Association of polypharmacy and hyperpolypharmacy with frailty states: a systematic review and meta-analysis



To investigate: (1) the cross-sectional association between polypharmacy, hyperpolypharmacy and presence of prefrailty or frailty; (2) the risk of incident prefrailty or frailty in persons with polypharmacy, and vice versa.


A systematic review and meta-analysis was performed according to PRISMA guidelines. We searched PubMed, Web of Science, and Embase from 01/01/1998 to 5/2/2018. Pooled estimates were obtained through random effect models and Mantel–Haenszel weighting. Homogeneity was assessed with the I2 statistic and publication bias with Egger’s and Begg’s tests.


Thirty-seven studies were included. The pooled proportion of polypharmacy in persons with prefrailty and frailty was 47% (95% CI 33–61) and 59% (95% CI 42–76), respectively. Increased odds ratio of polypharmacy were seen for prefrail (pooled OR = 1.52; 95% CI 1.32–1.79) and frail persons (pooled OR = 2.62, 95% CI 1.81–3.79). Hyperpolypharmacy was also increased in prefrail (OR = 1.95; 95% CI 1.41–2.70) and frail (OR = 6.57; 95% CI 9.57–10.48) persons compared to robust persons. Only seven longitudinal studies reported data on the risk of either incident prefrailty or frailty in persons with baseline polypharmacy. A significant higher odds of developing prefrailty was found in robust persons with polypharmacy (pooled OR = 1.30; 95% CI 1.12–1.51). We found no papers investigating polypharmacy incidence in persons with prefrailty/frailty.


Polypharmacy is common in prefrail and frail persons, and these individuals are also more likely to be on extreme drug regimens, i.e. hyperpolypharmacy, than robust older persons. More research is needed to investigate the causal relationship between polypharmacy and frailty syndromes, thereby identifying ways to jointly reduce drug burden and prefrailty/frailty in these individuals.

Prospero registration number


This is a preview of subscription content, access via your institution.

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6


  1. 1.

    Clegg A, Young J, Iliffe S et al (2013) Frailty in elderly people. Lancet (London, England) 381(9868):752–762

    Article  Google Scholar 

  2. 2.

    Dent E, Kowal P, Hoogendijk EO (2016) Frailty measurement in research and clinical practice: a review. Eur J Intern Med 31:3–10

    Article  Google Scholar 

  3. 3.

    Fried LP, Tangen CM, Walston J et al (2001) Frailty in older adults: evidence for a phenotype. J Gerontol Ser A Biol Sci Med Sci 56(3):M146–M156

    CAS  Article  Google Scholar 

  4. 4.

    Rockwood K, Song X, MacKnight C et al (2005) A global clinical measure of fitness and frailty in elderly people. CMAJ 173(5):489–495

    Article  Google Scholar 

  5. 5.

    Collard RM, Boter H, Schoevers RA et al (2012) Prevalence of frailty in community-dwelling older persons: a systematic review. J Am Geriatr Soc 60(8):1487–1492

    Article  Google Scholar 

  6. 6.

    Santos-Eggimann B, Cuenoud P, Spagnoli J et al (2009) Prevalence of frailty in middle-aged and older community-dwelling Europeans living in 10 countries. J Gerontol Ser A Biol Sci Med Sci 64(6):675–681

    Article  Google Scholar 

  7. 7.

    Beard JR, Officer A, de Carvalho IA et al (2016) The World report on ageing and health: a policy framework for healthy ageing. Lancet (London, England) 387(10033):2145–2154

    Article  Google Scholar 

  8. 8.

    Chowdhury R, Peel NM, Krosch M et al (2017) Frailty and chronic kidney disease: a systematic review. Arch Gerontol Geriatr 68:135–142

    Article  Google Scholar 

  9. 9.

    Marengoni A, Vetrano DL, Manes-Gravina E et al (2018) The relationship between COPD and frailty: a systematic review and meta-analysis of observational studies. Chest 154(1):21–40

    Article  Google Scholar 

  10. 10.

    Palmer K, Vetrano DL, Marengoni A et al (2018) The relationship between anaemia and frailty: a systematic review and meta-analysis of observational studies. J Nutr Ageing Health 22(8):965–974

    CAS  Article  Google Scholar 

  11. 11.

    Villani ER, Tummolo AM, Palmer K et al (2018) Special issue frailty—frailty and atrial fibrillation: a systematic review. Eur J Intern Med 56:33–38

    Article  Google Scholar 

  12. 12.

