Review
This narrative review compared tirzepatide (a dual GIP/GLP-1 receptor agonist) and semaglutide (a selective GLP-1 receptor agonist) across weight loss, glycemic control, cardiometabolic, and safety outcomes by synthesizing evidence from clinical trials, real-world observational studies, and cardiovascular outcome analyses. The authors found that in completed head-to-head randomized trials, tirzepatide consistently produced greater reductions in body weight and HbA1c compared with semaglutide in people with obesity or type 2 diabetes. Regarding cardiovascular outcomes, the review noted that semaglutide currently holds the most mature evidence for cardiovascular risk reduction, supported by the SUSTAIN-6, PIONEER-6, and SELECT trials. Tirzepatide's SURPASS-CVOT trial demonstrated non-inferiority to dulaglutide for cardiovascular outcomes along with improvements in cardiometabolic risk factors, but direct cardiovascular superiority data versus semaglutide remain limited. Real-world studies on cardiovascular outcomes were characterized as heterogeneous. The authors concluded that treatment selection should be individualized. Key limitations include the narrative (non-systematic) methodology, potential for selection bias in literature inclusion, and the absence of a completed direct head-to-head cardiovascular outcomes trial between the two agents.
Frontiers in medicine · Apr 2026DOI ↗ Limited · human
This large-scale observational study used a federated biomedical data platform to analyze 135,349 individuals treated with GLP-1 receptor agonists (GLP-1RAs) — specifically semaglutide (Wegovy) and tirzepatide (Zepbound) formulations — to characterize differences between "super responders" (>15% weight loss), "moderate responders" (5–15% weight loss), and a "minimal weight-loss" group. The study found substantial heterogeneity in weight-loss outcomes across patients receiving the same therapies. Notably, super responders to Zepbound showed reduced risk of developing certain comorbidities, including conditions at relative risks as favorable as 0.5 for osteoarthritis (P = .001), while Wegovy super responders showed an association with psoriasis (RR = 2.5, P = .03). The authors conclude that differences in weight trajectories likely reflect a combination of biological, behavioral, and social factors. Key limitations include the observational, retrospective design (which cannot establish causation), the reliance on federated real-world data (subject to coding variability), and lack of randomization. The authors call for prospective studies to develop more individualized weight-loss strategies.
Biology methods & protocols · Apr 2026DOI ↗ Limited · human
This real-world observational study examined weight trajectories in 4,182 patients during the 6 months following their last documented semaglutide or tirzepatide prescription, drawn from a federated health network. The study found that approximately two-thirds of the full cohort showed stable weight or continued weight loss after their final prescription. In a representative subset of 300 patients whose clinical notes were analyzed using a large language model (LLM), treatment discontinuation was confirmed in 119 patients (40%), and of those, 72% did not demonstrate weight regain. The study also noted that exercise counseling was documented more frequently among patients who maintained weight loss compared to those who experienced weight regain (26.2% vs. 14.7%; P = .04). Key limitations include the observational and retrospective design, reliance on documented prescriptions rather than confirmed medication use, potential incompleteness of clinical records, use of an LLM for data curation introducing possible inaccuracies, and the inability to establish causation. The authors acknowledge that further studies are needed to understand the mechanisms behind these real-world patterns of weight maintenance after GLP-1 receptor agonist discontinuation.
Biology methods & protocols · Apr 2026DOI ↗ Review
This systematic review (PRISMA-compliant, PROSPERO-registered) examined the association between GLP-1 receptor agonists (GLP-1 RAs) and hair loss by searching four major databases (PubMed, Embase, Scopus, Web of Science). Of 133 studies identified, 24 met inclusion criteria as primary articles. The review found that semaglutide and tirzepatide showed the highest reported incidence of hair loss and the strongest pharmacovigilance signals among GLP-1 RAs. The predominant subtypes reported were androgenetic alopecia and telogen effluvium, with telogen effluvium most frequently linked to tirzepatide—the agent associated with the greatest magnitude of weight loss. The authors noted that hair loss with semaglutide appeared dose-dependent, and that females were disproportionately affected. Rapid weight loss was identified as a potential contributing mechanism, especially for telogen effluvium. Other agents—liraglutide, dulaglutide, lixisenatide, and exenatide—had fewer studies and generally lower reported risk. Key limitations include the reliance on pharmacovigilance data and heterogeneous study designs, which preclude definitive causal conclusions. The authors call for large, prospective randomized trials to establish causality and temporal relationships.
