Statin use does not impair muscle health in older adults: findings from the SCOPE study

Abstract

Background

Statins are used for cardiovascular prevention, but their potential impact on muscle health in adults aged ≥ 75 years remains unclear.

Aims

To assess whether statin use is associated with adverse changes in muscle strength, skeletal muscle mass, and physical performance in older adults.

Methods

Data were drawn from the SCOPE study including 2,282 participants aged ≥ 75 years with complete baseline data on statin use and muscle outcomes. Muscle strength was assessed via handgrip strength, muscle mass via skeletal muscle index (SMI), and physical performance via the Short Physical Performance Battery (SPPB). Outcomes were measured at baseline and after two years. Associations with statin use were analysed cross-sectionally and longitudinally, stratified by sex, and adjusted for confounders.

Results

At baseline, 1,107 participants (48.5%) used statins (median age 79 years). Cross-sectional analyses showed no association between statin use and handgrip strength, SMI, or SPPB scores in either sex. Over two years, there were no significant between-group differences in changes over time in handgrip strength (men: − 3.1 vs. − 2.6 kg, p = 0.8; women: − 1.5 vs. − 2.5 kg, p = 0.6), SMI (men: +1.0 vs. − 0.6 kg/m², p = 0.1; women: +0.4 vs. − 0.1 kg/m², p = 0.4), or risk of SPPB decline (men: OR 1.3, 95% CI 0.9–1.8; women: OR 1.0, 95% CI 0.8–1.4).

Discussion

These findings support muscular safety of statins in well-functioning older adults, reducing concerns about potential harm.

Conclusions

In this large cohort of adults aged ≥ 75 years, statin use was not associated with adverse changes in muscle strength, muscle mass, or physical performance over two years.

Introduction

Statin therapy is widely prescribed for its lipid-lowering effects and plays a critical role in managing cardiovascular disease [1]. However, concerns persist regarding potential muscle-related side effects, including myalgia, muscle weakness, and, in severe cases, rhabdomyolysis [2–4]. In older individuals, even subtle impairments in muscle strength or physical performance can lead to functional decline, loss of independence, increased fall risk, and hospitalization [5, 6]. It is therefore essential to carefully evaluate the balance between cardiovascular benefits and muscular risks of statin use in older adults. Objective muscle health outcomes related to statin use remain uncertain, especially in older populations.

There are several potential biological pathways through which statins may impair muscle health. Statins inhibit HMG-CoA reductase, reducing cholesterol synthesis as well as levels of coenzyme Q10 (CoQ10), an essential molecule for mitochondrial function and energy production [7, 8]. Depletion of CoQ10 has been linked to mitochondrial dysfunction, impaired oxidative phosphorylation, and increased muscle cell apoptosis [9]. Additionally, sarcoplasmic reticulum calcium leakage may promote oxidative stress and mitochondrial injury [10], further contributing to muscle dysfunction. These mechanisms provide a plausible explanation for potential muscle-related adverse effects of statins.

Observational studies, however, have yielded controversial results regarding the potential effect of statins on objective muscle outcomes. Some report adverse effects, particularly in vulnerable populations such as individuals with pre-existing muscle symptoms, chronic obstructive pulmonary disease (COPD), or post-stroke sarcopenia [11, 12]. Conversely, other studies suggest neutral or even beneficial effects, for instance among patients with heart failure. However, these studies often focus on specific conditions that directly involve muscle impairments, creating a gap in the literature regarding the general older population with multimorbidity, many of whom may have been using statins for many years. A recent systematic review found no consistent evidence of a negative impact of statins on physical activity in older adults [13]. A recent systematic review found no consistent evidence of a negative impact of statins on physical activity in older adults. However, this review included a highly diverse mix of populations, heterogeneous study designs, and outcome measures related to physical activity, many of which were not validated. These inconsistencies limit the ability to draw reliable conclusions from the findings.

Notably, few studies have specifically examined older adults aged 75 and above, who are at highest risk of sarcopenia and functional decline. Many large trials exclude this age group altogether or rely on self-reported symptoms rather than standardized, objective assessments. This leaves a critical gap in the evidence base, particularly regarding long-term statin use and its association with muscle strength, mass, and physical performance in real-world ageing populations.

