Nutritional Approaches to Enhance GLP-1 Analogue Therapy in Obesity: A Narrative Review

Abstract

Glucagon-like peptide-1 receptor agonists (GLP-1RAs) are highly effective in the management of obesity; however, their efficacy and tolerability may be further optimized through complementary nutritional strategies. Such interventions may address key challenges associated with GLP-1RA therapy, including gastrointestinal adverse effects, lean mass loss, and reduced long-term adherence leading to weight regain. Evidence from preclinical and clinical studies indicates that omega-3 polyunsaturated fatty acids may enhance the metabolic benefits of GLP-1RAs and attenuate lean mass loss, primarily via anti-inflammatory pathways and modulation of protein synthesis. Synergistic effects have also been reported with other bioactive compounds—such as flavonoids and anthocyanins, which improve metabolic outcomes; probiotics and prebiotics, which may alleviate gastrointestinal intolerance; and high-quality protein sources, which support body composition preservation. Collectively, these findings suggest that nutritional adjuncts may complement GLP-1RA therapies through convergent physiological mechanisms, including the regulation of inflammation, gut microbiome composition, and cellular metabolism. While current data highlight the promise of integrated pharmaco-nutritional strategies as adjuncts to GLP-1-based obesity therapy, further randomized controlled trials are needed to establish the most effective interventions and protocols.

1. Introduction

In recent decades, the prevalence of obesity has increased significantly worldwide, affecting both developed and developing countries. This phenomenon reflects social, biological, demographic, and economic changes associated with the nutritional transition, characterized by declining nutritional deficiencies and rising rates of overweight and obesity [1,2,3]. According to the World Health Organization (WHO), obesity, defined as a body mass index (BMI) of 30 kg/m² or greater, is a severe worldwide public health problem affecting populations across the lifespan [4]. In 2022, 43% of the worldwide adult population were overweight (BMI ≥ 25 kg/m²), including 16% who were obese [2,5]. Among children and adolescents aged 5 to 19, the prevalence of overweight increased from 8% in 1990 to 20% globally [2,5]. By 2030, nearly half of the adult global population is projected to have high BMI [6].

Obesity is a chronic, complex, and multifactorial disease, characterized by low-grade inflammation [7] and excessive fat accumulation [2,8], which compromises quality of life and predisposes individuals to chronic non-communicable diseases (NCDs), including type 2 diabetes mellitus (T2DM), cardiovascular diseases, cancer, and stroke [6,9,10]. NCDs account for approximately 74% of global deaths [2,11,12] with 2.8 million deaths worldwide directly related to overweight and obesity, many of which could be prevented through effective weight management [2,11,12]. In this scenario, pharmacological interventions have gained prominence as therapeutic strategies due to the limited long-term effectiveness of diet and lifestyle modifications alone [13], and advances in the understanding of the physiological mechanisms underlying obesity, especially the regulation of appetite and energy metabolism.

Managing obesity requires a long-term, personalized multimodal approach aligned with the individual’s beliefs, expectations, and treatment goals [14]. Several anti-obesity drugs have been shown to promote weight loss, including orlistat, phentermine, phentermine–topiramate, naltrexone–bupropion, and glucagon-like peptide-1 receptor agonists (GLP-1RAs) [14,15]. Among the latter, semaglutide and liraglutide, and more recently dual glucose-dependent insulinotropic polypeptide (GIP)/GLP-1RAs such as tirzepatide, show robust efficacy, not only for weight reduction but also in glycemic control and cardiovascular risk reduction [13,16], achieving placebo-adjusted weight loss of 8–21% after one year [17,18,19].

The use of GLP-1RAs has increased markedly, with demand growing by more than 500% since 2018 [20]. By 2024, 12% of the US adult population had used GLP-1RAs, with 6% being current users [21]. This reached 22% among people diagnosed with overweight and obesity in the last five years [21].

Despite ample evidence of efficacy, challenges such as gastrointestinal (GI) side effects [13,22], inadequate nutritional intake with risk of micronutrient deficiency [22], hair loss and fatigue [13], as well as potential loss of muscle mass and bone density [23] contribute to high rates of discontinuation and subsequent weight regain [24,25,26]. Complementary nutritional interventions are therefore crucial for the long-term success of GLP-1RA therapy, with studies showing that nutritional counselling improves results and adherence through individualized guidance and management of adverse effects [27,28,29,30].

Considering the benefits and limitations of current therapies, nutrition emerges as a potential modulator of treatment response. This integrated approach may enhance clinical outcomes, promote adherence, and personalize care. However, direct clinical evidence combining nutritional interventions with GLP-1RAs remains limited. Therefore, this review synthesizes preclinical, indirect clinical evidence and direct clinical findings when available that provide a plausible rationale of nutritional interventions that may potentially influence the efficacy and safety of GLP-1RA therapy, emphasizing prevention of GI adverse effects and loss of lean mass, as well as amplification of metabolic and weight loss benefits, with the prospect that such strategies may contribute to maintaining results after treatment discontinuation. The focus is on bioactive nutrients with greater scientific support, including fibers, probiotics, protein sources (such as bovine colostrum, whey protein, and collagen), botanical actives and extracts (Momordica charantia, Cinnamomum zeylanicum, Psidium guajava, Zingiber officinale, Pinus pinaster, Citrus sinensis L. Osbeck, citrus flavonoids), and specific nutrients (chromium picolinate, L-glutamine, zinc, omega-3 fatty acids). Their potential as adjuvants in integrated pharmaconutritional strategies for managing obesity includes stimulating endogenous GLP-1 secretion, improving glycemic control, modulating intestinal microbiota, reducing inflammation, and preserving lean mass, fundamental elements for more personalized and effective therapies.

A targeted (non-systematic) search was conducted in PubMed, Scopus, Google Scholar, and Cochrane (up to September 2025), focusing on clinical and preclinical studies on nutritional and bioactive interventions as adjuncts to GLP-1RAs in obesity and T2DM. Search terms included “GLP-1”, “GLP-1 receptor agonists”, drug names (semaglutide, liraglutide, tirzepatide), intervention descriptors (“nutrition,” “dietary interventions,” “nutraceuticals”), and specific actives (“probiotics,” “fibers,” and “botanical extracts”). A manual search of references from key articles was also performed. We prioritized studies in English reporting metabolic and/or GI tolerability outcomes relevant to GLP-1RA therapy.

2. GLP-1 Receptor Agonists Therapy in Obesity Management

GLP-1 is an incretin hormone synthesized by intestinal L-cells, pancreatic α-cells, and neurons in the nucleus of the solitary tract in response to neuroendocrine stimulation and food intake, acting as an endogenous satiety signal [31,32,33,34]. GLP-1 plays a multifaceted role in lipid and glucose metabolism, as well as overall energy homeostasis [35,36]. It enhances glucose-dependent insulin secretion from pancreatic β-cells [32], stimulates somatostatin secretion from δ-cells, which suppresses glucagon secretion from α-cells [31], and exerts cytoprotective effects on β-cells by inhibiting apoptosis, inducing proliferation, and supporting insulin biosynthesis [31,36].

In lipid metabolism, GLP-1 upregulates ATP-binding cassette transporter A1 (ABCA1) and apolipoprotein AI (apoAI), promoting hepatic cholesterol efflux and homeostasis. In β-cells, it upregulates fibronectin type III domain-containing protein 5 (FNDC5) via the cAMP response element-binding protein (CREB) pathway, thereby stimulating browning of white adipose tissue. Additionally, GLP-1 enhances fatty acid oxidation and reduces hepatic lipid accumulation, contributing to the prevention of metabolic dysfunction-associated steatotic liver disease (MASLD) [35].

Within the central nervous system, GLP-1 regulates energy homeostasis by suppressing food intake, enhancing satiety, and modulating thermogenesis and metabolic rate, thereby promoting long-term weight control. It further exerts cardiovascular, neuroprotective, and glycemic regulatory effects, including the inhibition of hepatic glucose production [35,37]. In the GI tract, GLP-1 acts on myoenteric neurons and inhibits vagal activity, thereby delaying gastric emptying and lowering gastric acid secretion, which further promotes satiety and reduces caloric intake [38,39].

GLP-1 acts through activation of the GLP-1 receptor (GLP-1R), which is expressed not only in the pancreas but also in multiple organs and tissues, including the lungs, kidneys, liver, heart, bones, adipose tissue, and central nervous system, mediating its pleiotropic effects [31,33,35]. Despite its established therapeutic potential for obesity and T2DM, native GLP-1 is rapidly degraded by dipeptidyl peptidase-4 (DPP-4), with a plasma half-life of 1–2 min [33]. Structural modifications of the GLP-1 molecule led to the development of GLP-1RAs with prolonged half-life, enabling sustained glycemic control and weight reduction [33,38,40].