Science progress · Apr 2026DOI ↗ InsufficientPreprint
This narrative review examines the pharmacogenomics of GLP-1 receptor agonists — principally semaglutide (Ozempic®/Wegovy®) and the dual GIP/GLP-1 agonist tirzepatide (Mounjaro®/Zepbound®) — with a focus on explaining the wide inter-individual variability in efficacy and tolerability observed in clinical practice. The authors synthesise evidence around key genetic loci, including GLP1R, GIPR, ARRB1, TCF7L2, and MC4R, and highlight a purported April 2026 genome-wide association study (GWAS) conducted by 23andMe (n=27,885) as the largest pharmacogenomic study of GLP-1 therapies to date. The review also surveys the competitive landscape among Novo Nordisk, Eli Lilly, 23andMe Research Institute, and PGxAI, and dedicates substantial attention to South Asian and Indian populations, arguing that their large diabetes burden and undercharacterised pharmacogenomic profiles represent a critical gap. The authors conclude that GLP-1 pharmacogenomics has advanced from exploratory science toward actionable clinical discovery. Limitations include the narrative (non-systematic) design, reliance on a preprint-stage GWAS of uncertain peer-review status, and the absence of prospective clinical validation data for genotype-guided prescribing.
Unknown journal · Apr 2026DOI ↗ Review
This systematic review, conducted according to PRISMA 2020 guidelines, synthesized evidence from 15 studies evaluating GLP-1 receptor agonist and dual incretin-based pharmacotherapies for obesity management, including semaglutide, liraglutide, tirzepatide, dulaglutide, and dual GIP/GLP-1 receptor agonists. Study participants were predominantly female (up to 79.3%), ranging in mean age from 22.4 to 59.8 years, with BMIs between 29.3 and 43.0 kg/m², and frequent comorbidities such as type 2 diabetes, hypertension, dyslipidemia, and cardiovascular disease. The review found that weight loss was dose-dependent across agents, with dual GIP/GLP-1 therapy showing the greatest reductions. Cardiometabolic outcomes included reductions in HbA1c, systolic blood pressure, and LDL cholesterol across therapies. Gastrointestinal adverse events — particularly nausea, vomiting, and diarrhea — were commonly reported but generally mild, while serious events such as pancreatitis and gallbladder complications were rare. Treatment discontinuation rates were described as generally low. Limitations include the heterogeneity of included studies, variability in populations, and the review's reliance on previously published trial data rather than original participant-level analysis.
Disease-a-month : DM · Apr 2026DOI ↗ Animal only
This preclinical study investigated whether obesity could be reversed without activating the GLP-1 receptor (GLP-1R), which is commonly associated with adverse gastrointestinal side effects in current therapies. Using diet-induced obese (DIO) mice and rats, as well as GLP-1R knock-out (KO) mice, researchers tested selective, dual, and triple agonists targeting the GIP receptor (GIPR), glucagon receptor (GCGR), and GLP-1R in various combinations. Three independent experimental approaches — (1) administering the triagonist retatrutide to GLP-1R KO mice, (2) physically combining separate selective GIPR and GCGR agonists, and (3) testing a novel unimolecular GIPR:GCGR co-agonist called BWB3054 — all demonstrated meaningful reductions in body weight and improvements in blood glucose without meaningful GLP-1R engagement. BWB3054 showed potency at the mouse GIPR comparable to retatrutide, 4-fold reduced potency at the mouse GCGR, and more than 100-fold reduced potency at the mouse GLP-1R. Indirect calorimetry and pair-feeding studies were used to characterize mechanisms of weight loss. A key limitation is that all experiments were conducted in rodents, leaving the translatability of these findings to humans uncertain. The study raises the possibility that GLP-1R-independent obesity treatment strategies could avoid the GI tolerability issues seen with current agents.
Molecular metabolism · Apr 2026DOI ↗ Limited · human
This multicenter retrospective cohort study used the TriNetX database to examine whether preoperative exposure to GLP-1 receptor agonists (GLP-1 RAs) was associated with postoperative GLP-1 RA use following metabolic bariatric surgery (MBS). Researchers identified adults who underwent MBS and applied 1:1 propensity score matching to compare those with and without preoperative GLP-1 RA exposure (n = 2,811 per group). The study found that patients with prior GLP-1 RA exposure had more than twice the rate of postoperative GLP-1 RA initiation (15.3% vs. 7.6%; HR: 2.14, 95% CI: 1.81–2.52). The exposure group also showed a modestly higher prevalence of suboptimal weight control post-surgery (HR: 1.18), though rates of suboptimal glycemic control, hospitalization, and emergency department visits did not differ significantly between groups. These patterns were consistent across surgical subtypes and age groups. The authors interpret the findings as identifying a distinct patient phenotype with greater treatment complexity rather than a direct causal relationship. Key limitations include the retrospective design, reliance on a claims-based database, and potential residual confounding despite propensity score matching.
