Advertisement

Metabolic syndrome is associated with muscle symptoms among statin users

      Highlights

      • Prior studies show muscle symptoms associated with statin use.
      • Statin-associated muscle symptoms were assessed in relation to metabolic syndrome.
      • Metabolic syndrome predicted increased statin-associated muscle symptoms.

      Background

      Muscle symptoms have been associated with statin use, but the relationship of statin-associated muscle symptoms with metabolic syndrome (MS) has not been reported previously.

      Objective

      To evaluate the relationships between MS and its individual components with statin-associated muscle symptoms.

      Methods

      Data were analyzed from the Understanding Statin Use in America and Gaps in Education (USAGE) study. Modified criteria to define the MS were used based on self-reported survey data.

      Results

      Among USAGE subjects, the MS was present in 1364 of 3992 men (34.2%) and in 1716 women of 6149 women (27.9%). Subjects with the MS were 19% more likely (P = .0002) to report new or worsening muscle symptoms while on a statin. Three MS criteria—increased BMI, elevated triglycerides (TG), and low high-density lipoprotein cholesterol (HDL-C)—were associated with increased odds of muscle symptoms, by 18%, 32%, and 28%, respectively (all P < .001). The presence of MS also predicted increased odds of having discontinued a statin due to muscle symptoms (13% higher, P = .043). Among criteria for the MS, elevated TG (38% higher odds, P < .0001) and low HDL-C (37% higher odds, P = .0003) were positively associated with statin discontinuation, whereas hypertension (13% lower odds, P = .019) and diabetes mellitus (12% lower odds, P = .036) were inversely associated.

      Conclusion

      USAGE participants with MS were more likely to report experiencing muscle symptoms while taking a statin and to have discontinued a statin due to muscle symptoms. This appears to be attributable mainly to associations of muscle symptoms with elevated TG and low HDL-C levels. Additional research is warranted to confirm and further investigate these associations.

      Keywords

      Introduction

      Muscle symptoms, primarily pain or weakness, are reported commonly with statin use in clinical practice and may result in changes in, or discontinuation of, statin treatment.
      • Zhang H.
      • Plutzky J.
      • Skentzos S.
      • et al.
      Discontinuation of statins in routine care settings: a cohort study.
      The high frequency of muscle symptoms with clinical use of statin was highlighted by the results from the Understanding Statin Use in America and Gaps in Education (USAGE) study, an Internet-based survey of 10,138 adult US subjects who had been prescribed statins.
      • Cohen J.D.
      • Brinton E.A.
      • Ito M.K.
      • Jacobson T.A.
      Understanding Statin Use in America and Gaps in Patient Education (USAGE): an internet-based survey of 10,138 current and former statin users.
      Fully 29% of study participants reported new or worsening muscle symptoms while taking a statin. Furthermore, 15% of USAGE subjects reported having stopped a statin (at least temporarily) due to muscle symptoms during a mean of approximately 11 years between diagnosis of dyslipidemia and taking the survey.
      • Cohen J.D.
      • Brinton E.A.
      • Ito M.K.
      • Jacobson T.A.
      Understanding Statin Use in America and Gaps in Patient Education (USAGE): an internet-based survey of 10,138 current and former statin users.
      Subsequent analyses of the USAGE data set further explored the setting in which statins were changed or stopped (temporarily or permanently),
      • Wei M.Y.
      • Ito M.K.
      • Cohen J.D.
      • Brinton E.A.
      • Jacobson T.A.
      Predictors of statin adherence, switching, and discontinuation in the USAGE survey: understanding the use of statins in America and gaps in patient education.
      and the 28% of respondents with self-reported diabetes mellitus (DM) were found to have 13% lower odds for having discontinued statin treatment due to muscle symptoms, although they were no less likely to report such symptoms.
      • Ito M.K.
      • Maki K.C.
      • Brinton E.A.
      • Cohen J.D.
      • Jacobson T.A.
      Muscle symptoms in statin users, associations with cytochrome P450, and membrane transporter inhibitor use: a subanalysis of the USAGE study.
      It is speculated that the reason for the lower rate of statin discontinuation was that the respondents with DM were more likely to view statin therapy as important, or even life-saving, because DM is well-known to substantially increase the risk of atherosclerotic cardiovascular disease (ASCVD), and statins are well-established to reduce ASCVD risk.
      • Baigent C.
      • Blackwell L.
      • Emberson J.
      • et al.
      Efficacy and safety of more intensive lowering of LDL cholesterol: a meta-analysis of data from 170,000 participants in 26 randomised trials.
      DM is common in the US adult population, reported to be present in 29.1 million or 9.3% of adults, the overwhelming majority of whom have type 2 diabetes.
      Centers for Disease Control and Prevention
      National Diabetes Statistics Report: Estimates of Diabetes and Its Burden in the United States.
      The metabolic syndrome (MS) is a constellation of metabolic and hemodynamic abnormalities that often occur together and are pathophysiologically related to excess adiposity and insulin resistance.
      Centers for Disease Control and Prevention
      National Diabetes Statistics Report: Estimates of Diabetes and Its Burden in the United States.
      • Grundy S.M.
      Metabolic syndrome: connecting and reconciling cardiovascular and diabetes worlds.
      MS is nearly four-fold more common than DM, with an age-adjusted prevalence of 34.7% among US adults.
      • Aguilar M.
      • Bhuket T.
      • Torres S.
      • Liu B.
      • Wong R.J.
      Prevalence of the metabolic syndrome in the United States, 2003-2012.
      MS raises the risk of incident DM, and both MS and DM raise the risk of ASCVD events.
      • Grundy S.M.
      Metabolic syndrome: connecting and reconciling cardiovascular and diabetes worlds.
      • Mottillo S.
      • Filion K.B.
      • Genest J.
      • et al.
      The metabolic syndrome and cardiovascular risk a systematic review and meta-analysis.
      • Sperling L.S.
      • Mechanick J.I.
      • Neeland I.J.
      • et al.
      The CardioMetabolic Health Alliance: Working Toward a New Care Model for the Metabolic Syndrome.
      Given the well-established ability of statins to reduce ASCVD risk,
      • Baigent C.
      • Blackwell L.
      • Emberson J.
      • et al.
      Efficacy and safety of more intensive lowering of LDL cholesterol: a meta-analysis of data from 170,000 participants in 26 randomised trials.
      they are often indicated in MS patients. Importantly, however, statins also increase the risk of new-onset DM as documented both in randomized clinical trials
      • Sattar N.
      • Preiss D.
      • Murray H.M.
      • et al.
      Statins and risk of incident diabetes: a collaborative meta-analysis of randomised statin trials.
      • Waters D.D.
      • Ho J.E.
      • Boekholdt S.M.
      • et al.
      Cardiovascular event reduction versus new-onset diabetes during atorvastatin therapy: effect of baseline risk factors for diabetes.
      and in observational studies.
      • Corrao G.
      • Ibrahim B.
      • Nicotra F.
      • et al.
      Statins and the risk of diabetes: evidence from a large population-based cohort study.
      • Mansi I.
      Statin Adverse Events in Primary Prevention: Between Randomized Trials and Observational Studies.
      • Culver A.L.
      • Ockene I.S.
      • Balasubramanian R.
      • et al.
      Statin use and risk of diabetes mellitus in postmenopausal women in the Women's Health Initiative.
      • Maki K.C.
      • Ridker P.M.
      • Brown W.V.
      • Grundy S.M.
      • Sattar N.
      The Diabetes Subpanel of the National Lipid Association Expert P
      An assessment by the Statin Diabetes Safety Task Force: 2014 update.
      This increase is especially prominent in patients at higher underlying risk to develop DM, such as those with MS.
      • Waters D.D.
      • Ho J.E.
      • DeMicco D.A.
      • et al.
      Predictors of new-onset diabetes in patients treated with atorvastatin: results from 3 large randomized clinical trials.
      Unfortunately, despite both the heightened benefits and risks of statin use in MS, the relationships of MS, or its components, with the most common statin-related adverse event, muscle symptoms, are not well-known. The primary objective of the current analysis was to explore these relationships in the USAGE database by assessing whether those with MS differed from those without MS with respect to the frequency of reported muscle symptoms while on a statin, or the cessation of statin treatment in response to such symptoms.

