Importance: A 2016 review for the US Preventive Services Task Force (USPSTF) found use of statins for primary prevention of cardiovascular disease (CVD) was associated with reduced mortality and cardiovascular outcomes.

Objective: To update the 2016 review on statins for primary prevention of CVD to inform the USPSTF.

Data Sources: Ovid MEDLINE, Cochrane Central Register of Controlled Trials, and Cochrane Database of Systematic Reviews (to November 2021); surveillance through May 20, 2022.

Study Selection: Randomized clinical trials on statins vs placebo or no statin and statin intensity in adults without prior cardiovascular events; large cohort studies on harms.

Data Extraction and Synthesis: One investigator abstracted data; a second checked accuracy. Two investigators independently rated study quality.

Main Outcomes and Measures: All-cause and cardiovascular mortality,myocardial infarction, stroke, composite cardiovascular outcomes, and adverse events.

Results: Twenty-six studies were included: 22 trials (N = 90,624) with 6 months to 6 years of follow-up compared statins vs placebo or no statin, 1 trial (n = 5144) compared statin intensities, and 3 observational studies (n = 417,523) reported harms. Statins were significantly associated with decreased risk of all-cause mortality (risk ratio [RR], 0.92 [95% CI, 0.87 to 0.98]; absolute risk difference [ARD], −0.35% [95% CI, −0.57% to −0.14%]), stroke (RR, 0.78 [95% CI, 0.68 to 0.90]; ARD, −0.39% [95% CI, −0.54% to −0.25%]), myocardial infarction (RR, 0.67 [95% CI, 0.60 to 0.75]; ARD, −0.85% [95% CI, −1.22% to −0.47%]), and composite cardiovascular outcomes (RR, 0.72 [95% CI, 0.64 to 0.81]; ARD, −1.28% [95% CI, −1.61% to −0.95%]); the association with cardiovascular mortality was not statistically significant (RR, 0.91 [95% CI, 0.81 to 1.02]; ARD, −0.13%). Relative benefits were consistent in groups defined by demographic and clinical characteristics, although data for persons older than 75 years were sparse. Statin therapy was not significantly associated with increased risk of serious adverse events (RR, 0.97 [95% CI, 0.93 to 1.01]), myalgias (RR, 0.98 [95% CI, 0.86 to 1.11]), or elevated alanine aminotransferase level (RR, 0.94 [95% CI, 0.78 to 1.13]). Statin therapy was not significantly associated with increased diabetes risk overall (RR, 1.04 [95% CI, 0.92 to 1.19]), although 1 trial found high-intensity statin therapy was significantly associated with increased risk (RR, 1.25 [95% CI, 1.05 to 1.49]). Otherwise, there were no clear differences in outcomes based on statin intensity.

Conclusions and Relevance: In adults at increased CVD risk but without prior CVD events, statin therapy for primary prevention of CVD was associated with reduced risk of all-cause mortality and CVD events. Benefits of statin therapy appear to be present across diverse demographic and clinical populations, with consistent relative benefits in groups defined by demographic and clinical characteristics.

Cardiovascular disease (CVD) is highly prevalent and the leading cause of morbidity and mortality in the US. Statins are used to prevent CVD-associated morbidity and mortality because of their positive effects on lipid profiles as well as anti-inflammatory and other plaque-stabilization effects.

In 2016 the US Preventive Services Task Force (USPSTF) recommended that clinicians initiate statins for primary prevention in adults aged 40 to 75 years with at least 1 CVD risk factor and a calculated 10-year CVD event risk 10% or greater (B recommendation) and selectively offer statins in those with a 10-year risk of 7.5% to less than 10% (C recommendation). The recommendations were based on evidence that statins are associated with reduced risk of mortality and CVD events, with greater absolute benefits in persons at higher baseline risk. There was insufficient evidence to assess outcomes of statins in adults 76 years or older (I statement).¹

This evidence report was conducted to update the 2016 USPSTF review to inform the USPSTF for an updated recommendation statement on statins for primary prevention.^1,2 This review focused on adults 40 years or older; the USPSTF addressed lipid screening in children and adolescents as a separate topic.³

Detailed methods and evidence tables with additional study details are available in the full evidence report.⁴ Figure 1 shows the analytic framework and key questions that guided the review.

Data Sources and Searches

A research librarian searched MEDLINE, the Cochrane Central Register of Controlled Trials, and the Cochrane Database of Systematic Reviews to November 2021 for English-language publications (eMethods 1 in the JAMA Supplement). Searches were supplemented by reference list review of relevant articles; studies from the prior USPSTF review² meeting inclusion criteria were carried forward. Ongoing surveillance was conducted to identify major new studies published since November 2021 potentially affecting the conclusions or understanding of the evidence and the related USPSTF recommendation. The last surveillance was conducted on May 20, 2022, and identified no studies affecting review conclusions.

