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 Table of Contents  
ORIGINAL ARTICLE
Year : 2016  |  Volume : 23  |  Issue : 4  |  Page : 202-208

Difference in occurrence of muscle-related adverse effects of statins among male and female geriatric patients: A cross-sectional observational study


1 Department of Pharmacology, All India Institute of Medical Sciences, New Delhi, India
2 Department of Geriatric Medicine, All India Institute of Medical Sciences, New Delhi, India

Date of Web Publication20-Dec-2016

Correspondence Address:
Yogendra Kumar Gupta
Department of Pharmacology, All India Institute of Medical Sciences, New Delhi
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/1117-1936.196262

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  Abstract 

Background: Statins are the most widely used agents for the treatment of dyslipidaemias in geriatric patients. Muscle-related adverse effects (MRAE) are one of the most common toxicities of statins. Female gender has been mentioned as the risk factor for the development of MRAE of statins; however, there are inconclusive data regarding the difference in the occurrence of MRAE among male and female geriatric users.
Objectives: The main objective was to find the difference in the occurrence of MRAE of statins among male and female geriatric statin users.
Methods: In this cross-sectional, observational, comparative study, relevant patient information and MRAE associated with statin use were noted. Creatine phosphokinase (CPK) levels were obtained for all patients as this is considered as the marker for statin-induced muscle damage. The parameters were compared among male and female geriatric statin users.
Results: 172 geriatric patients (86 male and 86 female statin users) were enrolled in the study. 38 (22%) geriatric statin users were found to have MRAE and significantly more number of female patients had MRAE as compared to male patients (25 vs. 13 P = 0.02). Significantly more number of female patients had elevated CPK as compared to male patients (20 vs. 8, P = 0.01). No significant difference was observed in CPK levels among male and female statin users.
Conclusions: Statin-induced MRAE tend to occur with more frequency in geriatric female patients as compared to male geriatric patients; however, further research in the form of prospective studies is warranted.

Keywords: Atorvastatin, creatine phosphokinase, dyslipidaemia, gender, rosuvastatin


How to cite this article:
Singh H, Chakrawarti A, Guruprasad P, Singh H, Gupta YK. Difference in occurrence of muscle-related adverse effects of statins among male and female geriatric patients: A cross-sectional observational study. Niger Postgrad Med J 2016;23:202-8

How to cite this URL:
Singh H, Chakrawarti A, Guruprasad P, Singh H, Gupta YK. Difference in occurrence of muscle-related adverse effects of statins among male and female geriatric patients: A cross-sectional observational study. Niger Postgrad Med J [serial online] 2016 [cited 2020 Apr 1];23:202-8. Available from: http://www.npmj.org/text.asp?2016/23/4/202/196262


  Introduction Top


Statins or 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors are the most effective agents in reducing low-density lipoprotein-cholesterol and treatment of dyslipidaemias. [1] Apart from lipid lowering, they exert pleiotropic beneficial effects including decreased oxidative stress and vascular inflammation with increased stability of atherosclerotic lesions. [2] Muscle-related adverse effects (MRAE) of statins range from a painless increase in serum creatine phosphokinase (CPK) levels that do not exceed ten times the upper limit of normal (ULN), to a mild muscular discomfort (myalgia), to a potentially life-threatening rhabdomyolysis raising CPK levels to beyond ten times the ULN, leading to renal dysfunction or failure. [3],[4],[5] MRAE affect 10%-15% patients, [6] and they have not been addressed properly in most of the clinical trials and the real world prevalence is more [7],[8]

There are inconclusive data regarding the prevalence of MRAE among male and female statin users. In literature, the female gender has been mentioned as the risk factor for the development of MRAE of statins. [9],[10],[11],[12] Advancing age is associated with certain changes in body composition and function, including reduction in hepatic and renal functions that alter the pharmacodynamics and pharmacokinetics of drugs. [13] Other important factor is the likelihood of polypharmacy leading to interactions between statins and other drugs. The geriatric patients are more likely to experience consequences of drug intensification leading to the manifestation of adverse effects, such as statin-related MRAE. [14]

To date, there have been relatively few reports on relationships between advancing age and the gender-specific incidence of MRAE of statins. There are limited data indicating that women have increased risk of developing statin-induced MRAE compared with men. [3],[15]

Advancing age and female gender are likely to be associated with more MRAE of statins as compared to younger and male patients. There is a need to explore this relationship, i.e., advancing age, female gender and occurrence of MRAE of statins. In the relative vacuum of female-specific data on relationships between advancing age, statin use and muscle dysfunction, the main objective of this observational study was to find the difference in the occurrence of MRAE of statins in male and female geriatric patients.