      Methods

      USAGE study subjects

      Subjects for USAGE (Understanding Statin Use in America and Gaps in Education) were recruited from among participants in the Ailment Panel of Lightspeed Online Research (Lightspeed Consumer Panel 2009),
      • Cohen J.D.
      • Brinton E.A.
      • Ito M.K.
      • Jacobson T.A.
      Understanding Statin Use in America and Gaps in Patient Education (USAGE): an internet-based survey of 10,138 current and former statin users.
      who had previously consented to participate in periodic Internet-based surveys about health and health care and who were reasonably representative of the general US adult population.
      • Cohen J.D.
      • Brinton E.A.
      • Ito M.K.
      • Jacobson T.A.
      Understanding Statin Use in America and Gaps in Patient Education (USAGE): an internet-based survey of 10,138 current and former statin users.
      Of the 27,946 individuals with high cholesterol identified and invited by e-mail to participate in the survey, 15,346 (54.9%) responded, and of those, 10,138 were found to be eligible, having reported receiving a diagnosis of hypercholesterolemia from a health care provider from whom they also received at least one prescription for a statin. Participants completed an 89-question Internet survey.
      • Cohen J.D.
      • Brinton E.A.
      • Ito M.K.
      • Jacobson T.A.
      Understanding Statin Use in America and Gaps in Patient Education (USAGE): an internet-based survey of 10,138 current and former statin users.
      Prospective subjects were not informed of the purpose of the USAGE survey when they were recruited to participate, minimizing the likelihood of selection bias.

      Primary analyses

      This report focuses primarily on assessing the associations of MS with two dependent variables. First was the response to the question, “Have you ever experienced new or worsening muscle symptoms while taking a statin?” Muscle symptoms were defined in the survey as pain, weakness, cramps, or aching. Second was the response to the question “Have you ever stopped taking a statin for muscle symptoms?” No distinction was made between those who stopped a statin temporarily (then resumed) or switched to another statin. Those off of a statin at the time of the survey were not included in this analysis because their reason for “permanent” statin cessation was not queried.

