Restoring Fullness After GLP-1/GIP Treatments: Metabolism, Diet, and Gut Bacteria

This narrative review was conducted using a structured literature search approach to identify clinically relevant evidence on weight regain, metabolic adaptations, and nutritional factors associated with GLP-1 receptor agonists and dual GLP-1/GIP agonists.

Electronic databases including PubMed/MEDLINE and Google Scholar were searched for studies published between 2005 and 2026. The search strategy combined terms related to obesity pharmacotherapy and metabolic regulation, including: GLP-1 receptor agonists, GIP, tirzepatide, semaglutide, weight regain, adaptive thermogenesis, fat-free mass, protein intake, gut microbiota, short-chain fatty acids, satiety, and metabolic adaptation.

Priority was given to randomised controlled trials, systematic reviews, meta-analyses, and high-quality clinical studies, particularly those from the STEP and SURMOUNT trial programmes. Mechanistic studies and selected preclinical or translational research were included where necessary to support biological plausibility, with explicit recognition of their inferential nature.

Given the narrative design of the review, formal inclusion and exclusion criteria were not predefined; however, emphasis was placed on studies with clear clinical relevance to obesity management and post-treatment weight stability. Particular attention was given to evidence addressing the period following dose reduction or discontinuation of incretin-based pharmacotherapy. The final literature search was conducted in February 2026. Reference lists of key articles were additionally screened to identify relevant publications.

A key, unresolved question in contemporary obesity management is whether treatment with GLP-1 receptor agonists and dual GLP-1/GIP agonists should be regarded as a time-limited intervention or as chronic therapy, analogous to the treatment of hypertension or type 2 diabetes. This issue is particularly pertinent given evidence that the efficacy of these agents in weight reduction is closely dependent on continued use, whereas discontinuation is associated with biologically driven weight regain [3,4].

Randomised trials within the STEP programme have demonstrated that pharmacological enhancement in incretin signalling enables substantial weight loss during active treatment. In STEP 1, once-weekly semaglutide 2.4 mg resulted in clinically significant weight reduction and improvements in cardiometabolic parameters compared with placebo [1]. The STEP 5 trial showed that continued treatment maintained weight reduction for at least 104 weeks, indicating the durability of the therapeutic effect under sustained drug exposure [16].

However, in the STEP 1 extension, following semaglutide withdrawal, participants regained approximately two-thirds of their initial weight loss over one year, accompanied by partial reversal of metabolic improvements [4]. Similar findings emerged from STEP 4, where treatment discontinuation after an induction phase led to significant weight regain despite continued lifestyle advice, whereas ongoing treatment allowed for stabilisation or further reduction in body weight [3].

A comparable pattern of dependence on continued treatment has been demonstrated for the dual GLP-1/GIP agonist. In the SURMOUNT-4 trial, discontinuation of tirzepatide following an initial weight-loss phase resulted in weight regain, whereas continued treatment enabled maintenance and further reduction [17]. These data consistently indicate that, after discontinuation, weight regain is common; however, whether incretin-based pharmacotherapy leads to sustained normalisation of the biological mechanisms regulating energy balance remains insufficiently demonstrated. During active treatment, these agents appear to function primarily as modulators of disrupted energy homeostasis.

This interpretation aligns with current understanding of the metabolic adaptations accompanying weight loss. Following weight reduction, resting energy expenditure declines beyond what would be predicted from weight loss alone, a phenomenon termed adaptive thermogenesis [9]. Concurrently, alterations occur in the hormonal signalling that regulates appetite, including increased ghrelin levels and persistently reduced leptin concentrations, which favour increased hunger [5]. These mechanisms may persist long after weight loss and are thought to contribute to the biological drive toward weight regain. The duration of these adaptations is highly variable and may depend on the magnitude of weight loss, rate of regain, and individual metabolic phenotype. In this context, discontinuing GLP-1/GIP agonists may unmask compensatory mechanisms that were previously pharmacologically attenuated.

