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REVIEW URRENT C OPINION
Updates in nutrition and polypharmacy Milta O. Little
Purpose of review Medications have the potential to affect nutritional status in negative ways, especially as the number of medications increase. The inter-relation between polypharmacy and malnutrition is complex and not fully delineated in previous studies. More research has been done and compiled in the last year, which helps to clarify this relationship. This review brings together the most recent literature with the previous research to help healthcare providers to better assess and manage medication therapy in older adults. Recent findings Recent evidence confirms a synergistic negative effect of polypharmacy and malnutrition on outcomes of older adults. In addition, several drug classes, including common antihypertensive agents, acetylcholinesterase inhibitors, multivitamins, proton pump inhibitors, HMG-CoA reductase inhibitors (statins), antiplatelet agents and metformin, have been implicated in important drug–nutrient interactions. These are reviewed in detail here. Ongoing research endeavors are described. Summary Healthcare practitioners can use this review to identify potentially inappropriate medications and patients at highest risk of experiencing a medication-related adverse reaction in order to systematically deprescribe these high-risk medications. Keywords anorexia, malnutrition, polypharmacy, weight loss
INTRODUCTION Medicine is a collection of uncertain prescriptions, the results of which, taken collectively, are more fatal than useful to mankind. – Napoleon Bonaparte He who takes medicine and neglects diet wastes the skill of his doctors. – Chinese proverb Polypharmacy and malnutrition, which occur more commonly as people age, have been associated with adverse outcomes when considered as individual syndromes. There is some evidence on the interrelations between nutritional status and polypharmacy but previous reviews indicate a need for further research into this area [1,2]. This review focuses on the most recent publications that give further insight into drug–nutrient interactions and an exploration into further research that is needed.
DEFINITIONS AND IMPACT Polypharmacy has more than 24 distinct definitions in the literature but most consider polypharmacy to
be ‘extraordinary prescribing,’ where a person is taking more medications than necessary or medications are prescribed for an inappropriate indication [3]. The exact cutoff of the number of drugs required to be considered polypharmacy varies, usually ranging from more than 4 to more than 10. Inappropriate prescribing is associated with increased risks of medication nonadherence and adverse drug reactions [4], which lead to avoidable hospitalizations and excess financial cost. The more medications a person takes, the more likely he is to experience an adverse drug reaction. Older adults are two to three times more likely to experience an adverse drug reaction than younger adults, including a significant increase in frailty and falls [5–7]. Most importantly, polypharmacy has been associated with increased mortality, even after adjusting for comorbidities, especially in those with extreme Saint Louis University Medical Center, Saint Louis, Missouri, USA Correspondence to Milta O. Little, Saint Louis University Medical Center, 1402 S. Grand Blvd M238, Saint Louis, MO 63104, USA. Tel: +1 314 977 8462; fax: +1 314 771 8575; e-mail: [email protected] Curr Opin Clin Nutr Metab Care 2017, 20:000–000 DOI:10.1097/MCO.0000000000000425
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KEY POINTS Adverse effects of medications and malnutrition can synergistically contribute to the frailty cascade and other geriatric syndromes. Polypharmacy and inappropriate prescribing may contribute to the risk of malnutrition as people age. The impact of medications on sense of taste is common and can lead to weight loss and malnutrition. Assessment of the presence of dysgeusia and an evaluation of polypharmacy is a critical part of the work up of weight loss and malnutrition. Medication classes with potentially significant drug– nutrient interactions include antihypertensives (thiazide diuretics, angiotensin receptor blockers, angiotensinconverting enzyme inhibitors and potassium-sparing diuretics), AchEIs, PPIs, HMG-Co reductase inhibitors (statins), long-term, high-dose aspirin and metformin.
polypharmacy (defined as taking more than 10 medications) [8]. Like polypharmacy, malnutrition has been associated with an increased financial cost burden and risk of morbidity, hospitalizations and mortality [9] and older adults are at increased risk of experiencing nutritional deficiencies, even in the event of adequate food intake [10]. The prevalence of malnutrition has been reported to be 5–10% among independently living older individuals, 30–60% among institutionalized patients and 35–65% among hospitalized geriatric patients. A recent study found associations between poor lifestyle (including poor nutrition, defined as low fruit and vegetable intake) and polypharmacy (five or more medications) with potentially inappropriate medication (PIM) prescribing. Of note, combined risk factors have additive effect so that people with both nutritional deficiencies and polypharmacy are at much higher risk of experiencing a PIM and the potential adverse consequences than those with either risk factor alone [11]. Adverse effects of medications and/or malnutrition can contribute to the frailty cascade and other geriatric syndromes. Recent evidence shows polypharmacy to be an independent risk factor for urinary incontinence [12], recurrent falls [13], statin-induced diabetes (particularly in older adults) [14], low fitness levels [15] and xerostomia [16 ,17 ]. Most of these studies also assessed for malnutrition as a risk factor using the Mini Nutritional Assessment (MNA) and did not find significant associations. The combined effect of malnutrition and polypharmacy was not assessed in any of the aforementioned studies. &&
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Both polypharmacy and malnutrition were found to be risk factors for skin tears [18], fecal incontinence (however, when adjusted for sex, only polypharmacy remained significant for women and malnutrition for men) [19], poor self-perceived health [20] and increased hospital length of stay. The latter association was found when using a validated instrument called the Multidimentional Prognostic Index that includes assessments of nutrition and polypharmacy status [21,22]. One study looking specifically at risk factors for impairments in gait performance found that weight loss and certain drug classes (laxatives, psychotropic drugs, agents acting on sensory organs and drugs for peptic ulcer and reflux disease) were associated with lower walking speed and increased stride variability. Over 50% of this population exhibited polypharmacy [23]. Interestingly, counter to previous studies, malnutrition was not confirmed as a risk factor for recurrent falls in a cohort of older Taiwanese veterans [13].