Since the FDA approval of exenatide for the clinical treatment of T2DM, several GLP-1RAs have been developed, including lixisenatide, dulaglutide, liraglutide, albiglutide, and semaglutide [40,41]. More recently, multi-receptor agonists have been explored, such as tirzepatide, a dual GLP-1/GIP receptor agonist. GIP, an incretin hormone secreted by K-cells of the upper small intestine, complements GLP-1 in stimulating glucose-dependent insulin release, while also contributing to adipose tissue regulation [42,43,44,45]. Evidence from meta-analyses and clinical trials demonstrates that GLP-1RAs and GIP receptor agonists (GIPRAs) reduce glycated hemoglobin (HbA1c) levels, fasting plasma glucose, body weight, BMI, waist circumference, and triglyceride levels in T2DM patients [46,47,48,49]. Among individuals with overweight or obesity, with or without diabetes, GLP-1RA therapy results in significant weight reduction compared with placebo [50,51,52]. Notably, evidence suggests that these effects may be even more pronounced in overweight and obese individuals without T2DM [52], and studies support their safety and efficacy in pediatric populations as well [53,54].

GLP-1RAs, including semaglutide and tirzepatide, are among the most effective pharmacotherapies for obesity [55] and have demonstrated improvements in multiple obesity-related comorbidities, such as cardiovascular disease, prediabetes, chronic kidney disease, liver disease, osteoarthritis, obstructive sleep apnea, and substance use disorders [22].

Although GLP-1RAs induce substantial weight loss and metabolic improvements, their long-term effectiveness is limited by challenges such as weight regain after discontinuation, with up to two-thirds of the lost weight returning within one year [56,57,58]. Real-world effectiveness also appears lower than in clinical trials, partly due to limited adherence and insufficient lifestyle modification [59]. Furthermore, long-term therapy is associated with nutritional deficiencies, lean mass loss, and frequent GI adverse events, including nausea, vomiting, diarrhea, and constipation, which may affect up to 70–85% of patients and lead to treatment discontinuation [22,38,41,60,61]. These side effects are primarily related to delayed gastric emptying, altered GI motility, and potentially gut microbiota changes [61,62].

3. Integrating Nutritional Strategies into GLP-1 Receptor Agonist Therapy

Combining nutritional approaches into GLP-1RA therapy may be an encouraging way to address its key challenges by potentially improving effectiveness and tolerability, as well as sustaining long-term benefits [22]. Specific nutrients and bioactive compounds could potentially act through complementary mechanisms, such as stimulating endogenous incretin secretion, improving metabolism and GI health, modulating gut microbiota, and enhancing muscle mass. The following sections explore key bioactive compounds with scientific evidence supporting their physiological benefits, which, although mostly not studied in combination with GLP-1RAs, may theoretically act as adjuncts to optimize therapeutic outcomes, mitigate GI side effects, and preserve lean mass. Their key evidence with potential relevance to GLP-1RA therapy is summarized in

Table 1. Potential nutritional adjuncts to GLP-1RA therapy.

Nutritional Active	Evidence Type	Key Benefits/Outcomes	Relevance to GLP-1RA Therapy
Dietary fiber (especially soluble, such as psyllium, cRG-I, and GOS)	Clinical (RCTs, meta-analyses), preclinical, and expert consensus on GLP-1RA	↑ SCFAs, insulin, and endogenous GLP-1; ↓ HbA1c and glucose; ↓ diarrhea; improves microbiota, constipation, stool frequency/consistency; expert consensus recommends fiber to mitigate GLP-1RA constipation [61,72,73,74,126,127,128,129,130,131,132,133,134,135,136,137,138,139,140,141].	GI tolerability and metabolic potentiation; caution: excessive fiber may exacerbate delayed gastric emptying [60].
Probiotics	Clinical (meta-analysis, RCTs, and pilot on GLP-1RA), preclinical, expert consensus on GLP-1RA	↓ diarrhea; with low-dose GLP-1RA (liraglutide), multi-species probiotic achieved comparable weight loss to higher dose and reduced GI AEs; consensus supports probiotics for persistent diarrhea on GLP1RAs; ↓ visceral fat, BMI, waist, and hip circumferences for BNR17 [61,62,142,143,144,145,146,147].	GI tolerability, metabolic potentiation, and weight loss/maintenance; may allow a lower GLP-1RA dose while maintaining efficacy.
Protein (whey protein, collagen, general)	Clinical (RCTs, meta-analysis)	↑ plasma essential amino acid levels; ↑ protein synthesis, muscle mass, and fat-free mass; ↑ GLP-1, GIP, and insulin; ↓ gastric emptying, weight, waist, BMI, BP, and fatty liver index [32,148,149,150,151,152,153,154,155,156,157,158,159,160,161,162,163,164,165,166].	Weight loss/maintenance, lean mass preservation, and metabolic potentiation.
Bovine colostrum	Clinical (pilot in GLP-1RA users, RCTs in other settings, meta-analysis)	In GLP-1RA, colostrum + egg factors, ↓ GI AEs, and supported continuation; ↓ NSAID-induced permeability; ↓ diarrhea incidence and gut permeability; ↓ postprandial glucose, TC, and TG [167,168,169,170,171].	GI tolerability and metabolic potentiation.
Chromium picolinate	Clinical (RCTs, meta-analysis), preclinical	↑ insulin sensitivity and glycemic control; modest ↓ weight, BMI, body fat; ↓ hunger/cravings and food intake in overweight women [172,173,174,175,176].	Weight loss/maintenance, appetite/craving control, and metabolic potentiation.
L-glutamine	Clinical (RCTs, meta-analysis)	↓ IBS severity score; ↓ diarrhea, stool frequency, and gut permeability [177,178,179].	GI tolerability.
Zinc	Clinical (RCTs, meta-analyses), preclinical	↑ insulin level and sensitivity; ↓ inflammation and oxidative stress; improves body composition; ↓ diarrhea incidence and gut permeability [180,181,182,183,184,185].	Metabolic potentiation and GI tolerability.
Omega-3 PUFAs	Clinical (RCTs, meta-analyses)	↓ inflammation; ↑ fatty acid oxidation, insulin sensitivity, mTOR pathway, protein synthesis, lean mass, and muscle strength [186,187,188,189,190,191,192].	Metabolic potentiation and lean-mass preservation.
Bitter melon (Momordica charantia)	Clinical (RCTs and meta-analyses), preclinical	↑ GLP-1 and insulin; ↓ fasting glucose, HbA1c, TC, TG, LDL, and weight [193,194,195,196,197,198,199,200,201].	Metabolic potentiation and weight loss/maintenance.
Ceylon cinnamon (Cinnamomum zeylanicum)	Clinical (RCTs, meta-analyses), preclinical	↓ weight, BMI, body fat, waist circumference, fasting and postprandial glucose, HbA1c, insulin resistance, and gastric emptying; improves cholesterol profile; inhibits α-amylase/α-glucosidase [110,202,203,204,205].	Metabolic potentiation and weight loss/maintenance.
Guava leaf (Psidium guajava)	Clinical (RCTs), preclinical	Anti-spasmodic and antidiarrheal efficacy; improves stool frequency and consistency in diarrhea; ↓ glucose, insulin, TC, and TG; inhibits α-amylase/α-glucosidase [114,206,207,208,209,210,211,212].	GI tolerability and metabolic potentiation.
French maritime pine bark (Pinus pinaster)	Clinical (RCTs), preclinical	↓ fasting glucose, waist, BP, oxidative stress markers, LDL, and TG; ↑ HDL and adiponectin; improves endothelial function; inhibits α-amylase/α-glucosidase [213,214,215,216,217,218,219,220].	Metabolic potentiation and vascular health.
Citrus flavonoids	Clinical (RCTs), preclinical	↑ GLP-1; ↓ fasting glucose and glucose intolerance; improves insulin resistance and gut microbiota; ↓ systemic inflammation (IL-6, TNF-α, hs-CRP) [117,118,221,222].	Metabolic potentiation.
Moro Orange (Citrus sinensis L. Osbeck)	Clinical (RCTs)	↓ weight, BMI, waist and hip circumferences, and visceral and subcutaneous fat [120,121,223,224].	Weight loss/maintenance.
Ginger (Zingiber officinale)	Clinical (RCTs, meta-analyses), preclinical	↓ nausea, vomiting, hunger; ↑ gastric emptying; ↓ weight, waist, waist-to-hip ratio, body fat, fasting glucose, HbA1c, insulin resistance, and BP; inhibits α-amylase/α-glucosidase [225,226,227,228,229,230,231,232,233,234,235,236].	GI tolerability, weight loss/maintenance, and metabolic potentiation.

