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 ↗ 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 ↗ 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 ↗ Review
This review paper examines the emerging evidence for glucagon-like peptide-1 receptor agonists (GLP-1RAs) — specifically liraglutide, semaglutide, and tirzepatide — as potential interventions in prediabetes. The authors synthesize findings showing that GLP-1RAs were associated with reduced progression to type 2 diabetes mellitus (T2DM), with normoglycaemia achieved in a notable proportion of subjects (up to 66%, 81%, and 93.3% for liraglutide, semaglutide, and tirzepatide, respectively). However, these glycaemic benefits were only partially maintained after drug discontinuation. The review also highlights modest reductions in HbA1c, fasting glucose, body weight, and fat mass, alongside improvements in insulin sensitivity and β-cell function. Potential cardiovascular benefits — including reduced risk of atherosclerotic cardiovascular disease and heart failure — were noted, particularly with tirzepatide. Experimental data suggested possible benefits for metabolic dysfunction-associated steatotic liver disease (MASLD). The safety profile was described as acceptable, with mild-to-moderate gastrointestinal effects being the most commonly reported adverse events. The authors acknowledge that the current evidence base is limited and call for large, well-designed randomised controlled trials to define the precise role of GLP-1RAs in prediabetes management.
Diabetes therapy : research, treatment and education of diabetes and related disorders · Apr 2026DOI ↗ Review
This comprehensive narrative review examines nine therapeutic peptides with proposed applications in healthy aging and age-related conditions: tirzepatide (metabolic dysfunction), epitalon (telomere biology), GHK-Cu (dermal regeneration), BPC-157 and TB-500 (tissue repair), Semax (neuroprotection), CJC-1295 and ipamorelin (growth hormone modulation), and bremelanotide (sexual function). The authors searched PubMed, Scopus, and regulatory databases through January 2026, selecting 20 primary sources based on relevance and methodological quality. The review found that FDA-approved agents such as tirzepatide and bremelanotide have robust safety and efficacy data from large-scale trials, while investigational peptides such as epitalon, BPC-157, and TB-500 show promising signals primarily from preclinical and limited clinical studies. The authors highlight significant knowledge gaps, including the absence of long-term safety data for non-approved peptides, undefined optimal dosing regimens, unknown combination therapy effects, and lack of validated biomarkers for monitoring efficacy. The authors conclude that while therapeutic peptides offer mechanistically diverse approaches to aging hallmarks, investigational agents require rigorous clinical trial validation before clinical adoption. As a narrative review, findings are subject to selection bias and do not represent a quantitative synthesis of evidence.
Frontiers in aging · Apr 2026DOI ↗ 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 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 ↗ 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 ↗ 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 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 ↗ 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 ↗ Review
This review provides a broad educational overview of pharmacological agents used in diabetes management, spanning both traditional and newer-generation therapies, with particular attention to their off-label use for weight loss. The authors describe the mechanistic and clinical distinctions between type 1 and type 2 diabetes and survey established drug classes—insulin, metformin, sulfonylureas, and thiazolidinediones—noting their limitations such as hypoglycemia risk and weight gain. The review then highlights the clinical impact of incretin-based therapies, specifically GLP-1 receptor agonists and SGLT-2 inhibitors, which the authors associate with improved glycemic control, weight reduction, and cardiorenal benefits. Newer dual and triple agonists, including tirzepatide, are described as producing HbA1c and body weight reductions approaching those of bariatric surgery. The paper raises concerns about the rising off-label use of antidiabetic agents for weight management, citing gastrointestinal adverse effects and rare motility disorders. Limitations include the review's broad scope and lack of original data or formal systematic methodology. The authors call for ongoing pharmacovigilance, equitable access, and further research into long-term safety and emerging oral non-peptide incretin mimetics.
The Journal of pharmacy technology : jPT : official publication of the Association of Pharmacy Technicians · Feb 2026DOI ↗ Review
This Chinese clinical comprehensive evaluation systematically compared five long-acting GLP-1 receptor agonists (dulaglutide, semaglutide, polyethylene glycol loxenatide, tirzepatide, and mazdutide) for the management of type 2 diabetes within China's healthcare context. The researchers constructed a quantitative, six-dimensional scoring framework—covering efficacy, safety, economy, innovation, suitability, and accessibility—with indicator weights derived through a Delphi expert consultation process. Evidence sources included drug labels, systematic literature reviews, and real-world data. Semaglutide scored highest (76.6/100) followed by dulaglutide (72.6), polyethylene glycol loxenatide (64.8), tirzepatide (62.9), and mazdutide (55.1). Semaglutide and dulaglutide were classified as "Strong Recommendations," largely due to superior cardio-renal outcome evidence. Tirzepatide and polyethylene glycol loxenatide received "Conditional Recommendations," while mazdutide was "Not Recommended" owing to insufficient evidence, lack of national reimbursement listing, and high cost. Key limitations include the inherent subjectivity of the Delphi weighting process, the China-specific formulary and reimbursement context limiting global generalizability, and the composite nature of the scoring system potentially obscuring individual domain differences.