Obesity surgery · Apr 2026DOI ↗ Limited · human
This systematic review examined the effects of GLP-1 receptor agonists (GLP-1 RAs) on patients with hidradenitis suppurativa (HS), a chronic, painful inflammatory skin condition often associated with obesity and metabolic syndrome. Researchers searched Embase and PubMed, screening 300 papers and ultimately including 10 studies in the final analysis. The review found that HS patients using GLP-1 RAs tended to experience improvements in clinical course, including reductions in pain and suppuration, as well as improvements in quality of life and mental health. Cardiovascular risk markers also appeared to improve. Notably, inflammatory laboratory parameters did not show statistically significant changes. Higher drug doses were more frequently associated with clinical improvement, while reductions in weight or BMI did not consistently correlate with improvements in Hurley staging, pain, or depression scores. The authors suggest this raises the possibility that GLP-1 RAs may act through direct anti-inflammatory mechanisms beyond weight loss alone, though they acknowledge this remains unresolved. Key limitations include the small number of included studies (10), likely heterogeneous study designs across the included papers, and the inability to establish causality or rule out confounding. The authors call for further dedicated studies to clarify the mechanism of benefit.
Journal of clinical medicine · Apr 2026DOI ↗ Strong · human
This network meta-analysis pooled data from 11 randomized controlled trials (n = 83,215) to compare the cardiovascular (CV) efficacy and safety of GLP-1 receptor agonists (GLP-1RAs) in adults with type 2 diabetes and established cardiovascular disease or high CV risk. Trials were identified through a systematic search of five major databases up to December 2025. Using a frequentist random-effects framework, the authors found that several GLP-1RAs — including subcutaneous semaglutide, efpeglenatide, albiglutide, tirzepatide, oral semaglutide, liraglutide, and dulaglutide — significantly reduced three-point major adverse cardiovascular events (MACE) compared with placebo, with no detected heterogeneity or inconsistency. Subcutaneous semaglutide, efpeglenatide, and albiglutide ranked highest by P-score. No agent significantly reduced all-cause or CV mortality versus placebo. Tirzepatide and dulaglutide were associated with reduced stroke risk. Tolerability signals showed higher rates of discontinuation due to gastrointestinal adverse events with subcutaneous semaglutide, oral semaglutide, lixisenatide, and ITCA 650. The authors concluded that MACE reduction is the most consistent efficacy signal across GLP-1RAs in this population. Limitations include the indirect nature of network comparisons and differing trial designs and populations across included studies.
Canadian journal of diabetes · Apr 2026DOI ↗ 🧪 TrialInsufficient
Registered N/A interventional trial (recruiting). This pilot study will evaluate the feasibility, acceptability, and perceived usefulness of the SWITCH mobile nutrition behavioral intervention among adults receiving GLP-1 receptor agonist therapy for obesity and/or type 2 diabetes. Participants will complete baseline assessments, receive a 6-week app-based nutrition intervention consisting of daily dietary self-monitoring and weekly learning modules, and complete follow-up assessments and a structured interview.
ClinicalTrials.gov · Apr 2026View trial ↗ Moderate · human
This large genome-wide association study (GWAS) investigated whether genetic variants explain why people respond differently to GLP-1 receptor agonists (GLP-1 RAs) such as semaglutide and tirzepatide. Researchers analyzed self-reported weight loss and side effects in 27,885 individuals on GLP-1 RA therapy. The study identified a missense variant in the GLP1R gene significantly associated with greater weight loss efficacy, with carriers of the effect allele losing an additional estimated 0.76 kg per copy. Separate genetic associations were found linking variants in both GLP1R and GIPR to nausea or vomiting during GLP-1 RA treatment; notably, the GIPR association appeared specific to tirzepatide users, consistent with tirzepatide's dual GLP-1/GIP receptor mechanism. The authors built a broader predictive model incorporating these findings, suggesting the potential to stratify patients by expected efficacy and side effect risk—a step toward precision medicine for obesity. Key limitations include reliance on self-reported outcomes, which may introduce recall and reporting bias, and the observational nature of the design, which limits causal inference beyond the genetic associations themselves.