Abbreviations: AE, adverse event; BMI, body mass index; BP, blood pressure; cRG-I, carrot-derived rhamnogalacturonan-I; GI, gastrointestinal; GIP, glucose-dependent insulinotropic polypeptide; GLP-1, glucagon-like peptide-1; GLP-1RA, glucagon-like peptide-1 receptor agonist; GOS, galacto-oligosaccharide; HbA1c, glycated hemoglobin; HDL, high-density lipoprotein; hs-CRP, high-sensitivity C-reactive protein; IBS, irritable bowel syndrome; IL-6, interleukin-6; LDL, low-density lipoprotein; NSAID, nonsteroidal anti-inflammatory drug; PUFA, polyunsaturated fatty acid; RCT, randomized controlled trial; SCFA, short-chain fatty acid; TC, total cholesterol; TG, triglyceride; TNF-α; tumor necrosis factor α. Symbols: ↑ denotes increase; ↓ denotes decrease.

, and Supplementary Table S1 provides an overview of the dose and safety-related characteristics of the nutritional interventions discussed in this article [22,60,63,64,65,66,67,68,69,70,71,72,73,74,75,76,77,78,79,80,81,82,83,84,85,86,87,88,89,90,91,92,93,94,95,96,97,98,99,100,101,102,103,104,105,106,107,108,109,110,111,112,113,114,115,116,117,118,119,120,121,122,123,124,125].

3.1. Dietary Fibers and Prebiotics

Dietary fibers are carbohydrates that are neither digested nor absorbed in the small intestine and have a polymeric structure [237]. They perform multiple physiological functions, including increasing stool bulk, stimulating bowel motility, slowing gastric emptying and glucose absorption, enhancing fat excretion, reducing dysbiosis, preserving intestinal barrier integrity, regulating enteroendocrine function, and modulating gene expression and amino acid metabolic profile [238].

Low fiber intake coupled with a fat- and sugar-dense Western-style diet has been associated with the depletion of specific bacterial taxa in the gut microbiota [126]. Conversely, metabolic health and reduced risks for chronic diseases, including obesity, T2DM, and cardiovascular disease, have been associated with fiber intake [239,240]. Proposed mechanisms include slower digestion and nutrient absorption, increased satiety, modulation of GI neurotransmitters and hormone secretion (including GLP-1), and lower energy density in fiber-rich diets [239,241]. Gut microbiota ferment fibers into short-chain fatty acids (SCFAs) like acetate, propionate, and butyrate, which provide energy to colon cells and benefit metabolic health and gut barrier. SCFAs can stimulate GLP-1 and peptide YY (PYY) secretion by L-cells and leptin release by adipose tissue, while reduced SCFAs production is linked to T2DM’s pathophysiology [130,242].

Clinical⁠ evidence shows that dietary fibers, particularly soluble forms, modulate glucose metabolism [241,243,244]. A meta-analysis of nine T2DM studies demonstrated that fiber supplementation improves HbA1c, increases total SCFAs,⁠ and enhances Bifidobacterium abundance, supporting systemic metabolic benefits [126]. In more recent trials with T2DM and prediabetic patients, fiber consumption was associated with reduced HbA1c and fasting glucose, increased microbiota diversity, and elevated insulin and C-peptide levels [127,128].

Although few trials have investigated fiber-rich interventions on GI hormones, evidence suggests that soluble fibers may modulate incretin and appetite-regulating⁠ pathways, reducing⁠ GIP and gh⁠relin while increasing PYY an⁠d cholecystokinin (CCK) [244]. A randomized double-blind trial in healthy adults demons⁠trated that pectin-containing soluble fiber improved postprandial glycemic control likely via increased GLP-1 secretion [129]. In diabetic patients, a high-fibe⁠r diet compared with a standard diet improved microbiota composition, lowered HbA1c, and increas⁠ed circulating GLP-1 [130]. Collectively, thes⁠e findings support dietary fiber⁠s⁠ as potential adjuncts to GLP-1RA therapy, amplifying hormonal and metabolic benefits while supporting long-t⁠erm⁠ glycemic control.

Additionally, dietary fiber supplementation is a key strategy in managing GI symptoms and may help both diarrhea and constipation associated with GLP-1RAs [245,246]. Effective management of these GI side effects is crucial for treatment adherence [60], and expert consensus recommends advising patients receiving GLP-1RAs to increase fiber intake to mitigate constipation [61].

The potential of dietary fiber for GI health and disorders is linked to its effect on nutrient digestion and absorption, enhancing glycaemic and lipaemic responses, regulating plasma cholesterol through constraining bile salt resorption, and influencing gastric emptying, transit time, and microbiota metabolism [247]. In broad, soluble fibers (for instance, psyllium, pectin, polydextrose, and partly hydrolyzed guar gum) exert antidiarrheal effects by maintaining luminal water, forming soft and bulky stools, and serving as fermentable substrates that generate SCFAs, which contribute to motility, mucosal integrity, microbiota modulation, and GLP-1 secretion [60,131,247,248,249]. Insoluble fibers, in turn, increase fecal bulk and intestinal transit, alleviating constipation [131,247,248].

A meta-analysis of 16 randomized controlled trials in hospitalized patients on enteral nutrition demonstrated that fiber supplementation reduced diarrhea incidence by 36% compared with fiber-free formulas, with moderate certainty [131]. Benefit was fiber-type specific: mixed soluble/insoluble fibers and partially hydrolyzed guar gum significantly reduced risk by 46% and 53%, respectively, whereas psyllium and soy polysaccharides showed no effect.

Outside the enteral nutrition setting, psyllium has demonstrated mechanisms relevant to GLP-1RA-related GI adverse events, including constipation and irritable bowel syndrome (IBS) [64,250,251]. These involve favorable modulation of microbiota (increasing SCFA-producing bacteria such as Faecalibacterium), anti-inflammatory effects (reducing CRP, IL-1, and IL-6), and bowel-regulatory properties that may mitigate both diarrhea and constipation [64,132,251,252,253,254]. A meta-analysis of 16 randomized controlled trials with 1251 adults with chronic constipation showed that fiber, particularly psyllium at doses >10 g/day for ≥4 weeks, significantly improved stool frequency and consistency [132]. The highest efficacy occurs with adequate dosage (20–25 g/day) and fluid intake (~500 mL with 25 g fiber) [64,65].

Beyond generic fibers, emerging “precision prebiotic” fibers such as carrot-derived rhamnogalacturonan-I (cRG-I; BeniCaros^®,, NutriLeads BV, Wageningen, Netherlands) show promise in alleviating GI disturbances. This soluble fiber from carrot pomace, rich in complex pectin domains (RG-I), selectively modulates gut microbiota and enhances SCFA production, notably acetate and propionate [72,73,133]. These metabolites strengthen the intestinal epithelial barrier, reduce inflammation, and reduce diarrhea risk [133]. Despite marked SCFA production, cRG-I leads to lower gas production compared to other commonly used prebiotics like inulin, suggesting superior tolerability [73,133]. It also positively modulates Bifidobacterium, Bacteroides, Faecalibacterium, Akkermansia, and Roseburia, genera associated with metabolic health and reduced T2DM risks [126].

Consistent modulation has been observed across varied microbiota profiles [73,74,134]. Ex vivo, cRG-I stimulated beneficial commensals (including Faecalibacterium prausnitzii and Bifidobacterium spp.) across diverse human microbiomes, while increasing SCFA [73] and indole-3-propionic acid (IPA), a tryptophan-derived antioxidant [74], which was strongly correlated with Bifidobacterium longum abundance, suggesting systemic benefits including metabolic health and neuroprotection [74]. In a double-blind, randomized controlled trial, 8-week cRG-I supplementation also promoted a bifidogenic effect, stimulated SCFA-producers, and stabilized microbiome composition even at 300 g/day [134]. Hence, cRG-I may confer multi-faceted GI support during GLP-1RA therapy at low dosages.

Another relevant prebiotic soluble fiber is galacto-oligosaccharide (GOS), which selectively stimulates beneficial bacteria such as Bifidobacterium [135,136]. Although not tested with GLP-1RAs, GOS consistently increases Bifidobacterium and Lactobacillus, while reducing potentially pathogenic bacteria such as Bacteroides spp., Clostridium perfringens, Escherichia coli, Prevotella, and Gardnerella [135,136,137,138]. Clinically, GOS showed significant potential in reducing traveler’s diarrhea incidence and duration [139,140], in improving flatulence and bloating in IBS without excess gas, and in reducing the severity and incidence of GI symptoms in rugby athletes [141]. This favorable tolerability profile is attributed to its selective fermentation by Bifidobacterium, which does not produce gas as a metabolic byproduct [137,139].