      Definition of MS

      A commonly used definition of MS
      • Alberti K.G.
      • Eckel R.H.
      • Grundy S.M.
      • et al.
      Harmonizing the metabolic syndrome: a joint interim statement of the International Diabetes Federation Task Force on Epidemiology and Prevention; National Heart, Lung, and Blood Institute; American Heart Association; World Heart Federation; International Atherosclerosis Society; and International Association for the Study of Obesity.
      was adapted for use in the current analysis. It defines MS as the presence of 3 or more of 5 standard components, all based on objective data. Because, however, the USAGE study consisted solely of self-reported information, the components were modified to use available information (see Table 1).
      Table 1Operational definition of the metabolic syndrome (≥3 of the 5 criteria) used for the present study
      Metabolic syndrome componentCorresponding self-report criterion
      Elevated blood pressureDiagnosed hypertension
      Elevated waist circumferenceBMI ≥28.7 kg/m2 (men) or 26.2 kg/m2 (women)
      Estimated waist circumference >40 inches (101.6 cm; men) or >35 inches (88.9 cm; women) based on body mass index (BMI) calculated from reported height and weight. Calculated using the following regression equations: waist (men) in cm = 39.05 + (2.18 × BMI in kg/m2); waist (women) in cm = 35.20 + (2.05 × BMI in kg/m2) from Liu A et al. Nutr Metab Cardiovasc Dis 2011; 21:553–560.
      Elevated triglyceridesTriglycerides ≥150 mg/dL
      Reported triglycerides ≥150 mg/dL at diagnosis and/or at the most recent blood draw.
      Low HDL-CHDL-C <40 (men) or <50 mg/dL (women)
      Reported high-density lipoprotein cholesterol (HDL-C) <40 (men) or <50 (women) mg/dL at diagnosis and/or at the most recent blood draw.
      Elevated glucoseDiagnosed diabetes mellitus
      Estimated waist circumference >40 inches (101.6 cm; men) or >35 inches (88.9 cm; women) based on body mass index (BMI) calculated from reported height and weight. Calculated using the following regression equations: waist (men) in cm = 39.05 + (2.18 × BMI in kg/m2); waist (women) in cm = 35.20 + (2.05 × BMI in kg/m2) from Liu A et al. Nutr Metab Cardiovasc Dis 2011; 21:553–560.
      Reported triglycerides ≥150 mg/dL at diagnosis and/or at the most recent blood draw.
      Reported high-density lipoprotein cholesterol (HDL-C) <40 (men) or <50 (women) mg/dL at diagnosis and/or at the most recent blood draw.
      First, instead of having a measured blood pressure over the MS thresholds of 130/85-mm Hg for systolic or diastolic pressure, respectively, the survey provided had self-report of having received a diagnosis of “high blood pressure” or “hypertension” (not defined in the questionnaire but presumably meaning blood pressure >140/90 mm Hg). The 65.8% of participants who responded affirmatively were considered to have the elevated blood pressure criterion for MS.
      Second, although the USAGE survey asked about waist girth, directly or as pant size, only 64.0% of respondents provided either type of information. A much higher 96.4% of USAGE subjects provided their body weight and height, allowing calculation of an estimated body mass index (BMI) in nearly all subjects. Measured BMI is highly correlated with measured waist girth,
      • Liu A.
      • Abbasi F.
      • Reaven G.M.
      Adiposity indices in the prediction of metabolic abnormalities associated with cardiovascular disease in non-diabetic adults.
      whereas self-reported BMI correlated modestly with self-reported waist girth among USAGE respondents who gave both types of responses (r = 0.23 and 0.44 for men and women, respectively). Waist girth above 40 inches (101.6 cm) in men and 35 inches (88.9 cm) in women are thresholds for MS components from the original ATP III definition. Alternative thresholds have been suggested for specific ethnic and/or racial groups,
      • Alberti K.G.
      • Eckel R.H.
      • Grundy S.M.
      • et al.
      Harmonizing the metabolic syndrome: a joint interim statement of the International Diabetes Federation Task Force on Epidemiology and Prevention; National Heart, Lung, and Blood Institute; American Heart Association; World Heart Federation; International Atherosclerosis Society; and International Association for the Study of Obesity.
      but because ∼94% of USAGE respondents were non-Hispanic white or black, we chose a BMI above 28.7 kg/m2 for men and 26.2 kg/m2 for women as the marker for the increased waist girth criterion for MS for all participants in the current analysis. These cutoffs predict waist girth above the standard MS thresholds for Caucasians based on the regression equations published by Liu et al. as follows:
      • Liu A.
      • Abbasi F.
      • Reaven G.M.
      Adiposity indices in the prediction of metabolic abnormalities associated with cardiovascular disease in non-diabetic adults.
      Waist (men) in cm = 39.05 + (2.18 × BMI in kg/m2);
      Waist (women) in cm = 35.20 + (2.05 × BMI in kg/m2).
      In addition, the USAGE questionnaire asked participants to report whether their level of triglycerides (TG) was ≥150 mg/dL, and if their high-density lipoprotein cholesterol (HDL-C) level was <40 mg/dL (men) or <50 mg/dL (women) at diagnosis or at the time of their most recent lipid measurements. If they responded affirmatively for either or both time points, they were considered to have the elevated TG or low HDL-C criterion for MS, respectively.
      Finally, because individuals are unlikely to know if they have impaired fasting glucose, the USAGE questionnaire did not ask for that information but asked instead if the subject had received a diagnosis of diabetes mellitus (DM). Among USAGE subjects, 27.7% answered affirmatively to this question, and this criterion was used in the current analyses in place of the standard criterion of impaired fasting glucose.

      Statistical analyses

      Statistical analyses were completed using SAS, version 9.3, or higher (SAS Institute, Cary, NC). Inferential statistical tests were completed with alpha = 0.05, two-sided. Frequencies of dichotomous variables were reported as numbers and percentages of subjects (missing values were classified as “not present” for prevalence calculations), and continuous variables are reported as means with standard errors of the mean, standard deviation, or as medians with interquartile range limits. Chi-square tests and t tests were used to evaluate possible differences between groups for dichotomous and continuous variables, respectively. Univariate and multivariate logistic regression modeling were used to assess relationships between independent variables and each of the two primary dependent variables (new or worsening muscle symptoms while taming a statin and stopped a statin due to muscle symptoms), with calculation of odds ratios, 95% confidence intervals (CIs), and P values. Prevalence ratios between men and women are also reported for MS components.

