Review
This evidence review examines the evolving landscape of incretin-based pharmacotherapy, focusing on GLP-1 receptor agonists (GLP-1RAs) and newer multi-receptor co-agonists for cardiometabolic disease management. The paper surveys established GLP-1RAs — including liraglutide, dulaglutide, albiglutide, exenatide, and semaglutide — noting their reported benefits on glycated hemoglobin, body weight, lipid profiles, liver fat, and cardiovascular outcomes (reduction in major adverse cardiovascular events, or MACE). It also covers emerging agents: dual GIP/GLP-1 agonist tirzepatide (approved for diabetes and obesity), dual GLP-1/glucagon co-agonists (notable for synergistic weight loss), and triple GLP-1/GIP/glucagon receptor agonists such as retatrutide and efocipegtrutide, described as achieving the highest pharmacotherapy-associated weight loss observed to date. Additional novel classes reviewed include GLP-1/amylin agonists (CagriSema, Amycretin), non-semaglutide oral GLP-1 agents, and peptide YY/GLP-1 dual agonists. As a narrative review, the paper does not present original trial data, and its conclusions are based on synthesized existing literature, which may introduce selection bias. The authors anticipate that metabolic benefits will translate into cardiometabolic outcomes, though direct evidence for many newer agents remains limited.
World journal of cardiology · Aug 2025DOI ↗ Animal only
This preclinical study investigated whether three GLP-1-based receptor agonists — semaglutide (GLP-1 receptor agonist), tirzepatide (dual GLP-1/GIP receptor agonist), and retatrutide (triple GIP/GLP-1/glucagon receptor agonist) — could alter the interoceptive (subjective-like) effects of alcohol in rats. Using an operant drug discrimination paradigm in both male and female rats, researchers trained animals to distinguish alcohol from vehicle, then tested whether these compounds disrupted that learned discrimination. The study found that acute administration of all three agents attenuated alcohol's discriminative stimulus effects, suggesting modulation of how alcohol "feels" internally. Repeated semaglutide treatment maintained this effect over a 15-day period, and the effect reversed within three days of cessation. The authors suggest these findings may help explain clinically observed reductions in alcohol craving and drinking in humans receiving GLP-1 receptor agonists. Limitations include the exclusive use of animal models, meaning direct translation to human subjective alcohol experience remains uncertain, and the study does not assess long-term outcomes or dependence-related endpoints.
Psychopharmacology · Jul 2025DOI ↗ Strong · human
This Bayesian network meta-analysis (NMA) synthesized evidence from 19 randomized controlled trials (RCTs) enrolling 29,506 adults with overweight or obesity (BMI ≥ 25 kg/m²) to compare the weight-loss efficacy and safety of GLP-1 receptor agonists (liraglutide, semaglutide), dual agonists (tirzepatide, survodutide), and the triple agonist retatrutide against placebo over at least 36 weeks. The study found that retatrutide and dual agonists achieved equivalent mean weight loss (approximately −11.0 kg), both outperforming GLP-1 receptor agonists (approximately −9.0 kg). Retatrutide showed the highest odds of achieving ≥15% weight loss (OR 54.6), followed by dual agonists (OR 16.4) and GLP-1 receptor agonists (OR 9.0). However, retatrutide was also associated with the highest adverse event risk. Meta-regression analyses indicated that type 2 diabetes mellitus attenuated weight loss across all drug classes, while female-dominant and higher-BMI cohorts showed enhanced outcomes. Limitations include indirect comparisons inherent to NMA methodology, heterogeneity across trials in baseline characteristics, and the fact that retatrutide data remain from earlier-phase trials. The authors recommend individualized treatment selection based on patient-specific factors.