  Methods Top


The study was approved by the Institutional Ethics Committee of the All India Institute of Medical Sciences (AIIMS), New Delhi, India vide Ref No. IESC/T-270/23.06.2015. Written informed consent was obtained from all the patients before enrolling them in the study.

Study design and participants

This study was designed as a single centre, cross-sectional, observational study which was conducted in the Department of Geriatric Medicine and Department of Pharmacology of the AIIMS, New Delhi, India, for a duration of 4 months (from August to November, 2015). Geriatric statin users (age ≥60 years) were screened and enrolled in the study. Patients with a history of active trauma, active arthritis of any type, acute infectious diseases and other conditions presenting with myalgia and bodily pains were excluded from the study. Relevant patient information such as statin received, indication for statin, duration of treatment, any concomitant medications and MRAE associated with statin use was noted. CPK levels were obtained for all patients as this is considered as the marker for statin-induced muscle damage. Data obtained from all patients were noted in the case report form.

Statistical analysis

Assuming an effect size of 5%, the sample size for the difference in proportions was calculated with a precision of 3% and level of significance of 0.95, the sample size required was 172, i.e. 86 in each group. Data were analysed using the statistical software "R" version 3.2.2. Data were represented as percentages, mean ± standard deviation or median (interquartile range [IQR] 1 − IQR 3) wherever applicable. Categorical data were analysed using Chi-square test and Fisher exact test (wherever applicable). Continuous variables were analysed using t-test (for parametric data) or Mann-Whitney test (for non-parametric data) to find the difference among two groups and one-way ANOVA (for parametric data) to find the difference among more than two groups. Pearson's correlation method was used to find the correlation between doses of satins and CPK levels. P < 0.05 was considered statistically significant.


  Results Top


As per sample size calculation, 172 geriatric patients (86 male and 86 female statin users) were enrolled in this study. Various characteristics of male and female statin users and comparison of various parameters among them are given in [Table 1].
Table 1: Comparison of various parameters among male and female statin users


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Statins prescribed

Of 172 patients, 134 (78%) were taking atorvastatin and 38 (22%) were taking rosuvastatin. 73 male and 61 female patients were taking atorvastatin (no significant difference found, P = 0.21, Chi-square test) while 13 male and 25 female patients were taking rosuvastatin (significant difference found, P = 0.02, Chi-square test).

Dose of statins

Ninety-seven patients were taking atorvastatin in a dose of 10 mg/day, 31 were taking 20 mg/day and 6 were taking 40 mg/day. 29 patients were taking rosuvastatin in a dose of 5 mg/day, 8 were taking 10 mg/day, 1 was taking 20 mg/day and none of the patient had taken a dose >20 mg/day.

Duration of statin use

The median duration of statin use was 24 (6-36) months (24 [6-36] months in male patients vs. 24 [6-36] months in female patients, P = 1.00, Mann-Whitney test).

Number of concomitant drugs

The mean number of concomitant drugs was 3.6 ± 1.04 (3.6 ± 1.07 in male patients vs. 3.6 ± 1.01 in female patients, P = 0.9, t-test).

Muscle-related adverse effects

Thirty-eight (22%) geriatric statin users were found to have MRAE consisting of 25 females and 13 males. 29% of female and 15% of male patients were found to have MRAE (P = 0.02, Chi-square test, [Table 2]). The difference in the occurrence of MRAE among male and female statin users was found to be statistically significant. Of 38 patients with MRAE, 10 patients had myalgia, 21 had myositis and 7 patients had asymptomatically elevated CPK levels (without myalgia). Distribution of different types of MRAE is given in [Table 2].
Table 2: Comparison of number of different types of muscle-related adverse effects among male and female statin users


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Comparison of various parameters among statin users with and without muscle-related adverse effects

Various parameters were compared between patients who developed MRAE and who did not develop MRAE. [Table 3] summarises the characteristics and comparison of various parameters between statin users who developed MRAE with those who did not develop MRAE.
Table 3: Comparison of various parameters between patients who developed muscle-related adverse effects and who did not develop muscle - related adverse effects


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Comparison of various parameters among male and female statin users who developed muscle-related adverse effects

Various parameters were compared between male and female statin users who developed MRAE. [Table 4] summarises the characteristics and comparison of various parameters between male and female statin users who developed MRAE.
Table 4: Comparison of various parameters between male and female statin users who developed muscle - related adverse effects


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Muscle-related adverse effects with statins

Of 134 patients who were taking atorvastatin, 31 (23%) were found to have MRAE, and of 38 rosuvastatin users, 7 (18%) had MRAE. This difference was not found to be statistically significant (P = 0.53, Chi-square test).

