Abstract
Background and Aims
Patients with familial hypercholesterolemia (FH) may be at increased risk of statin-associated muscle symptoms since they require long-term treatment with high-intensity statin therapy. We sought to determine 1) whether other predisposing factors, including the well-known genetic variant associated with statin-associated muscle symptoms - solute carrier organic anion transporter family, member 1B1 (SLCO1B1) rs4149056 – also increase the risk of statin-associated muscle symptoms in FH patients, and 2) the natural history and management for FH patients with statin-associated muscle symptoms.
Methods
We queried electronic records (2004–2014) of 278 genetically screened FH patients (113 men, 165 women; mean [SD] pretreatment LDL-C 259 [72] mg/dL) recruited from lipid clinics in the Dallas, TX area from 2004 to 2014. Statin-associated muscle symptoms were defined as muscle symptoms arising while taking a statin and interrupting therapy.
Results
The risk of muscle symptoms was associated with age (OR 1.6, [95% CI 1.2, 2.2]), BMI in non-African-Americans (0.90 [0.83, 0.97]), and hypertension (0.4, [0.2, 0.9]). Simvastatin most commonly employed and most associated with muscle symptoms. Among FH patients with muscle symptoms, 41% (n = 40) reestablished statin therapy (“eventually tolerant”) and 29% (n = 28) never reestablished statin therapy (“never tolerant”). Rosuvastatin (43%) and pravastatin (30%) were the most common eventually-tolerated statins, and “eventually tolerant” patients achieved lower treated LDL-C levels (“eventually tolerant” 127 vs “never tolerant” 192 mg/dL, p < 0.001). “Never tolerant” patients also developed muscle symptoms on non-statins (16% vs. 50%, p = 0.003). SLCO1B1 rs4149056 genotyping revealed 224 wild-type patients (TT) and 49 heterozygotes (TC). SLCO1B1 genotype was not associated with the risk of statin-associated muscle symptoms (OR 1.40, [95% CI 0.74–2.64]).
Conclusion
Age, not SLCO1B1 rs4149056 genotype, was the strongest risk factor for statin-associated muscle symptoms in FH patients. After developing muscle symptoms, many patients reestablished statin therapy and achieved significant LDL-C reductions. Overall, 10% of all FH patients had statin-associated muscle symptoms and never re-established statin therapy. Such patients developed muscle symptoms even on non-statin lipid lowering drugs and continued to have elevations in LDL-C. Further insight is needed into the relationship of FH and statin-associated muscle symptoms so all FH patients can be adequately treated.
Keywords: familial hypercholesterolemia, statin-induced myopathy, statin-associated muscle symptoms, ezetimibe-induced myopathy
Introduction
Patients with familial hypercholesterolemia (FH) have lifelong elevations in low-density lipoprotein cholesterol (LDL-C), leading to a 20-fold increased risk of premature coronary heart disease (CHD).1–3 Three genes are known to cause this autosomal dominant disorder: low-density lipoprotein receptor (LDLR), apolipoprotein B (APOB), and proprotein convertase subtilisin/kexin type 9 (PCSK9).4
Most statin users with statin-associated muscle symptoms - also referred to as statin induced myopathy - report myalgia (e.g. muscle aches, weakness, cramps, stiffness, “heaviness,” flu-like symptoms), and fewer patients develop elevations in creatine kinase (CK) or rhabdomyolysis5,6. The exact pathology at the level of skeletal muscle remains unclear. Thus far, genetic studies have identified genes involved in the pharmacokinetics and pharmacodynamics of statin response with solute carrier organic anion transporter family member 1B1 (SLCO1B1) rs4149056 being the best-studied of these variants7. The minor C allele is associated with odds ratios as high as 4.5 for simvastatin-induced CK elevations7.
