The obesity epidemic is a major health burden that enhances susceptibility to a broad spectrum of metabolic-associated comorbidities, ranging from fatty liver disease and endocrine dysfunction to traditional risks like type 2 diabetes mellitus and cardiovascular disease. Glucagon-like peptide-1 receptor agonists, including semaglutide, facilitate weight loss alongside glucose metabolism. The dual therapy CagriSema, which combines semaglutide with cagrilintide was developed. We systematically searched MEDLINE (via PubMed), Web of Science, Scopus, and Cochrane Library, from inception to July 2025, for randomized controlled trials (RCTs) comparing CagriSema with semaglutide monotherapy or placebo in patients with obesity. Four RCTs ( n = 4,419) were included (CagriSema: 3,055; control: 1,364). Pooled analysis showed that CagriSema significantly reduced percent weight loss (Cohen’s d:-1.38; 95% CI:-1.84 to–0.91; I² = 94.8%). CagriSema also resulted in greater absolute weight loss (MD:–11 kg), waist circumference (MD:–9.41 cm), and systolic blood pressure (MD:–7.06 mmHg). Gastrointestinal adverse events were more frequent (RR: 1.32). CagriSema therapy was associated with superior weight reduction compared with semaglutide or placebo. In conclusion, CagriSema achieves greater weight loss than semaglutide or placebo but increases gastrointestinal adverse events, warranting careful tolerability monitoring and longer-term data.
Obesity is a chronic and complicated disease that increases the risk of cardiovascular complications. , Obesity is defined by a body mass index (BMI) of ≥30 kg/m 2. According to the World Health Organization (WHO), > 650 gt; 650 million adults are now classified as obese, while > 1.9 billion are considered overweight as of 2022. Obesity is associated with a substantial rise in morbidity, mortality, and healthcare expenditure, largely due to its strong association with type 2 diabetes mellitus (T2DM), hypertension, dyslipidemia, and other cardiovascular conditions. ,
T2DM, affecting > 530 gt; 530 million people globally, is strongly linked to obesity, a connection commonly termed “diabesity”. , Obesity plays a major role in insulin resistance, worsening glycemic imbalances, and complicating the management of diabetes. Although lifestyle modifications, as a healthy diet and different types of exercise, are central to obesity management, their long-term effectiveness is frequently limited, especially in morbid obesity. ,, As a result, there is growing reliance on pharmacological interventions to achieve sustained weight loss and improved metabolic outcomes. ,, Among the current pharmacological treatments available, glucagon-like peptide-1 receptor agonists (GLP-1 RAs), like semaglutide, have shown significant effectiveness in facilitating weight loss and improving glycemic control in obese individuals. GLP-1 RAs effects are sustained mainly by mechanisms that involve promoting insulin release, prolonging gastric emptying, and reducing appetite. , However, variations in individual responses and the ceiling effect noted in weight loss outcomes have made it crucial to explore combination therapies that target complementary physiological pathways. , Cagrilintide is a new, long-lasting analogue of amylin—a peptide released alongside insulin from pancreatic β-cells that manages satiety, delays gastric emptying, and reduces postprandial glucagon release. Cagrilintide’s method of action differs from GLP-1 RAs, yet it yields synergistic effects when given together. The pairing of cagrilintide and semaglutide, known as CagriSema, has surfaced as a hopeful dual-hormonal approach for attaining enhanced weight loss and metabolic regulation in those with obesity, irrespective of T2DM.
Although early randomized controlled trials (RCTs) have shown that CagriSema may offer superior weight loss and metabolic benefits compared to monotherapy, the consistency and generalizability of these effects remain uncertain. One prior meta-analysis has attempted to synthesize the evidence on CagriSema, reporting promising short-term results from available RCTs; however, it was limited by the inclusion of 3 trials with a relatively small sample size of 430 patients and a narrow assessment of outcomes according to available data back then.
Methods
This systematic review and meta-analysis were conducted and reported following the PRISMA 2020 guidelines. The methodologies proposed followed the Cochrane Handbook of Systematic Reviews and Meta-Analysis of Interventions. The review protocol was prospectively registered in the International Prospective Register of Systematic Reviews, PROSPERO (Identifier No: CRD420251108255).
Literature search
A comprehensive literature search was conducted on databases including MEDLINE (via PubMed), Scopus, Web of Science, and Cochrane Library from inception until July 2025, using the following search strings: (Cagrilintide OR Amylin OR “amylin analog” OR “amylin receptor agonist” OR “gastric emptying” OR satiety OR “appetite regulation” OR “peptide hormone” OR Semaglutide OR Ozempic OR Wegovy OR “GLP-1 receptor agonist” OR GLP-1RA OR “glucagon-like peptide-1”) AND (obesity OR overweight OR “body mass index” OR BMI) AND (“type 2 diabetes” OR T2D OR “non-insulin dependent diabetes”). The search strings were restricted to studies in the English language only. Additionally, the reference list of all included RCTs was manually searched to identify other relevant records. The detailed search strategy used for every database is reported in Supplementary Table S1 .