Onset of myalgia

Thirty-one patients (20 female and 11 male patients) developed myalgia with a median duration of 20 months from the start of therapy (22 months in female and 12 months in male patients). The difference in the duration of onset of myalgia from the start of therapy was not found to be statistically significant among male and female statin users (P = 0.07, [Table 4]).

Creatine phosphokinase levels

Twenty-eight statin users were found to have raised CPK levels (8 male stain users vs. 20 female statin users, P = 0.01, Chi-square test, [Table 1]). The mean CPK levels in all 172 patients were 136.4 U/L (minimum 17 U/L, maximum 567 U/L). The difference in CPK levels among male and female statin users was not found to be statistically significant (123 ± 100 U/L in male patients vs. 149.8 ± 95.6 U/L in female patients, P = 0.07, t-test, [Table 1]).

Significant difference was observed in CPK levels between statin users who developed MRAE and who did not develop MRAE, i.e., 240.5 U/L (194-298) versus 88.5 U/L (72-126), P < 0.001 (Mann-Whitney test) while no significant difference was observed in CPK levels among male and female statin users who developed MRAE, i.e., 241 U/L (149-356) versus 240 U/L (232-275), P = 0.91 (Mann-Whitney test). A weak positive but significant correlation was observed between different doses of atorvastatin and CPK levels as calculated by Pearson's correlation method (r = 0.27, P = 0.001). However, a weak negative but insignificant correlation was observed between different doses of rosuvastatin and CPK levels (r = −0.15, P = 0.35).

Comparison of creatine phosphokinase levels at different doses of statins in all patients

A dose-dependent increase in CPK levels was observed among patients taking different doses of atorvastatin, i.e., 120.6 ± 84.68 U/L at 10 mg, 176.8 ± 127.1 U/L at 20 mg and 215 ± 109.1 U/L at 40 mg (P = 0.003, one-way ANOVA). However, no dose-dependent trend was observed between different doses of rosuvastatin and CPK levels, i.e., 116 U/L (80-169.5 U/L) at 5 mg, 91 U/L (66.7-210.5 U/L) at 10 mg, P = 0.70; Note: data represented as median [IQR] and analysed by Mann-Whitney test).


  Discussion Top


This study was planned to explore the difference in the occurrence of statin-associated MRAE among male and female geriatric patients. The majority of the patients were taking atorvastatin. This finding is similar to that of study done by Choudhry et al., [16] in which they found that atorvastatin accounts for about 90% of prescription in India while rosuvastatin was prescribed in a fewer number of patients. In our study, 38 (22%) geriatric statin users were found to have MRAE and this percentage is higher than the most commonly described prevalence in literature, i.e., 10%-15%. [6],[7],[15] This percentage is also much higher than the data generated from randomised clinical trials. [7],[8]

Of 38 statin users (with MRAE), 10 had myalgia, 21 had myositis and 7 had asymptomatically elevated CPK levels and none of the patients presented with rhabdomyolysis. We found a dose-dependent trend in the occurrence of MRAE. The mean dose of atorvastatin was 17.1 ± 9.01 and 12.6 ± 6.09 in patients with MRAE and without MRAE, respectively (P < 0.001), while mean dose of rosuvastatin was 7.8 ± 2.67 in those with MRAE versus 6.1 ± 3.08 in those without MRAE (P = 0.002). In PRIMO study [17] done on 7924 French outpatients, 10.5% of patients had MRAE and atorvastatin 40-80 mg alone led to 14.9% of MRAE. Buettner et al. [18] in their study on 3580 adults over the age of 40 years found that 22% statin users had musculoskeletal pain in at least one anatomic region in the last 30 days, compared with 16.7% in non-statin users. Murakami et al. [19] reported that all 5 statins (pravastatin, simvastatin, atorvastatin, rosuvastatin and cerivastatin) were associated with 5 MRAE in both male and female patients. Our findings are similar to that of the above study as both atorvastatin and rosuvastatin led to MRAE.

