The Role of Statin Therapy in Older Adults: Best Practices and Unmet Challenges

Abstract

Introduction

Cardiovascular disease (CVD) is associated with significant morbidity, functional decline, and mortality in older adults. The role of statins for primary CVD prevention in older adults remains unclear, largely due to systematic exclusion of these individuals in trials that inform current practice guidelines, leading to conflicting national and international practice recommendations for statin use for primary prevention of CVD in adults aged 75 and older.

Areas covered

In this narrative review, we performed a literature review utilizing PubMed, and ultimately focus on seven major national and international guidelines of lipid lowering therapy. Through the lens of two clinical cases, we review physiologic changes in lipid metabolism with aging, discuss the relationship between cholesterol and cardiovascular events in older adults, examine the national and international guidelines and the available evidence informing these guidelines for statin use in primary prevention of CVD in older adults. Finally we review practical clinical considerations for drug monitoring and deprescribing in this population.

Expert opinion

Guidelines for the use of statins for primary CVD prevention in older adults is conflicting. Collectively, evidence to date suggests statin therapy may be beneficial for primary CVD prevention in older adults free of life-limiting comorbidities. Randomized controlled trials are currently underway to address current evidence gaps.

1. Introduction

Along with most of the world, the United States (U.S.) faces a significant demographic shift towards older age. Since 2010, the population above 65 has grown exponentially, with one in six Americans now falling within this demographic [1]. This trend is projected to continue, and by 2040, 22% of the total population is estimated to be older than 65 [2]. Age is one of the strongest, non-modifiable risk factors of cardiovascular disease (CVD), and by the age of 70, an estimated 70% of adults are diagnosed with CVD [3, 4]. The incidence and prevalence of CVD are expected to increase substantially with the changing population demographics. CVD inflicts a significant societal burden in terms of morbidity, mortality, and financial cost that was estimated at around $422.3 billion from 2019 to 2020 [3]. CVD in older adults is associated with dramatically higher mortality, along with a higher risk of functional decline and long-term institutionalization [5, 6].

If started early in life, the development and progression of CVD can be prevented or delayed by optimizing the “Life’s Essential 8” components, as outlined by the American Heart Association. This would also translate into a meaningful increase in quality of life and lifespan in older adults [7]. One of the Life Essential 8 components is optimal “cholesterol control” through lifestyle modification and lipid-lowering therapy utilizing statins. Statins have shown beneficial effects for the primary prevention of CVD in those up to age 75 [8]. However, evidence for the use of statins for primary prevention of CVD after age 75 is sparse, primarily due to the systematic exclusion of older adults in the trials that served as the basis for current practice recommendations [9]. As a result, current national and international guidelines have notable discrepancies in their recommendations, which has left clinicians and patients without clear guidance when considering initiating, continuing, or stopping statin therapy for primary CVD prevention in older adults.

In this article, we review the seven major guidelines from North America and Europe for statin use in the primary prevention of CVD in older adults, review available evidence informing these recommendations, and discuss practical considerations for drug initiation, monitoring, and deprescribing.

2. Cases

To guide this review, we present two cases:

Patient A is an 82-year-old community-dwelling male with adequately controlled hypertension and a previous 30-pack year smoking history (quit 25 years ago). He has no known history of atherosclerotic cardiovascular disease (ASCVD). He takes losartan 25 mg and amlodipine 5 mg daily for blood pressure control. He is physically active and independent in his activities of daily living (ADLs). Recently obtained routine lab work included a lipid profile that showed a total cholesterol of 227 mg/dL, triglycerides 170 mg/dL, high-density lipoprotein cholesterol (HDL-C) 41 mg/dL, and low-density lipoprotein cholesterol (LDL-C) 152 mg/dL. Should he be started on a statin?

Patient B is an 82-year-old female who recently transitioned to a long-term care facility due to advancing Alzheimer’s dementia. She has hypertension and chronic kidney disease that are managed with lisinopril 10 mg, donepezil 10 mg, and atorvastatin 20 mg daily. Before moving into long-term care, she had experienced a series of recurrent urinary tract infections, which ultimately resulted in poor appetite, weight loss, muscle wasting, and becoming increasingly bed-bound and reliant on her family and caregivers for assistance with her self-care. Her new geriatrician is reviewing her medications and is uncertain why the patient is taking a statin. Should her statin be continued for primary prevention?

3. Aging and frailty

As is evident in these two cases, despite their shared chronologic age, age alone does not provide a comprehensive picture of each patient’s health status, nor does it help predict future health outcomes [10]. However, measuring geriatric syndromes such as frailty can help contextualize an older adult’s chronologic age. Frailty is a clinical state characterized by poor physiologic reserve in multiple organ systems, resulting in an increased vulnerability to a variety of stressors. This ultimately predisposes to adverse health outcomes [4, 11-13]. Recognizing frailty allows clinicians to better understand the health status of individuals from a heterogeneous population.