Review
This narrative review examines the skeletal consequences of modern obesity treatments, particularly glucagon-like peptide-1 receptor agonists (GLP-1RAs) and bariatric/metabolic surgery. The authors challenge the historical assumption that obesity is bone-protective due to mechanical loading, citing emerging evidence of qualitative bone deterioration and site-specific fracture risks in individuals with obesity. The review synthesizes findings showing that intentional weight loss via caloric restriction or bariatric surgery consistently accelerates bone turnover and reduces bone mineral density (BMD), with surgical approaches carrying the most pronounced skeletal impact. Regarding GLP-1RAs, the authors report that available data suggest modest BMD declines largely proportional to the degree of weight loss, potentially driven by mechanical unloading. Interestingly, the review also notes that preclinical studies suggest GLP-1 signaling may have direct osteoanabolic and anti-resorptive properties, though these effects remain to be confirmed in humans. The authors recommend integrating resistance exercise, adequate calcium, vitamin D, and protein intake, and skeletal monitoring for high-risk patients into obesity care. Limitations include reliance on heterogeneous primary literature and the absence of long-term fracture outcome data for newer pharmacological agents.
Endocrinology and metabolism (Seoul, Korea) · Apr 2026DOI ↗ Animal only
This animal study compared the anti-atherosclerotic effects of tirzepatide (a dual GIP/GLP-1 receptor agonist) and semaglutide (a selective GLP-1 receptor agonist) in ApoE knockout mice. Mice were treated with streptozotocin to induce diabetes and divided into early diabetes, late diabetes, and non-diabetic groups, each receiving either agent or saline for 12 weeks. The study found that in the early diabetes group, both tirzepatide and semaglutide significantly reduced aortic plaque formation compared to controls, with modest improvements in blood glucose and lipid levels. No significant vascular effects were observed in the late diabetes or non-diabetic groups in terms of plaque reduction. Tirzepatide more broadly reduced inflammatory markers—including Mcp-1, Il-6, I-cam, and Cd68—compared to semaglutide. Anti-inflammatory effects were also detected in non-diabetic mice, suggesting possible vascular protective mechanisms independent of metabolic control. The authors conclude that dual incretin receptor agonism may offer cardiovascular benefits, though the specific contribution of GIP signaling requires further investigation. Key limitations include the use of an animal model, which may not translate directly to human cardiovascular disease.
Scientific reports · Apr 2026DOI ↗ Review
This comprehensive review examines the genetic underpinnings of obesity and the evolving landscape of pharmacological treatment informed by genetic insights. The authors distinguish between rare monogenic obesity — driven by mutations in single genes such as LEP, POMC, and MC4R within the leptin-melanocortin neuroendocrine signaling pathway — and common polygenic obesity, which results from the cumulative small effects of hundreds of genetic variants, including loci identified through genome-wide association studies (GWAS) such as FTO and SEC16B. The review also discusses how gene-environment interactions contribute to the heterogeneity of obesity phenotypes. On the pharmacotherapy side, the authors highlight recent advances including GLP-1 receptor agonists and dual/triple incretin agonists, noting their reported efficacy across diverse genetic backgrounds. The potential clinical utility of polygenic risk scores for early risk identification and prevention is explored. Limitations of this paper include its nature as a narrative review — it synthesizes existing literature rather than generating new empirical data — and it does not perform a systematic or meta-analytic evaluation. The authors acknowledge ongoing challenges in integrating genomic data into clinical practice and call for further research into genetic screening protocols and gene-environment interactions to advance precision medicine in obesity management.
Acta biochimica Polonica · Apr 2026DOI ↗ Review
This narrative review examines the expanding therapeutic landscape of glucagon-like peptide-1 receptor agonists (GLP-1 RAs) beyond their established roles in glycemic control and the metabolic-cardiovascular-renal axis. The authors searched PubMed, Scopus, and Google Scholar for publications from 2014 to 2026, with over 80% of included studies published between 2020 and 2026. The review synthesizes findings across a broad range of conditions, reporting associations between GLP-1 RA use and potential benefits in substance use disorders, mental health disorders, neurodegenerative diseases, liver disease (including reduced hepatic steatosis and lower risk of hepatocellular carcinoma), genitourinary disorders, polycystic ovary syndrome (PCOS), male fertility and libido, prostate cancer, osteoarthritis, and sleep apnea. The authors note that GLP-1 RAs currently represent the most effective pharmacological agents for obesity treatment. Key limitations include the narrative (non-systematic) review design, which is susceptible to selection bias, and the authors' own acknowledgment that much of the supporting evidence is preliminary, requiring further large-scale, well-designed clinical trials to establish efficacy and safety across these emerging indications.