While dietary fibers and prebiotics may help alleviate both constipation and diarrhea and promote a healthy microbiome, these potential benefits have not yet been demonstrated in clinical studies combining such interventions with GLP-1RAs therapy, so they remain unconfirmed. Additionally, a recent study also highlights the need for balanced recommendations, as excessive intake may further delay gastric emptying and exacerbate GI discomfort during GLP-1RA therapy [60]. Notably, fiber intake should be increased gradually [60].

3.2. Probiotics

Probiotic supplementation may be a promising adjunct to GLP-1RA therapy, offering both metabolic and GI benefits. GLP-1RAs can impair gut microbiome due to prolonged gastric stasis, exacerbating inflammation and GI side effects [62]. Probiotics may counteract these effects by restoring eubiosis and improving the gut barrier.

In a pilot study with 27 obese patients, co-administration of a multispecies probiotic (2.5 × 10⁹ CFU/g of five Bifidobacterium and Lactobacillus strains) with low-dose liraglutide led to comparable weight loss as higher-dose liraglutide alone, while significantly reducing GI side effects [62]. In the probiotic + GLP-1RA group, 59.3% reported only mild transient GI symptoms and none discontinued therapy, versus an 80.3% incidence of adverse events in a comparable high-dose liraglutide trial [62]. The authors attributed improved tolerability to restoration of microbiota diversity, normalization of luminal pH, gut barrier improvement, and reduction in low-grade inflammation [62].

Although direct studies on GLP-1RA GI side effects are limited, probiotics’ anti-diarrheal benefits are well documented. A meta-analysis confirmed that Lactobacillus rhamnosus GG, Saccharomyces boulardii, and probiotic mixtures can reduce antibiotic-associated and traveler’s diarrhea [142]. An expert consensus also recommends considering probiotics to mitigate persistent diarrhea during GLP-1RA treatment [61].

Probiotics have also attracted interest for obesity and diabetes management due to their influence on energy metabolism and gut-derived satiety signals [144,145,147,255,256]. For instance, Lactobacillus gasseri BNR17 (L. gasseri BNR17) has shown anti-obesity effects, which might amplify and sustain GLP-1RAs-induced weight loss, particularly by reducing abdominal adiposity [257].

In a 12-week randomized placebo-controlled trial, overweight adults (BMI 25–35) receiving L. gasseri BNR17 (10 billion CFU/day) had a ~22 cm² decrease in visceral adiposity and reduced waist circumference versus placebo [144]. Even low-dose L. gasseri BNR17 (1 billion CFU) reduced waist circumference [144]. Another trial observed reduced BMI and waist and hip circumferences compared to baseline in individuals with BMI ≥ 23 kg/m², even with no change in diet or behavior [143]. These findings align with preclinical evidence: in diet-induced overweight rodents, L. gasseri BNR17 attenuated weight gain and adiposity, and reduced adipocyte size [146,147], and in diabetic mice, improved fasting and postprandial glucose and glucose sensitivity [145].

A proposed mechanism for L. gasseri BNR17’s anti-obesity action is microbiome modulation and SCFAs production, which can enhance anorexigenic gut hormone release (including GLP-1 and PYY) and improve gut barrier integrity. Although specific data on L. gasseri BNR17 and GLP-1 are limited, related Lactobacillus strains increased intestinal GLP-1 expression in animal studies [145,147,222,256,258].

Thus, specific probiotics may support endogenous GLP-1 signaling and potentially complement GLP-1RAs by visceral fat, body weight, and waist circumference reduction [143,144,257]. Current evidence also supports that probiotics could improve GI tolerability. Nonetheless, evidence from trials directly combining probiotics with GLP-1RAs remains limited, highlighting the need for well-designed, placebo-controlled studies to substantiate these potential synergistic effects.

3.3. Protein Sources

Protein intake exerts multiple physiological effects relevant to obesity management, including greater satiety than carbohydrate or fat, enhanced thermogenesis, and preservation of fat-free mass through stimulation of muscle anabolism [259]. These mechanisms may synergize with GLP-1RA therapy by optimizing outcomes and mitigating lean mass loss, which is critical for preventing chronic diseases and enhancing quality of life [260].

Weight loss is frequently accompanied by lean mass reductions, accounting for 15–40% of total loss, primarily from skeletal muscle, while fat mass contributes 60–85% [261,262]. With GLP-1RA therapies, muscle mass reductions vary widely, ranging from 0% to 60% of total weight loss [263,264]. Therefore, body composition maintenance is crucial, as sustainable fat loss with preservation of lean mass is more important than overall weight reduction [261].

Strategies to preserve muscle include exercise, pharmacological interventions, and nutritional supplementation [261,262]. Among these, increasing protein intake appears particularly important in GLP-1RA therapy, as it may better preserve lean mass than lower-protein diets [263]. Protein stimulates muscle protein synthesis by providing both anabolic signaling and amino acid precursors [265].

Whey protein (WP), a high-quality milk-derived protein, contains all essential amino acids required for muscle growth and repair, supporting its applications in sports nutrition, weight management, and sarcopenia [156,266]. WP increases plasma essential amino acids; stimulates muscle protein synthesis; and, when combined with exercise, enhances protein kinase B/mammalian target of rapamycin (AKT/mTOR) signaling, promoting an increase in lean mass [149,150].

WP may exert beneficial effects in various populations. In T2DM, supplementation has been associated with skeletal muscle mass gain, with moderate certainty [151]. In healthy women, a meta-analysis of 15 studies found that WP improved lean mass, especially in weight loss programs [152]. These effects are enhanced when WP is combined with calorie restriction and exercise [153]. In older adults with sarcopenia, a meta-analysis (n = 1154) demonstrated that WP-enriched supplementation, with or without resistance training, improved appendicular skeletal muscle mass, muscle mass index, and gait speed, though not handgrip strength or overall body composition [154], findings corroborated by Al-Rawhani et al. (2024) [155].

Overall, moderately high protein intake (1.0–1.3 g/kg body weight/day), including supplementation, appears effective for preserving muscle mass in sarcopenic obesity [156]. Indeed, after bariatric surgery, WP may be particularly beneficial, as it promotes weight loss while preserving fat-free mass and muscle mass. In a clinical study with women, supplementation with 30 g of WP per day for 4 weeks resulted in greater reductions in body weight and fat mass, together with an increase in fat-free mass [267].

Protein also enhances GLP-1, GIP, and insulin secretion, increasing satiety, and delays gastric emptying [32,157,158,161], thereby contributing to weight loss and improved glucose control. A meta-analysis of 37 randomized controlled trials confirmed that higher protein intake reduced body weight by ~1.6 kg, with prediabetic subjects benefiting the most [163]. Small protein premeals appear particularly effective: a meta-analysis showed that WP premeals reduced peak glucose by −1.4 mmol/L and glucose area under the curve (AUC) by −0.9, while increasing GLP-1 and peak insulin and slowing gastric emptying. The glucose-lowering effect was most pronounced with higher WP doses and was sustained in T2DM [157]. WP has also been shown to improve systolic and diastolic blood pressure, waist circumference, triglycerides, cholesterol profile, fasting blood glucose, and insulin resistance in metabolic syndrome [159,160].

Beyond WP, collagen peptides, another source of protein, have also shown promising effects on weight management. In a recent randomized controlled study, post-exercise consumption of 15 g of bovine collagen increased GLP-1 and insulin and reduced subsequent energy intake by ~41 kcal (−10%) in active females [161]. In a 3-month trial, bovine collagen bar (20 g/day) before meals in overweight/obese individuals reduced body weight (−3 kg), BMI, waist circumference, systolic blood pressure, and fatty liver index, alongside improvements in fat-free mass and satiety [162].

Specific bioactive collagen peptides (~3 kDa, derived from type I collagen) have shown consistent clinical benefits [164]. Supplementation with 15 g/day for 12 weeks, combined with exercise, increased fat-free mass and muscle strength and reduced fat mass in elderly sarcopenic men [164] and premenopausal women [165]. Similar effects were observed in older adults (≥50 years) with habitual physical activity (reduced body fat) [166], healthy men (increased muscle volume and fat-free mass) [268,269], and middle-aged untrained men, where collagen peptides and WP elicited comparable improvements [270].