Study Selection

Two reviewers independently reviewed titles, abstracts, and full-text articles using predefined eligibility criteria (eMethods 2 in the JAMA Supplement). The population was adults 40 years or older without prior CVD events; studies of populations in which less than 10% of participants had prior CVD events were also eligible. Randomized clinical trials of statin therapy vs placebo or no statin, statin dosing strategies to target low-density lipoprotein cholesterol [LDL-C] level vs fixed-dose strategies, or higher- vs lower-intensity statin therapy that assessed all-cause or CVD mortality, fatal or nonfatal myocardial infarction (MI) or stroke, revascularization, composite CVD outcomes, or harms of treatment (including muscle injury, cognitive loss, incident diabetes, and hepatic injury) were included. For harms, large cohort (n >10,000) and case-control (>500 cases) studies of statin use vs nonuse were also eligible. The selection of literature is summarized in Figure 2.

Data Extraction and Quality Assessment

One investigator abstracted details about the study design, patient population, setting, screening method, interventions, analysis, and results. A second investigator verified the abstracted data. Statin intensity was categorized using published criteria, based on expected degree of LDL-C reduction (eTable 1 in the JAMA Supplement). Two investigators independently assessed the quality of each study as good, fair, or poor using predefined criteria developed by the USPSTF⁵ (eMethods 3 and eTable 2 in the JAMA Supplement). Discrepancies were resolved through a consensus process.

Data Synthesis and Analysis

Meta-analyses were conducted to calculate risk ratios (RRs) for statins vs placebo or no statin using the DerSimonian and Laird random effects model with Review Manager version 5.4.1 (Cochrane Collaboration Nordic Centre). Statistical heterogeneity was assessed using the I² statistic.⁶ When statistical heterogeneity was present (defined as I² > 30%), sensitivity analysis was performed with the profile likelihood method using Stata version 10.1 (StataCorp).⁷ Results using the profile likelihood method were very similar and are not discussed further.

Additional sensitivity and stratified analyses were conducted based on study quality, inclusion of patients with prior CVD events, follow-up duration, statin intensity,⁸ mean baseline LDL-C level, and whether the trial was stopped early. For analyses with at least 10 trials, funnel plots and the Egger test were used to detect small sample effects.⁹ All significance testing was 2-tailed; P values of .05 or less were considered statistically significant.

The aggregate internal validity (quality) of the body of evidence was assessed for each key question using methods developed by the USPSTF,⁵ based on the number, quality, and size of studies, consistency of results between studies, and directness of evidence.

A total of 26 studies were included (23 trials, 3 observational studies) (a full list of primary and secondary publications, including study acronyms, are reported in eAppendix 1 and eAppendix 2 in the JAMA Supplement).^10-32 Twenty-two randomized trials (N = 95,768, reported in 61 publications) assessed the effects of statins vs placebo (20 trials) or no statin (2 trials)^19,26 (Table 1).^10-32 All were included in the 2016 USPSTF review except for 1 new trial (TRACE-RA, n = 3002)²² and 2 previously excluded (exceeded the 10% threshold of secondary prevention participants) trials (ALLHAT-LLT [n = 10,355; 8880 primary prevention]¹⁸ and PROSPER [n = 5804; 3239 primary prevention]^30,34) that became eligible because of availability of separate primary prevention data. In addition, mixed primary and secondary prevention data (n = 6595) from WOSCOPS³³ (<10% secondary prevention participants) were replaced with recently published³¹ primary prevention data for benefits of statin therapy (n = 5529); harms data for WOSCOPS was reported only in publications that included both primary and secondary prevention populations.^33,35 The number of trial participants ranged from 95 to 17,802. Mean age ranged from 52 to 66 years in all trials except for 1 trial (PROSPER)³⁰ that enrolled persons aged 70 to 82 years (mean, 75 years). Ten trials restricted enrollment to persons 75 years or younger; 3 trials^18,27,32 had no upper age limit. All trials enrolled persons at increased cardiovascular risk. In 6 trials, the main enrollment criterion was dyslipidemia (mean LDL-C levels ranged from 150 to 192 mg/dL [to convert LDL-C values to mmol/L, multiply by 0.0259]);^{13,17,25,26,28,31,33} in 4 trials, diabetes;^12,15,20,23 in 3 trials, early asymptomatic carotid atherosclerosis;^16,19,24 in 2 trials, hypertension;^10,18 and in 1 trial each aortic stenosis,¹⁴ microalbuminuria,¹¹ or rheumatoid arthritis.²² Three trials^27,29,30 required presence of multiple cardiovascular risk factors (including dyslipidemia, elevated C-reactive protein level, elevated blood pressure, family history, mild kidney dysfunction, positive smoking status, or elevated cardiovascular risk score), and 1 trial³² enrolled patients with at least 1 cardiovascular risk factor (elevated waist-hip ratio, low high-density lipoprotein [HDL-C] level, current or recent tobacco use, dysglycemia, family history of early coronary heart disease, or mild kidney dysfunction). Across all trials, mean LDL-C levels ranged from 108 to 191 mg/dL, HDL-C levels ranged from 36 to 62 mg/dL, and total cholesterol levels ranged from 195 to 271 mg/dL (to convert HDL-C and total cholesterol values to mmol/L, multiply by 0.0259). Two trials enrolled some patients (<10%) with a history of clinical CVD.^11,29 The duration of follow-up was 1 to 6 years in all trials except for 1 trial²⁵ with 6-month follow-up. Three trials with planned 5-year follow-up were stopped after 2 to 3 years because of interim analyses indicating statin benefits^27,29 or low CVD event rates.²²

