Moderate · human
This network meta-analysis (NMA) systematically synthesized evidence from 25 randomized controlled trials across 12 interventions to compare the weight-loss efficacy and safety of four advanced anti-obesity medications — tirzepatide, semaglutide, cagrilintide, and the combination CagriSema (cagrilintide + semaglutide) — in adults with overweight or obesity. Searches were conducted across PubMed, Scopus, and Cochrane Central. Using random-effects NMA models, the study found that tirzepatide 15 mg produced the greatest mean percent body weight reduction (−17.97%), closely followed by CagriSema (−17.84%) and semaglutide 7.2 mg (−14.66%). For achieving ≥20% body weight loss, CagriSema showed the highest relative risk (RR 27.82), followed by tirzepatide 15 mg (RR 23.70). All agents increased gastrointestinal adverse events (RR 1.33–1.91) relative to placebo, with the highest treatment discontinuation seen with semaglutide 7.2 mg (RR 3.09). Serious adverse events were comparable to placebo across all regimens. Key limitations include reliance on indirect comparisons due to absence of head-to-head trials, potential heterogeneity across trial populations and follow-up durations, and the emerging/limited trial data for CagriSema specifically. The authors conclude that both tirzepatide and CagriSema represent leading options for substantial weight loss but call for direct comparative trials.
Endocrinology, diabetes & metabolism · Jul 2026DOI ↗ Strong · human
This living systematic review and network meta-analysis, commissioned by the American College of Physicians, synthesized evidence from 69 randomized controlled trials involving 112,511 adults with overweight or obesity (BMI ≥25 kg/m²) to compare pharmacologic weight-management treatments. Drugs examined included GLP-1 receptor agonists (semaglutide, liraglutide, dulaglutide, exenatide, lixisenatide), dual agonists (tirzepatide, retatrutide, semaglutide-cagrilintide), and other agents (naltrexone-bupropion, phentermine, phentermine-topiramate, orforglipron), with or without lifestyle intervention. The review found that nearly all studied interventions produced greater weight loss than placebo and/or lifestyle intervention alone. Semaglutide was found to probably reduce mortality and major adverse cardiovascular events (MACE). Semaglutide and tirzepatide demonstrated the greatest weight loss in both pairwise and network meta-analyses. However, nearly all active treatments were also associated with more treatment discontinuations due to adverse events compared with placebo. The authors noted that evidence for critical outcomes such as mortality, MACE, and serious adverse events remained limited, and direct head-to-head comparisons between treatments were scarce. Thirty-seven of the 69 included studies were rated at low risk of bias. The living review design allows for ongoing evidence updates as new trials emerge.
Annals of internal medicine · Jun 2026DOI ↗ Strong · human
The REIMAGINE 2 trial was a phase 3, double-blind, randomised, placebo- and active-controlled study evaluating the fixed-dose combination of cagrilintide (an amylin receptor agonist) and semaglutide (a GLP-1 receptor agonist), known as CagriSema, in 2,713 adults with inadequately controlled type 2 diabetes and overweight or obesity across 30 countries. Participants were on background metformin with or without an SGLT2 inhibitor and were followed for 68 weeks. The primary endpoint was change in HbA1c from baseline. The study found that the higher-dose CagriSema combination produced a statistically significantly greater reduction in HbA1c compared with semaglutide alone (-1.91 vs. -1.75 percentage points; treatment difference -0.16 percentage points; p=0.0035). Adverse events were more frequent in the combination group (86.9%) than in the semaglutide monotherapy group (81.2%), with gastrointestinal disorders being the most common across active treatment arms. Limitations include the relatively modest absolute difference in HbA1c reduction, a predominantly White study population, and industry funding by Novo Nordisk, which may introduce sponsorship bias.
The lancet. Diabetes & endocrinology · Jun 2026DOI ↗ Moderate · human
REIMAGINE 1 was a randomised, double-blind, placebo-controlled phase 3a trial evaluating once-weekly subcutaneous cagrilintide-semaglutide (CagriSema) — a combination of an amylin receptor agonist (cagrilintide) and a GLP-1 receptor agonist (semaglutide) — in 189 adults with type 2 diabetes inadequately controlled by diet and exercise alone. Conducted across 42 sites in six countries over 40 weeks, participants were assigned to one of two active dose levels or matched placebo. The primary endpoint was change in HbA1c from baseline to week 40. The study found that both active dose levels produced statistically significant and clinically meaningful reductions in HbA1c compared to placebo (estimated treatment differences of −1.7 and −1.4 percentage points for the higher and lower doses, respectively; p<0.0001 for both). Body weight reduction was a notable secondary finding. The safety profile was described as consistent with the GLP-1 receptor agonist class. Key limitations include the relatively small sample size (n=189), short 40-week duration, an early-stage diabetes population not on background glucose-lowering medications, and industry funding from Novo Nordisk, which may introduce bias. These results suggest CagriSema may be a promising therapeutic option for early-stage type 2 diabetes.