    Vetrano DL, Palmer K, Marengoni A et al (2018) Frailty and multimorbidity: a systematic review and meta-analysis. J Gerontol Ser A Biol Sci Med Sci.

  13. 13.

    Masnoon N, Shakib S, Kalisch-Ellett L et al (2017) What is polypharmacy? A systematic review of definitions. BMC Geriatr 17(1):230

    Article  Google Scholar 

  14. 14.

    Jokanovic N, Tan EC, Dooley MJ et al (2015) Prevalence and factors associated with polypharmacy in long-term care facilities: a systematic review. J Am Med Dir Assoc 16(6):535.e531–512

    Article  Google Scholar 

  15. 15.

    Vetrano DL, Villani ER, Grande G et al (2018) Association of polypharmacy with 1-year trajectories of cognitive and physical function in nursing home residents: results from a multicenter European study. J Am Med Dir Assoc 19(8):710–713

    Article  Google Scholar 

  16. 16.

    de Vries M, Seppala LJ, Daams JG et al (2018) Fall-risk-increasing drugs: a systematic review and meta-analysis: I Cardiovascular drugs. J Am Med Dir Assoc 19(4):371 e371–371 e379

    Article  Google Scholar 

  17. 17.

    Seppala LJ, van de Glind EMM, Daams JG et al (2018) Fall-risk-increasing drugs: a systematic review and meta-analysis: III. Others. J Am Med Dir Assoc 19(4):372 e371–372 e378

    Google Scholar 

  18. 18.

    Seppala LJ, Wermelink A, de Vries M et al (2018) Fall-risk-increasing drugs: a systematic review and meta-analysis: II. Psychotropics. J Am Med Dir Assoc 19(4):371 e311–371 e317

    Google Scholar 

  19. 19.

    Marengoni A, Onder G (2015) Guidelines, polypharmacy, and drug-drug interactions in patients with multimorbidity. BMJ 350:h1059

    Article  Google Scholar 

  20. 20.

    Maher RL, Hanlon J, Hajjar ER (2014) Clinical consequences of polypharmacy in elderly. Expert Opin Drug Saf 13(1):57–65

    Article  Google Scholar 

  21. 21.

    Palmer K, Marengoni A, Russo P et al (2016) Frailty and Drug Use. J Frailty Aging 5(2):100–103

    CAS  PubMed  Google Scholar 

  22. 22.

    Gutierrez-Valencia M, Izquierdo M, Cesari M et al (2018) The relationship between frailty and polypharmacy in older people: a systematic review. Br J Clin Pharmacol 84(7):1432–1444

    CAS  Article  Google Scholar 

  23. 23.

    Liberati A, Altman DG, Tetzlaff J et al (2009) The PRISMA statement for reporting systematic reviews and meta-analyses of studies that evaluate healthcare interventions: explanation and elaboration. BMJ (Clinical research ed) 339:b2700

    Article  Google Scholar 

  24. 24.

    Gnjidic D, Hilmer SN, Blyth FM et al (2012) High-risk prescribing and incidence of frailty among older community-dwelling men. Clin Pharmacol Ther 91(3):521–528

    CAS  Article  Google Scholar 

  25. 25.

    Saum KU, Schottker B, Meid AD et al (2017) Is polypharmacy associated with frailty in older people? Results from the ESTHER cohort study. J Am Geriatr Soc 65(2):e27–e32

    Article  Google Scholar 

  26. 26.

    Jung HW, Jang IY, Lee YS et al (2016) Prevalence of frailty and aging-related health conditions in older Koreans in rural communities: a cross-sectional analysis of the aging study of Pyeongchang rural area. J Korean Med Sci 31(3):345–352

    CAS  Article  Google Scholar 

  27. 27.

    Gutierrez-Valencia M, Izquierdo M, Lacalle-Fabo E et al (2018) Relationship between frailty, polypharmacy, and underprescription in older adults living in nursing homes. Eur J Clin Pharmacol 74(7):961–970

    Article  Google Scholar 

  28. 28.

    Eyigor S, Kutsal YG, Duran E et al (2015) Frailty prevalence and related factors in the older adult—FrailTURK Project. Age 37(3):1–13

    Article  Google Scholar 

  29. 29.

