Erfolgreich durch internationale Zusammenarbeit

Endocrinology and Metabolism

Cite as: Archiv EuroMedica. 2026. 16; 4. DOI 10.35630/2026/16/Iss.4.14

Received 19 July 2026;
Accepted 17 August 2026;
Published 21 August 2026

GLP-1-BASED THERAPIES BEYOND DIABETES: EMERGING CLINICAL APPLICATIONS AND FUTURE PERSPECTIVES

Anna Szeszko¹ , Małgorzata Lubowiecka² ,
Weronika Czernek¹ , Magdalena Cichorzewska¹ ,
Martyna Płachta¹ , Rafał Wojtan³

¹ University Clinical Hospital No. 2 of the Medical University of Lodz, Poland
² 4th Military Clinical Hospital in Wroclaw, Poland
³ Mikolaj Pirogow Provincial Specialist Hospital, Lodz, Poland

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  annaszeszko00@gmail.com

ABSTRACT

Background

Glucagon-like peptide-1 (GLP-1)-based therapies were initially developed for the treatment of type 2 diabetes mellitus, but their clinical use has expanded substantially because of their effects on body weight and obesity-related complications. GLP-1 receptor agonists, dual and triple receptor agonists, and GLP-1-containing combination therapies are now being evaluated across cardiovascular, hepatic, kidney, respiratory and musculoskeletal diseases, as well as other conditions with metabolic, neuroendocrine or behavioural components.

Aim

To critically summarise established and emerging clinical applications of GLP-1-based therapies beyond direct glucose lowering and to distinguish evidence-supported indications from preliminary or investigational uses.

Materials and Methods

A narrative review guided by the principles of the Scale for the Assessment of Narrative Review Articles was conducted. PubMed/MEDLINE, the Cochrane Library, major journal platforms, ClinicalTrials.gov and United States and European regulatory websites were searched for English-language evidence published between January 2015 and 10 July 2026. Seminal earlier studies were included when required. Randomised trials, observational studies, meta-analyses, guidance documents and regulatory materials were synthesised thematically.

Results

Fifty-three sources were included. Robust randomised evidence supports chronic weight management, reduction in the risk of progression to type 2 diabetes during active treatment in people with obesity and prediabetes, cardiovascular risk reduction in adults with overweight or obesity and established cardiovascular disease, and clinically relevant benefits in obesity-related heart failure with preserved ejection fraction and moderate-to-severe obstructive sleep apnoea. Histological improvements have been demonstrated in metabolic dysfunction-associated steatohepatitis with fibrosis, while semaglutide reduced major kidney outcomes in patients with type 2 diabetes and chronic kidney disease. In obesity-associated knee osteoarthritis, one phase 3 trial showed improvements in pain and physical function. Evidence for Parkinson disease and Alzheimer disease was inconsistent or negative, whereas evidence for alcohol use disorder and polycystic ovary syndrome remained preliminary. Many observed benefits may be mediated by weight loss, and direct organ-specific effects remain uncertain. Gastrointestinal adverse effects were most common, while long-term safety, durability after treatment discontinuation, preservation of muscle mass and physical function, and equitable access remain unresolved.

Conclusions

GLP-1-based therapies are increasingly used in the management of obesity and selected obesity-related chronic diseases. Their clinical value depends on the specific agent, dose, patient phenotype and outcome assessed. Weight-mediated improvements should be distinguished from direct pharmacological effects. Future organ-specific indications should be supported by reproducible clinical outcomes in clearly defined populations rather than by mechanistic plausibility, biomarker changes or the magnitude of weight loss alone.

Keywords: Glucagon-Like Peptide-1 Receptor Agonists; Obesity; Type 2 Diabetes Mellitus; Prediabetes; Cardiovascular Diseases; Heart Failure with Preserved Ejection Fraction; Sleep Apnea, Obstructive; Metabolic Dysfunction-Associated Steatohepatitis; Chronic Kidney Disease; Body Weight.

INTRODUCTION

Glucagon-like peptide-1 (GLP-1) is an incretin hormone that enhances glucose-dependent insulin secretion, suppresses glucagon secretion at elevated glucose concentrations, slows gastric emptying and promotes satiety. Pharmacological GLP-1 receptor activation increases cyclic adenosine monophosphate signalling and influences appetite, energy intake and cardiometabolic risk factors [1-4]. Degradation-resistant GLP-1 receptor agonists were initially developed as glucose-lowering treatments, followed by higher-dose obesity formulations, dual GIP/GLP-1 receptor agonists, triple GIP/GLP-1/glucagon receptor agonists and combinations that pair GLP-1 receptor agonism with other pathways, such as amylin signalling [5-10, 15, 43-47].

The clinical importance of these therapies now extends beyond glycaemic control. Obesity is a major driver of cardiovascular, heart-failure, respiratory, hepatic, kidney and musculoskeletal morbidity, and GLP-1-based therapies can simultaneously reduce adiposity and modify disease-specific outcomes. Randomised programmes have therefore evaluated cardiovascular events, heart-failure status, sleep-disordered breathing, liver histology, kidney outcomes, pain and physical function rather than body weight alone [10-33].