Recent systematic reviews confirm that weight regain after pharmacotherapy cessation is not limited to individual STEP trials. A systematic review on discontinuation of GLP-1 receptor agonists found that treatment cessation was associated with significant weight gain, irrespective of concurrent lifestyle interventions [5]. Similarly, a meta-analysis encompassing various classes of anti-obesity medications showed that stopping treatment led to rapid weight regain and partial loss of metabolic benefits, an effect also observed for incretin-based therapies [6]. At a population level, this suggests that pharmacotherapy alone may be insufficient to sustain control of the biological drivers of obesity after discontinuation.

In light of this, there is a growing consensus that obesity should be treated as a chronic disease requiring long-term pharmacotherapy in selected patients. This approach is partially reflected in international documents. The World Health Organization, in its guideline on the use of GLP-1 receptor agonists for obesity treatment, emphasises the need to embed pharmacotherapy within a long-term treatment plan, acknowledging the chronic nature of the disease [15].

Further dimension to this discussion is provided by data on hard endpoints. The SELECT trial demonstrated that semaglutide reduces the risk of cardiovascular events in patients with overweight or obesity and established cardiovascular disease, without type 2 diabetes [18]. This suggests that the benefits of therapy may extend beyond weight reduction alone, further supporting long-term use in patients at high cardiovascular risk.

At the same time, available data do not support the conclusion that GLP-1/GIP pharmacotherapy should be chronic for all patients. A more individualised approach appears appropriate, considering metabolic phenotype, degree of obesity, presence of comorbidities, rate of weight regain, and feasibility of implementing concurrent nutritional and behavioural strategies. It is important to emphasise that considering therapy potentially long-term does not imply its use in isolation. Failure to preserve fat-free mass, inadequate protein intake, or lack of strategies to stabilise energy balance may limit the possibility of safe discontinuation and promote weight regain [9,10].

Thus, in clinical practice, the question should not be solely “does the drug work?” but rather “in whom, in which metabolic context, and for how long does its use confer the greatest clinical benefit with an acceptable safety profile?” This perspective allows for reconciliation of the chronicity of obesity with the need for rational, individualised pharmacotherapy. This supports the need to conceptualise post-treatment care as a transition from pharmacologically supported appetite control to diet- and metabolism-supported satiety regulation.

In obesity, adipose tissue is not merely a passive energy store but functions as an active endocrine organ whose dysfunction significantly influences energy balance regulation and susceptibility to weight regain following reduction. In obesity, leptin resistance, reduced adiponectin concentrations, and increased production of pro-inflammatory cytokines such as TNF-α and IL-6 are observed, contributing to persistent low-grade systemic inflammation [7,19].

Chronic inflammation within adipose tissue is associated with macrophage infiltration and activation of NF-κB and JNK pathways, which are associated with impaired insulin and leptin signalling [19]. Central leptin resistance, despite high circulating leptin levels, limits the hypothalamus’s ability to appropriately suppress appetite and increase energy expenditure [20]. Consequently, after weight loss, a relative deficit in satiety signalling may emerge in relation to reduced adipose tissue mass, promoting compensatory increases in energy intake.

Concurrently, reduced adiponectin concentrations may impair metabolic flexibility and the ability to adapt to changes in energy supply. Weight loss does not always fully normalise the adipokine profile, and persistent endocrine dysfunction of adipose tissue may contribute to renewed energy storage after the cessation of a weight-loss intervention [7,19].

An important element in the pathophysiology of weight regain is metabolic liver dysfunction, particularly in the context of metabolic dysfunction-associated steatotic liver disease (MASLD) and hepatic insulin resistance [8]. These disturbances may contribute to dysregulation of gluconeogenesis, increased endogenous glucose production, and impaired metabolic flexibility, potentially influencing central processing of hunger and satiety signals.

The liver is a key component of the gut–liver–brain axis, integrating hormonal (GLP-1, PYY), metabolic (glucose, fatty acids), and neural (vagus nerve) signals [21]. Under conditions of hepatic insulin resistance, this axis may become dysregulated, and feedback between the availability of energy substrates and central signalling may be impaired.