      Results

      Characteristics of USAGE subjects

      Of the 10,138 subjects, 88% (n = 8918) reported current statin use, and 12% (n = 1220) reported no current statin use (former statin users).
      • Cohen J.D.
      • Brinton E.A.
      • Ito M.K.
      • Jacobson T.A.
      Understanding Statin Use in America and Gaps in Patient Education (USAGE): an internet-based survey of 10,138 current and former statin users.
      The mean age of the subjects was 61 years (Standard deviation, 9.9), and 61% were women. Detailed demographic information regarding the USAGE subjects has been published previously.
      • Cohen J.D.
      • Brinton E.A.
      • Ito M.K.
      • Jacobson T.A.
      Understanding Statin Use in America and Gaps in Patient Education (USAGE): an internet-based survey of 10,138 current and former statin users.

      Frequencies of MS and its components

      Frequencies of MS components in the overall USAGE sample and among those classified as having MS by gender are shown in Table 2. The most common criterion was elevated blood pressure in 65.8% of all subjects and 93.1% of those with MS. This was followed closely by elevated BMI (as a surrogate for increased waist girth) in 62.2% of all subjects and 91.3% of those with MS. The least commonly reported component was low HDL-C, reported only in 17.7% of the overall sample and 40.1% of those with MS.
      Table 2Prevalence of individual metabolic syndrome criteria in the overall sample and in subjects with metabolic syndrome (overall and by gender)
      Component
      Metabolic syndrome components defined as described in Table 1.
      AllMenWomenPrevalence ratio men/women, P value
      Number of participants (%)
      Overall sample10,138 (100.0)3992 (39.4)6146 (60.6)0.55
       Hypertension6667 (65.8)2838 (71.1)3829 (62.3)1.14, <.0001
       BMI6310 (62.2)2236 (56.0)4074 (66.3)0.84, <.0001
       Triglycerides2620 (34.6)1215 (40.0)1405 (31.0)1.29, <.0001
       HDL-C1141 (17.7)526 (20.1)615 (16.1)1.25, .0002
       Diabetes2807 (27.7)1289 (32.3)1518 (24.7)1.31, <.0001
      Metabolic Syndrome3080 (100.0)1364 (44.3)1716 (55.7)0.79
       Hypertension2868 (93.1)1277 (93.6)1591 (92.7)1.01, .6146
       BMI2813 (91.3)1200 (88.0)1613 (94.0)0.94, <.0001
       Triglycerides1713 (65.9)803 (68.4)910 (63.9)1.07, .0523
       HDL-C836 (40.1)399 (41.4)437 (38.9)1.06, .4944
       Diabetes2074 (67.3)959 (70.3)1115 (65.0)1.08, .0074
      BMI, body mass index; HDL-C, high-density lipoprotein cholesterol.
      Metabolic syndrome components defined as described in Table 1.
      In the overall study sample, all MS criteria had significantly 14%–31% higher prevalence in men than women, except elevated BMI, which was 16% less prevalent in men than women (P < .0001, Table 2). In contrast, among participants with the MS, only elevated BMI (6% less prevalent in men, P < .0001) and DM (8% more prevalent in men, P = .007) differed significantly between the genders, although high TG trended toward being higher (by 7%) in men (P = .052, see Table 2).
      The numbers of MS criteria present in the overall study sample and by gender are shown in Table 3. Among all participants, only 11.0% reported no MS criteria, 26.2% reported 1, 32.5% had 2, 21.5% had 3, 7.3% had 4, and 1.6% had all 5 criteria. Women were more likely to have 0 or 2 criteria (and trended more likely to have just one), whereas men were significantly more likely than women to have 3, 4, or 5 criteria (all P < .03, Table 3). Among all subjects, 30.4% (n = 3080) had MS, 34.2% (n = 1364) of men and 27.9% (n = 1716) of women, indicating a 23% higher relative MS prevalence among men (P < .0001).
      Table 3Number of metabolic syndrome components overall and by gender
      Number of metabolic syndrome componentsAll, N = 10,138Men, N = 3992Women, N = 6146Prevalence ratio men/women, P value
      Number of Participants (%)
      01111 (11.0)392 (9.8)719 (11.7)0.84, .0125
      12653 (26.2)1006 (25.2)1647 (26.8)0.94, .2022
      23294 (32.5)1230 (30.8)2064 (33.6)0.92, .0145
      32177 (21.5)911 (22.8)1266 (20.6)1.11, .0289
      4742 (7.3)360 (9.0)382 (6.2)1.45, <.0001
      5161 (1.6)93 (2.3)68 (1.1)2.09, <.0001

