Abstract
Introduction
Angiotensin-converting enzyme inhibitors (ACEI) may have several pleiotropic effects, but the literature regarding a possible relationship between ACEI use and frailty is limited. We investigated whether ACEI use is associated with lower risk of frailty in a cohort of North American individuals.
Methods
Data from the Osteoarthritis Initiative, a cohort study with 8 years of follow-up including community-dwelling adults with knee osteoarthritis or at high risk for this condition, were analyzed. ACEI use was defined through self-reported information and confirmed by a trained interviewer. Frailty was defined using the Study of Osteoporotic Fracture (SOF) index as the presence of at least two of the following criteria: (1) weight loss ≥ 5% between baseline and any subsequent follow-up visit; (2) inability to do five chair stands; and (3) low energy level according to the SOF definition. A multivariable Poisson regression analysis was used to assess the association between ACEI use at baseline and incident frailty. The data were reported as relative risks (RRs) with their 95% confidence intervals (CIs).
Results
The final sample consisted of 4295 adults (mean age 61.2 years, females 58.1%). At baseline, 551 participants (12.8%) used ACEI. After adjusting for 15 potential confounders, the use of ACEI was associated with a lower risk of frailty (RR 0.72; 95% CI 0.53–0.99). The adjustment for the propensity score substantially confirmed these findings (RR 0.75; 95% CI 0.54–0.996).
Conclusion
ACEI use may be associated with a reduced risk of frailty in individuals with/at risk of knee osteoarthritis, suggesting a potential role for ACI in the prevention of frailty.
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REFERENCES
Brown NJ, Vaughan DE. Angiotensin-converting enzyme inhibitors. Circulation. 1998;97(14):1411–20.
Køber L, Torp-Pedersen C, Carlsen JE, Bagger H, Eliasen P, Lyngborg K, et al. A clinical trial of the angiotensin-converting–enzyme inhibitor trandolapril in patients with left ventricular dysfunction after myocardial infarction. N Engl J Med. 1995;333(25):1670–6.
Parving H-H, Lehnert H, Bröchner-Mortensen J, Gomis R, Andersen S, Arner P. The effect of irbesartan on the development of diabetic nephropathy in patients with type 2 diabetes. N Engl J Med. 2001;345(12):870–8.
Cranney A. Is there a new role for angiotensin-converting-enzyme inhibitors in elderly patients? CMAJ Can Med Assoc J. 2007;177(8):891–2.
Ashdown-Franks G, Stubbs B, Koyanagi A, Schuch F, Firth J, Veronese N, et al. Handgrip strength and depression among 34,129 adults aged 50 years and older in six low- and middle-income countries. J Affect Disord. 2019;15(243):448–54.
Sumukadas D, Witham MD, Struthers AD, McMurdo ME. Effect of perindopril on physical function in elderly people with functional impairment: a randomized controlled trial. Can Med Assoc J. 2007;177(8):867–74.
Hutcheon S, Gillespie N, Crombie I, Struthers A, McMurdo M. Perindopril improves six minute walking distance in older patients with left ventricular systolic dysfunction: a randomised double blind placebo controlled trial. Heart (British Cardiac Society). 2002;88(4):373–7.
Clegg A, Young J, Iliffe S, Rikkert MO, Rockwood K. Frailty in elderly people. Lancet (London, England). 2013;381(9868):752–62.
Collard RM, Boter H, Schoevers RA, Oude Voshaar RC. Prevalence of frailty in community-dwelling older persons: a systematic review. J Am Geriatr Soc. 2012;60(8):1487–92.
Kojima G. Prevalence of frailty in nursing homes: a systematic review and meta-analysis. J Am Med Dir Assoc. 2015;16(11):940–5.
Veronese N, Cereda E, Stubbs B, Solmi M, Luchini C, Manzato E, et al. Risk of cardiovascular disease morbidity and mortality in frail and pre-frail older adults: results from a meta-analysis and exploratory meta-regression analysis. Ageing Res Rev. 2017;28(35):63–73.
