Review
This narrative review synthesizes evidence on how GLP-1-based therapies (liraglutide, semaglutide, tirzepatide, dulaglutide, exenatide) interact with the gut microbiome and influence metabolic dysfunction-associated steatotic liver disease (MASLD/MASH) in the context of type 2 diabetes mellitus (T2DM). The authors searched PubMed, Scopus, and ClinicalTrials.gov (2015–2026), ultimately including 33 studies (18 preclinical, 15 clinical) out of 363 identified. Preclinical findings suggest liraglutide normalized the Firmicutes/Bacteroidetes ratio and increased beneficial bacteria, while tirzepatide reduced hepatic steatosis and increased Akkermansia abundance in diabetic mice, and semaglutide improved gut barrier integrity in murine models. Clinically, tirzepatide achieved MASH resolution in 44–62% of patients in the phase 2 SYNERGY-NASH trial, and the FDA approved semaglutide for MASH with fibrosis in August 2025 based on the Phase 3 ESSENCE trial. A longitudinal study found baseline microbiome composition predicted glycemic response to semaglutide. Key limitations include the narrative (non-systematic) design, heavy reliance on preclinical data, and heterogeneous study populations. The authors conclude that personalized MASLD management informed by microbiome profiling warrants further dedicated clinical investigation.
Biomedicines · Apr 2026DOI ↗ Review
This narrative review synthesizes evidence from randomized controlled trials, meta-analyses, and observational studies through 2026 to examine the effects of glucagon-like peptide-1 receptor agonists (GLP-1 RAs) and dual incretin-based therapies on a range of ocular outcomes. The authors report that recent meta-analyses indicate an overall neutral long-term risk profile for diabetic retinopathy and macular edema with these agents. They describe a transient early worsening of diabetic retinopathy observed primarily in patients with advanced baseline disease undergoing rapid HbA1c reduction, framing this as a "metabolic transition phenomenon" rather than direct retinal toxicity—an interpretation supported by data from the SELECT trial, in which no increased ocular risk was found in a non-diabetic population. The review also notes observational signals suggesting possible protective associations with glaucoma and age-related macular degeneration, a potential safety concern regarding nonarteritic anterior ischemic optic neuropathy at low absolute incidence, and emerging evidence of benefit in ocular surface homeostasis and uveitis. Limitations include reliance on observational data for several signals and the inherent constraints of a narrative review design. The authors conclude that risk-stratified ophthalmic monitoring, aligned with a cited 2025 expert consensus, is preferable to routine treatment avoidance in high-risk diabetic patients.
Journal of obesity & metabolic syndrome · Apr 2026DOI ↗ Review
This narrative review synthesizes the evolution of incretin-based pharmacotherapies for metabolic disorders, drawing on literature from PubMed, Scopus, and Google Scholar up to July 2025. The authors trace the trajectory from DPP-4 inhibitors—noted for modest glycaemic benefits—through GLP-1 receptor agonists (GLP-1RAs) such as liraglutide and semaglutide, which pivotal trials have associated with meaningful weight loss and cardiometabolic protection, to next-generation agents. Dual GIP/GLP-1 agonist tirzepatide and triple agonist retatrutide are highlighted as demonstrating particularly substantial efficacy, with the review citing up to 24% body weight reduction alongside improvements in hepatic and inflammatory markers in included trials. Agents such as cotadutide and efinopegdutide are discussed in the context of expanding indications to MASLD and MASH. The authors acknowledge several limitations across the field: high cost and accessibility barriers, underrepresentation of low- and middle-income country populations in major trials, and pharmacogenomic variability that may modify therapeutic response. As a review, this paper does not generate new primary data. Its conclusions depend on the quality and representativeness of the underlying trials it synthesizes, and no independent meta-analytic pooling appears to have been conducted.
