Sarcopenia is associated with a greater risk of polypharmacy and number of medications: a systematic review and meta‐analysis

Abstract Polypharmacy in older adults is associated with multiple negative consequences that may affect muscular function, independently from the presence of medical conditions. The aim of this systematic review and meta‐analysis was to investigate the association of sarcopenia with polypharmacy and higher number of medications. A systematic literature search of observational studies using PubMed, Web of Science, Scopus and Cochrane Library databases was conducted from inception until June 2022. To determine if sarcopenia is associated with a higher risk of polypharmacy and increased number of medications, a meta‐analysis using a random‐effects model was used to calculate the pooled effects (CRD42022337539). Twenty‐nine studies were included in the systematic review and meta‐analysis. Sarcopenia was associated with a higher prevalence of polypharmacy (odds ratio [OR]: 1.65, 95% confidence interval [CI] [1.23, 2.20], I 2 = 84%, P < 0.01) and higher number of medications (mean difference: 1.39, 95% CI [0.59, 2.19], I 2 = 95%, P < 0.01) compared with individuals without sarcopenia. Using meta‐regression, a high variance was observed due to different populations (i.e., community‐dwelling, nursing home residents, inpatients, outpatients) for both outcomes of polypharmacy (r = −0.338, SE = 0.1669, 95% CI [−0.67, −0.01], z = −2.03, P = 0.04) and number of medications (r = 0.589, SE = 0.2615, 95% CI [0.08, 1.10], z = 2.25, P = 0.02). This systematic review and meta‐analysis reported a significantly increased risk of polypharmacy and higher number of medications in people with sarcopenia compared with individuals without this condition. Future research should clarify whether the specificity and number of medications is a direct contributor in accelerating the progression of muscle wasting and dysfunction contributing to sarcopenia in older adults.


Introduction
Polypharmacy is defined as the use of multiple concurrent medications or the simultaneous long-term use of different drugs by the same individual. 1 Despite that a univocal consensus has not yet established regarding the numerical definition of polypharmacy, several studies have reported that the concurrent use of five or more medications is usually sufficient for the definition of this condition. 1 The prevalence of polypharmacy in older people is extremely wide ranging, due to differences in age, current health condition, health care setting and geographic location. 2 Epidemiological data suggest that polypharmacy may affect more than one third of older people worldwide, [3][4][5] making this phenomenon of great relevance in geriatric medicine. It is widely known that polypharmacy in older populations has been associated with several negative healthcare outcomes, independent from the presence of medical conditions. For example, a large umbrella review found that, among 26 meta-analyses, polypharmacy was associated with multiple detrimental outcomes, including adverse drug reactions, adverse drug events, disability and hospitalizations. 6 Interestingly, frailty is associated with less polypharmacy and higher prevalence of symptomatic drugs (i.e., laxatives, paracetamol and opioids) use among nursing home residents compared with non-frail individuals that were prescribed primarily preventive drugs such as bisphosphonates and acetylsalicylic acid. 7 However, there is a growing concern about the clinical management of comorbidities and the impact of polypharmacy that could result in potentially inappropriate prescribing. [8][9][10] There has been an increasing interest in understanding the association between polypharmacy and sarcopenia-the pathological loss of muscle mass, strength and function in older people. 11 Sarcopenia is associated with an increased risk of impaired physical function, 12 hospitalization and mortality. 13 Polypharmacy, particularly specific drugs such as corticosteroids, 14 has shown to be associated with muscle weakness and low appendicular lean mass in older age. 15,16 On the other hand, there is some evidence that changes in body weight and composition as well as protein synthesis affect drug distribution and metabolism. 17 A recent scoping review of the literature found an association between sarcopenia and risk of sarcopenia and polypharmacy or the number of medications in community-dwelling older people, but not among residents of nursing homes or hospital inpatients. 9 The results of that review were based on cross-sectional data, identifying only an association rather than a causal relationship between sarcopenia and polypharmacy or number of medications. Nevertheless, the different existing definitions of sarcopenia and polypharmacy, the wide-ranging methods of sarcopenia assessment, and the health care setting of older populations have hindered the appropriate evaluation of the relationship between polyphar-macy and sarcopenia. 9 Specifically, antidiabetic drugs may induce transcription factors of myostatin 18 and blunt hypertrophic responses following exercise, 19 while beta-blockers could impair muscular adaptation to exercise, reducing endurance exercise capacity. 20 In addition, glucocorticoids and anti-proliferative drugs for cancer treatment could upregulate E3 ubiquitin ligases such as atrogin1, MuRF1, and MUSA1 14 and reduce the expression of mediators involved in mitochondrial function. 21 Finally, considering the association between polypharmacy and malnutrition 22,23 due to potential changes in gastrointestinal microenvironment and the gut microbiota, 24 deprescribing, that is, judiciously decreasing or stopping a number of medications, may improve nutritional status, 25 a key contributor in improving sarcopenia status.
There is currently no systematic review and meta-analysis exploring the quantitative differences regarding the prevalence of polypharmacy and number of medications between older adults with sarcopenia compared with those without sarcopenia. Therefore, in this meta-analysis, we aimed to investigate the extent at which sarcopenia may amplify the risk of polypharmacy and be associated with higher number of medications. Our analyses might shed light on how multiple variables, such as different definitions of sarcopenia and polypharmacy, body composition assessment tools, geographical location, study population, health status and different age groups among older populations, could impact a polypharmacy/sarcopenia relationship.