At the same time, the field has expanded faster than the certainty of the evidence. Observational and mechanistic findings have generated hypotheses in neurodegenerative, addiction-related and reproductive disorders, while clinical trials have produced mixed, preliminary or negative findings [34-42]. Next-generation agents can produce substantial short-term weight loss, but their long-term effects on cardiovascular, kidney, hepatic and functional outcomes remain uncertain [43-47].

Important uncertainties also concern how much benefit is mediated by weight loss rather than direct tissue effects; whether improvements persist after treatment discontinuation; and how gastrointestinal intolerance, delayed gastric emptying, gallbladder disease, nutritional compromise, lean-mass loss, cost, shortages and unequal access affect real-world implementation [48-53].

The scientific gap is therefore not whether GLP-1-based therapies have biological effects beyond glucose lowering, but which disease-specific benefits are clinically meaningful, reproducible, durable and applicable to defined patient phenotypes. Because the strength of evidence differs substantially across diseases, clinically established applications should be clearly distinguished from preliminary and investigational directions. This review evaluates the evidence by clinical domain, regulatory status, safety and remaining research needs.

AIMS

The overarching aim of this narrative review was to summarise the evidence on clinical applications of GLP-1 receptor agonists and related incretin-based therapies beyond direct glucose lowering in type 2 diabetes mellitus.

The specific objectives were to: 1) describe the mechanistic underpinnings linking GLP-1 signalling with obesity-related organ disease; 2) compare the strength and consistency of evidence across obesity and cardiovascular, kidney, liver, pulmonary, musculoskeletal, neurological, addiction-related and reproductive disorders; 3) distinguish approved uses from investigational applications; 4) summarise important practical considerations, safety concerns and barriers to implementation; and 5) identify priorities for future clinical trials and precision-treatment strategies in people with obesity-related comorbidities.

MATERIALS AND METHODS

Review design and reporting approach

This article was developed as a narrative review in accordance with the principles of the Scale for the Assessment of Narrative Review Articles. It was not designed as a systematic review or meta-analysis, and no pooled summary estimates were calculated. The research question, search scope, eligibility criteria and thematic framework were defined before manuscript drafting.

Information sources and search strategy

A structured search was conducted for literature published from 1 January 2015 to 10 July 2026. PubMed/MEDLINE and the Cochrane Library were searched and supplemented by targeted searches of NEJM.org, The Lancet, JAMA Network, Nature Portfolio, Wiley Online Library, ScienceDirect, SpringerLink and Diabetes Journals (American Diabetes Association), as well as ClinicalTrials.gov, the United States Food and Drug Administration website and the European Medicines Agency website. Seminal studies published before 2015 were included when required to explain GLP-1 physiology or the historical development of cardiovascular evidence.

Search terms were combined using Boolean operators and included: “glucagon-like peptide-1 receptor agonist”, “GLP-1”, “semaglutide”, “liraglutide”, “tirzepatide”, “retatrutide”, “orforglipron”, “cagrilintide”, “obesity”, “prediabetes”, “cardiovascular outcomes”, “heart failure with preserved ejection fraction”, “chronic kidney disease”, “metabolic dysfunction-associated steatotic liver disease”, “metabolic dysfunction-associated steatohepatitis”, “obstructive sleep apnea”, “knee osteoarthritis”, “Parkinson disease”, “Alzheimer disease”, “alcohol use disorder”, “addiction”, “polycystic ovary syndrome”, “adverse events”, “gastric emptying”, “perioperative”, and “regulatory approval”. Searches were restricted to English-language human studies for clinical conclusions. Preclinical information was used only to explain biological plausibility and was not treated as evidence of clinical efficacy.

Eligibility criteria

An evidence hierarchy prioritised randomised trials with clinically relevant outcomes, predefined trial extensions, prespecified major secondary analyses, systematic reviews and meta-analyses, consensus guidelines and regulatory documents. Observational studies were used when randomised evidence was unavailable or when rare safety outcomes were being investigated. Eligible populations included adults and adolescents receiving a GLP-1 receptor agonist, a dual GIP/GLP-1 receptor agonist or an investigational agent with GLP-1 receptor agonism for chronic weight management, prevention of progression from prediabetes to type 2 diabetes, an obesity-related complication or another proposed non-glycaemic indication.

Studies were excluded if they addressed only short-term glycaemic outcomes in type 2 diabetes, lacked a clinically relevant comparator, were available only as non-peer-reviewed commentary or duplicated data reported elsewhere. Conference abstracts were not used as the primary basis for efficacy conclusions when a peer-reviewed report was available. Regulatory communications were used to determine indication status and safety warnings but not as substitutes for peer-reviewed efficacy evidence.

Data extraction and synthesis

Data on population, intervention, comparator, treatment period, primary outcome, main efficacy data and any adverse effects or regulatory relevance were extracted from all qualifying documents. Evidence was organised by clinical domain rather than chronologically. The strength of evidence was assessed qualitatively according to trial phase, sample size, replication, objectivity of the endpoint, duration and consistency of findings.

Numerical data were reported as presented in the original sources, with appropriate rounding when this improved readability.

