In this prospective study of more than 25,000 women aged 65 years and older, current use of ACE inhibitors was not significantly related to the development of frailty at three years of follow-up. Risk of frailty was not related to duration or equivalent dose of ACE inhibitor exposure. Results were similar when we restricted the sample to those with hypertension or when frailty outcomes in the absence of intervening cardiovascular events were examined. However, when restricting the sample to those with hypertension taking one or less antihypertensive medication, we did find a reduced risk for frailty in those using low and medium equivalent doses.
To our knowledge, this is the first large prospective study to examine ACE inhibitor use in relation to incident frailty. Other studies that have reported beneficial effects of ACE inhibitor use in older adults beyond the known benefits in heart failure have examined related outcomes such as walking speed, muscle mass or weight loss. In an observational study of 641 disabled older women without heart failure, continuous users of ACE inhibitors over the three-year observation period had a slower decline of muscle strength and walking speed compared to users of other antihypertensive medications.9
In a cross sectional analysis of data from the Health, Aging and Body Composition study, use of ACE inhibitors was associated with larger lower extremity muscle mass compared with use of other antihypertensive agents.10
Data from the Cardiovascular Health Study suggest that in older individuals with hypertension, use of an ACE inhibitor was associated with less annual weight loss.21
However, these investigators did not find an association with ACE inhibitor use and upper extremity muscle strength as measured by grip strength. A recent randomized controlled trial in older adults with mobility or functional impairments without heart failure found that individuals receiving perindopril for 6 months were able to walk on average 30 meters longer in 6 minutes compared with placebo. Improvements were not found in secondary outcome measures that are more akin to the components of the frailty measure, such as timed up-and-go or repeated chair stands, although the study was not powered for these secondary outcomes.11
The authors commented that improvements in walking may have been in part due to improved cardiovascular function, rather than muscle strength. Furthermore, a cross-sectional analysis found no association between ACE-inhibitor use and walking speed or grip strength.22
Taken together, these studies suggest that ACE inhibitor use is not consistently associated with any particular component of the frailty construct, or the composite phenotype.
Confounding by indication is a source of bias that could obscure or mask completely any protective association between ACE inhibitor use and development of frailty. In the present study, we employed several strategies to address confounding by indication including multivariate adjustment, multinomial logistic regression, interaction testing, and restriction to address the problem that ACE inhibitors are disproportionately prescribed to older women with a greater risk of CVD events. In fact, when restricting the sample to those with hypertension using monotherapy or no medication for hypertension, the most homogenous group in terms of CVD risk, a reduced risk was found for those using for two years or more and for those using low or medium equivalent doses, with only the latter reaching statistical significance. These results should be interpreted with caution and require replication in other cohorts or randomized trials, since the analysis by dose was exploratory and the use of tablet strength as a proxy for dose.
ACE inhibitors may preserve skeletal muscle function through direct and indirect effects on skeletal muscle, involving inflammatory and metabolic pathways.7
ACE inhibitors may decrease inflammation by inhibiting interleukin-6 and TNF-α production,12, 13
factors that have been associated with lower muscle mass and strength.23
Treatment with ACE inhibitors improve metabolic efficiency by increased insulin sensitivity and glucose uptake by skeletal muscle 24, 25
and may delay or prevent muscle loss by modulation of the insulin-like growth factor (IGF) system.26,27
However, data are conflicting regarding whether the IGF system contributes to declining muscle strength and functional disability in older adults.28-30
Strengths of this study include its prospective design, objective assessment of ACE inhibitor use, inclusion of over 2000 current ACE inhibitor users, consideration of a large number of covariates related to the development of frailty, and the ability to separate out adjudicated, intervening CVD events. However a few limitations should be noted. Information was only available on the prescription strength and not actual dose of ACE inhibitor medication and medication adherence was unknown. The timing of initiation and discontinuation of ACE inhibitor use in relation to the onset of frailty during follow-up was not measured. Lack of physical performance measurements is another weakness. Finally, despite the measures we took to control for confounding such as stratification and adjustment, all observational studies of pharmacologic exposures are subject to issues related to confounding by indication.