Association of statin use in older people primary prevention group with risk of cardiovascular events and mortality: a systematic review and meta-analysis of observational studies
BMC Medicine volume 19, Article number: 139 (2021)
Current evidence from randomized controlled trials on statins for primary prevention of cardiovascular disease (CVD) in older people, especially those aged > 75 years, is still lacking. We conducted a systematic review and meta-analysis of observational studies to extend the current evidence about the association of statin use in older people primary prevention group with risk of CVD and mortality.
PubMed, Scopus, and Embase were searched from inception until March 18, 2021. We included observational studies (cohort or nested case-control) that compared statin use vs non-use for primary prevention of CVD in older people aged ≥ 65 years; provided that each of them reported the risk estimate on at least one of the following primary outcomes: all cause-mortality, CVD death, myocardial infarction (MI), and stroke. Risk estimates of each relevant outcome were pooled as a hazard ratio (HR) with a 95% confidence interval (CI) using the random-effects meta-analysis model. The quality of the evidence was rated using the GRADE approach.
Ten observational studies (9 cohorts and one case-control study; n = 815,667) fulfilled our criteria. The overall combined estimate suggested that statin therapy was associated with a significantly lower risk of all-cause mortality (HR: 0.86 [95% CI 0.79 to 0.93]), CVD death (HR: 0.80 [95% CI 0.78 to 0.81]), and stroke (HR: 0.85 [95% CI 0.76 to 0.94]) and a non-significant association with risk of MI (HR 0.74 [95% CI 0.53 to 1.02]). The beneficial association of statins with the risk of all-cause mortality remained significant even at higher ages (> 75 years old; HR 0.88 [95% CI 0.81 to 0.96]) and in both men (HR: 0.75 [95% CI: 0.74 to 0.76]) and women (HR 0.85 [95% CI 0.72 to 0.99]). However, this association with the risk of all-cause mortality remained significant only in those with diabetes mellitus (DM) (HR 0.82 [95% CI 0.68 to 0.98]) but not in those without DM. The level of evidence of all the primary outcomes was rated as “very low.”
Statin therapy in older people (aged ≥ 65 years) without CVD was associated with a 14%, 20%, and 15% lower risk of all-cause mortality, CVD death, and stroke, respectively. The beneficial association with the risk of all-cause mortality remained significant even at higher ages (> 75 years old), in both men and women, and in individuals with DM, but not in those without DM. These observational findings support the need for trials to test the benefits of statins in those above 75 years of age.
Cardiovascular disease (CVD) is the major cause of mortality worldwide [1,2,3]. More than 80% of the overall CVD death occurs in older people (aged ≥ 65 years) [2, 4]. In 2015, people aged ≥ 65 years represented 8.5% (617.1 million) of the global population (7.3 billion) . In 2030, this percentage is projected to reach 12% (1 billion) of the world population . In Europe, it is projected that almost 25% of its population will be aged ≥ 65 years by 2030, higher than any of the other continents [6, 7]. Therefore, efforts at the prevention of CVD in older people are important and will influence global healthcare policies.
The consideration of statins for primary CVD prevention in older people represents a dilemma in clinical practice unlike the secondary prevention, which is well-established and supported by a level (A) evidence, according to the most recent European Society of Cardiology (ESC)/European Atherosclerosis Society (EAS) guidelines [4, 8]. Current evidence on the use of statins for primary prevention of CVD in older people (especially those aged > 75 years) is still lacking. Statin therapy for primary prevention in people aged > 75 years (at high risk) was supported by level (B) evidence and considered as a class IIb recommendation in the 2019 ESC/EAS guidelines on dyslipidemias . The 2019 ESC/EAS guidelines advocate statins for primary prevention in older people aged ≤ 75 years (i.e., 65 to 75 years) as a class I recommendation, which is unlike the 2016 guidelines with a class ΙΙa recommendation and level (B) evidence [4, 9]. This change in recommendation class was based on an individual participant level-meta-analysis from 28 randomized controlled trials (RCTs) by the “Cholesterol Treatment Trialists’ Collaboration” [4, 10] that reported a significant 39% proportional reduction [rate ratio (RR) 0.61; 99% confidence interval (CI) 0.51 to 0.73] in major vascular events for every 1 mmol/L drop in low-density lipoprotein cholesterol (LDL-C) by statins (or more intensive statin therapy) in participants without vascular disease, aged > 65 and ≤ 70 years . This beneficial effect of statins was statistically insignificant for primary prevention in participants aged > 70 years .
One important limitation in the previous results is reporting only the treatment effect on a composite outcome (i.e., major vascular events) without reporting the results of its component outcomes [e.g., coronary artery disease death, stroke, myocardial infarction (MI), or coronary revascularization] that greatly varies in their individual clinical importance . Therefore, these results may be somewhat misleading. Moreover, other study-level meta-analyses did not report any significant effect of statins for primary prevention in older people on any of the components of the mentioned composite except on MI (and on stroke in one meta-analysis) [11,12,13,14]. As a result, this beneficial effect of statins on the major CVD events could be driven entirely by their effects only on MI and stroke.
Other limitations of the current evidence from RCTs include: (Ι) underrepresentation of the older people; most of the available data are from subgroup analyses, and (ΙΙ) relatively short follow-up durations; especially when evaluating the treatment effect on mortality and the potential development of some side effects such as cancer incidence and new onset diabetes mellitus (NODM) that may require longer durations for adequate assessment. Consequently, observational studies on statins for primary prevention in older people may extend the current limited evidence through their larger populations, longer durations of follow-up, and better clinical practice generalizability than the RCTs. To our knowledge, no former meta-analysis assessed such outcomes from observational studies.
To address this issue, we conducted a systematic review and meta-analysis of the observational studies to provide better evidence about the association of statin use in older people primary prevention group (especially those aged ≥ 75 years) with the risk of CVD and mortality.
We designed this study according to the Meta-analysis of Observational Studies in Epidemiology (MOOSE) guidelines (Supplementary Table 1) . This study protocol was not prospectively registered. Due to the design of the study, it did not need any Institutional Review Board approval or patient informed consent.
Literature search strategy
An electronic literature search of PubMed, Scopus, and Embase was conducted, without any restriction filters, from inception until March 18, 2021. We used a combination of relevant keywords and Medical Subject Headings (MeSH) terms reported in Supplementary Table 2. To avoid missing any related study, we conducted a manual search of the bibliographies of the included studies and of selected relevant reviews.
After removing the duplicates by Endnote X7 (Thompson Reuter, CA, USA), two independent authors (MM and MZ) performed a two-step screening of the remaining articles. Firstly, title/abstract screening then, full-text screening according to the predefined inclusion/exclusion criteria. Disagreement was resolved by the opinion of a third author (KA).
Original studies were included if they met the following criteria: (1) being an observational study (cohort or nested case-control), (2) compared using a statin (atorvastatin, fluvastatin, lovastatin, pitavastatin, pravastatin, rosuvastatin, or simvastatin) with no statins, (3) being restricted to or included a subgroup of older people aged ≥ 65 years and without established CVD (coronary artery disease, cerebrovascular disease, and peripheral vascular disease), and (4) reported the risk estimate as a hazard ratio (HR), odds ratio (OR) with its 95% CI on at least one of the following outcomes: all cause-mortality, CVD death, MI, and stroke.