Seven trials^{14,15,27,28,30-32} were rated good quality and 15 trials^{10-13,16-20,22-26,29} fair quality (eTable 2 in the JAMA Supplement). Methodological limitations in the fair-quality trials included unclear randomization or allocation concealment methods and open-label^18,21,26 design. Three trials^18,22,25 reported no industry funding; the rest were fully or partially industry funded.

In addition to the placebo-controlled trials, 1 new, fair-quality randomized trial (n = 5144) of higher- vs lower-intensity statin therapy²¹ (eAppendix 3 and eTable 2 in the JAMA Supplement) and 3 large observational studies^36-38 (n = 417,523; including 1 new study [n = 261,032]³⁶) on statin use and risk of incident diabetes were also included.

Benefits of Statin Treatment

Key Question 1a. What are the benefits of statins in reducing the incidence of CVD-related morbidity or mortality or all-cause mortality in asymptomatic adults without prior CVD events?

Statins, vs placebo or no statin, were associated with decreased risk of all-cause mortality(18 trials, n = 85,186; RR, 0.92 [95% CI, 0.87 to 0.98] after 1-6 years; I² = 0%; absolute risk difference [ARD], −0.35% [95% CI,−0.57% to −0.14%]; number needed to treat [NNT], 286 [95% CI, 175 to 714]) (Figure 3), fatal or nonfatal stroke (15 trials, n = 76,610; RR, 0.78 [95% CI, 0.68 to 0.90] at 1-6 years; I² = 22%; ARD, −0.39% [95% CI, −0.54% to −0.25%]; NNT, 256 [95% CI, 185 to 400]) (eFigure 1 in the JAMA Supplement), fatal or nonfatal MI (12 trials, n = 75,401; RR, 0.67 [95% CI, 0.60 to 0.75] at 2-6 years; I² = 14%; ARD, −0.85% [95% CI, −1.21% to−0.47%]; NNT, 118 [95% CI, 83 to 213) (eFigure 2 in the JAMA Supplement), revascularization (10 trials, n = 65,924; RR, 0.71 [95% CI, 0.63 to 0.80] at 2-6 years; I² = 15%; ARD, −0.59% [95% CI, −0.77% to −0.41%]; NNT, 169 [95% CI, 130 to 244) (eFigure 3 in the JAMA Supplement); and composite cardiovascular outcomes (15 trials, n = 74,390; RR, 0.72 [95% CI, 0.64 to 0.81] at 1-6 years; I² = 51%; ARD, −1.28% [95% CI, −1.61% to −0.95%]; NNT, 78 [95% CI, 62 to 105]) (eFigure 4 in the JAMA Supplement). The estimate for the association with cardiovascular mortality was not statistically significant (12 trials, n = 75,138; RR, 0.91 [95% CI, 0.81 to 1.02] at 2-6 years; I² = 0%; ARD, −0.13% [95% CI,−0.25% to −0.02]; NNT, 769 [95% CI, 400 to 5000]) (Figure 3). Estimates were imprecise and were not statistically significant for fatal MI (6 trials, n = 38,083; RR, 0.83 [95% CI, 0.51 to 1.37]; I² = 28%) (eFigure 5 in the JAMA Supplement) and fatal stroke (3 trials, n = 29,520; RR, 0.73 [95% CI, 0.35 to 1.50]; I² = 29%) (eFigure 6 in the JAMA Supplement). Results from individual trials are shown in eTable 3 in the JAMA Supplement.

