FormalPara Key Points

No positive association was found between the intake of angiotensin-converting enzyme (ACE) inhibitors and muscle strength, muscle quality or function.

Striking differences between parameters of absolute and relative lean mass in relation to the use of ACE inhibitors became evident. Users of ACE inhibitors had significantly lower relative muscle mass but higher absolute muscle mass.

Studies investigating the effects of drugs on lean mass should have carefully selected target parameters, taking into account the need to correct for factors contributing to lean mass such as height, weight and body mass index.

1 Introduction

Sarcopenia, the age-related loss of muscle mass, muscle strength and muscle function, has been linked to falls, disability, loss of independence, and increased morbidity and mortality [1–3]. Considering that all basic activities of daily life require a certain amount of intact muscle function, it is clear that the search for pharmaceutical agents and ideal treatment strategies to prevent or treat sarcopenia is an important healthcare topic and part of constant efforts in medical research. To date, exercise, e.g. resistance training, nutritional intervention such as adequate protein and energy intake, and correcting vitamin D deficiency are the most appropriate strategies in terms of a risk-benefit balance. However, recently, owing to the beneficial impact of some drugs on muscle tissue, alternative off-label pharmacological options for sarcopenia have been proposed [4]. Angiotensin-converting enzyme (ACE) inhibitors are prescribed mainly for patients with arterial hypertension, chronic heart failure and post-myocardial infarction where they yield considerable therapeutic benefits in reducing mortality and hospitalisation rates [5, 6]. Increased skeletal muscle blood flow mediated by enhanced endothelial function and anti-inflammatory effects via reduced production of proinflammatory cytokine levels have been suggested as possible mechanisms for preserving or improving muscular function [7, 8]. Effects on skeletal muscle have been observed both in cross-sectional analyses as well as in longitudinal studies, but results have been conflicting.

In the Health, Aging and Body Composition (Health ABC) Study, participants using ACE inhibitors had a larger lower extremity muscle mass than those using other antihypertensive drugs. Additionally, the time of exposure to ACE inhibitors tended to be associated with a larger muscle mass [9]. Moreover, in a cohort of the Women’s Health and Aging Study, continued users of ACE inhibitors showed a significantly lower decline in muscle strength after 3 years of follow-up compared with other groups [10]. In patients with chronic heart failure, treatment with the ACE inhibitor enalapril led to increased muscle fibre areas and lactate dehydrogenase activity in a small observational study. The authors concluded, however, that the extent to which this may also have been caused by increased physical activity remains unclear [11]. Randomised controlled trials investigating the effect of ACE inhibitors on physical function have to date led to inconsistent results [12–14].

The aim of this cross-sectional analysis in a large sample of community-dwelling older adults was (1) to assess differences in various established muscle mass parameters including the criteria for low lean mass recently defined by the Foundation for the National Institutes of Health Sarcopenia Project [15]; (2) to assess differences in functional parameters between participants with and without ACE inhibitor intake; and (3) to adjust all our analyses concerning lean mass for fat mass, to account for the effect of body composition.

2 Methods

2.1 Participants

All participants gave written informed consent and the Ethics Committee of the Charité-Universitätsmedizin Berlin approved the study (Approval No. EA2/029/09). Eight hundred and thirty-eight community-dwelling participants from the Berlin Aging Study-II (BASE-II) recruited as volunteers between 2009 and 2014 were included in this analysis. The eligibility criteria of BASE-II at the time of recruitment have been described previously in detail [16]. Briefly, participants were community dwelling, comparably healthy and independently living older subjects aged between 60 and 80 years. Exclusion criteria were: (1) reported difficulty in walking one-quarter of a mile without assistance, (2) known Parkinson’s disease, stroke or myocardial infarction, (3) previous head, heart or vascular surgery, or (4) known dementia or malignant disease. For this analysis, we also excluded participants using angiotensin receptor blockers to avoid potential confounding due to the similar mechanism of action.

Participants were examined by a study physician on the first study day and were excluded if showing signs of acute illness. No participants with possibly confounding conditions such as fever or oedema were included.

2.2 Angiotensin-Converting Enzyme Inhibitors

All individual types of ACE inhibitors were recorded and the duration of intake of ACE inhibitors was listed in years. Participants were divided into the two groups of non-users of ACE inhibitors and users of ACE inhibitors.

2.3 Anthropometric Measurements

Body weight was measured to the nearest 0.1 kg and height was determined to the nearest 0.1 cm using an electronic weighting and measuring station (seca 764; seca GmbH & Co. KG, Hamburg, Germany). Weight and height were used to calculate body mass index (BMI) (weight [kg]/height [m]2).