A total of 53 sources were included: 36 randomised trials or randomised extensions, 2 observational or secondary analyses, 9 meta-analyses, guidance documents or mechanistic reviews, and 6 regulatory documents. Three summary tables were prepared and are included in the main manuscript file.

RESULTS

Evidence base and interpretive framework

Because many benefits may be mediated by weight loss, organ-level improvements do not by themselves prove a direct receptor-mediated effect. Reductions in adiposity can improve haemodynamics, sleep-disordered breathing, liver fat, insulin resistance, joint loading and systemic inflammation. Results are therefore presented by disease area, with direct and indirect mechanisms distinguished only when supported by the design of the underlying studies. The comparative strength of evidence, regulatory status and principal limitations are summarised in Table 1.

Obesity, chronic weight management and risk of progression from prediabetes

In STEP 1, 1,961 adults with overweight or obesity without diabetes were randomised to once-weekly semaglutide 2.4 mg or placebo with a lifestyle intervention. Mean change in body weight over 68 weeks was -14.9% in the semaglutide group and -2.4% in the placebo group; 50.5% of those receiving semaglutide achieved a 15% or greater reduction in baseline weight [10]. In STEP 4, the effects of withdrawing therapy were observed: following a 20-week semaglutide run-in period, continued semaglutide treatment resulted in additional weight loss of 7.9% (weeks 20-68), whereas participants switching to placebo experienced a weight gain of 6.9% [11].

Weight maintenance over 104 weeks was confirmed in STEP 5, with mean body-weight changes of -15.2% with semaglutide and -2.6% with placebo [12]. An extension of STEP 1 showed that, one year after treatment withdrawal, participants had regained approximately two-thirds of the weight previously lost, accompanied by worsening of several cardiometabolic parameters [13].

Among adolescents with obesity, semaglutide produced a 16.1% reduction in body mass index, compared with a 0.6% increase with placebo after 68 weeks [14]. Gastrointestinal adverse events occurred more frequently in the semaglutide group than in the placebo group, and gallbladder disorders were also more frequent with semaglutide. These findings demonstrated substantial efficacy in adolescents, although questions remain regarding long-term growth and the optimal duration of treatment.

In SURMOUNT-1, mean body-weight changes at 72 weeks were −15.0%, −19.5% and −20.9% with tirzepatide doses of 5 mg, 10 mg and 15 mg, respectively, compared with −3.1% with placebo [15]. In SURMOUNT-3, participants receiving tirzepatide achieved an additional mean weight loss of −18.4%, compared with a mean gain of 2.5% with placebo after an intensive lifestyle intervention [16]. In SURMOUNT-4, open-label tirzepatide produced a mean body-weight reduction of −20.9%; continued treatment resulted in an additional loss of 5.5%, whereas participants switched to placebo regained 14.0% between weeks 36 and 88 [17].

The 176-week extension of the SURMOUNT-1 study included participants with obesity and prediabetes. Development of T2D was observed in 1.3% of participants treated with tirzepatide versus 13.3% of those on placebo during the treatment period, corresponding to a reported 94% relative reduction in the risk of progression [18]. In analyses of the STEP programme, semaglutide increased the rates of reversion from prediabetes to normoglycaemia while actively receiving treatment, though durability of the glycaemic advantage post-treatment cessation was less marked [19].

Gastrointestinal adverse events were the most common treatment-related events and occurred predominantly during dose escalation. Discontinuation rates were substantially lower than the frequencies of nausea or diarrhoea, indicating that most events were transient or manageable. However, all trials included structured follow-up and lifestyle support, which may limit generalisability to routine clinical practice.

Cardiovascular disease and obesity-related heart failure with preserved ejection fraction

SELECT enrolled 17,604 adults aged ≥45 years with existing cardiovascular disease and a body mass index (BMI) ≥ 27 kg/m² but no diabetes. After a median follow-up of 39.8 months, the primary composite endpoint of cardiovascular death, nonfatal myocardial infarction, or nonfatal stroke occurred in 6.5% of participants receiving semaglutide 2.4 mg and in 8.0% of those receiving placebo (hazard ratio, 0.80) [20]. The FDA subsequently approved semaglutide 2.4 mg for reducing cardiovascular death, nonfatal myocardial infarction, and nonfatal stroke in adults with established cardiovascular disease and overweight or obesity [21].

In STEP-HFpEF, which included 529 participants with obesity-related heart failure with preserved ejection fraction, the mean improvement in the Kansas City Cardiomyopathy Questionnaire clinical summary score at 52 weeks was 16.6 points with semaglutide and 8.7 points with placebo. Mean body-weight changes were -13.3% and -2.6%, respectively, while mean changes in six-minute walk distance were 21.5 m and 1.2 m, respectively [22]. In STEP-HFpEF DM, which included patients with the same heart failure phenotype but type 2 diabetes, symptom score, weight, and walking distance were all improved with semaglutide, though body-weight reduction was smaller than that observed in STEP-HFpEF participants without diabetes [23]. In SUMMIT, which evaluated tirzepatide in 731 patients with obesity-associated heart failure with preserved ejection fraction, the rate of cardiovascular death or heart failure worsening was 9.9% with tirzepatide and 15.3% with placebo, with a hazard ratio of 0.62 and a greater improvement in Kansas City Cardiomyopathy Questionnaire clinical summary score with tirzepatide compared to placebo [24]. The main reasons for discontinuation were gastrointestinal adverse events.

