Introduction

Cardiovascular diseases (CVD) are the most common cause of morbidity and mortality in Western societies [1]. Primary and secondary prevention strategies target predisposing risk factors (e.g. increased low-density lipoprotein [LDL] plasma concentrations or physical inactivity) using pharmacological and lifestyle-modification strategies. A prime example for pharmacological strategies is statin medication which is predominantly used to reduce LDL levels [2]. Possible non-pharmacological prevention modalities include increasing physical activity and dietary counselling. In the past a plethora of research has investigated the effectiveness and specificity of these prevention options [3,4]. However, possible interactions between drugs and lifestyle interventions are only beginning to be recognized [5].

Exercise is well known to increase endothelial nitric oxide bioavailability and improve endothelial function as well as decrease the overall inflammatory burden and vascular resistance [6–8]. The non-lipid pleiotropic effects of statins exert similar effects on these parameters [2,9]. Additionally, a previous randomized clinical trial reported that statin medication impaired training induced increases in exercise capacity [10]. Therefore, exercise and statins may interact with one another. Standardized cardiopulmonary exercise testing (CPET) is a standard method to determine exercise capacity. Currently there is a knowledge gap in the literature whether statins are related with CPET results. We explored the association of statin medication with CPET parameters in the general population. The aim of this study was to investigate if statins are associated with cardiorespiratory exercise capacity using cross-sectional data from two independent population-based cohorts (Study of Health in Pomerania [SHIP]). Based on the previous findings we hypothesized an inverse association between exercise capacity and statin medication.

Methods

Results

General characteristics

Descriptive statics of SHIP-1 and SHIP-T are provided in S1 Table and S2 Table. Of the 3,500 analyzed subjects in the merged data set a total of 1,752 were male (253 [14.4%] on statin medication) and 1,748 female (171 [9.8%] on statin medication) (Table 1). Study participants taking statins were significantly older, smoked less, and had higher BMI, more often hypertension as well as diabetes mellitus. Further, median plasma LDL and cholesterol concentrations were lower, while median TG concentration was higher in statin compared to non-statin taking subjects. Values for VO₂peak, VO₂@AT and eGFR were lower in statins users. Also, subjects on statins were more likely to receive beta blockers, calcium-channel blockers and angiotensin-converting enzyme blockers. Interestingly, in males but not in females median diastolic blood pressure was lower in statin users compared to non-users. However, females on statins had significantly higher median systolic blood pressure compared to females without statins. No such difference was found in males. Median O₂HR_max was significantly lower in males with statins compared to male subjects without this drug, while no difference was seen for females.

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Table 1. Descriptive statistics.

https://doi.org/10.1371/journal.pone.0179534.t001

The association between statin medication and VO₂peak

Since a significant sex–statin interaction was observed in the initial linear regression model all further group comparisons were stratified by sex (p < .001) (S3 Table). Results for the individual studies (SHIP-1 and SHIP-T) are provided in S4 and S5 Tables. In model 1 statin medication was inversely associated with VO₂peak in males (no statin: 2,337; 95%-confidence interval [CI]: 2,287–2,386 vs. statin: 2,091; 95%-CI: 2,032–2,150 ml/min; P < .0001) but not females (no statin: 1,467; 95%-CI: 1,417–1,517 vs. statin: 1,503: 95%-CI: 1,426–1,579 ml/min; P = 1.00). Model 2 showed similar results (male no statin: 2,268; 95%-CI: 2,214–2,321 vs. male statin: 2,035; 95%-CI: 1,975–2,096 ml/min; P < .0001; female no statin: 1,388; 95%-CI: 1,334–1,443 vs. female statin: 1,434; 95%-CI: 1,356–1,511 ml/min; P = 1.00).

Quantile regression analysis revealed a consistent effect throughout the range of observed values for both sexes. Specifically, statin usage was associated with a significantly reduced VO₂peak for all observed values between the 5^th and the 95^th percentile in males. Quantile regression analysis also confirmed that statin usage was not associated with reduced VO₂peak in females for the range of observed values (Fig 1).

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Fig 1.

Association between statin medication with VO₂peak for males (A) and females (B). The dashed line indicates a β-coefficient of “0”, which means that there are no significant differences in VO₂peak between statin users and non-users. The red line is representative of the overall β (i.e. the observed difference in VO₂peak between statin users and non-users). The quantiles on the x-axis are representative of exercise capacity. Subjects with the lowest VO₂peak are on the left and while the one with highest exercise capacity are on the right. Statin medication was associated with a significantly reduced VO₂peak in male between the 5^th and 95^th quantiles. For females no significant differences were observed.

https://doi.org/10.1371/journal.pone.0179534.g001

Discussion

Statins and exercise are life-saving therapeutics with systemic pleiotropic effects. This investigation explored a potential association between statins and cardiopulmonary exercise testing capacity in two independent cross-sectional population-based cohorts from Northeast Germany. We report that statin usage was inversely related with VO₂peak and VO₂@AT in males but not females. Male statin users had significantly lower VO₂peak between the 5^th and 95^th percentile. In females no association of statins with VO₂peak and VO₂@AT was observed throughout the range of observed values. In line with these findings, statin medication was also associated with reduced oxygen pulse in males but not females. In addition, the results of the investigated three-way interaction between sex, physical inactivity, and statin medication indicate that the relation between statins and reduced VO₂peak was dependent on sex but independent of physical activity. This is in contrast to previous findings which reported that physical activity decreased in elderly men after initiation of statin treatment [19].

