Table 1.

Summary of Randomized Controlled Trials Published in 2021 for Primary Prevention of ASCVD Events or Levels of ASCVD Risk Factors

Study	Study population	Intervention/study setting	Primary outcome	Secondary outcomes	Adverse outcomes
Obesity
REPOWER (Rural Engagement in Primary Care for Optimizing Weight Reduction) 1	1407 adults age 20–75 y and body mass index of 30–45 kg/m2	Cluster randomized trial among 36 clinics in rural Midwestern US; Clinics randomized to perform either in‐clinic individual visits, in‐clinic group visits, or telephone‐based group visits	Weight change at 24 mo A minimum clinically important difference was defined as 2.75 kg Mean weight loss at 24 mo was −4.4 kg (95% CI, −5.5 to −3.4 kg) in the in‐clinic group intervention, −3.9 kg (95% CI, −5.0 to −2.9 kg) in the telephone group intervention, and −2.6 kg (95% CI, −3.6 to −1.5 kg) in the in‐clinic individual intervention	At 6‐mo follow‐up, mean weight loss was −8.3 kg (95% CI, −9.2 to −7.4 kg) for in‐clinic group visits, −7.7 kg (95% CI, −8.6 to −6.8 kg) for telephone group visits, and −5.7 kg (95% CI, −6.7 to −4.8 kg) for in‐clinic individual visits At 24 mo, there was no significant difference between groups in the proportion of participants who achieved clinically meaningful weight loss >5%	Only 3 events were determined to be possibly study related (2 joint replacements and 1 cholecystectomy), and 1 probably related (recurrent syncope)
STEP (Semaglutide Treatment Effect in People with Obesity) 1 3	1961 adults with BMI ≥30 kg/m2 (or ≥27 kg/m2 with ≥1 weight‐related comorbidity) and without diabetes	68 wk of treatment with once‐weekly subcutaneous semaglutide 2.4 mg or placebo, plus lifestyle intervention	Mean change in body weight from baseline to week 68–14.9% with semaglutide and −2.4% with placebo, treatment difference −12.4 percentage points (95% CI −13.4 to −11.5); P<0.001	Weight loss of >5%, >10% and >15%, and >20% occurred in 86.4%, 69.1%, 50.5%, and 32.0%, respectively, with semaglutide vs 31.5%, 12.0%, 4.9%, and 1.7% with placebo Change in body weight from baseline to week 68 was −15.3 kg with semaglutide vs −2.6 kg with placebo group Change in SBP −6.16 mm Hg with semaglutide vs −1.06 mm Hg with placebo (P<0.001) Change in glycated hgb −0.45 percentage points with semaglutide vs −0.15 with placebo	Gastrointestinal disorders (typically nausea, diarrhea, vomiting, and constipation) were the most frequently reported events and occurred more often with semaglutide than placebo (74.2% vs 47.9%) Discontinuation of study drug more common with semaglutide, mainly from GI events (7.0% vs 3.1%) Serious adverse events 9.8% semaglutide and 6.4% of placebo
STEP (Semaglutide Treatment Effect in People with Obesity) 3 4	611 adults with BMI ≥30 kg/m2 (or ≥27 kg/m2 with ≥1 weight‐related comorbidity) and without diabetes	Once‐weekly subcutaneous semaglutide, 2.4 mg vs placebo combined with a low‐calorie diet for the first 8 wk and intensive behavioral therapy (ie, 30 counseling visits) during 68 wk	Mean body weight change from baseline to week 68 −16.0% for semaglutide vs −5.7% for placebo Treatment difference, −10.3 percentage points ([95% CI, −12.0 to −8.6]; P<0.001)	A higher proportion of participants in the semaglutide vs placebo group achieved weight losses of ≥10% or 15% (75.3% vs 27.0% and 55.8% vs 13.2%, respectively; P<0.001)	Gastrointestinal adverse events were more frequent with semaglutide (82.8%) vs placebo (63.2%) Treatment was discontinued owing to these events in 3.4% with semaglutide vs 0% placebo
