Micronutrient risk with GLP-1 receptor and dual incretin agonists in obesity: Mechanistic pathways, clinical signals, and a monitoring framework

Abstract

Background

Incretin-based pharmacotherapies, including GLP-1 receptor agonists and dual GIP/GLP-1 receptor agonists, have transformed obesity management by producing substantial weight loss through appetite suppression, reduced energy intake, and gastrointestinal effects. These mechanisms may also modify dietary intake, gastrointestinal physiology, and weight-loss–related metabolic adaptations, raising concern about micronutrient disturbances during long-term treatment.

Methods

This narrative clinical review synthesizes evidence on mechanistic pathways, clinical signals, and monitoring considerations related to micronutrient risk during incretin-based obesity pharmacotherapy. Evidence was integrated from dietary studies, observational cohorts, mechanistic investigations, clinical trials, pharmacovigilance reports, and literature on obesity-related micronutrient physiology.

Results

Micronutrient vulnerability appears to arise from the interaction between reduced food intake, lower dietary diversity, gastrointestinal intolerance, delayed gastric emptying, rapid weight loss, and baseline nutritional risk. The most relevant signals involve hematologic, fat-soluble, bone-related, trace element, and electrolyte domains, particularly iron, vitamin B12, vitamin D, calcium, magnesium, zinc, with additional context-dependent concerns involving thiamine, folate, vitamin A, other fat-soluble vitamins and potassium. Most abnormalities reported to date are subclinical or indirect, but clinically meaningful consequences may occur in susceptible individuals, including those with prior bariatric surgery, gastrointestinal disorders, poor baseline diet quality, older age, or prolonged nausea and vomiting.

Conclusion

Micronutrient risk during incretin-based obesity pharmacotherapy is likely multifactorial and patient-specific. Individualized nutritional assessment and targeted laboratory monitoring should be considered for high-risk patients, while prospective studies are needed to define incidence, clinical relevance, and evidence-based monitoring strategies.

Graphical abstract

1. Introduction

The management of obesity and type 2 diabetes mellitus (T2DM) is undergoing a profound transformation with the rapid clinical adoption of incretin-based pharmacotherapies [1]. Glucagon-like peptide-1 receptor agonists (GLP-1RAs), including Liraglutide and Semaglutide, as well as the dual glucose-dependent insulinotropic polypeptide (GIP) and GLP-1 receptor agonist Tirzepatide, have demonstrated levels of weight reduction previously observed primarily after metabolic and bariatric surgery [[2], [3], [4]]. In addition to their effects on body weight, these therapies provide clinically meaningful improvements in glycemic control, cardiometabolic risk factors, and inflammatory profiles [5,6]. As their use expands rapidly across obesity medicine and endocrinology, attention has begun to shift beyond efficacy toward the broader physiological consequences of sustained pharmacologically induced weight loss [[7], [8], [9], [10], [11]].

A growing area of concern is the potential for micronutrient insufficiency or deficiency during treatment with incretin-based therapies [12]. These agents exert powerful central and gastrointestinal effects that suppress appetite, slow gastric emptying, and reduce overall energy intake [[13], [14], [15]]. While these mechanisms are central to their therapeutic success, they also introduce a nutritional challenge: patients frequently experience marked reductions in food intake and altered dietary patterns that may compromise micronutrient adequacy if dietary quality is not carefully maintained [6,16,17]. Evidence for the magnitude of these effects is illustrated by large randomized clinical trial programs such as the STEP clinical trial program and the SURMOUNT clinical trial program, which evaluated semaglutide and tirzepatide for chronic weight management [[18], [19], [20], [21], [22], [23]]. Across these trials, mean weight reductions ranged from approximately 15% to more than 22% of baseline body weight [18,21,23,24]. Achieving these outcomes is consistently associated with substantial reductions in energy intake, with randomized and mechanistic studies demonstrating decreases of approximately 16–39% relative to baseline or placebo [25,26]. At these levels of caloric intake, meeting Dietary Reference Intakes (DRIs) for several essential vitamins and minerals becomes increasingly difficult unless dietary intake is specifically structured to maximize nutrient density, particularly in populations with pre-existing micronutrient vulnerability [27,28].

The risk of micronutrient imbalance is further compounded by the baseline nutritional status frequently observed in individuals with obesity. Although obesity is often associated with excess caloric intake, dietary patterns may be dominated by ultra-processed, energy-dense foods with relatively low micronutrient density [[29], [30], [31], [32], [33]]. As a result, pre-existing insufficiencies in nutrients such as iron, vitamin D, and certain trace elements are common [12,34]. When pharmacologically induced satiety and reduced food intake are superimposed on this background, individuals may be more likely to transition from marginal nutritional status to clinically relevant deficiency, particularly during periods of rapid weight loss [17].

Beyond reduced intake alone, several physiological processes associated with weight reduction may influence micronutrient homeostasis [35]. Rapid fat mass loss alters the storage and mobilization of fat-soluble vitamins [36], changes in iron metabolism occur as systemic inflammation declines [37], and accelerated bone remodeling during weight loss can affect calcium and vitamin D dynamics [38]. Gastrointestinal adverse effects (including nausea, vomiting, and early satiety) may further restrict food variety or tolerance of nutrient-dense foods [39,40]. Together, these factors create a multifactorial environment in which micronutrient disturbances may emerge even in the absence of structural gastrointestinal malabsorption.

In clinical practice, it is important to distinguish between biochemical insufficiency and clinical deficiency, as these represent different stages along the spectrum of nutritional compromise [41,42]. Biochemical insufficiency refers to laboratory evidence of suboptimal micronutrient levels without clear clinical manifestations. Examples include reduced serum ferritin, borderline vitamin B12 concentrations, or low serum 25-hydroxyvitamin D levels in otherwise asymptomatic individuals [[43], [44], [45]]. These findings may reflect early depletion of nutrient stores or negative nutrient balance during active weight loss [46]. Clinical deficiency, in contrast, represents the symptomatic consequences of prolonged nutrient depletion. Manifestations may include nutritional anemia resulting from iron, vitamin B12, or folate deficiency; neurological complications such as peripheral neuropathy or acute thiamine deficiency syndromes; and impaired skeletal health related to inadequate calcium and vitamin D status [46,47]. Emerging pharmacovigilance reports have also described neurological complications such as Wernicke encephalopathy in the context of severe vomiting and rapid weight loss during incretin therapy, although these events remain rare [48]. In addition, diffuse hair shedding (telogen effluvium) has been increasingly reported during the early months of treatment and is frequently attributed to rapid weight loss, reduced protein intake, and possible micronutrient deficits such as zinc or iron [49].

Despite the growing recognition of these potential nutritional implications, micronutrient status has rarely been systematically evaluated in major clinical trials of incretin-based obesity pharmacotherapy [2,12]. Consequently, clinicians currently lack clear guidance regarding which micronutrients warrant monitoring, which patient populations may be at greatest risk, and how laboratory findings should be interpreted during active pharmacologic weight loss. The objective of this narrative review is to synthesize current evidence regarding micronutrient risk associated with GLP-1 receptor agonists and dual incretin agonists used in obesity management. Specifically, we examine the mechanistic pathways that may predispose patients to micronutrient disturbances, summarize emerging clinical signals across major micronutrient groups, and propose a pragmatic framework for risk stratification and laboratory monitoring in clinical practice. By integrating physiological mechanisms with available clinical evidence, this review aims to clarify an increasingly relevant yet underexplored dimension of modern obesity pharmacotherapy.

2. Methodology

Given the heterogeneity of available evidence and the absence of standardized micronutrient endpoints in most clinical trials of incretin-based pharmacotherapy, a narrative synthesis approach was considered most appropriate. This review was conducted through a structured literature search of PubMed, Scopus, and other major biomedical databases from inception through February 2026. Search terms were combined using Boolean operators and included “obesity,” “GLP-1 receptor agonist,” “dual incretin agonist,” “GIP,” “semaglutide,” “tirzepatide,” “micronutrient deficiency,” “nutritional status,” “iron,” “vitamin B12,” “vitamin D,” “bone metabolism,” “dietary intake,” and “gastrointestinal adverse effects.”

Priority was given to randomized controlled trials, large observational studies, meta-analyses, and pharmacovigilance reports evaluating incretin-based therapies in obesity and T2DM. Given the limited availability of studies directly assessing micronutrient outcomes, additional evidence from dietary intake studies, mechanistic investigations, and literature on obesity-related micronutrient physiology and weight-loss–associated metabolic adaptations was incorporated to provide context. Reference lists of relevant articles and reviews were manually screened to identify additional sources, and selected grey literature was reviewed when relevant.

Due to variability in study design, outcome definitions, and reporting of micronutrient parameters, formal quantitative synthesis was not performed. Instead, findings were integrated using a thematic approach, focusing on mechanistic pathways, nutrient-specific clinical signals, and emerging evidence relevant to nutritional risk during incretin-based pharmacotherapy. The framework presented in this review is intended to organize existing evidence and highlight knowledge gaps, rather than to provide formal clinical recommendations. No formal risk-of-bias assessment was performed given the narrative design of the review.

To improve interpretability across heterogeneous sources, evidence was described according to its design and inferential strength throughout the manuscript. Dietary intake studies were interpreted primarily as evidence of nutritional exposure or inadequacy, mechanistic studies as short-term evidence of physiological plausibility, observational cohorts and administrative datasets as real-world clinical signals, and pharmacovigilance reports or case reports as hypothesis-generating evidence for rare but potentially severe outcomes. When available, study-level characteristics, including design, sample size, population, and duration of follow-up, were incorporated into the narrative synthesis.

During revision, a targeted supplemental literature check was performed to address reviewer comments regarding micronutrient scope, thiamine-related neurological risk, potassium and electrolyte disturbances, renal monitoring, and nutrition-care pathways during GLP-1 receptor agonist or dual incretin therapy. This supplemental check focused on nutrients and clinical scenarios specifically raised during peer review, including thiamine (vitamin B1), folate (vitamin B9), vitamin A, fat-soluble vitamins, potassium disturbances, dehydration, acute kidney injury, and registered dietitian nutritionist involvement. Newly incorporated evidence was interpreted using the same inferential framework described above: dietary studies were treated as evidence of intake inadequacy, observational studies as real-world clinical signals, pharmacovigilance and case reports as hypothesis-generating safety signals, prescribing information as regulatory safety context, and expert advisories as practice-oriented contextual evidence.

3. Therapy context relevant to nutrition

3.1. Appetite regulation, gastrointestinal effects, and changes in dietary intake

The recent expansion of incretin-based pharmacotherapies has substantially altered the therapeutic landscape of obesity management [50,51]. These agents mimic or enhance the activity of endogenous incretin hormones that are normally secreted in response to nutrient ingestion [52]. GLP-1, released from intestinal L-cells, and GIP, secreted from K-cells in the proximal intestine, contribute to the classical “incretin effect,” whereby oral glucose produces a greater insulin response than an equivalent intravenous glucose load [52]. While these hormones were initially studied primarily for their glucose-lowering properties, their extra-pancreatic actions on appetite regulation, gastrointestinal motility, and central reward pathways have proven central to their weight-reducing effects [53].