Eligibility criteria
Two independent authors (AFG, NH) screened the search results in a two-step approach after removing duplicates using Rayyan software. First, titles and abstracts for all citations were screened, then full-text screening was performed on select records based on the inclusion criteria. The studies were deemed eligble if they: (a) were RCTs, (b) included obese patients (with BMI ≥27 kg/m² and with or without diabetes mellitus type 2), (c) had patients treated with cagrilintide 2.4 mg plus semaglutide 2.4 mg (cagrisema) in one arm, (d) had patients treated with semaglutide 2.4 mg or placebo in the other arm, (e) and reported one of the relevant outcomes. The primary outcome of interest was the percentage reduction in body weight. Secondary outcomes were absolute reduction in body weight, waist-circumference reduction, percentage of patients achieving weight reduction by 10% and 15%, and hemoglobin A1c (HbA1c), fasting plasma glucose (FPG), and systolic blood pressure (SBP). The safety outcome was gastrointestinal adverse events. Further, observational studies, conference abstracts with unpublished full data, single-arm studies, case reports, reviews, expert commentary, editorials, and non-English studies were excluded.
Quality assessment
Two authors (AD, FA) evaluated the risk of bias in the included RCTs using the Cochrane Risk of Bias 2 tool (ROB2) for RCTs. This tool compares five domains: selection bias, performance bias, detection bias, attrition bias, and reporting bias. Each RCT was rated as having a high risk of bias, some concerns, or a low risk of bias. Any discrepancies in agreement were resolved through either mutual consensus or by consulting a third investigator (H.J.). The GRADE tool, which is used to assess how certain the evidence is from the studies, was also utilized. The GRADE tool rates the evidence as high, moderate, low, or very low, based on factors like the risk of bias, how consistent the results are, how directly the evidence applies to the question, and whether the results are precise enough.
Data extraction
A pre-piloted standard spreadsheet was used to extract the data from the included RCTs. The data were extracted by 2 independent authors (FA, AD). The standardized sheet included four domains: (1) summary of the included studies: country, trial phase, total number of patients, intervention details, comparator details, inclusion criteria, exclusion criteria, primary endpoint and the study duration; (2) characteristics of the included patients: number of participants, age, percetange of female participants, body weight, body mass index (BMI), waist circumference, glycated hemoglobin level (HbA1c), FPG, fasting serum insulin level, SBP, diastolic blood pressure (DBP), estimated glomerular filtration rate (eGFR), duration of diabetes, use of metformin, impact of weight on quality of life–lite clinical trials version score (IWQOL-LITE-CT), short form 36 version 2 score (SF-36V2), total cholesterol, low-density lipoprotein cholesterol (LDL), high-density lipoprotein cholesterol (HDL), non–high-density lipoprotein cholesterol (non-HDL), very-low-density lipoprotein cholesterol (VLDL), and triglycerides (TG); (3) risk of bias domains; and (4) data on relevant outcomes.
Statistical analysis
Continuous data were extracted as mean change between the baseline and the last point of the follow-up, standard deviation (SD), and total number of patients (N) included in each study. When the data were not presented in the full text, it was extracted from the depicted graphs. Standard error (SE) or coefficient of variance (CV) was converted to SD when SD was not reported. For each outcome, the Cohen’s d and its 95% confidence interval (CI) were pooled using the Random-effect REML model. Dichotomous data were extracted as the frequency of events and the total number of patients included at the latest follow-up duration from each study. The pooled risk ratio (RR) with its 95% confidence interval (CI) was calculated using the Random-effect REML model. The heterogeneity was assessed using the Cochrane Q test, and the I 2 measure was determined across all studies. A p -value < 0.05 and an I 2 value ≥50% were considered as significant heterogeneity among the included studies.
The Galbraith plot was also used for the primary outcome to identify outlier studies in case of significant heterogeneity. To assess the publication bias, doi plots were created to visualize the relationship between pooled effect sizes and standard error using the LFK index.
Additionally, Subgroup analysis was conducted based on the reception of placebo or semaglutide in the control group. STATA software version 19MP was used for all statistical analyses.