The Indian journal of medical research · Apr 2026DOI ↗ Review
This review examines the global burden of pediatric obesity and its cardiovascular consequences, drawing on data from PubMed, Scopus, and Springer databases. The authors report that over 381 million children worldwide are affected by obesity, and that childhood obesity substantially increases the risk of adult obesity and cardiovascular diseases (CVD) including atherosclerosis, coronary artery disease, hypertension, dysglycemia, dyslipidemia, arrhythmias, and stroke. The study identifies both genetic contributors (highlighted by genome-wide association studies) and lifestyle drivers such as physical inactivity, prolonged screen time, and poor diet. The authors evaluate public health frameworks including the WHO Global Action Plan on Physical Activity 2018–2030, as well as management strategies spanning lifestyle modification, pharmacotherapy (notably GLP-1 receptor agonists semaglutide and liraglutide), and bariatric surgery. They highlight data from the SURMOUNT-5 trial on tirzepatide and discuss emerging investigational agents including cagrilintide/semaglutide combination, orforglipron, danuglipron, and retatrutide. Gene therapy is noted as experimental. A key limitation is that this is a narrative review without systematic methodology or original data collection, limiting causal inference.
Clinical nutrition ESPEN · Mar 2026DOI ↗ Review
This narrative review examines emerging pharmacological approaches for managing obesity in patients with cardiovascular disease, with a focus on novel anti-obesity agents beyond the already-established semaglutide and tirzepatide. The authors surveyed the current landscape of investigational weight-lowering drugs, categorizing them by their primary mechanisms of action: reducing caloric intake, increasing basal metabolic rate, and increasing muscle mass. The review highlights that GLP-1 receptor agonists (GLP-1 RAs) have demonstrated both significant weight reduction and cardiovascular benefits, but notes a concern regarding muscle wasting associated with their use. The authors suggest that combination therapies using agents with complementary mechanisms may help mitigate this side effect. The review concludes that obesity treatment is likely to become more personalized over time and anticipates further cardiovascular benefits from pipeline agents. The authors also emphasize that the strongest evidence linking increased muscle mass and basal metabolic rate to improved cardiovascular health comes from diet and physical activity, positioning pharmacotherapy as a complement to—rather than a replacement for—healthy lifestyle changes. As a narrative review, this paper does not perform systematic synthesis or meta-analysis, and its conclusions reflect the authors' expert opinion rather than pooled quantitative data.
Biomedicines · Mar 2026DOI ↗ Moderate · human
This retrospective cohort study used the TriNetX global federated electronic health record (EHR) database to compare real-world cardiovascular outcomes between tirzepatide (a dual GIP/GLP-1 receptor agonist) and semaglutide (a GLP-1 receptor agonist) in non-diabetic adults treated for obesity. Patients who initiated either medication between November 2023 and August 2024 were included, with individuals having recent atherosclerotic events, prior heart failure, or treatment crossovers excluded. After 1:1 propensity score matching yielding 35,336 pairs, the study found that tirzepatide was associated with a statistically significantly lower incidence of the composite primary endpoint — all-cause death, acute coronary syndrome, stroke, or new-onset heart failure — at 12 months (1.90% vs. 2.18%; HR 0.86). This difference was primarily driven by a reduction in new-onset heart failure (both reduced and preserved ejection fraction). No significant differences were observed for all-cause mortality, acute coronary syndrome, or stroke individually. Tirzepatide also produced greater mean weight loss. Limitations include the retrospective observational design, reliance on EHR coding accuracy, inability to confirm medication adherence, short follow-up duration, and potential for residual confounding despite propensity matching.
Diabetes, obesity & metabolism · Mar 2026DOI ↗ Review
This narrative review synthesized evidence on injectable semaglutide for weight management specifically in non-diabetic adults, drawing on 27 studies (including RCTs, observational studies, and qualitative reports) identified through PubMed, Scopus, and Web of Science (2019–2025) using the SANRA framework. The authors found that, according to the included literature, semaglutide (2.4 mg) was associated with mean body weight reductions of approximately 14.9% in non-diabetic adults, compared to roughly 9.6% in diabetic populations. Beyond weight loss, the review reported improvements in cardiometabolic markers and quality-of-life measures. Gastrointestinal adverse effects were identified as the primary driver of treatment discontinuation. The review also highlighted practical barriers to real-world use, including high out-of-pocket costs, global supply constraints, and evidence of weight regain following cessation. Tirzepatide was used as a comparative benchmark. The authors conclude that semaglutide represents a meaningful advance in obesity pharmacotherapy but emphasize that its utility depends on integration into multimodal treatment strategies and resolution of structural access issues. Limitations include the narrative (non-systematic) design, potential for selection bias in study inclusion, and inability to pool effect sizes statistically.