Pharmacologic agents targeting these pathways include selective GLP-1 receptor agonists such as Liraglutide and Semaglutide, as well as the dual GIP/GLP-1 receptor agonist Tirzepatide [50]. Clinical trials evaluating these medications have demonstrated substantial weight loss in individuals with obesity. In a recent head-to-head randomized trial (SURMOUNT-5), tirzepatide produced greater weight reduction than semaglutide over 72 weeks, illustrating the increasing potency of newer incretin-based therapies [54]. These substantial effects on body weight are largely mediated through profound reductions in appetite and energy intake, which have important implications for nutritional adequacy [13].

3.2. Appetite suppression and reduced energy intake

The most consistently observed mechanism underlying weight loss with incretin-based therapies is a sustained reduction in total energy intake [26]. Short-term controlled feeding studies and randomized crossover trials have shown that GLP-1 receptor agonists significantly reduce ad libitum energy consumption, often across multiple eating occasions throughout the day [[55], [56], [57]]. In parallel, clinical trial evidence from liraglutide, oral semaglutide, once-weekly semaglutide, and tirzepatide indicates reductions in spontaneous energy intake ranging from approximately 16% to nearly 40% compared with placebo or baseline intake [58]. These findings should be interpreted as evidence of reduced nutritional exposure rather than direct evidence of micronutrient deficiency.

These effects are mediated through coordinated central and peripheral signaling pathways regulating appetite [59]. At the central nervous system level, GLP-1 receptor signaling modulates key hypothalamic and brainstem nuclei involved in energy homeostasis [60]. Experimental neurophysiological studies have demonstrated that GLP-1 signaling stimulates anorexigenic pro-opiomelanocortin (POMC) neurons while inhibiting orexigenic neuropeptide Y and agouti-related peptide (NPY/AgRP) pathways within the arcuate nucleus of the hypothalamus [[61], [62], [63]]. Additional integration of satiety signals occurs within the paraventricular nucleus and the nucleus tractus solitarius of the brainstem, where vagal afferent inputs from the gastrointestinal tract contribute to earlier meal termination [64,65]. These physiological effects are reflected in clinical measurements of appetite. Several randomized studies using validated visual analog scales have reported lower hunger ratings, reduced prospective food consumption, and increased perceptions of satiety and fullness in individuals treated with GLP-1 receptor agonists [26,57]. These appetite changes occur rapidly after treatment initiation and are maintained during long-term therapy [66].

Beyond homeostatic appetite regulation, incretin therapies also influence reward-related eating behaviors [12]. Functional neuroimaging studies and behavioral assessments suggest that GLP-1 receptor agonists modulate activity in mesolimbic brain regions, including the ventral tegmental area and nucleus accumbens, which are involved in food reward and hedonic eating [[67], [68], [69]]. Clinical studies have demonstrated reductions in food cravings, binge-eating episodes, and cognitive preoccupation with food, often described by patients as a reduction in “food noise” [70]. For example, a clinical study evaluating semaglutide in individuals with binge eating disorder demonstrated reductions in binge-eating severity scores and improvements in eating behavior regulation [71]. Observational surveys of patients receiving semaglutide or tirzepatide similarly report improvements in appetite control and a reduced drive to eat in response to environmental food cues rather than metabolic hunger [72].

While these effects represent a key therapeutic benefit, they also result in substantial decreases in total food volume and eating frequency [25,73]. Because micronutrient intake depends strongly on dietary variety and overall food consumption, sustained reductions in caloric intake may proportionally reduce intake of essential vitamins and minerals when dietary patterns are not deliberately optimized [74,75].

3.3. Changes in dietary patterns and food preferences

Incretin-based therapies may influence not only how much individuals eat but also what types of foods are consumed [55,76]. Evidence from short-term mechanistic feeding studies and secondary analyses of randomized trials have consistently demonstrated shifts away from highly palatable, energy-dense foods, particularly those rich in fat and simple carbohydrates [55,76]. For example, Kennedy et al., in a secondary analysis of a randomized clinical trial reported that tirzepatide significantly reduced preferences for foods high in fat and simple sugars and lowered craving scores for sweets and fast foods [77]. Similar findings have been observed in studies evaluating oral semaglutide, where reductions in total caloric intake were accompanied by decreased consumption of refined carbohydrates and sweets [76].

Behavioral surveys among patients receiving GLP-1 receptor agonists also describe broader changes in eating habits [78]. Many individuals report eating fewer meals, experiencing earlier satiation, and feeling less compelled to snack between meals [79]. Observational dietary evidence also supports this pattern. In a cross-sectional dietary assessment of individuals receiving GLP-1 receptor agonists, participants showed reduced consumption of energy-dense foods and added sugars, alongside overall shifts in dietary intake patterns [80]. Because these data are cross-sectional, they describe dietary patterns during therapy but cannot establish whether changes were caused by treatment initiation. While these dietary shifts may improve metabolic health, they may also reduce dietary diversity, particularly when smaller meal sizes or fewer eating occasions limit the inclusion of micronutrient-dense food groups such as lean meats, dairy products, legumes, and vegetables, which are key contributors to overall micronutrient adequacy [75,81,82].

Reduced dietary diversity is a well-established predictor of inadequate micronutrient intake across populations [75]. When daily caloric intake falls below approximately 1200 kcal in women or 1800 kcal in men, meeting recommended dietary allowances for multiple micronutrients becomes increasingly difficult without deliberate selection of nutrient-dense foods, as micronutrient inadequacies have been documented even at higher energy intakes [83,84]. Therefore, the reductions in food intake commonly observed during incretin therapy may create conditions in which micronutrient intake declines even when overall dietary patterns appear metabolically favorable [12,58].

3.4. Gastrointestinal effects and food tolerance

Gastrointestinal symptoms represent another important pathway through which incretin-based therapies may influence dietary intake [85,86]. Nausea, vomiting, diarrhea, constipation, and abdominal discomfort are among the most frequently reported adverse events in clinical trials of GLP-1 receptor agonists and dual incretin agonists [40,87]. Evidence from systematic reviews and pooled analyses of randomized trials indicate that approximately 15%–60% of participants experience gastrointestinal adverse events, particularly during the dose-escalation phase of therapy when symptoms such as nausea, vomiting, and diarrhea are most prominent [88,89]. These trial-level data provide relatively robust evidence for gastrointestinal intolerance as a common treatment-related exposure, although they do not directly quantify downstream micronutrient depletion.

These symptoms are believed to arise largely from centrally mediated mechanisms involving brainstem pathways that regulate nausea and visceral sensation, although they manifest peripherally through gastrointestinal discomfort [90,91]. While symptoms are typically transient and mild to moderate in severity, they can temporarily disrupt habitual eating patterns and reduce tolerance for certain foods [50,92]. Patients experiencing persistent nausea often report a preference for bland, carbohydrate-rich foods while avoiding protein-dense or high-fiber foods that may exacerbate gastrointestinal discomfort [6,87]. Such dietary adaptations may inadvertently reduce the intake of micronutrient-rich food groups [93].

A core pharmacologic action of GLP-1 receptor agonists is delayed gastric emptying, which contributes to improved glycemic control and prolonged satiety [15]. Experimental studies using gastric scintigraphy and related techniques have demonstrated increased gastric retention and prolonged half-emptying time of solid meals following administration of GLP-1 receptor agonists, with measurable delays in gastric emptying kinetics [15,94,95]. While this effect is beneficial for metabolic control, it may contribute to early satiety, abdominal fullness, and, in some individuals, symptoms of gastroesophageal reflux [15]. Slower gastric emptying may also alter the timing of nutrient delivery to the small intestine, with emerging data suggesting potential effects on the absorption of certain nutrients [96]. For example, limited short-term mechanistic data from Melis et al., a pilot study in patients with T2DM, reported reduced intestinal iron absorption after 10 weeks of semaglutide treatment, highlighting a possible interaction between gastrointestinal transit and micronutrient bioavailability [97]. In contrast, concerns regarding pancreatic exocrine insufficiency as a contributor to nutrient malabsorption during incretin therapy have not been supported by available human evidence [98]. A randomized study comparing short-acting and long-acting GLP-1 receptor agonists found no deterioration in fecal pancreatic elastase concentrations or other markers of pancreatic exocrine function, and no evidence of clinically significant fat malabsorption was observed [98].

Collectively, the appetite suppression, behavioral changes in eating patterns, and gastrointestinal effects associated with incretin-based pharmacotherapy create a physiological environment characterized by reduced food intake, smaller meal sizes, and potentially decreased dietary variety. As illustrated in Fig. 1, these pharmacological and behavioral pathways converge to reduce overall food volume and dietary diversity, factors that may influence micronutrient intake during sustained therapy. These changes are central to the therapeutic success of these medications but may simultaneously reduce exposure to micronutrients obtained from food [25]. Importantly, the magnitude of these effects appears to scale with the degree of weight loss achieved [99]. Dual incretin agonists such as tirzepatide generally produce greater weight reduction than single-receptor GLP-1 agonists, which may theoretically amplify reductions in food intake and dietary diversity [50].

Fig. 1.

Physiological and behavioral pathways through which incretin-based pharmacotherapy influences dietary intake and nutrient exposure. Glucagon-like peptide-1 receptor agonists (GLP-1RAs) and dual GIP/GLP-1 receptor agonists reduce body weight through coordinated central and gastrointestinal mechanisms. Incretin signaling activates neurons within key brainstem centers involved in appetite regulation, including the area postrema and the nucleus of the solitary tract, which integrate visceral and vagal afferent signals from the gastrointestinal tract. These brainstem nuclei transmit satiety signals to hypothalamic regions such as the arcuate nucleus, where GLP-1 signaling suppresses orexigenic agouti-related peptide (AgRP) neurons and enhances anorexigenic pathways, contributing to reduced hunger and earlier meal termination. Together with delayed gastric emptying and enhanced gut–brain signaling, these mechanisms promote earlier satiation and reduced food intake. These physiological effects translate into behavioral changes, including reduced energy intake, smaller meal sizes, fewer eating occasions, and decreased food reward or “food noise.” Sustained reductions in food volume and dietary variety may decrease overall exposure to micronutrients obtained from food (Fe, B₁₂, Vitamin D, Zn, Ca), providing a physiological context for the potential micronutrient vulnerabilities explored in subsequent sections [14,25,57,61,62,64,68,69,76,82]. Abbreviations: GLP-1, glucagon-like peptide-1; ↑, increase; ↓, decrease.

However, direct comparative evidence evaluating differences in micronutrient outcomes between mono-GLP-1 receptor agonists and dual GLP-1/GIP receptor agonists is currently lacking [12,100]. Existing clinical trials have largely focused on weight, glycemic outcomes, and cardiometabolic endpoints rather than systematic evaluation of micronutrient biomarkers [100]. Consequently, whether the degree of appetite suppression or weight reduction achieved with different incretin therapies translates into differential micronutrient risk remains uncertain and represents an important area for future investigation. Understanding how incretin-based therapies influence appetite regulation, dietary intake, and gastrointestinal physiology provides essential context for interpreting the potential nutritional consequences of pharmacologically induced weight loss. These mechanisms form the foundation for the mechanistic pathways through which micronutrient disturbances may arise, which are explored in the following section.

4. Mechanistic pathways to deficiency: physiological alterations and nutrient dynamics

Weight reduction induced by incretin-based pharmacotherapy is accompanied by a series of physiological adaptations that may influence micronutrient homeostasis [101]. Although reduced food intake represents the most immediate mechanism through which nutritional exposure may decline, emerging evidence suggests that alterations in gastrointestinal physiology, systemic inflammation, adipose tissue metabolism, and skeletal remodeling also contribute to changes in nutrient handling during pharmacologically induced weight loss. These processes highlight that micronutrient disturbances observed during incretin therapy cannot be explained solely by reduced caloric intake but may reflect complex interactions between metabolic regulation, nutrient absorption, and tissue remodeling [[102], [103], [104]].