Estimates for all-cause and cardiovascular mortality were slightly attenuated (smaller) than from the 2016 USPSTF review (all-cause mortality: 15 trials; RR, 0.86 [95% CI, 0.80 to 0.97]; ARD, 0.43%; cardiovascular mortality: 10 trials; RR, 0.82 [95% CI, 0.71 to 0.94]; ARD, 0.20%).² Differences were primarily due to the addition of primary prevention data from ALLHAT-LLT (RR, 1.00 [95% CI, 0.89 to 1.11] for all-cause mortality and RR, 1.00 [95% CI, 0.89 to 1.11] for cardiovascular mortality)¹⁸ and PROSPER (RR, 1.07 [95% CI, 0.86 to 1.35] for all-cause mortality; cardiovascular mortality not reported).³⁰ PROSPER enrolled older participants (mean, 75 years), compared with other primary prevention trials (mean, 52 to 66 years), and ALLHAT-LLT was open-label and reported a smaller than expected difference in the final LDL-C levels between the statin and no statin groups (14.2%, compared with 26.3% to 49.6% in other primary prevention trials),^17,27,32 likely related to high attrition in the statin therapy group, high crossover from usual care, and increased use of nonstatin therapies in the usual care group. Without ALLHATL-LT, the pooled estimate for cardiovascular mortality was statistically significant and very similar to the estimate in the prior USPSTF review (RR, 0.85 [95% CI, 0.73 to 0.98]; I² = 0%). For MI, stroke, and composite cardiovascular outcomes, benefits of statin therapy based on updated pooled estimates and the 2016 USPSTF review were very similar.

Estimates were similar in sensitivity analyses restricted to good-quality trials, primary prevention trials (trials with <10% secondary prevention participants excluded), or baseline LDL-C level 160 mg/dL or greater (eTable 4 in the JAMA Supplement). Estimates were also similar in sensitivity analyses restricted to trials that were not stopped early or had at least 3 years follow-up, except for all-cause mortality, which had slightly attenuated estimates that were no longer statistically significant. JUPITER,²⁷ the largest primary prevention trial (n = 17,802), had the greatest effect on both of these sensitivity analyses.

For outcomes with at least 10 trials, there was no funnel plot asymmetry and the Egger test was not statistically significant, except for cardiovascular mortality (P = .03; eFigure 7 in the JAMA Supplement). However, the funnel plot for cardiovascular mortality was difficult to interpret because there were few trials with small sample sizes.

Key Question 1b. Do the benefits of statin treatment vary in groups defined by demographic, clinical, or socioeconomic characteristics?

Ten trials (3 trials added for this update) stratified results according to demographic or clinical characteristics.^{15,17,26,27,29,30,32,33,39,40} For all outcomes, relative risk estimates were similar in groups defined by age (9 trials), sex (6 trials), race and ethnicity (2 trials), lipid parameters (6 trials), presence of hypertension (3 trials), cardiovascular risk score (3 trials), presence of kidney dysfunction (3 trials), presence of metabolic syndrome (2 trials), or presence of diabetes (2 trials); findings for presence of elevated C-reactive protein level were inconsistent (2 trials) (eTable 5 in the JAMA Supplement). Pooled estimates for persons older than 70 years were generally consistent with the overall pooled estimates but were based on 3 trials and imprecise^27,30,39 (eFigure 8 in the JAMA Supplement). No trial reported how benefits of statin therapy varied according to socioeconomic characteristics.

Although relative risk estimates were similar across groups, absolute benefits varied according to baseline risk. For example, in the JUPITER trial, relative benefits for the primary composite outcome (cardiovascular death, MI, stroke, revascularization, or hospitalization for unstable angina) were similar in persons with Framingham risk scores greater than 20% (hazard ratio [HR], 0.70 [95% CI, 0.43 to 1.14]) and those with Framingham risk scores less than 10% (HR, 0.67 [95% CI, 0.42 to 1.07]), but absolute benefits were larger among those at higher risk (ARD, −6.9 vs −2.0 per 1000 person-years [CIs not provided]).^27,41 In the HOPE-3 trial, relative benefits for the primary composite outcome (death, nonfatal MI, and nonfatal stroke) were similar for persons with higher and lower cardiovascular risk scores (HR, 0.77 [95% CI, 0.59 to 0.99] for INTERHEART score >16 vs HR, 0.85 [95% CI, 0.63 to 1.15] for INTERHEART score 13-16), but absolute benefits were larger in those with higher cardiovascular risk score (ARD, −1.43% [95% CI, −2.83% to −0.04%] vs −0.71% [95% CI, −2.00% to 0.58%]).³²

Key Question 1c. What are the benefits of statin treatment titrated to achieve target LDL-C levels vs a fixed-dose strategy?

No trial directly compared a strategy of titrating statin doses to achieve target LDL-C levels vs fixed statin dose. There were no statistically significant differences in estimates for any outcome between 3 trials^17,19,26 that permitted limited dose titration to achieve target cholesterol levels compared with the 19 fixed-dose trials, but data for dose titration were imprecise (eTable 6 in the JAMA Supplement).

Harms of Statin Treatment

Key Question 2a. What are the harms of statins in adults without prior CVD events?