Beyond glycaemic control, cardiovascular evidence includes one large atherosclerotic outcomes trial in people without diabetes and three dedicated trials in obesity-related heart failure with preserved ejection fraction. Comparable evidence is lacking for heart failure with reduced ejection fraction, acute coronary syndrome and primary prevention in people without diabetes or established cardiovascular disease.

Kidney outcomes

A prespecified analysis of SELECT also evaluated kidney outcomes among individuals without diabetes. Semaglutide reduced the incidence of the composite kidney outcome and attenuated the decline in estimated glomerular filtration rate compared with placebo; the largest absolute differences were observed in participants with lower kidney function at baseline or albuminuria [25]. These data may have implications for people with obesity and cardiovascular disease without diabetes; however, the number of severe kidney events was smaller than in dedicated kidney outcomes trials.

FLOW was a kidney-specific outcomes trial that enrolled 3,533 people with type 2 diabetes and chronic kidney disease. Once-weekly semaglutide reduced the risk of the primary composite of major kidney outcomes or death from kidney or cardiovascular causes by 24% compared with placebo and slowed the decline in estimated glomerular filtration rate [26]. Although FLOW did not include people without diabetes, it demonstrated organ-level kidney benefits and supported the biological plausibility of kidney protection in people with coexisting obesity and kidney dysfunction. Few dedicated kidney outcomes trials have been conducted in populations without diabetes.

Metabolic dysfunction-associated steatotic liver disease and steatohepatitis

In a phase 2 study of patients with biopsy-proven nonalcoholic steatohepatitis, daily semaglutide resulted in a greater frequency of resolution of steatohepatitis without worsening of fibrosis compared with placebo, although a statistically significant improvement in fibrosis stage was not shown [27]. The phase 3 ESSENCE study in patients with metabolic dysfunction–associated steatohepatitis and stage 2 or 3 fibrosis found that at week 72, rates of resolution of steatohepatitis without worsening of fibrosis were 62.9% for semaglutide and 34.3% for placebo, and improvement of at least one stage of fibrosis without worsening of steatohepatitis was observed in 36.8% and 22.4% of participants, respectively [28]. On the basis of interim ESSENCE data, the Food and Drug Administration approved semaglutide for adults with noncirrhotic metabolic dysfunction–associated steatohepatitis with moderate-to-advanced fibrosis using an accelerated approval mechanism, subject to confirmation of clinical benefit [29]. Data in people with decompensated cirrhosis and on the prevention of liver-related mortality remain inadequate.

SYNERGY-NASH assessed tirzepatide for 52 weeks in patients with metabolic dysfunction–associated steatohepatitis and stage 2 or 3 fibrosis. In the 5 mg, 10 mg, and 15 mg groups, 44%, 56%, and 62% of participants, respectively, showed resolution of steatohepatitis without worsening of fibrosis versus 10% in placebo. Fibrosis improvement without worsening of steatohepatitis was seen in approximately 50% of participants in the tirzepatide groups compared with 30% in placebo [30]. This phase 2 trial was not powered to assess liver-related clinical events.

Obstructive sleep apnoea

SURMOUNT-OSA included two phase 3 randomised clinical trials in adults with obesity and moderate-to-severe OSA; one enrolled participants who were not receiving positive airway pressure (PAP), whereas the other enrolled participants who were receiving PAP at baseline. After 52 weeks, tirzepatide significantly reduced the apnoea–hypopnoea index compared with placebo (mean reductions were 25.3 versus 5.3 events per hour in trial 1 and 29.3 versus 5.5 events per hour in trial 2) [31]. Improvements were also seen in weight, hypoxic burden, blood pressure and patient-reported sleep outcomes.

Consequently, tirzepatide has been approved for use in moderate-to-severe OSA in adults with obesity by the US Food and Drug Administration [32].

The trials did not establish that all patients could discontinue PAP therapy or that treatment resolves structural upper-airway abnormalities. Objective reassessment of sleep-disordered breathing after weight reduction therefore remains necessary.

Obesity-associated knee osteoarthritis

STEP 9 randomised 407 adults with obesity and moderate knee osteoarthritis with at least moderate pain to semaglutide 2.4 mg or placebo for 68 weeks. Mean change in body weight was -13.7% in the semaglutide arm and -3.2% in the placebo arm. Improvements in the Western Ontario and McMaster Universities Osteoarthritis Index pain score were -41.7 points with semaglutide and -27.5 points with placebo. Physical-function outcomes also improved to a greater extent with semaglutide [33].

This study tested a knee osteoarthritis phenotype associated with obesity and did not establish whether GLP-1 receptor agonism modifies cartilage structure. No information exists on osteoarthritis in lean individuals or in other joints, nor on the potential of GLP-1 receptor agonists to prevent or delay joint replacement over the long term.