2.4 Body Composition

Body composition was assessed with dual-energy X-ray absorptiometry (Hologic® QDR® Discovery™; Hologic, Inc., Bedford, MA, USA). Participants wore light clothes and a trained technician performed the dual-energy X-ray absorptiometry measurement protocol. The system software (APEX version 3.0.1., Hologic Inc. Bedford, MA,USA) provided the mass of lean soft tissue, fat and bone mineral content. Absolute appendicular lean mass (ALM) in kilograms was calculated as the sum of the regional lean mass of the four limbs and the skeletal muscle mass index (SMI) as ALM/height2 (kg/m2) was derived [17]. For comparison, the ALM adjusted to BMI (ALM/BMI) was calculated as the sum of the regional lean mass in kilograms divided by BMI in kg/m2 [18]. Further analyses were performed using established cut-points for sarcopenia defined by sex-specific low SMI and low ALM/BMI [1, 15, 17, 18]. The muscle mass of the lower extremity (LEMM) was calculated by summing the lean mass of right and left leg [9]. For relative leg muscle mass, LEMM in percentage (LEMM%) was calculated as the sum of the lean mass of both legs in kilograms divided by body mass in kilograms × 100.

2.5 Hand Grip Strength

Maximal isometric hand grip strength was measured in both hands using a Smedley Dynamometer (Scandidact, Odder, Denmark). While performing the test, the participants were standing and the shoulder was adducted and neutrally rotated on the tested side, the elbow was flexed to 90°, and the forearm and wrist were in a neutral position. The participants were then asked to perform a maximal isometric contraction, and the highest value was recorded after performing the test three times on each side. The cut-off values suggested by Fried et al. were used to identify reduced grip strength [19]. Further hand grip strength was corrected for arm lean mass to form an additional parameter reflecting arm muscle quality (AMQ) [20].

2.6 Timed “Up and Go” Test

To assess lower extremity muscle function, we used the timed “Up and Go” test (TUG) [21]. The participants were instructed to stand up from a standard chair, walk a distance of 3 m (marked by a line on the floor), turn and walk back to the chair and sit down again. The time was taken in seconds using a stop watch. Participants unable to complete the test in less than 10 s were considered to have impaired function [21].

2.7 Self-Reported Physical Performance

Participants were asked whether they had difficulties performing physical tasks such as climbing several flights of stairs or performing strenuous activities such as lifting or carrying heavy objects, walking fast or running (severe/moderate/no difficulties).

2.8 Co-Variables

Systolic and diastolic blood pressures were measured with an electronic sphygmomanometer (boso-medicus memory; Jung, Willingen, Germany) after a 5-min rest period in a sitting position on both arms and the mean value between both arms was chosen. Diseases were taken from the medical history recorded by a study physician. Furthermore, a morbidity index was computed based on participant-reported and physician-assessed medical diagnosis of diseases representing most of the Charlson Comorbidity Index [22] categories that have been described previously in detail [23]. The regression analysis was adjusted for arterial hypertension as the main indication for the use of ACE inhibitors and the morbidity index including cardiovascular disease.

2.9 Statistics

Statistical analyses were carried out using the software package IBM Statistics SPSS 21 (IBM, Armonk, NY). Data are given as median and interquartile distribution. A one-sample Kolmogorov–Smirnov test was performed to test variables for Gaussian distribution and Levene’s test was performed to test for homogeneity of variances. The bivariate relationship between the duration of intake of ACE inhibitors and muscle parameters was analysed using Spearman’s correlation. To compare means between users and non-users of ACE inhibitors, the Student’s t test was employed, provided that variables were normally distributed and showed homogeneity of variance. If these requirements were not given, a Mann–Whitney U test was employed to compare those groups. The chi-squared test was used to compare percentages between those groups in relation to categorical variables. Differences between the different types of ACE inhibitors and muscle parameters were assessed by either analysis of variance in the case of normally distributed variables or by the Kruskal–Wallis test in the case of non-parametric variables.

To assess the association between the intake of ACE inhibitors, muscle parameters, strength and function, a regression analysis for significant confounders was performed with the general linear model, allowing adjustment for both continuous and categorical variables. An acceptable level of statistical significance was established a priori at p < 0.05.