Exclusion criteria included any of the following: (1) RCTs, experimental studies, reviews, theses, and book chapters, (2) studies whose full-texts were not available or with non-English content, (3) studies that contained made-up data or were retracted by the journal, or (4) studies that missed any of the inclusion criteria.
Data extraction and outcomes of interest
Using preformatted tables, two independent authors (MM, MZ) reviewed the included articles and extracted the following data: (1) first author’s name, (2) year of publication, (3) study location, (4) study design, (5) follow-up duration, (6) study population characteristics, and (7) data regarding the relevant outcomes (i.e., the most adjusted risk estimates along with their 95% CI). Disagreements were resolved upon the opinion of another author (KA).
Primary outcomes were risk estimates of all cause-mortality, CVD death, MI, and stroke. Secondary outcomes included risk estimates on NODM and cancer incidence.
If a study reported its data on the older people as multiple age cohorts, in which participants of the first age cohort who survived to the next target age could have been a part of multiple age cohorts, we only extracted data of the age cohort with the largest sample size to avoid overlapped data.
Risk of bias assessment
Two reviewers (KA and MZ) independently used The Risk Of Bias In Non-randomized Studies of Interventions (ROBINS-I) tool for the risk of bias assessment of the included studies . This tool includes seven domains and rates the overall risk of bias as low, moderate, serious, critical, or unclear. Disagreements were resolved by discussion.
Quality of evidence assessment
The level of evidence of each primary outcome was rated as very low, low, moderate, or high quality using the Grading of Recommendation Assessment, Development and Evaluation (GRADE) approach . This rating system is based on five domains to downgrade the evidence level as follows: risk of bias, imprecision, inconsistency, indirectness, and publication bias; and other three domains for upgrading the evidence level as follows: large effect size, dose-response gradient, and all residual confounding reducing an effect size [18, 19].
Quantitative data synthesis
Odds ratios from nested case-control studies may be considered to be equivalent to HRs from cohort studies obtained by the Cox regression analysis [20, 21]. Therefore, the most adjusted risk estimates were pooled as a HR with a 95%CI in a meta-analysis model. Given the probable heterogeneity across the included observational studies, the random-effects model was used for the analysis.
Between-study heterogeneity was measured by I2 and Chi2 tests. Interpretation of these tests was done in accordance with the “Cochrane handbook for systematic reviews of interventions,” in which an alpha level (for Chi2 test) < 0.1 is considered as significant heterogeneity and the I2 test is read as follows: 0–40%, might not be important; 30–60%, may represent moderate heterogeneity; and 50–90%, may represent substantial heterogeneity .
To investigate the risk estimate across different older ages and to address the heterogeneity, a subgroup analysis (based on the availability of relevant data for the intended subgroups in the included studies) was conducted according to the age of the participants as follows: 65 to 75 years, ≥ 75 years, ≥ 80 years, and ≥ 85 years. Other subgroup analyses according to sex, presence of DM and risk of bias level were also conducted. Subgroups focused only on all-cause mortality outcome, which was sufficiently reported in most of the included studies.
To assess the impact of each study on the overall combined risk estimate (i.e., results robustness), we conducted “leave-one-out sensitivity analysis,” by omitting one study each time and repeating the analysis.
Potential publication bias was assessed by visual inspection of Begg’s funnel plot asymmetry and confirmed by Egger’s regression test . Funnel plot asymmetry (if present) was corrected using the “trim and fill” approach by imputing a number of theoretically missing studies . All analyses were done by MetaXL version 5.3 (add-in for meta-analysis in Microsoft Excel; www.epigear.com) and Comprehensive Meta-Analysis version 3 (Biostat, NJ, USA).
Flow and characteristics of included studies
The literature search yielded 9727 records. After removing the duplicates and the two-step screening, ten observational studies [25,26,27,28,29,30,31,32,33,34] with 815,667 relevant participants (without overlap) fulfilled our criteria and were included in this meta-analysis (see Fig. 1 for the PRISMA flow diagram). Supplementary Table 3 lists the excluded studies with reasons for exclusion.
Characteristics and baseline parameters of the included studies are shown in Table 1. Nine [25,26,27,28,29,30,31, 33, 34] of the included studies were cohort studies plus one  nested case-control study. The follow-up duration ranged from 4.7 to 24 years. The publication year ranged from 2002 to 2020. The included studies were conducted in Europe (n = 4), North America (USA; n = 4), and Asia (South Korea; n = 2). The covariates that were used for analysis adjustment in the included studies are shown in Supplementary Table 4.
Risk of bias in the included studies
According to the ROBINS-I tool, the risk of bias was rated as moderate in four included studies and as serious in six studies. One important source of the serious risk of bias in six included studies was including prevalent statin users (i.e., who initiated statin therapy prior to their inclusion in the study) instead of statins new users (i.e., who initiated statin therapy at their inclusion in the study). The risk of bias assessment is summarized in Supplementary Table 5.
Outcome overall analysis
Overall pooled analysis suggested that statin use was significantly associated with a lower risk of all-cause mortality (HR 0.86 [95% CI 0.79 to 0.93]; studies n = 9; Fig. 2A), CVD death (HR 0.80 [95% CI 0.78 to 0.81]; studies n = 4; Fig. 2B), and stroke (HR 0.85 [95% CI 0.76 to 0.94]; studies n = 8; Fig. 3) compared with statin non-use in the included population. A non-significant association was found between statin use and the risk of MI (HR 0.74 [95% CI 0.53 to 1.02]; studies n = 5; Fig. 4A). A significant heterogeneity was observed between the included studies in case of all-cause mortality (I2 = 90%, P value < 0.0001), stroke (I2 = 61%, P value < 0.0001), and MI (I2 = 85%, P value < 0.0001). No heterogeneity was observed in the case of CVD death (I2 = 0%, P value = 0.6). According to the GRADE approach, the level of evidence of all the primary outcomes was rated as “very low.” The quality of evidence assessment is summarized in Supplementary Table 6.
There was a non-significant association between statin use and the risk of T2DM (HR 0.90 [95% CI 0.72 to 1.12]; studies n = 2; Supplementary Figure 1A) or new-onset cancer (HR 1 [95% CI 0.94 to 1.06]; studies n = 3; Supplementary Figure 1B) compared with statin non-use. No significant heterogeneity was observed in the case of both outcomes (P value > 0.1).
Subgroup analysis suggested that statin use was significantly associated with a lower risk of all-cause mortality, compared with statin non-use, in all age subgroups as follows: 65 to 75 years (HR 0.84 [95% CI 0.81 to 0.88]; studies n = 3, Fig. 5), ≥ 75 years (HR 0.88 [95% CI 0.81 to 0.96]; studies n = 8; Fig. 5), ≥ 80 years (HR 0.84 [95% CI 0.79 to 0.89]; studies n = 3; Fig. 5), and ≥ 85 years (HR 0.88 [95% CI 0.79 to 0.99]; studies n = 2; Fig. 5). Heterogeneity became insignificant in case of “65 to 75 years” subgroup (I2 = 0%, P value = 0.57). There was still a significant heterogeneity in the other age subgroups (P value < 0.0001).
In the subgroup analysis according to sex, statin use was significantly associated with a lower risk of all-cause mortality, compared with statin non-use, in both men (HR 0.75 [95% CI 0.74 to 0.76]; studies n = 4; Fig. 5) and women (HR 0.85 [95% CI 0.72 to 0.99]; studies n = 4; Fig. 5). No significant heterogeneity was observed in both subgroups (P value > 0.1).
