Adam S. Grimaldi

Effect of Statins on Skeletal Muscle Function

Background— Many clinicians believe that statins cause muscle pain, but this has not been observed in clinical trials, and the effect of statins on muscle performance has not been carefully studied. Methods and Results— The Effect of Statins on Skeletal Muscle Function and Performance (STOMP) study assessed symptoms and measured creatine kinase, exercise capacity, and muscle strength before and after atorvastatin 80 mg or placebo was administered for 6 months to 420 healthy, statin-naive subjects. No individual creatine kinase value exceeded 10 times normal, but average creatine kinase increased 20.8±141.1 U/L (P<0.0001) with atorvastatin. There were no significant changes in several measures of muscle strength or exercise capacity with atorvastatin, but more atorvastatin than placebo subjects developed myalgia (19 versus 10; P=0.05). Myalgic subjects on atorvastatin or placebo had decreased muscle strength in 5 of 14 and 4 of 14 variables, respectively (P=0.69). Conclusions— These results indicate that high-dose atorvastatin for 6 months does not decrease average muscle strength or exercise performance in healthy, previously untreated subjects. Nevertheless, this blinded, controlled trial confirms the undocumented impression that statins increase muscle complaints. Atorvastatin also increased average creatine kinase, suggesting that statins produce mild muscle injury even among asymptomatic subjects. This increase in creatine kinase should prompt studies examining the effects of more prolonged, high-dose statin treatment on muscular performance. Clinical Trial Registration— URL: http://www.clinicaltrials.gov. Unique identifier: NCT00609063.

25(OH) Vitamin D is Associated with Greater Muscle Strength in Healthy Men and Women

PURPOSE The purpose of the study was to examine the relation between serum 25-hydroxy vitamin D (25(OH)D) levels and muscle strength in 419 healthy men and women over a broad age range (20-76 yr). METHODS Isometric and isokinetic strength of the arms and legs was measured using computerized dynamometry, and its relation to vitamin D was tested in multivariate models controlling for age, gender, resting HR, systolic blood pressure, diastolic blood pressure, body mass index, maximal oxygen uptake (VO(2max)), physical activity counts, and season of vitamin D measurement. RESULTS Vitamin D was significantly associated with arm and leg muscle strength when controlling for age and gender. When controlling for other covariates listed previously, vitamin D remained directly related to both isometric and isokinetic arm strength but only to isometric leg strength. CONCLUSION These data suggest that there may be a differential effect of vitamin D on upper and lower body strength. The mechanism for this difference remains unclear but could be related to differences in androgenic effects or to differences in vitamin D receptor expression. Our study supports a direct relation between vitamin D and muscle strength and suggests that vitamin D supplementation be evaluated to determine whether it is an effective therapy to preserve muscle strength in adults.

A Randomized Clinical Trial to Assess the Effect of Statins on Skeletal Muscle Function and Performance: Rationale and Study Design

Hydroxymethylglutaryl-coenzyme A reductase inhibitors or statins are the most effective medications for reducing elevated concentrations of low-density lipoprotein cholesterol (LDL-C). Statins reduce cardiac events in patients with coronary artery disease and previously healthy persons. Current recommendations for LDL-C treatment goals indicate that more patients will be treated with higher doses of these medications. Statins have been extremely well-tolerated in controlled clinical trials but are increasingly recognized to produce skeletal muscle myalgia, cramps, and weakness. The reported frequency of such mild symptoms is not clear, and muscle performance has not been examined with these medications. Accordingly, the present investigation, the Effect of Statins on Skeletal Muscle Function and Performance (STOMP) study, will recruit approximately 440 healthy persons. Participants will be randomly assigned to treatment with atorvastatin 80 mg/d or placebo. Handgrip, elbow and knee isometric and isokinetic strength, knee extensor endurance, and maximal aerobic exercise performance will be determined at baseline. Participants will undergo repeat testing after 6 months of treatment or after meeting the study definition of statin myalgia. This study will determine the effect of statins on skeletal muscle strength, endurance, and aerobic exercise performance and may ultimately help clinicians better evaluate statin-related muscle and exercise complaints.