Mechanistically, collagen peptides may stimulate anabolic pathways by providing glycine, proline, and hydroxyproline to support extracellular matrix remodeling and muscle repair [269], promote myoblast differentiation and myotube hypertrophy via mTOR activation and extracellular matrix protein synthesis, and stimulate satellite stem cells involved in hypertrophy [268]. Proteomic analyses demonstrated upregulation of proteins associated with signal transduction (including mitogen-activated protein kinase (MAPK)), myofibrillar and contractile function, cell cycle regulation, protein metabolism, and immune responses [271], while gene expression studies confirmed the activation of phosphatidylinositol-3-kinase/protein kinase B (PI3K/AKT) and MAPK pathways [272]. Collectively, these findings suggest that collagen peptides may improve body composition and muscle health, particularly with resistance training, through structural and metabolic mechanisms, potentially representing a valuable adjunct for GLP-1RA therapy.

Bovine colostrum, the antibody- and growth factor-rich first milk of cows, has also gained attention for its GI and metabolic benefits [273,274]. These properties may be relevant to GLP-1RA therapy by addressing both metabolic optimization and tolerability. Colostrum contains high levels of immunoglobulins (IgG, IgA), lactoferrin, insulin-like growth factors (IGF-1/2), transforming growth factor-β (TGF-β), and other bioactive peptides that enhance mucosal healing, reduce inflammation, neutralize pathogens, and support glucose and protein metabolism [274,275,276]. A pilot study in individuals initiating GLP-1RAs found that bovine colostrum (combined with chicken egg-derived factors) significantly alleviated common GI side effects affecting 60% of subjects on GLP-1RAs, such as nausea, bloating, or diarrhea, allowing them to continue therapy comfortably [167].

Colostrum’s gut-protective effects are well documented. Supplementation prevented the increase in intestinal permeability caused by non-steroidal anti-inflammatory drugs (NSAIDs) [168]; reduced the incidence, duration, and severity of pediatric infectious diarrhea [277,278,279,280,281]; and ameliorated gut dysfunction in malnutrition [282]. These outcomes were attributed to colostrum’s trophic effects on the gut lining and provision of passive immunity (neutralizing pathogens via bovine IgG). In adults, colostrum reduced gut permeability in critical illness [283] and, in athletes, a meta-analysis of 10 randomized trials demonstrated improvements in intestinal permeability via urinary lactulose/rhamnose and lactulose/mannitol ratios, supporting its role in gut barrier protection [169].

Beyond GI support, bovine colostrum may promote metabolic benefits. In T2DM patients, 4 weeks of supplementation (5 g twice a day) reduced glucose (2 and 8 h postprandial), total cholesterol, triglycerides, and ketone bodies levels, suggesting enhanced insulin signaling and metabolic control [170]. In healthy adults performing exercise, 8 weeks of colostrum increased lean mass and improved body composition compared to WP [171], suggesting potential to counteract GLP-1RA-induced muscle loss through muscle protein synthesis.

Lastly, emerging evidence suggests that proteins may act synergistically with calcium to stimulate GLP-1 secretion via activation of the extracellular calcium-sensing receptor (CaSR) and amino acid-sensitive pathways. This was demonstrated in preclinical and human studies, with protein-calcium co-ingestion producing marked postprandial GLP-1 increases, supporting their potential as adjuncts to GLP-1RA therapy to improve satiety and metabolic regulation [32].

Overall, protein sources, such as WP, collagen, and bovine colostrum, could complement GLP-1RAs by improving key factors for adherence and efficacy: GI tolerance, metabolic control (glycemic and lipid profiles), and muscle mass preservation. However, despite these potential benefits, few studies have directly assessed protein supplementation in combination with GLP-1RAs, and further clinical research is needed to confirm these effects.

3.4. Specific Nutrients

3.4.1. Chromium

Chromium is a trace mineral studied for its effects on glucose metabolism, insulin sensitivity, and appetite regulation [174,175,176]. It enhances insulin signaling by upregulating receptor kinase activity, thereby improving glycemic control [284]. A meta-analysis of 21 trials in overweight/obese individuals found small but significant reductions in body weight (~0.75 kg), BMI, and body fat with supplementation compared to placebo [172].

Chromium may also influence appetite: in a placebo-controlled trial of overweight women with cravings, 1 mg/day of chromium picolinate for 8 weeks reduced daily food intake, hunger, and cravings for fats, although weight reduction was not significant (p = 0.08) [173]. Animal studies from the same investigation indicated central appetite-suppressive effects of chromium picolinate administered into the third cerebral ventricle [173].

Taken together, while weight loss promoted by chromium supplementation is modest and variable [172], its potential to reduce food intake and cravings [173] may complement GLP-1RA therapy by potentially helping prevent post-therapy weight regain, sustaining some appetite suppression. Improvements in insulin sensitivity and glycemic control [174,175,176] could potentiate GLP-1RA efficacy, although chromium’s role may be supportive rather than primary. Notably, current evidence does not include trials combining it with GLP-1RAs.

3.4.2. L-Glutamine

L-Glutamine is a conditionally essential amino acid that serves as the primary fuel for enterocytes and is crucial for intestinal barrier integrity [179,285]. Glutamine exerts beneficial effects on GI health by promoting microbial homeostasis, enhancing barrier function, and modulating inflammation [177]. Given that GLP-1RA-induced GI side effects may be exacerbated by barrier disruption or inflammation [286], glutamine could potentially strengthen the mucosal barrier, reduce hyperpermeability, and mitigate symptoms like diarrhea and gut pain.

This efficacy is illustrated in post-infectious IBS. In a randomized controlled trial, with 106 patients, oral glutamine (15 g/day) for 8 weeks achieved the primary endpoint of ≥50 point reduction in IBS severity score in 79.6% of treated vs. 5.8% of placebo patients [178], reducing daily stool frequency (from 5.4 to 2.9) and normalizing permeability (lactulose/mannitol ratio) and stool form from the diarrhea end of the Bristol Stool Scale towards the ideal, normal range (from 6.5 to 3.9) [178]. These results may suggest similar benefits in GLP-1RA patients with diarrhea or gut inflammation.

A recent meta-analysis of 10 randomized controlled trials (n = 352) found that while glutamine overall did not significantly alter gut permeability, subgroup analyses revealed a reduction at doses >30 g/day for less than 2 weeks, supporting context-specific efficacy to strengthen the epithelial barrier [179].

Therefore, L-glutamine may represent a promising adjunct to address diarrhea during GLP-1RA therapy. Its inclusion alongside interventions that also reduce permeability (like probiotics and fibers) may improve comfort and adherence. However, clinical studies directly evaluating L-glutamine or these combined strategies with GLP-1RA therapy are still lacking.

3.4.3. Zinc

Zinc is an essential micronutrient obtained exclusively through diet and is the second most abundant microelement in the human body. It is present in all tissues and plays a pivotal role in several cellular processes, including protein synthesis, nucleic acid metabolism, gene transcription, cell proliferation, differentiation, and mitosis [287,288]. Beyond these fundamental functions, zinc exerts pleiotropic effects on glucose, lipid, and gastrointestinal metabolism, which are particularly relevant in the context of obesity and metabolic diseases.

In glucose homeostasis, zinc participates in the synthesis, storage, crystallization, and secretion of insulin in pancreatic β-cells, while also being involved in its intracellular action and translocation. Zinc enhances insulin sensitivity through the activation of the PI3K/AKT pathway and promotes glucose uptake in insulin-independent tissues, exerting an insulin-mimetic effect. Moreover, zinc has anti-inflammatory properties, suppressing pro-inflammatory cytokines such as interleukin-1β (IL-1β) and nuclear factor-κB (NF-κB), thereby protecting β-cell viability and insulin integrity [180,181,182]. Zinc also plays a role in lipid metabolism through antioxidant, anti-inflammatory, and other mechanisms that may modulate atherosclerosis and cardiovascular disease (CVD) risk [181]. Conversely, zinc deficiency disrupts glucose metabolism through β-cell dysfunction, oxidative stress, and inflammation [182].

Evidence from animal models shows that zinc supplementation reduces weight gain, abdominal fat accumulation, hyperinsulinemia, and leptin levels, while improving insulin resistance in obese mice fed a high-fat, high-fructose diet [183]. Clinical data further reinforce these findings. A systematic review of 25 studies (n = 1362) demonstrated that zinc supplementation improved glycemic control, reducing fasting blood glucose, postprandial blood glucose, and HbA1c, as well as lipid parameters, including total cholesterol, low-density lipoprotein cholesterol (LDL-c), and triglycerides in individuals with T2DM [289]. Similarly, a meta-analysis reported that modest increases in zinc intake (9.2–25 mg/day) over longer durations (≥12 weeks) were associated with improvements in insulin resistance, fasting glycemia, LDL-c, total cholesterol, and triglycerides, both in healthy and metabolically impaired populations [181].