    Moulis F, Moulis G, Balardy L et al (2015) Exposure to atropinic drugs and frailty status. J Am Med Dir Assoc 16(3):253–257

    Article  Google Scholar 

  30. 30.

    Diaz-Toro F, Nazal CN, Verdejo H et al (2017) Frailty in patients admitted to hospital with acute decompensated heart failure. Rev Medica Chile 145(2):164–171

    Article  Google Scholar 

  31. 31.

    Chang CI, Chan DC, Kuo KN et al (2011) Prevalence and correlates of geriatric frailty in a Northern Taiwan Community. J Formos Med Assoc 110(4):247–257

    Article  Google Scholar 

  32. 32.

    Serra-Prat M, Sist X, Saiz A et al (2016) Clinical and functional characterization of pre-frailty among elderly patients consulting primary care centres. J Nutr Health Aging 20(6):653–658

    CAS  Article  Google Scholar 

  33. 33.

    Serra-Prat M, Papiol M, Vico J et al (2016) Factors associated with frailty in community-dwelling elderly population. A cross-sectional study. Eur Geriatr Med 7(6):531–537

    Article  Google Scholar 

  34. 34.

    Herr M, Robine JM, Pinot J et al (2015) Polypharmacy and frailty: prevalence, relationship, and impact on mortality in a French sample of 2350 old people. Pharmacoepidemiol Drug Saf 24(6):637–646

    Article  Google Scholar 

  35. 35.

    Thai M, Hilmer S, Pearson SA et al (2015) Prevalence of potential and clinically relevant statin-drug interactions in frail and robust older inpatients. Drugs Aging 32(10):849–856

    CAS  Article  Google Scholar 

  36. 36.

    Jamsen KM, Bell JS, Hilmer SN et al (2016) Effects of changes in number of medications and drug burden index exposure on transitions between frailty states and death: the concord health and ageing in men project cohort study. J Am Geriatr Soc 64(1):89–95

    Article  Google Scholar 

  37. 37.

    Trevisan C, Veronese N, Maggi S et al (2017) Factors influencing transitions between frailty states in elderly adults: the Progetto Veneto Anziani longitudinal study. J Am Geriatr Soc 65(1):179–184

    Article  Google Scholar 

  38. 38.

    Wang R, Chen L, Fan L et al (2015) Incidence and effects of polypharmacy on clinical outcome among patients aged 80+ : a five-year follow-up study. PLoS One 10(11):e0142123

    Article  Google Scholar 

  39. 39.

    Gnjidic D, Hilmer SN, Blyth FM et al (2012) Polypharmacy cutoff and outcomes: five or more medicines were used to identify community-dwelling older men at risk of different adverse outcomes. J Clin Epidemiol 65(9):989–995

    Article  Google Scholar 

  40. 40.

    Blodgett JM, Theou O, Howlett SE et al (2016) A frailty index based on laboratory deficits in community-dwelling men predicted their risk of adverse health outcomes. Age Ageing 45(4):463–468

    Article  Google Scholar 

  41. 41.

    Veronese N, Stubbs B, Noale M et al (2017) Polypharmacy is associated with higher frailty risk in older people: an 8-year longitudinal cohort study. J Am Med Dir Assoc 18(7):624–628

    Article  Google Scholar 

  42. 42.

    Zheng Z, Guan SC, Ding H et al (2016) Prevalence and incidence of frailty in community-dwelling older people: Beijing longitudinal study of aging II. J Am Geriatr Soc 64(6):1281–1286

    Article  Google Scholar 

  43. 43.

    Woo J, Leung J (2014) Multi-morbidity, dependency, and frailty singly or in combination have different impact on health outcomes. Age (Dordrecht, Netherlands) 36(2):923–931

    Article  Google Scholar 

  44. 44.

    Nguyen TN, Cumming RG, Hilmer SN (2016) Atrial fibrillation in older inpatients: are there any differences in clinical characteristics and pharmacological treatment between the frail and the non-frail? Intern Med J 46(1):86–95

    CAS  Article  Google Scholar 

  45. 45.

    Mannucci PM, Nobili A (2014) Multimorbidity and polypharmacy in the elderly: lessons from REPOSI. Intern Emerg Med 9(7):723–734

    Article  Google Scholar 

  46. 46.

    Hanlon JT, Pieper CF, Hajjar ER et al (2006) Incidence and predictors of all and preventable adverse drug reactions in frail elderly persons after hospital stay. J Gerontol A Biol Sci Med Sci 61(5):511–515

    Article  Google Scholar 

  47. 47.