4.1. Reduced intake and nutrient exposure

The most direct pathway linking incretin therapy to micronutrient risk is the sustained reduction in energy intake described in the previous section. When caloric intake decreases substantially, total micronutrient exposure may decline proportionally unless dietary patterns are deliberately optimized for nutrient density [28].

Nutritional epidemiology studies have long shown that diets providing fewer than approximately 1200 kcal per day in women or 1800 kcal per day in men may struggle to meet recommended micronutrient requirements without targeted dietary planning [28,105]. Earlier satiation, smaller meal sizes, and reduced eating frequency may further limit the consumption of micronutrient-dense foods such as animal-source proteins, dairy products, legumes, and vegetables [106,107]. Because micronutrient adequacy depends not only on total caloric intake but also on dietary diversity and food volume, sustained reductions in food intake may gradually deplete nutrient stores even when macronutrient requirements appear to be met [75].

Reductions in energy intake during incretin therapy may also alter macronutrient distribution. Observational analyses have reported decreases in absolute protein intake during pharmacologically induced weight loss, particularly when appetite suppression is substantial [108]. Dietary evidence from Johnson et al., a cross-sectional study of 69 adults using GLP-1 receptor agonist–based therapy, showed that protein intake was frequently below recommended levels for lean mass preservation, with only a minority of participants achieving ≥1.6 g/kg/day [109]. Because this study lacked baseline dietary data and serial biomarkers, it should be interpreted as evidence of dietary inadequacy during treatment rather than proof of treatment-induced deficiency. Inadequate protein intake during weight reduction may contribute to the loss of lean body mass, which has increasingly been recognized as an important determinant of metabolic resilience [110]. Lean tissues participate in numerous micronutrient-dependent metabolic processes, and lower lean mass has been associated with reduced circulating levels of nutrients such as selenium, zinc, iron, vitamin B12, and vitamin D [111,112]. Consequently, the interaction between reduced intake, body composition changes, and nutrient metabolism may influence micronutrient status during sustained therapy [2,113].

4.2. Altered gastric emptying and gastrointestinal transit

Incretin-based therapies exert direct effects on gastrointestinal motility, particularly through delayed gastric emptying, a pharmacological mechanism that contributes to improved glycemic control and early satiation. Slower gastric emptying alters the timing and kinetics of nutrient delivery from the stomach to the small intestine, which may influence the efficiency of nutrient digestion and absorption [15,57]. Certain micronutrients are particularly sensitive to changes in gastric physiology. Iron absorption, for example, requires an acidic gastric environment to facilitate the solubilization of non-heme iron and its subsequent uptake in the proximal duodenum [114]. Prolonged gastric retention or reduced gastric acidity may impair this process. In clinical practice, proton pump inhibitors are frequently prescribed to manage reflux symptoms associated with delayed gastric emptying, and acid suppression can further impair iron solubilization and the release of vitamin B12 from dietary proteins [115,116]. Evidence supports the possibility that incretin therapies may directly influence micronutrient absorption. In a pilot clinical study assessing intestinal iron absorption before and after initiation of semaglutide, investigators observed a median reduction of approximately 13% in iron absorption after 10 weeks of treatment, with 17.6% of participants experiencing reductions exceeding 30% relative to baseline, suggesting a direct effect on nutrient handling beyond reduced intake [97]. Although long-term iron status was not evaluated in that study, the findings suggest that alterations in gastrointestinal motility and transit time may influence micronutrient handling beyond the effects of reduced dietary intake alone [97]. Conversely, some individuals receiving incretin therapy experience episodes of diarrhea, which may accelerate intestinal transit and reduce the contact time required for the absorption of certain minerals and fat-soluble vitamins [[117], [118], [119]]. While these symptoms are usually transient, prolonged gastrointestinal intolerance may contribute to decreased nutrient absorption and increased risk of micronutrient depletion.

4.3. Weight-loss physiology and iron regulation

Iron metabolism during weight loss is influenced not only by dietary intake but also by systemic inflammatory pathways. Obesity is characterized by chronic low-grade inflammation and elevated circulating levels of hepcidin, a key regulator of iron homeostasis [37,120,121]. Increased hepcidin activity reduces intestinal iron absorption and promotes sequestration of iron within macrophages, contributing to a state of functional iron deficiency despite adequate total body iron stores [37].

Weight reduction and improved metabolic control during incretin therapy may modify these inflammatory pathways [122,123]. Clinical studies have shown that GLP-1 receptor agonists can reduce markers of systemic inflammation, including C-reactive protein [123,124]. Experimental models further suggest that incretin signaling may influence hepatic and systemic iron regulation [125,126]. In preclinical studies of diet-induced obesity and hereditary iron overload, treatment with liraglutide altered the expression of iron-regulatory proteins, including reductions in transferrin receptor expression and increased ferroportin activity [127].

While these changes may improve iron distribution in conditions characterized by iron overload, they may also shift iron balance in individuals with marginal baseline stores. Combined with reduced consumption of iron-rich foods such as red meat during weight loss, these physiological changes may contribute to the development of iron deficiency in susceptible individuals [128,129].

4.4. Adipose tissue dynamics and fat-soluble vitamins

Adipose tissue serves as an important storage site for lipophilic vitamins, including vitamins A, D, E, and K [[130], [131], [132], [133]]. In individuals with obesity, expanded adipose mass may sequester these nutrients, reducing their circulating concentrations despite adequate total body stores. This phenomenon has been proposed as one explanation for the high prevalence of vitamin D deficiency observed in populations with obesity [134,135].

During rapid weight loss, mobilization of adipose tissue theoretically releases stored fat-soluble vitamins into the circulation, a process sometimes described as “auto-supplementation” [136,137]. However, clinical observations suggest that this mobilization may not fully compensate for reduced dietary intake or increased metabolic demands during active weight loss [138]. Vitamin D illustrates this complexity: although adipose mobilization may transiently increase circulating levels, long-term deficiency often persists or even worsens during weight loss when dietary intake and intestinal absorption remain insufficient [138,139]. Furthermore, reductions in dietary fat intake, commonly observed during weight loss, may impair the intestinal absorption of fat-soluble vitamins, since their uptake depends on micelle formation in the presence of dietary lipids [[140], [141], [142], [143]]. As a result, the net balance between adipose release, dietary intake, and intestinal absorption may determine whether circulating levels of fat-soluble vitamins improve or decline during pharmacologically induced weight reduction [133,138].

4.5. Bone remodeling and the gut-bone axis

Weight loss is frequently accompanied by alterations in bone metabolism [38,144]. Although individuals with obesity often exhibit higher bone mineral density due to greater mechanical loading and hormonal influences, adiposity is also associated with chronic inflammation, altered adipokine signaling, and increased marrow adipogenesis, all of which may negatively affect bone quality [[145], [146], [147]].

When body weight decreases, the skeleton experiences reduced mechanical loading, which can stimulate bone resorption [148]. Diet-induced weight loss has been associated with increases in bone resorption markers such as C-terminal telopeptide of type I collagen (CTX) and reductions in bone formation markers including procollagen type I N-terminal propeptide (P1NP) [149,150]. These changes may be particularly pronounced during rapid weight loss [151].

Incretin hormones themselves may also influence bone metabolism. Native GIP has been shown in experimental models to inhibit osteoclast activity and promote osteoblastic bone formation, raising the possibility that dual incretin agonists such as tirzepatide could exert partially protective skeletal effects [152,153]. GLP-1 receptors are also expressed in bone cells, although the net effect of pharmacologic GLP-1 receptor activation during weight loss remains uncertain [103,154].

Additional mechanisms linking weight loss to skeletal health include changes in adipokines such as leptin and adiponectin, reductions in insulin levels, and shifts in gut-derived hormones that influence bone turnover [155,156]. Emerging research also suggests that incretin therapies may alter the gut microbiome, potentially influencing bone metabolism through microbial metabolites that regulate osteoclast activity, although direct clinical evidence remains limited [[157], [158], [159]].

From a nutritional perspective, these skeletal adaptations are clinically relevant because bone remodeling increases the physiological demand for nutrients involved in bone metabolism, particularly calcium, vitamin D, magnesium, and phosphorus [160]. When dietary intake of these nutrients declines during weight loss, the imbalance between skeletal turnover and nutrient availability may contribute to long-term reductions in bone mineral density [150,161]. In a low-calorie diet study, individuals receiving calcium supplementation experienced significantly less bone mineral content loss compared with controls [162]. Another study showed that bone loss persisted during caloric restriction even with calcium intake, but higher calcium doses mitigated BMD decline [163].

Understanding these pathways provides a mechanistic framework for interpreting the emerging clinical signals of micronutrient insufficiency observed in patients undergoing pharmacologic weight reduction (Fig. 2). These mechanisms also inform the micronutrient patterns discussed in the following section, which maps the clinical signals reported across key nutrient groups.

Fig. 2.

Mechanistic pathways linking incretin-based pharmacotherapy to micronutrient disturbances. Incretin-based therapies influence micronutrient status through interacting mechanisms across multiple physiological levels. At the pharmacologic level, GLP-1 receptor agonists and dual incretin agonists reduce appetite and delay gastric emptying. These effects translate into distinct physiological pathways, including reduced dietary intake and diversity, altered gastrointestinal transit and absorption, changes in systemic inflammation and iron regulation, and shifts in body composition with loss of lean mass. These processes converge to affect specific micronutrient groups through nutrient-specific mechanisms, including reduced intake, impaired absorption, altered distribution, and increased metabolic demand. Thiamine (vitamin B1) is displayed separately to clarify that Wernicke encephalopathy is linked primarily to thiamine depletion in the setting of persistent vomiting or markedly reduced intake, rather than to fat-soluble vitamin deficiency. Vitamin B12 is linked to hematologic and neurological manifestations, whereas fat-soluble vitamins are shown as a distinct nutrient group affected mainly through intake, absorption, and weight-loss-related distribution pathways. The resulting disturbances may manifest clinically across hematologic, neurological, musculoskeletal, and integumentary systems. The figure illustrates conceptual pathways based on current evidence and does not imply direct causality for all nutrient–outcome relationships [12,38,56,88,97,100,102,107,111,114,117,120,123,127,135,138,141,151,160,161,164]. Abbreviations: GLP-1, glucagon-like peptide-1; ↑, increase; ↓, decrease.

