Background
Updates on CVOTs
Study name | Study status | Drug | Drug class | Intervention | Primary outcome | n | Median follow up | Start and end date | Clinicaltrials.gov ID |
---|---|---|---|---|---|---|---|---|---|
EMPEROR-preserved [37] | Completed | Empagliflozin | SGLT2 inhibitor | Empagliflozin 10 mg once daily vs. placebo | Composite of CV death or HHF | 5988 | 2.2 | 03.2017–04.2021 | NCT03057951 |
FIGARO-DKD [36] | Completed | Finerenone | Mineralocorticoid receptor antagonist | Finerenone 10 mg or 20 mg once daily vs. placebo | Composite of death from CV causes, nonfatal MI, nonfatal stroke, or HHF | 8246 | 3.4 | 09.2015–02.2021 | NCT02545049 |
AMPLITUDE-O [35] | Terminated | Efpeglenatide | GLP-1 receptor agonist | Efpeglenatide 4 mg or 6 mg subcutaneous once a week vs. placebo | Composite of nonfatal MI, nonfatal stroke, or death from CV or undetermined causes | 4077 | 1.8 | 04.2018–12.2020 | NCT03496298 |
EMPEROR-preserved [37] | ||
---|---|---|
Class and cardiovascular outcomes | HR (95% CI) | p-value |
Primary composite outcome | ||
Composite of cardiovascular death or hospitalization for heart failure | 0.79 (0.69–0.90) | < 0.001 |
Secondary outcome | ||
Total number of hospitalizations for heart failure | 0.73 (0.61–0.88) | < 0.001 |
Secondary outcome | ||
Mean slope of change in eGFR per year—ml/min/1.73 m2 | 1.36 (1.06–1.66) | < 0.001 |
Other prespecified analyses | ||
Change in KCCQ clinical summary score at week 52 | 1.32 (0.45–2.19) | |
Other prespecified analyses | ||
Total number of hospitalizations for any cause | 0.93 (0.85–1.01) | |
Other prespecified analyses | ||
Composite renal outcome | 0.95 (0.73–1.24) | |
Other prespecified analyses | ||
Onset of new diabetes in patients with prediabetes | 0.84 (0.65–1.07) | |
Other prespecified analyses | ||
Death from any cause | 1.00 (0.87–1.15) |
Adverse events | Event rate (%) active vs. placebo group | |
---|---|---|
Urinary tract infections | 9.9 vs. 8.1 | |
Genital infections | 2.2 vs. 0.7 | |
Hypotension | 10.4 vs. 8.6 |
FIGARO-DKD [36]—Finerenone | AMPLITUDE-O [35]—Efpeglenatide | ||
---|---|---|---|
Class and cardiovascular outcomes | HR (95% CI), p-value | Class and cardiovascular outcomes | HR (95% CI), p-value |
Number of participants | 7437 | Number of participants | 4076 |
Primary composite outcome | Primary composite outcome | ||
Composite of CV death, nonfatal MI, nonfatal stroke, and HHF | 0.87 (0.76–0.98), p = 0.03 | Incident MACE | 0.73 (0.58–0.92), +p < 0.001 |
Secondary outcome | Secondary outcome | ||
Composite of onset of kidney failure, sustained ≥ 40% eGFR decline or death from renal causes | 0.87 (0.76–1.01) | Expanded MACE composite outcome event | 0.79 (0.65–0.96), *p = 0.02 |
Secondary outcome | Secondary outcome | ||
Hospitalization for any cause | 0.97 (0.90–1.04) | Composite renal outcome event | 0.68 (0.57–0.79), *p < 0.001 |
Secondary outcome | |||
All-cause mortality | 0.89 (0.77–1.04) | ||
Secondary outcome | |||
Kidney composite outcome | 0.77 (0.60–0.99) |
Adverse events | Event rate (%) active vs. placebo group | Adverse events | Event rate (%) active vs. placebo group (p-value) |
---|---|---|---|
Hyperkalemia | 10.8 vs. 5.3 | Severe gastrointestinal event | 3.3 vs. 1.8 (p=0.009) |
Hypokalemia | 1.1 vs. 2.4 | ||
Gynecomastia | 0.1 vs. 0.1 |
SGLT2 inhibitors
EMPEROR-Preserved (Table 2: HF outcome)
GLP-1 receptor agonists
AMPLITUDE-O (Table 3: CV outcome)
Mineralocorticoid receptor antagonists
FIGARO-DKD (Table 3: CV outcome)
Glycemic outcome trials
SURPASS trials: (Tables 4 and 5)
Study name | Clinicaltrials.gov ID | Study status | n | Key inclusion criteria | Key exclusion criteria | Intervention | Adjunctive therapy |
---|---|---|---|---|---|---|---|
SURPASS-1 [38] | NCT03954834 | Completed | 478 | Naive to diabetes injectable therapies, HbA1c 7.0–9.5%, BMI ≥ 23 kg/m2 at screening | Use of any oral antihyperglycemic medications for 3 months before screening, eGFR < 30 ml/min/1.73m2 | Tirzepatide 5, 10, or 15 mg SC once a week vs. placebo | None |
SURPASS-2 [39] | NCT03987919 | Completed | 1879 | HbA1c 7.0–10.5%, BMI ≥ 25 kg/m2 at screening Stable background medications (metformin) | eGFR < 45 ml/min/1.73m2 | Tirzepatide 5, 10, or 15 mg SC once a week vs. semaglutide 1 mg once a week | Metformin |