Because of high baseline LDL-C levels, FH patients require long-term treatment with high potency statins, potentially raising their risk for statin-associated muscle symptoms. Since awareness of FH is increasing in the US8, adverse effects from statins may become a growing issue. For FH patients with statin-associated muscle symptoms, little is known about predisposing factors, the natural history, and management strategies. About ten percent of all FH patients developed muscle symptoms associated with statin therapy and never reestablished statin therapy.
To begin addressing these issues, we studied 1) characteristics predisposing FH patients to statin-associated muscle symptoms, including SLCO1B1 rs4149056, 2) differences between patients with muscle symptoms who reestablished statin therapy (eventually tolerant) and those who failed to do so (never tolerant), and 3) pharmacologic management strategies for FH patients who develop statin-associated muscle symptoms.
Methods
Study Design and Population
Adult patients with FH were ascertained from specialty lipid clinics in the Dallas, TX, area according to Simon-Broome criteria as previously described.4 Pretreatment LDL-C was ≥ 95th percentile for age and sex with one of the following criteria: 1) tendon xanthomas (proband or 1st degree relative), or 2) a 1st degree relative with either premature CHD (≤ 55 years in males or ≤ 65 years in females). All patients were examined for tendon xanthomas, which were considered to be present if tendons were diffusely enlarged or had focal nodularity.
Statin-associated muscle symptom was defined as developing muscle symptoms such as muscle aches, weakness, cramps, stiffness, “heaviness,” flu-like symptoms while taking a statin, severe enough to stop therapy. Electronic medical records and pharmacy databases, from 2004 to 2014, were reviewed for documentation consistent with our definition of statin-associated muscle symptoms as described above. At least two years of follow-up time was available for resumption of statin therapy following an interruption. These patients were divided into “eventually tolerant” and “never tolerant” groups based on their ability to be maintained on a statin without developing subsequent muscle symptoms for at least 3 months. We also documented incidences of rhabdomyolysis. We also performed interactions between race and each of the clinical characteristics (listed in Table 1) for the outcome muscle symptoms.
Table 1.
Clinical characteristics of familial hypercholesterolemia patients with and without statin-associated muscle symptoms
| No Muscle Symptoms (n=181) | Muscle Symptoms (n=97) | p-value | |
|---|---|---|---|
| Age at evaluation (years) | 54 (46–62) | 57 (50–64) | 0.006 |
| Female Gender (%) | 43 | 35 | 0.25 |
| Race/Ethnicity | 0.09 | ||
| African-American (%) | 45 | 30 | |
| Non-Hispanic white (%) | 27 | 35 | |
| Hispanic (%) | 18 | 22 | |
| Other (%) | 9 | 13 | |
| BMI (kg/m2) | 30 (26–35) | 28 (24–33) | 0.001 |
| Premature CHD | |||
| Premature CHD (%) | 36 | 18 | 0.001 |
| Age at premature CHD (years) | 43 (37–51) | 49 (38–55) | 0.24 |
| Diabetes | |||
| Diabetes (%) | 29 | 24 | 0.40 |
| Hemoglobin A1C (%) | 5.9 (5.6–6.4) | 5.8 (5.5–6.2) | 0.12 |
| Hypertension (%) | 71 | 55 | 0.01 |
| Kidney disease | |||
| BUN (mg/dL) | 14 (12–17) | 14 (12–17) | 0.89 |
| Creatinine (mg/dL) | 0.83 (0.72–0.99) | 0.81 (0.68–0.96) | 0.47 |
| Thyroid disease | |||
| TSH (mIU/L) | 1.7 (1.1–2.3) | 1.5 (1.2–2.3) | 0.36 |
| Free T4 (ng/dL) | 1.1 (1.0–1.2) | 1.1 (1.0–1.2) | 0.603 |
| Liver disease | |||
| Albumin (g/dL) | 4.4 (4.2–4.6) | 4.5 (4.3–4.7) | 0.15 |
| Alkaline phosphatase (U/L) | 73 (59–89) | 71 (57–87) | 0.46 |
| AST (U/L) | 21 (17–27) | 20 (17–25) | 0.31 |
| ALT (U/L) | 21 (15–33) | 20 (15–27) | 0.34 |