Neurodegenerative diseases

A phase 2 trial in early Parkinson disease (n=156) showed that lixisenatide was associated with a slower progression in the Movement Disorder Society-Unified Parkinson's Disease Rating Scale motor score at 12 months compared with placebo, with frequent gastrointestinal events (nausea approximately 50%; vomiting 13%) [34]. While there remained a between-group difference after a 2-month washout, the study was not powered to measure long-term disability or progression. A larger phase 3 study of weekly exenatide in Parkinson's disease failed to show an effect on the primary motor outcome after 96 weeks [35]. Differences in molecular structure, central nervous system penetration, disease stage, exposure and trial design preclude broad class-level conclusions; nevertheless, the negative phase 3 result challenges the assumption that metabolic or inflammatory signals necessarily predict clinical neuroprotection.

In Alzheimer’s disease, the ELAD phase 2b study of liraglutide reported effects on brain glucose metabolism and on specific structural and cognitive measures, but did not show clear evidence of reduced clinical progression [36]. The large EVOKE and EVOKE+ phase 3 studies of oral semaglutide in early symptomatic Alzheimer disease failed to meet their primary clinical efficacy endpoint, even though they showed changes in several disease biomarkers [37]. To date, no GLP-1 receptor agonist is approved for the prevention or treatment of a neurodegenerative disease.

Alcohol use disorder and reward-related conditions

In a phase 2 randomised trial of 48 adults with alcohol use disorder, low-dose semaglutide decreased laboratory-based alcohol self-administration, alcohol craving and certain weekly drinking metrics compared with placebo [38]. Given the small sample size, limited treatment duration, no assessment of sustained abstinence and lack of alcohol-related morbidity and mortality, the conclusions should be treated with caution. In a different randomised trial, once-weekly exenatide was no more effective than placebo in decreasing the number of heavy drinking days among the overall population of adults with alcohol use disorder, although a secondary analysis suggested a potential benefit among individuals with obesity [39]. The use of GLP-1 receptor agonists in the context of other addictive disorders (nicotine, stimulants, opioids, gambling, etc.) has not yet been sufficiently investigated to recommend their clinical use.

Polycystic ovary syndrome and reproductive outcomes

Women with PCOS more frequently have obesity and insulin resistance and face an increased lifetime risk of cardiometabolic disease. A randomised placebo-controlled trial found that liraglutide 3 mg reduced body weight and androgen measures in women with obesity and PCOS [40]. Long-term follow-up of a randomised trial comparing exenatide with metformin in infertile women with overweight or obesity found a higher spontaneous pregnancy rate after initial exenatide treatment but no significant difference in the overall pregnancy rate after subsequent infertility treatment [41]. One systematic review and meta-analysis suggested improvements in body weight and menstrual cyclicity across a small number of studies of GLP-1 receptor agonists, although limitations arising from heterogeneity, short duration, and minimal pregnancy safety data warranted low confidence [42]. These agents are not indicated for PCOS or for weight loss during pregnancy and should be discontinued before planned conception in accordance with product labelling.

Next-generation agonists and oral therapies

With oral and multi-receptor agents in development, the therapeutic scope of incretin-based therapies is likely to continue expanding. For example, in OASIS 1, oral semaglutide at a dose of 50 mg was associated with a mean weight loss of 15.1% at 68 weeks, compared with 2.4% with placebo, in adults with overweight or obesity without diabetes [43]. This treatment was recommended for marketing approval for chronic weight management in Europe by the European Medicines Agency’s Committee for Medicinal Products for Human Use in May 2026, but availability will be subject to national regulation [44].

Another agent, retatrutide, has combined effects at the GIP, GLP-1 and glucagon receptors; a phase 2 obesity trial demonstrated a mean weight loss of up to 24.2% with the highest dose after 48 weeks (phase 3 morbidity and mortality outcomes have not yet been reported) [45]. Orforglipron, an oral, nonpeptide GLP-1 receptor agonist, achieved dose-dependent weight loss up to approximately 14.7% after 36 weeks in a phase 2 study [46].

The cagrilintide–semaglutide combination comprises a long-acting amylin analogue administered with semaglutide. In REDEFINE 1, the combination produced mean weight loss of approximately 20% in adults with overweight or obesity without diabetes - significantly more than either component alone - although gastrointestinal tolerability and treatment discontinuation remained concerns [47]. Other agents in development include dual GLP-1/glucagon receptor agonists, biased GLP-1 receptor agonists and combinations designed to preserve lean body mass. Whether greater short-term weight loss translates into improved long-term cardiovascular, kidney, hepatic or functional outcomes remains uncertain. The designs and principal findings of pivotal randomized trials are summarized in Table 2.

Safety, tolerability and peri-procedural management

Decreased appetite and energy intake are expected pharmacodynamic effects. A controlled trial of semaglutide reduced ad libitum energy intake, hunger and food cravings and increased fullness [48]. Nausea, diarrhoea, vomiting, constipation, abdominal pain and dyspepsia are common in obesity trials. Symptoms usually occur early in treatment or during dose escalation and may lead to dehydration, acute kidney injury in predisposed patients, temporary treatment interruption or treatment discontinuation.