SURPASS-3 [40] | NCT03882970 | Completed | 1444 | HbA1c 7.0–10.5%, BMI ≥ 25 kg/m2 at screening Stable background medications (metformin ± SGLT2i) | eGFR < 45 ml/min/1.73m2 Other medications than metformin ± SGLT2i | Tirzepatide 5, 10, or 15 mg SC once a week vs. insulin degludec SC once a day | Metformin or metformin + SGLT2i |
SURPASS-4 [41] | NCT03730662 | Completed | 2002 | HbA1c 7.0–10.5%, BMI ≥ 25 kg/m2 at screening Increased risk of CV events Stable background medications (metformin ± sulfonylurea or SGLT2i) | Other medications than metformin ± sulfonylurea or SGLT2i | Tirzepatide 5, 10, or 15 mg SC once a week vs. insulin glargine SC once a day | Metformin or metformin + sulfonylurea or SGLT2i |
SURPASS-5 [42] | NCT04039503 | Completed | 457 | HbA1c 7.0–10.5%, BMI ≥ 23 kg/m2 at screening Stable background medications (insulin glargine (U100) ± metformin) | eGFR < 30 ml/min/1.73m2 (< 45 if treated with metformin) | Tirzepatide 5, 10, or 15 mg SC once a week vs. placebo | Insulin glargine or insulin glargine + metformin |
SURPASS-6 [57] | NCT04537923 | Active, not recruiting | 1182 | HbA1c 7.5–11%, BMI ≥ 23 and ≤ 45 kg/m2 at screening Stable background medications (insulin glargine (U100) ± metformin) | eGFR < 30 ml/min/1.73m2 (< 45 if treated with metformin) | Tirzepatide 5, 10, or 15 mg SC once a week vs. insulin lispro (U100) SC three times a day with insulin glargine (U100) SC | Insulin glargine or insulin glargine + metformin |
Study name | Primary/secondary endpoint(s) (weeks) | Mean HbA1c at baseline (%) | Mean HbA1c reduction from baseline (%) with tirzepatide 5/10/15 mg | Percentage of patients who met +HbA1c < 7.0%; #HbA1c ≤ 6.5% and *HbA1c < 5.7% with tirzepatide 5/10/15 mg | Mean body weight at baseline (kg) | Mean reduction in body weight from baseline (kg) with tirzepatide 5/10/15 mg | Percentage of patients who met a weight loss of a≥ 5%; b≥ 10%; and c≥ 15% with tirzepatide 5/10/15 mg |
---|---|---|---|---|---|---|---|
SURPASS-1 [38] | 40 | 7.94 | 1.87/1.89/2.07 | +87/92/88 #82/81/86 *34/31/52 | 85.9 | 7.0/7.8/9.5 | a67/78/77 b31/40 /47 c13/17/27 |
SURPASS-2 [39] | 40 | 8.28 | 2.01/2.24/2.30 | +82/86/86 #69/77/80 *27/40/46 | 93.7 | 7.6/9.3/11.2 | a65/76/80 b34/47/57 c15/24/36 |
SURPASS-3 [40] | 52 | 8.17 | 1.93/2.20/2.37 | +82/90/93 #71/80/85 *26/39/48 | 94.3 | 7.5/10.7/12.9 | a66/84/88 b37/56/69 c13/28/43 |
SURPASS-4 [41] | 52 | 8.52 | 2.24/2.43/2.58 | +81/88/91 #66/76/81 *23/33/43 | 90.3 | 7.1/9.5/11.7 | a63/78/85 b36/53/66 c14/24/37 |
SURPASS-5 [42] | 40 | 8.31 | 2.11/2.40/2.34 | +87/90/85 #74/86/80 *24/42/50 | 95.2 | 5.4/7.5/8.8 | a56/68/85 b24/49/48 c8/28/27 |
Obesity and overweight outcome trials
STEP trials: (Table 6)
Study name | Clinicaltrials.gov ID | Study status | n | Participants | Intervention | Primary outcome | Mean body weight at baseline (kg) | Mean percentage change in body weight from baseline semaglutide 2.4 mg vs. placebo | Percentage of patients who met a weight loss of ≥ 5% with semaglutide 2.4 mg vs. placebo |
---|---|---|---|---|---|---|---|---|---|
STEP 1 [43] | NCT03548935 | Completed | 1961 | With obesity or overweight, without T2D | Semaglutide 2.4 mg once a week vs. placebo | Percentage change in body weight and weight reduction of at least 5% at week 68 | 105.3 | − 14.9% vs. − 2.4% | 86.4% vs. 31.5% |
STEP 2 [44] | NCT03552757 | Completed | 1210 | With obesity or overweight, with T2D | Semaglutide 2.4 mg once a week vs. semaglutide 1.0 mg and placebo | Percentage change in body weight and weight reduction of at least 5% at week 68 | 99.8 | − 9.6% vs. − 3.4% | 68.8% vs. 28.5% |
STEP 3 [45] | NCT03611582 | Completed | 611 | With obesity or overweight, without T2D | Semaglutide 2.4 mg once a week vs. placebo in addition to intensive behavioral therapy | Percentage change in body weight and weight reduction of at least 5% at week 68 | 105.8 | − 16.0% vs. − 5.7% | 86.6% vs. 47.6% |
STEP 4 [46] | NCT03548987 | Completed | 902 | With obesity or overweight, without T2D | Semaglutide 2.4 mg once a week for the first 20 weeks, then random assignment: semaglutide 2.4 mg once a week vs. placebo for 48 weeks | Percent change in body weight from week 20 to week 68 | 107.2 | − 7.9% vs. + 6.9% | Not applicable |
STEP 5 [58] | NCT03693430 | Completed | 304 | With obesity or overweight, without T2D | Semaglutide 2.4 mg once a week vs. placebo | Percentage change in body weight and weight reduction of at least 5% at week 104 | 106.0 | − 15.2% vs. − 2.6% | 77.1% vs. 34.4 |