To address this gap, we investigated the possible association between statin use and muscle health in community-dwelling adults aged 75 years and older. Using validated instruments from the EWGSOP2 guideline [14]. We analyzed both cross-sectional and longitudinal data on grip strength, skeletal muscle index, and physical performance over a two-year period. By focusing on this underrepresented population, our study aims to strengthen the evidence base for prescribing statins in the context of ageing and multimorbidity.

Methods

Study design

This analysis was embedded in the multicenter, prospective Screening for Chronic Kidney Disease among Older People across Europe (SCOPE) project, which focuses on age-related health outcomes in older adults [15]. Participants were recruited from outpatient clinics across seven European countries. The current analysis uses data from the baseline visit and the two-year follow-up assessment.

Participants and eligibility criteria

Participants were community-dwelling adults aged ≥ 75 years. All participants signed an informed consent form approved by the Helsinki ethics committees in their countries. Exclusion criteria included end-stage renal disease (eGFR < 15 mL/min/1.73 m²), current dialysis, solid organ transplantation history, active malignancy within 24 months, life expectancy < 6 months, severe cognitive impairment (MMSE < 10), or inability to consent.

For this analysis, only participants with complete data on statin use and muscle health parameters at baseline were included.

Assessment of baseline participant characteristics

Participant characteristics were assessed at baseline through structured interviews, physical examinations, and clinical record reviews. Collected demographic information included age, sex, and living situation. Smoking status and daily alcohol consumption were self-reported. Body mass index (BMI) was calculated from measured weight and height using standardized equipment and protocols.

A comprehensive geriatric assessment (CGA) was performed to evaluate cognitive function, mood, functional status, nutritional status, and comorbidity burden. Cognitive function was assessed using the Mini-Mental State Examination (MMSE) [16], and depressive symptoms were measured with the 15-item Geriatric Depression Scale (GDS) [17]. Functional status was determined by self-reported performance in basic activities of daily living (ADL) and instrumental activities of daily living (IADL) [18, 19]. Nutritional status was evaluated with the Mini Nutritional Assessment (MNA). Comorbidity burden was quantified using the Cumulative Illness Rating Scale for Geriatrics (CIRS-G) [20].

Medication use was verified using prescription lists, clinical records, and packaging. The total number of medications was recorded. Polypharmacy was defined as the concurrent use of five or more medications. Medical diagnoses were based on clinical history and confirmed through available medical records.

Laboratory analyses were conducted in certified local laboratories following standardized protocols. Fasting blood samples were used to determine serum creatinine, total cholesterol, low-density lipoprotein (LDL), and high-density lipoprotein (HDL). The estimated glomerular filtration rate (eGFR) was calculated using the Berlin Initiative Study 1 (BIS1) equation, which is validated for use in older adults [21]:

Exposure assessment: statin use

Statin use was assessed at baseline via structured medication reviews cross-checked with clinical records. Use was categorized as present or absent. The specific statin type prescribed (e.g., atorvastatin, simvastatin) was documented for all statin users.

Daily doses were standardized using the WHO Defined Daily Dose (DDD) methodology [22]. For each participant, the prescribed daily dose was divided by the DDD of the specific statin compound (e.g., 20 mg for atorvastatin, 30 mg for simvastatin) to calculate statin exposure in DDD/day. Based on these values, participants were further categorized into low-dose (< 1 DDD/day) or standard-to-high dose (≥ 1 DDD/day). Additionally, median statin doses (in DDD/day) were calculated separately for men and women.

Assessment of muscle health parameters

Muscle health was assessed at baseline and two-year follow-up with parameters used in the EWGSOP2 guideline [14]. All assessments were performed by trained personnel using standardized procedures, calibrated equipment, and inter-site calibration for consistency.

Muscle strength was assessed using a handheld dynamometer (Jamar) with participants seated and elbows flexed at 90 degrees. The highest value from two trials per hand was recorded and analyzed as a continuous variable.

Physical performance was assessed using the Short Physical Performance Battery (SPPB) [23], comprising gait speed, static balance, and chair sit-to-stand tests:

• Gait speed: Participants were instructed to walk 4 m at their usual pace. Time was measured with a stopwatch, and walking speed was calculated in meters per second.