The lancet. Diabetes & endocrinology · Jun 2026DOI ↗ Strong · human
The REIMAGINE 3 trial investigated the combination of cagrilintide and semaglutide (CagriSema) as a weekly add-on to daily basal insulin in adults with type 2 diabetes and suboptimal glycaemic control (HbA1c 7.0–10.5%). In this 40-week, double-blind, placebo-controlled phase 3 study conducted across 46 centres in six countries, 274 participants were randomised to one of two active dose combinations (2.4 mg each or 1.0 mg each) or pooled placebo. The primary endpoint—change in HbA1c from baseline to week 40—was significantly greater with both CagriSema doses (–2.33% and –2.10%, respectively) compared with placebo (–0.66%). Both active groups also achieved substantial bodyweight reductions versus placebo, and no additional hypoglycaemia risk was observed. The safety profile was consistent with the GLP-1 receptor agonist class. Limitations include a relatively short 40-week duration, a moderately sized sample, and industry funding by Novo Nordisk. The study authors conclude that CagriSema meaningfully improved glycaemic control when added to basal insulin, without increasing hypoglycaemia risk.
Lancet (London, England) · Jun 2026DOI ↗ Limited · human
Two single-dose pharmacokinetic studies investigated whether renal or hepatic impairment affects how the body processes cagrilintide, a long-acting amylin agonist in development for weight management and type 2 diabetes (also studied in combination with semaglutide as "CagriSema"). In each study, adult participants were grouped by organ function (normal, mild, moderate, or severe impairment) and received a single subcutaneous dose of cagrilintide. The renal study enrolled 33 participants and the hepatic study enrolled 32. The primary measure was total drug exposure (AUC₀–∞), with secondary measures including peak concentration (Cmax) and time to peak (tmax). Both studies found that cagrilintide exposure was broadly similar across all impairment levels; estimated AUC ratios relative to normal function ranged from approximately 0.99 to 1.23, with overlapping confidence intervals. No serious adverse events, study withdrawals, or deaths occurred, and no increase in adverse events was observed with worsening organ impairment. The authors concluded that dose adjustment may not be necessary in these populations. Key limitations include small group sizes, single-dose design, and the inability to generalize to steady-state conditions or combined therapies.
Clinical pharmacokinetics · Jun 2026DOI ↗ Review
This review synthesizes evidence from randomized controlled trials and high-quality meta-analyses on approved and investigational obesity medications, examining their effects beyond weight loss alone. Medications reviewed include phentermine-topiramate, naltrexone-bupropion, GLP-1 receptor agonists (liraglutide, semaglutide), and newer multiagonist agents (tirzepatide, survodutide, mazdutide, retatrutide, cagrilintide-semaglutide, and amycretin). The authors evaluated impacts across a broad range of obesity-related comorbidities, including type 2 diabetes, metabolic dysfunction-associated steatotic liver disease, chronic kidney disease, heart failure, cardiovascular disease, obstructive sleep apnea, polycystic ovary syndrome, osteoarthritis, muscle mass, depression, quality of life, food cravings, binge-eating disorders, substance use disorders, and neurodegenerative diseases. The review concludes that GLP-1-based and multiagonist therapies demonstrate beneficial effects across these conditions. Notably, the authors report that while many benefits appear to be mediated through weight reduction, accumulating evidence suggests weight loss-independent mechanisms, particularly for GLP-1 receptor agonist-based therapies. Key limitations include its reliance on synthesized rather than primary data and variability in evidence quality across the individual conditions reviewed.