As for subgroups according to DM, a significant association was found between statin use and the risk of all-cause mortality only in older people with DM (HR 0.82 [95% CI 0.68 to 0.98]; studies n = 3; Fig. 5) but not in those without DM (HR 0.92 [95% CI 0.77 to 1.10]; studies n = 5; Fig. 5). A significant heterogeneity was observed in both subgroups (P value < 0.0001).
In the subgroup analysis according to risk of bias level within the included studies, statin use was significantly associated with a lower risk of all-cause mortality, compared with statin non-use, only in case of serious risk of bias (HR 0.82 [95% CI 0.76 to 0.88]; studies n = 5; Fig. 5) but not in case of moderate risk of bias (HR 0.90 [95% CI 0.78 to 1.04]; studies n=4; Fig. 5). A significant heterogeneity was observed in both subgroups (P value < 0.1).
The “leave-one-out” sensitivity analysis suggested that all overall combined risk estimates were robust except for MI outcome. As previously stated, the overall risk estimate for MI was as follows: (HR 0.74 [95% CI 0.53 to 1.02]; studies n = 5; Fig. 4A). After omitting the study by Jun et al. , this overall risk estimate became as follows: (HR 0.58 [95% CI 0.35 to 0.98]; studies n = 4; Fig. 4B), indicating a significant lower risk of MI with statin use compared with statin non-use.
Visual inspection of funnel plots asymmetry indicated a potential publication bias in terms of all relevant outcomes (Supplementary Figure 2). The effect estimates of the outcomes were corrected using the “trim and fill” method by imputing 1–4 hypothetically missing studies (for each outcome). The significance/insignificance of the effect estimates was not altered after the adjustment for all outcomes (Supplementary Table 7). Egger’s test suggested a potential publication bias only in terms of all-cause mortality (P value = 0.026), stroke (P value = 0.003), and new-onset cancer (P value = 0.042) and excluded the presence of publication bias for the rest of the outcomes (P value > 0.05; Supplementary Table 7).
This meta-analysis suggests that statin therapy may be associated with a significant lower risk of all-cause mortality, CVD death, and stroke in older people aged ≥ 65 years without CVD. The beneficial association of statins with the risk of all-cause mortality remained significant even at higher ages. It also was significant in both men and women. The association with all-cause mortality remained significant only in older people with DM but not in those without DM. A non-significant association was found between statins and MI, and this issue requires further investigation.
These results are of interest especially in the context of the involved mechanism(s). Several epidemiological studies revealed no association or even an inverse association between low total cholesterol (TC), specifically LDL-C, and all-cause mortality in older people . However, this paradox could be explained by some endogenous factors that may affect both TC and mortality, indicating reverse causation [36, 37]. One of these factors is “terminal decline”; in a cohort study with 99,758 participants aged 80 to 105 years, Charlton et al.  found a greater decline in TC levels in the last 2 years of life. Another factor is that low TC level was found to be a pre-diagnostic marker of several types of cancer [39, 40]. In addition, inflammation can reduce the serum LDL-C level through increasing the LDL receptor expression on the hepatocytes [41,42,43,44]. This response is mediated by the elevated cytokines; interleukin (IL)-1β, IL-6, tumor necrosis factor-α, and others [45, 46]. In this context, a recent meta-analysis of nine prospective studies (n = 9087 participants) revealed that high levels of IL-6 were associated with a higher risk of all-cause mortality in older people . In line with these possible explanations, Mendelian randomization found that elevated LDL-C still carries a higher risk of mortality even in the oldest old people (> 90 years) .
In a meta-analysis that included eight RCTs, Savarese et al.  found that statins significantly reduce the risk of stroke (RR 0.76 [95% CI 0.63 to 0.93], I2 = 43.7%, studies n = 5) compared with placebo in older participants without CVD. Our finding on stroke is in line with this meta-analysis. In contrast, a recent meta-analysis including nine RCTs conducted by Ponce et al.  suggested no benefit of statins on stroke prevention (RR 0.78 [95% CI 0.6 to 1.01], I2 = 58.1%, studies n = 6), compared with placebo, in older participants without CVD. However, the result of this meta-analysis , unlike Savarese et al. , was not robust according to the sensitivity analysis which was statistically significant (RR 0.51, 95% CI 0.33 to 0.78) when the analysis was limited to studies that only included older participants or had planned for a subgroup analysis according to age.
In contradistinction to the aforementioned meta-analyses of RCTs [12, 14], our study suggested a non-significant association between statin use and MI. This finding should be cautiously interpreted because the overall risk estimate of MI became significant after removing the study conducted by Jun et al. , which was the only included case-control study. Jun and colleagues explained their finding on MI by the possibility that most of the included participants could have received low- to moderate-intensity statins which are less effective than high-intensity statins for MI prevention .
Unlike the above-mentioned meta-analyses of RCTs [12, 14], our study suggested a beneficial association with statins in terms of all-cause mortality and CVD death. In a recent meta-analysis including 40 RCTs, Yebyo et al.  investigated the efficacy and safety of statins for primary prevention of CVD in 94,283 participants of a wide age range. They found that statins significantly reduced the risk of all-cause mortality (RR 0.89, 95% CI 0.85 to 0.93) in the included population. Interestingly, the observed association with all-cause mortality in our study (HR 0.86 [95% CI 0.79 to 0.93]) was similar to that in the meta-analysis by Yebyo et al. . In a recent Bayesian analysis of available data on older people from 35 RCTs, Kostis et al.  reported that people aged > 75 years on statins for primary prevention may have a lower mortality (p = 0.03). In line with our study, statin use for primary prevention was also associated with a lower risk of all-cause mortality (HR 0.83; p = 0.04) compared with statin non-use in a retrospective cohort included 1370 older Korean adults (aged ≥ 75 years); this observed association was more evident (HR 0.76; p = 0.01) in case of statin use for more than 5 years . However, our observational findings on all-cause mortality should be interpreted cautiously because, in clinical practice, older people with short life expectancy (e.g., with malignancy) are less likely to receive statins and this might have introduced bias into the observed results [52, 53]. Even so, the cumulating evidence seems to be broadly consistent. In the general population, statins seem to reduce all-cause mortality primarily by reducing CVD death, and this is in line with our significant result in terms of CVD death [49, 54]. Only one of the included studies reported the association of statins with the risk of non-vascular mortality . In this study, Kim et al.  observed that non-CVD deaths were less frequent in the statin users than non-users, but this was statistically non-significant.
In the present study, the observed beneficial association of statins with the risk of all-cause mortality remained significant even at higher ages. This finding is in line with the previously mentioned result from Mendelian randomization studies about the preserved risk role of elevated LDL-C in the oldest old people (> 90 years) . However, the subgroups of the highest ages (≥ 80 and ≥ 85 years) were derived from a small number of studies that included a relatively limited sample size of this population. According to the reported analysis based on DM presence, the beneficial association with statins in terms of all-cause mortality was only evident in participants with DM, which highlights the need to more use of statin therapy in older people with DM in primary prevention. The aforementioned finding is in line with data from the Age, Gene/Environment Susceptibility (AGES)-Reykjavik study . That prospective cohort study included 5,152 participants with an age range of 66 to 96 years, showing that statins were associated with a lower risk of all-cause mortality in DM participants comparable with non-DM, and regardless of coronary heart disease or glucose-lowering therapy . Diabetes mellitus is associated with a 2- to 4-fold higher risk of CVD events . Moreover, patients with longstanding DM (≥ 10 years), and without CVD, may be comparable to coronary heart disease (CHD) patients without DM in terms of future CHD events [57, 58]. Therefore, the above-mentioned result is clinically plausible.