Methods
This systematic review and meta-analysis was conducted in accordance with the updated 2020 Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. 26 The protocol has been registered in the International Prospective Register of Systematic Reviews (PROS-PERO) (CRD: 42022337539).

Search strategy
Two independent reviewers (K. P. and K. K. T.) searched PubMed, Scopus, Web of Science and Cochrane Library from inception until June 2022. The full search strategy and the search terms used are described in the Supporting information, Table S1). The searches were re-run before submission to retrieve any additional studies that met our inclusion criteria. Discrepancies in the literature search process were resolved by a third and fourth investigator (P. G. and K. S. K.).

Inclusion and exclusion criteria
Studies were included based on the following criteria: (i) baseline data from observational studies (i.e., cross-sectional, longitudinal and case-control); (ii) adults irrespective of health status; (iii) adults aged ≥60 years; (iv) clear diagnostic criteria for sarcopenia (i.e., EWGSOP 1 and 2, AWGS, FNIH, CHS); (v) clear criteria for polypharmacy (i.e., ≥5 medications); and (vi) studies had to include both adults with and without sarcopenia. Published articles were excluded if they (i) were reviews, letters, in vivo or in vitro experiments, commentaries or posters; (ii) were not published as a full text and in English; it appears to have little impact on the effect estimates and conclusions of systematic reviews 27 ; and (iii) included participants were below 60 years old.

Data extraction and risk of bias
Two authors (K. P. and K. K. T.) extracted data independently, which included the name of first author, date of publication, country of origin, participant age, study design, population studied, number of participants, health status, prevalence of polypharmacy, number of medications, and definition of polypharmacy and sarcopenia. Disagreements between authors were resolved by two independent reviewers (P. G. and K. S. K.). The quality of the included studies was evaluated using the Methodological index for non-randomized studies (MINORS) tool 28 and performed by three independent reviewers (K. P., K. K. T. and K. S. K.). MINORS is a comprehensive tool used to assess bias in nonrandomized controlled trials based on the following items: a clearly stated aim; inclusion of consecutive patients; prospective data collection; endpoints appropriate to study aim; unbiased assessment of study endpoint; follow-up period appropriate to study aim; <5% lost to follow-up; prospective calculation of study size; adequate control group; contemporary groups; baseline equivalence of groups; and adequate statistical analyses. According to the scoring system, MINORS' domains are scored as 0 if they are not reported, 1 when they have been reported but with inadequate details, and 2 when they have been reported while providing adequate information. The global ideal score is 16 for noncomparative studies, and a score below 8 was deemed as a high risk of bias and of some concerns, respectively.