Statin therapy, vs placebo or no statin, was not significantly associated with increased risk of study withdrawal due to adverse events (10 trials, n = 43,783; RR, 0.97 [95% CI, 0.78 to 1.19]; I² = 84%; ARD, 0.03% [95% CI, −1.21% to 1.26%]) (eFigure 9 in the JAMA Supplement), serious adverse events (10 trials, n = 55,419; RR, 0.97 [95% CI, 0.93 to 1.01]; I² = 0%; ARD, 0.09% [95% CI, −0.67% to 0.49%]) (eFigure 10 in the JAMA Supplement), any cancer (13 trials, n = 71,733; RR, 0.98 [95% CI, 0.91 to 1.04]; I² = 0%; ARD, −0.10% [95% CI, −0.38% to 0.18%]), fatal cancer (6 trials, n = 45,064; RR, 0.89 [95% CI, 0.66 to 1.19]; I² = 56%; ARD, −0.13% [95% CI −0.42% to 0.017%]) (eFigure 11 in the JAMA Supplement), myalgia (9 trials, n = 46,388; RR, 0.98 [95% CI, 0.86 to 1.11]; I² = 30%; ARD, 0.02% [95% CI, −0.44% to 0.40%]) (eFigure 12 in the JAMA Supplement), elevated alanine aminotransferase level (10 trials, n = 48,149; RR, 0.94 [95% CI, 0.78 to 1.13]; I² = 0%; ARD, −0.03% [95% CI,−0.20% to 0.14%]), or elevated aspartate aminotransferase level (4 trials, n = 17,534; RR, 1.30 [95% CI, 0.78 to 2.17]; I² = 35%; ARD, 0.21% [95% CI, −0.05% to 0.46%]) (eFigure 13 in the JAMA Supplement). Statins were also not significantly associated with increased risk of myopathy (3 trials, n = 33,345; RR, 1.09 [95% CI, 0.48 to 2.47]; I² = 0%; ARD, 0.00% [95% CI,−0.04% to 0.04%]), or rhabdomyolysis (4 trials, n = 59,672; RR, 1.54 [95% CI, 0.36 to 6.64]; I² = 0%; ARD, 0.01% [95% CI, −0.01% to 0.03%]) (eFigure 12 in the JAMA Supplement), but estimates were imprecise.

There was no significant association between statins and increased risk of (variably defined) incident diabetes (6 trials, n = 59,083 RR; 1.04 [95% CI, 0.92 to 1.19]; I² = 52%; ARD, 0.11% [95% CI,−0.32% to 0.55%]), although statistical heterogeneity was present. JUPITER, the only trial to evaluate high-intensity statin therapy, was also the only trial to find increased risk (n = 17,802; 3.0% vs 2.4; RR, 1.25 [95% CI, 1.05 to 1.49]).⁴² Three observational studies (n = 417,523)^36-38 reported mixed findings regarding the association between statin use and incident diabetes (eTables 7 and 8 in the JAMA Supplement).

Evidence on the association between statins and kidney or cognitive harms remained sparse and did not indicate increased risk. One trial in the 2016 USPSTF review found statin therapy associated with increased risk of cataract surgery (3.8% vs 3.1% after 6 years; RR, 1.24 [95% CI, 1.03 to 1.49]), which was unanticipated and not a predetermined trial outcome. No new primary prevention trial reported this outcome.

Key Question 2b. Do the harms of statin treatment vary in groups defined by demographic, clinical, or socioeconomic characteristics?

There were no differences in harms of statin therapy based on within-study analyses stratified according to age (4 trials),^39,40,43,44 sex (2 trials),^43,45 or race and ethnicity (1 trial) (eTable 9 in the JAMA Supplement).⁴⁶ In JUPITER, high-intensity statin therapy was associated with increased risk of incident diabetes in persons with 1 or more diabetes risk factors (including metabolic syndrome, impaired fasting glucose, body mass index greater than 30 [calculated as weight in kilograms divided by square of height in meters], and hemoglobin A1c level >6.0%) but not in those without any diabetes risk factor (HR, 1.28 [95% CI, 1.07 to 1.54] vs HR, 0.99 [95% CI, 0.45 to 2.21], respectively).⁴²

Benefits and Harms of Statin Treatment by Treatment Intensity

Key Question 3. How do benefits and harms of statin treatment vary according to its intensity?

The EMPATHY trial (n = 5144) found no differences between statin therapy targeted to LDL-C less than 70 mg/dL vs 100 to 120 mg/dL on cardiovascular outcomes in patients with diabetic retinopathy.²¹ However, there was little differential between groups in achieved LDL-C level (between-group difference, 27.7 mg/dL), and between-group differences in final statin dose were small (mean, 9.9 vs 7.3 mg pravastatin). Two trials included in the prior USPSTF review evaluated different statin intensities but were inadequately powered.^13,25