Although steatosis and hepatic insulin resistance often improve with clinically meaningful weight loss, more advanced components of MASLD, particularly fibrosis and macrophage-driven inflammation, may be more resistant to full resolution. Therefore, any proposed contribution of residual liver dysfunction to appetite regulation after GLP-1/GIP discontinuation should be interpreted cautiously.

The specific contribution of residual hepatic insulin resistance to appetite dysregulation after GLP-1/GIP discontinuation has not yet been demonstrated in clinical studies.

Individuals with obesity exhibit complex disturbances in the hormonal axis regulating appetite, involving ghrelin, peptide YY (PYY), cholecystokinin, and endogenous GLP-1 [20,22]. During weight loss, ghrelin concentrations increase, and anorexigenic signals are relatively weakened, which may contribute to heightened hunger and increased energy intake.

Studies have shown that hormonal changes after weight loss may persist for at least 12 months and are consistent with a biological “defence” of higher body weight [22,23]. The persistence of these adaptations is variable across studies and may depend on the magnitude of weight loss, rate of regain, and individual metabolic phenotype.

Pharmacological modulation of these mechanisms with GLP-1/GIP agonists effectively suppresses appetite during treatment, but after discontinuation, it remains unclear whether endogenous hunger–satiety signalling undergoes sustained normalisation, although weight regain is frequently observed.

Furthermore, chronic inflammation and insulin resistance may affect hypothalamic neurotransmission, weakening the postprandial satiety response [19,20]. Consequently, after pharmacotherapy ends, individuals may exhibit increased sensitivity to hunger stimuli alongside attenuated satiety signalling, which may contribute to susceptibility to weight regain.

An additional, often underestimated, contributor to weight regain is the loss of fat-free mass during weight reduction, particularly when energy and protein intakes are low. Weight loss is typically associated with a loss of approximately one-quarter of fat-free mass [10], which is associated with a reduction in basal metabolic rate.

Adaptive thermogenesis may persist long after weight loss, which may result in total energy expenditure remaining lower than predicted based on current body weight [9,24,25]. Combined with heightened hunger and impaired satiety signalling, this may create a metabolic environment conducive to weight regain.

These mechanisms may help explain why weight regain is not solely a consequence of eating behaviours but reflects persistent biological adaptations that extend beyond the period of active treatment [5,9,25].

Reduced fat intake may affect the bioavailability of fat-soluble vitamins (A, D, E, K), whose absorption depends on the presence of lipids in the intestinal lumen [28]. Additionally, reduced total food volume and limited intake of animal-derived products may be associated with reduced intake of vitamin B12, iron, and zinc. Although direct data evaluating the frequency of micronutrient deficiencies during GLP-1/GIP therapy remain limited, similar mechanisms have been described in other models of prolonged energy restriction [29]. These comparisons should be interpreted cautiously, as they are inferential rather than based on direct micronutrient deficiency data from GLP-1/GIP cohorts.

It is important to note that subclinical reductions in dietary quality or nutrient adequacy may occur without overt symptoms in the initial phase of treatment. Potential consequences may include impaired muscle function, concentration difficulties, or reduced exercise tolerance, which may become more apparent after pharmacotherapy cessation or during dose reduction, when pharmacological appetite suppression is reduced or withdrawn.

Protein intake is of particular importance in the context of incretin-based therapy. Reduced appetite and early satiety may contribute to a decrease in total protein consumption, which may be particularly relevant in older populations where the risk of sarcopenia is elevated. Earlier work by Wolfe and Miller suggested that standard protein intake recommendations (0.8 g/kg body weight) may be insufficient under conditions of weight loss and pronounced metabolic adaptations [12]. More recent recommendations in the context of incretin-based therapy provide a more directly applicable framework for protein intake and muscle preservation [11,12,30,31,32].

Recent recommendations for minimising muscle loss during incretin-based therapy emphasise the importance of protein intake in the range of at least 1.0–1.2 g/kg body weight, and in selected cases even higher, combined with resistance training [11]. Data from body composition analyses in the STEP and SURMOUNT programmes suggest that a proportion of weight loss constitutes fat-free mass reduction [10,16,17]. Although this proportion falls within the range observed in other weight-loss interventions, its clinical significance may increase with long-term treatment.