| Creatine kinase (U/L) | 122 (84–185) | 105 (63–144) | 0.05 |
| Ezetimibe Use (%) | 29.3% | 24.7% | 0.71 |
| Genetics | |||
| LDLR mutation (%) | 38 | 27 | 0.06 |
| APOB mutation (%) | 4 | 1 | 0.40 |
| SLCO1B1 TC genotype (%) | 22 | 16 | 0.32 |
Values represent median (IQR) unless otherwise specified. Abbreviations: CHD, coronary heart disease; BMI, body mass index; BUN, blood urea nitrogen; TSH, thyroid stimulating hormone; AST, Aspartate transaminase; ALT, alanine aminotransferase; LDLR, low density lipoprotein receptor; APOB, Apolipoprotein B; SLCO1B1 Solute Carrier Organic Anion Transporter Family, Member 1B1. Kidney disease is defined as CKD or ESRD. Thyroid disease includes either hypothyrodism or hyperthyroidism. Diabetes is defined as physician diagnosed diabetes. Premature CHD is defined as CHD ≤ 55 years old in men and ≤65 years old in women.
All patients gave written informed consent, and the Institutional Review Board of UT Southwestern Medical Center approved the protocol.
Candidate Gene Analysis
All 18 exons and the flanking intronic regions of LDLR and exon 26 of APOB were amplified and sequenced (Sanger) as previously described.4 Deletions and duplications of one or more exons of LDLR were detected with the SALSA Multiplex Ligation-dependent Probe Amplification (MLPA) kit.
Lipids, Lipoproteins, and other Labs
Upon ascertainment, all patients had labs drawn for routine chemistries, kidney function tests, thyroid function tests, and CK levels. Historical untreated and treated lipid levels were obtained by review of electronic medical records and clinical data repositories. All centers measured fasting total cholesterol, triglycerides, and HDL-C using enzymatic assays in commercial laboratories. LDL-C was estimated with the Friedewald equation.
Genotyping of SLCO1B1 gene
Genotyping of rs4149056 was performed by allelic discrimination using real-time polymerase chain reaction TaqMan assays (Applied Biosystems, Foster City, CA, USA).
Statistical Analysis
The Fisher Exact test was used to compare statin or other medication use between FH patients who developed muscle symptoms and those who did not, between “eventually tolerant” and “never tolerant” in patients who develop statin-associated muscle symptoms. Continuous variable were compared with the Wilcoxon Rank Sum test and are summarized as median and 25th – 75th percentiles. Multiple logistic regression analysis was performed to determine the factors predicting statin-associated muscle symptoms with the prevalence of muscle symptoms as the dependent variable and baseline characteristics (e.g., demographics, genetic mutations, laboratory values) as the independent variables. In these regression models continuous variables were not categorized and reported odds ratio are based on a 1 unit change. Interactions between multiple independent were evaluated. Since an interaction between African-American race and BMI was observed, race stratified results are presented for some analyses. A two-sided p-value < 0.05 was considered statistically significant. We performed statistical analyses using SAS version 9.4 (SAS Institute; Cary, NC).
The work was supported by grants from the Southwest Medical Foundation, Center for Human Nutrition at UT Southwestern, and from the National Institutes of Health (NIH) K23 HL114884and CTSA Grant UL1TR001105 for REDCap. The authors are solely responsible for the design and conduct of this study, all study analyses, the drafting and editing of the paper and its final contents.
Results
A total of 278 unrelated FH patients (113 M, 165 F) were enrolled. Of these, 99 patients had mutations: 93 had heterozygous LDLR mutations; 6 had heterozygous APOB p.R3500Q mutation; and the rest (179) did not have identifiable mutations.