5. Micronutrient signal map

The preceding sections described the pharmacologic, dietary, gastrointestinal, and weight-loss–related mechanisms through which incretin-based therapies may influence micronutrient status. This section does not restate those pathways in detail; instead, it maps the nutrient-specific clinical signals that have emerged across dietary studies, mechanistic investigations, observational cohorts, administrative datasets, and case-based reports. Taken together, these data suggest that micronutrient vulnerability during GLP-1 receptor agonist and dual incretin agonist therapy is not random but tends to cluster into a small number of biologically plausible domains: hematologic nutrients, fat-soluble vitamins, bone-related minerals, and selected trace elements or electrolytes [2,100,165]. The nutrients highlighted in this review were prioritized because they met at least one of the following criteria: plausible relevance to reduced intake, gastrointestinal intolerance, altered absorption, weight-loss physiology, or obesity-related baseline vulnerability; emerging dietary, biomarker, administrative, pharmacovigilance, or case-based signals; or potential for clinically important outcomes even when incidence data remain limited [17,109,166]. This approach includes nutrients with more converging incretin-specific evidence, such as iron, vitamin D, vitamin B12, calcium, magnesium, and zinc, as well as nutrients that are clinically relevant but less systematically characterized in this setting, such as thiamine (vitamin B1), folate (vitamin B9), vitamin A, vitamins E and K, selenium, iodine, phosphate, and potassium [164,166,167]. These patterns are summarized in Table 1. Because the strength of evidence varies across nutrients, the signal map should be interpreted as a framework for organizing current evidence rather than as a definitive incidence profile.

Table 1.

Micronutrient signal map during incretin-based therapy: biologic rationale, observed signals, and strength of evidence.

Micronutrient	Baseline Vulnerability	Mechanistic Drivers	Evidence Type/Signal	Clinical Relevance
Iron	Functional deficiency (↑ hepcidin, inflammation) [[1], [2], [3], [4], [5]]	↓ intake (meat), ↓ absorption (gastric changes), ↓ iron mobilization [[6], [7], [8]]	Mechanistic + observational signal: ↓ ferritin in registry/observational data; ↓ iron absorption (∼13% median reduction after 10 weeks of semaglutide) [9,10]	Iron deficiency anemia, fatigue [3,10]
Vitamin B12	Variable; metformin-related malabsorption [[11], [12], [13], [14]]	↓ gastric acid, ↓ intake (animal protein), metformin co-use [[15], [16], [17]]	Biochemical signal in selected high-risk cohorts: Declining levels over time; ↓ B12 in semaglutide cohorts [[17], [18], [19]]	Neuropathy, anemia [13,14]
Thiamine (B1)	Low reserves during prolonged poor intake or vomiting	Persistent nausea/vomiting, markedly reduced intake, rapid weight loss	Pharmacovigilance signal and case reports of Wernicke encephalopathy during GLP-1RA therapy [20,21]	Wernicke encephalopathy, neurological dysfunction [[20], [21], [22], [23], [24]]
Folate	Diet-quality dependent [[25], [26], [27]]	↓ vegetables, ↓ intake with caloric restriction [25,28,29]	Low intake and suboptimal in dietary studies [25]	Macrocytosis, hyperhomocysteinemia [25,30,31]
Vitamin D	↓ 25(OH)D (adipose sequestration) [[32], [33], [34]]	↓ intake, ↓ fat absorption, limited adipose release [[35], [36], [37]]	Administrative/observational signal: Deficiency: 7.5% → 13.6% (6–12 months) [10]	Bone loss, immune effects [32]
Vitamin A	↓ carotenoids (inflammation) [[38], [39], [40]]	↓ intake (animal/plant sources) [39,41]	Low intake signals [38,40]	Vision, immune function [41]
Vitamin E/K	Variable; there is no consistent deficiency pattern	↓ fats, ↓ oils, ↓ leafy greens [[42], [43], [44]]	Dietary inadequacy [44,45]	Coagulation (K), oxidative stress (E) [44,46]
Calcium	Often low intake, ↓ vitamin D [[47], [48], [49]]	↓ dairy intake, ↓ absorption, ↑ bone turnover [2,19,48,50]	Dietary signal: Intake < DRI common [51]	Bone loss, secondary hyperparathyroidism [[48], [49], [50],52]
Magnesium	Low intake common [[53], [54], [55]]	↓ intake, ↓ diet quality [53,56,57]	Intake below DRI; associated with metabolic dysregulation [58,59]	Neuromuscular, metabolic effects [56]
Phosphate	Usually normal [60]	Weight loss + bone remodeling [61,62]	Limited data	Bone metabolism [63]
Zinc	↓ levels in obesity [[64], [65], [66]]	↓ protein intake, ↓ intake (animal foods) [67,68]	↓ serum zinc (semaglutide cohorts) [17,69]	Hair loss, immunity [67,70]
Selenium	Diet-dependent [71,72]	↓ protein intake [73]	Theoretical or indirect dietary risk; limited data	Thyroid, antioxidant function [71,73,74]
Iodine	Variable [75]	↓ dairy, ↓ iodized salt [76,77]	Theoretical risk	Thyroid function [78,79]
Potassium	Low intake common [80,81]	↓ fruits/vegetables [82]	Intake ∼2100 mg vs 4700 mg target [19,81]	BP, muscle function [83]

Abbreviations: ↑, increased; ↓, decreased; DRI, Dietary Reference Intake; 25(OH)D, 25-hydroxyvitamin D; BP, blood pressure. Mechanistic drivers are summarized in the table to avoid repetition of pathways described in Sections 3, 4. The text below focuses primarily on the evidence signal, its strength, and its clinical interpretation.

5.1. Hematologic micronutrients

Among hematologic nutrients, iron currently has the strongest and most coherent signal. Building on the mechanisms outlined in Section 4, the iron signal is supported by three complementary evidence layers: short-term mechanistic absorption data, real-world administrative diagnoses, and dietary intake studies [37,114]. Limited mechanistic evidence from Melis et al., a short-term pilot study in patients with T2DM, showed that semaglutide initiation attenuated intestinal iron absorption after 10 weeks, with a median relative reduction of 13% and a substantial subset of participants showing reductions of 30% or more. Although this study did not assess long-term anemia outcomes, it provides direct evidence that incretin therapy may alter iron handling beyond simple caloric restriction [97]. Because this study did not assess long-term ferritin trajectories or anemia outcomes, it supports biological plausibility rather than clinical incidence. Observational signals from administrative data reinforce the clinical relevance of this pathway. Scott Butsch et al., in a large retrospective observational cohort of 461,382 adults with T2DM prescribed GLP-1 receptor agonists, reported increasing ICD-coded nutritional deficiencies and related complications over 6 and 12 months; iron deficiency anemia codes were documented in 3.2% of patients by 12 months [166]. Because these outcomes were based on diagnosis codes rather than protocolized laboratory testing, they likely reflect clinically recognized deficiency and may underestimate subclinical abnormalities. Dietary evidence points in the same direction. Johnson et al., in a cross-sectional study of 69 adults using incretin-based therapy, reported iron intake below dietary reference levels in a substantial proportion of participants, alongside low intake of vegetables, grains, dairy, and other nutrient-dense foods [109]. These findings are important because they suggest that iron risk during therapy may arise from the convergence of reduced intake, lower absorption efficiency, and pre-existing obesity-related iron dysregulation [109,168].

Vitamin B12 is another hematologic and neurological nutrient of concern, but the evidence base is smaller and more concentrated in high-risk populations [17,169]. Rather than a consistent class-wide signal, current data suggest vulnerability in patients with additional risk factors such as prior bariatric surgery, reduced animal-protein intake, metformin use, or acid-suppressive therapy [116,170,171]. In addition, many patients with obesity and T2DM receiving GLP-1-based therapy are also treated with metformin, which independently impairs vitamin B12 absorption and may amplify risk [172]. Biochemical evidence comes mainly from selected high-risk cohorts. Kanai et al., in a retrospective cohort of 29 Japanese patients with obesity and T2DM treated with once-weekly semaglutide after sleeve gastrectomy, reported declines in serum vitamin B12 concentrations over 12 months, alongside deterioration in zinc status and a dietary shift away from protein-rich foods [169]. Because this was a small post-bariatric cohort, the findings should be interpreted as evidence of vulnerability in high-risk patients rather than as a generalizable class-wide incidence estimate.

Evidence for folate is more limited and largely indirect [173,174] Current support comes from dietary inference rather than serial biomarker studies: reduced intake of folate-rich food groups may occur during sustained caloric restriction, but incretin-specific studies have not systematically reported longitudinal folate biomarkers [174]. Because Johnson et al. reported adequate intake of most B vitamins in their cross-sectional GLP-1RA dietary study, folate (vitamin B9) should not be presented as an established or common treatment-associated deficiency based on current incretin-specific intake data [109]. Nevertheless, folate remains clinically relevant because broader obesity literature recognizes folate inadequacy among nutritional vulnerabilities in individuals with overweight or obesity, and because folate contributes to erythropoiesis and one-carbon metabolism [167]. Therefore, folate may be considered alongside iron and vitamin B12 when evaluating macrocytosis, anemia, or hyperhomocysteinemia in patients with prolonged dietary restriction, poor diet quality, or additional risk factors during therapy [167]. [109]At present, folate should be regarded as a biologically credible but under-studied contributor to macrocytosis, hyperhomocysteinemia, and nutritional anemia during prolonged therapy or poor-quality weight loss [173,[175], [176], [177]].

5.2. Fat-soluble vitamins

Among fat-soluble vitamins, vitamin D has the strongest signal and appears to be the most frequently documented vitamin abnormality during incretin-based therapy [100,166]. Because the mechanistic basis for altered fat-soluble vitamin handling during weight loss was described in Section 4.4, this section focuses on the observed evidence. Observational evidence from Scott Butsch et al.’s retrospective administrative cohort of 461,382 adults with T2DM prescribed GLP-1 receptor agonists showed that ICD-coded vitamin D deficiency increased from 7.5% at 6 months to 13.6% at 12 months [166]. These figures likely underestimate biochemical insufficiency, since diagnosis codes generally capture recognized clinical abnormalities rather than all low 25-hydroxyvitamin D concentrations [166,178]. Reviews of obesity-related micronutrient physiology consistently identify vitamin D as one of the most prevalent baseline abnormalities in obesity, which makes worsening or persistent deficiency during pharmacologically induced weight loss clinically credible [138]. Dietary studies support this concern. In the cross-sectional nutrient-intake study of incretin users, vitamin D intake was markedly inadequate relative to dietary recommendations, along with low intakes of vitamins A, E, and K [109]. Consistent with this, a secondary analysis of a randomized trial including GLP-1 receptor agonist therapy showed that weight loss was associated with modest increases in circulating 25-hydroxyvitamin D, indicating that adipose mobilization contributes to circulating levels but does not necessarily normalize vitamin D status [139]. Since these nutrients depend on both food selection and, to varying degrees, adequate lipid intake for absorption, they may be especially vulnerable when patients reduce total intake and concurrently restrict high-fat foods [179].

For vitamin A, vitamin E, and vitamin K, the current evidence is mainly indirect and dietary rather than based on serial biomarkers. Available studies suggest reduced intake of vitamin-rich food groups during treatment, but direct longitudinal evidence linking incretin therapy to biochemical deficiency of these vitamins remains limited [180,181]. Vitamin A should nevertheless remain visible in the signal map because cross-sectional dietary data in GLP-1RA users show intake below DRI, and broader obesity literature recognizes vitamin A inadequacy as part of baseline nutritional vulnerability in individuals with overweight or obesity [109,167]. Lower intake of vitamin A-rich foods may occur when overall intake declines and when patients eat fewer animal-source foods, dairy products, and carotenoid-rich vegetables [181,182]. Obesity itself has also been associated with lower circulating carotenoids and altered vitamin A distribution, likely reflecting inflammation, oxidative stress, and altered tissue partitioning [183,184]. Although randomized clinical data are limited, interventional studies in individuals with obesity have demonstrated that serum retinol concentrations are responsive to metabolic and nutritional changes, supporting the concept that vitamin A status is dynamically regulated in the context of adiposity and dietary intake [185]. During incretin therapy, these baseline vulnerabilities may be compounded by reduced food variety, but direct longitudinal vitamin A biomarker data remain scarce.