    Kuijpers MA, van Marum RJ, Egberts AC et al (2008) Relationship between polypharmacy and underprescribing. Br J Clin Pharmacol 65(1):130–133

    Article  Google Scholar 

  48. 48.

    Dalleur O, Boland B, De Groot A et al (2015) Detection of potentially inappropriate prescribing in the very old: cross-sectional analysis of the data from the BELFRAIL observational cohort study. BMC Geriatr 15:156

    Article  Google Scholar 

  49. 49.

    Chang CB, Chen JH, Wen CJ et al (2011) Potentially inappropriate medications in geriatric outpatients with polypharmacy: application of six sets of published explicit criteria. Br J Clin Pharmacol 72(3):482–489

    Article  Google Scholar 

  50. 50.

    Cadogan CA, Ryan C, Hughes CM (2016) Appropriate polypharmacy and medicine safety: when many is not too many. Drug Saf 39(2):109–116

    Article  Google Scholar 

  51. 51.

    Pasina L, Brucato AL, Falcone C et al (2014) Medication non-adherence among elderly patients newly discharged and receiving polypharmacy. Drugs Aging 31(4):283–289

    CAS  Article  Google Scholar 

  52. 52.

    Onder G, Vetrano D, Marengoni A et al (2018) Accounting for frailty when treating chronic diseases. Eur J Intern Med 56:49–52

    Article  Google Scholar 

  53. 53.

    Rosted E, Schultz M, Sanders S (2016) Frailty and polypharmacy in elderly patients are associated with a high readmission risk. Dan Med J 63(9):A5274

    PubMed  Google Scholar 

  54. 54.

    Bouillon K, Batty GD, Hamer M et al (2013) Cardiovascular disease risk scores in identifying future frailty: the Whitehall II prospective cohort study. Heart 99(10):737–742

    CAS  Article  Google Scholar 

  55. 55.

    Gill TM, Baker DI, Gottschalk M et al (2002) A program to prevent functional decline in physically frail, elderly persons who live at home. N Engl J Med 347(14):1068–1074

    Article  Google Scholar 

  56. 56.

    O’Mahony D, O’Sullivan D, Byrne S et al (2015) STOPP/START criteria for potentially inappropriate prescribing in older people: version 2. Age Ageing 44(2):213–218

    Article  Google Scholar 

  57. 57.

    Pazan F, Weiss C, Wehling M et al (2016) The FORTA (Fit fOR The Aged) list 2015: update of a validated clinical tool for improved pharmacotherapy in the elderly. Drugs Aging 33(6):447–449

    Article  Google Scholar 

  58. 58.

    Ballew SH, Chen Y, Daya NR et al (2017) Frailty, kidney function, and polypharmacy: the atherosclerosis risk in communities (ARIC) study. Am J Kidney Dis 69(2):228–236

    Article  Google Scholar 

  59. 59.

    Bonaga B, Sánchez-Jurado PM, Martínez-Reig M et al (2018) Frailty, polypharmacy, and health outcomes in older adults: the frailty and dependence in Albacete study. J Am Med Dir Assoc 19(1):46–52

    Article  Google Scholar 

  60. 60.

    Buttery AK, Busch MA, Gaertner B et al (2015) Prevalence and correlates of frailty among older adults: findings from the German health interview and examination survey. BMC Geriatr 15:22

    Article  Google Scholar 

  61. 61.

    Cakmur H (2015) Frailty among elderly adults in a rural area of Turkey. Med Sci Monit 21:1232–1242

    Article  Google Scholar 

  62. 62.

    Castell MV, Sanchez M, Julian R et al (2013) Frailty prevalence and slow walking speed in persons age 65 and older: implications for primary care. BMC Fam Pract 14:86

    Article  Google Scholar 

  63. 63.

    Cheung SC, Ahmad LA, Hardy JE et al (2017) A prospective cohort study of older surgical inpatients examining the prevalence and implications of frailty. J Clin Gerontol Geriatr 8(2):71–76

    Google Scholar 

  64. 64.

    Closs VE, Ziegelmann PK, Gomes I et al (2016) Frailty and geriatric syndromes in elderly assisted in primary health care. Acta Sci Health Sci 38(1):9–18

    Article  Google Scholar 

  65. 65.