Statin-associated muscle symptoms were observed in 36% (n = 97; 63 M, 34 F) of the 278 FH patients. Clinical characteristics of FH patients who developed muscle symptoms and those that did not (no muscle symptoms) are shown in Table 1. One patient reported a history of rhabdomyolysis while taking simvastatin. He also developed muscle symptoms on pravastatin as well as ezetimibe and never tolerated lipid-lowering therapy. One patient suffered muscle symptoms with documented increase with creatine kinase (CK 335 U/L, reference range 40–210) after being started on simvastatin. This patient also developed muscle symptoms to fenofibrate and never tolerated any lipid lowering therapy. Another patient also suffered muscle symptoms with documented increase in creatine kinase (CK 963 U/L) after being started on simvastatin. This patient also developed muscle symptoms on atorvastatin (dose unknown), and was eventually tolerant of only colestipol.
Muscle Symptoms vs. No Muscle Symptoms
Muscle symptoms were more common with increased age (median [IQR] muscle symptoms 57 [46–62] vs. no muscle symptoms 54 [50–64] years, p = 0.0064) and lower BMI (28 [24–33] vs 30 [26–35] kg/m2, p = 0.01). Muscle symptoms were less common with hypertension (55% vs 71%, p = 0.011), premature coronary heart disease (18 vs 36%, p = 0.006), and lower baseline CK levels (median 105 [63–144] vs 122 [84–185] U/L, p = 0.049). Other patient characteristics such as gender, diabetes, kidney disease, thyroid disease, liver disease, and presence of LDLR or APOB mutations did not differ.
Multiple logistic regression analysis identified several variables associated with developing muscle symptoms in FH patients (Figure 1): age (OR 1.6, 95% CI 1.2 to 2.2), and hypertension (OR 0.4, 95% CI 0.2 to 0.9). An interaction between race and BMI (p=0.03) indicated that lower BMI was associated with muscle symptoms (OR 0.90, 95% CI 0.83 to 0.97) in non-African-Americans but was nonsignificant in African-Americans (OR 1.02, 95% CI 0.94 to 1.11).
Figure 1.
Odds ratio for statin-associated muscle symptoms associated with selected variables in multiple logistic regression analysis. For continuous variables (age and BMI) odds ratios are based on a 1 unit change.
Eventually Tolerant vs Never Tolerant
A total of 68 out of 97 medical charts of FH patients with statin-associated muscle symptoms had data we were able to extract. The remaining 29 patients lacked data due to several reasons: incomplete documentation in medical records and pharmacy records, lost to clinic follow-up, and lack of access to medical records.
Of the 68 patients with available data, 58.8% (n = 40) eventually tolerated a statin (eventually tolerant), and 41.2% (n = 28) never tolerated a statin (never tolerant). Simvastatin was the most commonly employed statin to cause muscle symptoms in both groups (eventually tolerant 52.5% vs never tolerant 60.7%, p = 0.31, Table 2). Patients in both groups were exposed mostly to moderate intensity statin therapy (76.7% vs 64.3%, p = 0.14) prior to developing muscle symptoms for roughly 10 months (median time interval exposed to any type of statin, 10 months vs 10.4 months, p = 0.97). After cessation of the statin that is associated with muscle symptoms, a gap occurred until lipid lowering therapy was reestablished (1 month vs 2.6 months, p=0.16, Table 3).
Table 2.