      Relationships between reported muscle symptoms with MS and its components

      As reported previously, new or worsening muscle symptoms while taking a statin were reported by 29.0% of the USAGE study sample, whereas 15.0% of respondents reported having discontinued a statin due to muscle symptoms.
      • Cohen J.D.
      • Brinton E.A.
      • Ito M.K.
      • Jacobson T.A.
      Understanding Statin Use in America and Gaps in Patient Education (USAGE): an internet-based survey of 10,138 current and former statin users.
      The current analysis found that both were less common in men than in women, with 25.8% vs 31.0% reporting muscle symptoms and 11.6% vs 17.2% changing or discontinuing a statin for these symptoms in men vs women, respectively.
      Univariate logistic regression analyses were conducted to assess the relationships of new or worsening muscle symptoms and having stopped a statin due to muscle symptoms with MS and its component criteria (Table 4). In the overall sample, MS was associated with 19% higher odds for having reported new or worsening muscle symptoms while on a statin (P = .0002). Furthermore, three of the MS criteria—increased BMI, elevated TG and low HDL-C—were associated with increased odds for new or worsening muscle symptoms while on a statin, by 18%, 32% and 28%, respectively (all P < .001). In gender-specific analyses, the association of MS per se with muscle symptoms was somewhat stronger in men (29% higher odds) than women (17% higher odds), but this difference was not sufficiently large to show statistical heterogeneity at the 5% level of significance. In addition, the same three MS criteria that were significant predictors of muscle symptoms in the overall sample were significant predictors within each gender (Table 4).
      Table 4Univariate relationships of metabolic syndrome
      Metabolic syndrome components defined as described in Table 1.
      and its components with (A) new or worsening muscle symptoms while taking a statin, and (B) having stopped a statin due to new or worsening muscle symptoms (overall and by gender)
      Univariate factorOdds ratio95% CIP value
      A. New or worsening muscle symptoms while taking a statin
       All participants
      Metabolic syndrome1.191.09, 1.31.0002
      Hypertension1.000.91, 1.09.9217
      BMI1.181.08, 1.29.0003
      Triglycerides1.321.19, 1.47<.0001
      HDL cholesterol1.281.11, 1.46.0005
      Diabetes1.010.92, 1.12.7928
       Men
      Metabolic syndrome1.291.12, 1.50.0006
      Hypertension0.940.80, 1.10.4135
      BMI1.171.02, 1.36.0285
      Triglycerides1.371.17, 1.62.0001
      HDL cholesterol1.291.04, 1.59.0205
      Diabetes1.100.94, 1.27.2331
       Women
      Metabolic syndrome1.171.04, 1.31.0115
      Hypertension1.060.95, 1.19.2753
      BMI1.141.01, 1.28.0299
      Triglycerides1.341.17, 1.54<.0001
      HDL cholesterol1.311.09, 1.57.0036
      Diabetes1.000.88, 1.13.9737
      B. Stopped taking or changed a statin due to muscle symptoms
       All participants
      Metabolic syndrome1.131.00, 1.27.0430
      Hypertension0.870.78, 0.98.0191
      BMI1.070.96, 1.20.2407
      Triglycerides1.381.21, 1.57<.0001
      HDL cholesterol1.371.16, 1.62.0003
      Diabetes0.880.77, 0.99.0358
       Men
      Metabolic syndrome1.251.03, 1.53.0276
      Hypertension0.780.64, 0.96.0195
      BMI1.140.94, 1.39.1877
      Triglycerides1.521.21, 1.91.0003
      HDL cholesterol1.481.12, 1.96.0062
      Diabetes0.890.72, 1.10.2817
       Women
      Metabolic syndrome1.120.97, 1.30.1182
      Hypertension0.970.85, 1.11.6416
      BMI0.970.84, 1.11.6321
      Triglycerides1.421.20, 1.66<.0001
      HDL cholesterol1.391.12, 1.72.0028
      Diabetes0.920.79, 1.08.2958
      CI, confidence interval; BMI, body mass index; HDL-C, high-density lipoprotein cholesterol.
      Metabolic syndrome components defined as described in Table 1.
      MS was a marginally significant predictor of having ever discontinued statin use due to muscle symptoms in the overall sample (13% higher odds, P = .043, Table 4). Among MS criteria, only elevated TG (38% higher odds, P < .0001) and low HDL-C (37% higher odds, P = .0003) were positively associated with discontinuing a statin for muscle symptoms. In contrast, two of the MS criteria, hypertension (13% lower odds, P = .019) and DM (12% lower odds, P = .036) were inversely associated. MS appeared to be a stronger predictor of statin discontinuation in men (25% increased odds, P = .028) than in women (12% increased odds, P > .05), but this difference was not statistically significant. Elevated TG and low HDL-C were both significant (P < .01) positive predictors of statin discontinuation in both men and women. In contrast, hypertension was a significant inverse predictor (22% lower odds, P = .02) in men. The other MS components showed no statistically significant associations, although the patterns in men and women were similar to those in the overall sample (Table 4).
      Multivariate logistic regression models were used to evaluate the associations between MS and the two primary dependent variables after adjusting for other factors (see results in Table 5). Consistent with the univariate analyses, in models containing MS, age category, sex, and presence of DM, the presence of MS was associated with 30% higher odds for having reported new or worsening muscle symptoms while on a statin and 37% higher odds for reporting having discontinued a statin due to muscle symptoms (P < .0001 for both). For both dependent variables, older age (≥65 years) was associated with increased odds, whereas both male sex and DM were inversely associated (P < .05 for all 3 independent variables, see Table 5). MS remained a statistically significant (P < .01) predictor, with age and sex as the only additional factors in the model (omitting DM), but the magnitude of the relationship was somewhat diminished, showing 22% higher odds for the new or worsening muscle symptoms variable and 17% higher odds for the stopping a statin due to muscle symptoms. Finally, adjustment for other conditions including concomitant medical conditions, BMI by categories, or BMI as a continuous variable, did not materially alter the associations between MS and the two dependent variables (data not shown).
      Table 5Multivariate relationships of metabolic syndrome and selected additional variables with the presence of new or worsening muscle symptoms while taking a statin and having stopped or changed a statin due to new or worsening muscle symptoms
      Univariate factorOdds ratio95% CIP value
      New or worsening muscle symptoms while taking a statin
       Metabolic syndrome1.301.16, 1.46<.0001
       Age ≥65 y1.141.04, 1.24.0046
       Male0.760.70, 0.83<.0001
       Diabetes0.880.78, 1.00.0424
      Stopped taking a statin due to new or worsening muscle symptoms
       Metabolic syndrome1.371.18, 1.58<.0001
       Age ≥65 y1.251.11, 1.39.0001
       Male0.620.55, 0.70<.0001
       Diabetes0.750.65, 0.88.0003