• Static balance: Participants attempted to maintain balance in three progressively more difficult positions: side-by-side stance, semi-tandem, and full tandem. Each position was held for up to 10 s.

• Chair stands: Participants were asked to rise from a seated position five times as quickly as possible, with arms crossed over the chest. Time to completion was recorded.

Each subtest was scored from 0 to 4, yielding a composite score (range 0–12). SPPB scores were analyzed categorically: low (0–6), moderate (7–9), and high (10–12) [24].

Muscle mass was estimated using bioelectrical impedance analysis (BIA) under standardized hydration and fasting conditions, employing the AKERN BIA 101 New Edition 50 kHz monofrequency device (AKERN SRL, Florence, Italy). BIA estimates muscle mass indirectly based on electrical conductivity. Participants with a pacemaker or implantable cardioverter-defibrillator (ICD) were excluded from this assessment. Appendicular skeletal muscle mass (ASM) was calculated using the Sergi et al. Equation [25], validated for use in older European populations. ASM was normalized for height squared to derive the Skeletal Muscle Index (SMI, kg/m²), in accordance with EWGSOP2 recommendations [14].

Statistical analysis

Analyses were performed with IBM SPSS Statistics (version 30.0.0.0). A two-sided p-value < 0.05 was considered statistically significant. Descriptive statistics were used to summarize baseline characteristics. Continuous variables were tested for normality using the Shapiro–Wilk test and reported as mean ± standard deviation (SD) or median with interquartile range (IQR), as appropriate. Categorical variables were summarized as frequencies and percentages. Differences between statin users and non-users were assessed using independent-sample t-tests or Mann–Whitney U tests for continuous variables, and Chi-square tests for categorical variables.

Cross-sectional analysis

At baseline, associations between statin use and muscle health parameters were assessed separately in men and women. Analysis of covariance (ANCOVA) was used to analyze handgrip strength and skeletal muscle index (SMI) as continuous outcomes. Multinomial logistic regression was performed to investigate the association between statin use (yes/no) and categorized physical performance, as measured by the Short Physical Performance Battery (SPPB), with three categories: poor (0–6), moderate (7–9), and good (10–12, reference category). Analyses were stratified by sex and adjusted for age, body mass index (BMI), estimated glomerular filtration rate (eGFR), polypharmacy (≥ 5 medications), and total score on the Cumulative Illness Rating Scale for Geriatrics (CIRS-G).

Longitudinal analysis

Longitudinal analysis was assessed separately in men and women. Changes in muscle strength and skeletal muscle mass over the two-year follow-up were analyzed using ANCOVA. For each participant, the percentage change (Δ%) in handgrip strength and SMI was calculated as:

These Δ% values were used as outcome variables in the ANCOVA models. Models were adjusted for age, BMI, estimated glomerular filtration rate (eGFR), and total CIRS-G score.

Changes in physical performance were evaluated using logistic regression to estimate the odds of a decline in SPPB score, defined as a decrease of ≥ 1 point from baseline. Models were adjusted for the same covariates.

Additional analysis was performed within the subgroup of statin users. To examine potential dose–response relationships, statin use was categorized into two groups: non-use (0) and high-dose use (≥ 1 DDD/day). Differences in continuous muscle outcomes between these groups were analyzed using ANCOVA models. For categorical outcomes, such as SPPB scores, logistic regression was performed. All analyses were stratified by sex and adjusted for the same covariates as in the primary models (age, BMI, baseline eGFR, CIRS-G total score, and polypharmacy).

Results

Baseline characteristics

Of the original 2,446 participants enrolled in the SCOPE study, 2,282 individuals were included in the present analysis based on the availability of relevant covariate information, including statin use. Statin users (n = 1,107, 48.5%) were significantly younger (median age 79 years; IQR: 77–83) than non-users (median 80 years; IQR: 77–83; p = 0.005). Statin users had higher BMI (28.3 ± 4.4 vs. 27.4 ± 4.5 kg/m²; p < 0.001), greater instrumental ADL dependency (44.7% vs. 39.0%; p = 0.006), higher medication burden (average medications: 8.1 vs. 5.4; p < 0.001), and more prevalent polypharmacy (86.1% vs. 55.7%; p < 0.001). Prevalence of cardiovascular conditions, including hypertension, diabetes mellitus, and myocardial infarction, was significantly higher among statin users (p < 0.001 for all). Complete information on baseline characteristics can be found in Table 1.