Among familial hypercholesterolemia patients with statin-associated muscle symptoms, characteristics of lipid lowering therapy that is associated with muscle symptoms in patients who reestablished statin therapy (Eventually Tolerant) vs those who did not (Never Tolerant)
| Eventually Tolerant n=40 | Never Tolerant n=28 | p-value | |
|---|---|---|---|
| Duration of treatment on statin that is associated with muscle symptoms, years, median [IQR] | 10 [3–20] | 10.4 [3–24] | 0.97 |
| Statin that is associated with muscle symptoms | |||
| Lovastatin (%) | 0 | 3.57 | 0.31 |
| Fluvastatin (%) | 0 | 0 | |
| Pravastatin (%) | 5 | 3.57 | |
| Simvastatin (%) | 52.5 | 60.7 | |
| Atorvastatin (%) | 32.5 | 14.3 | |
| Rosuvastatin (%) | 10 | 17.9 | |
| Pitavastatin (%) | 0 | 0 | |
| Intensity* of statin that is associated with muscle symptoms | |||
| High (%) | 23.3 | 21.4 | 0.14 |
| Moderate (%) | 76.7 | 64.3 | |
| Low (%) | 0 | 14.3 | |
| Concomitant interacting drugs** | |||
| None | 73.7 | 86.4 | 0.79 |
| Fenofibrate (%) | 2.63 | 0 | |
| Gemfibrozil (%) | 2.63 | 4.55 | |
| Antifungals (azoles) (%) | 0 | 4.55 | |
| Amlodipine (%) | 13.2 | 4.55 | |
| Colchicine (%) | 2.63 | 4.55 | |
| Daptomycin (%) | 2.63 | 0 | |
| Niacin (%) | 2.63 | 0 | |
| Concomitant non-statin lipid lowering drugs | |||
| Cholesytramine (n,%) | 2 (5.1%) | 0 | |
| Ezetemibe (%) | 5 (12.8%) | 5 (18.5%) | |
| Fenofibrate (%) | 1 (2.6%) | 0 | |
| Fish oil (%) | 2 (5.1%) | 2 (7.4%) | |
| Gemfibrozil (%) | 1 (2.6%) | 1 (3.7%) | |
| Niacin (%) | 1 (2.6%) | 0 | |
| Slco1b1 TC genotype (%) | 18.4 | 18.5 | 1.0 |
High intensity is defined as atorvastatin 40–80mg qd, and rosuvastatin 20–40mg qd. Moderate intensity is defined as atorvastatin 10 or 20mg qd, rosuvastatin 5 or 10mg qd, simvastatin 20–40 qd, pravastatin 40 qd, lovastatin 40 mg qd, fluvastatin 40mg bid or xl 80mg qd, or pitavastatin 204mg qd). low intensity is defined as simvastatin 10mg qd, pravastatin 10–20mg qd, lovastatin 20mg qd, fluvastatin 20–40mg qd, or pitavastatin 1mg qd
No patients were on the following drugs known to interact with statins: cyclosporine, macrolides, protease inhibitors, amiodarone, verapamil, diltiazem, ranolazine and rifampin
Table 3.
Management of familial hypercholesterolemia patients with statin-associated muscle symptoms who reestablished statin therapy (Eventually Tolerant) vs those who did not (Never Tolerant)
| Eventually Tolerant n=40 | Never Tolerant n=28 | p-value | |
|---|---|---|---|
| Time between cessation of muscle symptom-causing statin and reestablishment of lipid lowering therapy (months) | 1 [0–2.4] | 2.6 [0–15] | 0.16 |
| Statin eventually tolerated n (%) | |||
| Pravastatin | 12 (30.0%) | ||
| Simvastatin | 6 (15.0%) | ||
| Atorvastatin | 5 (12.5%) | ||
| Rosuvastatin | 17 (42.5%) | ||
| Intensity* of statin eventually tolerated | |||
| High (%) | 25.6 | ||
| Moderate (%) | 48.7 | ||
| Low (%) | 12.8 | ||
| Alternative dosing (%) | 12.8 | ||
| Non-statin lipid lowering therapy on eventually tolerated regimen | |||
| None (%) | 83.3 | 30.7 | 0.53 |
| Colesevelam (%) | 0 | 23.1 | |
| Colestipol (%) | 0 | 7.7 | |
| Ezetemibe (%) | 16.7 | 15.4 | |
| Fish oil (%) | 0 | 15.4 | |
High intensity is defined as atorvastatin 40–80mg qd, and rosuvastatin 20–40mg qd. Moderate intensity is defined as atorvastatin 10 or 20mg qd, rosuvastatin 5 or 10mg qd, simvastatin 20–40 qd, pravastatin 40 qd, lovastatin 40 mg qd, fluvastatin 40mg bid or xl 80mg qd, or pitavastatin 204mg qd). low intensity is defined as simvastatin 10mg qd, pravastatin 10–20mg qd, lovastatin 20mg qd, fluvastatin 20–40mg qd, or pitavastatin 1mg qd
In the eventually tolerant group, 55% needed to try only one new statin to reestablish therapy. About half (48.7%) of patients could take a moderate intensity statin (see Table 3 for definitions of intensities), and 17% added ezetimibe. About 25% used high-intensity statins, and 13% used low-intensity statins. About 13% were on alternative dosing, ranging from every other day, twice weekly, once a week, to every other week (Table 3). Rosuvastatin and pravastatin were the most commonly employed and tolerated statins (rosuvastatin: 43%, n = 17 and pravastatin: 30%, n = 12, Table 3). Details of tolerated doses are described in Table 7. 92.3% of eventually tolerant patients were on a different statin compared to the statin that is associated with myopathy, and 7.7% were able to tolerate the same statin.