Gallbladder disorders occur more frequently after rapid or substantial weight loss and are included in product information. Pancreatitis is an infrequently observed but labelled adverse event. Patients with significant gastrointestinal symptoms or signs of gastroparesis, obstruction or gallbladder disease should undergo appropriate clinical assessment. A pharmacoepidemiologic study reported an elevated frequency of selected gastrointestinal symptoms in users of GLP-1 agonists for the treatment of obesity; however, limited sample size and residual confounding precluded firm causal conclusions [49].

Multisociety guidance on peri-procedural management advises against routine discontinuation in all patients and recommends an individualised risk-benefit assessment. Risk may be increased in patients with active gastrointestinal symptoms, recent dose escalation, higher doses or comorbidities that delay gastric emptying. Risk-reduction strategies include a pre-procedural liquid diet, modifications to anaesthetic management, point-of-care gastric ultrasonography and postponement in selected patients [50]. The European Medicines Agency classified non-arteritic anterior ischaemic optic neuropathy as a very rare adverse effect of semaglutide, potentially affecting up to 1 in 10,000 treated people [51]. In January 2026, following a review, the United States Food and Drug Administration requested the removal of warning language concerning suicidal behaviour and ideation from the labelling of weight-management GLP-1 receptor agonists [52].

Product labels state that semaglutide and tirzepatide should not be used in individuals with a personal or family history of medullary thyroid carcinoma or multiple endocrine neoplasia syndrome type 2. The risk of hypoglycaemia is low during monotherapy but increases when these agents are combined with insulin or sulfonylureas. Factors requiring individualised consideration include pregnancy, severe GI disease, frailty, sarcopenia risk, eating disorders, active gallbladder disease, and complex polypharmacy. Clinical practice guidelines suggest slow titration, optimal nutrition, sufficient protein, resistance training and assessment of functional status during substantial weight loss [53]. Practical safety and monitoring considerations are presented in Table 3.

DISCUSSION

Comparative clinical significance across disease domains

The clinical significance of the evidence differs by outcome type. Cardiovascular event reduction represents a hard morbidity endpoint, whereas heart-failure, sleep-apnoea and knee-osteoarthritis trials primarily establish benefits in symptoms, function or validated physiological measures. Liver trials demonstrate histological improvement, but confirmation that these changes reduce decompensation, transplantation or mortality is still required. Kidney evidence is strongest in people with type 2 diabetes and chronic kidney disease, with supportive but less definitive data in populations without diabetes [20, 22-33].

These distinctions matter because a statistically positive result does not automatically establish disease modification, broad class efficacy or applicability to all phenotypes. Benefits observed in obesity-related heart failure with preserved ejection fraction, obstructive sleep apnoea and knee osteoarthritis should not be extrapolated to heart failure with reduced ejection fraction, sleep apnoea without obesity, lean osteoarthritis or other joints. Likewise, accelerated regulatory approval based on histology should be separated from proof of long-term clinical-event benefit. Clinical claims should therefore reflect the endpoint tested, the population enrolled, the duration of follow-up and whether findings have been replicated.

Weight-mediated and potentially weight-independent effects

Many benefits are likely mediated primarily by reductions in total and visceral adiposity. Loss of visceral and ectopic fat can improve insulin sensitivity, blood pressure, ventricular loading, respiratory mechanics, hepatic steatosis and joint loading. The association between the magnitude of weight loss and symptom improvement supports this interpretation [10, 15, 22-24, 31, 33].

Nevertheless, in SELECT, cardiovascular event curves diverged during sustained treatment, and data from FLOW and earlier cardiovascular outcome trials suggest that additional haemodynamic, inflammatory or vascular mechanisms may also contribute [5-9, 20, 26]. In several human tissues, direct GLP-1 receptor expression remains uncertain, and receptor localisation reported in nonclinical studies cannot be directly generalised to clinical settings [1-4]. Future mediation analyses should quantify the proportions of individual organ outcomes explained by total weight reduction, loss of visceral adiposity, glycaemic changes, blood-pressure changes, inflammatory biomarkers and other potential mediators. Head-to-head trials of agents producing different degrees of fat loss would provide valuable evidence but should be powered for clinical rather than surrogate outcomes.

Limits of extrapolation in preliminary and investigational indications

Evidence becomes substantially less certain when studies are small, short, exploratory or dependent on biomarkers and secondary endpoints. The contrasting Parkinson disease programmes and the negative phase 3 Alzheimer trials show that biological plausibility, central nervous system biomarker changes and early-phase signals cannot be assumed to represent a class effect or clinical disease modification [34-37]. Molecule-specific pharmacology, brain penetration, disease stage and trial design may all influence results, but these explanations require prospective testing rather than post hoc attribution.

Alcohol use disorder and polycystic ovary syndrome are supported by limited and heterogeneous trials that were not designed to establish durable abstinence, alcohol-related morbidity, fertility outcomes or pregnancy safety [38-42]. These therapies may still be appropriate when a patient independently meets criteria for an approved obesity or diabetes indication, but current evidence does not justify prescribing solely for these investigational conditions.