The lancet. Diabetes & endocrinology · May 2026DOI ↗ Strong · human
This systematic review and meta-analysis pooled data from four randomized controlled trials (n = 5,023 adults with overweight or obesity) to evaluate the efficacy and safety of cagrilintide — a long-acting amylin analogue — and its combination with semaglutide (CagriSema) versus placebo. The primary outcome was percent change in body weight. The authors followed PRISMA 2020 and AMSTAR 2 guidelines and used Cochrane RoB 2 for bias assessment, with random-effects models throughout. Key findings: cagrilintide alone was associated with a mean body weight reduction of approximately 6.1% versus placebo (95% CI: −8.0% to −4.1%), and CagriSema with approximately 6.0% (95% CI: −10.6% to −1.3%). CagriSema also significantly reduced waist circumference and HbA1c; cagrilintide alone showed modest blood pressure improvements without significant glycemic effects. Adverse events were more frequent with active treatment, though discontinuation rates were comparable to placebo. Notable limitations include the small number of pooled trials (n = 4) and potential heterogeneity across study populations and durations. The authors conclude that both therapies show clinically meaningful weight loss and acceptable tolerability, positioning them as emerging options in obesity pharmacotherapy.
Journal of diabetes and metabolic disorders · May 2026DOI ↗ Review
This narrative review examines the relationship between diabetes mellitus (DM) and stroke, and evaluates the cerebrovascular potential of glucagon-like peptide-1 receptor agonists (GLP-1 RAs) and dual GLP-1/GIP receptor agonists (e.g., tirzepatide). The authors summarize evidence from large cardiovascular outcome trials (CVOTs), noting that agents such as semaglutide and liraglutide were associated with reductions in non-fatal stroke incidence, fewer hospitalizations, and improved neurological outcomes in patients with prior stroke or high cardiovascular risk. The review highlights that stroke reduction may represent a class effect of GLP-1 RAs, though differences between individual agents exist, attributed to variations in pharmacokinetics, receptor affinity, and study populations. Evidence in the acute stroke setting is described as preliminary, coming largely from early-phase or ongoing trials. The authors also discuss emerging agents—orforglipron, retatrutide, Maridebart cafraglutide, and CagriSema—as potential future options. Limitations acknowledged include the narrative (non-systematic) design, reliance on trial-level rather than individual patient data, and the absence of large-scale, long-term randomized trials specifically targeting post-stroke populations. The authors conclude that GLP-1-based therapies should currently be considered tools for long-term vascular risk reduction rather than established acute stroke treatments.
Pharmaceutics · May 2026DOI ↗ Moderate · human
This network meta-analysis (NMA) synthesized evidence from six randomized controlled trials (N = 4,642; durations 12–68 weeks) to compare novel amylin-based therapies (ABTs) — amycretin, eloralintide, and cagrilintide/semaglutide (CagriSema) — against placebo and established anti-obesity agents (semaglutide 2.4 mg, liraglutide 3.0 mg) in adults with overweight or obesity without diabetes. Using a frequentist random-effects framework, the study found that high-dose subcutaneous amycretin produced the largest estimated reduction in percent body weight versus placebo (mean difference approximately −24%), followed by high-dose eloralintide (−18%) and high-dose CagriSema (−17%), all exceeding reductions seen with semaglutide 2.4 mg (−11%) and liraglutide 3.0 mg (−6%). Similar ranking patterns emerged for absolute weight, BMI, waist circumference, and categorical weight-loss thresholds. Gastrointestinal adverse events — particularly nausea, vomiting, and constipation — were more frequent with high-dose ABTs, and only high-dose CagriSema significantly increased treatment-discontinuation due to adverse events. The authors acknowledge that the included trials are few, relatively short-to-medium term, and carry low certainty of evidence, characterizing findings as preliminary and requiring confirmation in larger trials.
Endocrinology, diabetes & metabolism · May 2026DOI ↗ InsufficientPreprint
This study analyzed a large, publicly available independent testing dataset of 6,441 samples spanning fourteen peptide compounds sold through largely unregulated gray market channels directly to consumers. Compounds examined included BPC-157, semaglutide, tirzepatide, PT-141, TB-500, thymosin beta-4, and others marketed for purposes such as injury recovery, muscle growth, fat loss, and athletic performance. Researchers applied two quality acceptance frameworks — one approximating standards for 503A compounded medications and a stricter model reflecting FDA-approved drug production standards — to assess purity, measured abundance, and endotoxin burden. The study found that between 41.6% and 71.1% of samples failed to meet basic quality criteria depending on the framework applied, and measurable endotoxin contamination was detected in 15% of samples. Gray market peptides were consistently cheaper than FDA-approved alternatives, though cost differentials varied widely (e.g., 72.8% higher for tirzepatide vs. 3,850% higher for PT-141 when comparing FDA-approved options). The authors concluded that consumer-directed third-party testing improves transparency but captures only a fraction of the full safety profile relevant to patients self-administering injectable compounds. Key limitations include reliance on a secondary dataset not collected under controlled research conditions and the inability to assess many other safety dimensions beyond purity and endotoxin levels.