      Discussion

      This analysis of the USAGE survey is the one of the first large studies to explore the relationship between MS and muscle symptoms occurring with statin use. Respondents with MS were more likely to report new or worsening muscle symptoms on statin therapy and to have discontinued statins for muscle symptoms than were those without MS, even after correcting for age, sex, DM, and other variables. Paradoxically, this higher prevalence was opposite the lower likelihood of statin discontinuation related to muscle symptoms in participants with DM, as previously reported.
      • Ito M.K.
      • Maki K.C.
      • Brinton E.A.
      • Cohen J.D.
      • Jacobson T.A.
      Muscle symptoms in statin users, associations with cytochrome P450, and membrane transporter inhibitor use: a subanalysis of the USAGE study.
      The opposite directions of the relationships of MS vs DM with muscle symptoms are surprising given the pathophysiological similarities between MS and DM, the strong relationship seen in USAGE (67.7% of the MS participants having DM), and the use of DM as one of the 5 criteria for MS in the current analysis.
      It might be hypothesized that DM was associated with less discontinuation of statin use due to muscle symptoms as a result of attenuation of muscle symptoms due to decreased pain sensation from diabetic neuropathy. However, this seems unlikely because reported muscle symptoms (as opposed to statin discontinuation for symptoms) were no different in respondents with DM (Table 4). Another possibility is that lower prevalence of statin discontinuation in patients with DM is due to the appreciation of the importance of statin treatment by patients and clinicians, resulting in a greater willingness to continue statins despite muscle symptoms. The finding of similarly lower prevalence in statin discontinuation for muscle symptoms in hypertension, also widely appreciated by the lay public and clinicians as an ASCVD risk factor, reinforces this impression. The contrasting higher prevalence of statin discontinuation for muscle symptoms in subjects with MS suggest that the increased ASCVD risk with MS may be less well appreciated by patients and clinicians. It is reasonable to speculate that informing individuals with MS of their increased ASCVD risk might improve persistence with statin therapy.
      In contrast to the lower prevalence of statin cessation due to muscle symptoms in respondents with DM, both high TG and low HDL-C were positively associated with both increased muscle symptoms and statin cessation for those symptoms. Indeed, these two MS criteria appeared to drive the primary study finding of a net increase in likelihood of the study endpoints in MS overall.
      By what mechanism might high TG and low HDL-C be associated with an increased likelihood of reported muscle symptoms and resulting statin cessation? To the authors' knowledge, neither of these lipid disorders has previously been reported to associate with increased statin myopathy. Both high TG and low HDL-C are associated with insulin resistance, however, of which the TG/HDL-C ratio is an especially strong predictor.
      • McLaughlin T.
      • Reaven G.
      • Abbasi F.
      • et al.
      Is there a simple way to identify insulin-resistant individuals at increased risk of cardiovascular disease?.
      • Quispe R.
      • Martin S.S.
      • Jones S.R.
      Triglycerides to high-density lipoprotein-cholesterol ratio, glycemic control and cardiovascular risk in obese patients with type 2 diabetes.
      • Bertsch R.A.
      • Merchant M.A.
      Study of the Use of Lipid Panels as a Marker of Insulin Resistance to Determine Cardiovascular Risk.
      Insulin resistance is reported to be associated with increased intramyocellular lipid, decreased skeletal muscle blood flow, and mitochondrial dysfunction.
      • Putti R.
      • Migliaccio V.
      • Sica R.
      • Lionetti L.
      Skeletal muscle mitochondrial bioenergetics and morphology in high fat diet induced obesity and insulin resistance: focus on dietary fat source.
      • Lambadiari V.
      • Triantafyllou K.
      • Dimitriadis G.D.
      Insulin action in muscle and adipose tissue in type 2 diabetes: The significance of blood flow.
      One or more of these mechanisms might relate to asymptomatic skeletal muscle dysfunction, which in turn could be worsened by statin use, which might account for the higher prevalence of statin-related muscle symptoms in respondents with insulin resistance. Of further interest, both high TG and low HDL-C are associated with increased risk of new-onset DM with statin use.
      • Waters D.D.
      • Ho J.E.
      • Boekholdt S.M.
      • et al.
      Cardiovascular event reduction versus new-onset diabetes during atorvastatin therapy: effect of baseline risk factors for diabetes.
      The concurrence of both higher prevalence of muscle symptoms and of new-onset diabetes with statin use in patients with high TG and/or low HDL-C might have important clinical implications and should thus be studied further.
      One recently reported study may be pertinent to the findings reported here.
      • Mikus C.R.
      • Boyle L.J.
      • Borengasser S.J.
      • et al.
      Simvastatin impairs exercise training adaptations.
      In a group of overweight patients at risk for the metabolic syndrome, simvastatin attenuated the increase in cardiorespiratory fitness and a marker for skeletal muscle mitochondrial content associated with exercise training. According to Mikus,
      • Mikus C.R.
      • Boyle L.J.
      • Borengasser S.J.
      • et al.
      Simvastatin impairs exercise training adaptations.
      in response to exercise training, statins may induce mitochondrial oxidative stress, activate pathways of apoptosis or autophagy, and thus attenuate increases in mitochondrial content and function. Whether this is limited to those with MS is unknown.
      • Thompson P.D.
      • Parker B.
      Statins, exercise, and exercise training.
      However, this finding provides evidence for potentially adverse effects of statin therapy on skeletal muscle metabolism in insulin resistance, which could have relevance to the susceptibility to statin-associated muscle symptoms.
      Important strengths of the present study include the large and well-characterized USAGE survey sample, which was recruited without mention of statin use (reducing selection bias). Additional strengths are the relative consistency of the study findings between genders and the persistence of the relationships of statin-associated muscle symptoms and discontinuation of statin use for muscle symptoms with elevated TG and low HDL-C levels in multivariate analyses. This finding provides a plausible mechanistic link between insulin resistance and statin-associated muscle symptoms, which is deserving of additional investigation.
      Study limitations include the cross-sectional and observational nature of the study data, which renders its findings hypothesis-generating only. Also, the USAGE survey lacked objective confirmation of statin use or cessation. Furthermore, the lack of any measured anthropometric and laboratory data resulted in our need to modify all MS criteria. Self-reported values for the MS criteria undoubtedly misclassifies the MS components to varying extents compared to direct measurement; however, the prevalence of MS and its individual criteria in the present study are reasonably similar to those found by direct observation in the National Health and Nutrition Examination Survey of US adults aged 60 years and older.
      • Aguilar M.
      • Bhuket T.
      • Torres S.
      • Liu B.
      • Wong R.J.
      Prevalence of the metabolic syndrome in the United States, 2003-2012.
      • Ervin R.B.
      Prevalence of metabolic syndrome among adults 20 years of age and over, by sex, age, race and ethnicity, and body mass index: United States, 2003-2006, National health statistics reports; vol. 13.
      Another limitation relates to the general characteristics of the study population. There were few non-Caucasians (<8%) and subjects were members of a pre-defined group of volunteers with internet access, able to fill out a long and complicated survey. Nevertheless, the study sample appears to be reasonably representative of statin-treated individuals in the United States.
      • Cohen J.D.
      • Brinton E.A.
      • Ito M.K.
      • Jacobson T.A.
      Understanding Statin Use in America and Gaps in Patient Education (USAGE): an internet-based survey of 10,138 current and former statin users.