Obesity (Silver Spring, Md.) · Jul 2025DOI ↗ 🧪 TrialInsufficient
Registered observational trial (enrolling by invitation). This observational study will explore how Wegovy® (Semaglutide) is used in everyday situations, how it might affect things like weight, body mass index (BMI) and waist circumference, and what kind of impact it could have on overall quality of life. The overall purpose of this study is to understand how Wegovy impacts weight when used as part of regular medical care. Participants will be treated with Wegovy as prescribed to the participant by their doctor, in accordance with normal clinical practice. The study will last for about two yea
ClinicalTrials.gov · Jul 2025View trial ↗ Animal only
This study investigated the mechanisms underlying weight loss produced by CagriSema — a combination of cagrilintide (an amylin analogue) and semaglutide (a GLP-1 analogue) — in a rat model. Researchers quantified the contributions of reduced energy intake versus preserved energy expenditure to overall weight loss. Rats treated with CagriSema achieved approximately 12% body weight loss alongside a 39% reduction in food intake. To isolate the role of energy intake, the authors used two comparison conditions: pair-feeding (matching food intake to CagriSema-treated animals) and weight matching (determining how much food restriction alone would be needed to achieve equivalent weight loss, which required a 51% reduction in intake). The gap between these conditions suggested that roughly one-third of CagriSema's weight loss effect was attributable to blunting of metabolic adaptation — the phenomenon where the body typically reduces energy expenditure in response to caloric restriction. Limitations include that findings are from an animal model and may not directly translate to humans, and the study does not address long-term outcomes. The authors conclude that CagriSema's dual action on both energy intake and expenditure may contribute to its potential effectiveness as an obesity treatment.
Nature metabolism · Jul 2025DOI ↗ Moderate · human
This multicentre retrospective observational study used TriNetX, a global healthcare data platform, to examine real-world associations between semaglutide use and survival outcomes in adults with type 2 diabetes (T2D) and chronic kidney disease (CKD). Researchers identified over 1.1 million eligible patients, of whom 14,511 initiated semaglutide and 69,700 initiated sitagliptin between 2018 and 2020. After propensity score matching to balance baseline characteristics, 13,703 patients were included in each group. The study found that the semaglutide group had a significantly lower 3-year incidence of all-cause death (7.2% vs. 9.5%) compared with the sitagliptin group. Secondary outcomes including acute heart failure, acute myocardial infarction, and stroke also favored semaglutide. The authors note these findings are consistent with the randomized FLOW trial. Key limitations include the retrospective, non-randomized design, potential for residual confounding despite propensity score matching, reliance on administrative coding data, and the inability to account for medication adherence or dosing details. Findings should be interpreted as associative, not causal.
Open heart · Jul 2025DOI ↗ Review
This review paper provides a comprehensive overview of the current and emerging pharmacological landscape for metabolic dysfunction-associated steatohepatitis (MASH), the progressive inflammatory form of metabolic dysfunction-associated steatotic liver disease (MASLD). The authors describe MASH as a growing global health burden, closely tied to obesity and type 2 diabetes, and carrying significant risks of cirrhosis, hepatocellular carcinoma, and liver failure. The review synthesizes evidence from advanced-stage clinical trials evaluating several therapeutic classes, including incretin-based therapies (GLP-1 receptor agonists, dual, and triple agonists such as semaglutide, tirzepatide, and survodutide), metabolic modulators (PPAR agonists like lanifibranor, FGF21 analogues like pegozafermin, and thyroid hormone receptor-beta agonists like resmetirom), and novel agents such as fatty acid synthase inhibitors. The authors note that regulatory endpoints currently rely on histological assessment, while noninvasive biomarkers and personalized approaches are gaining traction. Genetic factors, such as PNPLA3 polymorphisms, and artificial intelligence are highlighted as emerging tools for patient stratification and trial design. Key limitations acknowledged include unresolved questions about treatment duration, response heterogeneity, long-term adherence, and the evolving definition of therapeutic success.
The Journal of clinical investigation · Jul 2025DOI ↗ Limited · human
This retrospective observational study used the TriNetX database of de-identified electronic health records (January 2018–December 2020) to compare cardiovascular outcomes between semaglutide and dulaglutide in adults with type 2 diabetes. From a pool of nearly 4.7 million patients with type 2 diabetes, 231,075 semaglutide initiators and 189,103 dulaglutide initiators were identified. Propensity score matching yielded 171,105 patients per group. Over a 3-year follow-up, the study found that semaglutide was associated with statistically significantly lower rates of all-cause death (4.2% vs. 5.6%; HR 0.75, 95% CI 0.72–0.78), acute myocardial infarction (5.2% vs. 5.6%; HR 0.94), stroke (5.8% vs. 6.4%; HR 0.90), and acute heart failure hospitalization (5.3% vs. 6.1%; HR 0.88) compared with dulaglutide. Key limitations include the observational, non-randomized design, which is susceptible to residual confounding despite propensity score matching; reliance on administrative/EHR coding for outcome ascertainment; and the inability to distinguish between semaglutide formulations (oral vs. injectable) or account for dosing differences between agents.