A similar pattern applies to vitamin E and vitamin K. Intake may decline when consumption of nuts, seeds, oils, and leafy vegetables decreases, particularly in patients who simplify their diets because of nausea, fullness, or reduced motivation to prepare meals [133,186,187]. In GLP-1RA users, Johnson et al. reported inadequate dietary intake of vitamins E and K relative to DRI, supporting their classification as dietary signals rather than established biochemical deficiencies [109]. However, direct biochemical evidence linking incretin therapy to vitamin E or vitamin K deficiency is still limited. At present, these vitamins are best interpreted as nutrients with a plausible intake-mediated risk signal but insufficient direct longitudinal evidence [12,100].

5.3. Bone-related minerals

Bone-related nutrients deserve particular attention because incretin-based therapy occurs in the broader physiologic context of active weight loss, altered mechanical loading, and changes in bone turnover [148,188]. Clinical evidence from a secondary analysis of a randomized clinical trial showed that liraglutide-based weight-loss treatment without exercise was associated with reductions in hip and spine bone mineral density compared with placebo or exercise-based strategies. This trial evidence supports skeletal vulnerability during pharmacologic weight loss but does not directly establish calcium or vitamin D deficiency [151]. [151] Within this context, calcium intake is a recurring concern. Dietary evidence from Johnson et al.’s cross-sectional study of 69 incretin users showed average calcium intake below recommended levels, together with low dairy intake [109]. This matters because reduced calcium intake during active weight loss may compound the skeletal consequences of lower mechanical loading and changing endocrine signals [189,190]. Since calcium intake often tracks with overall dietary volume and dairy consumption, it may fall substantially when patients reduce meal size or eliminate entire food groups perceived as difficult to tolerate [189,191].

Magnesium showed a similar dietary signal in the same study, with intake below recommended levels. These findings support inadequate nutrient exposure but should not be interpreted as biochemical depletion in the absence of serial calcium, magnesium, vitamin D, or bone-turnover biomarker data [109]. Magnesium participates in vitamin D metabolism, neuromuscular function, glucose homeostasis, and bone health. In obesity, magnesium status is often already suboptimal because of poor diet quality, and weight-loss-related reductions in food volume may worsen this baseline tendency [160,192]. Thus, magnesium inadequacy may act less as an isolated deficiency than as an amplifier of metabolic and skeletal vulnerability [193,194].

Evidence for phosphate is comparatively sparse. Given tight physiological regulation of serum phosphate, clinically meaningful depletion is unlikely to be detected without severe dietary restriction, broader malnutrition, renal disease, vitamin D deficiency, or prolonged gastrointestinal intolerance [195,196]. This interpretation is consistent with GLP-1RA dietary data showing adequate phosphorus intake in the available cross-sectional study, although dietary adequacy does not exclude abnormalities in selected patients with renal disease, severe malnutrition, or complex metabolic disturbances [109]. For that reason, phosphate is mechanistically relevant to bone remodeling during weight loss, but the current incretin literature provides little direct evidence of consistent phosphate depletion. It may be more appropriate to discuss phosphate as a monitored mineral in selected clinical contexts rather than as a proven class-wide signal.

5.4. Trace elements and electrolytes

Among trace elements, zinc has a stronger signal than selenium or iodine because both dietary and biochemical evidence are available [197,198]. Kanai et al., in a small retrospective cohort of 29 Japanese post-sleeve patients with obesity and T2DM treated with semaglutide, reported significant declines in serum zinc over 12 months [169]. This provides biochemical evidence of zinc depletion in a selected high-risk population, although it should not be generalized to all incretin users. Clinically, zinc is relevant not only for immune function and epithelial integrity, but also because symptoms such as diffuse hair shedding, poor wound healing, dysgeusia, or reduced appetite may overlap with the clinical picture of poorly tolerated rapid weight loss [[199], [200], [201]]. In contrast, Johnson et al. reported adequate average zinc intake in their cross-sectional GLP-1RA dietary study, reinforcing that zinc should be interpreted as an emerging and context-dependent signal rather than a uniformly documented intake deficiency [109].

Selenium and iodine remain largely theoretical or indirect concerns. Their relevance derives mainly from dependence on diet quality and specific food sources, but direct incretin-specific biomarker evidence is lacking [202,203]. Since reduced protein intake is common during incretin therapy, selenium inadequacy is plausible, particularly in individuals with already restrictive dietary patterns [113]. However, available cross-sectional GLP-1RA dietary data reported adequate average selenium intake, supporting a cautious interpretation of selenium as a theoretical or selected-risk nutrient rather than a consistent class-wide signal [109]. At present, however, literature provides more biologic rationale than direct outcome data. Selenium is therefore best characterized as a nutrient of theoretical and nutritional interest rather than one with a robust clinical signal specific to GLP-1-based therapy.

Iodine is similarly under-studied. Reduced dairy intake, lower iodized salt use, and reduced grain consumption could plausibly decrease iodine exposure, but this remains a theoretical dietary risk rather than an established biochemical or clinical outcome during incretin therapy [204]. This possibility is relevant because thyroid function can be sensitive to both iodine status and rapid weight change [[204], [205], [206]]. Nonetheless, direct evidence linking incretin therapy to iodine deficiency is currently lacking, so this remains a theoretical concern rather than an established outcome.

Among electrolytes, potassium is best interpreted as a dietary adequacy signal rather than a documented biochemical deficiency signal. Johnson et al.’s cross-sectional study of 69 incretin users reported potassium intake below recommended levels, reflecting low intake of fruits, vegetables, legumes, and dairy products. The co-occurrence of low potassium intake with low magnesium and low fiber suggests that potassium may serve as a marker of global diet quality deterioration during therapy [109]. Potassium inadequacy may not present as a classical deficiency syndrome in most ambulatory patients, but it is clinically relevant because it may intersect with blood pressure regulation, muscle symptoms, constipation, and poor overall diet quality [[207], [208], [209]]. However, potassium risk during incretin-based therapy should not be framed only as low intake. Hyperkalemia may also occur when gastrointestinal adverse effects contribute to dehydration, renal insufficiency, or acute kidney injury, particularly in patients with chronic kidney disease, diabetes, older age, or concomitant use of medications that impair renal potassium excretion [[210], [211], [212]]. Accordingly, serum potassium should be interpreted together with hydration status, kidney function, medication profile, and the direction of dietary change rather than as a unidirectional marker of dietary inadequacy [211,212]. [213,214].

5.5. Integrative interpretation of the signal map

Although most evidence in this field concerns dietary inadequacy or biochemical risk, rare clinically overt deficiency states have been described in pharmacovigilance analyses and case reports. Lev et al., in a pharmacovigilance study and literature review, identified reported cases of Wernicke encephalopathy associated particularly with semaglutide and tirzepatide, while individual case reports have described thiamine deficiency in the setting of prolonged vomiting and markedly reduced intake. Because spontaneous reporting cannot establish causality or incidence, these data should be interpreted as safety signals that highlight high-risk clinical contexts rather than as estimates of population-level risk [164,215]. [164] This distinction is important for the interpretation of the broader micronutrient signal map. The literature does not suggest that all patients receiving incretin therapy will develop clinically important deficiencies. Rather, it indicates that dietary inadequacy is common, biochemical decline is beginning to be documented for selected nutrients, and overt clinical deficiency appears most likely in the setting of baseline vulnerability, severe gastrointestinal symptoms, prolonged low intake, or coexisting risk factors such as prior bariatric surgery.

Taken together, the strongest current signals involve iron and vitamin D, followed by vitamin B12, calcium, magnesium, potassium, and zinc. Thiamine (vitamin B1) represents a distinct high-severity safety signal in the setting of prolonged vomiting or markedly reduced intake, whereas folate (vitamin B9), vitamin A, vitamins E and K, selenium, iodine, phosphate, and potassium remain biologically plausible or clinically relevant but less consistently characterized by direct longitudinal biomarker data [164,167,215]. Representative studies supporting these observations are summarized in Table 2. For folate, vitamins A/E/K, selenium, iodine, and phosphate, the biologic rationale is credible, but the evidence remains comparatively limited and often based on dietary inference rather than serial biomarker assessment. The existing literature therefore supports a tiered interpretation: some micronutrients already have converging dietary, mechanistic, and clinical signals, whereas others remain plausible candidates requiring prospective study. This signal-based approach is useful because it reflects the current state of the field more accurately than a simple binary classification of “deficient” versus “not deficient.” It also provides the conceptual bridge to the next section, where the clinical consequences of these abnormalities and the patient profiles most likely to manifest them can be examined in greater detail.

Table 2.

Representative evidence linking incretin-based therapy to micronutrient-related outcomes.

Study/Design	Population	Therapy	Outcome	Key Finding	Limitation
Large retrospective cohort (N = 461,382) [18]	Adults with T2D	GLP-1RA (class)	ICD-coded deficiencies	↑ vitamin D deficiency (7.5 → 13.6%); anemia, B deficiencies	No biomarkers; detection bias
Cross-sectional dietary study (N = 69) [84]	Adults on therapy	Semaglutide, tirzepatide	Nutrient intake	Low intake: Ca, Fe, Mg, K, vitamins A/D/E/K; low diet quality	No baseline; no biomarkers
Cross-sectional diet quality study [85]	Adults on GLP-1RA	GLP-1RA	Diet pattern	Low HEI score; ↓ fruits, veg, dairy, protein	Observational
Retrospective cohort (N = 29) [17]	Post-sleeve + T2D	Semaglutide	Biochemical markers	↓ B12, ↓ zinc; macronutrient shift	Small, high-risk population
Mechanistic absorption study [6]	T2D patients	Semaglutide	Iron absorption	↓ iron absorption (∼13%; ≥30% in subset)	Short duration
Pharmacovigilance (FAERS) [86]	Post-marketing	GLP-1RA	Adverse events	Strong signal for dehydration; supports concern regarding volume depletion and renal complications in susceptible patients	No causality
Pharmacovigilance study + literature review (Lev et al.) + case reports [20]	Clinical cases	Semaglutide, tirzepatide	Thiamine deficiency	Reported cases of Wernicke encephalopathy associated with prolonged vomiting, poor intake, and nutritional compromise	Spontaneous reporting; cannot establish incidence or causality

Abbreviations: ↑, increased; ↓, decreased; GLP-1RA, glucagon-like peptide-1 receptor agonist; T2D, type 2 diabetes; ICD, International Classification of Diseases; HEI, Healthy Eating Index; FAERS, FDA Adverse Event Reporting System.

6. Clinical impact and high-risk profiles

The clinical relevance of micronutrient disturbances during incretin-based pharmacotherapy lies not only in biochemical abnormalities but in their potential to influence treatment tolerance, functional capacity, and long-term health outcomes [41,46]. Although most available data describe early or subclinical changes, emerging evidence indicates that micronutrient inadequacy may translate into clinically meaningful consequences in selected individuals, particularly when rapid weight loss, reduced intake, and gastrointestinal intolerance coexist [100,216]. Importantly, the clinical manifestations of micronutrient imbalance during incretin therapy may be non-specific, delayed, or overlapping with obesity- or diabetes-related symptoms, which can complicate recognition in routine practice [217]. As such, understanding the spectrum of potential clinical effects and identifying vulnerable populations is essential for contextualizing the micronutrient signals described in the preceding section.