Among community-dwelling adults, the prevalence of frailty approaches 60% in individuals with CVD compared to 10% among those without CVD [14, 15]. Frailty and CVD have reciprocal relationships in which one of these conditions is associated with an increased likelihood of developing the other [14]. Importantly, in patients with CVD, the presence and severity of frailty are associated with cardiovascular mortality and major cardiovascular events [13, 14, 16]. This is evident in a retrospective analysis of 3 million U.S. Veterans, which found that the hazard ratio (HR) of cardiovascular death in frail versus non-frail individuals increased along with frailty severity, with respective HR of 1.6 in pre-frail, 2.7 in mildly frail, 4.3 in moderately frail, and 7.9 in severely frail patients [16]. Another prospective study of 4,656 adults aged 65 and older who participated in the National Health and Aging Trends Study reported that frail individuals had significantly higher rates of incident major adverse cardiovascular events (MACE) [HR 1.77, 95% CI 1.53-2.06], death (HR 2.70, 95% CI 2.16-3.38), acute myocardial infarction (MI) [HR 1.95, 95% CI 1.31-2.90], stroke (HR 1.71, 95% CI 1.34-2.17), peripheral vascular disease (HR 1.80, 95% CI 1.44-2.27), and coronary artery disease (CAD) [HR 1.35, 95% CI 1.11-1.65] compared to those who were non-frail [17].

4. Lipids, atherosclerosis, and aging

Elevated plasma cholesterol levels, particularly LDL-C, are critical in the development and progression of ASCVD [18]. Endothelial dysfunction and damage are initial steps in atherogenesis, resulting from insults such as elevated LDL-C, hypertension, diabetes, or free radicals generated from cigarette smoking [19-22]. LDL particles then accumulate within the intimal layer of the arterial wall, resulting in subsequent modification and coalescence within the intima. This leads to a cytokine-mediated inflammatory response, including macrophage recruitment, foam cell formation, smooth muscle cell migration and proliferation, and extracellular matrix expansion, ultimately forming a fibrofatty atheroma [19-22].

Aging plays a vital role in key changes in lipid metabolism. Total cholesterol concentrations increase in puberty and peak by ages 45 to 55 in men and 55 to 65 in women, and then decline in the ensuing decades, in part due to reduced hepatic synthetic function [23]. A “survivor bias” has been hypothesized to explain a decline in LDL-C over time, where individuals with low LDL-C are more likely to survive to late life. However, this has not been proven in prospective studies [7, 23]. Decreased levels of estrogen in post-menopausal women may underly higher triglyceride levels in women compared to men [7]. Finally, comorbidities such as obesity, metabolic syndrome, diabetes mellitus, hypothyroidism, and catabolic conditions such as renal disease and malignancy all contribute to changes in lipid levels over time [7, 23]. In addition to these changes in lipid metabolism with increasing age, excessive oxidative stress that accompanies aging may induce a combination of endothelial dysfunction and platelet/clotting factor activation that portends adverse cardiovascular events over time [24].

Several retrospective and prospective studies have shown conflicting evidence for the association between total cholesterol and LDL-C and the risk of ASCVD events in older adults. In an Italian cohort of 3,257 subjects aged 65 to 95, total cholesterol directly predicted coronary mortality in men. However, lower total cholesterol levels were also associated with increased cancer mortality in women and non-CVD mortality in both sexes [25]. Similarly, in a multicenter longitudinal study of 4,066 individuals with a mean age of 79, borderline (200-239 mg/dL) and elevated (≥240 mg/dL) total cholesterol was associated with a significant increase in the risk of death from coronary heart disease (RR 1.45, 95% CI 1.02-2.08 and RR 1.57, 95% CI 1.06-2.34 respectively) [26]. In a meta-analysis of 61 observational prospective studies including 900,000 individuals between ages 40 and 89 without ASCVD, lower total cholesterol was associated with lower ischemic heart disease mortality in both sexes. However, the strength of association attenuated with increasing age (HR 0.44 in ages 40-49 [95% CI 0.42-0.48], HR 0.66 in ages 50-69 [95% CI 0.65-0.68], and HR 0.83 in ages 70-89 [95% CI 0.81-0.85]) [27].

In comparison, a Dutch cohort of 5,750 individuals aged ≥ 85 years reported a 21% reduction in CVD mortality (HR 0.79, 95% CI 0.67-0.94; p=0.001) and a 12% reduction in non-CVD mortality (HR 0.88, 95% CI 0.85-0.93; p<0.001) for every one mmol/L increase in total serum cholesterol [28]. Similar findings were reported in another Dutch cohort of 724 individuals, median age 89 years, with a one mmol/L increase in total cholesterol corresponding with a 15% decrease in overall mortality (RR 0.85, 95% CI 0.79-0.91) [29]. Finally, in a Finnish cohort of 490 home-dwelling individuals ≥ 75 years, subjects with a higher total cholesterol also had a lower risk of all-cause mortality over 6 years of follow-up [30].

When considering LDL-C levels, the data again is conflicting. A systematic review of 19 cohort studies comprising 68,094 individuals aged ≥ 60 reported either a lack of association or inverse association between LDL-C and all-cause mortality [31]. Similarly, in a retrospective study of 69,824 individuals, a mean age of 73, lower LDL-C, and total cholesterol levels were associated with an increased risk of all-cause mortality [32]. In a cohort of 2,277 individuals aged 65 to 98 without dementia, those with lower levels of total cholesterol, non-HDL-C, and LDL-C were twice as likely to die versus those with higher cholesterol levels, even after adjusting for morbidities and smoking [33]. In contrast, in a primary prevention cohort of 91,131 Dutch subjects, elevated LDL-C was associated with a higher absolute risk of MI and ASCVD in individuals aged 70 to 100 as compared to those aged 20 to 69 [34].

