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 ↗ 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 ↗ 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 ↗ Moderate · human
This systematic review and meta-analysis evaluated the efficacy and safety of cagrisema (a fixed-ratio combination of the amylin analogue cagrilintide and the GLP-1 receptor agonist semaglutide) and cagrilintide monotherapy compared with semaglutide monotherapy for obesity management. Researchers searched five major databases and ClinicalTrials.gov, ultimately including three randomized controlled trials comprising 3,545 participants. Using a random-effects model, the study found that cagrisema produced statistically significantly greater reductions in percentage body weight (mean difference –7.47%, 95% CI: –10.58 to –4.36) and absolute body weight compared with semaglutide alone. Cagrisema also demonstrated superior improvements in glycemic markers, including fasting plasma glucose and HbA1c, and in BMI. Lipid parameters and safety profiles were reported as broadly comparable between groups. The authors concluded that cagrisema showed greater weight-loss efficacy and glycemic benefit than semaglutide, with an acceptable tolerability profile. Limitations include the small number of included trials (n=3), potential heterogeneity across trial designs, and the relatively short follow-up durations typical of early-phase RCTs in this therapeutic area.
Diabetes, obesity & metabolism · Mar 2026DOI ↗ Moderate · human
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 ↗ Moderate · human
This systematic review and meta-analysis examined the weight-loss efficacy and safety of cagrilintide (an amylin analogue) alone and in combination with semaglutide 2.4 mg (referred to as "Cagrisema") compared to placebo or active comparators (semaglutide or liraglutide) in adults with obesity. Researchers searched electronic databases and identified 3 eligible randomized controlled trials encompassing 430 participants. The pooled analysis found that Cagrisema was associated with significantly greater percentage and absolute body weight reduction compared to semaglutide 2.4 mg alone over 20–32 weeks, though with notably high statistical heterogeneity (I² up to 98%). Cagrilintide monotherapy showed statistically similar weight loss to semaglutide or liraglutide over 26–32 weeks. Regarding safety, treatment-emergent and serious adverse events were broadly comparable across groups; however, gastrointestinal adverse events and vomiting were significantly more frequent with Cagrisema versus semaglutide, while vomiting was significantly lower with cagrilintide monotherapy versus semaglutide or liraglutide. Key limitations include the very small number of included trials (n=3), limited total sample size, short-to-medium follow-up durations, and very high heterogeneity, which tempers confidence in the pooled estimates.
Indian journal of endocrinology and metabolism · Sep 2024DOI ↗