Indirect, across-study comparisons found that risk estimates for all-cause mortality overlapped for trials of low-intensity statins (2 trials, n = 8400; RR, 0.72 [95% CI, 0.52 to 1.00]; I² = 0%),^10,26 moderate-intensity statins (10 trials, n = 46,873; RR,0.95 [95% CI, 0.89 to 1.02]; I² = 0%),^{11,12,15,18,23,28-32} and high-intensity statins (3 trials,n = 21,785; RR, 0.81 [95% CI, 0.68 to 0.97]; I² = 0%; P = .08 for interaction), without a dose response.^16,22,27 Estimates for composite cardiovascular outcomes were also similar for low-intensity statins (2 trials, n = 8400; RR, 0.68 [95% CI, 0.51 to 0.90]; I² = 0%; ARD, −0.86% [95% CI, −1.48% to −0.23%]),^10,26 moderate intensity statins (9 trials, n = 37,662; RR, 0.79 [95% CI, 0.70 to 0.90]; I² = 46%; ARD, −1.42% [95% CI, −2.07% to −0.76%]),^{11,12,15,20,23,29-32} and high-intensity statins (2 trials, n = 20,804; RR, 0.58 [95% CI, 0.48 to 0.70]; I² = 0%; ARD, −1.16% [95% CI,−1.56% to −0.76%];^22,47 P = .03 for interaction).

In adults at increased cardiovascular risk but without prior CVD events, statin therapy was associated with reduced risk of clinical outcomes compared with placebo or no statin, based on 22 trials with 6 months to 6 years of follow-up. The evidence is summarized in Table 2 and Figure 4.

Compared with the 2016 USPSTF review, estimated benefits of statin therapy on mortality were slightly attenuated (smaller). The difference was largely due to the addition of primary care prevention data from ALLHAT-LLT^18,39 and PROSPER,^30,34,48,49 which each found statins not associated with decreased risk of all-cause or cardiovascular mortality. The observed lack of benefit could have been related to enrollment of older patients in PROSPER and methodological limitations in ALLHAT-LLT, with smaller than expected statin lipid-lowering effects. For cardiovascular mortality, the pooled estimate was no longer statistically significant, and the estimated benefit was smaller. However, updated pooled results continued to indicate a statistically significant decreased risk of all-cause mortality, and estimates for stroke, MI, revascularization, and composite cardiovascular outcomes were similar to those in the 2016 USPSTF review. Results were generally consistent in sensitivity and stratified analyses.

Benefits of statins appeared similar in patient groups defined by demographic characteristics, such as sex and race and ethnicity, and clinical characteristics, such as presence of diabetes or kidney dysfunction. Evidence on how statin benefits vary by age remains limited for older (>70 or >75 years) persons. Although within-study analyses indicated no differences in benefits when patients were stratified according to age, all studies except for 1 trial²⁷ stratified patients using lower age (55, 60, or 65-year) cutoffs. A pooled analysis from 3 trials with data for patients older than 70 years reported results generally consistent with overall pooled estimates, but results were imprecise.^27,30,39 Benefits of statins were not restricted to patients with severely elevated lipid levels, because similar relative risk estimates were observed in subgroups stratified according to baseline lipid levels.^{15,17,26,27,32,33} Risk estimates were similar in patients classified as being at higher or lower baseline global cardiovascular risk.^17,27,32 Given similar RR estimates, the absolute benefits of statin therapy will be proportionately greater in patients at higher baseline risk.^27,32,41,50

The findings of this review regarding benefits of statin therapy were generally consistent with findings from other high-quality systematic reviews^48,51-53 that primarily focused on patients without prior CVD events, despite some differences in inclusion criteria and analytic methods. This review provides a more comprehensive and up-to-date analysis compared with other systematic reviews, because it includes trials published subsequent to the prior reviews, including HOPE-3,³² and additional data on primary prevention participants from ALLHAT-LLT,¹⁸ WOSCOPS,³¹ and PROSPER.³⁰

As in the 2016 USPSTF review, this review found no evidence that statins were associated with increased risk of withdrawal because of adverse events, serious adverse events, cancer, or elevated liver enzyme levels vs placebo or no statin therapy. These findings are generally consistent with those from recent systematic reviews, some of which also included trials of statins for secondary prevention.^51,54-56 Similar to meta-analyses of primary and secondary prevention trials,^57,58 statins were not associated with increased risk of muscle-related harms. Although observational studies of patients taking statins for various indications have found an increased risk of myopathy,⁵⁹ as well as study withdrawal due to adverse events or muscle symptoms, these findings could be due to expectations regarding adverse effects and nocebo effects.^60,61 HOPE-3 found statin therapy associated with increased risk of cataract surgery, an unanticipated finding.³² No other primary prevention trials evaluated risk of cataracts or cataract surgery. A systematic review that included secondary prevention trials and observational studies reported statins associated with decreased risk of incident cataracts (odds ratio [OR], 0.81 [95% CI, 0.71 to 0.93]) and cataract surgery (OR, 0.66 [95% CI, 0.61 to 0.71]).⁶² Limited evidence indicated no association between statin use and kidney or cognitive harms. The findings for cognitive harms are consistent with a systematic review of randomized clinical trials and observational studies and a scientific statement issued by the American Heart Association.^54,63