Health science reports · Mar 2026DOI ↗ Limited · human
This pharmacovigilance study compared post-marketing adverse event reporting patterns for tirzepatide (a dual GIP/GLP-1 receptor agonist) against semaglutide and liraglutide (GLP-1 receptor agonists) using aggregated Individual Case Safety Reports (ICSRs) from the EudraVigilance database. Researchers applied pairwise disproportionality analyses using reporting odds ratios (RORs) at the System Organ Class (SOC) level, with false discovery rate correction and sensitivity analyses limited to serious and healthcare professional-reported cases. The study found that, compared with semaglutide, tirzepatide was associated with higher relative reporting for immune system disorders (ROR 1.97) and hepatobiliary disorders (ROR 1.71). Compared with liraglutide, tirzepatide showed higher reporting for musculoskeletal (ROR 2.02) and psychiatric disorders (ROR 2.14), but lower reporting for neoplasms (ROR 0.28). Eight SOCs remained significant across all analytical conditions. The authors emphasize that these findings are hypothesis-generating only, as disproportionality analyses cannot establish causality, do not adjust for exposure levels, and are subject to reporting biases inherent in spontaneous pharmacovigilance databases. Confirmation in exposure-adjusted studies is recommended.
International journal of molecular sciences · Mar 2026DOI ↗ Limited · human
This study characterizes PG-102, a bispecific Fc fusion protein that co-activates both GLP-1 and GLP-2 receptors, combining preclinical animal work with a Phase I human trial. In db/db mice (a model of advanced type 2 diabetes with hyperglycemia and catabolic weight loss), PG-102 demonstrated superior and more sustained glycemic control compared to semaglutide or tirzepatide while preserving body weight — an effect attributed to β-cell preservation and enhanced glucose uptake rather than acute insulin stimulation. Mechanistic experiments suggested that dual receptor engagement was necessary for these benefits, with PG-102 also promoting coordinated, delayed receptor internalization compared to monospecific agents. The Phase I randomized, double-blind, placebo-controlled trial enrolled 24 adults with overweight (BMI 25–30 kg/m²) across three dose cohorts, with 18 receiving PG-102 and 6 receiving placebo. The primary endpoint was safety and tolerability. Treatment-emergent adverse events occurred in 83.3% of PG-102 participants and 66.7% of placebo participants; gastrointestinal events were mild to moderate. No serious adverse events or treatment discontinuations were reported. Limitations include the small sample size, single-center design, overweight-only population, and lack of efficacy endpoints in the human portion of the study.
Nature communications · Mar 2026DOI ↗ Review
This review synthesizes evidence for glucagon-like peptide-1 receptor agonists (GLP-1RAs) as treatments for metabolic dysfunction-associated steatotic liver disease (MASLD) and its more advanced form, metabolic dysfunction-associated steatohepatitis (MASH), with particular attention to the liver-heart connection. The authors draw on mechanistic studies, biopsy-based randomized trials, real-world data, and cardiovascular outcome trials. Key trial findings highlighted include: liraglutide (LEAN trial) achieving steatohepatitis resolution in 39% vs. 9% of placebo recipients; semaglutide showing dose-dependent histologic resolution (up to 59% vs. 17% in Phase 2) and meeting dual histologic endpoints in F2–F3 MASH at interim analysis; and tirzepatide (SYNERGY-NASH) demonstrating MASH resolution in 44–62% vs. 10% with fibrosis improvement signals. Cardiovascular outcome benefits were observed across LEADER, SUSTAIN-6, SELECT, and REWIND trials. Mechanistically, GLP-1RAs are described as reducing hepatic lipogenesis, inflammation, and insulin resistance while improving systemic cardiometabolic risk factors. The review concludes that semaglutide and tirzepatide may serve as foundational therapies for high-risk MASLD patients, while noting gaps in long-term durability data, optimal treatment duration, and evidence in cirrhosis.
