Clinical Trials of glucagon-like peptide-1 receptor agonists (GLP-1Ras) in cardiometabolic diseases.
| Drugs | Name of the study | Type of the study | Research area | Participants | Key findings | Conclusion | Reference |
|---|---|---|---|---|---|---|---|
| Semaglutide | STEP 1 clinical trials | Randomized, double-blind, placebo-controlled, multicenter, phase 3 trial | Overweight and obesity | 1,961 patients with BMI ≥ 30 (or ≥ 27 with ≥ 1 weight-related comorbidity) and without diabetes | Semaglutide 2.4 mg once weekly led to a mean weight loss of 14.9% (vs 2.4% with placebo) and a mean weight reduction of 15.3 kg (vs 2.6 kg with placebo) over 68 weeks. | Semaglutide 2.4 mg once weekly achieved significant weight loss in participants with overweight or obesity | [14] |
| Semaglutide | STEP 2 clinical trials | Randomized, double-blind, double-dummy, placebo-controlled, multicenter, superiority, phase 3 trial | Overweight and obesityT2DM | 1,210 patients with BMI ≥ 27 and T2DM | Semaglutide 2.4 mg once weekly resulted in a mean weight loss of 9.6% (vs 3.4% with placebo) | Semaglutide 2.4 mg once weekly achieved significant weight loss in adults with overweight or obesity and T2DM | [44] |
| Semaglutide | STEP 4 clinical trials | Randomized, double-blind, placebo-controlled withdrawal study, phase 3 trial | Overweight and obesity | 803 patients with BMI ≥ 30 (or ≥ 27 with ≥ 1 weight-related comorbidity) and without diabetes | Continued semaglutide treatment resulted in sustained weight loss, with a mean weight change of –7.9% from week 20 to week 68, compared to +6.9% with placebo | Continued semaglutide treatment sustained weight loss over 48 weeks | [15] |
| Semaglutideliraglutide | STEP 8 clinical trials | Randomized, double-blind, placebo-controlled open-label, phase 3b trial | Overweight and obesity | 338 patients with BMI ≥ 30 (or ≥ 27 with ≥ 1 weight-related comorbidity) and without diabetes | Semaglutide (2.4 mg) led to a mean weight loss of 15.8%, compared with 6.4% for liraglutide (3.0 mg) at 68 weeks | Semaglutide resulted in significantly greater weight loss than liraglutide | [45] |
| Tirzepatide | SURMOUNT-1 clinical trials | Randomized, double-blind, placebo-controlled, phase 3 trial | Overweight and obesity | 2,539 patients with BMI ≥ 30 (or ≥ 27 with ≥ 1 weight-related comorbidity) and without diabetes | At week 72, tirzepatide (5 mg, 10 mg, 15 mg) led to mean weight loss of 15.0%, 19.5%, and 20.9%, respectively, compared to 3.1% with placebo. | Tirzepatide achieved significant and sustained weight loss in participants with obesity | [46] |
| Tirzepatide | SURMOUNT-2 clinical trials | Randomized, double-blind, multicentre, placebo-controlled, phase 3 trial | Overweight and obesityT2DM | 1,514 adults with BMI ≥ 27 and glycated hemoglobin (HbA1c) of 7–10% (53–86 mmol/mol) | At week 72, tirzepatide (10 mg, 15 mg) achieved mean weight loss of 12.8%, 14.7% vs 3.2% with placebo. | Tirzepatide resulted in significant weight loss in adults with obesity and T2DM | [47] |
| Semaglutide Cagrilintide (Dual Amylin–Calcitonin Receptor Agonist) | REDEFINE 1 clinical trials | Randomized, multicenter, double-blind, placebo-controlled, active-controlled, phase 3a trial | Overweight and obesity | 3,417 patients with BMI ≥ 30 (or ≥ 27 with ≥ 1 weight-related comorbidity) and without diabetes | At week 68, the combination of semaglutide 2.4 mg and cagrilintide 2.4 mg (CagriSema) led to a mean weight loss of –20.4% vs –3.0% with placebo; 91.9% of participants receiving CagriSema achieved at least a 5% weight reduction | CagriSema significantly reduced body weight in adults with overweight or obesity | [49] |