As in the 2016 USPSTF review, statins were not associated with increased risk of incident diabetes. However, results of individual studies were inconsistent, with 1 large trial (JUPITER) showing increased diabetes risk.²⁷ This could be due to JUPITER being the only trial to use high-potency statin therapy; other analyses that included trials of statins for secondary prevention suggest an association between intensity of statin dose and risk of incident diabetes.^52,64-66 In JUPITER, among patients with diabetes risk factors, 134 CVD events were prevented for every 54 additional incident cases of diabetes, while among persons without diabetes risk factors, 86 CVD events were prevented with no incident diabetes cases.⁴²

No study directly compared treatment with statins titrated to attain target cholesterol levels vs fixed-dose statins. Although indirect comparisons showed no differences between dosing strategies, only 317,^19,26 of 22 primary prevention trials permitted dose titration. Further, dose titration was limited (statin therapy did not go from low- to high-intensity in any trial, and 1 trial only titrated within the low-intensity category), precluding strong conclusions.

Little direct evidence was available to determine effects of statin therapy intensity. One new trial found no difference between more vs less intensive statin therapy based on LDL-C targets but achieved little differential between groups in LDL-C level or statin dose.²¹ Indirect comparisons based on trials of statins vs placebo or no statin stratified according to statin intensity showed no clear dose-response effect, but most trials evaluated moderate-intensity therapy and estimates for low- and high-intensity statins were imprecise. Other analyses have found an association between higher statin intensity and reduced risk of cardiovascular outcomes but were based on LDL-C response, included trials of secondary prevention, defined statin intensity inadequately, or included nonstatin lipid-lowering therapies.^52,67,68

Additional research is needed to clarify benefits and harms of statins in older patients, including those older than 80 years. Evidence is also needed to directly compare effects of statin therapy to target lipid levels vs fixed-dose therapy and higher- vs lower-intensity statin therapy; to more definitively determine whether statin therapy is associated with increased cataract surgery risk; and to clarify how statin intensity and other factors affects diabetes risk.

Limitations

This review had several limitations. First, the meta-analysis used the Dersimonian-Laird random-effects model to pool studies, which can result in overly narrow confidence intervals when heterogeneity is present, particularly when there are few studies.⁷ Therefore, analyses were repeated using the profile likelihood method when statistical heterogeneity was present, which resulted in similar findings. Second, the reviewers did not have access to individual patient data; findings were based on analyses of study-level data and within study stratified analyses. Third, 2 mixed (primary and secondary prevention) trials^11,29 met inclusion criteria (<10% secondary prevention), potentially reducing applicability to primary prevention. However, excluding these trials from analyses did not affect findings. Fourth, direct evidence was unavailable or limited on effects of dose titration vs fixed-dose therapy or statin intensity on clinical outcomes. Therefore, this review primarily was based on analyses of placebo-controlled trials stratified according to use of dose titration or statin intensity; such indirect comparisons should be interpreted cautiously.⁶⁹ Fifth, the review excluded non–English-language articles and formally assessed for publication bias only when there were at least 10 studies, because research indicates that such methods can be misleading with fewer studies.⁹

In adults at increased CVD risk but without prior CVD events, statin therapy for primary prevention of CVD was associated with reduced risk of all-cause mortality and CVD events. Benefits of statin therapy appear to be present across diverse demographic and clinical populations, with consistent relative benefits in groups defined by demographic and clinical characteristics.

Source: This article was first published online in the Journal of the American Medical Association on August 23, 2022 (JAMA. 2022;328(8):754-771. doi:10.1001/jama.2022.12138).

Conflict of Interest Disclosures: Dr Ferencik reported receiving grants from the American Heart Association and serving as a consultant for Biograph Inc. No other disclosures were reported.

Funding/Support: This research was funded under contract HHSA290201500007i; Group A, Task Order 75Q80119F32009, from the Agency for Healthcare Research and Quality (AHRQ), US Department of Health and Human Services, under a contract to support the US Preventive Services Task Force (USPSTF).

Role of the Funder/Sponsor: Investigators worked with USPSTF members and AHRQ staff to develop the scope, analytic framework, and key questions for this review. AHRQ had no role in study selection, quality assessment, or synthesis. AHRQ staff provided project oversight, reviewed the report to ensure that the analysis met methodological standards, and distributed the draft for peer review. Otherwise, AHRQ had no role in the conduct of the study; collection, management, analysis, and interpretation of the data; and preparation, review, or approval of the manuscript findings. The opinions expressed in this document are those of the authors and do not reflect the official position of AHRQ or the US Department of Health and Human Services.

Additional Contributions: We thank the following individuals for their contributions to this project: Jennifer Lin, MD, MCR, Kaiser Permanente Evidence-based Practice Center, Portland, Oregon; Christina Bougatsos, MPH, Oregon Health & Science University, Portland; Yun Yu, MS, Oregon Health & Science University, Portland; Howard Tracer, MD, Agency for Healthcare Research and Quality; as well as the USPSTF. We also acknowledge past and current USPSTF members who contributed to topic deliberations. The USPSTF members, external reviewers, and federal partner reviewers did not receive financial compensation for their contributions.