In addition to metabolic effects, zinc contributes to gastrointestinal health by enhancing epithelial barrier function, modulating mucosal integrity, and exerting gastroprotective and anti-inflammatory actions. Zinc strengthens tight junctions through regulation of occludin proteolysis and claudin-3 transcription [290], increases mucus production, and reduces gastric acid secretion [184,291,292], while also promoting wound healing [293]. These mechanisms make zinc a promising intervention for diarrhea [184], as shown in a systematic review of 38 clinical trials, where supplementation shortened the duration and improved recovery in children with acute and persistent diarrhea [185]. Preclinical data also suggest that zinc may enhance GLP-1 secretion, potentially mediated by improved intestinal villi proliferation [294].

Considering the evidence, zinc supplementation has been associated with improvements in glucose and lipid metabolism, inflammation, and gastrointestinal integrity. However, most findings are derived from studies conducted in other populations or from mechanistic data, and direct clinical evidence combining zinc supplementation with GLP-1RA therapy is lacking. Notably, excessive zinc intake may inhibit iron and copper absorption, so intake should not exceed 25 mg/day (tolerable upper intake level set by the European Food Safety Authority (EFSA)) [101].

3.4.4. Omega-3 Polyunsaturated Fatty Acids

Omega-3 polyunsaturated fatty acids (PUFAs) are essential structural components of cell membranes [295]. High intake of PUFAs eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) has been associated with various health benefits [296] and may potentially complement GLP-1RA therapy by exerting multiple molecular mechanisms that modulate adipose tissue, inflammation, and energy metabolism; however, no studies to date have investigated their combined use.

Omega-3 PUFAs modulate adipogenesis through the activation of nuclear receptors such as peroxisome proliferator-activated receptors (PPAR) γ/δ, promoting smaller, metabolically healthier adipocytes, and they attenuate chronic low-grade inflammation associated with obesity by inhibiting NF-κB and NLRP3 inflammasome activation, reducing interleukin (IL)-1, IL-6, and secreting tumor necrosis factor (TNF)-α. Through interaction with free fatty acid receptors (FFARs), particularly FFAR4, they contribute to macrophage polarization toward the anti-inflammatory M2 phenotype, thereby decreasing immune cell infiltration into adipose tissue, increasing fibroblast growth factor-21 (FGF21) levels, and improving glycogen synthesis and insulin sensitivity [186,187,188].

In addition, omega-3 PUFAs act as agonists of FFAR4, stimulating CCK secretion to support appetite regulation and metabolic homeostasis, while also contributing to the production of endocannabinoids, key lipid mediators that control food intake. They also promote fatty acid oxidation and reduce lipogenesis via sterol-regulatory element-binding protein-1 (SREBP-1c), carbohydrate response element binding protein (ChREBP), AMP-activated protein kinase (AMPK), and PPAR-α, fostering an energy balance that limits fat accumulation. Omega-3 PUFAs also reduce hepatic very-low-density lipoprotein (VLDL) and modulate cholesteryl ester transfer protein-mediated lipid exchanges, leading to increased high-density lipoprotein (HDL) and potentially higher apolipoprotein A-1 [186,187,188]. Other mechanisms include promoting mitochondrial biogenesis, thermogenesis, and enhanced blood flow to skeletal muscle during exercise, facilitating lipid utilization. Taken together, omega-3 PUFA may contribute to obesity management by reducing inflammation, improving metabolic regulation, and supporting healthier body composition [187,188].

A case study suggests that omega-3 may enhance fat metabolism and, with dietary modifications, reduce fat mass and body weight in obesity [297]. A meta-analysis of 11 RCTs (n = 617) reported decreases in waist circumference and triglycerides in overweight/obese adults [187]. In T2DM, a meta-analysis of 46 randomized controlled trials (n = 4991) demonstrated improvements in total cholesterol, triglycerides, HDL, HbA1c, and C-reactive protein (CRP) [298]. Furthermore, a meta-analysis of 90 RCTs (n = 72,598) demonstrated a dose-response relationship between omega-3 intake and reductions in triglycerides and non-HDL cholesterol, particularly in hyperlipidemia, overweight/obesity, or coronary heart disease, and more evident with doses >2 g/day or in those on lipid-lowering therapy [299]. Collectively, these data suggest that omega-3 PUFAs may benefit GLP-1RA users in the management of weight and dyslipidemia.

Beyond metabolic benefits, omega-3 PUFAs may contribute to skeletal muscle protection, protein synthesis, strength, physical performance, and immune function following intense exercise [189,190,191,192], though evidence is mixed. In older adults, >2 g/day was associated with modest gains in muscle mass (0.67 kg) and improvements in walking speed, particularly after interventions > 6 months (1.78 m/s; 95% CI: 1.38–2.17) [190]. Conversely, a meta-analysis including 14 trials with 1443 healthy young and older adults reported only minimal improvements in muscle strength, with no significant effects on muscle mass or function [300]. More recently, a systematic review and meta-analysis of 4 studies suggested enhanced maximal muscle strength when combined with resistance training, although again without significant changes in muscle mass [301].

Regardless of the evidence on omega-3 PUFA remains inconclusive, krill oil (KO) supplementation has demonstrated promising effects on muscle health. KO is a sustainable and safe source of EPA and DHA primarily in phospholipid form, which enhances bioavailability and minimizes the fishy aftertaste of fish oil [302,303,304,305,306]. In a randomized controlled trial with healthy older adults, including overweight or with type I obesity, 4 g/day of KO for 6 months improved muscle outcomes, including increases in knee extensor maximal torque (9.3%), grip strength (10.9%), and vastus lateralis muscle thickness (3.5%), supporting clinically relevant gains in muscle function and size [307]. Another randomized controlled trial with 41 overweight/obese adults undergoing an alternate-day fasting regimen showed that KO (4 g/day, SuperbaBoost™, Aker BioMarine ASA, Lysaker, Norway) for 8 weeks attenuated declines in fat-free mass (−0.2 ± 0.9 kg) and handgrip strength (−0.2 ± 0.5 kg) observed in the placebo group [308].

Taken together, these findings indicate that omega-3 PUFAs could hypothetically act as a supportive adjuvant in GLP-1RA therapy, contributing to metabolic health and preservation of lean mass and muscle strength during weight loss, although direct evidence in GLP-1RA users is lacking.

3.5. Botanical Actives

3.5.1. Bitter Melon (Momordica charantia) Extract

Momordica charantia, commonly known as bitter melon or bitter gourd, is traditionally used in Asia, Africa, and the Caribbean for culinary and medicinal purposes, with a long-standing role in traditional Chinese and Ayurvedic medicine due to its reported antidiabetic properties [200,309]. It can markedly stimulate endogenous GLP-1 secretion. In in vitro studies using the enteroendocrine cell line (STC-1), bitter melon extracts dose-dependently increase GLP-1 release, an effect partially blocked by a bitter taste receptor antagonist (probenecid) and by a phospholipase Cβ2 inhibitor (U-73122), suggesting a taste receptor-mediated mechanism [193]. In mice, acute administration raised circulating GLP-1 and insulin, improving glucose tolerance, an effect abrogated by a GLP-1 receptor antagonist (exendin-9), indicating an incretin-mediated hypoglycemic action [193]. Hence, bitter melon could potentially amplify GLP-1RA activity or help sustain GLP-1 effects after drug discontinuation.

Clinically, bitter melon supplementation has demonstrated modest benefits in weight and glycemic control. A meta-analysis of 8 randomized trials (n = 507) found reductions in fasting glucose (~25 mg/dL), HbA1c (0.2%), LDL, total cholesterol, triglycerides, and body weight (~3.45 kg vs. placebo) [194]. These improvements in glucose homeostasis were confirmed by a later meta-analysis of 10 studies (1045 T2DM patients) [198] and several more recent trials in prediabetic and diabetic individuals [195,196,197]. A separate meta-analysis (8 studies, 423 participants) showed significant reductions in total cholesterol and triglyceride, particularly at ≤2g/day and ≤8 weeks, with the greatest benefits in diabetic and prediabetic individuals [199].

Bitter melon’s bioactives (e.g., cucurbitane triterpenoids) may activate pathways convergent with GLP-1 signaling, such as AMPK and PPARs, and modulate FGF21, a hormone involved in energy balance [200,201,310]. Animal studies confirm anti-obesity effects, with reduced adiposity and upregulation of metabolic regulators [200,201].