Rizzoli R, Reginster JY, Arnal JF, Bautmans I, Beaudart C, Bischoff-Ferrari H, et al. Quality of life in sarcopenia and frailty. Calcif Tissue Int. 2013;93(2):101–20.
Robine J-M, Michel J-P. Looking forward to a general theory on population aging. J Gerontol Ser A Biol Sci Med Sci. 2004;59(6):M590–7.
Gray SL, LaCroix AZ, Aragaki AK, McDermott M, Cochrane BB, Kooperberg CL, et al. Angiotensin-converting enzyme inhibitor use and incident frailty in women aged 65 and older: prospective findings from the Women’s Health Initiative Observational Study. J Am Geriatr Soc. 2009;57(2):297–303.
Onder G, Penninx BW, Balkrishnan R, Fried LP, Chaves PH, Williamson J, et al. Relation between use of angiotensin-converting enzyme inhibitors and muscle strength and physical function in older women: an observational study. Lancet (London, England). 2002;359(9310):926–30.
Eby GA, Eby KL. Rapid recovery from major depression using magnesium treatment. Med Hypotheses. 2006;67(2):362–70.
Veronese N, Stubbs B, Noale M, Solmi M, Pilotto A, Vaona A, et al. Polypharmacy is associated with higher frailty risk in older people: an 8-year longitudinal cohort study. J Am Med Dir Assoc. 2017;18:624–8.
Bolzetta F, Wetle T, Besdine R, Noale M, Cester A, Crepaldi G, et al. The relationship between different settings of medical service and incident frailty. Exp Gerontol. 2018;15(108):209–14.
Veronese N, Stubbs B, Maggi S, Notarnicola M, Barbagallo M, Firth J, et al. Dietary magnesium and incident frailty in older people at risk for knee osteoarthritis: an eight-year longitudinal study. Nutrients. 2017;9(11):E1253.
Misra D, Felson DT, Silliman RA, Nevitt M, Lewis CE, Torner J, et al. Knee osteoarthritis and frailty: findings from the Multicenter Osteoarthritis Study and Osteoarthritis Initiative. J Gerontol Ser A Biol Sci Med Sci. 2015;70(3):339–44.
Veronese N, Cereda E, Solmi M, Fowler SA, Manzato E, Maggi S, et al. Inverse relationship between body mass index and mortality in older nursing home residents: a meta-analysis of 19,538 elderly subjects. Obes Rev. 2015;16(11):1001–15.
Ware J, Kosinski M, Keller SD. A 12-Item Short-Form Health Survey: construction of scales and preliminary tests of reliability and validity. Med Care. 1996;34(3):220–33.
Allen KD, Golightly YM. Epidemiology of osteoarthritis: state of the evidence. Curr Opin Rheumatol. 2015;27(3):276–83.
Lewinsohn PM, Seeley JR, Roberts RE, Allen NB. Center for Epidemiologic Studies Depression Scale (CES-D) as a screening instrument for depression among community-residing older adults. Psychol Aging. 1997;12(2):277–87.
Washburn RA, McAuley E, Katula J, Mihalko SL, Boileau RA. The physical activity scale for the elderly (PASE): evidence for validity. J Clin Epidemiol. 1999;52(7):643–51.
Katz JN, Chang LC, Sangha O, Fossel AH, Bates DW. Can comorbidity be measured by questionnaire rather than medical record review? Med Care. 1996;34(1):73–84.
Veronese N, Koyanagi A, Stubbs B, Cooper C, Guglielmi G, Rizzoli R, et al. Statin use and knee osteoarthritis outcomes: a longitudinal cohort study. Arthritis Care Res. 2018;1:1. https://doi.org/10.1002/acr.23735.
Miles J. Tolerance and variance inflation factor. Wiley StatsRef: Statistics Reference Online; 2009.