Table 7.
Eventually tolerated statins with dosing
| 2.5mg | 5mg | 10mg | 20mg | 40mg | 80mg | Alternative Dosing | |
|---|---|---|---|---|---|---|---|
| Lovastatin | – | – | – | – | – | – | – |
| Fluvastatin | – | – | – | – | – | – | – |
| Pravastatin | – | – | 3 | 2 | 5 | 1 | 1 |
| Simvastatin | – | – | – | 2 | 2 | 1 | – |
| Atorvastatin | – | – | 1 | 1 | 2 | – | – |
| Rosuvastatin | – | 2 | 2 | 3 | 7 | – | 3 |
| Pitavastatin | – | – | – | – | – | – | – |
Alternative dosing for Pravastatin includes 40 every other day, and Rosuvastatin 2.5 very other week, skip every fourth, 5 once a week, 20 twice weekly. There was one unknown dose for simvastatin.
The never tolerant FH patients had to use non-statin lipid lowering agents (23% colesevelam, 8% colestipol, 15% ezetimibe, 15% fish oil). 31% were on no lipid lowering therapy at all. Ezetimibe was associated with muscle symptoms more commonly in the never tolerant group (eventually tolerant 8% vs never tolerant 43%, p = 0.008).
Overall, about ten percent of all FH patients enrolled in this study developed muscle symptoms associated with statin therapy and never re-established statin therapy.
Effect of statin tolerance on cholesterol levels
To assess whether patients with statin-associated muscle symptoms could eventually achieve adequate LDL-C reduction, we compared LDL-C pretreatment (while taking the statin associated with muscle symptoms) to LDL-C on eventually tolerated therapy (Figure 2). Eventually tolerant patients achieved lower treated LDL-C levels (eventually tolerant 127 [109–157] vs. never tolerant 192 [160–212] mg/dL, p < 0.001, Table 5) as well as lower treated total cholesterol levels (283 [242–315] vs. 206 [191–236] mg/dL, p < 0.001).
Figure 2.
a) Untreated lipid levels and treated lipid levels of FH patients with no muscle symptoms, b) Untreated lipid levels, treated lipid levels on statin that is associated with muscle symptoms; treated lipid levels on eventually tolerated statin in FH muscle symptom patients who eventually re-established statin therapy (Eventually Tolerant); Untreated lipid levels, treated lipid levels on statin that is associated with muscle symptoms, and treated lipid levels on eventual (non-statin) lipid-lowering therapy in FH muscle symptomt patients who never re-established statin therapy (Never Tolerant).
Table 5.