Unknown journal · Apr 2026DOI ↗ In vitro
This in vitro study examined the effects of three incretin-based therapies — semaglutide (GLP-1 receptor agonist), tirzepatide (dual GLP-1/GIP agonist), and cagrilintide (amylin analogue) — on mitochondrial function in C2C12 skeletal muscle myotubes under both normal and lipotoxic conditions. Lipotoxicity was induced using palmitic acid (PA), which significantly reduced basal oxygen consumption rate and ATP production in treated cells. The study used Seahorse XFp metabolic flux analysis, mitochondrial DNA copy number quantification (qPCR), and oxidative phosphorylation complex protein expression (western blotting), with key findings replicated in primary human skeletal muscle cells. The researchers found that semaglutide and cagrilintide transiently reduced basal respiration in healthy myotubes, while tirzepatide demonstrated more sustained improvements in mitochondrial respiration under both healthy and lipotoxic conditions. The study's primary limitations include its reliance on cell culture models, meaning findings may not directly translate to whole-organism physiology, and the use of a single lipotoxic stimulus. The partial replication in human primary cells adds some translational relevance, but in vivo validation remains absent.
Journal of cachexia, sarcopenia and muscle · Apr 2026DOI ↗ Review
This narrative review examines the rapidly evolving landscape of obesity pharmacotherapy, moving beyond currently approved injectable GLP-1 receptor agonists (GLP-1RAs). The authors contextualize the global obesity burden—affecting over 2 billion adults—and acknowledge the transformative but limited success of existing GLP-1-based therapies, citing weight loss plateaus, high inter-individual variability, and weight regain upon discontinuation as key unresolved challenges. The review synthesizes emerging drug classes including: oral GLP-1 agonists (e.g., orforglipron) aimed at improving global accessibility; multi-receptor agonists such as triple GLP-1/GIP/glucagon agonists (e.g., retatrutide, reportedly achieving 20–24% weight reduction) and dual GLP-1/glucagon agonists (e.g., survodutide, mazdutide) with potential benefits in metabolic-associated steatotic liver disease; novel dosing strategies via GLP-1/GIP combination agents (e.g., maridebart cafraglutide); amylin pathway agents (e.g., cagrilintide, amycretin); lean-mass-preserving agents (e.g., bimagrumab); and precision approaches for monogenic obesity (e.g., setmelanotide). The authors call for phenotype-stratified trials, long-term safety data, pediatric research, and equitable implementation. As a review, it does not present original trial data and is inherently subject to selection and interpretation bias.
Metabolism open · 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 ↗ 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 ↗ Strong · human
This systematic review and meta-analysis evaluated the efficacy and safety of CagriSema — a dual therapy combining the GLP-1 receptor agonist semaglutide with the amylin analogue cagrilintide — compared to semaglutide monotherapy or placebo in adults with obesity. The authors searched four major databases through July 2025 and identified four eligible randomized controlled trials encompassing 4,419 participants (CagriSema: 3,055; controls: 1,364). Pooled analyses found that CagriSema was associated with significantly greater percent body weight loss (Cohen's d: −1.38; 95% CI: −1.84 to −0.91), greater absolute weight reduction (mean difference: −11 kg), reductions in waist circumference (−9.41 cm), and lower systolic blood pressure (−7.06 mmHg) versus comparators. However, gastrointestinal adverse events occurred more frequently with CagriSema (relative risk: 1.32). Notable limitations include high statistical heterogeneity (I² = 94.8%) across the included trials, the small number of studies (n = 4), and the absence of long-term safety and cardiovascular outcomes data. The authors conclude that CagriSema demonstrates superior weight reduction compared with semaglutide or placebo, but that tolerability monitoring and longer-term evidence are warranted.