6.1. Nutritional anemia and functional capacity

Among the most clinically relevant consequences is the development of nutritional anemia, driven primarily by deficiencies in iron, vitamin B12, and, to a lesser extent, folate [218,219]. As outlined in Section 5, multiple converging mechanisms, including reduced dietary intake, altered absorption, and baseline inflammation-related iron dysregulation, may contribute to declining hematologic status during incretin therapy [177]. From a clinical perspective, anemia may manifest as fatigue, reduced exercise tolerance, dyspnea on exertion, and impaired functional capacity. These symptoms are particularly relevant in the context of obesity treatment, where increased physical activity is often encouraged as part of comprehensive care [[220], [221], [222], [223]]. Observational signals from large real-world datasets suggest that iron deficiency anemia may be clinically recognized in a subset of GLP-1 receptor agonist users. In Scott Butsch et al.’s retrospective observational cohort of 461,382 adults with T2DM, ICD-coded iron deficiency anemia was documented in 3.2% of patients by 12 months. Because these data were based on administrative diagnoses rather than standardized hemoglobin, ferritin, transferrin saturation, or B12 testing, they likely capture clinically detected anemia and do not quantify subclinical hematologic decline [166,224]. Because fatigue and reduced energy are also common in individuals with obesity and T2DM, anemia-related symptoms may be under-recognized or attributed to other causes, potentially delaying diagnosis [225,226].

6.2. Neurological complications and severe deficiency states

Although uncommon, neurological complications related to micronutrient deficiency represent some of the most serious reported adverse outcomes during incretin-based therapy [164]. Thiamine (vitamin B1) deficiency is of particular concern in the setting of prolonged nausea, vomiting, or markedly reduced oral intake. Case reports and pharmacovigilance analyses have described instances of Wernicke encephalopathy occurring in patients treated with GLP-1 receptor agonists, particularly in those experiencing sustained gastrointestinal intolerance [164,215]. Clinical features include confusion, ataxia, and visual disturbances, reflecting acute neurocognitive dysfunction associated with thiamine depletion [[227], [228], [229]]. While these events appear to be rare, their severity underscores the importance of recognizing prolonged low intake and gastrointestinal symptoms as potential risk contexts for acute deficiency. Chronic deficiencies of vitamin B12 and, less commonly, vitamin E may also manifest neurologically, presenting as peripheral neuropathy, paresthesias, or gait disturbances. In individuals with T2DM, these symptoms may overlap with or be misattributed to diabetic neuropathy, complicating clinical differentiation [230,231]. Accordingly, thiamine-related neurological risk should be conceptualized as an acute low-intake or vomiting-associated complication, distinct from the pathways involving fat-soluble vitamin handling during weight loss [164,215].

6.3. Hair loss and integumentary manifestations

Hair loss has emerged as a relatively frequent, although often under-discussed, clinical signal during incretin-based weight loss [232]. Reports summarized in the literature indicate that alopecia occurs in a minority of individuals treated with GLP-1 receptor agonists in clinical trials, typically in the low single-digit range, although substantially higher rates have been observed in real-world observational cohorts [233]. The underlying mechanism is most consistent with telogen effluvium, a reversible condition characterized by premature transition of hair follicles into the resting phase in response to physiological stress [49]. Rapid weight loss itself is a recognized trigger, but nutritional factors, including inadequate intake of protein, iron, and zinc, are thought to contribute [234].

6.4. Lean mass, sarcopenia, and bone health

Body composition changes during incretin-based weight loss extend beyond fat mass reduction [235]. Several studies have shown that a proportion of weight loss, often estimated at 20–40%, may derive from lean body mass, particularly when protein intake and resistance exercise are not maintained [108,236,237]. Loss of lean mass has important clinical implications, including reduced strength, impaired physical function, and increased risk of frailty, particularly in older adults [238,239]. In this context, micronutrient adequacy may play a supportive role, as nutrients such as vitamin D, magnesium, and certain trace elements contribute to neuromuscular function and metabolic processes within skeletal muscle [240,241].

In parallel, changes in bone metabolism may occur during weight loss. Clinical studies have demonstrated reductions in bone mineral density and shifts in bone turnover markers during GLP-1RA-associated weight loss, particularly in the absence of exercise [151]. These skeletal effects are multifactorial, involving reduced mechanical loading, hormonal changes, and altered nutrient availability. From a nutritional perspective, inadequate intake of calcium and vitamin D, combined with increased bone turnover, may contribute to long-term skeletal vulnerability [148,242]. Although the net effect of incretin therapies on fracture risk remains uncertain, the convergence of weight loss, nutrient inadequacy, and altered bone remodeling highlights a clinically relevant area requiring further study.

6.5. High-risk populations and vulnerability profiles

Not all individuals receiving incretin-based therapy appear to be equally susceptible to micronutrient disturbances. Emerging data suggest that risk is influenced by baseline nutritional status, comorbid conditions, treatment-related factors, and demographic characteristics [12,243,244]. Older adults represent a particularly vulnerable group. Age-related changes in appetite, gastrointestinal function, and muscle mass, combined with a higher susceptibility to dehydration and sarcopenia, may increase the clinical impact of reduced intake and gastrointestinal adverse effects during therapy [245].

Individuals with a history of bariatric surgery constitute another high-risk population [[246], [247], [248]]. These patients often have pre-existing alterations in nutrient absorption, particularly for iron, vitamin B12, and fat-soluble vitamins [131]. The addition of incretin-based pharmacotherapy for weight regain or glycemic control may further reduce intake and exacerbate existing deficiencies, as suggested by small cohort studies demonstrating declines in micronutrient levels during semaglutide treatment in post-surgical patients [169,249,250].

Finally, individuals with pre-existing gastrointestinal disorders, such as celiac disease [251], chronic gastritis [252], or conditions affecting gastric acidity, may be more susceptible to impaired absorption of micronutrients, particularly iron and vitamin B12 [253,254]. When combined with the gastrointestinal effects of incretin therapy, these conditions may amplify the risk of clinically relevant deficiency.

Taken together, the clinical consequences of micronutrient disturbances during incretin-based therapy range from subtle functional impairments to rare but severe deficiency syndromes. While most patients are unlikely to develop overt complications, the convergence of reduced intake, gastrointestinal effects, and baseline vulnerability may lead to clinically meaningful outcomes in selected individuals. These observations reinforce the importance of interpreting micronutrient signals not in isolation, but within the broader clinical context of weight loss trajectory, dietary patterns, and patient-specific risk factors.

7. Risk stratification, monitoring, and evidence gaps

The expanding use of incretin-based pharmacotherapy for obesity has outpaced the development of structured approaches to nutritional surveillance [6]. In contrast to metabolic and bariatric surgery, where standardized micronutrient monitoring protocols are well established, there are currently no formal guidelines addressing micronutrient assessment during treatment with GLP-1 receptor agonists or dual incretin agonists [2]. Nonetheless, the convergence of baseline micronutrient vulnerability in obesity, sustained reductions in dietary intake, and emerging clinical and biochemical signals suggests that a structured, evidence-informed approach to monitoring may be useful for organizing clinical care and future research.

The framework outlined in this section is not intended as a clinical guideline. Rather, it represents a conceptual synthesis of current evidence, integrating known mechanisms of nutrient depletion, observed dietary and biochemical patterns, and clinical signals reported during incretin-based therapy. Its purpose is to provide a pragmatic structure for interpreting micronutrient risk across different phases of treatment.

A practical way to conceptualize micronutrient risk during incretin therapy is to align surveillance with the temporal phases of treatment, recognizing that the magnitude of weight loss, dietary restriction, and gastrointestinal effects varies over time (Fig. 3). This approach is supported indirectly by clinical trial data demonstrating that the most pronounced reductions in body weight and energy intake occur during the first 6–12 months of therapy, a period characterized by dose escalation, maximal appetite suppression, and higher rates of gastrointestinal adverse events [99,260,261].

Fig. 3.

Conceptual framework for micronutrient risk stratification and monitoring during incretin-based obesity pharmacotherapy. Micronutrient risk during incretin-based therapy can be conceptualized across distinct phases of treatment, reflecting changes in weight trajectory, dietary intake, and gastrointestinal tolerance over time. At baseline, pre-existing nutritional variability in obesity, including altered vitamin D status and functional iron deficiency, provides the starting context for interpretation. During the early phase of treatment, rapid reductions in energy intake and gastrointestinal adverse effects may contribute to acute nutritional stress, particularly in individuals with reduced oral intake or dehydration. The subsequent active weight-loss phase is characterized by sustained dietary restriction and cumulative nutrient deficits, with emerging biochemical signals involving hematologic and bone-related nutrients. During long-term maintenance, persistent dietary patterns and chronic therapy may influence ongoing micronutrient balance. Across all phases, individual risk is modified by factors such as age, prior bariatric surgery, gastrointestinal comorbidities, and symptom burden [6,37,89,243,252,[255], [256], [257], [258], [259]]. This framework is intended to organize current evidence and does not represent a formal clinical guideline. Abbreviations: ↓, decreased.

At baseline, prior to treatment initiation, the primary objective is to identify pre-existing micronutrient abnormalities [257]. This step is particularly relevant given the high prevalence of subclinical deficiencies in obesity, including low vitamin D status, functional iron deficiency, and inadequate intake of magnesium and other micronutrients [37,255,256]. Baseline assessment therefore provides a reference point against which subsequent changes can be interpreted and may help distinguish treatment-emergent abnormalities from pre-existing conditions [262,263].

During the active weight-loss phase, typically encompassing the first 6 months of therapy, the principal concern is the interaction between reduced dietary intake, gastrointestinal symptoms, and underlying nutritional status [89,260]. Observational signals from administrative datasets, including Scott Butsch et al.’s retrospective cohort of 461,382 adults with T2DM, indicate that nutrition-related diagnoses become increasingly documented at 6 and 12 months after GLP-1 receptor agonist prescription [166]. Although such data are based on diagnostic coding rather than systematic biochemical assessment, they suggest that this phase represents a period of heightened nutritional vulnerability.

A first-year reassessment is particularly informative in individuals who have experienced substantial weight loss, prolonged gastrointestinal intolerance, or significant dietary restriction [6,16,258,259]. Dietary evidence from cross-sectional studies of incretin users, including Johnson et al.’s 69-person dietary intake study, has demonstrated widespread inadequacy of calcium, iron, magnesium, potassium, and fat-soluble vitamin intake relative to recommended levels [12,34,109]. In parallel, smaller longitudinal or retrospective cohorts, such as Kanai et al.’s 12-month post-sleeve semaglutide cohort of 29 patients, have begun to document measurable declines in selected biomarkers, including vitamin B12 and zinc [12,169].

Beyond the first year, during the maintenance phase, evidence becomes more limited. Long-term trials of incretin therapies have primarily focused on weight and cardiometabolic outcomes, with minimal systematic assessment of micronutrient status [264,265]. As a result, the long-term trajectory of micronutrient balance during sustained pharmacologic weight loss remains incompletely characterized. Nevertheless, continued reductions in dietary intake, recurrent dieting behaviors, and persistent alterations in eating patterns may plausibly sustain nutritional risk even after weight stabilizes [65,266].