Table 1.

Characteristics of participants according to Statin use

	No Statin (n = 1175)	Statin (n = 1107)	P-value
General
Age, years	80 [77–83]	79 [77–83]	0.005
Women	707 [60.2%]	566 [51.1%]	< 0.001
BMI, kg/m²	27.4 ± 4.5	28.3 ± 4.4	< 0.001
MNA-total, score	27.0 [25.0–28.0]	26.5 [25.0-27.5]	< 0.001
MMSE, score	28.0 [26.3–29.0]	28.0 [26.0–29.0]	0.1
GDS, score	2 [1–4]	2 [1–4]	0.3
Current daily alcohol drinker	309 (26.3%)	277 (25.0%)	0.9
Current Smoker	61 (5.2%)	40 (3.6%)	0.07
Former Smoker	415 (37.3%)	451 (42.3%)	0.02
ADL-dependance	53 (4.5%)	65 (5.9%)	0.1
IADL-dependance	458 (39.0%)	494 (44.7%)	0.006
Laboratory results
Serum Creatinine, mg/dL	0.9 [0.8–1.2]	1.0 [0.8–1.3]	< 0.001
eGFR, mL/min/1.73 m²	53.6 ± 14.3	51.6 ± 14.9	< 0.001
Total Cholesterol, mg/dL	201.3 ± 42.5	171.7 ± 44.3	< 0.001
LDL, mg/dL	128.1 ± 35.8	92.9 ± 31.5	< 0.001
HDL, mg/dL	58.9 ± 19.2	55.7 ± 15.3	< 0.001
Medication use
No. of Medications	5.4 ± 3.3	8.1 ± 3.3	< 0.001
Polypharmacy (≥ 5 medications)	655 (55.7%)	953 (86.1%)	< 0.001
Antihypertensive medication	590 (50.2%)	733 (66.2%)	< 0.001
Antidiabetic medication	144 (12.3%)	308 (27.8%)	< 0.001
Comorbidity
CIRS-G, Total Score	8.0 ± 4.3	9.3 ± 4.9	< 0.001
CIRS-G, Severity Index	1.5 [1.2–1.8]	1.5 [1.3–1.8]	0.007
Hypertension	866 (73.7%)	946 (85.5%)	< 0.001
Diabetes Mellitus	207 (17.6%)	388 (35.0%)	< 0.001
Atrial fibrillation	175 (14.9%)	183 (16.5%)	0.3
Stroke or TIA	110 (9.4%)	188 (17.0%)	< 0.001
Myocardial infarction	44 (3.7%)	193 (17.4%)	< 0.001
Angina	43 (3.7%)	99 (8.9%)	< 0.001
Asthma	66 (5.6%)	63 (5.7%)	0.9
Cancer	206 (17.5%)	197 (17.8%)	0.9
COPD	138 (11.7%)	142 (12.8%)	0.4
Hip fracture	72 (6.1%)	42 (3.8%)	0.01
Osteoporosis	391 (33.3%)	337 (30.4%)	0.1
Parkinson	30 (2.6%)	16 (1.4%)	0.06

Data are presented as median [interquartile range], mean ± SD, or number (percentage), as appropriate. Antihypertensives include all classes such as diuretics, beta-blockers, calcium channel blockers, and renin-angiotensin system inhibitors. Antidiabetic medication refers to non-insulin glucose-lowering agents

Abbreviations: ADL, activities of daily living; BMI, body mass index; CIRS-G, Cumulative Illness Rating Scale for Geriatrics; COPD, chronic obstructive pulmonary disease; eGFR, estimated glomerular filtration rate; GDS, Geriatric Depression Scale; HDL, high-density lipoprotein; IADL, instrumental activities of daily living; LDL, low-density lipoprotein; MNA, Mini Nutritional Assessment; MMSE, Mini-Mental State Examination; SD, standard deviation; TIA, transient ischemic attack

Statin use distribution

Atorvastatin (38.4%) and simvastatin (36.0%) were most frequently prescribed, comprising approximately three-quarters of all statin prescriptions (Fig. 1). Median daily doses were higher in men (1.00 DDD/day; IQR: 0.67–1.33) compared to women (0.67 DDD/day; IQR: 0.50–1.00).