Next-generation oral, dual, triple and combination therapies should also be judged separately from established GLP-1 receptor agonists. Large short-term reductions in body weight are promising, but they do not substitute for comparative evidence on cardiovascular, kidney, hepatic, functional and long-term safety outcomes [43-47].

Patient selection and integration into specialist care

The expanding evidence base supports a phenotype-guided approach to the use of GLP-1-based therapies. In adults with overweight or obesity, established cardiovascular disease and no diabetes, semaglutide may be considered to reduce the risk of major adverse cardiovascular events [20, 21]. In patients with obesity-related heart failure with preserved ejection fraction, semaglutide may improve symptoms, physical limitations and exercise capacity, whereas tirzepatide has also been shown to reduce the risk of worsening heart failure or cardiovascular death [22-24]. Treatment should be integrated into the overall management of heart failure and should take account of the individual clinical phenotype, contraindications, tolerability, regulatory status and access.

Tirzepatide may be considered in adults with obesity and moderate-to-severe obstructive sleep apnoea [31, 32]. However, pharmacological treatment should not be regarded as an immediate substitute for positive airway pressure therapy. The need for continued positive airway pressure should be reassessed objectively after treatment and weight reduction.

In patients with noncirrhotic MASH and moderate-to-advanced fibrosis, semaglutide has demonstrated histological benefit, whereas tirzepatide has shown favourable phase 2 results [28-30]. Treatment decisions should take account of fibrosis stage, the presence of cirrhosis, associated cardiometabolic disease and the limitations of the available evidence.

Multidisciplinary care may involve primary care physicians, obesity specialists, dietitians, cardiologists, hepatologists, nephrologists, sleep specialists and anaesthetists. During substantial weight loss, particular attention should be paid to nutritional intake, hydration, muscle strength and physical function, especially in older adults and patients with frailty, chronic kidney disease, malabsorption or low baseline muscle mass. Adequate protein intake and resistance exercise should be encouraged when clinically appropriate [53].

Duration, discontinuation and long-term safety

Withdrawal trials consistently demonstrate weight regain, showing that pharmacotherapy suppresses but does not eliminate the biological mechanisms driving obesity. This should not be interpreted as medication addiction but as evidence of the chronic, relapsing nature of obesity. Before treatment, patients should be informed about the likely need for long-term therapy, possible dose adjustments and the risk of weight regain and recurrence of comorbidities after discontinuation [11, 13, 17].

The long-term effects and risks of decades of exposure, substantial weight loss, repeated treatment cessation, pregnancy, changes in bone health, functional outcomes in older adults and loss of lean body mass remain incompletely defined and may vary by population and outcome measure. Trials should include body composition, muscle strength and physical function as secondary outcomes or, where appropriate, primary endpoints [12, 18, 20, 24].

Peri-procedural management should be individualised. Universal discontinuation may worsen glycaemia, disrupt obesity treatment and compromise continuity of care, whereas continued treatment may increase anaesthetic risk in patients undergoing recent dose escalation or experiencing significant gastrointestinal symptoms because of increased residual gastric contents. Shared decision-making should consider the procedure, anaesthetic plan, symptoms, treatment phase and local availability of point-of-care gastric ultrasonography [50].

Regulatory status, access and equity

Regulatory authorisation of GLP-1-based therapies varies across regions, products and specific obesity-related indications [21, 29, 32, 44]. Access may also be limited by high treatment costs, reimbursement restrictions, supply shortages and differences in healthcare infrastructure. These factors may delay treatment initiation, interrupt treatment continuity or lead to premature discontinuation for reasons unrelated to efficacy or tolerability.

The conditions under which these therapies were evaluated in clinical trials may differ substantially from routine care. Trial participants generally receive structured follow-up, gradual dose titration, dietary counselling and regular assessment of adverse effects, whereas these resources may be less consistently available in clinical practice. These differences should be considered when interpreting treatment persistence, tolerability and effectiveness outside clinical trials.

Because obesity is a chronic disease characterised by persistent biological mechanisms promoting weight regain, interruption of effective treatment may be followed by recurrence of excess weight and associated cardiometabolic abnormalities [11, 13, 17]. Continuity of access is therefore relevant not only to adherence but also to the durability of clinical benefit.

Cardiovascular and heart-failure outcome trials have strengthened the clinical rationale for treatment in selected high-risk phenotypes [20, 24]. However, extension of treatment to broader populations should be based on clearly demonstrated clinical benefit, baseline cardiometabolic risk, disease phenotype, safety, feasibility of long-term therapy and responsible allocation of healthcare resources.

Pharmacological treatment should complement, rather than replace, nutritional management, physical activity and other established components of comprehensive obesity care [53]. Wider population-level measures aimed at preventing obesity and reducing inequalities in access to treatment remain necessary.

Future research priorities

Clinical outcomes trials of next-generation compounds are essential, rather than inferences based solely on the magnitude of weight loss. Such trials should evaluate cardiovascular, kidney, hepatic, functional and long-term safety outcomes for retatrutide, orforglipron and the cagrilintide–semaglutide combination [43-47]. Further studies should determine the optimal sequencing or combination of incretin-based therapies with sodium–glucose cotransporter-2 inhibitors, mineralocorticoid receptor antagonists, lipid-lowering therapies, positive airway pressure, bariatric surgery and liver-directed treatments.