Interpreting micronutrient biomarkers during active weight loss requires careful consideration of physiological and analytical confounders. Several commonly used laboratory markers may be influenced by factors independent of true nutrient status [[267], [268], [269]]. Ferritin, for example, is an acute-phase reactant and may remain within normal ranges despite depleted iron stores in the context of chronic low-grade inflammation associated with obesity [270]. This phenomenon of functional iron deficiency, mediated in part by elevated hepcidin levels, can obscure the interpretation of iron status and may lead to under-recognition of deficiency when ferritin is considered in isolation [271].

Similarly, vitamin B12 assessment may be complicated by the limited sensitivity of serum B12 measurements, particularly in the borderline range [272,273]. Functional biomarkers such as methylmalonic acid can improve diagnostic accuracy but may be influenced by renal function, which is frequently altered in individuals with T2DM [274]. These factors highlight the importance of interpreting laboratory results within the broader clinical context, including dietary patterns, symptoms, and comorbid conditions.

Analytical interference represents an additional consideration. High-dose biotin supplementation, commonly used for hair and nail concerns, has been shown to interfere with certain immunoassays, producing falsely elevated or reduced results depending on assay design [275,276]. In patients reporting supplement use, unexpected laboratory findings should therefore be interpreted cautiously [277]. Taken together, these considerations underscore that laboratory data should be viewed as part of an integrated clinical assessment rather than as isolated indicators of nutritional status.

In the absence of formal guidelines, a useful approach is to consider a core set of micronutrients that consistently emerge across mechanistic, dietary, and clinical evidence, and to complement this with targeted evaluation based on individual risk factors. Across the available literature, the most consistent signals involve iron, vitamin D, and vitamin B12, reflecting their central roles in hematologic function, neurological health, and skeletal metabolism. These nutrients are also commonly abnormal in obesity prior to treatment and are repeatedly implicated in observational and dietary studies of incretin-based therapy.

Additional micronutrients (including Ca, Mg, Zn, thiamine, folate and selected electrolytes such as K) may be relevant in specific contexts, particularly in individuals with reduced dietary diversity, prolonged gastrointestinal symptoms, or clinical features suggestive of deficiency. For example, evaluation of thiamine status may be warranted in the setting of persistent vomiting, given the small but clinically significant number of reported cases of Wernicke encephalopathy associated with prolonged nutritional compromise [164,215]. In patients with persistent vomiting, diarrhea, poor fluid intake, known chronic kidney disease, or other risk factors for volume depletion, monitoring should extend beyond micronutrient biomarkers to include renal function and electrolytes, including serum potassium. This is consistent with prescribing information for semaglutide and tirzepatide, which advises renal monitoring when gastrointestinal adverse reactions may lead to volume depletion, particularly during treatment initiation and dose escalation [[210], [211], [212]]. Importantly, this framework is best understood as adaptive and context-dependent. Rather than applying a fixed panel universally, it provides a structure for prioritizing assessment based on the interaction between treatment phase, symptom burden, dietary intake, and baseline risk.

7.1. Evidence gaps and future directions

Despite the rapid expansion of incretin-based therapies, the evidence base supporting micronutrient monitoring remains limited. Most available data derive from retrospective administrative analyses, cross-sectional dietary studies, pharmacovigilance reports, case reports, and small short-term mechanistic investigations. These study designs provide complementary but non-equivalent evidence: dietary studies identify inadequate exposure, mechanistic studies support biological plausibility, administrative cohorts detect clinically coded outcomes, and pharmacovigilance reports highlight rare safety signals. However, none of these designs can establish the true incidence, causal attribution, or natural history of micronutrient changes during long-term incretin therapy [18,19,21,265,278].

Additional uncertainties include the long-term trajectory of micronutrient status during chronic therapy, the extent to which greater weight loss achieved with dual incretin agonists modifies nutritional risk, and the interaction between lean mass loss, protein intake, and micronutrient metabolism. Furthermore, several nutrients with plausible biological relevance, including iodine, selenium, and vitamin K, remain poorly characterized in the context of incretin therapy.

Finally, there is a need to better understand how nutrition care delivery influences outcomes. Observational data suggest that nutritional deficiencies are more frequently documented in individuals who receive dietitian support, likely reflecting increased detection rather than increased risk. This highlights the possibility that micronutrient disturbances may be under-recognized in routine practice and underscores the importance of integrating nutritional assessment into obesity pharmacotherapy.

While definitive guidance is lacking, the available evidence supports a structured, phase-based approach to understanding micronutrient risk during incretin-based therapy, grounded in the interplay between reduced intake, gastrointestinal effects, and weight-loss physiology. The framework presented here is intended to organize current knowledge and highlight areas of uncertainty, rather than to prescribe specific clinical actions. These considerations provide the foundation for future work aimed at defining optimal monitoring strategies and improving the nutritional safety of pharmacologic obesity treatment.

8. Clinical nutrition strategies to prevent and manage micronutrient risk

Translating micronutrient risk signals into clinical practice requires moving beyond laboratory surveillance alone toward proactive nutrition management integrated throughout the treatment pathway [6,17,92,264]. While most individuals receiving incretin-based pharmacotherapy are unlikely to develop overt deficiency syndromes, reduced appetite, lower food volume, gastrointestinal adverse effects, and rapid weight loss create a nutritional context in which preventive dietary strategies become clinically relevant [6,92]. Importantly, preservation of micronutrient status during therapy should not be conceptualized solely as a supplement-based approach, because dietary quality, symptom tolerance, protein adequacy, hydration, and behavioral support are central components of nutrition care during GLP-1–based treatment [17,279]. In many patients, the first-line intervention is optimization of dietary quality, meal structure, symptom management, and individualized nutrition support [244]. This perspective aligns with the broader principle that pharmacologic obesity treatment is most effective when embedded within structured multidisciplinary care [280].

8.1. Nutrient density under reduced appetite

A defining characteristic of GLP-1 receptor agonist and dual incretin therapy is a marked reduction in spontaneous energy intake, which increases the clinical importance of nutrient density at each eating occasion [92,264]. Under conditions of reduced intake, caloric restriction may proportionally reduce micronutrient exposure unless diet quality is deliberately maintained or supplementation is provided when indicated [28,281]. When total food intake declines, patients may no longer be able to rely on habitual eating patterns to meet micronutrient requirements, particularly if prior diets were dominated by energy-dense but nutrient-poor foods. A practical clinical priority is therefore to improve nutrient density rather than focusing exclusively on calorie reduction [282]. Foods that simultaneously provide protein and key micronutrients may be especially valuable during therapy. Examples include dairy products or fortified alternatives (calcium, vitamin B12, iodine), eggs (vitamin B12, selenium, choline), legumes (iron, folate, magnesium), seafood (iodine, selenium, zinc), lean meats (iron, zinc, vitamin B12), nuts and seeds (magnesium, vitamin E), and vegetables rich in folate, carotenoids, potassium, and vitamin K [[282], [283], [284], [285]]. Encouraging regular inclusion of these foods may help preserve nutritional adequacy despite lower intake volume. In practice, the clinical question often shifts from how much the patient is eating to which nutrients are represented in the foods they are still willing and able to consume [17,264]. This principle is particularly relevant during early treatment phases, when appetite suppression may be strongest and meal size declines rapidly. Patients who consume only one or two small meals per day may require explicit counseling to prioritize nutrient-rich foods before discretionary items [244,264]. In this context, structured guidance can prevent an unintended transition from therapeutic calorie reduction to progressive nutritional inadequacy.

8.2. Meal structure and intake distribution

Beyond food selection, meal patterning is an important determinant of nutritional adequacy during incretin therapy. Reduced hunger frequently leads to skipped meals, prolonged fasting intervals, or reliance on highly palatable convenience foods consumed in very small amounts. Although total energy intake may remain low, these patterns can further reduce exposure to protein, vitamins, and minerals across the day [28,244]. A pragmatic strategy is to encourage a predictable meal structure based on smaller, well-tolerated eating occasions rather than waiting for hunger cues alone [86,87,259]. For many individuals, three modest meals or two meals plus one planned nutrient-dense snack may be more effective than irregular grazing or a single large meal. Smaller portions are often better tolerated in the setting of delayed gastric emptying, while more frequent opportunities to eat may improve cumulative nutrient intake [259]. Protein distribution deserves particular attention because protein-containing foods are also major sources of iron, zinc, selenium, vitamin B12, and other micronutrients [282]. When appetite is limited, patients may benefit from a “protein-first” strategy in which the most nutrient-dense protein component of the meal is consumed first, followed by vegetables, legumes, fruit, or other complementary foods as tolerated. Although primarily aimed at preserving lean mass, this approach may simultaneously support micronutrient adequacy.

8.3. Symptom-adapted nutrition during gastrointestinal intolerance

Gastrointestinal symptoms are among the most common barriers to adequate intake during incretin therapy and often represent the point at which nutritional risk becomes clinically significant [92]. Nausea, early satiety, vomiting, reflux, constipation, and food aversion may substantially narrow dietary variety or reduce total intake for prolonged periods if not actively addressed. Nutritional management should therefore be symptom-responsive rather than generic. In patients with nausea or early fullness, temporary use of smaller meals, slower eating pace, reduced meal fat load, and avoidance of large mixed meals may improve tolerability [86,87]. Some individuals benefit from separating fluid intake from meals when postprandial fullness is prominent [286]. During periods of active nausea, bland but protein-containing foods (such as yogurt, eggs, soups with legumes, or simple dairy-based options) may be more realistic than idealized dietary prescriptions. For reflux symptoms, earlier evening meals, smaller portions, and avoidance of lying supine after eating may be useful adjunctive strategies. In constipation, gradual fiber titration, adequate hydration, physical activity, and attention to potassium- and magnesium-rich foods may help restore bowel regularity. Importantly, symptom-driven dietary simplification should be viewed as a temporary adaptation rather than a long-term pattern [87]. Once symptoms improve, food variety should be progressively re-expanded to restore broader nutrient exposure. Persistent vomiting requires particular caution because it may signal acute nutritional risk beyond routine micronutrient insufficiency [87,164]. In this setting, dehydration, thiamine depletion, and clinically meaningful undernutrition should be considered early, especially when oral intake has been markedly reduced for several days [164,287]. Because severe or persistent gastrointestinal symptoms may also lead to volume depletion and deterioration in renal function, renal function and electrolytes, including potassium, should be assessed when dehydration, kidney disease, or acute kidney injury is clinically suspected [210].

8.4. Targeted supplementation rather than universal supplementation

Current evidence does not support universal routine supplementation for all individuals receiving incretin-based pharmacotherapy. However, selective supplementation may be reasonable in defined clinical contexts where dietary intake is inadequate, baseline risk is high, or biochemical abnormalities are documented [287]. A targeted rather than universal approach is consistent with the heterogeneity of nutritional risk observed during treatment [17]. Higher-risk scenarios may include prior bariatric surgery, vegan or highly restrictive dietary patterns, prolonged gastrointestinal intolerance, recurrent vomiting, rapid or excessive weight loss, older age with low muscle reserve, chronic use of acid-suppressive therapy, metformin co-treatment, or pre-existing deficiencies identified at baseline [286,287]. In such patients, use of a standard multivitamin–mineral supplement or nutrient-specific supplementation may be appropriate depending on the clinical scenario and local practice standards. Targeted correction of documented deficiencies remains particularly important. Iron supplementation may be indicated when iron deficiency is confirmed; vitamin B12 replacement may be appropriate in low or declining status, especially with metformin exposure; calcium and vitamin D support may be considered when intake is low or skeletal risk is elevated; and thiamine should be prioritized urgently when prolonged vomiting or severe low intake raises concern for acute deficiency. Supplementation should ideally be paired with efforts to restore food quality and intake adequacy rather than replacing dietary care altogether [287]. Common clinical triggers, suggested biomarkers, and first-line management considerations for selected high-priority micronutrients are summarized in Table 3.