| Semaglutide Cagrilintide (Dual Amylin–Calcitonin Receptor Agonist) | REDEFINE 2 clinical trials | Randomized, international, double-blind, placebo-controlled, phase 3 trial | Overweight and obesityT2DM | 1,206 patients with BMI ≥ 27, a HbA1c level of 7 to 10%, and T2DM | At week 68, cagrilintide-semaglutide (2.4 mg each) led to a mean weight loss of –13.7% vs –3.4% with placebo; 86.5% of participants in the CagriSema group achieved at least a 5% weight reduction | CagriSema significantly reduced body weight in adults with obesity and T2DM | [50] |
| Mazdutide | GLORY-1 clinical trials | Randomized, double-blind, parallel-group, phase 3 trial | Overweight and obesity | 610 patients with BMI ≥ 28 (or ≥ 24 with ≥ 1 weight-related comorbidity) | At week 48, Mazdutide (4mg, 6mg) achieved mean weight loss of 11.00% and 14.01% vs 0.30% with placebo | Mazdutide significantly reduced body weight in adults with overweight or obesity and was well tolerated | [57] |
| Maridebart Cafraglutide | MARITIME-1clinical trials | Randomized, double-blind, parallel-group, phase 2 trial | Overweight and obesityT2DM | 465 patients with obesity and 127 individuals with obesity and diabetes | At week 52, Maridebart-cafraglutide achieved mean weight loss of –12.3% to –16.2% in the obesity cohort and –8.4% to –12.3% in the obesity-diabetes cohort, compared to –2.5% and –1.7% with placebo | Maridebart cafraglutide significantly reduced body weight in participants with obesity, with or without T2DM | [58] |
| Ecnoglutide | SLIMMER clinical trials | Randomized, double-blind, multicenter, placebo-controlled, phase 3 trial | Overweight or obesity | 882 patients with BMI ≥ 28 (or ≥ 24 with ≥ 1 weight-related comorbidity) without diabetes | At week 40, mean weight loss was –9.1% (1.2 mg), –10.9% (1.8 mg), and –13.2% (2.4 mg) vs 0.1% (placebo). At least 5% weight reduction was achieved by 77% (1.2 mg), 84% (1.8 mg), and 87% (2.4 mg) vs 16% (placebo). | Ecnoglutide significantly reduced weight with a favorable safety profile | [59] |
| Semaglutide VS Dulaglutide | SUSTAIN 7 clinical trials | Randomized, open-label, parallel-group, phase 3b trial | T2DM | 1,201 patients aged 18 years or older with T2DM with HbA1c 7.0–10.5% (53.0–91.0 mmol/mol) on metformin monotherapy | At week 40, semaglutide 0.5 mg reduced HbA1c by 1.5% vs 1.1% with dulaglutide 0.75 mg, and semaglutide 1.0 mg reduced HbA1c by 1.8% vs 1.4% with dulaglutide 1.5 mg. Semaglutide led to weight loss of –4.6 kg with 0.5 mg vs –2.3 kg with 0.75 mg dulaglutide and –6.5 kg with 1.0 mg vs –3.0 kg with 1.5 mg dulaglutide. | Semaglutide was superior to dulaglutide in improving glycemic control and reducing body weight, with a similar safety profile | [22] |
| Semaglutide | STEP-HFpEF DM clinical trials | Randomized, international, double-blind, placebo-controlled, phase 3 trial | CVDObesityT2DM | 616 patients who had HFpEF, BMI ≥ 30 kg/m2 and T2DM | Semaglutide led to a mean KCCQ-CSS improvement of 13.7 points and a mean weight loss of 9.8%, compared to 6.4 points and 3.4% with placebo | Semaglutide resulted in greater reductions in symptoms and weight loss than placebo in patients with HFpEF, obesity, and T2DM | [60] |