      Conclusion

      In conclusion, this analysis suggests that individuals with MS may be predisposed toward new or worsening muscle symptoms while taking a statin and also toward stopping the statin due to such symptoms. The higher odds of statin discontinuation related to muscle symptoms in MS might be at least partly attributable to an under-appreciation by patients and even health care providers of the strength of the association between MS and elevated ASCVD risk and thus of the potential benefits of statin therapy in this regard. The associations of statin-associated muscle symptoms and discontinuation of statin use due to such symptoms may also have a biological explanation, possibly related to mitochondrial dysfunction associated with insulin resistance. These findings are hypothesis generating, and further research is warranted to confirm or refute them and, if confirmed, to explore potential mechanistic and behavioral determinants explanations.

      Acknowledgment

      The authors would like to acknowledge Marjorie Huebner (statistical analyses), Robert Talbert, Esq. (project management) of the National Lipid Association, Orsolya M. Palacios, RD, PhD (editing and formatting) and Kristin M. Nieman, PhD (editing) of MB Clinical Research, Glen Ellyn, Illinois for their contributions.

      Financial disclosures

      The National Lipid Association was a partner in conducting the survey. None of the authors received compensation for study design, study analysis, or manuscript preparation. Dr. Maki is an employee of MB Clinical Research, which received payment for work done by other employees for statistical analyses, manuscript editing, and formatting. The authors maintained full editorial control of the manuscript content and the decision to submit for publication. Financial disclosures for authors for research grants, consulting fees and other honoraria are as follows: Dr Brinton: Aegerion, Alexion, Amarin Pharmaceuticals, Amgen, Aralez, AstraZeneca, Genzyme, Janssen Pharmaceuticals, Kowa Pharmaceuticals, Merck, Regeneron, Sanofi, and Takeda Pharmaceuticals. Dr Maki: Amgen, AstraZeneca, Eli Lilly, Ionis/Akcea, Matinas BioPharma, and Sancilio and Co. Dr Jacobson: Amarin, Amgen, AstraZeneca, Merck, Regeneron, and Sanofi. Dr Cohen: Pfizer and Sanofi. Dr Sponseller is an employee of Kowa Pharmaceuticals America, Inc.