LINK BETWEEN MEDICATION INTAKE AND NUTRITIONAL STATUS Age-related physiologic, pathologic and environmental changes place older adults at increased risk of polypharmacy and malnutrition. These changes include the increased prevalence of chronic medical conditions, reduced senses of thirst and taste (which can increase the risk of fluid and electrolyte imbalances), dry mouth, and increased difficulty with accessing and consuming a nutritionally adequate diet because of disability and environmental changes that create food deserts. Polypharmacy and inappropriate prescribing may contribute to the risk of malnutrition as people age. Previous evidence has shown an inverse relationship between medication use and nutritional status with 50% of those taking 10 or more medications found to be malnourished or at risk of malnourishment [24]. More recent evidence confirms that association. A Spanish cohort study found that polypharmacy was one of the three main determinants (along with living alone and dysphagia) of disease-related malnutrition [9]. Further studies are being planned to investigate the impact of continued monitoring and interventions for these factors on nutritional status in a larger cohort. In an Italian study, which included over 1300 participants, older adults with diabetes taking more than five medications (51% of the study population) had higher body mass indices, suggesting obesity-related malnutrition, and were twice as likely to be malnourished or at risk for malnourishment [25]. In addition, the patients who screened as malnourished or at risk of malnutrition were more frequently receiving polypharmacy. The classic Volume 20 Number 00 Month 2017
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‘chicken versus egg’ argument applies to this study as it is not clear which is the risk factor for the other or if interventions targeting either will have a significant positive impact. Another population-based cohort study done in Spain, which included over 700 community-dwelling older adults, found a statistically significant association between malnutrition or risk of malnutrition and increased number of prescription medications. Multivariate analyses found that of the five main determinates of malnutrition (higher BMI, depressive symptoms, frailty, poor self-rated health and polypharmacy), polypharmacy was consistently shown to be a strong predictor for both men and women [26]. A 2016 systematic review of six longitudinal studies found that excessive polypharmacy (defined here as taking 10 medications) was a statistically significant risk factor for malnutrition in older women, but not in older men. Interestingly, taking 1–2 medications was associated with a lower risk of malnutrition in the female cohort than taking no medications [10].
SPECIFIC DRUG CLASSES AND THEIR RELATIONSHIP TO MALNUTRITION AND POLYPHARMACY Over 250 medications have been implicated as having the potential to negatively affect nutritional
status through alterations in taste, intestinal absorption and metabolism or elimination of vitamins and minerals [27,28]. Practitioners should be aware of the medications with common gastrointestinal sideeffects (e.g. nausea, anorexia and dry mouth) or the potential for drug–drug, drug–disease or drug– nutrient interactions. See Table 1 for the medication classes included in this review with the most recent evidence. Adverse nutrient/drug interactions often arise with medications that have a small therapeutic window and with medications taken long term. The impact of medications on sense of taste is common (reported in up to 75% of adverse drug reactions) and can lead to weight loss and malnutrition [28]. Assessment of the presence of dysgeusia and an evaluation of polypharmacy is a critical part of the work up of weight loss and malnutrition. In addition, zinc deficiency is a common culprit in the loss of taste sensation so monitoring for deficiency and replacing when low is important to prevent and treat dysgeusia. In addition to dysgeusia, zinc deficiency is associated with poor appetite, impotence, lethargy and poor wound healing and is best assessed through measurement of plasma or urinary zinc levels. Several antihypertensive agents, including thiazide diuretics, angiotensin receptor blockers, angiotensin-converting enzyme inhibitors and potassium-sparing diuretics, have been shown to lower levels of zinc [27]. Consideration should be given for monitoring zinc levels in patients treated
Table 1. Recent evidence of drug–nutrient interactions Medication class
Drug–nutrient interaction
Effect
Suggested monitoring
Antihypertensives: thiazide diuretics, angiotensin receptor blockers, angiotensin-converting enzyme inhibitors and potassium-sparing diuretics Acetylcholinesterase inhibitors
Zinc deficiency
Dysgeusia, anorexia, impotence, lethargy and poor wound healing
Measurement of plasma or urinary zinc levels. Blood pressure monitoring to determine need for continued use
Unknown
Nausea, vomiting, diarrhea and anorexia
Monitor for appetite change and weight loss. Assess actual benefit of use against risk of malnutrition
Proton pump inhibitors
B12 deficiency
Clostridium difficile diarrhea, pneumonia and hip fracture
Measurement of B12 levels and FRAX score
HMG-Co reductase inhibitors (statins)
Reductions in CoQ10, a-tocopherol, b-carotene and lycopene
Myopathy
Consider coadministration of CoQ10 Assess need for continued use >75 years of age.
Long-term, high-dose aspirin
Vitamin C deficiency
Thinning of gastric mucosa
Use low-dose aspirin long-term (80–400 mg/day) Vitamin C supplementation if high-doses required
Metformin
B12 deficiency
Anemia, fatigue and cognitive impairment
Monitor B12 levels and replace if low Consider routine replacement with long-term use
Assess need for continuing medications
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with these antihypertensives over the long term. There are no data confirming improved outcomes with zinc supplementation in these patients. Hypovitaminosis D is the current ‘hot topic’ in medicine because of growing evidence that low levels of circulating vitamin D are associated with poor outcomes. In patients not taking supplemental vitamin D, circulating levels are inversely associated with lower rates of malnutrition and polypharmacy [29]. It is not completely clear if this association is due to frailty-induced or druginduced vitamin D deficiency or if vitamin D deficiency is a risk factor for the former. This study also did not assess the impact of vitamin D supplementation (in its various forms) on nutritional status or medication use/PIMs [29]. Other drug classes that have recent evidence of drug–nutrient interaction include acetylcholinesterase inhibitors (AchEIs), multivitamins, proton pump inhibitors (PPIs), HMG-CoA reductase inhibitors (statins), antihypertensives, antiplatelet agents and metformin. AchEIs are commonly used to treat the dementias of Alzheimer’s, Lewy body and vascular disease. Commonly known side-effects are gastrointestinal intolerance (nausea, vomiting and diarrhea) and anorexia. Weight loss has been reported in the first 3 months of use but in previous studies, did not appear to be sustained. It is