Chronic diseases and translational medicine · Mar 2026DOI ↗ Review
This narrative review examines the evolving role of glucagon-like peptide-1 receptor agonists (GLP-1RAs) in managing chronic kidney disease (CKD), particularly in patients with type 2 diabetes, obesity, and established cardiovascular disease. The authors summarize evidence from cardiovascular outcomes trials showing that GLP-1RAs are associated with reduced albuminuria and slower estimated glomerular filtration rate (eGFR) decline, with effects that appear additive to those of SGLT2 inhibitors. They highlight dedicated kidney trials—notably with semaglutide—suggesting slowed CKD progression and reduced mortality in diabetic patients with CKD. The review situates GLP-1RAs within a broader therapeutic framework alongside ACE inhibitors/ARBs, SGLT2 inhibitors, and non-steroidal mineralocorticoid receptor antagonists. The authors acknowledge key evidence gaps, including limited data in non-diabetic CKD populations and uncertainty around oral GLP-1RA efficacy and newer dual/triple agonists (GLP-1/GIP/glucagon). As a review, it does not generate new primary data and is subject to potential selection bias in the literature it incorporates. The authors conclude that GLP-1-based therapies represent a potentially transformative approach to improving weight, cardiovascular, and kidney outcomes in high-risk populations.
International journal of nephrology and renovascular disease · Mar 2026DOI ↗ Limited · human
This pharmacovigilance study analyzed ocular adverse event (AE) reports associated with five GLP-1 receptor agonists (exenatide, tirzepatide, dulaglutide, liraglutide, and semaglutide) using the FDA Adverse Event Reporting System (FAERS) from 2005 to 2024. Ocular AEs comprised 3.61% of all GLP-1 RA-related reports; the median patient age was 63 years, and 62.6% of reports involved female patients. Disproportionality analysis using reporting odds ratios (RORs) identified a statistically significant signal for ocular AEs associated with semaglutide, while exenatide showed a significant annual decline in proportional reporting (-5.15% per year). The authors note that semaglutide's signal may partly reflect its growing market dominance rather than a true differential risk. Key limitations acknowledged by the study include the absence of exposure denominators and comparator groups, vulnerability of FAERS to reporting bias (including under- and over-reporting), and inability to establish causality. The authors characterize the findings as hypothesis-generating and recommend clinician vigilance regarding ocular monitoring, particularly in populations already at elevated risk for diabetic eye disease, while calling for further prospective research to validate these associations and explore potential mechanisms.
Journal of clinical medicine · Mar 2026DOI ↗ Moderate · human
This systematic review and meta-analysis evaluated the efficacy and safety of cagrisema (a fixed-ratio combination of the amylin analogue cagrilintide and the GLP-1 receptor agonist semaglutide) and cagrilintide monotherapy compared with semaglutide monotherapy for obesity management. Researchers searched five major databases and ClinicalTrials.gov, ultimately including three randomized controlled trials comprising 3,545 participants. Using a random-effects model, the study found that cagrisema produced statistically significantly greater reductions in percentage body weight (mean difference –7.47%, 95% CI: –10.58 to –4.36) and absolute body weight compared with semaglutide alone. Cagrisema also demonstrated superior improvements in glycemic markers, including fasting plasma glucose and HbA1c, and in BMI. Lipid parameters and safety profiles were reported as broadly comparable between groups. The authors concluded that cagrisema showed greater weight-loss efficacy and glycemic benefit than semaglutide, with an acceptable tolerability profile. Limitations include the small number of included trials (n=3), potential heterogeneity across trial designs, and the relatively short follow-up durations typical of early-phase RCTs in this therapeutic area.
