Review
This narrative review examines how rapidly advancing obesity pharmacotherapies — particularly GLP-1 receptor agonists, dual and triple incretin agonists, and amylin-based combination therapies — are challenging the longstanding criteria used to determine eligibility for bariatric surgery. The authors note that current surgical guidelines were established when effective medical alternatives were limited, and argue that newer agents achieving 15–25% body weight reduction now approach outcomes historically associated only with surgery. The review compares surgical and pharmacologic interventions across dimensions of efficacy, safety, metabolic benefit, and cost-effectiveness, and considers whether a stepwise, pharmacotherapy-first approach may be appropriate — particularly for individuals with a BMI of 30–40 kg/m². The authors also discuss potential roles for pharmacotherapy in perioperative care and long-term obesity management, and call for personalized treatment strategies. As a narrative review, the paper does not conduct a systematic search or meta-analysis, which limits its ability to make definitive comparative claims. It reflects the authors' interpretive synthesis of existing literature rather than new primary data, and is subject to selection bias inherent to the narrative format.
Medicina (Kaunas, Lithuania) · Jul 2025DOI ↗ 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 ↗ 🧪 TrialInsufficient
Registered Phase 2 interventional trial (recruiting). Background: People with alcohol use disorder (AUD) often develop metabolic alcohol-associated liver disease (MetALD). MetALD is a term for the heart, liver, obesity, and other issues that can accompany AUD. MetALD can be fatal. An approved weight management drug (Tirzepatide) may be able to help people with AUD and MetALD control their alcohol intake. Objective: To test Tirzepatide in people with AUD and MetALD. Eligibility: People aged 21 years and older with AUD and MetALD. Design: Participants will be screened. They will have a physical
ClinicalTrials.gov · Jul 2025View trial ↗ 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 ↗ Review
This review paper examines whether two major antihyperglycemic drug classes — sodium-glucose co-transporter-2 (SGLT2) inhibitors and glucagon-like peptide-1 receptor agonists (GLP-1 RAs) — may have a therapeutic role in gout management, particularly in patients who also have type 2 diabetes mellitus (T2DM). The authors describe gout as the most common form of inflammatory arthritis, driven by hyperuricemia that leads to monosodium urate crystal deposition in joints and tissues. The review summarizes evidence from multiple clinical studies suggesting that SGLT2 inhibitors lower serum urate (SU) levels, likely by promoting urinary uric acid excretion, which could benefit gout patients with comorbid T2DM. The paper also notes that SGLT2 inhibitors have demonstrated reductions in cardiovascular and renal events. By contrast, the effect of GLP-1 RAs on SU levels and urinary uric acid excretion in humans is described as unclear. The authors review mechanisms of action, structure-activity relationships, uricosuric effects, pharmacokinetic profiles, and adverse effects for both drug classes. Key limitations include the review design, reliance on studies conducted primarily in T2DM populations, and the absence of dedicated gout-specific clinical trials for either drug class.
Pharmaceutics · Jun 2025DOI ↗ Animal only
This preclinical study investigated whether mazdutide — a dual glucagon-like peptide-1 receptor (GLP-1R) and glucagon receptor (GCGR) agonist — could improve cognition in a mouse model of type 2 diabetes mellitus (T2DM). Male db/db mice (a well-established T2DM model characterized by obesity and hyperglycemia) were treated with mazdutide and compared against dulaglutide, a GLP-1R-only agonist. Researchers assessed cognitive function via behavioral tests and examined brain pathology for neurodegenerative markers. They also applied transcriptomic, proteomic, and metabolomic (multi-omics) analyses to explore underlying molecular mechanisms. The study found that mazdutide-treated mice showed greater improvements in cognitive performance compared to dulaglutide-treated mice, along with better neuronal structure and brain tissue integrity. Multi-omics data implicated molecular pathways related to neuroprotection, energy metabolism, and synaptic plasticity as potential contributors to these effects. Key limitations include exclusive use of male mice, meaning results cannot be generalized to females, and the entirely preclinical nature of the study. No human data were collected, so whether these findings translate to people with T2DM remains unknown. The authors suggest mazdutide may warrant further investigation as a treatment for metabolic disorder-associated cognitive decline.