Taken together, evidence indicates that bitter melon could enhance the weight loss and glycemic benefits of GLP-1RAs by increasing endogenous GLP-1 and by improving metabolic profiles [193,194,198,199]. However, no trials have yet assessed their combined use with GLP-1RAs, so these benefits remain unconfirmed.

3.5.2. Ceylon Cinnamon (Cinnamomum zeylanicum) Extract

Cinnamomum zeylanicum (or C. verum), known as Ceylon or “true” cinnamon, differs from other species (such as C. cassia or C. aromaticum) by its negligible coumarin content, conferring a safer phytochemical profile [311,312]. Due to its well-known benefits for glucose metabolism, it may complement GLP-1RA therapy through improved glycemic control and insulin sensitivity.

Preclinical studies have shown that cinnamon, especially the Ceylon cinnamon variety, has antidiabetic properties and improves lipid and glucose metabolism in rodent models of diabetes and diet-induced obesity [313,314,315,316,317,318,319,320]. Moreover, two meta-analyses of clinical trials reported that it can positively affect obesity measures (body weight, BMI, body fat, and waist circumference), lower fasting plasma glucose, and improve lipid parameters [202,203]. In a recent 12-week randomized controlled trial with 150 adults, 1 g/day of Ceylon cinnamon extract reduced fasting glucose by 8.6 mg/dL, with the greatest effect in T2DM [110]. Another trial in T2DM patients showed that 3 months of cinnamon (1 g/day) decreased fasting and postprandial glucose, HbA1c, fasting insulin, insulin resistance, body weight, BMI, body fat (including visceral fat), and improved cholesterol profiles, with greater benefits in overweight individuals (BMI ≥ 27) [204].

Mechanistically, cinnamon polyphenols may act through complementary pathways: they may inhibit intestinal α-glucosidase and pancreatic α-amylase, delaying carbohydrate digestion and reducing postprandial glucose [321,322,323]. In a clinical study with 14 healthy subjects, supplementation decreased gastric emptying and postprandial glucose [205], mimicking GLP-1RAs and potentially synergizing for postprandial control. Cinnamon also enhances insulin signaling and sensitivity: in obese diabetic rodents, Ceylon cinnamon extract improved insulin action in peripheral tissues and brain, reducing hepatic fat [320]. Additionally, its anti-inflammatory and antioxidant properties may alleviate obesity-related inflammation, potentially amplifying the pro-insulinotropic and β-cell protective effects of GLP-1 [204,324,325].

Taken together, these data suggest cinnamon may potentially serve as an adjunct to GLP-1RAs by improving glycemic control, modulating digestive enzymes, and supporting insulin sensitivity. Continued use after GLP-1RA discontinuation might help maintain glycemic control and mitigate rebound hyperglycemia or weight regain [110,202,203,204,321,322]. To date, no clinical trials have directly evaluated the combined use of cinnamon extract with GLP-1RA therapy, and its potential benefits in this context remain hypothetical.

3.5.3. Guava (Psidium guajava) Leaf Extract

Guava (Psidium guajava) leaf extract has emerged as a promising nutraceutical with multi-faceted benefits for glycemic control and metabolic syndrome that could complement GLP-1RA therapy. Rich in polyphenols (such as quercetin derivatives), its glucose-lowering effects occur through inhibition of carbohydrate-digesting enzymes and enhancement of insulin action [326,327]. In vitro, it inhibits α-glucosidase and α-amylase, potentially delaying carbohydrate absorption [207]. In animal models, guava leaf extract reduced fasting glucose and HbA1c, improved glucose tolerance and insulin resistance, and increased hepatic glycogen storage, likely via activation of AMPK and suppression of gluconeogenesis [328,329,330,331,332,333,334,335].

Guava leaf also improves lipid metabolism and hepatic health. In diet-induced obesity, guava leaf lowered fat deposition, prevented hepatic steatosis, and improved plasma triglycerides and cholesterol [336]. In diabetic mice, its flavonoids reduced total cholesterol, LDL, and triglycerides, while improving hepatocyte morphology [328]. Importantly, guava leaf’s benefits extend to vascular function: in obese mice, it improved endothelial function alongside lowered glucose [211], and in diabetic rats, it normalized lipid profiles and plasma glucose while restoring vascular reactivity, further supporting its potential to reduce cardiovascular risk [337].

Human data support these findings. In Asia, guava leaf tea has been used as an adjunct for diabetes management. A clinical study reported it decreases postprandial glucose, an effect attributed to α-amylase, maltase, and sucrase inhibition observed in vitro [208,210]. Also, daily consumption for 12 weeks in prediabetic and mild diabetic subjects led to reductions in insulin, homeostasis model assessment for insulin resistance (HOMA-IR), cholesterol, and triglycerides [209,210,211]. More recently, a quasi-experimental study in diabetic patients showed that consuming 250 mL/day of guava leaf decoction for 14 days significantly reduced blood glucose [338].

Besides metabolic benefits, guava leaf extract is a traditional anti-diarrheal that has gained scientific support [115] and may be potentially useful for GLP-1RA-related diarrhea. Its polyphenols (such as quercetin and catechins) exhibit antispasmodic, anti-secretory, anti-microbial, and anti-inflammatory effects [326].

An early controlled clinical study demonstrated the intestinal antispasmodic effect of a phytodrug from guava leaf, reducing abdominal pain in 100 patients with acute diarrheic disease [206]. In another randomized clinical trial, 109 adults with acute diarrhea given guava leaf decoction experienced shorter diarrhea duration and improved stool frequency and consistency compared to standard rehydration therapy, without side effects or constipation, a common side effect of anti-motility agents [114].

Preclinical data reinforce these findings. In rodents, guava leaf aqueous extract produced dose-dependent protection against castor oil-induced diarrhea, reducing stool frequency, prolonging transit, and reducing intestinal fluid secretion [339]. Additionally, animal studies suggested broad-spectrum antidiarrheal and antimicrobial benefits by restoring microbial diversity, increasing beneficial genera [212], by reducing bacterial load and virulence factors [340,341], as well as by protecting enterocytes lining from damage, necrosis, and ulceration [341,342,343].

Overall, guava leaf extract emerges as a potential adjunct to GLP-1RAs by enhancing glycemic and lipid control, inhibiting digestive enzymes, supporting cardiovascular health, and alleviating diarrhea and abdominal discomfort, with a favorable safety profile. However, studies in GLP-1RA therapy are lacking, so its potential role as a complementary strategy remains hypothetical and should be further investigated.

3.5.4. French Maritime Pine (Pinus pinaster) Bark Extract

French maritime pine bark extract, derived from Pinus pinaster and rich in procyanidin, is a well-researched botanical with multiple clinically demonstrated benefits, including for metabolic, cardiovascular, and cognitive health [344]. Its antioxidant, anti-inflammatory, and endothelial-protective actions align well with the pathophysiology of metabolic syndrome [214]. Clinical studies show improvements in glucose, lipids, blood pressure, and central obesity. In T2DM patients, supplementation reduced fasting glucose and improved insulin sensitivity [214].

In metabolic syndrome, pine bark extract (150 mg/day, for 6 months) improved key risk factors: it lowered fasting glucose (~123 to ~105 mg/dL), reduced waist circumference (−7.9 cm in men and −7.3 cm in women), increased adiponectin, and reduced blood pressure and oxidative stress markers [213]. Lipid profile also improved, with reductions in LDL and triglycerides, and a rise in HDL [213,214]. In T2DM patients, 100 mg/day for 12 weeks reduced plasma glucose and improved endothelial markers endothelin-1 and 6-keto-prostaglandin F1α, suggesting improved vascular and glycemic control [215].

Mechanistically, as clinically demonstrated, pine bark’s bioflavonoids activate endothelial nitric oxide synthase (eNOS), increasing nitric oxide (NO)-mediated vasodilation and overall cardiovascular health [216]. Pine bark extract also inhibits α-amylase and α-glucosidase, supporting its glucose-lowering effects [217,218,219].

Preclinically, it reduced obesity in high-fat diet ApoE-deficient mice by promoting lipolysis and browning of white adipose tissue, upregulating lipolytic enzymes (ATGL and HSL) and thermogenic markers (UCP1), and activating the protein kinase A (PKA) pathway [220]. Collectively, these mechanisms may complement GLP-1RAs by improving cardiometabolic health and sustaining benefits when the therapy is discontinued. However, clinical studies specifically evaluating these effects in combination with GLP-1RAs are needed to confirm their relevance.