The beneficial association with statins in terms of all-cause mortality was still evident in the subgroup that included studies with serious risk of bias but not in that with moderate risk of bias studies. Inclusion of prevalent statin users instead of statin new users in all the studies with serious risk of bias, denoting the long-term effect of statins, may explain this observed result [59, 60]. However, other sources of bias (e.g., bias due to confounding) might have affected this result.
The older population has a higher risk of drugs adverse effects because of multiple comorbidities, polypharmacy, and altered pharmacokinetics and pharmacodynamics [61,62,63,64,65,66]. Statin safety in this population is a point of concern as statin-related adverse effects are the most common cause of statin discontinuation [67,68,69]. In a meta-analysis that included more than 3 million older subjects, only 47.9% of statin users were adherent to therapy after one year of follow-up for primary prevention . In terms of safety, our study found no significant association between statin use and the risk of incident T2DM or new-onset cancer. These findings are in line with evidence from primary prevention RCTs of older people [12, 13, 71,72,73,74] and even of participants with a wide age range . In contrast, evidence including general mixed population (i.e. primary and secondary CVD prevention) reported a 9 to 55% increased risk of T2DM in statin users compared with statin non-users [75,76,77]. In a recent meta-analysis/meta-regression with more than 4 million participants (statins vs no statins) aged ≥ 30 years, older participants were associated with a decreased risk of T2DM (RR 0.79 [95% CI 0.63–0.98] per 10-year older) compared with younger participants . The reported increase in statin-associated T2DM risk is mainly evident in participants who already are at a high risk to acquire DM (e.g., people with other elements of the metabolic syndrome) [75, 78].
None of the included studies reported data on other statin safety concerns in older people, including statin-associated muscle symptoms (SAMS) or cognitive impairment except one study by Zhou et al.  that reported a nonsignificant association between statins and risk of dementia (HR 1.14 [95% CI 0.94 to 1.39]). Current evidence from individual RCTs [72, 73, 79,80,81] and meta-analyses [82,83,84,85] reported no increased risk of SAMS with statins in older people or of cognitive impairment in the general population. As for evidence from observational studies, a meta-analysis of 25 prospective cohorts of the cognitively healthy general population found that statin use was associated with a lower risk of all-cause dementia (mean age 59.3 years), mild cognitive impairment (mean age 68.4 years), and Alzheimer’s disease (mean age 71.3 years) but not of vascular dementia (mean age 77.2 years) . In terms of SAMS, an observational study including 4355 participants aged ≥ 75 years from the Netherlands found no difference in the prevalence of self-reported muscle symptoms in statin users compared with statin non-users (OR 1.39; 95% CI 0.94 to 2.05) regardless of CVD history . Table 2 shows a comparison between results from meta-analyses of RCTs and our study or other observational studies in older people for statins used in primary prevention.
Older people are heterogenous in many aspects (i.e., clinically, demographically, and functionally) . They were underrepresented in the available RCTs especially those aged ≥ 75 years, and this may limit the generalizability of their findings to the clinical practice. On the other hand, our study was based on data from observational studies, which are more generalizable. Another limitation of the evidence from older people RCTs is the relatively short follow-up durations that ranged from 1 to 5.2 years . However, the follow-up durations of the included cohort studies in the current meta-analysis were longer (ranged from 4.7 to 24 years). Larger included number of participants, longer durations of follow-up, residual confounders, and inclusion of prevalent statin users instead of statin new users in some of the included observational studies are possible explanations for the observed differences between our study and RCTs in case of some outcomes (as presented above). Some previous meta-analyses of RCTs reported statins effect on composite outcomes of several components that significantly varies in their clinical importance (e.g. coronary revascularization versus CVD death) [10, 13]. It is recommended to avoid combining composite outcomes in meta-analyses to avoid any misleading results . In our study, we only combined data of single components, and we filled some gaps in the evidence about people aged ≥ 75 years, while awaiting the results of The STAREE (STAtins for Reducing Events in the Elderly) trial (NCT02099123) and the PREVENTABLE (Pragmatic Evaluation of Events and Benefits of Lipid-Lowering in Older Adults) trial (NCT04262206).
This meta-analysis has several limitations. First, it is based only on observational studies. One critical source of bias in six included studies was including prevalent statin users instead of statins new users. Thus, the present results might have been influenced by residual confounding. Second, unresolved heterogeneity was reported in terms of all-cause mortality, stroke, and MI. Clinical diversity (e.g., variability in the participant characteristics) and methodological diversity (e.g., different risk of bias sources and varied follow-up durations) among the included studies are possible causes of this observed heterogeneity. However, we addressed this heterogeneity by applying the random-effects model in the analysis and conducting subgroup analyses. Third, potential publication bias was observed in all relevant outcomes. Fourth, data on relevant outcomes (except for all-cause mortality) were not sufficient for further subgroup analyses. Fifth, none of the included studies reported data on any of the relevant outcomes stratified by the participants’ baseline CVD risk score except the study by Gitsels et al. ; they grouped the included participants according to the QRISK2 score. Sixth, data on statins safety outcomes (especially SAMS) were not sufficiently reported in the included studies. Seventh, data on nutraceuticals and special diets that may affect the participants’ lipid profile were not reported . Eighth, potential confounders included for the risk estimates adjustment differed among the eligible studies. Finally, this study protocol was not prospectively registered. Most of these limitations reflected on the evidence level, which was rated as “very low” by the GRADE approach. As a result, making clinical recommendations based on the current evidence level is limited. However, our study is complementary to the available evidence from RCTs and can inform future research.
Future studies should employ a randomized design with long-term follow-up periods. A consensus set of standardized outcomes should be provided to and followed by future trialists. The development and validation of a risk score for older people to predict the risk of cardiovascular events can inform the clinical applicability of statin use in this population. In addition, safety outcomes should be a culprit in future studies in this high-risk population, and outcomes that relate to cost-effectiveness and quality of life should also be considered.
In conclusion, statin therapy appears to be associated with a significantly lower risk of all-cause mortality, CVD death, and stroke (by 14%, 20%, and 15% respectively) in older people aged ≥ 65 years and without CVD. The beneficial association of statins with the risk of all-cause mortality remained significant even at different higher ages. It also was significant in both men and women. However, the association with all-cause mortality remained significant only in older people with DM but not in those without DM. There was no association between statin use and the risk of MI, incident T2DM, or new-onset cancer. These findings suggest statins may offer benefits in the older people in primary prevention setting especially those at the higher risk of CVD (i.e., with DM). As such, these findings support the need for ongoing trials of statins in older adults.
Availability of data and materials
The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.
Roth GA, Mensah GA, Johnson CO, Addolorato G, Ammirati E, Baddour LM, et al. Global burden of cardiovascular diseases and risk factors, 1990–2019: update from the GBD 2019 study. J Am Coll Cardiol. 2020;76(25):2982–3021.
Benjamin EJ, Blaha MJ, Chiuve SE, Cushman M, Das SR, Deo R, et al. Heart Disease and Stroke Statistics-2017 update: a report from the american heart association. Circulation. 2017;135(10):e146–603. https://doi.org/10.1161/CIR.0000000000000485.