Scientific reports · Jul 2025DOI ↗ Animal only
This study introduces a biodegradable buccal suction patch designed to improve the systemic delivery of therapeutic peptides by bypassing gastrointestinal degradation. The researchers replaced previously used non-degradable silicone materials with biodegradable copolyesters, which were thermally crosslinked via a scalable mold-casting process. Mechanical testing identified the best-performing polymer formulation, and degradation was confirmed in both aqueous media and simulated waste environments. An ex vivo model using porcine buccal tissue demonstrated enhanced permeation of a poorly permeable dye when a chemical permeation enhancer was co-applied. In a beagle dog in vivo model, the biodegradable patch substantially improved the bioavailability of semaglutide (4.11 kDa) compared to a commercially available oral tablet within a 10-minute application window. The patch also achieved a relative bioavailability of approximately 26% for bremelanotide (1.03 kDa) versus subcutaneous injection. Key limitations include the use of an animal model rather than human subjects, a relatively small study scope, and the need for further safety and efficacy validation before clinical translation. The work highlights a promising, more sustainable alternative to silicone-based buccal delivery devices for peptide therapeutics.
Journal of controlled release : official journal of the Controlled Release Society · Jun 2025DOI ↗ Moderate · human
This systematic review and network meta-analysis evaluated the comparative efficacy and safety of dual and triple incretin-based agonists — compounds targeting combinations of GLP-1, GIP, and glucagon receptors — versus standard therapies for type 2 diabetes mellitus (T2DM). Researchers searched PubMed, Web of Science, Cochrane Library, and Embase through July 2024, identifying randomized controlled trials assessing outcomes including body weight, HbA1c, fasting blood glucose (FBG), adverse events (AEs), and serious adverse events (SAEs). The analysis found that Retatrutide (a triple agonist) was associated with the greatest weight reduction, while Tirzepatide (a dual GLP-1/GIP agonist) showed the largest reductions in both FBG and HbA1c. Regarding safety, Tirzepatide and Cotadutide were associated with increased AEs, whereas Semaglutide was associated with reduced SAEs. The authors suggest that receptor-specific targeting may help personalize T2DM treatment. Key limitations include small sample sizes in some included trials, short study durations, and reliance on indirect comparisons in the network meta-analysis. The authors acknowledge that direct head-to-head trials are needed to confirm these findings. The study was prospectively registered (PROSPERO: CRD42024532368).
Acta diabetologica · Jun 2025DOI ↗ 🧪 TrialInsufficient
Registered Phase 1 interventional trial (recruiting). The primary objective of Study GZQG is to compare the effect of retatrutide and placebo on total clamp disposition index (cDI) after 28 weeks of treatment.
ClinicalTrials.gov · May 2025View trial ↗ Limited · human
This cross-sectional study examined self-reported outcomes among 486 adults in Kuwait who were using or had previously used GLP-1 receptor agonist (GLP-1 RA) injections — Semaglutide (n=181), Liraglutide (n=152), or Tirzepatide (n=132) — for weight loss, surveyed between February and May 2024. Participants completed an online questionnaire covering demographics, weight change, side effects, and quality of life. The study found that Tirzepatide users reported the highest average monthly and annual weight loss, along with the greatest satisfaction (88%) and most frequently reported improvements in quality of life (60%) compared to the other two agents. Side-effect profiles differed across groups: Tirzepatide users more commonly reported belching, while Liraglutide users reported higher rates of anxiety and were more likely to switch medications. No statistically significant differences were observed between groups in BMI, dietary adherence, or treatment compliance. Key limitations include the cross-sectional, self-report design, recruitment via online survey (introducing selection bias), lack of clinical verification of outcomes, and the inability to establish causality. The study also does not account for differences in duration of use, dosing, or baseline characteristics across groups.