The American journal of cardiology · Feb 2026DOI ↗ Review
This review examines the development and clinical progress of long-acting amylin-related peptides as treatments for obesity and type 2 diabetes. It traces the field from the first-generation amylin receptor (AMYR) agonist pramlintide—which acts centrally to induce satiety, suppress glucagon, and reduce post-meal hyperglycemia but had limited use as an insulin adjunct—to a new generation of non-aggregating, long-acting analogues. The authors describe advances in understanding the heterodimeric structure of amylin-calcitonin receptor complexes that have guided the rational design of these newer agents. Highlighted compounds include the dual AMYR/calcitonin-receptor agonist cagrilintide, the combination product CagriSema (cagrilintide plus semaglutide), and the unimolecular tri-agonist amycretin. Several monotherapy candidates (eloralintide, petrelintide, Met-233, AZD6234) are also discussed. The review notes that gastrointestinal side effects—chiefly nausea—are common during initiation but typically resolve with continued use, and highlights emerging preclinical and early clinical signals for potential benefits in fatty liver disease, diabetic kidney disease, and resistant hypertension. As a narrative review, it synthesizes heterogeneous sources and does not itself generate new primary data.
Review
This review examines the evolving therapeutic role of amylin, a pancreatic peptide hormone, in managing "diabesity" — the coexistence of diabetes and obesity — over the past five years. The authors describe amylin's physiological mechanisms, including postprandial glucose regulation through delayed gastric emptying and glucagon suppression, as well as appetite control via central nervous system pathways. The review covers preclinical development of long-acting amylin analogs with improved pharmacokinetics and reduced aggregation, which demonstrated significant metabolic benefits in animal models. Clinically, the review highlights pramlintide, a synthetic amylin analog shown to modestly improve glycemic control and promote weight loss in diabetic patients. It also discusses cagrilintide, a newer long-acting analog, which the authors report has produced substantial weight reduction in individuals with obesity. Notably, the review emphasizes that combining amylin analogs with GLP-1 receptor agonists may achieve synergistic weight loss exceeding 15%. Limitations include the inherent constraints of a review design — it does not present new primary data, and the breadth of evidence cited spans preclinical to early clinical stages, meaning conclusions about long-term efficacy and safety remain preliminary.
Journal of obesity & metabolic syndrome · Jan 2026DOI ↗ Moderate · human
The REDEFINE 1 trial was a phase 3a, 68-week randomized controlled trial that evaluated the blood pressure (BP) effects of CagriSema (a fixed-dose combination of semaglutide 2.4 mg and cagrilintide 2.4 mg) in 3,417 adults without diabetes who had overweight or obesity, with or without obesity-related complications. Participants were randomized to once-weekly CagriSema, semaglutide alone, cagrilintide alone, or placebo, alongside lifestyle intervention. Secondary and post hoc analyses focused on antihypertensive outcomes. The study found that CagriSema was associated with greater reductions in systolic BP (−10.9 vs. −2.8 mmHg) and diastolic BP (−5.4 vs. −1.7 mmHg) compared to placebo at week 68. A higher proportion of CagriSema participants reached BP targets (63.0% vs. 32.0%). Among those with resistant hypertension at baseline, BP target attainment was 42.0% vs. 29.3% (OR 1.7; 95% CI 0.7–4.4), though the confidence interval crossed 1. Notably, 39.6% of CagriSema participants on antihypertensive medications reduced or stopped treatment versus 18.8% with placebo. Limitations include that BP outcomes were secondary/post hoc endpoints, not primary, which limits causal inference strength for these specific findings.
Hypertension (Dallas, Tex. : 1979) · Dec 2025DOI ↗ Moderate · humanPreprint
This systematic review and meta-analysis (PROSPERO-registered) pooled data from four randomized controlled trials (n = 4,810 adults with overweight or obesity) to compare the fixed-dose combination of cagrilintide and semaglutide (CagriSema) against semaglutide alone, cagrilintide alone, or placebo. The authors found that, across all comparators, CagriSema was associated with statistically greater percent body weight reduction: approximately 7.4 percentage points more than semaglutide, 8.8 percentage points more than cagrilintide, and 13.9 percentage points more than placebo. The likelihood of achieving ≥15% or ≥20% weight loss was reported to be 2–3 times higher with the combination. Waist circumference was also significantly reduced with CagriSema versus placebo (mean difference approximately −10.9 cm). No consistent differences in HbA1c were observed across comparisons. Gastrointestinal adverse events were more frequent with CagriSema, and treatment discontinuation rates were correspondingly higher in the combination group. Limitations include the small number of included trials (four), preprint status introducing risk of non-peer-reviewed data, and potential heterogeneity across trial designs and populations.
Unknown journal · Nov 2025DOI ↗