Diabetes, metabolic syndrome and obesity : targets and therapy · Feb 2026DOI ↗ Review
This commentary argues that the rising popularity of GLP-1 receptor agonists and dual GIP/GLP-1 agonists (such as tirzepatide) for obesity treatment risks overshadowing the need for structural, population-level interventions targeting the food environment. The authors highlight several limitations of a pharmacotherapy-centered approach: high and rising costs (citing recent tirzepatide price increases in the United Kingdom), unequal access across health systems, and the well-documented tendency for weight regain following cessation of these medications. The paper contends that obesity is fundamentally driven by structural factors — including the pervasive availability, marketing, and placement of ultra-processed and high-fat, salt, or sugar (HFSS) foods, alongside limited access to nutritious options. The authors call for complementary population-level policies such as mandatory food reformulation, restrictions on HFSS food marketing, and improved affordability and access to minimally processed foods. The paper acknowledges that medications may provide individual-level benefit but concludes that only comprehensive food-system reform can achieve sustainable reductions in obesity and diet-related disease. As a commentary, it presents no original empirical data, and its conclusions rest on cited evidence rather than new research.
Public health nutrition · Feb 2026DOI ↗ Review
This narrative review examines three incretin-based therapies — liraglutide, semaglutide, and tirzepatide — approved for weight management in non-diabetic individuals with obesity. The authors provide background on the physiological roles of the incretin hormones GIP and GLP-1 in the gastrointestinal tract, explaining how pharmacological analogues of these hormones, initially developed for type 2 diabetes, were subsequently found to produce clinically meaningful weight reduction. The review compares the three agents across efficacy, safety, cost-effectiveness, and real-world clinical trends. Lifestyle interventions (dietary modification, physical activity, sleep, and stress management) are discussed as foundational components of obesity management. The authors highlight that all three agents are now regulatory-approved for obesity in non-diabetic patients. As a narrative review, the paper synthesizes existing literature rather than generating new primary data, and is therefore subject to selection bias in the studies chosen. It does not conduct a formal systematic search or meta-analysis, limiting the objectivity of comparisons. No new clinical trial data are presented, and conclusions about relative efficacy and cost-effectiveness are drawn from the authors' interpretation of the existing evidence base.
Rambam Maimonides medical journal · Jan 2026DOI ↗ Review
This commentary is aimed at clinicians and provides practical guidance for counseling patients who are hesitant about starting glucagon-like peptide-1 receptor agonist (GLP-1RA) therapy due to concerns about its perceived "newness" or unproven long-term safety. The paper briefly traces the history of GLP-1, from its discovery in the 1980s through nearly two decades of clinical use, to contextualize these agents as well-established rather than experimental. It distinguishes native GLP-1 from structurally modified agents such as semaglutide and tirzepatide, arguing that modifications prolong drug action without fundamentally changing the hormone's core mechanism. The authors summarize available safety data, noting that known side effects are predominantly mild and transient gastrointestinal in nature, and that there is currently no established evidence linking GLP-1RAs to feared risks such as cancer. The paper includes a practical counseling checklist and sample patient-friendly language intended to support shared decision-making conversations. Key limitations include the absence of original data, lack of systematic literature review methodology, and potential for author bias in evidence selection. Findings and reassurances are the authors' interpretive positions rather than conclusions drawn from a primary study.
American journal of preventive cardiology · Jan 2026DOI ↗ Review
This paper examines the growing use of glucagon-like peptide-1 (GLP-1) receptor agonists — specifically semaglutide and tirzepatide — in the context of obesity management. The authors discuss how these medications have meaningfully shifted the landscape of obesity care, while simultaneously raising important questions about their safety profile, long-term outcomes, and the risks associated with unregulated or compounded versions of these products. The paper highlights the tension between rapidly increasing patient demand and the need for robust clinical oversight. Key concerns addressed include adverse side effects, the consequences of unsupervised use, and the importance of coordinated clinical frameworks to ensure patients access these therapies safely. The authors advocate for structured monitoring systems and regulatory vigilance to keep pace with the surge in prescribing. As a review or commentary piece rather than an original clinical trial, the paper does not generate new primary data; its conclusions are based on synthesis of existing evidence and expert perspective. This limits its ability to independently establish causality or quantify risk with precision, and readers should interpret its claims in that context.
PLoS medicine · Jan 2026DOI ↗ Review
This narrative review synthesizes mechanistic and clinical trial evidence on incretin-based therapies — GLP-1 receptor agonists (GLP-1RA), DPP-4 inhibitors, and newer dual/triple agonists — for cardiovascular (CV) and renal protection in type 2 diabetes (T2DM) and related conditions. The authors draw on multiple pivotal randomized cardiovascular outcome trials (CVOTs), including SELECT (semaglutide in obesity without diabetes), FLOW (semaglutide in chronic kidney disease), SOUL (oral semaglutide in T2DM with ASCVD/CKD), and SURPASS-CVOT (tirzepatide vs. dulaglutide). Key findings attributed to these trials include reductions in major adverse cardiovascular events (MACE), CV and all-cause mortality, heart-failure hospitalization, and hard kidney endpoints across GLP-1RA programs. A 2019 pooled analysis and a 2025 update reportedly confirm these cardiorenal benefits independent of baseline HbA1c. Mechanistically, the review describes GLP-1R signaling via Gs-cAMP/PKA, β-arrestin, and Gq pathways, linked to anti-inflammatory, natriuretic, and antifibrotic effects. Oral small-molecule GLP-1R agonists (e.g., orforglipron) showed phase 2 efficacy but lacked long-term outcome data at time of publication. As a narrative review, it is subject to selection bias and does not conduct formal meta-analytic pooling.
Diabetes therapy : research, treatment and education of diabetes and related disorders · Jan 2026DOI ↗