3 Results

3.1 Characteristics of the Study Population

Eight hundred and thirty-eight participants were included in this analysis. The median age was 68 years and ranged from 60 to 82 years. Table 1 shows the characteristics of the study population according to the use of ACE inhibitors and stratified by sex. Overall prevalence of self-reported arterial hypertension was 38.1 % and the prevalence of self-reported congestive heart failure as well as that of coronary artery disease was 2.7 %. Of all 838 participants, 169 (20.2 %) were using ACE inhibitors. The most frequently taken ACE inhibitor was ramipril, which accounted for 65.7 % of prescribed ACE inhibitors, followed by enalapril (17.8 %), lisinopril (8.3 %), quinapril (2.4 %), captopril (1.8 %), fosinopril (1.8 %) and spirapril (1.2 %). At the other end, perindopril and benazepril were taken by only one participant each (0.6 %).

Table 1 Differences in parameters of body composition, hand grip strength and arm muscle quality according to the use of ACE inhibitors
Full size table

The duration of ACE inhibitor intake ranged between 1 and 30 years with a median intake of 3 years. As can be seen in Table 1, users of ACE inhibitors significantly more often had a history of arterial hypertension, whereas there were no significant differences regarding blood pressure, congestive heart failure and coronary artery disease except for coronary artery disease in women. Although morbidity was overall low, users of ACE inhibitors exhibited a higher morbidity as measured by the morbidity index. Users of ACE inhibitors also had a significantly higher BMI and higher total body fat percentage and significantly lower lean/fat mass ratio. Comparing the groups of users of ACE inhibitors vs. non-users of ACE inhibitors, we found that significantly more men (30.4 %) than women (22.1 %) were using ACE inhibitors (p = 0.041). Therefore, all analyses regarding parameters of muscle mass and strength were stratified according to sex.

3.2 Differences in Absolute Muscle Mass and Skeletal Muscle Mass Index

As shown in Table 1, both ALM and SMI were significantly higher in men using ACE inhibitors. Although statistical significance was not reached, women using ACE inhibitors tended to have higher ALM and SMI than those not using ACE inhibitors. LEMM showed no significant difference between users and non-users. Significantly fewer male participants with the intake of ACE inhibitors showed a SMI below the sex-specific cut-off for sarcopenia (Table 1).

3.3 Differences in Relative Muscle Mass and Appendicular Lean Muscle Mass/Body Mass Index

When analysing the relative amount of leg lean mass (LEMM%) and lean mass adjusted for BMI (ALM/BMI), we obtained contrasting results as LEMM% and ALM/BMI were significantly lower in both male and female users of ACE inhibitors (Table 1).

3.4 Muscle Strength, Muscle Quality and Muscle Function

Whereas no overall differences were found in hand grip strength between users and non-users of ACE inhibitors, arm muscle quality was significantly lower in male and female ACE inhibitor users (Table 1). Moreover, significantly more female participants taking ACE inhibitors showed grip strength below established cut-off values. The TUG time as a functional parameter did not differ significantly in participants with an intake of ACE inhibitors.

3.5 Self-Reported Physical Performance

Participants taking ACE inhibitors reported severe difficulties in climbing several flights of stairs and performing strenuous activities (only women) significantly more often than non-ACE inhibitor users (Table 1).

After adjusting for age, total fat mass, indication of drug use (arterial hypertension) and morbidity (morbidity index), we found no significant effect of ACE inhibitor use on SMI, ALM/BMI, AMQ and TUG time (Table 2). As anticipated, age showed a significant influence on ALM/BMI and TUG time in both sexes and on grip strength corrected by arm muscle mass (AMQ) in men only and total fat mass showed a significant influence on SMI and ALM/BMI as well. Moreover, TUG time was influenced by total fat mass and comorbidity in women (Table 2).

Table 2 Regression analysis for differences in relative and absolute muscle mass, grip strength, AMQ and TUG time according to the use of ACE inhibitors
Full size table

There was no correlation between the duration of intake of ACE inhibitors and LEMM, LEMM%, SMI, ALM/BMI, grip strength, arm muscle quality and TUG time. Likewise, no differences between those parameters were observed with regard to different types of ACE inhibitors. These results remained stable after ruling out those types with the lowest group size, e.g. perindopril.

4 Discussion

Previous studies have suggested a positive impact of ACE inhibitor use on skeletal muscle. In this study, we analysed the association between the use of ACE inhibitors and several functional and muscle mass-related parameters, taking whole body composition as a potential confounder into account. The main finding in our study was that whereas absolute muscle mass (SMI) was indeed higher in male participants using ACE inhibitors, ACE inhibitor treatment was associated with significantly lower, relative BMI-adjusted muscle mass (ALM/BMI) in both men and women. Grip strength did not differ significantly between users and non-users of ACE inhibitors, whereas arm muscle quality (grip strength corrected for arm muscle mass) was significantly lower in those taking ACE inhibitors. After adjustment for the most notable potential confounders such as age, fat mass, indication of drug use and other morbidities, no significant differences in SMI, ALM/BMI, arm muscle quality and TUG time remained.