Overall, the association between total cholesterol, LDL-C, and CVD in older adults remains unclear. Studies have failed to demonstrate a clear association between total cholesterol or LDL-C and cardiovascular outcomes, all-cause mortality, or CVD-specific mortality [35-37]. This uncertainty on the role of cholesterol for cardiovascular outcomes in older adults has contributed to the debate on the role of statins in this population, although this perspective fails to recognize the additional effect of statins in lowering inflammation, another primary pathology of CVD [38-40].

5. Current cholesterol guidelines

There are seven leading national and international guidelines for the management of cholesterol for the primary prevention of CVD, including:

• 2018 AHA/ACC Guideline on Management of Blood Cholesterol [41]

• 2019 ACC/AHA Guideline on Primary Prevention of Cardiovascular Disease [9]

• 2022 USPSTF Recommendation Statement on Statin Use for the Primary Prevention of Cardiovascular Disease in Adults [42]

• 2020 VA/DoD Clinical Practice Guideline for Management of Dyslipidemia for Cardiovascular Risk Reduction [43]

• 2019 ESC/EAS Guidelines for Management of Dyslipidaemias [44]

• 2021 CCS Guidelines for Management of Dyslipidemia for Prevention of Cardiovascular Disease in Adults [45]

• 2023 NICE UK Guidelines for Cardiovascular Disease: Risk Assessment and Reduction, including Lipid Modification [46]

Table 1 reviews each guideline’s indications for statin therapy for primary CVD prevention across multiple age ranges, associated ASCVD risk tool assessment, and the strength of each recommendation. These guidelines vary in two key categories: method of ASCVD risk assessment and age ranges to consider statin therapy [47]. The various ASCVD risk assessment tools referenced by these guidelines include the ACC/AHA Pooled Cohort Equation (PCE), Systematic Coronary Risk Estimation (SCORE), QRISK3, Framingham Risk Score (FRS), VA Risk Score-CVD (VARS-CVD), and Cardiovascular Life Expectancy Model (CLEM) [9, 41-46]. These risk assessment tools are validated in individuals of a maximum age of 65 (SCORE) to 84 (QRISK3).

Table 1.

National and international guidelines for statin use in primary prevention of cardiovascular disease in older adults.

Guideline	Year	Risk Assessment	Age (years)
			40	45	50	55	60	65	70	75	80	85	90
AHA/ACCa	2018	PCEb
			LDL-C 70-189 mg/dL and 10-year risk ≥ 7.5%c							IIbh
ACC/AHAa	2019	PCEb
			LDL-C 70-189 mg/dL and 10-year risk ≥ 7.5%c
USPSTFa	2022	PCEb
			10-year risk ≥ 10% and risk factord
VA/DoDa	2020	VARS-CVD/PCE/FRSb
			10-year risk ≥ 12%
ESC/EASa	2019	SCOREb
			LDL > 100 mg/dL and 10-year risk 5-9.9%					"According to level of risk" e		IIbi
			LDL > 70 mg/dL and 10-year risk ≥ 10%
CCSa	2021	FRS/CLEMb
			10-year risk ≥ 20% OR 10-19.9% and risk factorf
NICE UKa	2023	QRISK3b
			10-year risk ≥ 10%g
Recommendation Strength				I		IIb		Strength of Recommendation Absent			Indeterminate		No Recommendation

^a2018 AHA/ACC Guideline on the Management of Blood Cholesterol; 2019 ACC/AHA Guideline on the Primary Prevention of Cardiovascular Disease; 2022 United States Preventative Services Task Force (USPSTF) Recommendation Statement for Statin Use for the Primary Prevention of Cardiovascular Disease in Adults; 2020 VA/DoD Clinical Practice Guideline For The Management of Dyslipidemia For Cardiovascular Risk Reduction; 2019 ESC/EAS Guidelines for the Management of Dyslipidaemias: Lipid Modification to Reduce Cardiovascular Risk; 2021 Canadian Cardiovascular Society (CCS) Guidelines for the Management of Dyslipidemia for the Prevention of Cardiovascular Disease in Adults; 2023 NICE UK Guideline for Cardiovascular Disease: Risk Assessment and Reduction, Including Lipid Modification.

^bPooled Cohort Equation (PCE), VA Risk Score-CVD (VARS-CVD), Framingham Risk Score (FRS), Systematic Coronary Risk Estimation (SCORE), Cardiovascular Life Expectancy Model (CLEM), QRISK3.

^cAdults aged 40-75 with diabetes mellitus or 20-75 with LDL-C ≥ 190 mg/dL are also recommended for therapy.

^dRisk factors (RF) include dyslipidemia, diabetes mellitus, hypertension, or smoking.

^eRecommend statin treatment for primary prevention ≤ 75 "according to level of risk," although SCORE is notably only validated until age 65.

^fLDL-C ≥ 3.5 mmol/L OR Non-HDL-C ≥ 4.2 mmol/L OR ApoB ≥ 1.05 g/L OR Men ≥ 50 years/Women ≥ 60 years with one RF (low HDL-C, high waist circumference, smoking, hypertension) OR one RF (high-sensitivity CRP ≥ 2.0 mg/L, CAC > 0 AU, family history of premature CAD, Lp(a) ≥ 50 mg/dL).

^gIf 10-year risk < 10%, can consider statins in patients that have " an informed preference for taking a statin or there is concern that risk may be underestimated."

^hStatin therapy "may be reasonable" in adults > 75 with an LDL-C 70-189 mg/dL. "Functional decline, multimorbidity, frailty, or reduced life expectancy" may be reasons for statin discontinuation in adults > 75. In adults 76-80 with an LDL-C 70-189 mg/dL, it "may be reasonable" to measure CAC, as a CAC score of zero may avoid statin therapy.