unclear whether these side-effects lead in the long-term to significant malnutrition and weight loss, but the concern for this is obvious and a big reason for avoiding use in frail or anorexic older adults. One small study done in Turkey aimed to help answer the question of whether AchEIs cause significant nutritional deficiencies. This 6-month study of 116 communitydwelling older adults with newly diagnosed dementia found no difference in nutritional parameters or BMI between the users and nonusers of AchEI, regardless of any changes in cognition [30 ]. This study did include people who were taking the transdermal formulation of an AchEI, which is less likely to cause gastrointestinal side-effects and therefore could have been a significant contributor to these findings. Given the small sample size, lack of randomization and relatively short duration, it is still unclear whether oral AchEIs have a significant longterm impact and so caution is advised. The potential for weight loss should still be a consideration when prescribing these medications and should be part of the discussion when educating patients about potential side-effects. A recent analysis of the Physician Health Study II aimed to assess the association between reported multivitamin use and cardiovascular disease risk in a population cohort of generally healthy community&
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dwelling older male physicians living in the United States. This study did not report polypharmacy, nor did it use a validated scale for nutrition assessment, instead used a food frequency questionnaire. Despite the limitations of the study, it did reveal that regardless of reported food intake (i.e. whether nutritionally complete or depleted), the addition of a vitamin supplement did not have a cardiovascular or mortality benefit [31]. This is one more study that adds to the growing body of evidence that speaks against the routine use of multivitamin supplementation. PPIs are commonly prescribed inappropriately [32] and long-term use (longer than 6 weeks) has been associated with Clostridium difficile diarrhea, pneumonia, hip fracture and B12 deficiency [33 ]. The relationship between PPI use and nutritional status is unknown. A small cohort (190) of elderly patients in Japan who were experiencing long-term hospitalization or rehabilitation stays overall showed no significant differences in nutritional parameters between PPI users and nonusers but after multivariate analysis, longer term users showed significant improvement in nutritional parameters. The median prescription was 3 months, with a range of 51–227 days [33 ]. This study examined nutrition using the Mini MNA, Short Form. Although a reassuring finding, this study does not provide enough evidence to substantiate the safety of long-term PPI use. Thirteen studies of people with hyperlipidemia treated with statins examined the effect of statins on nutritional status, namely on circulating levels of coenzyme Q10 (CoQ10) and other important antioxidants. Overall, a systematic review of the combined studies showed a significant reduction in CoQ10, a-tocopherol, b-carotene and lycopene [27]. Reduction in these antioxidants is thought to be the main driver of statin-induced myopathy. Coadministration of CoQ10 may help to ameliorate the effects, but additional studies are needed to confirm this, especially in older adults who are already experiencing or are at risk of polypharmacy. Long-term, high-dose aspirin use has been associated with decreased vitamin C levels, which can lead to thinning of gastric mucosa with subsequent gastritis, peptic ulcer disease, nausea, anorexia and malnutrition [27]. It is important to note that the doses used for primary and secondary prophylaxis of cardiovascular disease are much lower than those reported in these studies. There is currently no evidence that suggests a similar reduction in vitamin C or a need for vitamin C supplementation in chronic low-dose aspirin users. Metformin leads to vitamin B12 deficiency in a both dose-dependent and duration-dependent manner, with a more than two-fold increase in risk &&
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of deficiency with every 1 g per day increase in dose [27]. As B12 deficiency is associated with significant negative outcomes, such as anemia and cognitive impairment, people taking metformin should have B12 levels regularly checked and repleted if low.
FURTHER RESEARCH IS NEEDED Although many studies have assessed the risk of a variety of commonly experienced geriatric syndromes, including polypharmacy and malnutrition/anorexia, few have adequately evaluated the synergistic effect of the presence of both polypharmacy and malnutrition as opposed to either alone. In addition, further research of targeted interventions needs to be done to see if they can improve outcomes at the individual and population levels. The Multidimensional Prognostic Index [21,22] can serve as a starting point for these studies as it is a validated assessment tool for hospitalized patients that can help drive targeted interventions. This tool would also need to be validated in other settings for inclusion in studies of community or postacute and long-term care populations. Further evidence is needed to confirm that addressing these issues in the various care settings improves outcomes when polypharmacy and malnutrition are discovered. In addition, further work is needed to assess the impact of prevention versus treatment of these conditions. Several studies are planned and currently underway to help answer these remaining questions. An ongoing observational study is looking at the influence of the timing of drug administration in relationship to meals and its impact on nutritional status in older hospitalized patients. The goal is to gain a better understanding of the optimal time for medication intake that will have the least impact on the oral intake of food (ClinicalTrials.gov identifier: NCT02894827). A randomized controlled trial with the goal of enrolling 75 participants between the ages of 45 and 75 will test whether 16-week treatment with a multivitamin-multimineral supplement (versus placebo) will improve the nutritional status of adults at increased risk of micronutrient deficiency induced by commonly used medications, specifically diuretics, metformin and PPIs. The study investigators will measure a variety of biomarkers of ‘metabolic health’ as well as the plasma status of several vitamins and minerals, including vitamin B12, vitamin C and zinc (ClinicalTrials.gov identifier: NCT03061409).
CONCLUSION Polypharmacy and malnutrition are significant geriatric syndromes that need to be assessed and treated in all older adults. Practitioners should be aware of
the potential impact of individual medication classes as well as extreme polypharmacy on nutritional status and work to reduce the impact through targeted interventions. Research continues that will help define best practice models to prevent and treat the synergistic impact of these syndromes. Acknowledgements None. Financial support and sponsorship None. Conflicts of interest The author has no conflicts of interest to disclose.