STEP (Semaglutide Treatment Effect in People with Obesity) 4 5	902 adults with BMI ≥30 kg/m2 (or ≥27 kg/m2 with ≥1 weight‐related comorbidity) and without diabetes	Once‐weekly subcutaneous semaglutide, 2.4 mg for 20 wk, then randomized to placebo or continued semaglutide for weeks 20–68 (both with lifestyle intervention)	Mean weight loss for all participants during 1st 20 wk 10.6% With continued semaglutide, mean body weight change from week 20 to week 68 was −7.9% vs +6.9% with the switch to placebo (difference, −14.8 percentage points [95% CI, −16.0 to −13.5]; P<0.001)	Several parameters improved with continued s.c. semaglutide vs placebo (all P<0.001) Waist circumference (−9.7 cm [95% CI, −10.9 to −8.5 cm]), SBP (−3.9 mm Hg [95% CI, −5.8 to −2.0 mm Hg]), and SF‐36 physical functioning score (2.5 [95% CI, 1.6–3.3])	Gastrointestinal events were reported in 49.1% participants who continued subcutaneous semaglutide vs 26.1% with placebo; similar proportions discontinued treatment because of adverse events with continued semaglutide (2.4%) and placebo (2.2%)
Cardiometabolic and chronic kidney disease
PROPEL (Promoting Successful Weight Loss in Primary Care in Louisiana) 7	Health coaches embedded in 18 primary care clinics serving low‐income patients (803 patients total)	Usual care received their normal primary care; Intensive lifestyle intervention (ILI) group received a 24‐mo high‐intensity lifestyle‐based obesity treatment program, embedded in clinics, delivered by health coaches in weekly sessions	Secondary analysis of previously published trial in which % weight loss at 24 mo was significantly greater with ILI (change in body weight, −4.99%; 95% CI, −6.02 to −3.96) than usual‐care (−0.48%; 95% CI, −1.57 to 0.61) In current analyses no change in fasting glucose, total and HDL cholesterol or SBP at 24 mo Increases in HDL‐C greater with ILI than usual care (mean difference at 24 mo, 4.6 mg/dL [95% CI, 2.9–6.3]; P<0.01)	NA	None
SCORED (Effect of Sotagliflozin on Cardiovascular and Renal Events in Patients with Type 2 Diabetes and Moderate Renal Impairment Who Are at Cardiovascular Risk) trial 9	10 584 patients with T2DM (glycated hemoglobin level, ≥7%), chronic kidney disease (estimated glomerular filtration rate, 25–60 mL/min per 1.73 m2)	Sotagliflozin (200 mg once daily, increase to 400 mg as tolerated) vs placebo	Composite of the total number of deaths from cardiovascular causes, hospitalizations for heart failure, and urgent visits for heart failure 5.6 events per 100 patient‐years in the sotagliflozin group and 7.5 events per 100 patient‐years in the placebo group (hazard ratio, 0.74; 95% CI, 0.63–0.88; P<0.001)	First occurrence of death from cardiovascular causes, nonfatal MI, or nonfatal stroke, the HR was 0.84 (95% CI, 0.72–0.99)	Side effects more common with sotagliflozin than placebo Diarrhea 8.5% vs 6.0% Genital mycotic infections (2.4% vs 0.9%) DKA (0.6% vs 0.3%)
FIGARO‐DKD (Finerenone in Reducing Cardiovascular Mortality and Morbidity in Diabetic Kidney Disease) 10	7437 participants with either stage 2–4 CKD and moderately elevated albuminuria or stage 1 or 2 CKD and severely increased albuminuria	Finerenone 10–20 mg vs placebo	Composite of death from cardiovascular causes, nonfatal MI, nonfatal stroke, or hospitalization for heart failure occurred in 12.4% with finerenone vs 14.2% with placebo (HR=0.87, P=0.03), median follow up 3.4 y	Composite of kidney failure, a sustained decrease from baseline of at least 40% in the eGFR, or death from renal causes (9.5%) in the finerenone group and in 395 (10.8%) in the placebo group (hazard ratio, 0.87; 95% CI, 0.76–1.01)	Hyperkalemia‐related discontinuation of the trial regimen was higher with finerenone (1.2%) than with placebo (0.4%)
Hypertension
SSaSS (Salt Substitute and Stroke Study) 11	600 rural Chinese villages; Eligible participants (n=20 995) included adults with poorly controlled blood pressure (≥140 mm Hg with or 160 mm Hg without medication) and age >60 y (27.4%) or prior stroke (72.6%)	Salt substitute (75% sodium chloride and 25% potassium chloride) free of charge vs sodium chloride 100%	Over a median follow‐up of 5.1 y there was a significant reduction in stroke with the salt substitute (29.14 vs 33.65/1000 person‐years, P=0.006)	Reduction in MACE with salt substitute (49.1 vs 56.3/1000 person‐years, P<0.001)	No significant difference in the incidence of definite hyperkalemia