Table 3.

Key micronutrients at risk: Clinical triggers, biomarkers, and first-line management.

Micronutrient	Common Clinical Trigger	Suggested Biomarker(s)	First-Line Management
Thiamine [22,87,88]	Persistent vomiting, prolonged poor intake	Clinical suspicion; whole-blood thiamine or thiamine pyrophosphate when available	Urgent replacement, hydration support, and assessment for Wernicke encephalopathy
Vitamin B12 [14,[89], [90], [91], [92]]	Metformin use, vegan diet	Serum B12 ± MMA	Replacement; review dietary intake
Folate (Vitamin B9) [[25], [26], [27], [28], [29], [30], [31]]	Restrictive diet, low vegetable intake, macrocytosis, anemia evaluation	Serum folate if clinically indicated	Improve dietary quality; supplementation when deficiency is documented
Iron [3,4,[93], [94], [95], [96]]	Fatigue, hair loss, anemia risk	Ferritin, TSAT, hemoglobin	Iron replacement and dietary optimization
Vitamin D [34,35,47,[97], [98], [99], [100]]	Low intake, low sun exposure	25-hydroxyvitamin D	Supplementation and reassessment
Calcium [[47], [48], [49],101]	Dairy avoidance, low intake	Dietary assessment ± labs	Fortified foods; supplement if needed
Magnesium [[53], [54], [55], [56], [57], [58], [59],61]	Poor diet quality, low intake, muscle cramps, constipation	Serum magnesium when indicated	Improve intake; targeted supplementation if needed
Zinc [65,67,69,100]	Hair loss, restrictive diets	Serum/plasma zinc if indicated	Review intake; targeted supplementation
Vitamin A/E/K (selected patients) [38,39,41,42,[44], [45], [46]]	Markedly reduced dietary diversity, low fat intake, prior bariatric surgery, or fat-malabsorption concern	Retinol, alpha-tocopherol, PT/INR, or vitamin K testing if clinically indicated	Dietary optimization; targeted supplementation if deficiency is documented
Potassium/Electrolytes [84,[102], [103], [104]]	Low fruit/vegetable intake; vomiting; diarrhea; dehydration; CKD; suspected AKI	Serum potassium; creatinine/eGFR; electrolytes	Assess hydration, renal function, diet quality, and medications; avoid empiric potassium supplementation in CKD or hyperkalemia risk

Abbreviations: 25(OH)D, 25-hydroxyvitamin D; MMA, methylmalonic acid; PTH, parathyroid hormone; TSAT, transferrin saturation.

8.5. Referral pathways and multidisciplinary care

Although many nutritional issues can be addressed within routine obesity practice, some patients require more specialized support [244,279]. Registered dietitian nutritionist (RDN) involvement should not be reserved only for patients who have already developed biochemical abnormalities or overt complications. Rather, nutrition professionals may contribute proactively at baseline, during dose escalation, and throughout follow-up by helping identify pre-existing nutritional risk, preserve dietary quality during appetite suppression, manage gastrointestinal intolerance, and support early recognition of emerging nutrition-related problems [17]. Older adults and those with previous bariatric surgery may also benefit from closer nutritional follow-up given their higher vulnerability to functional consequences of inadequate intake [286,287]. Early RDN involvement may also be particularly useful for individuals with persistent poor intake, recurrent gastrointestinal symptoms, rapid or excessive weight loss, hair loss, fatigue, suspected sarcopenia, complex dietary restrictions, or repeated difficulty meeting protein and hydration targets [17]. The role of nutrition professionals extends beyond prescribing meal plans. Structured assessment of dietary adequacy, symptom-linked food tolerance, body composition risk, supplement appropriateness, and long-term maintenance behaviors may improve treatment persistence and reduce preventable complications. This preventive role parallels best-practice principles in metabolic and bariatric surgery, where nutrition care is used not only to treat established deficiencies but also to prevent nutrition-related complications and support long-term outcomes [286]. As incretin therapies move increasingly into primary care and general medical settings, access to practical nutrition expertise may become a key determinant of real-world treatment quality [92,244].

8.6. From monitoring to action

Micronutrient surveillance is most clinically useful when linked to actionable nutritional responses [287]. Laboratory abnormalities should prompt reassessment of dietary intake, symptom burden, treatment tolerability, weight-loss trajectory, and relevant comorbidities rather than isolated prescription of supplements alone. Conversely, the absence of abnormal laboratory values should not exclude intervention when substantial dietary compromise is evident [164]. Taken together, current evidence supports a pragmatic hierarchy of care: first, optimize food quality, meal structure, hydration, and symptom management; second, identify and correct patient-specific risk factors; third, use targeted laboratory evaluation and supplementation when clinically indicated; and fourth, integrate RDN and multidisciplinary support early for high-risk patients and escalate the intensity of care when poor intake, gastrointestinal intolerance, biochemical abnormalities, renal/electrolyte disturbances, or functional decline persist [17,211]. Framed in this way, micronutrient management becomes an integral component of effective obesity pharmacotherapy rather than a separate or reactive concern. An integrated clinical pathway linking baseline risk assessment, early RDN-supported nutrition care, symptom-adapted nutrition strategies, targeted laboratory testing, supplementation, escalation, and longitudinal reassessment is proposed in Fig. 4.

Fig. 4.

From monitoring to action: clinical algorithm for the prevention and management of micronutrient risk during incretin-based therapy. This practical framework integrates nutritional risk assessment into routine care for patients receiving GLP-1 receptor agonists or dual incretin therapy. Key steps include baseline risk screening, assessment of gastrointestinal symptoms and dietary intake, early involvement of a registered dietitian nutritionist or nutrition team when baseline risk, dietary restriction, gastrointestinal intolerance, or rapid weight loss is present, symptom-guided nutrition strategies, hydration support, targeted laboratory testing, correction of documented deficiencies, escalation in high-risk scenarios, and longitudinal reassessment of weight trajectory, dietary adequacy, lean mass risk, and biochemical status. The algorithm emphasizes that RDN involvement may serve preventive, therapeutic, and early-detection functions, rather than being limited to management after deficiencies have already occurred. It also distinguishes dietary potassium inadequacy from clinically important electrolyte disturbances, emphasizing renal function and electrolyte assessment when persistent gastrointestinal symptoms, dehydration, CKD, or suspected AKI are present. This algorithm is intended as a pragmatic clinical framework and does not represent a formal clinical guideline [17,280,282,[285], [286], [287]]. Abbreviations: CKD, chronic kidney disease; GI, gastrointestinal; GLP-1RA, glucagon-like peptide-1 receptor agonist; IBD, inflammatory bowel disease; PPI, proton pump inhibitor; PTH, parathyroid hormone; WL, weight loss; 25(OH)D, 25-hydroxyvitamin D.

9. Conclusion

Incretin-based pharmacotherapy has redefined the management of obesity by enabling substantial and sustained weight loss through coordinated central and gastrointestinal mechanisms. However, this therapeutic success is accompanied by a distinct nutritional phenotype characterized by reduced energy intake, altered dietary patterns, gastrointestinal effects, and weight-loss–related physiological adaptations. The available evidence, derived from dietary studies, mechanistic investigations, real-world cohorts, and pharmacovigilance data, consistently identifies signals of micronutrient vulnerability, particularly affecting iron, vitamin B12, vitamin D, calcium, magnesium, potassium, and zinc. Additional nutrients, including thiamine (vitamin B1), folate (vitamin B9), vitamin A, other fat-soluble vitamins, potassium, selenium, iodine, and phosphate, may also be clinically relevant in selected patients, although the strength of direct incretin-specific evidence varies across nutrients. These disturbances appear to arise from the interaction between baseline nutritional status in obesity, treatment-induced reductions in food intake and diversity, and alterations in absorption, metabolism, and tissue dynamics during active weight loss.

Although most patients are unlikely to develop overt deficiency, clinically relevant consequences may emerge in susceptible individuals, especially in the context of rapid weight loss, prolonged gastrointestinal symptoms, or pre-existing nutritional risk. Current evidence remains limited by the absence of prospective studies with systematic micronutrient assessment and by the heterogeneity of available data. Framing micronutrient risk through a phase-based and mechanism-informed lens may help integrate existing knowledge and guide future investigation. As incretin-based therapies continue to expand in clinical use, there is a clear need for longitudinal studies that define the natural history of micronutrient changes, identify high-risk populations, and clarify how nutritional factors influence both safety and long-term treatment outcomes.

9.1. Clinical takeaway messages

• •Micronutrient risk during incretin-based obesity pharmacotherapy should be interpreted as a patient-specific vulnerability rather than as a universal class-wide deficiency. The risk is shaped by baseline nutritional status, reduced food intake, lower dietary diversity, gastrointestinal tolerance, and the magnitude and pace of weight loss.
• •Clinicians should consider targeted nutritional assessment and laboratory monitoring in high-risk patients, particularly older adults, individuals with prior bariatric surgery, pre-existing gastrointestinal disorders, poor baseline diet quality, rapid weight loss, prolonged nausea or vomiting, or symptoms suggestive of anemia, neuropathy, hair loss, muscle weakness, or skeletal compromise.
• •Persistent vomiting, diarrhea, dehydration, chronic kidney disease, or suspected acute kidney injury should prompt evaluation beyond micronutrient biomarkers to include renal function and electrolytes, including potassium, because potassium disturbances may be bidirectional in this clinical context.
• •Registered dietitian nutritionist involvement should be considered proactively for patients with high baseline nutritional risk, persistent poor intake, recurrent gastrointestinal intolerance, complex dietary restrictions, rapid or excessive weight loss, or difficulty meeting protein and hydration targets, rather than being reserved only for established deficiencies or complications.
• •Future prospective studies should systematically evaluate dietary intake, micronutrient biomarkers, body composition, gastrointestinal symptoms, and clinical outcomes across treatment phases to define the incidence, clinical relevance, and optimal monitoring strategies for micronutrient disturbances during long-term incretin therapy.

Author contributions

Conceptualization: D.S.-R., C.R.-G., and L.S.; Methodology: D.S.-R., and C.R.-G.; Investigation: M.C.-D., G.R., L.C., V.P., F.F.-S., D.J., and C.S.; Writing—original draft: D.S.-R., M.C.-D., G.R., L.C., V.P., F.F.-S., D.J., C.S., and C.R.-G.; Writing—review and editing: D.S.-R., M.C.-D., G.R., L.C., V.P., F.F.-S., D.J., C.S., C.R.-G., and L.S.; Supervision: D.S.-R., C.R.-G., and L.S. All authors have read and agreed to the published version of the manuscript.

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Declaration of artificial intelligence (AI) and AI-assisted technologies

During the preparation of this work, the author(s) used artificial intelligence (AI)–assisted tools solely for language editing and grammar checking to improve clarity and readability of the manuscript. After using this tool, the authors reviewed and edited the content as needed and took full responsibility for the content of the publication.

Funding

This research received no external funding.

Conflicts of interest

The authors declare no conflicts of interest.