Our results show no statistically significant improvements in a well-established measure of physical performance (i.e., the Short Physical Performance Battery) and a commonly adopted marker of muscle strength (i.e., hand grip strength) after a 6-month fosinopril intervention. These negative findings were not substantially modified when analyses were restricted to the most compliant participants and/or those receiving the maximum ACE inhibitor dosage.
During the last decade, ACE inhibitors have growingly been indicated as potentially able to prevent and/or delay the disabling process. This hypothesis is mainly funded on a large body of evidence (mostly from observational studies) suggesting ACE inhibition as able to reduce the inflammatory status and improve body composition. To our knowledge, very few clinical trials have specifically explored the effects of an ACE inhibitor intervention on measures of physical function.
Recently, Sumukadas and colleagues12
reported positive findings from a double-blind randomized clinical trial evaluating the effect of a perindopril intervention on physical function in 130 older persons (aged 65 years and older) with self-reported mobility or functional impairment. In particular, Authors tested whether a 20-week perindopril intervention was able to improve results at the 6-minute walking test (primary outcome of the study). Participants in the perindopril intervention group reported a significant mean improvement (about 31.4 meters) in the 6-minute walking test compared to participants in the placebo group at the end of the study. Similar findings had previously been reported from analyses conducted by Cleland and colleagues20
and by Hutcheon and colleagues21
in older persons with heart failure.
Differently from these previous studies, our analyses failed to report significant improvements in physical performance and muscle strength following the ACE inhibitor intervention. Although a class effect is usually considered for ACE inhibitors32-34
, it is noteworthy that studies reporting positive findings used perindopril12, 20, 21
, while different ACE inhibitors did not significantly affect physical function in our study (adopting fosinopril as study drug) and in the Zi and colleagues’ study22
Other possible explanations can also be provided to explain the different results obtained by these trials. For example, it is noteworthy that, among the secondary analyses performed by Sumukadas and colleagues12
, negative results (consistently with ours) were reported for the sit-to-stand test (similar to the chair stand test included in the Short Physical Performance Battery and used in this study). It is possible that the reported positive results were specifically due to some specific characteristics of the 6-minute walking test. Shorter length walking tests and muscle strength measures (as those considered in our study, or the sit-to-stand test) may differently stress those organism subsystems required for functioning.
The different characteristics of the study samples should also be noted. In our study, we recruited participants with a high risk cardiovascular profile due to the need to maximize those biological pathways (e.g., inflammation, endothelial dysfunction, hemostatis modifications,…) associated with the atherosclerotic disease and potentially influenced by the ACE inhibition (as the TRAIN primary objective required). Sumukadas and colleagues12
performed their study in an older sample population (mean age 78.7 years old) characterized by mobility and/or functional limitation. Other studies were specifically designed in patients with heart failure20-22
. It might be that the better physical function showed by our participants might have determined a “ceiling effect” in the reported results.
Despite our negative findings, we cannot ignore the growing body of evidence proposing an important role of ACE inhibitors in the maintenance of physical function at older age. The nature of these positive effects has not yet been biologically clarified. However, the cardiovascular protection properties of ACE inhibitors are well-established in literature5, 10, 39, 40
. The role played by a healthy cardiovascular status on successful aging should not be underestimated41, 42
. In fact, the beneficial effects of ACE inhibitors on physical performance might be simply due to the activation of a virtuous cycle determined by an improved cardiovascular system.
Several limitations of our study should be acknowledged. First of all, it is possible that our analyses had not the adequate statistical power to exclude the risk of type II errors. We have estimated that our sample size was sufficient to detect true differences (with statistical power=0.80, and α=0.05) of ±0.039 points, ±0.035 m/sec, and ±0.716 kg at the Short Physical Performance Battery total score (ranging from 0 to 3), the 4-meter walking speed, and the hand grip strength, respectively. Moreover, to date, this is one of the largest randomized clinical trial with longer follow-up on this topic. As previously mentioned, the characteristics of our sample population as well as the adopted ACE inhibitor (i.e., fosinopril) may limit the generalizability of our findings. It is also possible that the detection of significant modifications in physical function measures following ACE inhibition may need a longer exposure to be captured. Before clinical changes might be evident, relevant and prolonged improvements of the pathophysiological pathways responsible for the disabling cascade may be required. However, in this context, it is important to take into account the negative effects of ACE inhibition on biomarkers of inflammation we previously reported24
. Finally, the cross-over design of the TRAIN study might have influenced our findings if the intervention during the first period cured the studied condition (so that the participant could not return to the initial state during the wash-out phase). In other words, our analyses imply that the study drug had no carry-over effect on the outcomes after the participant was taken off ACE inhibition.