RADIANCE‐HTN TRIO 13	136 patients with resistant hypertension, defined as blood pressure >140/90 mm Hg with at least 3 antihypertensive medications, including a diuretic	Renal denervation vs sham procedure	Additional reduction in systolic blood pressure was −4.5 mm Hg (95% CI –8.5 to −0.3, P=0.002) greater than with the sham procedure at 2 mo	At 2 mo 35% of renal denervation group and 21% of sham group had controlled blood pressure (<135/85 mm Hg)	None
SPRINT (final report) 14	9361 with hypertension and ≥1 marker of cardiovascular risk	SBP targets of <120 mm Hg vs <140 mm Hg	Significant reduction in composite of MI, other ACS, stroke, acute decompensated heart failure, or death from cardiovascular causes persisted with intensive treatment (1.77% per year vs 2.4% per year, P<0.001)	All‐cause mortality decreased with intensive treatment, 1.06% per year vs 1.41% per year; hazard ratio, 0.75; 95% CI, 0.61–0.92	Higher incidence of hypotension (2.1% vs 1.2%, P=0.001) and electrolyte abnormalities (2.9% vs 2.2%, P=0.03) with intensive treatment
STEP (Chinese the Strategy of Blood Pressure Intervention in the Elderly Hypertensive Patients) 15	8511 adults with hypertension	SBP targets 110 to <130 or 130 to <150 mm Hg	Composite of stroke, ACS, ADHF, coronary revascularization, AF, or death from cardiovascular causes was significantly lower in the intensive vs standard‐treatment group (3.5% vs 4.6%, P=0.007) over 3.3 y	Individual components of primary outcome favored intensive treatment: HR stroke 0.67 (95% CI, 0.47–0.97), ACS 0.67 (0.47–0.94), ADHF 0.27 (0.08–0.98), coronary revascularization 0.69 (0.40–1.18), AF 0.96 (0.55–1.68), and death from cardiovascular causes 0.72 (0.39–1.32)	Hypotension greater with intensive treatment (3.4% vs 2.6%, P=0.03) No difference in syncope, reduction in eGFR
CLICK (Chlorthalidone in Chronic Kidney Disease) trial 16	160 Adults with stage 4 kidney disease, poorly controlled HTN	Chlorthalidone vs placebo	Change in 24‐h ambulatory systolic blood pressure from baseline to 12 wk; between‐group difference −10.5 mm Hg (95% CI, −14.6 to −6.4) (P<0.001) with chlorthalidone	Percent change in urinary albumin‐to creatinine ratio from baseline to 12 wk −52% with chlorthalidone and −4% with placebo, (between‐group difference, −50 percentage points; 95% CI, −60 to −37)	Increases in serum creatinine >25% from baseline 45% with chlorthalidone and 13% with placebo; OR for an increase in creatinine >25% with chlorthalidone 1.9 (95% CI, 0.4–10.3) among patients who were not on loop diuretics at baseline and 9.2 (95% CI, 3.0–31.3) among those who were
TRIUMPH study 17	140 adults with resistant hypertension	4‐mo program of lifestyle modification (C‐LIFE [Center‐Based Lifestyle Intervention]) including dietary counseling, behavioral weight management, and exercise, or a single counseling session providing SEPA (Standardized Education and Physician Advice)	Reduction in clinic systolic BP was greater in C‐LIFE (−12.5 [95% CI, −14.9 to −10.2] mm Hg) compared with SEPA (−7.1 [−95% CI, 10.4 to −3.7] mm Hg) (P=0.005)	24‐h ambulatory systolic BP also was reduced in C‐LIFE (−7.0 [95% CI, −8.5 to −4.0] mm Hg), with no change in SEPA (−0.3 [95% CI, −4.0 to 3.4] mm Hg) (P=0.001)	N/A
Polypill and fixed dose combination treatments
TIPS‐3 18	5713 men ≥50, women ≥55 y with an INTERHEART risk score ≥10, or men and women ≥65 y with an INTERHEART risk score of ≥5; no prior ASCVD	4.6 y study, 2×2 factorial design of polypill (40 mg of simvastatin, 100 mg of atenolol, 25 mg of hydrochlorothiazide, and 10 mg of ramipril or placebo; ASA 81 mg or placebo)	Polypill: death from cardiovascular causes, myocardial infarction, stroke, resuscitated cardiac arrest, heart failure, or revascularization 4.4% polypill vs 5.5% placebo (HR 0.79 [0.63–1.00]). ASA: death from cardiovascular causes, myocardial infarction, or stroke 4.1% ASA vs 4.7% placebo (HR 0.86 [0.67–1.10]). Combined treatment 4.1% combined vs 5.8% placebo (HR 0.69 [0.50–0.97]).	Polypill: Death from cardiovascular causes, MI, stroke 3.9% vs 4.9% (HR 0.79 [0.61–1.01]). ASA: death from cardiovascular causes, MI, stroke, cancer 5.3% vs 6.2% (HR 0.86 [0.69–1.07])	Dizziness or hypotension 2.7% polypill vs 1.1% placebo; Major bleeding 0.7% ASA vs 0.7% placebo