| Semaglutide | STEP-HFpEF clinical trials | Randomized, international, double-blind, placebo-controlled, phase 3 trial | ObesityCVD | 529 patients who had HFpEF and BMI ≥ 30 kg/m2 | Semaglutide (2.4 mg) significantly improved symptoms and physical limitations, with a mean KCCQ-CSS increase of 16.6 points and a mean weight loss of 13.3%, compared to 8.7 points and 2.6% with placebo | Semaglutide (2.4 mg) led to greater improvements in symptoms, physical limitations, and weight loss than placebo in patients with HFpEF and obesity | [61] |
| Semaglutide | SELECT clinical trials | Randomized, double-blind, multicenter, placebo-controlled, event-driven superiority trial | CVDOverweight or obesity | 17,604 patients aged 45 or older with preexisting CVD and BMI ≥ 27 kg/m2 without diabetes | Primary cardiovascular events occurred in 6.5% of the semaglutide group vs 8.0% of the placebo group (HR 0.80; 95% CI 0.72–0.90; P < 0.001) | Semaglutide reduced cardiovascular events in patients with CVD and overweight/obesity without diabetes | [9] |
| Dulaglutide | REWIND clinical trials | Randomized, double-blind, multicenter, placebo-controlled trial | CVDT2DM | 9,901 patients aged 45 or older with T2DM who had either a previous cardiovascular event or cardiovascular risk factors | Dulaglutide reduced major adverse cardiovascular events (MACE) by 12% in patients with T2DM and cardiovascular risk factors. The primary composite outcome occurred in 12.0% of participants in the dulaglutide group vs 13.4% in the placebo group during a median follow-up of 5.4 years | Dulaglutide demonstrated significant cardiovascular protection in patients with T2DM and cardiovascular risk factors | [26] |
| Semaglutide | SOUL clinical trials | Randomized, double-blind, placebo-controlled, event-driven, superiority trial | CVDT2DMCKD | 9,650 patients aged 50 years or older with T2DM (HbA1c 6.5%–10.0%) and atherosclerotic CVD, CKD, or both | After a mean follow-up of 47.5 months, the incidence of major adverse cardiovascular events (MACE) was 12.0% in the semaglutide group and 13.8% in the placebo group | Semaglutide significantly reduced the risk of major adverse cardiovascular events without increasing the incidence of serious adverse events | [62] |
| Semaglutide | FLOW clinical trials | Randomized, double-blind, International, parallel-group, phase 3 trial | CKDT2DM | 3,533 patients with T2DM and CKD (defined by an estimated glomerular filtration rate [eGFR] of 50 to 75 mL per minute per 1.73 m2 of body-surface area and a urinary albumin-to-creatinine ratio [with albumin measured in milligrams and creatinine measured in grams] of > 300 and < 5,000 or an eGFR of 25 to < 50 mL per minute per 1.73 m2 and a urinary albumin-to-creatinine ratio of > 100 and < 5,000) | Semaglutide reduced the risk of major kidney disease events by 24% and major cardiovascular events by 18% | Semaglutide significantly lowered the risk of kidney failure and cardiovascular death in patients with T2DM and CKD | [8] |
| Semaglutide | Tirzepatide in MASH | Randomized, double-blind, multicenter, placebo-controlled, ongoing phase 3 trial | Metabolic dysfunction-associated steatohepatitis (MASH) | 1,197 patients with biopsy-defined MASH and fibrosis stage 2 or 3 | At week 72, semaglutide resolved steatohepatitis in 62.9% of patients vs 34.3% with placebo and reduced liver fibrosis in 36.8% vs 22.4% with placebo | Semaglutide significantly improved liver histology in patients with MASH and moderate to advanced fibrosis | [63] |
BMI: body mass index; CKD: chronic kidney disease; CVD: cardiovascular disease; HFpEF: heart failure with preserved ejection fraction; T2DM: type 2 diabetes mellitus.