    Hasan SS, Kow CS, Verma RK et al (2017) An evaluation of medication appropriateness and frailty among residents of aged care homes in Malaysia. Medicine (United States) 96(35):e7929

    Google Scholar 

  66. 66.

    Herr M, Sirven N, Grondin H et al (2017) Frailty, polypharmacy, and potentially inappropriate medications in old people: findings in a representative sample of the French population. Eur J Clin Pharmacol 73(9):1165–1172

    Article  Google Scholar 

  67. 67.

    Jankowska-Polańska B, Dudek K, Szymanska-Chabowska A et al (2016) The influence of frailty syndrome on medication adherence among elderly patients with hypertension. Clin Interv Aging 11:1781–1790

    Article  Google Scholar 

  68. 68.

    Maclagan LC, Maxwell CJ, Gandhi S et al (2017) Frailty and potentially inappropriate medication use at nursing home transition. J Am Geriatr Soc 65(10):2205–2212

    Article  Google Scholar 

  69. 69.

    Merchant RA, Chen MZ, Tan LWL et al (2017) Singapore healthy older people everyday (HOPE) study: prevalence of frailty and associated factors in older adults. J Am Med Dir Assoc 18(8):6

    Article  Google Scholar 

  70. 70.

    Pegorari MS, Tavares DMD (2014) Factors associated with the frailty syndrome in elderly individuals living in the urban area. Rev Latino Am Enfermagem 22(5):874–882

    Article  Google Scholar 

  71. 71.

    Poudel A, Peel NM, Nissen LM et al (2016) Adverse outcomes in relation to polypharmacy in robust and frail older hospital patients. J Am Med Dir Assoc 17(8):767.e769–767.e713

    Article  Google Scholar 

  72. 72.

    Sutorius FL, Hoogendijk EO, Prins BA et al (2016) Comparison of 10 single and stepped methods to identify frail older persons in primary care: diagnostic and prognostic accuracy. BMC Fam Pract 17:102

    Article  Google Scholar 

  73. 73.

    Tan LF, Lim ZY, Choe R et al (2017) Screening for frailty and sarcopenia among older persons in medical outpatient clinics and its associations with healthcare burden. J Am Med Dir Assoc 18(7):583–587

    Article  Google Scholar 

  74. 74.

    Turner J, Shakib S, Singhal N et al (2014) Prevalence and factors associated with polypharmacy in older people with cancer. Support Care Cancer 22(7):1727–1734

    Article  Google Scholar 

  75. 75.

    Woo J, Yu R, Wong M et al (2015) Frailty screening in the community using the FRAIL scale. J Am Med Dir Assoc 16(5):412–419

    Article  Google Scholar 

  76. 76.

    Woo J, Zheng Z, Leung J et al (2015) Prevalence of frailty and contributory factors in three Chinese populations with different socioeconomic and healthcare characteristics. BMC Geriatr 15:163

    Article  Google Scholar 

Download references


Composition of European Geriatric Medicine Society special interest group on Pharmacology: Marit Bakken, Jean-Pierre Baeyens, Athanase Benetos, Antonio Cherubini, Peter Crome, Alfonso J. Cruz-Jentoft, Michael Denkinger, Tomas Frühwald, Paul Gallagher, Adalsteinn Guðmundsson, Stephen Jackson, Paul Jansen, Wilma Knol, Denis O’Mahony, Graziano Onder, Desmond O’Neill, Mirko Petrovic, Alberto Pilotto, Elina Ronnemaa, Jens-Ulrik Rosholm, José Antonio Serra, George Soulis, Tischa JM van der Cammen, Nathalie van der Velde, Rob van Marum, Martin Wehling, Gijsbertus Ziere.

Author information




Corresponding author

Correspondence to Katie Palmer.

Ethics declarations

Conflict of interest

The authors have no conflict of interest to declare.

Ethical approval

This article does not contain any studies with human participants or animals performed by any of the authors.

Informed consent

For this kind of study formal consent is not required.

Additional information

The European Geriatric Medicine Society Pharmacology special interest group members are listed in the Acknowledgement section.

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Palmer, K., Villani, E.R., Vetrano, D.L. et al. Association of polypharmacy and hyperpolypharmacy with frailty states: a systematic review and meta-analysis. Eur Geriatr Med 10, 9–36 (2019).

Download citation


  • Frail
  • Prefrail
  • Polypharmacy
  • Drugs
  • Ageing
  • Medications
  • Hyperpolypharmacy