Journal of clinical medicine · Apr 2026DOI ↗ Review
This review examines the acute contractile effects of glucagon-like peptide-1 receptor (GLP-1R) agonists on the human heart, with a focus on isolated atrial and ventricular cardiac preparations from both failing and non-failing hearts. The paper discusses how GLP-1R stimulation in cell cultures, neonatal cardiomyocytes, and adult atrial cardiomyocytes elevates adenylyl cyclase activity and increases cAMP levels, a key intracellular signaling pathway. The authors explore the expanding landscape of receptor agonists — including single GLP-1R agonists as well as dual and triple agonists targeting the glucagon receptor (GCGR) and/or the GIP receptor (GIPR) — in the context of treating type 2 diabetes, obesity, liver disease, and cardiovascular conditions. GLP-1R expression across different cardiac regions of the human heart is also reviewed. The paper critically evaluates existing experimental and clinical data, notes that several newer agents remain in early clinical development phases, and identifies gaps requiring further research. A key limitation is that the review synthesizes heterogeneous experimental and early-phase clinical data rather than presenting original controlled trial findings, limiting the strength of conclusions about cardiac efficacy or safety in humans.
Pharmaceutics · Apr 2026DOI ↗ Strong · human
This systematic review and network meta-analysis compared the weight-loss efficacy and safety of three FDA-approved agents—tirzepatide (a dual GIP/GLP-1 agonist), semaglutide, and liraglutide—in non-diabetic adults with obesity. Researchers searched four major databases through May 2025 and identified 15 Phase 3 RCTs encompassing 14,059 patients. Using a frequentist random-effects network meta-analysis, the authors found that all three agents produced statistically significant body weight reductions compared to placebo. Ranking by magnitude of effect, the highest tolerated dose of tirzepatide demonstrated the greatest weight reduction, followed by lower tirzepatide doses, then semaglutide, and finally liraglutide. On the safety side, tirzepatide and semaglutide were each associated with a higher risk of any adverse event compared to placebo, while liraglutide was not. The authors note that the analysis was limited to Phase 3 RCTs and did not assess long-term outcomes such as weight regain after discontinuation, metabolic endpoints, cost-effectiveness, or patient preferences, which they identify as priorities for future research.
Obesity (Silver Spring, Md.) · Apr 2026DOI ↗ Moderate · human
This systematic review and meta-analysis pooled data from three head-to-head randomized or controlled trials comparing tirzepatide (a dual GIP/GLP-1 receptor agonist) with semaglutide (a selective GLP-1 receptor agonist) in adults with obesity and/or type 2 diabetes. Studies were identified through searches of PubMed, Embase, and ScienceDirect up to February 2026. Using a random-effects model, the authors found that tirzepatide was associated with significantly greater weight reduction compared to semaglutide (pooled mean difference: −5.19 kg) and a higher likelihood of achieving ≥10% weight loss (pooled risk ratio: 1.50). No statistically significant differences were observed in overall adverse events or gastrointestinal events between the two agents; however, serious adverse events were reported more frequently with tirzepatide (risk ratio: 1.83). Key limitations include a very small number of included studies (n=3), substantial statistical heterogeneity in weight-related outcomes (I² >86%), and insufficient follow-up duration to draw conclusions about long-term cardiovascular safety. The authors note that further studies with longer follow-up are needed to confirm the cardiometabolic safety profile of tirzepatide relative to semaglutide.
Nepal journal of epidemiology · Apr 2026DOI ↗ In vitro
This in vitro study examined the effects of three incretin-based therapies — semaglutide (GLP-1 receptor agonist), tirzepatide (dual GLP-1/GIP agonist), and cagrilintide (amylin analogue) — on mitochondrial function in C2C12 skeletal muscle myotubes under both normal and lipotoxic conditions. Lipotoxicity was induced using palmitic acid (PA), which significantly reduced basal oxygen consumption rate and ATP production in treated cells. The study used Seahorse XFp metabolic flux analysis, mitochondrial DNA copy number quantification (qPCR), and oxidative phosphorylation complex protein expression (western blotting), with key findings replicated in primary human skeletal muscle cells. The researchers found that semaglutide and cagrilintide transiently reduced basal respiration in healthy myotubes, while tirzepatide demonstrated more sustained improvements in mitochondrial respiration under both healthy and lipotoxic conditions. The study's primary limitations include its reliance on cell culture models, meaning findings may not directly translate to whole-organism physiology, and the use of a single lipotoxic stimulus. The partial replication in human primary cells adds some translational relevance, but in vivo validation remains absent.
Journal of cachexia, sarcopenia and muscle · Apr 2026DOI ↗