In our study, significantly more number of MRAE occurred in patients who were taking more number of concomitant drugs. Any concomitant use of drugs that could increase plasma concentration of statins or alter statin pharmacodynamics, including statin response at the tissue level, increases the risk for developing MRAE. Furthermore, significantly more number of patients with MRAE were taking fibrates as compared to patients without MRAE (13 vs. 3, P < 0.001). Two patients were taking gemfibrozil while 11 were taking fenofibrate among those patients who developed MRAE. Fibrates can increase plasma levels of statins and, thus, the risk for muscle toxicity. An increased risk of muscle toxicity, as high as 1%-5%, has been described with the fibrates. [20],[21] Graham et al. found that average incidence of hospitalisation for rhabdomyolysis was 5.98 per 10,000 patient-years for patients treated with statins in combination with a fibrate and this was approximately 10-fold higher with the combination of fibrates and statins than with statin monotherapy. [22]

Although fenofibrate carries a lower risk for causing MRAE as compared to gemfibrozil, the literature suggests few reports of statin plus fenofibrate combination as well as fenofibrate monotherapy-associated MRAE. [23],[24],[25] Proposed mechanisms for this interaction are: both fibrates and statins are highly protein bound, displacement of statins by fibrates may lead to MRAE, fibrates also interfere with OATP1B1-mediated transport of the statin into the hepatocytes and a previously unrecognised metabolic pathway for elimination of the hydroxy acid forms of statins through glucuronidation have been proposed. [24],[25]

Hypothyroidism (untreated) has also been described as a risk factor for the development of MRAE of statins. [9],[10],[11],[12] Possible explanations for how hypothyroidism might enhance statin myopathy include decreased clearance of CPK or decreased drug catabolism, resulting in higher serum statin levels. [26],[27],[28] In our study, a total of 10 patients were found to have hypothyroidism, but no significant difference was observed with respect to number of hypothyroid patients who had MRAE and who had no MRAE (4 vs. 6, P = 0.23). The possible explanation for this is that all 10 patients were taking treatment for hypothyroidism. We did not estimate the thyroid functions in our study patients, and therefore, we are not able to comment on the possibility of inclusion of some undiagnosed hypothyroid patients.

We did not observe any significant difference among patients who developed MRAE and those who did not develop MRAE regarding the number of potential interacting drugs (CYP inhibiting drugs). Few patients in our study were taking CYP 3A4 inhibiting drugs, but the difference across patients with and without MRAE was not statistically significant. In literature, many potential clinically significant interactions have been described; however, these generally occur at higher doses of statins and most of these reports recommend lowering of the dose of statins. [29],[30],[31]

We observed that patients with MRAE had significantly lower body weight as compared to those without MRAE (P = 0.006, [Table 3]). We also observed lower mean height and lower body mass index (BMI) among patients who developed MRAE as compared to those without MRAE (though not significant). In the literature, lower BMI, lower body weight, frailty and short body stature have been described as the risk factors for the development of statin-induced MRAE [9],[10],[11],[12] because these can lead to more muscle damage.

In our study, the median time for onset of myalgia was 20 months (22 months in female and 12 months in male patients with a range of 0.36-83 months). The difference in the duration of onset of myalgia was not significant [Table 4], but male users had a trend of lower duration for the onset of myalgia as compared to female patients. Our finding differs from that of study done by Hansen et al., [32] in which they found a mean duration of statin therapy before symptom onset of 6.3 months with a range from 0.25 to 8 months.

We found a statistically significant gender-based difference with regard to the occurrence of MRAE: 25 female statin users (29%) and 13 male statin users (17.4%) were found to have statin-associated MRAE (P = 0.02, [Table 2]). The current findings regarding gender-associated risks with statin use are equivocal, and we came across only one study which obtained similar results. In a retrospective study (Fung and Crook) [33] done on 1056 stain users, 10.5% were found to have MRAE. They also found a significant gender-based difference with regard to the occurrence of MRAE. [33] A recent meta-analysis did not detect any gender-specific difference in statin-related adverse effects. However, the authors reported that women seemed to be underrepresented in clinical trials involving statins. [34]

In our study, 23% atorvastatin users (n = 31) and 18% (n = 7) rosuvastatin users were found to have MRAE. All 13 male patients with MRAE were taking atorvastatin (surprisingly none of the male patients developed MRAE with rosuvastatin) while out of 25 female patients with MRAE, 18 were taking atorvastatin and 7 were taking rosuvastatin. The difference in number of patients who developed MRAE with different doses of statins was not found to be statistically significant.