REFERENCES AND RECOMMENDED READING Papers of particular interest, published within the annual period of review, have been highlighted as: & of special interest && of outstanding interest 1. Jyrkka J, Mursu J, Enlund H, Lonnroos E. Polypharmacy and nutritional status in elderly people. Curr Opin Clin Nutr Metab Care 2012; 15:1–6. 2. Zadak Z, Hyspler R, Ticha A, Vlcek J. Polypharmacy and malnutrition. Curr Opin Clin Nutr Metab Care 2013; 16:50–55. 3. Gillette C, Prunty L, Wolcott J, Broedel-Zaugg K. A new lexicon for polypharmacy: implications for research, practice, and education. Res Social Adm Pharm 2015; 11:468–471. 4. Charlesworth CJ, Smit E, Lee DS, et al. Polypharmacy among adults aged 65 years and older in the United States: 1988–2010. Biol Sci Med Sci 2015; 70:989–995. 5. Zia A, Kamaruzzaman SB, Tan MP. Polypharmacy and falls in older people: balancing evidence-based medicine against falls risk. Postgrad Med 2015; 127:330–337. 6. Moulis F, Moulis G, Balardy L, et al. Searching for a polypharmacy threshold associated with frailty. J Am Med Dir Assoc 2015; 16:259–261. 7. Chiu MH, Lee HD, Hwang HF, et al. Medication use and fall-risk assessment for falls in an acute care hospital. Geriatr Gerontol Int 2015; 15:856–863. 8. Gomez C, Vega-Quiroga S, Bermejo-Pareja F, et al. Polypharmacy in the elderly: a marker of increased risk of mortality in a population-based prospective study (NEDICES). Gerontology 2015; 61:301–309. 9. Burgos R JC, Blay C, Ledesma A, Figueiras G,Pe´rez-Portabella C, Granados A, Go´mez D, Gonza´lez A, Sarquella E, Amil P, Vaque´ C, editor Strategy to fight against malnutrition in chronic patients with complex health needs. 16th International Conference on Integrated Care; 2016; Barcelona: International Journal of Integrated Care. 10. Favaro-Moreira NC, Krausch-Hofmann S, Matthys C, et al. Risk factors for && malnutrition in older adults: a systematic review of the literature based on longitudinal data. Adv Nutr 2016; 7:507–522. A systematic review of six studies of good quality, longitudinal design to delineate the risk factors of malnutrition in older adults. Described and appraised the studies for common factors. 11. Projovic I, Vukadinovic D, Milovanovic O, et al. Risk factors for potentially & inappropriate prescribing to older patients in primary care. Eur J Clin Pharmacol 2016; 72:93–107. This is a small retrospective study done in Serbia that is important because of being one of the most recent to show an additive effect of polypharmacy and malnurition on a higher risk of being prescribed a PIM, thus increasing the risk of adverse effects. 12. Wang CJ, Hung CH, Tang TC, et al. Urinary incontinence and its association with frailty among men aged 80 years or older in Taiwan: a cross-sectional study. Rejuvenation Res 2017; 20:111–117. 13. Hung CH, Wang CJ, Tang TC, et al. Recurrent falls and its risk factors among older men living in the veterans retirement communities: a cross-sectional study. Arch Gerontol Geriatr 2017; 70:214–218. 14. Millan Nunez-Cortes J, Cases Amenos A, Ascaso Gimilio JF, et al. Consensus on the statin of choice in patients with impaired glucose metabolism: results of the DIANA study. Am J Cardiovasc Drugs 2017; 17:135–142. 15. Pannu T, Sharkey S, Burek G, et al. Medication use by middle-aged and older participants of an exercise study: results from the Brain in Motion study. BMC Complement Altern Med 2017; 17:105.
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Aging: biology and nutrition 16. Viljakainen S, Nykanen I, Ahonen R, et al. Xerostomia among older home care clients. Community Dent Oral Epidemiol 2016; 44:232–238. 17. Tiisanoja A, Syrjala AM, Komulainen K, et al. Sedative load and salivary secretion and xerostomia in community-dwelling older people. Gerodontology 2016; 33:177–184. 18. Benbow M. Assessment, prevention and management of skin tears. Nurs Older People 2017; 29:31–39. 19. Tamanini JT, de Jesus FA, Castro RA, et al. The prevalence of fecal incontinence and associated risk factors in older adults participating in the SABE study. Neurourol Urodyn 2016; 35:959–964. 20. Machon M, Vergara I, Dorronsoro M, et al. Self-perceived health in functionally independent older people: associated factors. BMC Geriatr 2016; 16:66. 21. Pilotto A, Sancarlo D, Pellegrini F, et al. The Multidimensional Prognostic Index predicts in-hospital length of stay in older patients: a multicentre prospective study. Age Ageing 2016; 45:90–96. 22. Volpato S, Daragjati J, Simonato M, et al. Change in the Multidimensional Prognostic Index score during hospitalization in older patients. Rejuvenation Res 2016; 19:244–251. 23. de Groot MH, van Campen JP, Kosse NM, et al. The association of medication-use and frailty-related factors with gait performance in older patients. PLoS One 2016; 11:e0149888. 24. Bernstein M, Munoz N; Academy of Nutrition and Dietetics. Position of the Academy of Nutrition and Dietetics: food and nutrition for older adults: promoting health and wellness. J Acad Nutr Diet 2012; 112: 1255–1277. 25. Noale M, Veronese N, Cavallo Perin P, et al. Polypharmacy in elderly patients with type 2 diabetes receiving oral antidiabetic treatment. Acta Diabetol 2016; 53:323–330. 26. Maseda A, Gomez-Caamano S, Lorenzo-Lopez L, et al. Health determinants of nutritional status in community-dwelling older population: the VERISAUDE study. Public Health Nutr 2016; 19:2220–2228.
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27. Fenton R, Brook-Barclay L, Delaney CL, et al. Do medications commonly prescribed to patients with peripheral arterial disease have an effect on nutritional status? A review of the literature. Ann Vasc Surg 2016; 32:145–175. This review aimed to review the effect of medications commonly used in peripheral arterial disease on nutritional status: statins, aspirin, antihypertensives and metformin. The studies included in the review were not studies of peripheral arterial disease and therefore are applicable more generally. 28. Syed Q, Hendler KT, Koncilja K. The impact of aging and medical status on dysgeusia. Am J Med 2016; 129:753; e1-6. 29. van Orten-Luiten AC, Janse A, Dhonukshe-Rutten RA, Witkamp RF. Vitamin D deficiency as adverse drug reaction? A cross-sectional study in Dutch geriatric outpatients. Eur J Clin Pharmacol 2016; 72:605–614. 30. Soysal P, Isik AT. Effects of acetylcholinesterase inhibitors on nutritional & status in elderly patients with dementia: a 6-month follow-up study. J Nutr Health Aging 2016; 20:398–403. A retrospective study of 116 patients with a recent diagnosis of dementia treated with AchEIs and had MNA data at 6-month intervals found no adverse effect on nutritional parameters, including weight, over a 6-month time period. Previous studies found anorexia and weight loss in the first 3 months of treatment. This effect was not sustained in this study. 31. Rautiainen S, Gaziano JM, Christen WG, et al. Effect of baseline nutritional status on long-term multivitamin use and cardiovascular disease risk: a secondary analysis of the physicians’ health study ii randomized clinical trial. JAMA Cardiol 2017; 2:617–625. 32. Kurlander JE, Kolbe M, Scheiman JM, et al. The right idea for the wrong patient: results of a national survey on stopping PPIs. Clin Gastroenterol Hepatol 2017; 15:1475–1476. 33. Nakamichi M, Wakabayashi H. Effect of long-term proton pump inhibitor therapy on nutritional status in elderly hospitalized patients. J Nutr Sci Vitaminol 2016; 62:330–334.