Roth GA, Abate D, Abate KH, Abay SM, Abbafati C, Abbasi N, et al. Global, regional, and national age-sex-specific mortality for 282 causes of death in 195 countries and territories, 1980–2017: a systematic analysis for the Global Burden of Disease Study 2017. Lancet. 2018;392(10159):1736–88. https://doi.org/10.1016/S0140-6736(18)32203-7.
Mach F, Baigent C, Catapano AL, Koskinas KC, Casula M, Badimon L, et al. 2019 ESC/EAS Guidelines for the management of dyslipidaemias: lipid modification to reduce cardiovascular risk: The Task Force for the management of dyslipidaemias of the European Society of Cardiology (ESC) and European Atherosclerosis Society (EAS). Eur Heart J. 2019;41(1):111–88. https://doi.org/10.1093/eurheartj/ehz455.
He W, Goodkind D, Kowal P. An Aging World: 2015. https://www.census.gov/content/dam/Census/library/publications/2016/demo/p95-16-1.pdf. Accessed 20 Nov 2020.
Ferrucci L, Giallauria F, Guralnik JM. Epidemiology of aging. Radiol Clin N Am. 2008;46(4):643–52, v. https://doi.org/10.1016/j.rcl.2008.07.005.
Dicker D, Nguyen G, Abate D, Abate KH, Abay SM, Abbafati C, et al. Global, regional, and national age-sex-specific mortality and life expectancy, 1950-2017: A systematic analysis for the Global Burden of Disease Study 2017. Lancet. 2018;392(10159):1684–735. https://doi.org/10.1016/S0140-6736(18)31891-9.
Gurwitz JH, Go AS, Fortmann SP. Statins for primary prevention in older adults: uncertainty and the need for more evidence. JAMA. 2016;316(19):1971–2. https://doi.org/10.1001/jama.2016.15212.
Catapano AL, Graham I, De Backer G, Wiklund O, Chapman MJ, Drexel H, et al. 2016 ESC/EAS Guidelines for the Management of Dyslipidaemias. Eur Heart J. 2016;37(39):2999–3058. https://doi.org/10.1093/eurheartj/ehw272.
Armitage J, Baigent C, Barnes E, Betteridge DJ, Blackwell L, Blazing M, et al. Efficacy and safety of statin therapy in older people: a meta-analysis of individual participant data from 28 randomised controlled trials. Lancet. 2019;393(10170):407–15. https://doi.org/10.1016/S0140-6736(18)31942-1.
Armstrong PW, Westerhout CM. Composite end points in clinical research: a time for reappraisal. Circulation. 2017;135(23):2299–307. https://doi.org/10.1161/CIRCULATIONAHA.117.026229.
Savarese G, Gotto AM, Paolillo S, D’Amore C, Losco T, Musella F, et al. Benefits of statins in elderly subjects without established cardiovascular disease: a meta-analysis. J Am Coll Cardiol. 2013;62(22):2090–9. https://doi.org/10.1016/j.jacc.2013.07.069.
Teng M, Lin L, Zhao YJ, Khoo AL, Davis BR, Yong QW, et al. Statins for primary prevention of cardiovascular disease in elderly patients: systematic review and meta-analysis. Drugs Aging. 2015;32(8):649–61. https://doi.org/10.1007/s40266-015-0290-9.
Ponce OJ, Larrea-Mantilla L, Hemmingsen B, Serrano V, Rodriguez-Gutierrez R, Spencer-Bonilla G, et al. Lipid-lowering agents in older individuals: a systematic review and meta-analysis of randomized clinical trials. J Clin Endocrinol Metab. 2019;104(5):1585–94. https://doi.org/10.1210/jc.2019-00195.
Stroup DF, Berlin JA, Morton SC, Olkin I, Williamson GD, Rennie D, et al. Meta-analysis of observational studies in epidemiology: a proposal for reporting. JAMA. 2000;283(15):2008–12. https://doi.org/10.1001/jama.283.15.2008.
Sterne JA, Hernán MA, Reeves BC, Savović J, Berkman ND, Viswanathan M, et al. ROBINS-I: A tool for assessing risk of bias in non-randomised studies of interventions. BMJ. 2016;355. https://doi.org/10.1136/bmj.i4919.
Guyatt GH, Oxman AD, Vist GE, Kunz R, Falck-Ytter Y, Alonso-Coello P, et al. GRADE: An emerging consensus on rating quality of evidence and strength of recommendations. BMJ. 2008;336(7650):924–6. https://doi.org/10.1136/bmj.39489.470347.ad.
Schünemann HJ, Mustafa RA, Brozek J, Steingart KR, Leeflang M, Murad MH, et al. GRADE guidelines: 21 part 1. Study design, risk of bias, and indirectness in rating the certainty across a body of evidence for test accuracy. J Clin Epidemiol. 2020;122:129–41. https://doi.org/10.1016/j.jclinepi.2019.12.020.
Schünemann HJ, Mustafa RA, Brozek J, Steingart KR, Leeflang M, Murad MH, et al. GRADE guidelines: 21 part 2. Test accuracy: inconsistency, imprecision, publication bias, and other domains for rating the certainty of evidence and presenting it in evidence profiles and summary of findings tables. J Clin Epidemiol. 2020;122:142–52. https://doi.org/10.1016/j.jclinepi.2019.12.021.
Essebag V, Platt RW, Abrahamowicz M, Pilote L. Comparison of nested case-control and survival analysis methodologies for analysis of time-dependent exposure. BMC Med Res Methodol. 2005;5(1). https://doi.org/10.1186/1471-2288-5-5.
Rothman K, Greenland S, Lash T. Modern epidemiology. 2008. https://www.google.com/books?hl=en&lr=&id=Z3vjT9ALxHUC&oi=fnd&pg=PR7&dq=Rothman+KJ,+Greenland+S,+Lash+TL.+Modern+Epidemiology,+3rd+edn.+Philadelphia,+USA:+Lippincott+Williams+%26+Wilkins,+2008.&ots=aSFFfKWNaX&sig=StY2RJEPS9bGCrn7LS4dj2j8Nx4. Accessed 16 Oct 2020.
Higgins JPT, Thomas J, Chandler J, Cumpston M, Li T, Page MJ, et al. Cochrane Handbook for Systematic Reviews of Interventions. https://training.cochrane.org/handbook. Accessed 5 Jun 2020.
Egger M, Davey Smith G, Schneider M, Minder C. Bias in meta-analysis detected by a simple, graphical test. BMJ. 1997;315(7109):629–34. https://doi.org/10.1136/bmj.315.7109.629.
Duval S, Tweedie R. Trim and fill: a simple funnel-plot-based method of testing and adjusting for publication bias in meta-analysis. Biometrics. 2000;56(2):455–63. https://doi.org/10.1111/j.0006-341X.2000.00455.x.
Alpérovitch A, Kurth T, Bertrand M, Ancelin ML, Helmer C, Debette S, et al. Primary prevention with lipid lowering drugs and long term risk of vascular events in older people: population based cohort study. BMJ. 2015;350(may19 2):h2335. https://doi.org/10.1136/bmj.h2335.
Bezin J, Moore N, Mansiaux Y, Steg PG, Pariente A. Real-life benefits of statins for cardiovascular prevention in elderly subjects: a population-based cohort Study. Am J Med. 2019;132:740–8.e7. https://doi.org/10.1016/j.amjmed.2018.12.032.