ⁱInitiation of statin therapy for primary prevention in adults > 75 may be considered if at "high-risk."

Despite utilizing the PCE for CVD risk assessment, the 2018 AHA/ACC Guideline on Management of Blood Cholesterol, 2019 ACC/AHA Guideline on Primary Prevention of Cardiovascular Disease, and 2022 USPSTF Recommendation Statement provide differing recommendations for statin therapy in adults older than 75. [9, 41-42]. The 2018 AHA/ACC guidelines provide a class IIb recommendation that moderate-intensity statin therapy “may be reasonable” in adults older than 75 with an LDL-C level of 70-189 mg/dL, and suggest utilizing coronary artery calcification (CAC) scores in patients aged 76-80 in aiding in this decision [41]. Specifically, they note that a CAC score of 0 may suggest against the initiation of statin therapy. In regards to statin discontinuation in adults older than 75, these guidelines are unique, stating that “functional decline (physical or cognitive), multimorbidity, frailty, or reduced life expectancy” may all be reasons to stop statins [41]. In comparison, the 2019 ACC/AHA and 2022 USPSTF guidelines either do not provide explicit recommendations for adults older than 75 or cite insufficient evidence to provide a recommendation [9, 42].

The 2020 VA/DoD guidelines are specific to patients older than 40 that are eligible for care in the VA/DoD healthcare system and are unique in that they do not provide a precise age cutoff for considering statin therapy for primary prevention of CVD [43].

The 2019 ESC/EAS guideline utilizes the SCORE tool in assessing cardiovascular risk, which is only validated in adults up to 65-years of age. Notably, the guidelines provide a class I recommendation for statins for primary prevention of CVD in adults ≤ 75 “according to the level of risk,” although they do not specify how to estimate risk without the ability to use SCORE. In addition, the authors provide a class IIb recommendation for initiating statins in adults older than 75 who are at “high risk,” but similar to individuals aged 65 to 75 years of age, they do not specify how clinicians should estimate CVD risk [44].

The 2021 CCS guidelines provide little guidance for statin therapy in adults older than 75, offering that “accumulating evidence suggests continued benefits of lipid-lowering for primary prevention” in this group [45].

Finally, the 2023 NICE UK guidelines reference QRISK3, the only risk assessment tool validated in individuals older than 80 (validated until 84). These recommendations suggest initiating atorvastatin 20 mg daily for a QRISK3 score ≥ 10%. However, it is worth noting that males ≥ 61 and females ≥ 68, without any other risk factors for ASCVD, would qualify for moderate-intensity statins based on age alone per the QRISK3 and NICE UK guidelines, which questions the tool’s utility in stratifying risk among adults over 80 [46, 48].

6. Available evidence for statins for primary prevention in older adults

Despite their discrepancies, the available guidelines for cholesterol management for primary prevention of CVD in older adults are derived from the same body of available evidence, including the following: The PROSPER trial was one of the first major trials to evaluate statin (pravastatin) use for primary and secondary prevention of ASCVD, specifically in older adults aged 70 to 82 years. Analysis from the primary prevention cohort showed no significant decrease in all-cause mortality, risk of stroke, or composite cardiovascular outcomes for those randomized to pravastatin vs placebo (RR 0.94, 95% CI 0.78-1.14) [49]. Similar results were seen in a post-hoc secondary analysis of the ALLHAT-LLT trial, which randomized adults >65 with hypertension and moderate hyperlipidemia to pravastatin for primary prevention. In fact, in adults ≥ 75, a non-significant trend toward increased mortality was observed in the pravastatin group [50]. These findings are limited by the trial’s open-label design, high loss to follow-up, and high crossover from the usual care to treatment group [42].

In contrast, in a meta-analysis of 28 RCTs involving 14,483 participants ≥ 75 years, statin therapy (primary and secondary prevention) was associated with a 24% proportional reduction in major coronary events per 1.0 mmol/L reduction in LDL-C. However, the efficacy of the use of statins for primary prevention in reducing major vascular events attenuated with increasing age, and in individuals > 70, with loss of statistically significant reduction, perhaps due to the relatively small sample size of patients in this age group [8]. Another meta-analysis of 8 RCTs evaluating 24,674 adults without ASCVD with a mean age of 73 years found that statin use was significantly associated with a reduction in risk of MI by 39.4% and stroke by 23.8% with no impact on all-cause or cardiovascular mortality [51, 52]. In comparison, a secondary analysis of age-specific outcome data from JUPITER and HOPE-3 found that statin use for primary prevention in patients ≥ 70 was significantly associated with a 26% risk reduction in non-fatal MI, non-fatal stroke, and CVD mortality. The authors did not observe any evidence of heterogeneity by age in this analysis [53].

In direct comparison, as a part of a reanalysis of data from the SPRINT trial evaluating 3,054 individuals ≥ 70 without known ASCVD but at high risk of future ASCVD development (estimated 10-year risk of 22-25%), self-reported statin use was not associated with a significant difference in the composite event rate of MI, ACS, stroke, heart failure, or cardiovascular mortality. The authors note that these findings are limited by the low overall events and non-randomized secondary analysis evaluating relationships that the original study was not powered for [54].