Haukoos JS, Lewis RJ. The Propensity Score. JAMA. 2015;314(15):1637–8.
Gutiérrez-Valencia M, Izquierdo M, Cesari M, Casas-Herrero Á, Inzitari M, Martínez-Velilla N. The relationship between frailty and polypharmacy in older people: a systematic review. Br J Clin Pharmacol. 2018;84(7):1432–44.
Veronese N, Stubbs B, Noale M, Solmi M, Pilotto A, Vaona A, et al. Polypharmacy is associated with higher frailty risk in older people: an 8-year longitudinal cohort study. J Am Med Dir Assoc. 2017;18(7):624–8.
Kitakaze M, Node K, Minamino T, Asanuma H, Ueda Y, Kosaka H, et al. Inhibition of angiotensin-converting enzyme increases the nitric oxide levels in canine ischemic myocardium. J Mol Cell Cardiol. 1998;30(11):2461–6.
Stamler JS, Meissner G. Physiology of nitric oxide in skeletal muscle. Physiol Rev. 2001;81(1):209–37.
Koh TJ, Tidball JG. Nitric oxide synthase inhibitors reduce sarcomere addition in rat skeletal muscle. J Physiol. 1999;519(1):189–96.
Kortekaas KE, Meijer CA, Hinnen JW, Dalman RL, Xu B, Hamming JF, et al. ACE inhibitors potently reduce vascular inflammation, results of an open proof-of-concept study in the abdominal aortic aneurysm. PLoS One. 2014;9(12):e111952.
Soysal P, Stubbs B, Lucato P, Luchini C, Solmi M, Peluso R, et al. Inflammation and frailty in the elderly: a systematic review and meta-analysis. Ageing Res Rev. 2016;31:1–8.
Bano G, Trevisan C, Carraro S, Solmi M, Luchini C, Stubbs B, et al. Inflammation and sarcopenia: a systematic review and meta-analysis. Maturitas. 2017;96:10–5.
Barberi L, Scicchitano BM, Musarò A. Molecular and cellular mechanisms of muscle aging and sarcopenia and effects of electrical stimulation in seniors. Eur J Transl Myol. 2015;25(4):231–6.
Ferder L, Inserra F, Romano L, Ercole L, Pszenny V. Effects of angiotensin-converting enzyme inhibition on mitochondrial number in the aging mouse. Am J Physiol. 1993;265(1 Pt 1):C15–8.
Hicks BM, Filion KB, Yin H, Sakr L, Udell JA, Azoulay L. Angiotensin converting enzyme inhibitors and risk of lung cancer: population based cohort study. BMJ. 2018;363:k4209.
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This study was funded by five contracts (N01-AR-2-2258; N01-AR-2-2259; N01-AR-2-2260; N01-AR-2-2261; N01-AR-2-2262) from the National Institutes of Health, a branch of the Department of Health and Human Services, and conducted by the OAI Study Investigators. Private funding partners include Merck Research Laboratories; Novartis Pharmaceuticals Corporation, GlaxoSmithKline; and Pfizer, Inc. Private-sector funding for the OAI is managed by the Foundation for the National Institutes of Health. This manuscript was prepared using an OAI public use data set and does not necessarily reflect the opinions or views of the OAI investigators, the NIH, or the private funding partners.
Conflict of interest
Veronese, Stubbs, Smith, Maggi, Jackson, Soysal, Demurtas, Celotto and Koyanagi declare that they have no potential conflicts of interest that might be relevant to the contents of this manuscript.
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Veronese, N., Stubbs, B., Smith, L. et al. Angiotensin-Converting Enzyme Inhibitor Use and Incident Frailty: A Longitudinal Cohort Study. Drugs Aging 36, 387–393 (2019). https://doi.org/10.1007/s40266-019-00642-3
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DOI: https://doi.org/10.1007/s40266-019-00642-3