Increases in creatine kinase with atorvastatin treatment are not associated with decreases in muscular performance

BACKGROUND The present study examined if increases in creatine kinase (CK) levels during high-dose atorvastatin treatment are associated with changes in skeletal muscle function and symptoms. METHODS The Effect of Statins on Muscle Performance study (STOMP) investigated the effects of atorvastatin 80 mg daily for 6 months on muscle performance, exercise capacity, and the incidence of statin-associated muscle complaints in healthy adults. RESULTS CK levels increased with atorvastatin (n = 202) from 132.3 ± 120.9 U/L (mean ± SD) at baseline to 159.7 ± 170.4 and 153.1 ± 139.4 U/L at 3 and 6 months, respectively (P ≤ 0.002 for both). Changes in CK with atorvastatin treatment were not associated with changes in muscle function or the incidence of myalgia. More subjects on atorvastatin (n = 24) compared to placebo (n = 12 of 217) doubled their CK level at 6 months (P = 0.02). No differences in muscle function or physical activity were observed between atorvastatin-treated subjects who did or did not double their CK. CONCLUSIONS Results of the present investigation extend the findings of STOMP by demonstrating that greater increases in CK levels with high-dose atorvastatin treatment did not deleteriously impact skeletal muscle function or predict skeletal muscle complaints. This study was registered at ClinicalTrials.gov (NCT00609063).

The Effect of Atorvastatin on Habitual Physical Activity among Healthy Adults

PURPOSE Statin therapy can result in muscle pain, cramps, and weakness that may limit physical activity, although reports are mixed. We conducted a randomized control trial to examine the effect of atorvastatin on habitual physical activity levels in a large sample of healthy adults. METHODS Participants (n = 418) were statin-naive adults (44.0 ± 16.1 yr (mean ± SD)) who were randomized and double-blinded to 80 mg · d(-1) of atorvastatin or placebo for 6 months. Accelerometers were worn for 96 h before and after drug treatment. Repeated-measures analysis tested physical activity levels after versus those before drug treatment among groups with age and VO2max as covariates. RESULTS In the total sample, sedentary behavior increased (19.5 ± 5.1 min · d(-1)), whereas light-intensity (9.1 ± 3.0 min · d(-1)) and moderate-intensity (9.7 ± 2.8 min · d(-1)) physical activity decreased, as did total activity counts (17.8 ± 6.3 d × 10(-3)) over 6 months (P < 0.01), with no differences between groups. The atorvastatin group increased sedentary behavior (19.8 ± 7.4 min · d(-1)) and decreased light-intensity (10.7 ± 4.3 min · d(-1)) and moderate-intensity (8.5 ± 4.0 min · d(-1)) physical activity (P < 0.05). On the other hand, the placebo group increased sedentary behavior (19.2 ± 7.1 min · d(-1)) and decreased moderate-intensity (11.0 ± 3.8 min · d(-1)) and total physical activity counts (-23.8 ± 8.8 × 10(-3) d(-1)) (P < 0.05). CONCLUSIONS Time being sedentary increased and physical activity levels decreased in the total sample over 6 months of drug treatment, independent of group assignment. Our results suggest that statins do not influence physical activity levels any differently from placebo, and the lack of inclusion of a placebo condition may provide insight into inconsistencies in the literature.

Effect of exercise training on hippocampal volume in humans: a pilot study.

The hippocampus is the primary site of memory and learning in the brain. Both normal aging and various disease pathologies (e.g., alcoholism, schizophrenia, and major depressive disorder) are associated with lower hippocampal volumes in humans ( Agartz, Momenan, Rawlings, Kerich, & Hommer, 1999; Barta, Dhingra, Royall, & Schwartz, 1997; Jernigan et al., 2001; McKinnon, Yucel, Nazarov, & MacQueen, 2009; Meisenzahl et al., 2009), and hippocampal atrophy predicts progression of Alzheimers disease (Henneman et al., 2009). In animals, there is convincing evidence that exercise training increases hippocampal volume (Van der Borght, Havekes, Bos, Eggen, & Van der Zee, 2007; van Praag, Shubert, Zhao, & Gage, 2005;). A recent cross-sectional study in older humans demonstrated a positive relation between aerobic fitness and hippocampal volume (Erickson et al., 2009). Moreover, a recent study found that a year of aerobic exercise training increases hippocampal volume by 2% in older adults (Erickson et al., 2011). Accordingly, in the current preliminary study we sought to confirm the direct effect of supervised exercise training on magnetic resonance imaging (MRI) estimates of hippocampal volume in healthy humans. Method

Atorvastatin increases exercise leg blood flow in healthy adults.