Additional Information: A draft version of this evidence report underwent external peer review from 3 content experts (Jacquelyn Kulinski, MD, Medical College of Wisconsin, Milwaukee; Bruce Warden, PharmD, Oregon Health & Science University, Portland; Eugene Yang, MD, MS, University of Washington School of Medicine, Seattle); and 1 federal partner from the Centers for Disease Control and Prevention (CDC). Comments were presented to the USPSTF during its deliberation of the evidence and were considered in preparing the final evidence review.

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Evidence reviews for the US Preventive Services Task Force (USPSTF) use an analytic framework to visually display the key questions that the review will address to allow the USPSTF to evaluate the effectiveness and safety of a preventive service. The questions are depicted by linkages that relate to interventions and outcomes. Further details are available from the USPSTF Procedure Manual.⁵
CHD indicates coronary heart disease; CVA, cerebrovascular accident (stroke); CVD, cardiovascular disease; KQ, key question.

^a Other sources include prior reports, reference lists of relevant articles, systematic reviews, etc.
^b Some studies were included for multiple key questions (KQs).
^c KQ1b and KQ2b were not included in the prior review, although prior included studies provided evidence for the KQs.
^d KQ1c was KQ1b in the prior review.
KQ indicates key question; RCT, randomized clinical trial.

A list of trial names is available in eAppendix 2 in the JAMA Supplement. The size of the data markers indicates the weight of the study in the analysis.

^a Primary prevention population only.

AE indicates adverse event; ALT, alanine aminotransferase; CV, cardiovascular; MA,meta-analysis; MI,myocardial infarction; RR, relative risk; SOE, strength of evidence.

Abbreviations: ACAPS, Asymptomatic Carotid Artery Progression Study; ACR, American College of Radiologists; AFCAPS/TexCAPS, Air Force/Texas Coronary Atherosclerosis Prevention Study; ALLHAT-LLT, Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial–Lipid-Lowering Trial; ALT, alanine aminotransferase; ASCOT-LLA, Anglo-Scandinavian Cardiac Outcomes Trial–Lipid Lowering Arm; ASPEN, Atorvastatin Study for Prevention of Coronary Heart Disease Endpoints in Non-insulin Dependent Diabetes Mellitus; ASTRONOMER, Aortic Stenosis Progression Observation: Measuring Effects of Rosuvastatin; BMI, body mass index; BP, blood pressure; CAD, coronary artery disease; CAIUS, Carotid Atherosclerosis Italian Ultrasound Study; CARDS, Collaborative Atorvastatin Diabetes Study; CHD, coronary heart disease; CIMT, carotid intima-media thickness test; CRP, C-reactive protein; CVD, cardiovascular disease; DBP, diastolic blood pressure; ECG, electrocardiogram; HbA_1c, hemoglobin A_1c; HDL-C, high-density lipoprotein cholesterol; HOPE-3, Heart Outcomes Prevention Evaluation; HYRIM, Hypertension High Risk Management; IGF, insulin-like growth factor; IGT, impaired glucose tolerance; JUPITER, Justification for the Use of Statins in Prevention: an Intervention Trial Evaluating Rosuvastatin; KAPS, Kuopio Atherosclerosis Prevention Study; LDL-C, low-density lipoprotein cholesterol; LVH, left ventricular hypertrophy; MEGA, Management of Elevated Cholesterol in the Primary Prevention Group of Adult Japanese; METEOR, Measuring Effects on Intima-Media Thickness: an Evaluation of Rosuvastatin; MI, myocardial infarction; NR, not reported; PREVEND-IT, Prevention of Renal and Vascular Endstage Disease Intervention Trial; PROSPER, Prospective Study of Pravastatin in the Elderly at Risk; PVD, peripheral vascular disease; RA, rheumatoid arthritis; SBP, systolic blood pressure; TC, total cholesterol; TIA, transient ischemic attack; TRACE-RA, Trial of Atorvastatin for the Primary Prevention of Cardiovascular Events in Patients with Rheumatoid Arthritis; ULN, upper limit of normal; WOSCOPS, West of Scotland Coronary Prevention Study Group.

SI conversion factors: To convert HDL-C, LDL-C, and total cholesterol values to mmol/L, multiply by 0.0259; to convert triglyceride values to mmol/L, multiply by 0.0113.

^a Calculated as weight in kilograms divided by square of height in meters.
^b Duration of follow-up for ASPEN is for all patients (primary and secondary population); follow-up was shorter for the primary prevention population because of later recruitment but is not reported separately.
^c Primary publication.

Abbreviations: AE, adverse event; ALT, alanine aminotransferase; ARD, absolute risk difference; CVD, cardiovascular disease; KQ, key question; LDL-C, low-density lipoprotein cholesterol; MI, myocardial infarction; RCT, randomized clinical trial; RR, risk ratio.