Maximal oxygen consumption is a very well established predictor for mortality in healthy populations [20] and in patients with coronary heart disease [21]. The positive outcomes of participating in structured exercise programs for patients who experienced acute cardiovascular events are well established [22,23]. Also, patients with heart failure [24] and coronary heart disease [25], who receive statins, cannot just safely participate in endurance and interval training protocols, but also increase their cardiopulmonary exercise capacity. However, some previous studies suggest that statins may also worsen cardiac function. In a very small trial, 14 patients without previous myocardial function and heart failure were given 20 mg of atorvastatin per day [26]. A total of 10 patients showed a worsening of diastolic ventricular function (e.g. 10% decrease in the E/A ratio, a 10% increase in E-wave DT, or a 10% increase in IVRT). The authors of the trial reported that affected patients had very low coenzyme Q₁₀ which can be further reduced by statins [27]. In line with this, a very recent clinical trial with 420 heart failure patients reported that coenzyme Q₁₀ supplementation significantly reduced major adverse cardiovascular events [28].

Statins are also recommended for subjects without cardiovascular disease but who have an increased risk for CVD [29,30]. The separate efficacy of either exercise or statins in primary CVD prevention has been well established [31,32]. To demonstrate the suitability of statins for subjects without cardiovascular disease, previous studies have reported that statins did not decrease VO₂peak [33]. However, these results have to be taken with caution since they are based on a small sample size of 28. Also, large epidemiological studies reported an additive effect of statins and physical activity on mortality reduction in dyslipidaemic and hypertensive individuals [34,35]. Interestingly, Kokkinos et al. reported that the fittest study participants had the lowest risk of mortality independent of statin usage [34]. However, while in secondary disease prevention, subjects were able to increase their VO₂peak with exercise training; this may not be the case in primary prevention. Mikus et al. recently showed that statins impaired the beneficial effects of a twelve week supervised aerobic endurance exercise training protocol in obese subjects [10]. Their investigation was the first to compare two exercise groups to assess the additional effect of statins on top of exercise on trainability. Statins inhibited an increase in VO₂peak. We report that in males from a general population cohort current statin usage was associated with significantly lower VO₂peak independent of age, previous myocardial infarction, physical activity behavior, BMI, diabetes, hypertension, beta blocker usage, calcium channel blockers, and angiotensin converting enzyme blockers. Further research is warranted to understand which subjects benefit most from statins and/or exercise.

In addition to lower VO₂peak, statin usage was related with lower VO₂@AT in males, but not females. In contrast to our data, a human trial which investigated cardiopulmonary exercise capacity in patients with statin induced myotoxicity reported that the aerobic threshold was not impacted by statin medication in their control group [36]. The authors speculated that an increased resting respiratory exchange ratio due to statins may impair the lipid metabolism during exercise. Our findings point to a more nuanced interpretation, since our results suggest sex specific relation of statins with cardiopulmonary exercise capacity. Nonetheless, we acknowledge that our results are based on observational data and not based on a randomized controlled trial (RCT). Hence, our results are subject to bias and confounding. Overall, these effects deserve further research.

Several studies have explored the impact of statins on physical fitness and activity [10,19,34,37–44]. However, these investigations are very heterogeneous in terms of participants and experimental design. For example, Sinzinger and O’Grady examined the impact of statins on muscle pain in elite athletes with familial hypercholesterolemia. They reported that merely 20% tolerated statin treatment without reporting any adverse effects [37]. Contrarily, in healthy individuals with increased LDL concentration, simvastatin treatment for 12 weeks was not associated with decreases in cardiopulmonary exercise capacity and muscle function [38]. In a large observational study with 1,201 patients undergoing cardiac rehabilitation significant improvements in VO₂peak were reported for statin users and non-users alike [40]. In a large very recent epidemiological study Williams and Thompson investigated the role of statins in more than 60,000 runners and walkers [44]. Statins did not influence exercise activity or duration in individuals who developed hypercholesterolemia. Lastly, in the The Henry Ford Exercise Testing (FIT) Project statin usage was not associated with decreased VO₂peak in males or females [42]. These data suggest that statins may not adversely influence physical activity and capacity.