Gitsels LA, Kulinskaya E, Steel N. Survival benefits of statins for primary prevention: a cohort study. PLoS One. 2016;11(11):e0166847. https://doi.org/10.1371/journal.pone.0166847.
Kim K, Lee CJ, Shim CY, Kim JS, Kim BK, Park S, et al. Statin and clinical outcomes of primary prevention in individuals aged > 75 years: The SCOPE-75 study. Atherosclerosis. 2019;284:31–6. https://doi.org/10.1016/j.atherosclerosis.2019.02.026.
Orkaby AR, Gaziano JM, Djousse L, Driver JA. Statins for primary prevention of cardiovascular events and mortality in older men. J Am Geriatr Soc. 2017;65(11):2362–8. https://doi.org/10.1111/jgs.14993.
Ramos R, Comas-Cufí M, Martí-Lluch R, Balló E, Ponjoan A, Alves-Cabratosa L, et al. Statins for primary prevention of cardiovascular events and mortality in old and very old adults with and without type 2 diabetes: Retrospective cohort study. BMJ. 2018;362:k3359. https://doi.org/10.1136/bmj.k3359.
Lemaitre RN, Psaty BM, Heckbert SR, Kronmal RA, Newman AB, Burke GL. Therapy with hydroxymethylglutaryl coenzyme A reductase inhibitors (statins) and associated risk of incident cardiovascular events in older adults: Evidence from the cardiovascular health study. Arch Intern Med. 2002;162(12):1395–400. https://doi.org/10.1001/archinte.162.12.1395.
Jun JE, Cho IJ, Han K, Jeong IK, Ahn KJ, Chung HY, et al. Statins for primary prevention in adults aged 75 years and older: a nationwide population-based case-control study. Atherosclerosis. 2019;283:28–34. https://doi.org/10.1016/j.atherosclerosis.2019.01.030.
Orkaby AR, Driver JA, Ho Y-L, Lu B, Costa L, Honerlaw J, et al. Association of Statin Use With All-Cause and Cardiovascular Mortality in US Veterans 75 Years and Older. JAMA. 2020;324(1):68–78. https://doi.org/10.1001/jama.2020.7848.
Zhou Z, Ofori-Asenso R, Curtis AJ, Breslin M, Wolfe R, McNeil JJ, et al. Association of statin use with disability-free survival and cardiovascular disease among healthy older adults. J Am Coll Cardiol. 2020;76(1):17–27. https://doi.org/10.1016/j.jacc.2020.05.016.
Ravnskov U, Diamond DM, Hama R, Hamazaki T, Hammarskjöld B, Hynes N, et al. Lack of an association or an inverse association between low-density-lipoprotein cholesterol and mortality in the elderly: a systematic review. BMJ Open. 2016;6(6):e010401. https://doi.org/10.1136/bmjopen-2015-010401.
Strandberg TE. Role of Statin Therapy in Primary Prevention of Cardiovascular Disease in Elderly Patients. Curr Atheroscler Rep. 2019;21(8):28. https://doi.org/10.1007/s11883-019-0793-7.
Iribarren C, Reed DM, Chen R, Yano K, Dwyer JH. Low serum cholesterol and mortality: Which is the cause and which is the effect? Circulation. 1995;92(9):2396–403. https://doi.org/10.1161/01.CIR.92.9.2396.
Charlton J, Ravindrarajah R, Hamada S, Jackson SH, Gulliford MC. Trajectory of total cholesterol in the last years of life over age 80 years: cohort study of 99,758 participants. J Gerontol Ser A. 2018;73(8):1083–9. https://doi.org/10.1093/gerona/glx184.
Ahn J, Lim U, Weinstein SJ, Schatzkin A, Hayes RB, Virtamo J, et al. Prediagnostic total and high-density lipoprotein cholesterol and risk of cancer. Cancer Epidemiol Biomark Prev. 2009;18(11):2814–21. https://doi.org/10.1158/1055-9965.EPI-08-1248.
Alford SH, Divine G, Chao C, Habel LA, Janakiraman N, Wang Y, et al. Serum cholesterol trajectories in the 10 years prior to lymphoma diagnosis. Cancer Causes Contrl. 2018;29(1):143–56. https://doi.org/10.1007/s10552-017-0987-7.
Carpentier YA, Scruel O. Changes in the concentration and composition of plasma lipoproteins during the acute phase response. Curr Opin Clin Nutr Metab Care. 2002;5(2):153–8. https://doi.org/10.1097/00075197-200203000-00006.
Sammalkorpi K, Valtonen V, Kerttula Y, Nikkilä E, Taskinen MR. Changes in serum lipoprotein pattern induced by acute infections. Metabolism. 1988;37(9):859–65. https://doi.org/10.1016/0026-0495(88)90120-5.
Akgün S, Ertel NH, Mosenthal A, Oser W. Postsurgical reduction of serum lipoproteins: Interleukin-6 and the acute-phase response. J Lab Clin Med. 1998;131(1):103–8. https://doi.org/10.1016/S0022-2143(98)90083-X.
DiNicolantonio JJ, McCarty MF. Is interleukin-6 the link between low LDL cholesterol and increased non-cardiovascular mortality in the elderly? Open Hear. 2018;5(1):e000789. https://doi.org/10.1136/openhrt-2018-000789.
Stopeck AT, Nicholson AC, Mancini FP, Hajjar DP. Cytokine regulation of low density lipoprotein receptor gene transcription in HepG2 cells. J Biol Chem. 1993;268(23):17489–94. https://doi.org/10.1016/S0021-9258(19)85360-7.
Gierens H, Nauck M, Roth M, Schinker R, Schürmann C, Scharnagl H, et al. Interleukin-6 stimulates LDL receptor gene expression via activation of sterol-responsive and Sp1 binding elements. Arterioscler Thromb Vasc Biol. 2000;20(7):1777–83. https://doi.org/10.1161/01.ATV.20.7.1777.
Li H, Liu W, Xie J. Circulating interleukin-6 levels and cardiovascular and all-cause mortality in the elderly population: a meta-analysis. Arch Gerontol Geriatr. 2017;73:257–62. https://doi.org/10.1016/j.archger.2017.08.007.
Postmus I, Deelen J, Sedaghat S, Trompet S, de Craen AJM, Heijmans BT, et al. LDL cholesterol still a problem in old age? A Mendelian randomization study. Int J Epidemiol. 2015;44(2):604–12. https://doi.org/10.1093/ije/dyv031.
Yebyo HG, Aschmann HE, Kaufmann M, Puhan MA. Comparative effectiveness and safety of statins as a class and of specific statins for primary prevention of cardiovascular disease: a systematic review, meta-analysis, and network meta-analysis of randomized trials with 94,283 participants. Am Heart J. 2019;210:18–28. https://doi.org/10.1016/j.ahj.2018.12.007.
Kostis JB, Giakoumis M, Zinonos S, Cabrera J, Kostis WJ. Meta-analysis of usefulness of treatment of hypercholesterolemia with statins for primary prevention in patients older than 75 years. Am J Cardiol. 2020;125(8):1154–7. https://doi.org/10.1016/j.amjcard.2020.01.020.
Kim S, Choi H, Won CW. Effects of statin use for primary prevention among adults aged 75 years and older in the National Health Insurance Service senior cohort (2002– 2015). Ann Geriatr Med Res. 2020;24(2):91–8. https://doi.org/10.4235/AGMR.20.0028.