Frontiers in nutrition · May 2025DOI ↗ 🧪 TrialInsufficient
Registered Phase 4 interventional trial (not yet recruiting). The rapid emergence of new and highly effective obesity medications has turned the field of pediatric weight management on its head. Adolescents living with obesity, their caregivers, healthcare providers, healthcare systems, policymakers, and payors are now wondering what role health behavior and lifestyle treatment (HBLT) has in terms of body mass index (BMI) reduction, improvements in quality of life and cardiometabolic health, and mitigating nutritional concerns when medications are used. Is intensive HBLT needed or could low in
ClinicalTrials.gov · May 2025View trial ↗ Moderate · human
This systematic review and meta-analysis compared the weight-loss effectiveness of tirzepatide versus semaglutide in humans by searching PubMed, Scopus, and Web of Science through January 2025. From 751 initial records, seven studies were ultimately included — two randomized controlled trials (RCTs) and five retrospective cohort studies. Using a random-effects model in RStudio, the authors pooled mean differences (MDs) in body weight change between the two agents. The analysis found that tirzepatide was associated with statistically significantly greater weight loss compared to semaglutide (MD = 4.23 kg; 95% CI: 3.22–5.25). Subgroup analyses suggested that higher tirzepatide doses (>10 mg) and longer treatment durations (>6 months) were associated with progressively larger weight differences. Study quality was assessed using the Newcastle-Ottawa Scale for observational studies and the Cochrane Risk of Bias version 2 tool for RCTs; the authors reported high quality and low risk of bias overall. Publication bias was evaluated via forest plots and Egger's test. Limitations include the small number of included studies (only two RCTs), reliance on retrospective real-world data for most of the analysis, potential heterogeneity across study populations, and the possibility of residual confounding in the observational studies.
Journal of clinical medicine research · May 2025DOI ↗ Review
This review examines amylin, a neuroendocrine hormone co-secreted with insulin, exploring its physiological mechanisms and therapeutic potential in diabetes and obesity. The authors describe how amylin suppresses glucagon secretion, delays gastric emptying, increases energy expenditure, and promotes satiety — making it a candidate for addressing multi-hormonal dysregulation in both type 1 and type 2 diabetes. The paper notes that amylin is deficient in people with diabetes and that pramlintide, currently the only approved amylin analog, has shown efficacy in improving postprandial and overall glycemic control without increasing hypoglycemia risk or promoting weight gain in people with advanced β-cell dysfunction. The authors also discuss barriers to broader clinical translation, including complex receptor biology, amyloidogenic properties, and pharmacokinetic challenges. Emerging strategies covered include PEGylation, carbohydrate conjugation, oral formulations, and combination therapies — notably CagriSema, a co-formulation of a GLP-1 receptor agonist and an amylin agonist showing early promise in weight management and glucose regulation. As a narrative review, this paper synthesizes existing literature rather than generating new primary data, which limits its ability to establish causation or provide definitive efficacy conclusions.
Diabetes therapy : research, treatment and education of diabetes and related disorders · May 2025DOI ↗ Review
This review article examines the management of type 2 diabetes and obesity, with a particular focus on CagriSema, an investigational combination drug pairing cagrilintide (an amylin analog) with semaglutide (a GLP-1 receptor agonist). The authors begin by contextualizing the scale of diabetes in the United States—affecting over 37 million people—and highlight the interplay between obesity and type 2 diabetes, noting that genetic and physiological barriers often make weight loss difficult without pharmacological support. The article reviews the pathophysiology of diabetes, current clinical guidelines, and the risks associated with intensive glycemic control, particularly hypoglycemic events such as cardiac arrhythmias, confusion, coma, and death. It then surveys the existing evidence for approved weight loss and antidiabetic medications before summarizing recent clinical trial data on CagriSema, which is being investigated as a potentially superior agent for reducing both HbA1c and body weight. The authors argue that CagriSema may offer a favorable safety and efficacy profile, though they acknowledge the drug remains under investigation. Key limitations include the review format itself—primary trial data are summarized rather than independently analyzed—and the absence of long-term safety data for CagriSema in the published literature reviewed.