Fig. 1.

This histogram illustrates the distribution of statin types among participants. Atorvastatin was the most commonly used statin, accounting for 39% of the sample, followed by simvastatin. Rosuvastatin represented 15%, pravastatin 6%, fluvastatin 2%, and lovastatin 1%

Cross-sectional analysis

Among men, grip strength was comparable in both groups (statin users: 32.7 kg ± 8.5; non-users: 32.1 kg ± 8.8; p = 0.2). Similarly, skeletal muscle index (SMI) values did not significantly differ between groups (both groups: 10.0 kg/m²; p = 0.7) (Table 2). Statin use was not significantly associated with the odds of moderate (OR: 1.05, 95% CI: 0.77–1.44, p = 0.74) or poor (OR: 1.26, 95% CI: 0.85–1.88, p = 0.25) physical performance compared to good performance (Table 3).

Table 2.

Comparison of grip strength and skeletal muscle index by Statin use, stratified by sex

		No statins	Statins	P-value
Men	Grip strength, kg	N = 455 32.1 (31.3–32.8)	N = 525 32.7 (32.0–33.4)	0.2
	SMI, kg/m²	N = 317 10.0 (9.9–10.1)	N = 303 10.0 (9.9–10.2)	0.7
Women	Grip strength, kg	N = 651 19.7 (19.2–20.1)	N = 525 19.6 (19.1–20.1)	0.8
	SMI, kg/m²	N = 494 7.3 (7.2–7.4)	N = 330 7.3 (7.1–7.4)	0.9

Values are presented as mean (95% confidence interval). All analyses were adjusted for age, body mass index (BMI), estimated glomerular filtration rate (eGFR) at baseline, polypharmacy, and total score on the Cumulative Illness Rating Scale for Geriatrics (CIRS-G)

Abbreviations: SMI, skeletal muscle mass index; CI, confidence interval; SD, standard deviation; BMI, body mass index; eGFR, estimated glomerular filtration rate; CIRS-G, Cumulative Illness Rating Scale for Geriatrics

Table 3.

Relationship between SPPB score categories and Statin use, stratified by sex

	SPPB Category	OR	95% CI	P-value
Men	Good (10–12)	1.00	Reference	–
	Moderate (7–9)	1.05	0.77–1.44	0.74
	Poor (0–6)	1.26	0.85–1.88	0.2
Women	Good (10–12)	1.00	Reference	–
	Moderate (7–9)	0.96	0.72–1.28	0.76
	Poor (0–6)	0.99	0.74–1.35	0.93

Odds ratios (OR) and 95% confidence intervals (CI) represent the odds of having moderate or poor physical performance (SPPB 0–9), compared to good performance (SPPB 10–12), among statin users versus non-users. Results are stratified by sex. In men, 540 were statin users and 468 were non-users. In women, 566 were statin users and 707 were non-users. All analyses were adjusted for age, body mass index (BMI), estimated glomerular filtration rate (eGFR) at baseline, polypharmacy, and total score on the Cumulative Illness Rating Scale for Geriatrics (CIRS-G)

Among women, grip strength showed no significant difference between groups (statin users: 19.6 kg ± 5.8; non-users: 19.7 kg ± 5.6; p = 0.8). SMI was also comparable between groups (both 7.3 kg/m²; p = 0.9) (Table 2). Similarly, the odds of moderate (OR: 0.96, 95% CI: 0.72–1.28, p = 0.759) or poor (OR: 0.99, 95% CI: 0.74–1.35, p = 0.926) physical performance were not significantly different between statin users and non-users (Table 3).