The sex specific results of our analysis are of particular interest. Even though, we acknowledge that our population-based approach is observational, it is well established that statin therapy increases the risk for skeletal muscle myopathy. This side effect primarily impacts glycolytic type II muscle and not oxidative type I fibers [45,46]. Since women have more type I fibers compared to men [47], males may be at a higher risk to experience statin induced muscle damage. Interestingly, previous experimental evidence demonstrated higher rates of statin induced muscle problems in women [48]. A second possible explanation is that lipophilic statins (i.e. lovastatin, simvastatin, fluvastatin, atorvastatin, and pivastatin) are metabolized in first-pass in the liver through the hepatic cytochrome enzyme system [49]. The enzyme responsible for this reaction is cytochrome P450 3A4 (CYP3A4). Women have been found to have higher concentrations of CYP3A4 [50,51]. Hence, females may be able to metabolize statins more quickly and thus reduce their efficacy. The third possible reason as to why a sex-specific association was observed in our investigation may be due to the difference in O₂HR_max. While statin taking males had lower O₂HR_max compared to non-users, female statin takers and non-takers had similar O₂HR_max. Since O₂HR_max is strongly related with left ventricular ejection fraction (LVEF), the inverse association between statin usage and VO₂peak in males may be a result of lower LVEF which was not evident in female statin users. A reduced LVEF in male statin users may be partly responsible for their lower cardiopulmonary exercise capacity. Overall, at least three explanations (e.g. effect of statins on type I skeletal muscle fibers, sex-specific CYP3A4 concentration and/or differences in O₂HR_max) for the observed sex-specific associations between statins and CPET parameters are likely. Nonetheless, we are currently unable to unequivocally determine the underlying reason for our observations.

Our findings are in contrast to previous observations that reported an increased incidence of statin adverse effects in women compared to men [48]. Further, in a randomized controlled trial (RCT) women receiving statins experienced more fatigue compared to men [52]. These observed side effects of statins were related to alterations in mitochondrial function [48]. Since mitochondrial function is associated with cardiopulmonary exercise capacity [53], one would propose that statins show an inverse association with VO₂peak. One may speculate the different results are due to the fact that we analyzed data from a general populated based cohort while the above mentioned RCT recruited subjects from a primary prevention population without overt cardiovascular disease or diabetes.

One of the reasons for the statin treatment in our population was most likely increased circulating LDL and cholesterol. Altered lipid metabolism is an early hallmark of subclinical cardiovascular disease and may therefore influence cardiopulmonary exercise capacity. We assessed the association between circulating LDL and cholesterol with VO₂peak in subjects not taking statin medication. We report an inverse association between VO₂peak to LDL and cholesterol in males but not females. Interestingly, the parameter estimate for LDL points to an inverse association for both sexes. This agrees with the common thought that increased LDL is associated with subclinical CVD and therefore reduced cardiopulmonary exercise capacity. However, the parameter estimate for the association between VO₂peak and cholesterol is inverse for males but positive for females. Future analyses need to verify this finding as it may just be a result of chance.

We acknowledge that based on the cross-sectional analysis of observational data we cannot conclusively determine the direction of the investigated associations. Further, the cross sectional design only allows for the comparison of current statin users and non-users. Since CPET was voluntary in our cohort, a potential bias may have been introduced due to more fit individuals selecting to participate in this test. Nonetheless, the strength of our study is the population-based design. This may allow drawing inferences for the general population from our results. However, we are aware that only a small number of participants took statins, which in turn may be a realistic assumption about the general population. In addition, we employed a highly standardized quality control during the course of the study. Lastly, we recognize our analysis would benefit from information regarding the duration and dose of statin treatment as well as possible muscle symptoms. Unfortunately this data is not available for our cohorts. Our findings may be influenced by residual confounding since we included variables which are strongly predictive of cardiopulmonary exercise capacity and have a large degree of variability. Most importantly we were unable to adjust to lipid levels prior to statin treatment.

One may argue that the observed associations between VO₂peak and VO₂@AT with present statin medication are the result of an observational bias due to comparing healthy with sick sub-populations. To investigate whether this was the case, we used propensity scores in a sensitivity analysis as a method to overcome this potential shortcoming. The propensity scores were calculated using a logistic regression adjusted for age, sex, BMI, diabetes, hypertension, previous myocardial infarction and usage of beta-blockers, calcium channel blockers, and angiotensin-converting enzyme blockers. Thereafter, we matched subjects with and without statins according to a very stringent caliper of 0.1. This means that the difference in propensity scores has to be less than 0.1. This method is more rigorous than using nearest neighbor matching which is exemplified by the fact that we were unable to match all statin taking subjects. A paired t-test between matched male subject pairs demonstrated that statin users had significantly lower VO₂peak and VO₂@AT compared to non-users. No significant difference was observed for females. Therefore, the propensity score analysis confirmed the results of the regression analysis.

Conclusion

We report that present statin medication was related with impaired cardiopulmonary exercise capacity in male but not female subjects in a cross-sectional population based study from northeast Germany. Based on previous research, statins may inhibit increases in VO₂peak due to exercise training in primary, but not secondary disease prevention. Therefore, whether subjects in primary cardiovascular prevention aiming to increase their cardiopulmonary exercise capacity should take this medication deserves further research. Future research should use a randomized design to test whether our observational results can be confirmed to assess whether exercise and not drug usage is more suitable as a first frontier in primary disease prevention.

Supporting information

Acknowledgments

The authors acknowledge and greatly appreciate the work of all study nurses and technicians who helped collect data for the SHIP study. Further, the authors thank all SHIP participants for their contribution to science by participating in the study.