Predictive biomarkers of treatment response and intolerance should be developed using baseline eating patterns, visceral adiposity, fibrosis stage, kidney function, heart-failure phenotype, gastrointestinal symptoms, age, sex, ethnicity, genetic variation and previous weight-cycling patterns. Predictive models should undergo independent validation and demonstrate incremental value beyond established clinical risk factors.

Hypotheses concerning neurological effects and addiction require adequately powered trials using clinically relevant cognitive, functional and behavioural endpoints [34-39]. The negative phase 3 Alzheimer programme illustrates that retrospective observations and biomarker changes cannot substitute for clinical outcomes.

Finally, future trials should include patient-reported outcomes, treatment burden, adherence and discontinuation patterns, body composition, nutritional status, physical capacity, fertility, pregnancy planning and access to treatment [40-42].

Limitations

This review has several methodological and evidence-related limitations. As it was designed as a narrative rather than a systematic review, study selection and evidence weighting were performed by the authors, and formal risk-of-bias assessment and meta-analysis were not undertaken. The literature search was restricted to English-language publications and included PubMed/MEDLINE, the Cochrane Library, selected journal platforms, ClinicalTrials.gov and United States and European regulatory websites. Relevant studies indexed elsewhere or published after 10 July 2026 may therefore not have been identified.

The available evidence is highly heterogeneous. The therapies evaluated differ in molecular structure, receptor profile, dose, titration regimen and central nervous system penetration. Study populations also differ in diabetes status, degree of obesity, cardiovascular risk, fibrosis stage, age and background treatment. Outcomes range from histological and physiological measures to symptoms, biomarkers, physical function and major clinical events. Several investigational indications are supported only by small phase 2 trials, secondary analyses or limited sample sizes.

In several clinical domains, the magnitude of improvement appeared to be associated with the degree of weight loss. However, it is often not possible to distinguish weight-mediated effects from direct pharmacological effects. In addition, the structured monitoring, adherence support and lifestyle counselling provided in clinical trials may limit the generalisability of persistence, tolerability and effectiveness findings to routine clinical practice. Regulatory status also varies by country and may change over time.

Evidence remains limited regarding long-term changes in lean mass, frailty, bone health, pregnancy outcomes, treatment extending beyond several years and the consequences of repeated treatment interruption.

Given these limitations, class effects should not be assumed, and findings should not be extrapolated to unstudied populations, agents or investigational indications.

CONCLUSIONS

Robust randomised evidence supports chronic weight management, reduction in the risk of progression to type 2 diabetes during active treatment in people with obesity and prediabetes, cardiovascular risk reduction in adults with overweight or obesity and established cardiovascular disease, and clinically relevant benefits in obesity-related heart failure with preserved ejection fraction and moderate-to-severe obstructive sleep apnoea. However, the durability of diabetes-risk reduction after treatment discontinuation remains uncertain.

Histological benefits have also been demonstrated in metabolic dysfunction-associated steatohepatitis with fibrosis, but it has not yet been established whether these changes translate into lower rates of cirrhosis, hepatic decompensation, transplantation or liver-related mortality. In obesity-associated knee osteoarthritis, one phase 3 trial showed improvements in pain and physical function, without establishing structural modification of joint disease. In patients with type 2 diabetes and chronic kidney disease, semaglutide reduced the risk of major kidney outcomes, whereas evidence in non-diabetic kidney disease remains less complete.

Evidence for Parkinson disease and Alzheimer disease is inconsistent or negative, while evidence for alcohol use disorder and polycystic ovary syndrome remains preliminary and does not support disease-specific use. Retatrutide, high-dose oral semaglutide for obesity, orforglipron and cagrilintide-semaglutide combinations have demonstrated substantial weight-loss efficacy, but their long-term cardiovascular, kidney, hepatic and functional outcomes have not yet been established.

Long-term safety, durability of benefit after treatment discontinuation, preservation of muscle mass and physical function, and equitable access to continuous therapy remain unresolved. Future organ-specific indications should therefore be supported by reproducible clinical outcomes in clearly defined populations rather than by mechanistic plausibility, biomarker changes or the magnitude of weight loss alone.

DISCLOSURE

Author Contributions

Conceptualization: Anna Szeszko. Methodology: Magdalena Cichorzewska. Data curation: Małgorzata Lubowiecka. Formal analysis: Rafał Wojtan. Writing, original draft: Martyna Płachta. Writing, review and editing: Weronika Czernek. Supervision: Anna Szeszko.

All authors reviewed and approved the final version of the manuscript and accept responsibility for its content.

Funding

The authors received no specific funding for this work.

Conflicts of Interest

The authors declare no conflicts of interest.

Use of Artificial Intelligence

Generative artificial intelligence was used to assist with language drafting, structural organisation, and editorial refinement. It was not used to generate scientific data or perform statistical analyses. The authors independently verified the cited evidence, critically revised the manuscript, and remain fully responsible for its accuracy, originality, and conclusions.

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