OBJECTIVES We sought to examine the effect of atorvastatin therapy on exercise leg blood flow in healthy middle-aged and older-men and women. BACKGROUND The vasodilatory response to exercise decreases in humans with aging and disease and this reduction may contribute to reduced exercise capacity. METHODS We used a double-blind, randomly assigned, placebo-controlled protocol to assess the effect of atorvastatin treatment on exercising leg hemodynamics. We measured femoral artery blood flow (FBF) using Doppler ultrasound and calculated femoral vascular conductance (FVC) from brachial mean arterial pressure (MAP) before and during single knee-extensor exercise in healthy adults (ages 40-71) before (PRE) and after (POST) 6 months of 80 mg atorvastatin (A: 14 men, 16 women) or placebo (P: 14 men, 22 women) treatment. FBF and FVC were normalized to exercise power output and estimated quadriceps muscle mass. RESULTS Atorvastatin reduced LDL cholesterol by approximately 50%, but not in the placebo group (p < 0.01). Atorvastatin also increased exercise FBF from 44.2 ± 19.0 to 51.4 ± 22.0 mL/min/W/kg muscle whereas FBF in the placebo group was unchanged (40.1 ± 16.0 vs. 39.5 ± 16.1) (p < 0.01). FVC also increased with atorvastatin from 0.5 ± 0.2 to 0.6 ± 0.2 mL/min/mmHg/W/kg muscle, but not in the placebo subjects (P: 0.4 ± 0.2 vs. 0.4 ± 0.2) (p < 0.01). CONCLUSIONS High-dose atorvastatin augments exercising leg hyperemia. Statins may mitigate reductions in the exercise vasodilatory response in humans that are associated with aging and disease.

Atorvastatin Treatment Does Not Alter Pulse Wave Velocity in Healthy Adults

Introduction. Both statins and regular physical activity (PA) reduce arterial stiffness. The present post hoc analysis examined if arterial stiffness was improved with high-dose atorvastatin treatment in healthy adults and whether PA levels magnified this response. We utilized data from a double-blind, random-assignment clinical trial investigating the effects of atorvastatin 80 mg/d for 6 mo on skeletal muscle symptoms. Methods. Central and peripheral arterial pulse wave velocity (PWV) were measured and PA levels assessed at baseline and 6 mo in subjects randomized to atorvastatin (n = 21, 9 men) or placebo (n = 29, 16 men). Results. Baseline participant characteristics, PWV, and PA levels were not different between treatments. Central (means ± SD; 8.7 ± 2.6 to 9.0 ± 2.5 m/sec) and peripheral PWV (9.9 ± 1.3 to 9.8 ± 1.6 m/sec) were unchanged from baseline following atorvastatin treatment (time × drug interaction: P ≥ 0.13). Similarly, PA levels were unaffected by time or treatment. In sex and age adjusted models, baseline levels of PA were not related to changes in PWV with atorvastatin treatment. Conclusion. These data indicate that high-dose atorvastatin treatment for 6 mo does not influence arterial stiffness in healthy adults. Participation in habitual PA did not magnify the vascular effects of statin therapy. This study was registered with ClinicalTrials.gov NCT00609063.

Effects of Atorvastatin on Resting and Peak Exercise Blood Pressure among Normotensive Men and Women

Statins are the most widely prescribed and effective medication for reducing low density lipoprotein cholesterol. Statins may also lower resting blood pressure (BP); however, results are inconsistent. We sought to determine if the maximum dose of atorvastatin reduces resting BP and the peak systolic BP (SBP) achieved on a graded exercise stress test (GEST) among a large sample of 419 healthy men (48%) and women (52%). Subjects (419, 44.1 ± 0.8 yr) were double-blinded and randomized to 80 mg·d−1 of atorvastatin (n = 202) or placebo (n = 217) for 6 mo. Among the total sample, there were no differences in resting BP (SBP, P = 0.30; diastolic BP [DBP], P = 0.69; mean arterial pressure (P = 0.76); or peak SBP on a GEST (P = 0.99)) over 6 mo, regardless of drug treatment group. However, among women on atorvastatin, resting SBP/DBP (3.7±1.5 mmHg, P = 0.01/3.2±0.9 mmHg, P = 0.02) and peak SBP on a GEST (6.5±1.5 mmHg, P = 0.04) were lower versus men. Atorvastatin lowered resting BP 3-4 mmHg and peak SBP on a GEST ~7 mmHg more among women than men over 6 mo of treatment. The inconsistent findings regarding the antihypertensive effects of statins may be partially explained by not accounting for sex effects.