Although trial data are limited, several observational studies have examined the role of statins in adults aged 75 and older. A retrospective cohort study in Spain of 46,868 adults ≥ 75 without ASCVD found that statin use in individuals with type-2 diabetes mellitus was significantly associated with a 24% reduction in incident ASCVD and 16% reduction in all-cause mortality. However, this association lost statistical significance in adults ≥ 85 and was absent in adults without type-2 diabetes mellitus [55]. A population-based cohort study in France described similar findings, noting that statin use for primary prevention in adults ≥ 75 with modifiable risk factors (defined as the presence of diabetes mellitus or prescribed cardiovascular medications) was significantly associated with a lower risk of acute coronary syndrome (ACS) and all-cause mortality. This association was absent in individuals treated with statins but without modifiable risk factors [56]. In a prospective cohort study of 7,213 male physicians in the Physicians’ Health Study with a median age of 77, statin use was associated with an 18% lower risk of all-cause mortality (HR 0.82, 95% CI 0.69-0.98) and a non-significant lower risk of cardiovascular events (HR 0.86, 95% CI 0.70-1.06) and stroke (HR 0.70, 95% CI 0.45-1.09). These results did not vary according to age group (70 to 76 versus > 76) or functional status [57]. Finally, in a retrospective cohort study of 326,981 U.S Veterans ≥ 75 without ASCVD, statin use was associated with a 25% lower risk of all-cause mortality, 20% lower risk of cardiovascular mortality, and an 8% lower risk of a composite of atherosclerotic events [58].

Additionally, recent data suggests that the benefit of statin therapy may extend to older males experiencing frailty. In a retrospective study of 710,313 U.S. Veterans ≥ 65 without CVD, of which 12% were frail based on a validated 31-item frailty index, statin therapy was associated with a 39% lower risk of mortality and 14% lower risk of first MACE, independent of frailty status. Notably, among patients who were frail, statins were associated with the same or greater reduction in all-cause mortality and cardiovascular events as compared to non-frail patients [59].

From a health systems perspective, statins for primary prevention of CVD in older adults may ultimately be cost-effective. Odden et al. performed a forecasting study reviewing statin use in primary prevention in U.S. adults aged 75 to 94 years over ten years. They projected that treatment of all adults in this cohort with statin therapy would result in an 8-million new statin users and prevent 105,000 incident MI and 68,000 coronary heart disease deaths at an incremental cost per disability-adjusted life year of $25,200. Of note, the cardiovascular benefits may be offset with just a mild increase in adverse effects such as functional limitation or mild cognitive impairment (RR 1.10 to 1.29) [60].

Non-statin options for CVD prevention include ezetimibe which has some data for use in older adults. The EWTOPIA 75 trial was a prospective, multicenter, randomized open-label trial enrolling 3,796 patients across 363 sites in Japan. This trial randomized patients ≥ 75 years with elevated LDL-C but without coronary artery disease to ezetimibe 10 mg once daily versus usual care. Over the course of 4.1 years of median follow-up, patients that received ezetimibe had a lower incidence of the composite primary outcome of sudden cardiac death, myocardial infarction, coronary revascularization, or stroke (HR 0.66, 95% CI 0.50-0.86; p=0.002) as well as the composite secondary outcome of composite cardiac events (HR 0.60, 95% CI 0.37-0.98; p=0.039) and coronary revascularization (HR 0.38, 95% CI 0.18-0.79; p=0.007). The authors do note that the significance of these findings may be limited by challenges with follow-up and premature termination [61].

Finally, it is worth noting that little controversy exists regarding the benefit of statin therapy for secondary prevention in older adults. The 2018 AHA/ACC Guideline on Management of Blood Cholesterol provides a class IIa recommendation that for patients ≥ 75 years with clinical ASCVD, it is “reasonable” to initiate or continue statin therapy for secondary prevention after considering potential adverse effects, drug-drug interactions, patient frailty, and patient preferences [41].

7. Safety monitoring and deprescribing

The potential harms of treatment are an important factor in the decision-making process for initiating or continuing statin therapy in older adults. Older adults are more likely to experience polypharmacy, frailty, and multimorbidity, all of which complicate the potential risk/benefit profile of statin therapy [62]. In considering statin therapy in older adults, clinicians should consider the risk of muscle-related complications, incident diabetes, and cognitive effects following statin initiation.

7.1. Statin-associated muscle symptoms

Potential statin-associated muscle symptoms (SAMS) include myalgia, myopathy, myositis, or rhabdomyolysis [63]. In a review of 12,066 individuals in the Netherlands over the age of 75, of which 28.5% had a history of CVD and 29% were taking a statin at baseline, investigators found no significant difference in the prevalence of self-reported “hindering” muscle complaints in statin versus non-statin users (3.3% versus 2.5%; OR 1.39, 95% CI 0.94-2.05; p=0.98) over 9-months of follow-up. Additionally, the discontinuation of statins in this review was independent of self-reported muscle complaints [64]. Similarly, in a meta-analysis of 18,845 subjects over the age of 65 followed for 2.9 years, there was no significant difference in the risk of myalgias (OR 1.02, 95% CI 0.90-1.17; p=0.66), combined adverse muscle events (OR 1.03, 95% CI 0.91-1.18; p=0.61), or rhabdomyolysis (OR 2.93, 95% CI 0.30-28.18; p=0.35) in statin versus placebo groups [65].

Patients of East Asian ethnicity may be at higher risk of statin-associated adverse events including myopathy, which may be related to higher plasma levels of certain statins or their active metabolites in these individuals as compared to Caucasian patients. The significance of this potential relationship in older adults is unknown [66].