Ofori-Asenso R, Ilomäki J, Tacey M, Zomer E, Curtis AJ, Bell JS, et al. Predictors of statin use among older adults: a nationwide cross-sectional study. J Clin Lipidol. 2019;13:156–62.e1. https://doi.org/10.1016/j.jacl.2018.10.002.
van der Ploeg MA, Streit S, Achterberg WP, Beers E, Bohnen AM, Burman RA, et al. Patient characteristics and general practitioners’ advice to stop statins in oldest-old patients: a survey study across 30 countries. J Gen Intern Med. 2019;34(9):1751–7. https://doi.org/10.1007/s11606-018-4795-x.
Cholesterol Treatment Trialists’ (CTT) Collaboration CTT (CTT), Baigent C, Blackwell L, Emberson J, Holland LE, Reith C, et al. Efficacy and safety of more intensive lowering of LDL cholesterol: a meta-analysis of data from 170,000 participants in 26 randomised trials. Lancet. 2010;376:1670–81. https://doi.org/10.1016/S0140-6736(10)61350-5.
Olafsdottir E, Aspelund T, Sigurdsson G, Thorsson B, Eiriksdottir G, Harris TB, et al. Effects of statin medication on mortality risk associated with type 2 diabetes in older persons: the population-based AGES-Reykjavik Study. BMJ Open. 2011;1(1):e000132. https://doi.org/10.1136/bmjopen-2011-000132.
Bertoluci MC, Rocha VZ. Cardiovascular risk assessment in patients with diabetes. Diabetol Metab Syndr. 2017;9(1):25. https://doi.org/10.1186/s13098-017-0225-1.
Rana JS, Liu JY, Moffet HH, Jaffe M, Karter AJ. Diabetes and prior coronary heart disease are not necessarily risk equivalent for future coronary heart disease events. J Gen Intern Med. 2016;31(4):387–93. https://doi.org/10.1007/s11606-015-3556-3.
Katsiki N, Banach M, Mikhailidis DP. Is type 2 diabetes mellitus a coronary heart disease equivalent or not? Do not just enjoy the debate and forget the patient! Arch Med Sci. 2019;15(6):1357–64. https://doi.org/10.5114/aoms.2019.89449.
Nayak A, Hayen A, Zhu L, McGeechan K, Glasziou P, Irwig L, et al. Legacy effects of statins on cardiovascular and all-cause mortality: a meta-analysis. BMJ Open. 2018;8(9):e020584. https://doi.org/10.1136/bmjopen-2017-020584.
Takata K, Psaltis PJ, Nicholls SJ. Investigating the long-term legacy of statin therapy. J Thorac Dis. 2017;9:936–9. https://doi.org/10.21037/jtd.2017.03.10.
Wilmot KA, Khan A, Krishnan S, Eapen DJ, Sperling L. Statins in the elderly: a patient-focused approach. Clin Cardiol. 2015;38(1):56–61. https://doi.org/10.1002/clc.22338.
Bhardwaj S, Selvarajah S, Schneider EB. Muscular effects of statins in the elderly female: a review. Clin Interv Aging. 2013;8:47–59. https://doi.org/10.2147/CIA.S29686.
Banach M, Serban M-C. Discussion around statin discontinuation in older adults and patients with wasting diseases. J Cachexia Sarcopenia Muscle. 2016;7(4):396–9. https://doi.org/10.1002/jcsm.12109.
Routledge PA, O’Mahony MS, Woodhouse KW. Adverse drug reactions in elderly patients. Br J Clin Pharmacol. 2004;57(2):121–6. https://doi.org/10.1046/J.1365-2125.2003.01875.X.
Banach M, Rizzo M, Toth PP, Farnier M, Davidson MH, Al-Rasadi K, et al. Position paper Statin intolerance – an attempt at a unified definition. Position paper from an International Lipid Expert Panel. Arch Med Sci. 2015;1(1):1–23. https://doi.org/10.5114/aoms.2015.49807.
Szadkowska I, Stanczyk A, Aronow WS, Kowalski J, Pawlicki L, Ahmed A, et al. Statin therapy in the elderly: a review. Arch Gerontol Geriatr. 2010;50(1):114–8. https://doi.org/10.1016/j.archger.2008.12.012.
Maningat P, Gordon BR, Breslow JL. How do we improve patient compliance and adherence to long-term statin therapy? Curr Atheroscler Rep. 2013;15(1):291. https://doi.org/10.1007/s11883-012-0291-7.
Bradley CK, Wang TY, Li S, Robinson JG, Roger VL, Goldberg AC, et al. Patient-reported reasons for declining or discontinuing statin therapy: insights from the PALM Registry. J Am Heart Assoc. 2019;8(7):e011765. https://doi.org/10.1161/JAHA.118.011765.
Cohen JD, Brinton EA, Ito MK, Jacobson TA. Understanding Statin Use in America and Gaps in Patient Education (USAGE): an internet-based survey of 10,138 current and former statin users. J Clin Lipidol. 2012;6(3):208–15. https://doi.org/10.1016/j.jacl.2012.03.003.
Ofori-Asenso R, Jakhu A, Zomer E, Curtis AJ, Korhonen MJ, Nelson M, et al. Adherence and persistence among statin users aged 65 years and over: a systematic review and meta-analysis. J Gerontol Ser A. 2017;73(6):813–9. https://doi.org/10.1093/gerona/glx169.
Downs JR, Clearfield M, Weis S, Whitney E, Shapiro DR, Beere PA, et al. Primary prevention of acute coronary events with lovastatin in men and women with average cholesterol levels: results of AFCAPS/TexCAPS. J Am Med Assoc. 1998;279(20):1615–22. https://doi.org/10.1001/jama.279.20.1615.
Glynn RJ, Koenig W, Nordestgaard BG, Shepherd J, Ridker PM. Rosuvastatin for primary prevention in older persons with elevated C-reactive protein and low to average low-density lipoprotein cholesterol levels: exploratory analysis of a randomized trial. Ann Intern Med. 2010;152(8):488–96. https://doi.org/10.7326/0003-4819-152-8-201004200-00005.
Collier DJ, Poulter NR, Dahlöf B, Sever PS, Wedel H, Buch J, et al. Impact of atorvastatin among older and younger patients in the Anglo-Scandinavian Cardiac Outcomes Trial Lipid-Lowering Arm. J Hypertens. 2011;29(3):592–9. https://doi.org/10.1097/HJH.0b013e328342c8f7.
Han BH, Sutin D, Williamson JD, Davis BR, Piller LB, Pervin H, et al. Effect of statin treatment vs usual care on primary cardiovascular prevention among older adults: The ALLHAT-LLT randomized clinical trial. JAMA Intern Med. 2017;177(7):955–65. https://doi.org/10.1001/jamainternmed.2017.1442.
Sattar N, Preiss D, Murray HM, Welsh P, Buckley BM, de Craen AJM, et al. Statins and risk of incident diabetes: a collaborative meta-analysis of randomised statin trials. Lancet. 2010;375(9716):735–42. https://doi.org/10.1016/S0140-6736(09)61965-6.
Engeda JC, Stackhouse A, White M, Rosamond WD, Lhachimi SK, Lund JL, et al. Evidence of heterogeneity in statin-associated type 2 diabetes mellitus risk: a meta-analysis of randomized controlled trials and observational studies. Diabetes Res Clin Pract. 2019;151:96–105. https://doi.org/10.1016/j.diabres.2019.04.005.