Atorvastatin is a lipophilic statin while rosuvastatin is hydrophilic in nature. Theoretically, lipophilic statins are supposed to cause more muscle damage as they penetrate myocyte membrane more efficiently as compared to hydrophilic. Females tend to have a higher percentage of body fat, which affects the volume of distribution of some drugs and can significantly increase the half-life of lipophilic statins. [10],[13] Drug doses in geriatric patients are rarely titrated based on body weight and this may expose elderly female to higher doses. Significantly higher mean physiological levels of CoQ10 have been reported in males compared to females. [10] In our study, we did not estimate the levels of CoQ10; therefore, we are not able to comment on the possibility of association of lower CoQ10 levels with MRAE. Furthermore, there is a tendency for females to be more sensitive to pain and to describe pain as being more severe and recurrent in nature compared with males. [10],[35]

In our study, 28 patients were found to have elevated levels of CPK. Significantly higher number of female statin users had elevated levels of CPK as compared to male users (20 vs. 8, P = 0.01, [Table 1]). We observed a significant difference in CPK levels among patients who developed MRAE and those who did not develop MRAE (P < 0.001, [Table 3]). Female statin users had higher means levels (but not significant) of CPK as compared to male statin users and no statistically significant difference in CPK levels was observed among male and female statin users who developed MRAE.

We observed a dose-dependent pattern between increasing doses of pattern and CPK levels as higher values of CPK were observed in patients taking atorvastatin 20 and 40 mg/day (P = 0.003) as compared to those taking atorvastatin 10 mg/day. Dose-dependent nature of MRAE (including CPK levels) is commonly described in literature; [16],[18],[19],[23],[26],[33] however, we are not able to comment on this finding as our study was not adequately powered to detect this difference. Elevated CPK is a marker of muscle damage, but we observed inconsistent findings in our study as all patients with MRAE did not present with raised CPK levels (10 patients had myalgia without elevated CPK) and 7 patients had raised CPK levels without myalgia.

Our finding of raised CPK among patients with MRAE is similar to that of study done by Fung and Crook, [33] in which they also observed a significance difference in CPK levels (P = 0.02) among patients who developed MRAE and who did not develop MRAE. Our finding of normal CPK in few patients with myalgia is similar to that of study done by Phillips et al., [36] where they reported that some patients who develop muscle symptoms while receiving statin therapy have demonstrable weakness and histopathologic findings of myopathy despite normal serum CPK levels. We did not perform muscle biopsy of patients with MRAE; hence, we are not able to comment on the relationship of raised CPK levels with the histopathological changes of muscle damage, if any, in our study patients who had muscle symptoms. Furthermore, baseline CPK levels were not obtained, and therefore, we are not able to comment on the change in CPK levels after starting statin therapy. The American College of Cardiology/American Heart Association/National Heart, Lung and Blood Institute guidelines [6] recommend baseline measurements of CPK to evaluate muscle complaints. Although some experts [6],[37] have advocated discontinuing statin therapy with symptomatic CPK elevation >10 times the ULN, others [38],[39] have recommended more conservative management by discontinuing statins with a lesser CPK elevation (3-10 times of ULN) or an asymptomatic CPK elevation.

Strengths of our study

1. To the best of our knowledge, this is the first study in India which attempted to find the gender-based difference in occurrence of statin-induced MRAE among geriatric patients

2. The primary objective of our study was a safety parameter which is different from many other studies which addressed statin-induced MRAE as a secondary objective.

Limitations of our study

1. No follow-up was done

2. We did not obtain muscle biopsy for patients who had MRAE. However, we obtained CPK levels for all study participants

3. Myalgia is a subjective symptom and pain perception may vary from patient to patient.


  Conclusions Top


Statin-induced MRAE tend to occur with more frequency in female geriatric patients as compared to male geriatric patients. However, due to cross-sectional nature of this study and other limitations, the results cannot be generalised and require further validation.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.

 
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  [Table 1], [Table 2], [Table 3], [Table 4]



 

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