Nevertheless, patients of any age may develop minor aches and pains after initiating statin therapy due to the “nocebo effect,” which may disproportionately affect older adults with existing mobility limitations [7, 67]. These symptoms are typically non-specific and may be due to underlying conditions such as liver disease, renal dysfunction, and vitamin D deficiency. Statin-associated muscle symptom clinical index (SAMS-CI) can be used to assess the probability that muscle symptoms are due to statin use [68]. Although most of these symptoms resolve despite continued statin use, some patients may experience persistent complaints, which ultimately can be managed further by changing the statin formulation, reducing dose, or trialing every other day schedules [7].

7.2. Incident diabetes mellitus

The potential development of new type-2 diabetes mellitus following statin therapy initiation is another important consideration. The JUPITER trial randomized a total of 17,802 individuals (men ≥ 50, women ≥ 60) without CVD and with LDL-C ≤ 130 mg/dL as well as high-sensitivity C-reactive protein ≥ 2.0 mg/L to rosuvastatin 20 mg daily or placebo. Upon 1.9 years of follow-up, physician-reported diabetes was significantly more frequent in the rosuvastatin group than placebo (270 reports versus 216 reports, respectively; p=0.01) [69].

A subsequent analysis of the JUPITER study found that rosuvastatin use was associated with a 28% increase in the incidence of diabetes only in patients who had risk factors for developing diabetes. Despite this increased risk, an estimated total of 134 vascular events or deaths were avoided for every 54 new cases of diabetes diagnosed in this cohort. Compared to placebo, statin use accelerated the average time to diagnosis of diabetes by just 5.4 weeks. These results suggest that statins’ cardiovascular and mortality benefits exceed the risk of developing diabetes [70]. Multiple other meta-analyses suggest that the risk of incident diabetes mellitus secondary to statin therapy may be directly related to increasing age and statin intensity, although it is important to note that most older adults, including those with prediabetes, do not progress to developing diabetes [71-73].

7.3. Cognitive effects

There is little evidence to suggest that statins are related to cognitive harms or benefits [74]. Initial data from case reports and observational studies indicated that statins may be associated with changes in cognition. Two RCTs assessing the effects of lovastatin and simvastatin on cognitive function in patients aged 24 to 70 collectively found minor decrements in cognitive performance with unclear influence on long-term cognitive function [75, 76].

In comparison, extensive systematic reviews and meta-analyses have not found an association between statin use and adverse cognitive effects. In a systematic review conducted by Richardson et al., there was moderate quality evidence to suggest that statins were not associated with an increased incidence of dementia, mild cognitive impairment, or any change in cognitive performance related to executive function, processing speed, or declarative memory [77]. A meta-analysis of 24 RCTs involving 46,838 subjects found no significant adverse effects of statins on all cognition tests in cognitively normal subjects or subjects with Alzheimer’s Disease [78]. Adhikari et al. reviewed data from observational and randomized control studies evaluating statin use and cognitive function in approximately 1.4 million subjects over 60 for 3 to 15 years of follow-up. The authors found no evidence of statin use related to the incidence of dementia or deterioration in global cognition or specific cognitive domains [79].

In fact, a few larger reviews have even reported a potential cognitive benefit of statins, with a reduced the risk of incident dementia by 18 to 29% [80, 81].

7.4. Elevated liver enzymes

Within the first 12-weeks of initiating statin therapy, it is important for clinicians to recognize that statin-induced liver injury is a possible, though less common, adverse effect, which typically develops in a hepatocellular pattern [63, 82]. Reassuringly, it is very uncommon for statins to induce outright liver failure [63]. Routine LFT monitoring is not currently recommended following the initiation of statin therapy at this time [63].

7.5. Statin discontinuation

Much like the unclear indications for statin therapy in older adults, guidance for deprescribing statins in older statins remains sparse. A systematic review evaluating available recommendations for statin discontinuation in older adults treated for primary prevention of CVD investigated 33 guidelines across 11 countries. Amongst the reviewed guidelines, 45% did not provide any recommendations for statin discontinuation in older adults. Reviewing the remaining guidelines, two themes emerged as consistent potential reasons for statin discontinuation: statin intolerance (including muscle symptoms, liver toxicity, cognitive dysfunction, or contraindication) and health status (limited life expectancy, multimorbidity, frailty, or functional decline). Notably, none of these guidelines provide specific instructions for statin discontinuation in older adults [83].

Older patients experiencing advanced, life-limiting illness may be one group that derives benefit from statin discontinuation. In a multi-center, parallel-group, unblinded, randomized controlled trial, 381 participants (mean age 74.1) with an estimated life expectancy between 1 month and 1 year who had been taking statin therapy for at least 3 months for primary or secondary CVD prevention and with a recent deterioration in functional status were randomized to continuing or discontinuing statin therapy. Participants were followed for 1-year. Investigators found no significant difference in the proportion of participants who died within 60 days of statin discontinuation compared to the continuation group. Notably, quality of life (QOL) was significantly better in the statin discontinuation group (mean McGill QOL score 7.07 versus 6.74; p=0.03), and individuals who discontinued statins experienced a mean cost savings of $716 per patient. This study suggests that discontinuing statins in the setting of advanced life-limiting illness could be safe with potential benefits such as improved QOL and cost savings [84].