EBioMedicine · 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 ↗ In vitro
This study reports the first-in-class design of unimolecular "tetra-agonists" — single peptide molecules engineered to simultaneously activate four metabolically relevant receptors: GLP-1R, GIPR, GcgR (all class B GPCRs), and Y2R (a class A GPCR). Prior work had yielded dual and triple agonists exploiting sequence homology among class B GPCR ligands, but incorporating Y2R agonism was considered a major challenge due to the structural and sequence divergence between class A and class B GPCRs. The researchers used rational chimeric peptide design to overcome these topological constraints, producing high-potency tetra-agonists. They further showed that lipidation of the scaffold was well tolerated, potentially improving therapeutic viability. The study also explored biased agonism at GLP-1R, demonstrating that cAMP signaling could be selectively amplified while minimizing β-arrestin recruitment — a mechanism that may reduce receptor desensitization. A tunable framework for modulating β-arrestin engagement without compromising cAMP potency is also described. Limitations include that all experiments appear to be conducted in vitro (cell-based receptor activation and signaling assays), with no animal or human efficacy data reported. The work is primarily a molecular pharmacology and peptide chemistry study establishing proof-of-concept at the receptor level.
Journal of the American Chemical Society · Jun 2025DOI ↗ Strong · human
The GLORY-1 trial was a phase 3, randomized, double-blind, placebo-controlled study conducted in China evaluating mazdutide — a once-weekly injectable glucagon-like peptide-1 (GLP-1) and glucagon receptor dual agonist — for weight management in adults with overweight or obesity. A total of 610 participants (mean BMI 31.1, mean body weight 87.2 kg) were randomly assigned 1:1:1 to receive one of two doses of mazdutide or placebo for 48 weeks. The two co-primary endpoints at week 32 were percent change in body weight and the proportion achieving at least 5% weight reduction, analyzed using a treatment-policy estimand. The study found that both mazdutide groups achieved statistically significant and clinically meaningful reductions in body weight compared to placebo at week 32, with the higher dose group achieving a greater mean reduction than the lower dose group; the placebo group had a marginal mean weight gain. The proportions achieving ≥5% weight loss were substantially higher in both active treatment groups versus placebo. Limitations include the single-country (China) design, limiting generalizability, and the 32-week primary endpoint in a 48-week trial. Safety data were not detailed in the abstract.
The New England journal of medicine · May 2025DOI ↗ Review
This review examines metabolic dysfunction-associated steatotic liver disease (MASLD) as it specifically affects people with HIV (PWH). The authors highlight that MASLD is highly prevalent in this population and follows a more aggressive clinical course than in HIV-negative individuals. The review discusses how HIV-specific factors — including altered body composition, chronic immune activation, enhanced gut permeability, and antiretroviral therapy (ART) side effects — compound the common pathogenic mechanisms of MASLD, accelerating disease progression. The authors note the recent adoption of updated MASLD nomenclature and the first FDA-approved MASLD therapy, emphasizing that these advances have not yet been adequately studied in PWH. They identify a critical evidence gap in evaluating emerging MASLD therapies specifically within this population. Among interventions studied in PWH, the review highlights early promise from glucagon-like peptide-1 (GLP-1) receptor agonists and the growth hormone-releasing hormone analog tesamorelin. The authors conclude that MASLD is a meaningful driver of both liver-related and cardiovascular morbidity in PWH, and that the distinct pathophysiology of MASLD-HIV necessitates tailored diagnostic and management strategies. Limitations include the review format and the scarcity of dedicated clinical trial data in PWH.
Current opinion in HIV and AIDS · May 2025DOI ↗ 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 ↗ 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 narrative review examines the current landscape and future directions of Type 2 Diabetes Mellitus (T2DM) treatment. The authors begin by describing conventional therapies — including metformin, sulfonylureas, and insulin — noting their limitations such as adverse effects, declining efficacy over time, and suboptimal glycemic control in many patients. The review then surveys a range of emerging therapeutic strategies. Dual incretin receptor agonists (e.g., tirzepatide), which co-activate GLP-1 and GIP receptors, are highlighted for their effects on insulin secretion, glucagon suppression, and weight loss. Dual SGLT1/2 inhibitors (e.g., sotagliflozin) are discussed for their dual gut-and-kidney glucose-lowering mechanism. Additional experimental approaches covered include glucagon receptor antagonists, GPR119 agonists, FGF21 analogs, AMPK activators, and CRISPR-Cas9 gene editing technologies. The authors acknowledge that while these novel therapies demonstrate promise in early-stage research, long-term safety and efficacy data in humans remain limited. As a narrative review, this paper does not present original clinical data, does not include a systematic search protocol or meta-analytic methodology, and is subject to selection bias in the literature discussed.
Biochemistry and biophysics reports · 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 ↗