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Volume 20 Number 00 Month 2017
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MCO 210103
REVIEW URRENT C OPINION
Updates in nutrition and polypharmacy Milta O. Little
Purpose of review Medications have the potential to affect nutritional status in negative ways, especially as the number of medications increase. The inter-relation between polypharmacy and malnutrition is complex and not fully delineated in previous studies. More research has been done and compiled in the last year, which helps to clarify this relationship. This review brings together the most recent literature with the previous research to help healthcare providers to better assess and manage medication therapy in older adults. Recent findings Recent evidence confirms a synergistic negative effect of polypharmacy and malnutrition on outcomes of older adults. In addition, several drug classes, including common antihypertensive agents, acetylcholinesterase inhibitors, multivitamins, proton pump inhibitors, HMG-CoA reductase inhibitors (statins), antiplatelet agents and metformin, have been implicated in important drug–nutrient interactions. These are reviewed in detail here. Ongoing research endeavors are described. Summary Healthcare practitioners can use this review to identify potentially inappropriate medications and patients at highest risk of experiencing a medication-related adverse reaction in order to systematically deprescribe these high-risk medications. Keywords anorexia, malnutrition, polypharmacy, weight loss
INTRODUCTION Medicine is a collection of uncertain prescriptions, the results of which, taken collectively, are more fatal than useful to mankind. – Napoleon Bonaparte He who takes medicine and neglects diet wastes the skill of his doctors. – Chinese proverb Polypharmacy and malnutrition, which occur more commonly as people age, have been associated with adverse outcomes when considered as individual syndromes. There is some evidence on the interrelations between nutritional status and polypharmacy but previous reviews indicate a need for further research into this area [1,2]. This review focuses on the most recent publications that give further insight into drug–nutrient interactions and an exploration into further research that is needed.
DEFINITIONS AND IMPACT Polypharmacy has more than 24 distinct definitions in the literature but most consider polypharmacy to
be ‘extraordinary prescribing,’ where a person is taking more medications than necessary or medications are prescribed for an inappropriate indication [3]. The exact cutoff of the number of drugs required to be considered polypharmacy varies, usually ranging from more than 4 to more than 10. Inappropriate prescribing is associated with increased risks of medication nonadherence and adverse drug reactions [4], which lead to avoidable hospitalizations and excess financial cost. The more medications a person takes, the more likely he is to experience an adverse drug reaction. Older adults are two to three times more likely to experience an adverse drug reaction than younger adults, including a significant increase in frailty and falls [5–7]. Most importantly, polypharmacy has been associated with increased mortality, even after adjusting for comorbidities, especially in those with extreme Saint Louis University Medical Center, Saint Louis, Missouri, USA Correspondence to Milta O. Little, Saint Louis University Medical Center, 1402 S. Grand Blvd M238, Saint Louis, MO 63104, USA. Tel: +1 314 977 8462; fax: +1 314 771 8575; e-mail: [email protected] Curr Opin Clin Nutr Metab Care 2017, 20:000–000 DOI:10.1097/MCO.0000000000000425
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KEY POINTS Adverse effects of medications and malnutrition can synergistically contribute to the frailty cascade and other geriatric syndromes. Polypharmacy and inappropriate prescribing may contribute to the risk of malnutrition as people age. The impact of medications on sense of taste is common and can lead to weight loss and malnutrition. Assessment of the presence of dysgeusia and an evaluation of polypharmacy is a critical part of the work up of weight loss and malnutrition. Medication classes with potentially significant drug– nutrient interactions include antihypertensives (thiazide diuretics, angiotensin receptor blockers, angiotensinconverting enzyme inhibitors and potassium-sparing diuretics), AchEIs, PPIs, HMG-Co reductase inhibitors (statins), long-term, high-dose aspirin and metformin.
polypharmacy (defined as taking more than 10 medications) [8]. Like polypharmacy, malnutrition has been associated with an increased financial cost burden and risk of morbidity, hospitalizations and mortality [9] and older adults are at increased risk of experiencing nutritional deficiencies, even in the event of adequate food intake [10]. The prevalence of malnutrition has been reported to be 5–10% among independently living older individuals, 30–60% among institutionalized patients and 35–65% among hospitalized geriatric patients. A recent study found associations between poor lifestyle (including poor nutrition, defined as low fruit and vegetable intake) and polypharmacy (five or more medications) with potentially inappropriate medication (PIM) prescribing. Of note, combined risk factors have additive effect so that people with both nutritional deficiencies and polypharmacy are at much higher risk of experiencing a PIM and the potential adverse consequences than those with either risk factor alone [11]. Adverse effects of medications and/or malnutrition can contribute to the frailty cascade and other geriatric syndromes. Recent evidence shows polypharmacy to be an independent risk factor for urinary incontinence [12], recurrent falls [13], statin-induced diabetes (particularly in older adults) [14], low fitness levels [15] and xerostomia [16 ,17 ]. Most of these studies also assessed for malnutrition as a risk factor using the Mini Nutritional Assessment (MNA) and did not find significant associations. The combined effect of malnutrition and polypharmacy was not assessed in any of the aforementioned studies. &&
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Both polypharmacy and malnutrition were found to be risk factors for skin tears [18], fecal incontinence (however, when adjusted for sex, only polypharmacy remained significant for women and malnutrition for men) [19], poor self-perceived health [20] and increased hospital length of stay. The latter association was found when using a validated instrument called the Multidimentional Prognostic Index that includes assessments of nutrition and polypharmacy status [21,22]. One study looking specifically at risk factors for impairments in gait performance found that weight loss and certain drug classes (laxatives, psychotropic drugs, agents acting on sensory organs and drugs for peptic ulcer and reflux disease) were associated with lower walking speed and increased stride variability. Over 50% of this population exhibited polypharmacy [23]. Interestingly, counter to previous studies, malnutrition was not confirmed as a risk factor for recurrent falls in a cohort of older Taiwanese veterans [13].