Longitudinal analysis

At two-year follow-up, data availability was reduced due to mortality and loss to follow-up. Of the 2,282 participants at baseline, follow-up data were available for 1,510 participants for grip strength, 865 for SMI, and 1,697 for SPPB. Men showed significant declines in grip strength in both groups (statin users: − 3.1 kg; non-users: − 2.6 kg), but the between-group difference was not significant (p = 0.8). Changes in SMI were minimal and non-significant (statin users: +1.0 kg/m²; non-users: − 0.6 kg/m²; p = 0.1). These findings are visualized in Fig. 2. The adjusted odds for a decline in physical performance according to SPPB did not differ significantly between groups (OR: 1.3; 95% CI: 0.9–1.8; p = 0.1).

Fig. 2.

Mean percentage change in grip strength and skeletal muscle index (SMI) over a 2-year follow-up, according to statin use and stratified by sex. Negative values indicate decline. Bars represent adjusted mean percentage changes with 95% confidence intervals. Blue tones represent men and red tones represent women, with darker shades indicating statin users. No statistically significant differences were observed between statin users and non-users. Abbreviations: SMI, skeletal muscle index

Women showed small, non-significant reductions in grip strength (statin users: − 1.5 kg; non-users: − 2.5 kg; p = 0.6) and negligible changes in SMI (statin users: +0.4 kg/m²; non-users: − 0.1 kg/m²; p = 0.4). These results are also shown in Fig. 2. Similarly, the odds of SPPB decline were unaffected by statin use (OR: 1.0; 95% CI: 0.8–1.4; p = 0.8).

Supplementary data including unadjusted models for cross-sectional and longitudinal analyses are available in Supplementary materials.

Dose response analysis

Dose–response analysis revealed no significant differences between high-dose statin users and non-users regarding any of the muscle strength, mass, or physical performance outcomes (data not shown).

Discussion

In this large, prospective cohort of individuals aged 75 years and older, statin use did not impair muscle health outcomes. There was no association between statin use and change in muscle strength, skeletal muscle mass, or physical performance over two years. High daily statin dose use did not negatively impact muscle strength, skeletal muscle mass, or physical performance over time.

Several observational studies using objective assessments have similarly reported neutral associations, consistent with the findings of the present study. For instance, a cross-sectional study in community-dwelling older Japanese adults found no independent relationship between statin use and either grip strength or physical performance after adjustment for confounders [26]. A similar pattern was observed in home-dwelling older adults with polypharmacy in Norway (mean age 83 years). No significant differences in grip strength, gait speed, or SPPB scores were found between statin users and non-users, although estimates modestly favored users [27]. These previous studies offer valuable insights, but their results are limited by several methodological considerations. Specifically, the relatively small sample sizes limit statistical power, increasing the risk of type II errors. Additionally, cross-sectional designs inherently restrict causal inference, as temporality between statin use and muscle outcomes cannot be clearly established. Furthermore, generalizability is also limited, as study populations were often being restricted to specific cultural or geographic groups such as older Japanese adults or subgroups with particular clinical characteristics, like those exposed to polypharmacy. Consequently, these findings might not adequately represent broader, more diverse populations or fully capture the complexity of long-term statin use and muscle health interactions.

The longitudinal findings of the present study are in line with previous literature. In a cohort of older women, no consistent association was found between statin use and changes in grip strength or chair stand performance [28]. Among older male veterans, one-year changes in chair stand performance were comparable between statin users and non-users [29]). Another community-based cohort showed no link between statin use and grip strength decline over 4.4 years [30]. Most recently, a large Japanese study found no increased risk of incident sarcopenia, or reductions in muscle mass, strength, or performance among long-term statin users compared to matched controls [31].