Loss of fat-free mass is associated with a reduction in resting energy expenditure and total energy expenditure [10,24,25]. These adaptations may persist after weight loss cessation and may increase susceptibility to a positive energy balance even with moderate energy intake. In this context, GLP-1/GIP pharmacotherapy, while effective in initiating weight loss, may not fully counteract mechanisms that may promote weight regain if not accompanied by strategies to preserve muscle mass and dietary quality.

A growing number of authors emphasise that pharmacological appetite suppression is not equivalent to fully restoring physiological satiety mechanisms or improving micronutrient status [11,33]. The absence of adequate nutritional support during treatment may result in substantial weight loss accompanied by compromised body composition and metabolic reserves. In the post-treatment period, reduced energy expenditure, muscle loss, and potential micronutrient deficiencies may contribute to an environment conducive to weight regain and deterioration of metabolic function [9,10,14].

From a clinical perspective, this highlights the importance of treating GLP-1/GIP therapy not merely as a pharmacological intervention but as part of an integrated care model that includes monitoring protein intake, assessing body composition, and, where appropriate, periodic evaluation of selected micronutrients.

Vitamins A, D, E, and K require the presence of fat in the intestinal lumen and proper micellization for effective absorption; therefore, long-term maintenance of very low-fat diets may limit their bioavailability [28]. For this reason, it may be reasonable to maintain a minimum dietary fat intake and to include sources of dietary fat, such as plant-based oils (e.g., olive oil, rapeseed oil, oils rich in ALA), particularly in patients who adhere to low-fat diets due to gastrointestinal symptoms [28,36].

Vitamin D plays a role not only in calcium-phosphate homeostasis but also in the modulation of the inflammatory response, muscle function, and insulin sensitivity. Vitamin D deficiency is common among individuals with obesity and may persist after weight loss, particularly in the context of limited dietary fat intake and low UV exposure [35,37]. Vitamin D supplementation may be tailored to baseline 25(OH)D levels and clinical risk, according to local recommendations [37]. Depending on the clinical context, assessment of vitamin K status may also be considered (particularly when supplementing vitamin D), although current data do not support universal “D3 + K2” supplementation strategies for all patients after pharmacotherapy.

Vitamin B12 is essential for neurological and haematological function, and its intake may be suboptimal with low consumption of animal products and under conditions of reduced energy intake. In some patients (particularly those >50 years of age), the risk of B12 deficiency may increase due to impaired intrinsic factor-dependent absorption [38]. In cardiovascular and neurological contexts, it should be noted that homocysteine metabolism depends on B12, B6, and folates; correction of deficiencies may be relevant in selected patient groups, although routine empirical (“blind”) supplementation is not justified without clinical and/or laboratory assessment [38].

Magnesium plays a role in the regulation of glucose metabolism, muscle function, and nerve conduction. Magnesium deficiency is associated with poorer glycaemic control and may exacerbate fatigue and reduce exercise tolerance, potentially limiting the ability to engage in physical activity that is important for weight maintenance [39]. In patients with symptoms suggestive of deficiency or those on low-fibre/low-whole-grain diets, assessment of magnesium intake and possible supplementation may be considered.

Omega-3 fatty acids (EPA/DHA) have been shown to exert anti-inflammatory effects and may influence metabolic parameters, although the magnitude of clinical effects depends on dose, endpoints, and population [40]. In the context of obesity and inflammation, omega-3s may represent a supportive component of the overall metabolic strategy but do not replace foundational interventions such as protein intake, diet quality, and physical activity.

In summary, micronutrient support may be considered an element of integrated care for patients treated with GLP-1/GIP agents and may include risk assessment for deficiencies, prioritisation of likely deficiencies, and monitoring (clinical and, when justified, laboratory), particularly during the tapering phase of pharmacotherapy [11,35,37].

No new data were created or analysed in this study.