LINK BETWEEN MEDICATION INTAKE AND NUTRITIONAL STATUS Age-related physiologic, pathologic and environmental changes place older adults at increased risk of polypharmacy and malnutrition. These changes include the increased prevalence of chronic medical conditions, reduced senses of thirst and taste (which can increase the risk of fluid and electrolyte imbalances), dry mouth, and increased difficulty with accessing and consuming a nutritionally adequate diet because of disability and environmental changes that create food deserts. Polypharmacy and inappropriate prescribing may contribute to the risk of malnutrition as people age. Previous evidence has shown an inverse relationship between medication use and nutritional status with 50% of those taking 10 or more medications found to be malnourished or at risk of malnourishment [24]. More recent evidence confirms that association. A Spanish cohort study found that polypharmacy was one of the three main determinants (along with living alone and dysphagia) of disease-related malnutrition [9]. Further studies are being planned to investigate the impact of continued monitoring and interventions for these factors on nutritional status in a larger cohort. In an Italian study, which included over 1300 participants, older adults with diabetes taking more than five medications (51% of the study population) had higher body mass indices, suggesting obesity-related malnutrition, and were twice as likely to be malnourished or at risk for malnourishment [25]. In addition, the patients who screened as malnourished or at risk of malnutrition were more frequently receiving polypharmacy. The classic Volume 20 Number 00 Month 2017
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‘chicken versus egg’ argument applies to this study as it is not clear which is the risk factor for the other or if interventions targeting either will have a significant positive impact. Another population-based cohort study done in Spain, which included over 700 community-dwelling older adults, found a statistically significant association between malnutrition or risk of malnutrition and increased number of prescription medications. Multivariate analyses found that of the five main determinates of malnutrition (higher BMI, depressive symptoms, frailty, poor self-rated health and polypharmacy), polypharmacy was consistently shown to be a strong predictor for both men and women [26]. A 2016 systematic review of six longitudinal studies found that excessive polypharmacy (defined here as taking 10 medications) was a statistically significant risk factor for malnutrition in older women, but not in older men. Interestingly, taking 1–2 medications was associated with a lower risk of malnutrition in the female cohort than taking no medications [10].
SPECIFIC DRUG CLASSES AND THEIR RELATIONSHIP TO MALNUTRITION AND POLYPHARMACY Over 250 medications have been implicated as having the potential to negatively affect nutritional
status through alterations in taste, intestinal absorption and metabolism or elimination of vitamins and minerals [27,28]. Practitioners should be aware of the medications with common gastrointestinal sideeffects (e.g. nausea, anorexia and dry mouth) or the potential for drug–drug, drug–disease or drug– nutrient interactions. See Table 1 for the medication classes included in this review with the most recent evidence. Adverse nutrient/drug interactions often arise with medications that have a small therapeutic window and with medications taken long term. The impact of medications on sense of taste is common (reported in up to 75% of adverse drug reactions) and can lead to weight loss and malnutrition [28]. Assessment of the presence of dysgeusia and an evaluation of polypharmacy is a critical part of the work up of weight loss and malnutrition. In addition, zinc deficiency is a common culprit in the loss of taste sensation so monitoring for deficiency and replacing when low is important to prevent and treat dysgeusia. In addition to dysgeusia, zinc deficiency is associated with poor appetite, impotence, lethargy and poor wound healing and is best assessed through measurement of plasma or urinary zinc levels. Several antihypertensive agents, including thiazide diuretics, angiotensin receptor blockers, angiotensin-converting enzyme inhibitors and potassium-sparing diuretics, have been shown to lower levels of zinc [27]. Consideration should be given for monitoring zinc levels in patients treated
Table 1. Recent evidence of drug–nutrient interactions Medication class
Drug–nutrient interaction
Effect
Suggested monitoring
Antihypertensives: thiazide diuretics, angiotensin receptor blockers, angiotensin-converting enzyme inhibitors and potassium-sparing diuretics Acetylcholinesterase inhibitors
Zinc deficiency
Dysgeusia, anorexia, impotence, lethargy and poor wound healing
Measurement of plasma or urinary zinc levels. Blood pressure monitoring to determine need for continued use
Unknown
Nausea, vomiting, diarrhea and anorexia
Monitor for appetite change and weight loss. Assess actual benefit of use against risk of malnutrition
Proton pump inhibitors
B12 deficiency
Clostridium difficile diarrhea, pneumonia and hip fracture
Measurement of B12 levels and FRAX score
HMG-Co reductase inhibitors (statins)
Reductions in CoQ10, a-tocopherol, b-carotene and lycopene
Myopathy
Consider coadministration of CoQ10 Assess need for continued use >75 years of age.
Long-term, high-dose aspirin
Vitamin C deficiency
Thinning of gastric mucosa
Use low-dose aspirin long-term (80–400 mg/day) Vitamin C supplementation if high-doses required
Metformin
B12 deficiency
Anemia, fatigue and cognitive impairment
Monitor B12 levels and replace if low Consider routine replacement with long-term use
Assess need for continuing medications
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with these antihypertensives over the long term. There are no data confirming improved outcomes with zinc supplementation in these patients. Hypovitaminosis D is the current ‘hot topic’ in medicine because of growing evidence that low levels of circulating vitamin D are associated with poor outcomes. In patients not taking supplemental vitamin D, circulating levels are inversely associated with lower rates of malnutrition and polypharmacy [29]. It is not completely clear if this association is due to frailty-induced or druginduced vitamin D deficiency or if vitamin D deficiency is a risk factor for the former. This study also did not assess the impact of vitamin D supplementation (in its various forms) on nutritional status or medication use/PIMs [29]. Other drug classes that have recent evidence of drug–nutrient interaction include acetylcholinesterase inhibitors (AchEIs), multivitamins, proton pump inhibitors (PPIs), HMG-CoA reductase inhibitors (statins), antihypertensives, antiplatelet agents and metformin. AchEIs are commonly used to treat the dementias of Alzheimer’s, Lewy body and vascular disease. Commonly known side-effects are gastrointestinal intolerance (nausea, vomiting and diarrhea) and anorexia. Weight loss has been reported in the first 3 months of use but in previous studies, did not appear to be sustained. It is