3.5.5. Citrus Flavonoids

Citrus flavonoids, particularly from lemon (eriocitrin, hesperidin, and naringin), have shown benefits for glycemic control and may directly interact with the GLP-1 pathway. In a 12-week randomized trial in subjects with prediabetes, supplementation with a lemon flavonoid extract (Eriomin^®, Ingredients by Nature™, Montclair, NJ, USA) reduced fasting glucose and glucose intolerance (5% and 7% decrease, respectively), and improved insulin resistance by 7% [117]. It also reduced systemic inflammation markers IL-6 (−13%), TNF-α (−11%), and high-sensitivity C-reactive protein (hsCRP, −12%) [117], which could potentially complement GLP-1RA’s known reduction in inflammatory markers [345].

Notably, citrus flavonoids stimulate endogenous incretin secretion: the same trial reported a 15% increase in plasma GLP-1 [117], and another crossover trial found a ~17% increase with improved glucose metabolism [118]. Mechanistically, they may modulate gut microbiota and SCFA production, promoting L-cell secretion of GLP-1 [221,222]. In prediabetics, 200 mg/day for 12 weeks favorably shifted gut microbiota (increasing Ruminococcaceae and decreasing dysbiosis-associated Lachnospiraceae), correlating with better glycemic outcomes [221].

Animal studies also show citrus flavonoids reduce weight gain and adiposity by activating AMPK and upregulating adipocyte thermogenesis [346,347], suggesting weight-modulating effects.

In summary, citrus flavonoids may improve glycemic control, increase GLP-1 secretion, lower inflammation, and support weight management, making them potential adjunctive candidates to GLP-1RAs [117,118,347], though no clinical studies have directly evaluated their combined use.

3.5.6. Moro Orange (Citrus sinensis L. Osbeck) Extract

Moro blood orange (Citrus sinensis L. Osbeck) is rich in anthocyanins, such as cyanidin-3-glucoside, and other polyphenols investigated for weight management [223,224]. A Moro orange extract has shown clinical efficacy in reducing body weight and abdominal fat [120,121]. In randomized, double-blind trials with overweight individuals, 400 mg/day for 12 weeks or 6 months significantly reduced body weight, BMI, waist and hip circumferences, and visceral and subcutaneous fat, without affecting lean mass [120,121].

Anthocyanins exert anti-obesity effects via modulation of lipid metabolism, enhancement of energy expenditure, regulation of appetite, alteration of gut microbiota, and reduction in lipid absorption [223]. Specifically, moro anthocyanins activate AMPK, enhance lipolysis, and suppress adipogenesis, reducing fat accumulation in experimental models [348,349]. Additionally, moro orange extract has antioxidant and anti-inflammatory properties, which may improve adipose tissue inflammation and insulin sensitivity [224].

Although direct studies evaluating moro extract with GLP-1RAs are lacking, current evidence supports its inclusion in a multi-targeted obesity regimen [120,348].

3.5.7. Ginger (Zingiber officinale)

Ginger (Zingiber officinale) has a long history as an antiemetic and digestive aid, and clinical evidence validates its use for reducing nausea, a primary GI side effect of GLP-1RAs. Its active compounds (gingerols and shogaols) act through multiple mechanisms: antagonism of 5-HT3 receptors, vagal modulation, and acceleration of gastric emptying [225,226,227,228]. In a randomized, double-blind study with 24 healthy adults, 1.2 g of oral ginger accelerated gastric emptying (half-emptying time after a meal 13 min vs. 27 min with placebo), and increased gastric antral contractions without adverse symptoms [350]. This prokinetic effect may mitigate GLP-1RA-induced nausea, potentially improving treatment tolerability [61].

Clinical trials across various settings confirm ginger’s antiemetic efficacy, as corroborated by an overview of 15 meta-analyses [229]. A meta-analysis of 13 randomized control trials (n = 1174) found that ginger significantly improves overall pregnancy-associated nausea and vomiting, comparable to vitamin B6 [230] and as effective as standard antiemetics like dimenhydrinate [231]. Two meta-analyses also showed benefits in postoperative nausea [232] and acute chemotherapy-induced vomiting [233].

Besides antiemetic effects, ginger supports metabolic health. It has been shown to lower blood pressure, body weight, blood glucose, lipid levels (VLDL and LDL), and atherosclerotic plaques, with no serious adverse effects [351,352]. Mechanisms include anti-inflammatory and antioxidant effects, inhibition of digestive enzymes (α-glucosidase and α-amylase), enhancement of glucose transport via GLUT-4, improved insulin sensitivity through adiponectin and PPAR-γ pathways, protection of β-cells, and AMPK activation [353,354]. Ginger may also preserve GLP-1 activity by increasing plasma GLP-1, inhibiting DPP-4 by 40–50% (which would preserve GLP-1 from degradation), and activating cAMP/PKA/CREB signaling [351,355].

Clinical studies corroborate these effects. A meta-analysis of 14 randomized controlled trials with 473 overweight/obese subjects found significant reductions in body weight, waist-to-hip ratio, and hip ratio [236]. Another meta-analysis of 27 randomized controlled trials (n = 1309) reported weight loss of 1.52 kg, with decreases of waist circumference and body fat, most effective at 2 g/day [234]. Additional meta-analyses confirmed benefits, especially in T2DM and overweight/obese individuals, with improvements in fasting glucose, HbA1c, insulin resistance (HOMA-IR), and systolic and diastolic blood pressure, though effects on total cholesterol, LDL, and triglycerides were mostly nonsignificant [235,236].

Ginger may also affect satiety. In a randomized crossover pilot study with 10 overweight men, 2 g of ginger powder significantly reduced hunger by 43%, decreased food intake, and increased thermogenesis (+43 kcal/day) [356]. The authors discuss that these effects likely occur through activation of transient-receptor potential vanilloid 1 (TRPV1) channels, which stimulate sympathetic nervous system pathways that enhance thermogenesis and satiety [356].

Taken together, current evidence indicates that ginger may potentially complement GLP-1RAs by benefiting weight management, glucose control, satiety, cardiovascular health markers, and alleviating nausea, thereby supporting both effectiveness and adherence. Although direct clinical trials combining ginger with GLP-1RAs are lacking, a multidisciplinary expert consensus recommends its use to help manage nausea in individuals undergoing GLP-1RA therapy [61].

4. Conclusions

For optimal results and treatment adherence, several scientific societies recommend that GLP-1RA therapy be accompanied by a comprehensive lifestyle approach, including physical activity programs, management of side effects, adequate sleep, stress reduction, minimization of substance use, cultivation of positive social connections, and nutritional strategies. Additionally, certain approaches, such as adequate protein intake, ginger consumption, as well as dietary fiber and probiotic supplementation, are supported by expert consensus for preserving lean mass and enhancing gastrointestinal tolerability in individuals receiving GLP-1RAs. Beyond these practice-reasonable strategies, several other nutritional compounds discussed here offer potential mechanisms of action that may possibly complement or converge to GLP-1RAs therapeutic effects, including stimulation of endogenous GLP-1 secretion (bitter melon, citrus flavonoids, proteins), increase in satiety (chromium, proteins, ginger), improvement of glycemic control and insulin sensitivity (dietary fibers, probiotics, cinnamon, pine bark, chromium, zinc, omega-3 PUFAs, guava leaf, citrus flavonoids, ginger), decrease in adiposity and weight (proteins, moro orange, L. gasseri BNR17, bitter melon, ginger), anti-inflammatory and antioxidant effects (zinc, pine bark, cinnamon, citrus flavonoids, ginger), and improved GI tolerability (dietary fibers, probiotics, colostrum, zinc, guava leaf, L-glutamine, ginger). Furthermore, they could potentially aid in lean mass preservation (colostrum, proteins, omega-3 PUFAs) and mitigate weight regain when discontinuing GLP-1RA by sustaining these various effects. Figure 1 and Figure 2 illustrate the main physiological actions of GLP-1RAs and highlight potential sites of synergy with nutritional adjuncts, as well as their putative mechanisms of action. It is also important to recognize that nutritional supplements differ from pharmacological agents in their regulatory classification and intended use, and they are not subject to the same level of pre-market clinical validation as drugs. Furthermore, while current evidence is encouraging, direct studies evaluating the combined use of these interventions with GLP-1RAs remain scarce. Nevertheless, all nutritional interventions reviewed here have a favorable safety profile and are generally regarded as safe within recommended intake levels. As with any bioactive substance, caution is advised in vulnerable populations, including pregnant/lactating women, older adults, critically ill patients, individuals with hepatic or renal impairment, and those using hepatotoxic or nephrotoxic medications. Clinical monitoring and individualized assessment by healthcare professionals are recommended. Future randomized studies should evaluate the additive effects of these nutritional interventions with GLP-1RAs in obese/diabetic populations. In the meantime, clinicians and researchers may consider their biologic rationale and safety profiles for future research and when personalizing obesity treatment.