Statistical analysis
Quantitative data were treated as continuous measurements, and changes in outcomes from sarcopenic and non-sarcopenic individuals were compared between groups to calculate mean differences (MDs) in number of medications and the odds ratio (OR) regarding the prevalence of polypharmacy. When studies provided interquartile ranges (IQR), the formula 'standard deviation (SD) = width of IQR/1.35' was used to approximately calculate the missing SDs. 29 Statistical significance was assessed using the random-effects model and inverse-variance method.
Statistical heterogeneity of outcome measurements between different studies was assessed using the overlap of their confidence interval (95% CI) and expressed as measurements of Cochran's Q (Chi-square test) and I 2 . The classification of data as having low heterogeneity were based on I 2 from 30% to 49%, moderate heterogeneity from 50% to 74% and high heterogeneity from 75% and above. 30 In case of high heterogeneity, a random-effects meta-regression was conducted to explore potential sources of variability that could affect estimate rates among studies. 31 Subgroup analyses based on age, population studied, similar health status, definition of polypharmacy, definition of sarcopenia and geographical location were performed. Moreover, sensitivity analyses were performed to evaluate the robustness of reported statistical results by discounting the effect of existing comorbidities and risk of malnutrition that would differ between sarcopenic and non-sarcopenic groups on outcome measurements and according to risk of bias of the included cohort studies. Further sensitivity analysis was intended to improve the accuracy of our findings by excluding studies conducted in populations with additional comorbidities in the sarcopenic compared with the group without sarcopenia that could interfere with the number of medications and/or prevalence of polypharmacy. The meta-analysis was synthesized using Review Manager (RevMan 5.4.1) software. A P value of <0.05 was considered statistically significant.
For the evaluation of unexplained variance among studies with substantial heterogeneity, meta-regressions were performed on the number of medications and prevalence of polypharmacy using a random-effects model. Six and seven covariates were included in the meta-regression related to the number of medications and prevalence of polypharmacy, respectively. Particularly, age, population of study, geographical area, risk of bias, muscle mass assessment tool, definition of sarcopenia and definition of polypharmacy were all used as individual covariates using STATA/MP 13.0.

Literature search
The initial literature search provided 7426 publications. Following the exclusion of duplicates and abstracts, 43 full texts were identified as eligible for inclusion in the systematic review and meta-analysis. Of these 43 studies, two studies were dismissed due to missing data 32,33 and five studies because of usage of a screening tool for the diagnosis of sarcopenia. [34][35][36][37][38] Additionally, three studies were excluded due to lack of polypharmacy definition [39][40][41] and another two 42,43 due to being part of other studies, albeit one measured the number of medications 44 while the other polypharmacy prevalence. 45 In total, 29 studies were included in the systematic review and meta-analysis exploring the prevalence of polypharmacy and number of medications in people with sarcopenia compared with those without sarcopenia ( Figure 1).

Number of medications in older subjects with sarcopenia versus those without sarcopenia
Our main analysis (k = 13; 1312 subjects with sarcopenia and 3470 subjects without sarcopenia) showed that the number of medications was significantly higher in older subjects with sarcopenia compared with those without sarcopenia (MD: 1.39, 95% CI [0.59, 2.19], I 2 = 95%, P < 0.01) (Figure 3).
Following multiple sensitivity analyses, no changes from the main analysis were detected following the deletion of studies that included subjects with osteoporosis (MD: 1.

Meta-regression analyses
The increased heterogeneity observed for the prevalence of polypharmacy and number of medications in individuals with vs. without sarcopenia was further investigated via meta-regression analyses. Differences in study population, age, risk of bias, geographical location, sarcopenia and polypharmacy definition, and muscle mass assessment tool did not explain the potentially high heterogeneity among studies in individuals with and without sarcopenia.
Regarding the prevalence of polypharmacy between individuals with and without sarcopenia, variance among studies was observed due to different populations (i.e., community dwelling, nursing home residents, inpatients and outpatients) (r = À0.338, SE = 0.1669, 95% CI [À0.67, À0.01], z = À2.03, P = 0.04), while no other covariates (i.e., age, risk of bias, geographical location, sarcopenia definition and muscle mass assessment tool) were considered potential sources of variance among included studies. Similarly, in studies measuring the number of medications, variance was explained due to different population groups (r = 0.589, SE = 0.2615, 95% CI [0.08, 1.10], z = 2.25, P = 0.02). Meta-regression analysis according to participant health status was not feasible, considering the heterogeneity of different comorbidities assessed in multiple studies.