unclear whether these side-effects lead in the long-term to significant malnutrition and weight loss, but the concern for this is obvious and a big reason for avoiding use in frail or anorexic older adults. One small study done in Turkey aimed to help answer the question of whether AchEIs cause significant nutritional deficiencies. This 6-month study of 116 communitydwelling older adults with newly diagnosed dementia found no difference in nutritional parameters or BMI between the users and nonusers of AchEI, regardless of any changes in cognition [30 ]. This study did include people who were taking the transdermal formulation of an AchEI, which is less likely to cause gastrointestinal side-effects and therefore could have been a significant contributor to these findings. Given the small sample size, lack of randomization and relatively short duration, it is still unclear whether oral AchEIs have a significant longterm impact and so caution is advised. The potential for weight loss should still be a consideration when prescribing these medications and should be part of the discussion when educating patients about potential side-effects. A recent analysis of the Physician Health Study II aimed to assess the association between reported multivitamin use and cardiovascular disease risk in a population cohort of generally healthy community&
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dwelling older male physicians living in the United States. This study did not report polypharmacy, nor did it use a validated scale for nutrition assessment, instead used a food frequency questionnaire. Despite the limitations of the study, it did reveal that regardless of reported food intake (i.e. whether nutritionally complete or depleted), the addition of a vitamin supplement did not have a cardiovascular or mortality benefit [31]. This is one more study that adds to the growing body of evidence that speaks against the routine use of multivitamin supplementation. PPIs are commonly prescribed inappropriately [32] and long-term use (longer than 6 weeks) has been associated with Clostridium difficile diarrhea, pneumonia, hip fracture and B12 deficiency [33 ]. The relationship between PPI use and nutritional status is unknown. A small cohort (190) of elderly patients in Japan who were experiencing long-term hospitalization or rehabilitation stays overall showed no significant differences in nutritional parameters between PPI users and nonusers but after multivariate analysis, longer term users showed significant improvement in nutritional parameters. The median prescription was 3 months, with a range of 51–227 days [33 ]. This study examined nutrition using the Mini MNA, Short Form. Although a reassuring finding, this study does not provide enough evidence to substantiate the safety of long-term PPI use. Thirteen studies of people with hyperlipidemia treated with statins examined the effect of statins on nutritional status, namely on circulating levels of coenzyme Q10 (CoQ10) and other important antioxidants. Overall, a systematic review of the combined studies showed a significant reduction in CoQ10, a-tocopherol, b-carotene and lycopene [27]. Reduction in these antioxidants is thought to be the main driver of statin-induced myopathy. Coadministration of CoQ10 may help to ameliorate the effects, but additional studies are needed to confirm this, especially in older adults who are already experiencing or are at risk of polypharmacy. Long-term, high-dose aspirin use has been associated with decreased vitamin C levels, which can lead to thinning of gastric mucosa with subsequent gastritis, peptic ulcer disease, nausea, anorexia and malnutrition [27]. It is important to note that the doses used for primary and secondary prophylaxis of cardiovascular disease are much lower than those reported in these studies. There is currently no evidence that suggests a similar reduction in vitamin C or a need for vitamin C supplementation in chronic low-dose aspirin users. Metformin leads to vitamin B12 deficiency in a both dose-dependent and duration-dependent manner, with a more than two-fold increase in risk &&
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of deficiency with every 1 g per day increase in dose [27]. As B12 deficiency is associated with significant negative outcomes, such as anemia and cognitive impairment, people taking metformin should have B12 levels regularly checked and repleted if low.
FURTHER RESEARCH IS NEEDED Although many studies have assessed the risk of a variety of commonly experienced geriatric syndromes, including polypharmacy and malnutrition/anorexia, few have adequately evaluated the synergistic effect of the presence of both polypharmacy and malnutrition as opposed to either alone. In addition, further research of targeted interventions needs to be done to see if they can improve outcomes at the individual and population levels. The Multidimensional Prognostic Index [21,22] can serve as a starting point for these studies as it is a validated assessment tool for hospitalized patients that can help drive targeted interventions. This tool would also need to be validated in other settings for inclusion in studies of community or postacute and long-term care populations. Further evidence is needed to confirm that addressing these issues in the various care settings improves outcomes when polypharmacy and malnutrition are discovered. In addition, further work is needed to assess the impact of prevention versus treatment of these conditions. Several studies are planned and currently underway to help answer these remaining questions. An ongoing observational study is looking at the influence of the timing of drug administration in relationship to meals and its impact on nutritional status in older hospitalized patients. The goal is to gain a better understanding of the optimal time for medication intake that will have the least impact on the oral intake of food (ClinicalTrials.gov identifier: NCT02894827). A randomized controlled trial with the goal of enrolling 75 participants between the ages of 45 and 75 will test whether 16-week treatment with a multivitamin-multimineral supplement (versus placebo) will improve the nutritional status of adults at increased risk of micronutrient deficiency induced by commonly used medications, specifically diuretics, metformin and PPIs. The study investigators will measure a variety of biomarkers of ‘metabolic health’ as well as the plasma status of several vitamins and minerals, including vitamin B12, vitamin C and zinc (ClinicalTrials.gov identifier: NCT03061409).
CONCLUSION Polypharmacy and malnutrition are significant geriatric syndromes that need to be assessed and treated in all older adults. Practitioners should be aware of
the potential impact of individual medication classes as well as extreme polypharmacy on nutritional status and work to reduce the impact through targeted interventions. Research continues that will help define best practice models to prevent and treat the synergistic impact of these syndromes. Acknowledgements None. Financial support and sponsorship None. Conflicts of interest The author has no conflicts of interest to disclose.