Beyond the context of end-of-life care, discontinuing statin therapy for primary prevention of CVD may be associated with significant cardiovascular morbidity for older adults. In a French cohort of 120,173 subjects ≥ 75 taking statins for primary prevention of CVD, 14.3 % of individuals discontinued statins for at least 3 consecutive months. Statin discontinuation was significantly associated with a 33% increased risk of any cardiovascular event, 46% increased risk of coronary events, and 26% increased risk of cerebrovascular events [85]. In a Danish cohort of 27,463 individuals ≥ 75 taking statins for at least five consecutive years for primary prevention, individuals who discontinued statins experienced a higher rate of MACE than those who continued [86].

8. Practical clinical considerations

In the context of ambiguous guidelines coupled with a lack of quality data examining the role of statin therapy for primary prevention of CVD in our oldest patients, critical factors in the decision-making process for initiating or continuing statin therapy in this population include a patient’s functional status, multiple comorbidities, time to benefit (TTB) versus life expectancy, potential harms of treatment, and goals of care.

Hawley et al. provide a practical approach to initiating, continuing, and deprescribing statins for primary prevention of CVD in older adults utilizing the Geriatric 5Ms and the estimated TTB of statin therapy [47]. The Geriatric 5Ms include mind (cognition, memory, mood), mobility (gait, balance, falls, and function), medications (polypharmacy, adverse effects, deprescribing), multi-complexity (multimorbidity, biopsychosocial context), and matters most (individual goals and preferences) [47]. TTB for statins in primary prevention of cardiovascular events in individuals with hyperlipidemia ranges from 2 to 5 years, depending on the population of interest [87, 88].

In returning to our cases, Patient A is a functionally independent 82-year-old without multimorbidity and a low risk of polypharmacy. He has multiple risk factors for CVD and has an estimated life expectancy of < 10 years, which suggests that he would benefit from statin therapy in terms of reduced risk of MI and stroke and prolonged disease-free survival time [89, 90]. Based on the patient’s preference, statin therapy can be started, though if more granular risk stratification is needed, a CAC score may be beneficial. Older adults with a CAC score of 0 are at low risk of ASCVD events. In these individuals, statin initiation can be deferred and revisited 3-5 years later, depending on risk factors, functional status, comorbidities, and life expectancy [91, 92].

In direct comparison, Patient B has physical, cognitive, and social frailty due to existing multiple chronic comorbidities. As a result, the decision to continue or discontinue statin therapy for Patient B is likely more complex. Patient B’s six-month mortality is estimated between 49% and 62% [89]. Given that Patient B has already been on statin therapy for an unspecified amount of time, it becomes more difficult to directly compare statin therapy’s TTB with her expected life expectancy, as she may have already experienced, and thus unknowingly benefited from, a successfully prevented cardiac event secondary to statin therapy [47]. In the context of Patient B’s frailty, recent functional decline, and high six-month mortality, the decision to discontinue her statin may provide a QOL, financial, and polypharmacy benefit [84]. On the other hand, if the patient and her caregivers value preventing future ASCVD events and the associated morbidity thereof, it may be reasonable to continue her statin [86, 87]. The question of deprescribing Patient B’s statin highlights the importance of shared decision-making based on the values and goals of each patient.

9. Future directions

The discrepancies and ambiguity in the national and international guidelines for statin therapy in the primary prevention of CVD in older adults are primarily due to the exclusion of older adults. Fortunately, multiple ongoing RCTs seek to provide further evidence to provide additional guidance to this clinical question.

The Statins in Reducing Events in the Elderly (STAREE) trial is a double-blinded, placebo-controlled RCT randomizing over 9,000 independent, community-dwelling adults ≥ 70 in Australia, without a history of CVD, diabetes, or dementia to atorvastatin 40 mg daily versus placebo and will examine co-primary clinical endpoints of disability-free survival and major adverse cardiac events [93]. Another double-blinded, placebo-controlled RCT, the Pragmatic Evaluation of Events and Benefits of Lipid-Lowering in Older Adults (PREVENTABLE) trial, plans to enroll 20,000 community-dwelling adults ≥ 75 in the US, without CVD, dementia, or significant disability to atorvastatin 40 mg daily or placebo. It will examine survival free of new dementia or persistent disability as the primary outcome [94].

Importantly, two additional ongoing RCTs are evaluating the effect of statin deprescribing in older adults. The Statins In The Elderly (SITE) trial is an open-label RCT with 1,230 multimorbid individuals ≥ 75 taking statins for primary prevention. It will randomize enrollees to either stop or continue their statin [95]. After 36 months of follow-up, this trial will measure outcomes, including overall mortality, incremental cost per quality-adjusted life years gained, QOL, cardiovascular events, diabetes, and cognitive disorders. In addition, the Statins in Multimorbid Older Adults Without Cardiovascular Disease (STREAM) trial is a multicenter, non-inferiority RCT in Switzerland with an estimated enrollment of 1,800 multimorbid individuals ≥ 70 taking statin for primary prevention to discontinuing or continuing their statin [96]. With a planned mean follow-up of 24 months, the investigators will measure major outcomes, including all-cause death and major non-fatal cardiovascular events.