Results
Literature search and characteristics
The initial literature search yielded 828 records. Of these, 121 were duplicates, and 707 records were subjected to title and abstract screening. Finally, A total of 11 articles underwent full-text evaluation, of which 7 were excluded for the following reasons: irrelevant population ( n = 2), intervention not of interest ( n = 2), review article ( n = 1), and single-arm study design ( n = 2), and four RCTs were finally included in the analysis. ,,, The PRISMA flow diagram depicting the study selection process is shown in Figure 1 .
PRISMA flow diagram of the study selection process.
A total of four RCTs included 4419 patients: 3055 patients (69.1%) received CagriSema, and 1364 patients (30.9%) received the standard therapy: either placebo (1007 patients (73.8%)), semaglutide (333 patients (24.4%)), or semaglutide with placebo (24 patients (1.8%)). Detailed baseline characteristics and a summary of the included studies are reported in Tables 1 and 2 .
Table 1
Summary characteristics of the included studies.
| Study ID | Trial name | Country | Phase | Total participants | Intervention (in details: dose, escalation, maintenance) | Administration | Comparator | Inclusion criteria | Exclusion criteria | Primary endpoints | Study duration |
|---|---|---|---|---|---|---|---|---|---|---|---|
| Davies 2025 | REDEFINE 2 | Multicentric, in 12 countries | Phase 3a | 1206 | CagriSema initiated at 0.25 mg of each drug, increased every 4 weeks until the maximum dose of 2.4 mg of each drug was reached by week 16. | Once-weekly subcutaneous injection via a dual-chamber, single-dose, single-use pen device | Placebo | Adults with a body-mass index (BMI) of 27 or more, a glycated hemoglobin (HbA1c) level of 7 to 10%, and type 2 diabetes diagnosed at least 180 days before screening. | Previous surgical or pharmacologic treatment for obesity within 90 days before screening. |
the percent
change in body weight and the percentage of patients with a reduction in body weight of 5% or more from baseline to week 68 |
68 weeks |
| Garvey 2025 | REDEFINE 1 | Multicentric, in 22 countries | Phase 3a | 3417 | CagriSema initiated at 0.25 mg of each drug, increased every 4 weeks until the maximum dose of 2.4 mg of each drug was reached by week 16. | Once-weekly subcutaneous injection via a dual-chamber, single-dose, single-use pen device | Semaglutide 2.4 mg and Placebo | Adults with a BMI of 30 or higher, or a BMI of 27 or higher with at least one obesity-related complication. | Diabetes, surgical treatment for obesity, or treatment with a glucose-lowering agent, GLP-1 receptor agonist, or antiobesity medication within 90 days before screening. |
Relative change in body weight from baseline to week 68 with CagriSema as compared with placebo.
A reduction of 5% or more in body weight from baseline to week 68 with CagriSema as compared with placebo. |
68 weeks |
| Frias 2023 | – | USA | Phase 2 | 92 | CagriSema initiated at 0.25 mg of each drug, increased every 4 weeks until the maximum dose of 2.4 mg of each drug was reached by week 16. | Once-weekly subcutaneous injection | Semaglutide 2.4 mg | Adults with type 2 diabetes, BMI of 27 kg/m² or higher, and HbA1c between 7.5% and 10.0%. Participants were on a stable daily dose of metformin with or without an SGLT2 inhibitor for at least 90 days before screening. | Renal impairment, uncontrolled and potentially unstable diabetic retinopathy or maculopathy. | Change from baseline in HbA1c to week 32 | 32 weeks |
| Enebo 2021 | – | USA | Phase 1b | 95 | CagriSema initiated at 0.25 mg of each drug, increased every 4 weeks until the maximum dose of 2.4 mg of each drug was reached by week 16. | Once-weekly subcutaneous injection | Semaglutide 2.4 mg with Placebo | Individuals aged 18–55 years with a BMI of 27.0 − 39.9 kg/m² and who were otherwise healthy. | Individuals aged 40 years or older with an estimated 10-year atherosclerotic cardiovascular disease risk of 5% or higher at screening. | Treatment-emergent adverse events from baseline to end of follow-up | 25 weeks |
Table 2
Baseline characteristics of the included patients.