REFERENCES AND RECOMMENDED READING Papers of particular interest, published within the annual period of review, have been highlighted as: & of special interest && of outstanding interest 1. Jyrkka J, Mursu J, Enlund H, Lonnroos E. Polypharmacy and nutritional status in elderly people. Curr Opin Clin Nutr Metab Care 2012; 15:1–6. 2. Zadak Z, Hyspler R, Ticha A, Vlcek J. Polypharmacy and malnutrition. Curr Opin Clin Nutr Metab Care 2013; 16:50–55. 3. Gillette C, Prunty L, Wolcott J, Broedel-Zaugg K. A new lexicon for polypharmacy: implications for research, practice, and education. Res Social Adm Pharm 2015; 11:468–471. 4. Charlesworth CJ, Smit E, Lee DS, et al. Polypharmacy among adults aged 65 years and older in the United States: 1988–2010. Biol Sci Med Sci 2015; 70:989–995. 5. Zia A, Kamaruzzaman SB, Tan MP. Polypharmacy and falls in older people: balancing evidence-based medicine against falls risk. Postgrad Med 2015; 127:330–337. 6. Moulis F, Moulis G, Balardy L, et al. Searching for a polypharmacy threshold associated with frailty. J Am Med Dir Assoc 2015; 16:259–261. 7. Chiu MH, Lee HD, Hwang HF, et al. Medication use and fall-risk assessment for falls in an acute care hospital. Geriatr Gerontol Int 2015; 15:856–863. 8. Gomez C, Vega-Quiroga S, Bermejo-Pareja F, et al. Polypharmacy in the elderly: a marker of increased risk of mortality in a population-based prospective study (NEDICES). Gerontology 2015; 61:301–309. 9. Burgos R JC, Blay C, Ledesma A, Figueiras G,Pe´rez-Portabella C, Granados A, Go´mez D, Gonza´lez A, Sarquella E, Amil P, Vaque´ C, editor Strategy to fight against malnutrition in chronic patients with complex health needs. 16th International Conference on Integrated Care; 2016; Barcelona: International Journal of Integrated Care. 10. Favaro-Moreira NC, Krausch-Hofmann S, Matthys C, et al. Risk factors for && malnutrition in older adults: a systematic review of the literature based on longitudinal data. Adv Nutr 2016; 7:507–522. A systematic review of six studies of good quality, longitudinal design to delineate the risk factors of malnutrition in older adults. Described and appraised the studies for common factors. 11. Projovic I, Vukadinovic D, Milovanovic O, et al. Risk factors for potentially & inappropriate prescribing to older patients in primary care. Eur J Clin Pharmacol 2016; 72:93–107. This is a small retrospective study done in Serbia that is important because of being one of the most recent to show an additive effect of polypharmacy and malnurition on a higher risk of being prescribed a PIM, thus increasing the risk of adverse effects. 12. Wang CJ, Hung CH, Tang TC, et al. Urinary incontinence and its association with frailty among men aged 80 years or older in Taiwan: a cross-sectional study. Rejuvenation Res 2017; 20:111–117. 13. Hung CH, Wang CJ, Tang TC, et al. Recurrent falls and its risk factors among older men living in the veterans retirement communities: a cross-sectional study. Arch Gerontol Geriatr 2017; 70:214–218. 14. Millan Nunez-Cortes J, Cases Amenos A, Ascaso Gimilio JF, et al. Consensus on the statin of choice in patients with impaired glucose metabolism: results of the DIANA study. Am J Cardiovasc Drugs 2017; 17:135–142. 15. Pannu T, Sharkey S, Burek G, et al. Medication use by middle-aged and older participants of an exercise study: results from the Brain in Motion study. BMC Complement Altern Med 2017; 17:105.
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Aging: biology and nutrition 16. Viljakainen S, Nykanen I, Ahonen R, et al. Xerostomia among older home care clients. Community Dent Oral Epidemiol 2016; 44:232–238. 17. Tiisanoja A, Syrjala AM, Komulainen K, et al. Sedative load and salivary secretion and xerostomia in community-dwelling older people. Gerodontology 2016; 33:177–184. 18. Benbow M. Assessment, prevention and management of skin tears. Nurs Older People 2017; 29:31–39. 19. Tamanini JT, de Jesus FA, Castro RA, et al. The prevalence of fecal incontinence and associated risk factors in older adults participating in the SABE study. Neurourol Urodyn 2016; 35:959–964. 20. Machon M, Vergara I, Dorronsoro M, et al. Self-perceived health in functionally independent older people: associated factors. BMC Geriatr 2016; 16:66. 21. Pilotto A, Sancarlo D, Pellegrini F, et al. The Multidimensional Prognostic Index predicts in-hospital length of stay in older patients: a multicentre prospective study. Age Ageing 2016; 45:90–96. 22. Volpato S, Daragjati J, Simonato M, et al. Change in the Multidimensional Prognostic Index score during hospitalization in older patients. Rejuvenation Res 2016; 19:244–251. 23. de Groot MH, van Campen JP, Kosse NM, et al. The association of medication-use and frailty-related factors with gait performance in older patients. PLoS One 2016; 11:e0149888. 24. Bernstein M, Munoz N; Academy of Nutrition and Dietetics. Position of the Academy of Nutrition and Dietetics: food and nutrition for older adults: promoting health and wellness. J Acad Nutr Diet 2012; 112: 1255–1277. 25. Noale M, Veronese N, Cavallo Perin P, et al. Polypharmacy in elderly patients with type 2 diabetes receiving oral antidiabetic treatment. Acta Diabetol 2016; 53:323–330. 26. Maseda A, Gomez-Caamano S, Lorenzo-Lopez L, et al. Health determinants of nutritional status in community-dwelling older population: the VERISAUDE study. Public Health Nutr 2016; 19:2220–2228.
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27. Fenton R, Brook-Barclay L, Delaney CL, et al. Do medications commonly prescribed to patients with peripheral arterial disease have an effect on nutritional status? A review of the literature. Ann Vasc Surg 2016; 32:145–175. This review aimed to review the effect of medications commonly used in peripheral arterial disease on nutritional status: statins, aspirin, antihypertensives and metformin. The studies included in the review were not studies of peripheral arterial disease and therefore are applicable more generally. 28. Syed Q, Hendler KT, Koncilja K. The impact of aging and medical status on dysgeusia. Am J Med 2016; 129:753; e1-6. 29. van Orten-Luiten AC, Janse A, Dhonukshe-Rutten RA, Witkamp RF. Vitamin D deficiency as adverse drug reaction? A cross-sectional study in Dutch geriatric outpatients. Eur J Clin Pharmacol 2016; 72:605–614. 30. Soysal P, Isik AT. Effects of acetylcholinesterase inhibitors on nutritional & status in elderly patients with dementia: a 6-month follow-up study. J Nutr Health Aging 2016; 20:398–403. A retrospective study of 116 patients with a recent diagnosis of dementia treated with AchEIs and had MNA data at 6-month intervals found no adverse effect on nutritional parameters, including weight, over a 6-month time period. Previous studies found anorexia and weight loss in the first 3 months of treatment. This effect was not sustained in this study. 31. Rautiainen S, Gaziano JM, Christen WG, et al. Effect of baseline nutritional status on long-term multivitamin use and cardiovascular disease risk: a secondary analysis of the physicians’ health study ii randomized clinical trial. JAMA Cardiol 2017; 2:617–625. 32. Kurlander JE, Kolbe M, Scheiman JM, et al. The right idea for the wrong patient: results of a national survey on stopping PPIs. Clin Gastroenterol Hepatol 2017; 15:1475–1476. 33. Nakamichi M, Wakabayashi H. Effect of long-term proton pump inhibitor therapy on nutritional status in elderly hospitalized patients. J Nutr Sci Vitaminol 2016; 62:330–334.
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