Diabetes, obesity & metabolism · Mar 2026DOI ↗ Moderate · human
This retrospective cohort study used electronic health records from a large health system in Ohio and Florida (January 2021–June 2025) to examine real-world obesity treatment patterns and weight changes among adults who discontinued injectable semaglutide or tirzepatide within 3–12 months of initiation. A total of 7,938 patients (mean age ~56 years; ~64% female) were included. The study found that within one year of discontinuation, roughly 19.6% restarted the same medication and 35.2% received an alternative obesity treatment (most commonly another medication). Patients treated for obesity lost a mean of 8.4% of body weight before discontinuation, while those treated for type 2 diabetes lost 4.4%. In the year following discontinuation, the average weight change was modest (+0.5% for obesity indication; −1.3% for T2D indication), but with considerable individual-level variability—meaning some patients regained weight substantially while others did not. Key limitations include the retrospective, observational design (precluding causal inference), potential confounding by unmeasured factors, and restriction to a single health system in two U.S. states, which may limit generalizability.
Diabetes, obesity & metabolism · Mar 2026DOI ↗ Review
This narrative review compares two incretin-based therapies — semaglutide, a selective GLP-1 receptor agonist, and tirzepatide, a dual GIP/GLP-1 receptor agonist — across their mechanisms of action, clinical efficacy, therapeutic indications, and cardiovascular/renal evidence. The authors describe semaglutide as having a well-established clinical profile with demonstrated benefits in glycaemic control, body weight reduction, and cardiovascular and renal outcomes. Tirzepatide is presented as a newer agent offering superior weight loss and improvements in insulin sensitivity, with an expanding range of therapeutic indications, though the authors note its cardiovascular outcomes evidence is less mature than that of semaglutide. The review emphasizes that despite shared benefits in reducing HbA1c and body weight, the two molecules differ meaningfully in their pharmacological mechanisms and evidence bases, requiring individualized clinical decision-making. The authors frame both agents within a broader "incretin revolution" relevant to cardio-reno-metabolic prevention. As a narrative review, this paper synthesizes existing literature rather than generating new primary data, and therefore does not provide independent experimental evidence to confirm or quantify any specific clinical claims.
European heart journal supplements : journal of the European Society of Cardiology · Mar 2026DOI ↗ Limited · human
This Brazilian retrospective regulatory surveillance study examined patterns of GLP-1 receptor agonist (GLP-1 RA) consumption, pharmacovigilance reports, and product falsification alerts between 2020 and 2024. Researchers triangulated data from three official sources: national pharmaceutical sales records classified by the Anatomical Therapeutic Chemical (ATC) system, adverse event reports submitted to Vigimed (Brazil's national pharmacovigilance platform linked to the global VigiBase), and official counterfeit product alerts. The study found that semaglutide was the dominant GLP-1 RA in the Brazilian market. Consumption was heavily concentrated in higher-GDP regions, revealing a geographic and economic disparity that did not align with regional diabetes prevalence rates. Pharmacovigilance data revealed a notable proportion of reports associated with off-label use, suggesting potential gaps in clinical practice and regulatory oversight. Additionally, documented cases of counterfeit GLP-1 RA products highlighted supply chain vulnerabilities. The authors concluded that rising demand, widespread off-label use, and product falsification collectively require a coordinated regulatory response. Limitations include the retrospective and observational nature of the data, reliance on administrative and surveillance databases, and the potential for underreporting in pharmacovigilance systems.
Diabetes, obesity & metabolism · Mar 2026DOI ↗ Limited · human
This qualitative, multi-method study explored how adults living with obesity make decisions about initiating pharmacotherapy. Researchers used three complementary methods — semi-structured interviews (n=15), a Photovoice study (n=12), and focus group discussions (n=12) — to purposively recruit adults aged 18–70 with a BMI ≥27 kg/m² and at least one obesity-related complication, all of whom were naïve to obesity medications. Through triangulation of findings across all three methods, the study identified five key factors shaping patient preferences: (1) anticipated treatment efficacy, (2) adequacy of information and community support, (3) safety and tolerability profile, (4) treatment burden and lifestyle integration, and (5) logistical and structural barriers. Tirzepatide was the most preferred agent across all methods, largely due to its perceived weight-reduction potential, while semaglutide ranked second, aided by its broader societal familiarity. Perceived efficacy and information trustworthiness emerged as the dominant drivers of preference, with safety concerns consistently moderating enthusiasm. The study is limited by its qualitative design, modest sample sizes, and the fact that all participants were medication-naïve, which may limit transferability to experienced patients. The authors recommend clinicians engage in shared decision-making tailored to individual information needs and social contexts.