Cardiology in review · May 2025DOI ↗ Review
This scoping review systematically examined clinical research on anti-obesity medications (AOMs) conducted in Arab countries, drawing on five databases and covering publications up to October 2024. Researchers identified 59 eligible clinical studies published between 2014 and 2024, the large majority of which (89.8%) were observational in design. Most research originated from Saudi Arabia (40.7%) and the United Arab Emirates (20.3%). Glucagon-like peptide-1 (GLP-1) receptor agonists were the most studied drug class, appearing in 72.9% of studies, with liraglutide being the single most investigated agent (54.2%). The primary efficacy outcomes reported across studies were changes in total body weight, body mass index, and proportion of weight loss. Gastrointestinal side effects were noted in 32.2% of patients across studies. Risk of bias was assessed using the Newcastle-Ottawa scale and a modified randomized controlled trial tool. The authors highlight a notable gap: newer agents such as semaglutide and tirzepatide are underrepresented in the literature. Key limitations include the predominance of observational designs, geographic concentration, and limited data on diverse Arab subpopulations, which collectively constrain causal inference and generalizability.
Saudi medical journal · May 2025DOI ↗ In vitroPreprint
This preprint describes a computational study aimed at designing improved semaglutide analogues — variants of the GLP-1 receptor agonist used in weight-loss and diabetes treatment — in the context of the underperforming CagriSema Phase III trial. The researchers used an automated "natural amino acid scanning" approach, systematically introducing single amino acid mutations across the semaglutide peptide backbone. Using the crystal structure of the GLP-1–GLP-1R complex (PDB: 4ZGM) as a structural template, they performed high-throughput computational modeling with Modeller and estimated binding affinities (Kd) using the Prodigy tool. From this pipeline, the study identified 564 computationally designed semaglutide analogues predicted to show improved binding affinity to the extracellular domain (ECD) of GLP-1R. The authors propose a conceptual "interfacial electrostatic scaffold" consisting of four salt bridges at the peptide–receptor interface as a framework for next-generation GLP-1R agonist development, drawing an analogy to the century-long iterative optimization of insulin. Key limitations include the fully computational nature of the study — no experimental validation (biochemical, cellular, or in vivo) is presented — and reliance on a single structural template and computational binding affinity estimators, which may not fully capture dynamic receptor behavior.
Unknown journal · Apr 2025DOI ↗ Animal onlyPreprint
This preclinical study examined whether three incretin-based receptor agonists — semaglutide (GLP-1 receptor agonist), tirzepatide (dual GLP-1/GIP receptor agonist), and retatrutide (triple GIP/GLP-1/glucagon receptor agonist) — could alter the interoceptive (subjective) effects of alcohol in rats using an operant drug discrimination paradigm. Male and female rats were trained to discriminate alcohol from saline, then tested after acute or repeated drug administration. The study found that acute administration of all three compounds reduced alcohol's discriminative stimulus effects, suggesting each compound modulated how the animals internally perceived alcohol. Repeated semaglutide treatment sustained this effect across a 15-day period, though discrimination returned to baseline levels within three days of stopping treatment. The authors interpret these findings as potentially relevant to understanding why GLP-1 receptor agonists reduce drinking behavior in humans, hypothesizing that blunting alcohol's subjective effects may be a contributing mechanism. Key limitations include the exclusive use of an animal model, meaning translation to human subjective experience remains uncertain, and the study does not establish clinical efficacy or safety in people with alcohol use disorder.
Unknown journal · Apr 2025DOI ↗ Strong · human
This network meta-analysis synthesized evidence from 39 randomized clinical trials (99,599 patients) to compare the efficacy and safety of three drug classes — SGLT-2 inhibitors, GLP-1 receptor agonists, and the non-steroidal mineralocorticoid receptor antagonist Finerenone — in adults with type 2 diabetes mellitus (T2DM) and non-dialysis chronic kidney disease (CKD). Databases were searched through November 2023, and methodological quality was assessed using the Cochrane RoB 2.0 tool. The study found that, compared to placebo, SGLT-2 inhibitors were most effective at reducing HbA1c, systolic and diastolic blood pressure, and body weight. Among GLP-1 receptor agonists, Liraglutide showed the greatest LDL-C reduction. Finerenone significantly reduced systolic blood pressure versus placebo. SUCRA rankings highlighted Empagliflozin for HbA1c and DBP reduction, Semaglutide for eGFR preservation, and Canagliflozin for blood pressure and weight loss. Safety profiles were generally favorable, with notable differences across agents in rates of urinary tract infection, hypoglycemia, and acute kidney injury. Limitations include indirect comparisons inherent to network meta-analysis, potential heterogeneity across trials, and the restriction to non-dialysis CKD populations, limiting broader generalizability.
Frontiers in pharmacology · Mar 2025DOI ↗