In contrast, a few studies have reported significant associations between statin use and muscle health, though these arise from specific clinical contexts. A retrospective study in post-stroke patients with sarcopenia found that statin use was associated with reduced grip strength recovery during rehabilitation, but not with muscle mass [11]. This cohort differed markedly from the study population in the present study, since the participants included in the study were acutely ill, recovering from stroke, and were already sarcopenic. Another study assessed muscle function before and after statin discontinuation in older adults [32]. Modest improvements in muscle discomfort and performance were observed after discontinuation. However, the study lacked a control group, had a small sample size (n = 98), short follow-up, and was open-label. All features that increase the risk of expectation bias and limit interpretability, especially for subjective endpoints like myalgia. A prospective cohort of community-dwelling older adults found greater declines in leg strength and muscle quality, and a higher risk of falls among statin users over 2.6 years [33] when compared to those who had ceased statin use at follow-up. While the setting was more comparable to the present study, key differences exist. Muscle outcomes were based on leg-specific measures rather than standardized multidomain criteria, the mean age was lower (62 years), and results were not stratified for participants aged ≥ 75 years. Moreover, frailty and multimorbidity were not fully accounted for, which are important confounders in geriatric research. These factors limit the relevance of the findings to very old adults, as they may underestimate age-related vulnerability and miss important confounding effects common in older populations.

There are several mechanisms that might explain our findings as well the inconsistencies reported in previous literature. These likely reflect complex and sometimes opposing biological effects of statins on muscle health. As previously discussed, statins reduce cholesterol synthesis and levels of coenzyme Q10 (CoQ10) and isoprenoids, potentially causing mitochondrial dysfunction and increased apoptosis [7, 9, 10]. In rare cases, statin use can lead to immune-mediated necrotizing myopathy (IMNM), a severe muscle complication. While uncommon, IMNM underscores the complex nature of statin-related muscle effects and should be considered in patients with unexplained muscle weakness or pain [34]. Conversely, experimental studies have identified protective effects of statins on mitochondrial function. Statins have shown the ability to mitigate calcium-induced oxidative stress by reducing mitochondrial nitric oxide synthase activity, thereby limiting the production of reactive nitrogen species. Additionally, statins may inhibit cytochrome c release, a critical step in apoptotic pathways, and preserve mitochondrial membrane potential, essential for mitochondrial integrity [35]. Statins also enhance antioxidant defenses by inhibiting NADPH oxidase and increasing activity of antioxidant enzymes like superoxide dismutase and catalase, thereby reducing oxidative damage [36]). These opposing biological mechanisms likely contribute to the variability observed in clinical outcomes.

Our longitudinal analysis found no significant differences in muscle strength, mass, or physical performance changes between statin users and non-users. A plausible explanation for these neutral results is that, particularly among relatively healthy and high-functioning older adults, the beneficial mitochondrial and antioxidant effects of statins may effectively counterbalance their potential adverse impacts. This balance would help maintain overall muscle health and could explain why significant adverse effects were not observed in our study. Moreover, our findings are particularly notable given that statin users in our cohort had a higher burden of cardiovascular comorbidities at baseline. Despite this, they demonstrated similar functional trajectories to non-users, which may suggest a protective or stabilizing role of statins in the context of multimorbidity. This observation appears counterintuitive, as a higher degree of comorbidity is generally associated with worse functional outcomes. However, these findings emphasize the critical importance of objective, standardized muscle assessments rather than relying solely on subjective symptoms to evaluate statin safety.

The present study has several strengths. It leverages a large, multinational cohort of community-dwelling adults aged ≥ 75 years from multiple European countries, recruited under broad inclusion criteria. Including individuals with diverse comorbidity profiles and medication use enhances the real-world relevance and supports generalizability to geriatric clinical practice. The availability of comprehensive clinical data, captured through structured geriatric assessments, enabled robust adjustment for key confounders. These assessments covered somatic, functional, cognitive, and psychosocial domains, offering a multidimensional view of participants’ health complexity. Muscle outcomes were assessed using standardized, objective methods endorsed by the EWGSOP2, increasing the reliability of the findings. The inclusion of grip strength, skeletal muscle index (SMI), and the Short Physical Performance Battery (SPPB) allowed for evaluation of distinct yet complementary domains of muscle health, all validated in older populations. The two-year longitudinal follow-up captured gradual functional changes over time, which is critical for understanding aging trajectories. Additionally, incorporating the defined daily dose (DDD) enabled an exploratory analysis of statin dose–response effects, an aspect often neglected in comparable studies [2], despite its clinical relevance.