Casula M, Mozzanica F, Scotti L, Tragni E, Pirillo A, Corrao G, et al. Statin use and risk of new-onset diabetes: a meta-analysis of observational studies. Atherosclerosis. 2017;263:e262–3. https://doi.org/10.1016/j.atherosclerosis.2017.06.850.
Mortensen MB, Falk E. Primary prevention with statins in the elderly. J Am Coll Cardiol. 2018;71:85–94.
Colhoun HM, Betteridge DJ, Durrington PN, Hitman GA, Neil HAW, Livingstone SJ, et al. Primary prevention of cardiovascular disease with atorvastatin in type 2 diabetes in the Collaborative Atorvastatin Diabetes Study (CARDS): multicentre randomised placebo-controlled trial. Lancet. 2004;364(9435):685–96. https://doi.org/10.1016/S0140-6736(04)16895-5.
Shepherd J, Blauw GJ, Murphy MB, Bollen ELEM, Buckley BM, Cobbe SM, et al. Pravastatin in elderly individuals at risk of vascular disease (PROSPER): a randomised controlled trial. Lancet. 2002;360(9346):1623–30. https://doi.org/10.1016/S0140-6736(02)11600-X.
Bruckert E, Lièvre M, Giral P, Crepaldi G, Masana L, Vrolix M, et al. Short-term efficacy and safety of extended-release fluvastatin in a large cohort of elderly patients. Am J Geriatr Cardiol. 2003;12(4):225–31.
Zhou Z, Albarqouni L, Curtis AJ, Breslin M, Nelson M. The safety and tolerability of statin therapy in primary prevention in older adults: a systematic review and meta-analysis. Drugs Aging. 2020;37(3):175–85. https://doi.org/10.1007/s40266-019-00736-y.
Iwere RB, Hewitt J. Myopathy in older people receiving statin therapy: a systematic review and meta-analysis. Br J Clin Pharmacol. 2015;80(3):363–71. https://doi.org/10.1111/bcp.12687.
Ott BR, Daiello LA, Dahabreh IJ, Springate BA, Bixby K, Murali M, et al. Do statins impair cognition? A systematic review and meta-analysis of randomized controlled trials. J Gen Intern Med. 2015;30(3):348–58. https://doi.org/10.1007/s11606-014-3115-3.
Mcguinness B, Craig D, Bullock R, Passmore P. Statins for the prevention of dementia. Cochrane Database Syst Rev. 2016;2016. https://doi.org/10.1002/14651858.CD003160.pub3.
Chu CS, Tseng PT, Stubbs B, Chen TY, Tang CH, Li DJ, et al. Use of statins and the risk of dementia and mild cognitive impairment: a systematic review and meta-analysis. Sci Rep. 2018;8(1):5804. https://doi.org/10.1038/s41598-018-24248-8.
Van Der Ploeg MA, Poortvliet RKE, Van Blijswijk SCE, Den Elzen WPJ, Van Peet PG, De Ruijter W, et al. Statin use and self-reported hindering muscle complaints in older persons: a population based study. PLoS One. 2016;11(12):e0166857.
Cordoba G, Schwartz L, Woloshin S, Bae H, Gøtzsche PC. Definition, reporting, and interpretation of composite outcomes in clinical trials: Systematic review. BMJ. 2010;341:381.
Cicero AFG, Colletti A, Bajraktari G, Descamps O, Djuric DM, Ezhov M, et al. Lipid lowering nutraceuticals in clinical practice: Position paper from an International Lipid Expert Panel. Arch Med Sci. 2017;13:965–1005. https://doi.org/10.5114/aoms.2017.69326.
Ethics approval and consent to participate
Consent for publication
Gregory Y. H. Lip: consultant for Bayer/Janssen, BMS/Pfizer, Medtronic, Boehringer Ingelheim, Novartis, Verseon and Daiichi-Sankyo; speaker for BMS/Pfizer, Medtronic, Boehringer Ingelheim, and Daiichi-Sankyo. No fees are directly received personally; Michael J. Blaha: grants; FDA, NIH, AHA, Aetna Foundation, Amgen Foundation; advisory board/consultant; Amgen, Sanofi, Regeneron, Kowa, Novartis, Novo Nordisk, Bayer, 89Bio, Akcea, Gilead; Carl J. Lavie: speaker and consultant for Regeneron, Sanofi, Amgen, and Esperion on non-statin lipid medications; Peter P. Toth: speakers bureau; Amarin, Amgen, Esperion, Novo-Nordisk; consultant; Amarin, Amgen, bio 89, Kowa and Novartis; J. Wouter Jukema/his department has received research grants from and/or was a speaker (with or without lecture fees) on a.o.(CME accredited) meetings sponsored by Amgen, Athera, Astra-Zeneca, Biotronik, Boston Scientific, Dalcor, Daiichi Sankyo, Lilly, Medtronic, Merck-Schering-Plough, Pfizer, Roche, Sanofi Aventis, The Medicine Company, the Netherlands Heart Foundation, CardioVascular Research the Netherlands (CVON), the Netherlands Heart Institute and the European Community Framework KP7 Programme; Naveed Sattar has consulted for Amgen, Astrazeneca, Boehringer Ingelheim, Eli-Lilly, MSD, Novo Nordisk, Pfizer and Sanofi, and received Grant income from Boehringer Ingelheim; Maciej Banach: speakers bureau; Abbott/Mylan, Abbott Vascular, Actavis, Akcea, Amgen, Biofarm, KRKA, MSD, Polpharma, Sanofi-Aventis, Servier and Valeant; consultant to Abbott Vascular, Akcea, Amgen, Daichii Sankyo, Esperion, Freia Pharmaceuticals, Lilly, MSD, Polfarmex, Resverlogix, Sanofi-Aventis; Grants from Sanofi and Valeant; Kamal Awad, Maged Mohammed, Mahmoud Mohamed Zaki, and Abdelrahman I. Abushouk have no conflict of interest.
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Forest plot displaying the results of the meta-analysis of observational studies that compared statin use with non-use in older people aged ≥65 years and without cardiovascular disease – A: in terms of type 2 diabetes mellitus and B: in terms of new-onset cancer. HR, hazard ratio; CI, confidence interval; T2DM, type 2 diabetes mellitus.
The corrected funnel plots displaying publication bias in the observational studies that compared statin using with non-using in older people aged ≥65 years and without cardiovascular disease – A: in terms of all-cause mortality; B: in terms of cardiovascular death; C: in terms of myocardial infarction; D: in terms of stroke; E: in terms of type 2 diabetes mellitus and F: in terms of new-onset cancer.
MOOSE Checklist for Meta-analyses of Observational Studies.
Literature search strategy for each relevant database.
List of excluded studies and reasons for exclusion.
Covariates adjustment in the included studies.
Risk of bias of included studies using Risk of Bias in Non-randomized Studies of Interventions (ROBINS-I) Tool.
GRADE assessment of quality of evidence.
Results of publication bias assessment using funnel plot asymmetry, trim and fill method, and Egger’s test
About this article
Cite this article
Awad, K., Mohammed, M., Zaki, M.M. et al. Association of statin use in older people primary prevention group with risk of cardiovascular events and mortality: a systematic review and meta-analysis of observational studies. BMC Med 19, 139 (2021). https://doi.org/10.1186/s12916-021-02009-1
- Primary prevention
- Myocardial infarction