, adverse event; GI, gastrointestinal; MD, Mediterranean diet; VLEKT, very-low–energy ketogenic therapy

The following considerations, drawn from the authors’ clinical experience, aim to highlight the specific contributions of each professional within an integrated care approach: From the endocrinologist’s perspective, baseline evaluation involves assessing the patient’s eligibility for treatment through a detailed clinical history, identification of comorbidities and contraindications, and review of laboratory findings, including metabolic profile and renal, hepatic, and pancreatic function. Upon initiating therapy, the endocrinologist ensures appropriate dose titration to minimise GI side effects, provides education on injection technique and timing, and establishes therapeutic goals, such as glycaemic control, weight reduction, and improvement in cardiometabolic risk. During follow-up, the endocrinologist is responsible for monitoring vital signs (e.g. blood pressure), metabolic parameters (e.g. glycated haemoglobin), and treatment tolerability. Dose adjustments or therapeutic changes may be implemented based on individual response to ensure safety and efficacy over time.

At the start of the process, the nutritionist conducts a comprehensive baseline assessment of the patient that includes evaluation of dietary habits, anthropometric measurements (e.g. weight, circumferences), and BC using tools such as bioelectrical impedance vector analysis (BIVA), nutritional tissue ultrasound (to assess subcutaneous fat and muscle tissue), and handgrip strength testing. The risk of sarcopenia and overall quality of life are also assessed using reliable and validated tools. the nutritionist works closely with the patient to select the most appropriate dietary approach—whether it is the MD, the KD, or another plan—based on the patient’s needs and tolerance. They also offer practical advice to help manage GI symptoms through tailored food choices, meal composition and frequency, and hydration strategies. Nutrition education and counselling are essential to enhance adherence and support long-term dietary compliance. During follow-up, the nutritionist re-evaluates dietary adherence, anthropometric and BC parameters, and functional status. The nutritional plan is adjusted as needed, and in cases of MM reduction, targeted amino acid supplementation may be considered. This ongoing evaluation ensures that nutritional interventions remain aligned with evolving therapeutic goals and patient-specific needs.

Regardless of the healthcare professional involved, patients should always be informed about their treatment options and actively engaged in decisions that reflect their individual health goals. When discussing pharmacological and dietary strategies, it is essential to consider not only clinical factors but also patient preferences and potential personal barriers. Adherence remains a key determinant of success [31], and models such as the ‘5A’s’ (Ask, Assess, Advise, Agree, Assist) provides a structured and patient-centred framework to guide patient–clinician interactions [95]. In a narrative review, Almandoz described its application to obesity care, and the model was further expanded with a 6th A-step, ‘Arrange’, to reflect the chronic nature of obesity and the need for regular follow-up and treatment adjustments. This structured approach enhances clinical outcomes and supports long-term adherence in obesity management [95]. The model is summarised in Fig. 5.

Fig. 5.

Schematic representation of the ‘5A’s’ model of obesity care, extended to include a sixth step (arrange). The model outlines a structured, patient-centred process: Ask. (permission to discuss weight), Assess (health status and contributing factors), Advise (evidence-based recommendations), Agree (shared goals), Assist (resources and support), and Arrange (regular follow-up to ensure continuity of care).

Conclusion

This review has outlined the clinical rationale for combining pharmacological therapy, particularly GLP-1 RAs like semaglutide, with personalised dietary strategies in the treatment of obesity. Beyond promoting significant weight loss, semaglutide exerts multifaceted effects on BC, appetite regulation, glycaemic control, and obesity-related comorbidities, which can be synergistically enhanced through targeted nutritional interventions. Dietary strategies play a central role not only in supporting FM reduction and preserving LBM but also in improving the tolerability of pharmacological treatment. While semaglutide provides substantial metabolic benefits, its GI AEs, most notably nausea, vomiting, diarrhoea, and constipation, can compromise treatment adherence, particularly during the early dose-escalation phase. However, adherence to specific dietary modifications, such as reducing portion sizes, limiting dietary fat and poorly digestible fibres, spacing meals, and ensuring adequate hydration, has proven effective in mitigating these side effects. Nutritionists thus play a crucial role in educating and guiding patients through individualised dietary adjustments to support continued treatment adherence and maximise therapeutic outcomes.

Moreover, evidence suggests that structured dietary approaches such as the MD or the VLEKT may further enhance the efficacy and tolerability of semaglutide. While the former is generally recommended for patients with uncomplicated obesity, while the latter may be more suitable for individuals with multiple cardiometabolic comorbidities. When appropriately prescribed and monitored, these regimens contribute to improved satiety, better glycaemic control, and maintenance of functional MM, thereby preventing sarcopenic obesity and reducing the risk of weight regain. Drawing on current evidence and clinical experience, a synergistic approach that combines GLP-1 RAs with targeted MNT appears to be the most effective strategy to support sustainable weight loss while preserving MM. Importantly, interindividual variability, including gender differences, hormonal patterns, BC, and microbiota profile, should guide dietary and pharmacological choices. In this context, routine assessment of BC and functional parameters should become a clinical priority, shifting the focus from weight alone to the broader concept of quality weight loss.