Risk of bias of included studies
The overall quality of the included studies was considered high (Table S4), although two studies were considered having a high risk of bias. 45,70

Discussion
In this systematic review with meta-analysis, including 29 studies, we found that older subjects with sarcopenia had an increased prevalence of polypharmacy and a mean higher number of medications compared with those without sarcopenia. The meta-regression analysis explained only a limited part of the heterogeneity found.
Both polypharmacy and sarcopenia are very common conditions among older adults. 9 Overall, the findings of the present study suggest that among sarcopenic older adults, the number of medications is, in mean, 1.39 higher and the prevalence of polypharmacy is 65% higher, compared with their counterparts without sarcopenia. Of importance, the association between sarcopenia and polypharmacy seems to be significant among outpatients and community dwellers, but not in hospitalized people and nursing home patients. Moreover, the diagnostic criteria used seem another important factor to consider because the association with sarcopenia was observed when this condition was diagnosed using EWGSOP criteria, but not those proposed by AWGS underlining new potential areas of research. However, it is worth noting that this observation may also be attributed to differences in populations due to variety of ethnicities and geographical areas.
Ageing itself may increase the vulnerability to a variety of adverse effects, 72 further complicating the importance of poly- pharmacy in older people having sarcopenia. In this regard, even if the studies included did not report detailed information regarding the categories of medications used, we can argue that certain medications may influence body composition, whereas other drugs may have negative effects on muscles mainly leading to malnutrition (e.g., increasing nausea or diarrhoea). 9 Traditionally, some medications commonly used in older people, such as glucocorticoids and antidepressants are associated with muscle toxicity, whereas others (e.g., beta blockers or non-steroidal anti-inflammatory drugs [NSAIDS]) might cause detrimental metabolic effects, such as mitochondrial dysfunction, diminished blood flow and electrolyte, hormonal or acid-base alterations. 54 Further, they may also suppress acute exercise-induced responses via reduction of gene transcription regulators such as mitogen-activated protein kinases (MAPKs) and nuclear factor-kappa beta (NF-κB), 73 necessary for exercise-stimulated adaptations of the skeletal muscle. 74 These chronic alterations may lead to blunted strength and muscle hypertrophic adaptations, 75 although research in this area is inconclusive. 76 Generally, polypharmacy can only be considered as an indicator for several adverse clinical outcomes, 6 even if a direct relationship with these outcomes has not been yet established. 9 It is therefore imperative to assess whether polypharmacy may play a causative role in the occurrence of sarcopenia since sarcopenia itself is associated with an increased risk of several devastating health outcomes, including disability, higher rate of surgical complications and increased mortality. 77 At present, we can hypothesize that the association between polypharmacy and sarcopenia might be mediated by other conditions, in particular malnutrition. 26

Strengths and limitations
This is the first study assessing quantitatively the relationship of polypharmacy in people living with sarcopenia and those without. We could not reliably assess publication bias because observational studies that report prevalence rates do not indicate positive or negative results, and there is currently no established method to test for publication bias. In addition, publication bias could not have been established also due to the small number of studies per definition of sarcopenia classification (i.e., EWGSOP 1 and 2) and the high heterogeneity among studies. Based on current recommendations, if the heterogeneity is high, at least 10 studies are needed to examine reporting bias using funnel plots. 78 Furthermore, we found that those with sarcopenia below 80 years old were at an increased risk of polypharmacy versus those without sarcopenia, albeit no significant differences were found among individuals aged 80 years and above. These results raise questions in relation to the confounding factors that could have mediated this relationship between the two ageing groups; however, these covariates were not available to be accounted for in the analyses. Accordingly, a critical limitation is the lack of information on medications compiling polypharmacy in the studies included in our analysis. For example, certain medications may improve an individual's condition that may (in)directly reduce the risk of sarcopenia; hence, attention should be raised regarding appropriate versus inappropriate drug prescription. Finally, it is worth stating the possible inflation pertaining to the number of medications, which could overestimate polypharmacy status, considering the errors that may emerge by inaccurate coding of drug prescription and/or incorrect tabulations conducted electronically.

Conclusions
This systematic review and meta-analysis clearly reported that the problem of polypharmacy in people with sarcopenia may be critical, considering its significantly increased prevalence compared with populations without sarcopenia. Polypharmacy is associated with several negative clinical outcomes in older people, including sarcopenia, raising critical questions regarding appropriate versus inappropriate drug prescription. Future research should clarify if polypharmacy is a direct contributor in accelerating the progression of sarcopenia and if inappropriate deprescribing could decelerate its progression.