These ongoing RCTs will provide much needed high-quality evidence to begin to address current knowledge gaps and ultimately guide future practice. Although these trials are well overdue, there remain notable gaps in their design, and thus, future applicability. For instance, less than 50% of STAREE’s enrollees are 75 years or older, which may limit this trial’s application to our oldest patients in which data is already sparse [97]. In addition, the inclusion criteria for both PREVENTABLE and STAREE exclude patients with dementia as well as those not living independently in the community, which may self-select a study population not experiencing frailty, multimorbidity, or polypharmacy. In comparison, SITE and STREAM have notably enrolled cohorts of older adults that are experiencing multiple chronic conditions (including dementia), and may be most applicable to the group of older patients that have previously been underrepresented in clinical trials and not to healthy older adults wondering about continuing their statin.

10. Conclusion

CVD prevention and management decisions are complex in older patients due to the heterogeneity of aging and co-existing multi-morbidity, polypharmacy, and frailty. Statins are the mainstay for primary prevention of CVD in younger and middle-aged adults at higher risk of CVD. However, data on older adults remains sparse. Limited evidence shows that primary prevention use of statins is beneficial in appropriately selected older adults who are free of multimorbidity and have a life expectancy long enough to derive a benefit. Geriatric 5 M’s, CAC, personal wishes, and shared decision-making can help clinicians and patients to navigate these challenging decisions. Further research for lipid-lowering therapy involving older adults, including those experiencing frailty and multimorbidity, is urgently needed to guide care.

11. Expert opinion

As global population demographics continue to trend towards older age, the anticipated future impact of CVD poses significant challenges for healthcare systems and patients alike. Although statin therapy has demonstrated beneficial effects for the primary prevention of CVD in adults up to age 75, there remains limited available evidence to guide the use of statins in adults 75 and older, particularly in individuals experiencing frailty and multimorbidity. This discrepancy is a direct result of historic exclusion of these individuals from clinical trials that inform current practice recommendations. Thus, the decision to initiate, continue, or discontinue statin therapy for the primary prevention of CVD in older adults remains challenging.

The association of total cholesterol and LDL-C with CVD in older adults is unclear, which has brought uncertainty in utilizing these biomarkers for risk stratification in considering statin therapy. Although statins lower cholesterol, additional benefits such as anti-inflammatory and anti-aging effects may explain statin’s efficacy in older adults.

Existing data investigating the use of statin therapy for primary prevention in adults over the age of 75 is limited, and has been derived from a handful of RCTs, meta-analyses, and prospective and retrospective cohort studies. Collectively, this evidence does show that statin therapy is beneficial for primary prevention of CVD in older adults free of life-limiting comorbidities, although more recent evidence suggests that these benefits may extend to individuals experiencing frailty.

There is little evidence to suggest that statin use is associated with SAMS or cognitive impairment in older adults, and although there may be a slightly higher risk of incident diabetes in this population, the cardiovascular benefits of therapy outweigh these risks. Statin discontinuation in older adults may be reasonable in the context of end-of-life care, although significant cardiovascular morbidity may result from discontinuation outside of this setting.

Further research is urgently needed to begin to address current knowledge gaps pertaining to statin use for the primary prevention of CVD in older adults, particularly in those over the age of 75 and experiencing geriatric syndromes. Ongoing randomized trials include STAREE, PREVENTABLE, STREAM, and SITE. STAREE and PREVENTABLE are both double-blinded, placebo controlled RCTs randomizing community-dwelling adults (aged ≥ 70 or ≥ 75, respectively) without ASCVD to statin therapy versus placebo, and will consider primary clinical endpoints such as disability-free survival, MACE, new dementia, or persistent disability. In comparison, STREAM and SITE will randomize older adults (≥ 70 or ≥ 75, respectively) with multiple chronic conditions to discontinuing versus continuing statin therapy for primary prevention of CVD, and will consider numerous outcomes including overall mortality, QOL, major non-fatal cardiovascular events, and cognitive disorders.

In the context of the available evidence, existing guidelines, and ongoing research, we recommend utilizing considerations such as statin TTB versus life expectancy, existing geriatric syndromes such as frailty, multimorbidity, and polypharmacy, and personal wishes based on the Geriatric 5M’s (mind, mobility, medications, multi-complexity, and matters most) into shared decision making with patients and caregivers. Additionally, in select patients, obtaining a CAC score may be beneficial in providing further risk stratification. Ultimately, the decision to initiate, continue, or discontinue is multi-faceted and specific to each individual patient, and the careful integration of previously reviewed clinical and personal factors are paramount for decision making.

Article highlights.

• Evidence for the use of statins for primary prevention of cardiovascular disease (CVD) in older adults, particularly those over the age of 75, is limited due to exclusion of these individuals from informing clinical trials.

• Leading national and international guidelines for the management of cholesterol for the primary prevention of CVD provide variable recommendations as to the method of calculating risk of future atherosclerotic cardiovascular disease (ASCVD) and optimal age ranges for statin therapy.

• The relationship between total cholesterol and low-density lipoprotein cholesterol (LDL-C) with cardiovascular outcomes in older adults is unclear, which may suggest that the benefit of statins in this population is related to their anti-inflammatory effect.

• There is limited evidence to suggest that statin use is associated with statin-associated muscle symptoms (SAMS) or cognitive impairment in older adults, and the overall cardiovascular benefit of statin therapy outweighs the slightly increased of diabetes mellitus in this population.

• Limited evidence suggests that statins are beneficial in appropriately selected older adults. Important considerations to assist clinicians, patients, and caregivers with decision-making include statin time to benefit (TTB), life expectancy, frailty, multimorbidity, polypharmacy, and patient preferences, which can be elicited with the use of the Geriatric 5M’s.