At the same time, it is important to acknowledge the limitations of pivotal trials such as STEP and SELECT, whose generalisability is constrained by relatively short follow-up, notable dropout rates, and the predominance of Western cohorts. Future research should aim to generate robust real-world evidence that better reflects diverse populations, longer treatment horizons, and everyday clinical practice.

To address the multifactorial nature of obesity, a shift toward integrated, multidisciplinary care is essential. Pharmacologists, endocrinologists, nutritionists, and behavioural health professionals must collaborate to deliver coordinated, patient-centred interventions that reflect both biological complexity and social determinants of health. Recognising these limitations while adopting a multidimensional approach may help ensure that treatment strategies are both clinically effective and sustainable in the long term. Further research is needed to refine treatment algorithms, identify predictors of response, and establish sustainable models of care. Until then, a tailored and collaborative approach remains the cornerstone of effective obesity management.

Key References

• Mechanick JI, Butsch WS, Christensen SM, Hamdy O, Li Z, Prado CM, et al. Strategies for minimizing muscle loss during use of incretin‐mimetic drugs for treatment of obesity. Obesity Reviews. 2025;26:e13841. 10.1111/obr.13841.

  • Incretin-mimetic drugs for obesity, such as semaglutide and tirzepatide, may lead to significant muscle mass loss; therefore, adequate nutrition and resistance training are essential to preserve muscle function and optimise therapeutic outcomes.

• Yang Y, He L, Han S, Yang N, Liu Y, Wang X, et al. Sex Differences in the Efficacy of Glucagon‐Like Peptide‐1 Receptor Agonists for Weight Reduction: A Systematic Review and Meta‐Analysis. Journal of Diabetes. 2025;17:e70063. 

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  • Females experience greater weight loss than males with GLP-1RAs, particularly when used for obesity treatment, with differences increasing alongside weight reduction magnitude.

• Gentinetta S, Sottotetti F, Manuelli M, Cena H. Dietary Recommendations for the Management of Gastrointestinal Symptoms in Patients Treated with GLP-1 Receptor Agonist. DMSO. 2024;Volume 17:4817–24. 10.2147/DMSO.S494919.

  • GLP-1RAs may delay gastric emptying and cause gastrointestinal symptoms; tailored dietary advice, particularly for evening meals, can help mitigate these effects and support treatment adherence.

• Guney-Coskun M, Basaranoglu M. Interplay of gut microbiota, glucagon-like peptide receptor agonists, and nutrition: New frontiers in metabolic dysfunction-associated steatotic liver disease therapy. World J Gastroenterol. 2024;30:4682–8.

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  • This practical guide outlines the safe and effective use of medically supervised, multistep ketogenic nutritional therapy with meal replacements for managing obesity and related comorbidities.

Abbreviations

AEs

adverse events

BC

body composition

BHB

β-hydroxybutyrate

BIA

bioelectrical impedance analysis

BIVA

bioelectrical impedance vector analysis

BMI

body mass index

BW

body weight

CT

computed tomography

CVD

cardiovascular disease

FM

fat mass

FFM

free fat mass

GI

gastrointestinal

GLP-1

glucagon-like peptide-1

GLP-1RA

glucagon-like peptide-1 receptor agonist

HFpEF

heart failure with preserved ejection fraction

KD

ketogenic diet

LBM

lean body mass

MASH

metabolic dysfunction-associated steatohepatitis

MD

Mediterranean diet

MEAL

Muscle maintenance, Energy balance, Avoid side effects, Liquid intake

MM

muscle mass

MNT

medical nutrition therapy

MRI

magnetic resonance imaging

PUFA

polyunsaturated fatty acids

RCTs

randomised controlled trials

SCFAs

short-chain fatty acids

STEP

Semaglutide Treatment Effect in People with obesity

T2D

type 2 diabetes

TNF

tumor necrosis factor

VLCKDs

very-low-calorie ketogenic diets

VLEKT

very low energy ketogenic therapy

WC

waist circumference

WHO

World Health Organization

Author Contributions

Conceptualization: LV, GM. Literature search: GA, LV, and MG; Original draft preparation: LB and GM; Writing—review and editing: LB, GA, LV, MG, and GM; Supervision: AC, SS, LB and GM. All authors reviewed the manuscript.

Funding

The authors did not receive support from any organisation for the submitted work. Medical writing assistance was provided by Clariscience S.r.l. (Padua, Italy), supported by an unconditional grant from Novo Nordisk S.p.A. The authors are fully responsible for the content and conclusions of the publication. Novo Nordisk had no influence on, and was not involved in, the content presented in the manuscript.

Data Availability

No datasets were generated or analysed during the current study.

Declarations

Ethics Approval and Consent to Participate

This article does not contain any studies with human subjects performed by any of the authors.

Competing interests

The authors declare no competing interests.