      References

        • Zhang H.
        • Plutzky J.
        • Skentzos S.
        • et al.
        Discontinuation of statins in routine care settings: a cohort study.
        Ann Intern Med. 2013; 158: 526-534
        • Cohen J.D.
        • Brinton E.A.
        • Ito M.K.
        • Jacobson T.A.
        Understanding Statin Use in America and Gaps in Patient Education (USAGE): an internet-based survey of 10,138 current and former statin users.
        J Clin Lipidol. 2012; 6: 208-215
        • Wei M.Y.
        • Ito M.K.
        • Cohen J.D.
        • Brinton E.A.
        • Jacobson T.A.
        Predictors of statin adherence, switching, and discontinuation in the USAGE survey: understanding the use of statins in America and gaps in patient education.
        J Clin Lipidol. 2013; 7: 472-483
        • Ito M.K.
        • Maki K.C.
        • Brinton E.A.
        • Cohen J.D.
        • Jacobson T.A.
        Muscle symptoms in statin users, associations with cytochrome P450, and membrane transporter inhibitor use: a subanalysis of the USAGE study.
        J Clin Lipidol. 2014; 8: 69-76
        • Baigent C.
        • Blackwell L.
        • Emberson J.
        • et al.
        Efficacy and safety of more intensive lowering of LDL cholesterol: a meta-analysis of data from 170,000 participants in 26 randomised trials.
        Lancet. 2010; 376: 1670-1681
        • Centers for Disease Control and Prevention
        National Diabetes Statistics Report: Estimates of Diabetes and Its Burden in the United States.
        US Department of Health and Human Services, Atlanta, GA2014
        • Grundy S.M.
        Metabolic syndrome: connecting and reconciling cardiovascular and diabetes worlds.
        J Am Coll Cardiol. 2006; 47: 1093-1100
        • Aguilar M.
        • Bhuket T.
        • Torres S.
        • Liu B.
        • Wong R.J.
        Prevalence of the metabolic syndrome in the United States, 2003-2012.
        JAMA. 2015; 313: 1973-1974
        • Mottillo S.
        • Filion K.B.
        • Genest J.
        • et al.
        The metabolic syndrome and cardiovascular risk a systematic review and meta-analysis.
        J Am Coll Cardiol. 2010; 56: 1113-1132
        • Sperling L.S.
        • Mechanick J.I.
        • Neeland I.J.
        • et al.
        The CardioMetabolic Health Alliance: Working Toward a New Care Model for the Metabolic Syndrome.
        J Am Coll Cardiol. 2015; 66: 1050-1067
        • Sattar N.
        • Preiss D.
        • Murray H.M.
        • et al.
        Statins and risk of incident diabetes: a collaborative meta-analysis of randomised statin trials.
        Lancet. 2010; 375: 735-742
        • Waters D.D.
        • Ho J.E.
        • Boekholdt S.M.
        • et al.
        Cardiovascular event reduction versus new-onset diabetes during atorvastatin therapy: effect of baseline risk factors for diabetes.
        J Am Coll Cardiol. 2013; 61: 148-152
        • Corrao G.
        • Ibrahim B.
        • Nicotra F.
        • et al.
        Statins and the risk of diabetes: evidence from a large population-based cohort study.
        Diabetes Care. 2014; 37: 2225-2232
        • Mansi I.
        Statin Adverse Events in Primary Prevention: Between Randomized Trials and Observational Studies.
        Am J Med Sci. 2015; 350: 330-337
        • Culver A.L.
        • Ockene I.S.
        • Balasubramanian R.
        • et al.
        Statin use and risk of diabetes mellitus in postmenopausal women in the Women's Health Initiative.
        Arch Intern Med. 2012; 172: 144-152
        • Maki K.C.
        • Ridker P.M.
        • Brown W.V.
        • Grundy S.M.
        • Sattar N.
        • The Diabetes Subpanel of the National Lipid Association Expert P
        An assessment by the Statin Diabetes Safety Task Force: 2014 update.
        J Clin Lipidol. 2014; 8: S17-S29
        • Waters D.D.
        • Ho J.E.
        • DeMicco D.A.
        • et al.
        Predictors of new-onset diabetes in patients treated with atorvastatin: results from 3 large randomized clinical trials.
        J Am Coll Cardiol. 2011; 57: 1535-1545
        • Alberti K.G.
        • Eckel R.H.
        • Grundy S.M.
        • et al.
        Harmonizing the metabolic syndrome: a joint interim statement of the International Diabetes Federation Task Force on Epidemiology and Prevention; National Heart, Lung, and Blood Institute; American Heart Association; World Heart Federation; International Atherosclerosis Society; and International Association for the Study of Obesity.
        Circulation. 2009; 120: 1640-1645
        • Liu A.
        • Abbasi F.
        • Reaven G.M.
        Adiposity indices in the prediction of metabolic abnormalities associated with cardiovascular disease in non-diabetic adults.
        Nutr Metab Cardiovasc Dis. 2011; 21: 553-560
        • McLaughlin T.
        • Reaven G.
        • Abbasi F.
        • et al.
        Is there a simple way to identify insulin-resistant individuals at increased risk of cardiovascular disease?.
        Am J Cardiol. 2005; 96: 399-404
        • Quispe R.
        • Martin S.S.
        • Jones S.R.
        Triglycerides to high-density lipoprotein-cholesterol ratio, glycemic control and cardiovascular risk in obese patients with type 2 diabetes.
        Curr Opin Endocrinol Diabetes Obes. 2016; 23: 150-156
        • Bertsch R.A.
        • Merchant M.A.
        Study of the Use of Lipid Panels as a Marker of Insulin Resistance to Determine Cardiovascular Risk.
        Perm J. 2015; 19: 4-10
        • Putti R.
        • Migliaccio V.
        • Sica R.
        • Lionetti L.
        Skeletal muscle mitochondrial bioenergetics and morphology in high fat diet induced obesity and insulin resistance: focus on dietary fat source.
        Front Physiol. 2015; 6: 426
        • Lambadiari V.
        • Triantafyllou K.
        • Dimitriadis G.D.
        Insulin action in muscle and adipose tissue in type 2 diabetes: The significance of blood flow.
        World J Diabetes. 2015; 6: 626-633
        • Mikus C.R.
        • Boyle L.J.
        • Borengasser S.J.
        • et al.
        Simvastatin impairs exercise training adaptations.
        J Am Coll Cardiol. 2013; 62: 709-714
        • Thompson P.D.
        • Parker B.
        Statins, exercise, and exercise training.
        J Am Coll Cardiol. 2013; 62: 715-716
        • Ervin R.B.
        Prevalence of metabolic syndrome among adults 20 years of age and over, by sex, age, race and ethnicity, and body mass index: United States, 2003-2006, National health statistics reports; vol. 13.
        National Center for Health Statistics, Hyattsville, MD2009