In our study, users of ACE inhibitors had a significantly higher BMI and greater fat mass, accounting for their lower relative muscle mass and unfavourable ratio of muscle to fat. Relative muscle mass has previously been shown to be a better predictor of physical performance and mobility than absolute muscle mass [24–26] because higher fat mass and fat-to-lean mass ratio are associated with impaired physical performance and functional limitation [27, 28].

Prior studies have all used different methodology, which hampers comparisons. As mentioned in Sect. 1, the Health ABC study participants using ACE inhibitors had a larger LEMM than those using other antihypertensive drugs but not than those with no drug intake in a cross-sectional analysis [9]. In our study, we found significantly lower values in the users of ACE inhibitors even after correcting LEMM for weight.

Results from longitudinal studies on changes in muscle mass, strength or function after treatment with ACE inhibitors have hitherto been conflicting. Enalapril seems to be able to ameliorate weight loss associated with cachexia and linked to impaired survival as was shown retrospectively in a study investigating 1929 patients with chronic heart failure from the Studies of Left Ventricular Dysfunction (SOLVD) [29]. However, the extent to which this is attributable to preservation of muscle tissue in particular and applicable to sarcopenic patients without heart failure is unclear. ACE inhibitor intake was associated with weaker grip strength at baseline in the Women’s Health Initiative Clinical Trial (WHICT), but showed no significant effect on the mean annual change over time [30]. Similarly, in the Hertfordshire Cohort Study (HCS), use of ACE inhibitors was not associated with differences in grip strength at baseline nor after follow-up [31]. In the Women’s Health and Aging Study (WHAS), however, no differences between ACE inhibitor users and non-users were seen at baseline, but the mean 3-year decline in knee extension strength and walking speed was significantly lower in those using ACE inhibitors continuously compared with those taking other antihypertensive drugs and those with no drug use at all [10]. However, the participants in the WHAS were frail and disabled, which may have led to greater effect sizes than in comparably healthier and younger cohorts as in the WHICT and HCS. Finally, in randomised controlled trials in older patients with (1) a high cardiovascular risk profile or (2) functional impairment without heart failure, ACE inhibitor treatment had no impact on physical performance or muscle strength over a period of 20–24 weeks [12, 14]. In a meta-analysis of three randomised controlled trials, although with a limited number of participants, grip strength was not significantly different between users of ACE inhibitors and those taking placebo or other antihypertensives [32].

Although the duration of ACE inhibitor intake would likely influence any muscle-related outcome, we found no difference when analysing the time of exposure to ACE inhibitors. This finding must, however, be interpreted with caution because it has been shown that a gradual reactivation of the conversion of angiotensin I to angiotensin II occurs under long-term therapy with lisinopril [33]. It is therefore tempting to speculate that possible benefits of ACE inhibitor therapy in skeletal muscle decrease over time as negative effects of angiotensin II on muscle tissue, which have been demonstrated in animal models, become more prominent [34–36].

The cross-sectional study design of our study obviously limits interpretation of causality. Furthermore, because ACE inhibitor treatment was prescribed on medical indication, we were not able to compare ACE inhibitor users in our study with a control group of healthy ACE inhibitor users. Likewise, it was not possible to compare subgroups of participants taking ACE inhibitors but no other antihypertensive drugs with those who were not taking ACE inhibitors but were taking other antihypertensive agents (e.g. β-blockers) because the small sample sizes involved were not sufficient to allow useful statistical analysis. The sample size of participants with coronary heart disease and heart failure was, moreover, too small for sub-group analyses. We might postulate that ACE inhibitors would have better effects on muscle tissue in more severe cardiovascular diseases or in adults aged over 75 years, where loss of weight and strength is more pronounced.

5 Conclusions

In summary, we found no positive relationship between the intake of ACE inhibitors and skeletal muscle mass, strength, muscle quality or function. Taking body composition into account, we even found lower relative muscle mass and strength in ACE inhibitor users. This finding may in part be owing to the chronic medical conditions that underlie the need for ACE inhibitor use. Given these results, previous studies demonstrating improvement in muscle mass with ACE inhibitor use should be interpreted with caution because muscle mass was not adjusted for body composition in most studies. As a result of the above-mentioned limitations, and the relative lack of clinical trials that extend over several years in older adults, we cannot however preclude a positive effect of ACE inhibitor treatment on muscle in the very old or in severe disease states. Future studies, especially interventional trials in which muscle mass is determined as an outcome parameter, should take into account the contrasting results concerning parameters of absolute and relative muscle mass.