| Study ID | Groups | Number | Age (years), mean (SD) | Female, n (%) | Body weight (Kg), n (%) | BMI, mean (SD) | WC (cm), mean (SD) | Hba1c level (%), mean (SD) | FBG level, (mmol/L), mean (SD) | FSI (pmol/L), mean (SD) | SBP, (mm Hg), mean (SD) | DPB (mm Hg), mean (SD) | eGFR (mL/min/1.73 m2), mean (SD) | Duration of diabetes (years), mean (SD) | Metformin, n (%) | IWQOL-Lite-CT score, mean (SD) | SF-36v2 score, mean (SD) | Total cholesterol (mg/dl), mean (SD) | LDL (mg/dl), mean (SD) | HDL (mg/dl), mean (SD) | non-HDL (mg/dl), mean (SD) | VLDL (mg/dl), mean (SD) | Triglycrides (mg/dl), mean (SD) |
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Davies 2025 29 a | CagriSema | 904 | 55.9 (11.8) | 429 (47.5) | 101.9 (22.6) | 36.1 (6.7) | 115.6 (14.7) | 8 (0.8) | 9.3 (2.4) | 113.6 (82.6) | 130.2 (14) | 80.4 (9.6) | 94.2 (19.3) | 8.5 (6.3) | 773 (85.5) | 59 (24.3) | 44.8 (9.8) | 166.9 (42.2) | 81.6 (41.6) | 43.3 (11.3) | 120.5 (42.2) | 32.7 (17.36) | 166.5 (92.6) |
| Placebo | 302 | 56.5 (10.7) | 140 (46.4) | 103.3 (23.5) | 36.4 (7.1) | 116.4 (15.2) | 8 (0.8) | 9.5 (2.8) | 117.2 (80) | 130.2 (13.8) | 80.4 (9.3) | 93.4 (17.2) | 8.7 (5.9) | 263 (87.1) | 59.7 (24) | 44.6 (9.6) | 168.6 (40.3) | 83.6 (38.9) | 43.8 (11.4) | 121.7 (39.55) | 32.6 (16.79) | 164.8 (88.8) | |
| Garvey 2025 30 a | CagriSema | 2108 | 47.1 (11.9) | 1441 (68.4) | 107.2 (23.2) | 38 (6.8) | 115 (15.7) | 5.5 (0.4) | 5.5 (0.7) | 103.5 (72.76) | 126.8 (14.1) | 82 (9.2) | – | – | – | 54 (23.3) | 45.7 (8.9) | 190 (38.4) | 112.1(33.5) | 48.7 (12) | 138.8(37.6) | 24 (11.8) | 120.7 (59.9) |
| Semaglutide | 302 | 47.4 (11.5) | 199 (65.9) | 105.9 (20.7) | 37.4 (5.9) | 114.2 (15.3) | 5.5 (0.4) | 5.5 (0.7) | 105.7 (72) | 127 (14.8) | 81.8 (9.4) | – | – | – | 55.2 (22.4) | 46.6 (8.6) | 186.7 (37.3) | 107 (37) | 48.8 (13) | 135.4 (36.3) | 24.2 (12.4) | 121.8 (65.2) | |
| Placebo | 705 | 46.7 (11.9) | 461 (65.4) | 106.6 (23.7) | 37.8 (7.1) | 114.1 (15.3) | 5.5 (0.4) | 5.5 (0.7) | 104.7 (75.7) | 128.1 (14.7) | 82.5 (9.2) | – | – | – | 54.7 (23.8) | 45.7 (8.9) | 190 (38.19) | 111.1 (33.2) | 48.9 (12.4) | 138.4 (37.1) | 24.2 (12.4) | 122.3 (63.8) | |
| Frias 2023 a | CagriSema | 31 | 56 (10) | 13 (42) | 104.3 (23.2) | 35.9 (5.7) | – | 8.5 (0.8) | 10 (3.2) | 114.3 (79.55) | 130 (15) | 80 (7) | 94 (12) | 6.4 (3.8) | 23 (74) | – | – | 150.8 (40.4) | 69.6 (38.6) | 38.7 (11.96) | – | 34.8 (16.6) | 168.3 (79.6) |
| Semaglutide | 31 | 57 (10) | 13 (42) | 105.4 (24.9) | 36.2 (7.2) | – | 8.6 (0.7) | 9.8 (2.1) | 111.8 (101.85) | 128 (13) | 79 (11) | 90 (18) | 9.2 (8.3) | 23 (74) | – | – | 170.1 (34.7) | 88.9 (28.5) | 42.5 (9.27) | – | 34.8 (16.15) | 168.3 (78.1) | |
| Enebo 2021 | CagriSema | 12 | 43 (8·1) | 7 (58) | 92·1 (11·9) | 32·2 (2·5) | – | 5·2 (0·4) | – | – | – | – | – | – | – | – | – | – | 123.7 (23.2) | 54.1 (15.5) | – | – | 105.4 (32.8) |
| Semaglutide with Placebo | 24 | 41 (8·8) | 8 (33) | 99·6 (15·6) | 32·2 (3) | – | 5·4 (0·4) | – | – | – | – | – | – | – | – | – | – | 131.5 (23.2) | 50.3 (11.6) | – | – | 117.8 (76.2) |
Stay updated, free articles. Join our Telegram channel
Full access? Get Clinical Tree