Obesity pillars · Mar 2026DOI ↗ Moderate · human
This large retrospective cohort study examined real-world trends in 1-year treatment persistence and adherence among commercially insured adults without diabetes who newly initiated high-potency, weight loss-indicated GLP-1 receptor agonists (GLP-1RAs) — specifically semaglutide (Wegovy) and tirzepatide (Zepbound) — between January 2021 and June 2024. Using integrated medical and pharmacy claims data from approximately 17.9 million members, researchers identified 33,607 eligible new initiators. The study found that 1-year persistence nearly doubled over the observation period, rising from 33.2% in 2021 to 60.9% in the first half of 2024. Tirzepatide demonstrated notably higher persistence (approximately 64%) compared to semaglutide during overlapping availability years. The authors suggest that resolution of GLP-1RA product shortages, improved side effect and dose escalation management, and lifestyle support programs may have contributed to improving persistence trends. Key limitations include reliance on claims data (which cannot capture clinical nuance or patient-reported reasons for discontinuation), a commercially insured-only population limiting generalizability, and the inability to distinguish voluntary discontinuation from access-related gaps. The authors call for further research into discontinuation reasons and long-term cost-effectiveness.
Journal of managed care & specialty pharmacy · Mar 2026DOI ↗ Limited · human
This retrospective, claims-based observational study examined real-world persistence, adherence, and weight-loss effectiveness of GLP-1 receptor agonists (semaglutide/Wegovy) and the dual GLP-1/GIP agonist (tirzepatide/Zepbound) among 7,493 adults enrolled in Massachusetts Medicaid (MassHealth) who initiated treatment between July and December 2024. At 6 months, the study found moderate rates of persistence (60.8%, defined as no gap greater than 56 days between fills) and adherence (60.1%, defined as proportion of days covered ≥80%). Male sex and younger age were among the member-specific factors associated with lower persistence and adherence. In a subgroup of highly persistent and adherent members with prior authorization recertification data, both tirzepatide and semaglutide were associated with at least 5% body weight reduction at 6 months. Key limitations include the retrospective claims-based design, which cannot establish causality, the restriction to a Medicaid population limiting generalizability, and the weight-loss outcome being measured only in a select, highly adherent subgroup rather than the full cohort.
Journal of managed care & specialty pharmacy · Mar 2026DOI ↗ Review
This review examines the landscape of next-generation glucagon-like peptide-1 (GLP-1)-based therapeutics in clinical development for type 2 diabetes and obesity, building on the established success of semaglutide and tirzepatide. The authors survey a broad range of investigational agents that target multiple gastro-entero-pancreatic hormone receptors simultaneously — including GIP, glucagon, amylin, and peptide YY receptors — to produce synergistic effects on energy intake, storage, and expenditure. Specific agents discussed include maridebart cafraglutide (GLP-1 agonism/GIP antagonism), survodutide and mazdutide (GLP-1/glucagon coagonists), cagrilintide combined with semaglutide (CagriSema), amycretin (amylin/GLP-1 dual agent), and retatrutide (GIP/GLP-1/glucagon triple agonist). The review also highlights the emergence of oral small-molecule GLP-1 receptor agonists such as danuglipron and orforglipron, which resist enzymatic degradation and may improve patient convenience. The paper does not present original clinical trial data; it synthesizes existing preclinical and clinical development evidence. As a narrative review, it does not meta-analytically pool outcomes, and the included agents are largely at Phase 1–3 stages, meaning long-term efficacy and safety data remain limited.
Endocrine reviews · Mar 2026DOI ↗