QUARTET trial 19	591 Australian adults untreated or receiving montherapy, and elevated blood pressure (ie: systolic ≥140 or ≥130 mm Hg, respectively, or other comparable criteria)	Phase 3 trial, quadpill (irbesartan at 37.5 mg, amlodipine 1.25 mg, indapamide 0.625 mg, and bisoprolol 2.5 mg) vs irbesartan 150 mg indistinguishable monotherapy control. 12 wk follow up and 12 mo extended follow‐up subgroup	Difference in unattended office systolic blood pressure at 12 wk 6.9 mm Hg lower in quadpill vs control (95% CI 4.9–8.9; P<0.0001). At 52 wk 7.7 mm Hg lower quadpill group (95% CI 5.2–10.3)	Blood pressure control <140/90 mm Hg at 12 wk quadpill 76% vs control 58%; relative risk (RR) 1.30, (95% CI 1.15–1.47; P<0.0001). 52 wk 81% quadpill vs 62% control	Dizziness 31% quadpill vs 25.4% control (P=0.07). No difference in rates of serious events
Omega 3 fatty acids
OMEMI (Omega‐3 Fatty acids in Elderly with Myocardial Infarction) Trial 20	1014 older men and women who had suffered an MI in the past 2–8 wk	Omega 3 fatty acids (1.8 g daily–930 mg EPA/660 mg DHA) vs a placebo (corn oil)	Recurrent non‐fatal MI, unscheduled revascularization, heart failure hospitalization, stroke, and all‐cause death. Over 2 y of follow‐up there were 210 total primary events with no reduction in those randomized to omega 3 fatty acid supplementation vs placebo (HR 1.08 [95% CI, 0.82–1.41])	Atrial fibrillation occurred in 28 (7.2%) patients on n‐3 PUFA vs 15 (4.0%) on placebo (1.84 [0.98–3.45]; P=0.06)	Major bleeding occurred in 54 (10.7%) and 56 (11.0%) in the n‐3 PUFA and placebo groups, respectively (P=0.87)
STRENGTH (Long‐Term Outcomes Study to Assess Statin Residual Risk with Epanova in High Cardiovascular Risk Patients with Hypertriglyceridemia) trial 21	10 382 adults with established ASCVD, T1DM or T2DM with additional risk factors, or age >50 for men and 60 for women with additional risk factors. Lipid criteria for all were LDL <100 mg/dL on a maximally tolerated dose of a statin, HDL <42 mg/dL, TG 180–500 mg/dL	4 g daily of ω‐3 carboxylic acid (CA) vs corn oil placebo	Secondary analysis of previously published trial to determine whether achieved plasma levels of EPA and DHA were associated with a composite of cardiovascular death, nonfatal MI, nonfatal stroke, coronary revascularization, or unstable angina requiring hospitalization. Compared with corn oil, adjusted HR for the highest tertile of achieved plasma levels were 0.98 (95% CI, 0.83–1.16; P=0.81) for EPA, and 1.02 (95% CI, 0.86–1.20; P=0.85) for DHA		N/A
Diet
WAHA (Walnuts and Healthy Aging) 22	708 cognitively healthy adults ages 63–79 y, without major comorbidities; trial performed in Barcelona, Spain and California	Walnut‐free (control) or walnut‐supplemented diet (≈15% of energy, 30–60 g/d)	Secondary analysis from a study whose primary outcome was cognitive decline Walnut diet significantly decreased (mg/dL) total cholesterol (mean − 8.5 [95% CI, −11.2 to −5.4]), LDL‐C (mean −4.3 [−6.6 to −1.6])	Total LDL particles and small LDL particle number decreased by 4.3% and 6.1%	None

AF indicates atrial fibrillation; ASA, aspirin; ASCVD, atherosclerotic cardiovascular disease; BMI, body mass index; BP, blood pressure; eGFR, estimated glomerular filtration rate; GI, gastrointestinal; HDL, high density lipoprotein cholesterol; ILI, intensive lifestyle intervention; LDL, low density lipoprotein cholesterol; MACE, major adverse cardiovascular events; MI, myocardial infarction; SBP, systolic blood pressure; T1DM, type 1 diabetes; T2DM, type 2 diabetes; and TG, triglycerides.