Nonetheless, several limitations should be acknowledged. First, the observational design precludes causal inference, and potential confounding by unmeasured variables, such as physical activity and other lifestyle factors, remains possible. However, studies on exercise interventions have shown improvements in muscle outcomes in both statin users and non-users, suggesting that physical activity does not significantly alter the relationship between statin use and muscle health [37–39]. While the absence of objective data on physical activity in our study is unlikely to have substantially affected our results, it remains an interesting area to follow in future intervention studies to further elucidate the effects of statins on muscle outcomes. Second, although multimorbidity was common, participants were generally high-functioning at baseline, potentially limiting generalizability to frail or more clinically complex populations. Participants with high levels of disability or advanced disease may have been underrepresented due to selective non-participation or dropout. Third, the statistical model accounted only for the prescribed dose of statins, not the duration of use. This omission could introduce bias, particularly in assessing the cumulative effects of statins. Unfortunately, data on statin duration, as well as statin-related symptoms, adherence, prior intolerance, and timing of initiation, were not available. These factors may influence treatment adherence and patient-reported outcomes. Although previous research suggests that perceived symptoms and dose intensity contribute to statin discontinuation [2, 40], their relationship with objectively measured muscle outcomes remains inconsistent [41, 42]. Ideally, future studies should include statin duration for a more comprehensive analysis.

Finally, the two-year follow-up provides valuable insights into the short- to medium-term effects of statin use. Given that participants in our study may have already been using statins for an extended period prior to baseline, our cross-sectional analysis offers valuable insight into the potential effects of long-term statin use. Even with two years of follow-up, we did not observe any significant changes in muscle strength, mass, or physical performance. However, to fully evaluate the cumulative effects of prolonged statin use on muscle health in older adults, longer follow-up periods might be of additional value.

Despite these limitations, this study combines validated outcome measures, statin dose–intensity analysis, and detailed clinical characterization within a large, well-defined older population. The design and scope of the study provide a solid foundation for interpreting the association between statin use and muscle health. Our findings can help to clarify the safety profile of statins in older adults and set the stage for the concluding interpretation of their clinical implications.

Conclusion

In this large, prospective cohort of individuals aged 75 years and older, statin use did not impair muscle strength, skeletal muscle mass, or physical performance. These findings support the muscular safety of statin therapy in relatively well-functioning older individuals and counter concerns about potential harm. Despite a higher burden of comorbidities, which we adjusted for, statin users exhibited similar functional trajectories in muscle health compared to non-users., Within the context of appropriate prescribing, statins can be continued without compromising physical function. These results contribute to the growing evidence base guiding statin use in the expanding population of older adults.

Clinical implications

These results reinforce the continued use of statins for cardiovascular prevention in older adults, including those aged ≥ 75 years, without undue concern for muscle-related functional decline. However, clinical vigilance remains essential, particularly in patients with low muscle reserve, multimorbidity, or emerging symptoms suggestive of muscle intolerance. Individualized prescribing that accounts for baseline function, comorbidities, and patient experience may further optimize statin use in older adults. Future research should focus on identifying subgroups at elevated risk for muscle-related effects and evaluate the role of modifiable lifestyle factors, such as physical activity, in maintaining muscular resilience during long-term statin therapy.

Author contributions

SDF, LT, and FMR conceived the study design. SDF conducted the statistical analyses and drafted the manuscript. PF, AC, RK, CCS, RRW, GW, IY, IM, TK, AG, ACC, FF, RMG, FL, and FMR contributed to data interpretation, critically revised the manuscript, and approved the final version.

Funding

This study received no specific funding for the analysis presented. The SCOPE project was funded by the European Union Horizon 2020 program (Grant Agreement No. 634869).

Data availability

Data will be available for members of the SCOPE consortium on reasonable request from the principal investigator, Fabrizia Lattanzio, Italian National Research Center on Aging (IRCCS INRCA), Ancona, Fermo, and Cosenza, Italy ( f.lattanzio@inrca.it ).

Declarations

Conflict of interest

The authors declare that they have no conflicts of interest relevant to the content of this manuscript.

Ethics approval

The SCOPE study was conducted in accordance with the Declaration of Helsinki and approved by the local ethics committees of each participating center.

Consent for publication

Not applicable.

Consent to participate

Written informed consent was obtained from all participants.