Lipid levels (mg/dL) of Eventually Tolerant vs Never Tolerant FH patients with statin-associated muscle symptoms
| Eventually Tolerant | Never Tolerant | p-value | |
|---|---|---|---|
| On statin that is associated with muscle symptoms | |||
| Total cholesterol | 204 (174–265) | 249 (168–287) | 0.50 |
| Triglycerides | 122 (89–164) | 106 (95–176) | 0.93 |
| LDL-C | 119 (91–177) | 153 (94–210) | 0.32 |
| HDL-C | 50 (41–61) | 46 (43–57) | 0.62 |
| Non-HDL-C | 145 (114–195) | 203 (119–239) | 0.30 |
| On eventually tolerated therapy | |||
| Total cholesterol | 206 (191–236) | 283 (242–315) | <0.001 |
| Triglycerides | 120 (90–165) | 138 (102–216) | 0.2 |
| LDL-C | 127 (109–157) | 192 (160–212) | <0.001 |
| HDL-C | 51 (42–73) | 58 (46–73) | 0.46 |
| Non-HDL-C | 153 (130–180) | 221 (196–236) | <0.001 |
Values represent median (IQR) unless otherwise specified; Abbreviations: FH denotes familial hypercholesterolemia; LDL-C low density lipoprotein-cholesterol, HDL-C high-density lipoprotein-cholesterol
SLCO1B1 rs4149056 Genotyping
SLCO1B1 rs4149056 genotyping revealed 224 wild-type patients (TT) and 49 heterozygotes (TC). The patient with a reported history of rhabdomyolysis was found to be a heterozygote (TC), while the two patients with documented statin-induced increases in CK levels were both wild-type (TT).
The C allele was present in 21% of FH patients with muscle symptoms versus 16% with no muscle symptoms and the C allele was not associated with the risk of statin-associated muscle symptoms (OR 1.40, [95% CI 0.74–2.64], p = 0.3) in this FH patient sample.
Of the patients taking simvastatin (n =37), 81% were wild-type (TT) and 19% were heterozygous (TC). The risk of muscle symptoms with simvastatin was not increased by the C allele (OR 0.86 [0.16–4.5], p = 0.86)
We identified certain populations that have a lower percentage of the SLCO1B1 TC (heterozygous) genotype: African Americans (TC 24.5% vs TT 44.2%, p=0.0454, Table 6) and diabetic patients (TC 16.3% vs TT 30.3%, p=0.0531, Table 6).
Table 6.
Clinical characteristics of FH patients with SLCO1B1 TC genotype vs TTgenotype
| Slco1b1 TC genotype (%) | Slco1b1 TT genotype (%) | p-value | |
|---|---|---|---|
| Female gender | 55.1 | 60.7 | 0.5212 |
| Non-black | 61.2 | 45.5 | 0.0454 |
| Black | 24.5 | 44.2 | 0.0454 |
| Current smoker | 16.3 | 11.5 | 0.6213 |
| Family history of FH | 76.2 | 75.1 | 1 |
| Family history of premature CHD | 32.7 | 28.6 | 0.6046 |
| PAD | 6.1 | 8.3 | 0.7746 |
| CVD | 18.4 | 9.6 | 0.129 |
| Diabetes | 16.3 | 30.3 | 0.0531 |
| Hypertension | 72.9 | 65 | 0.3169 |
| LDLR mutation | 30.6 | 35 | 0.6203 |
| APOB mutation | 2.6 | 3.2 | 1 |
Discussion
In a cohort of FH patients recruited from specialty lipid clinics, we identified several risk factors for statin-associated muscle symptoms, including age, BMI, hypertension, and premature CHD. SLCO1B1 rs4149056 genotype, however, was not a risk factor.
Our findings regarding age and BMI are consistent with prior reports that increased age and smaller body frames are risk factors for statin-associated muscle symptoms.6,9,10 FH patients with statin-associated muscle symptoms had a lower prevalence of both premature CHD and hypertension, suggesting that patients without CHD risk factors may be more aware – or more likely to complain - of muscle symptoms. The patients with CHD and hypertension are also likely more accustomed to taking medications important for their health. Lower CK levels in muscle symptom patients suggest that muscle symptoms likely occur below the threshold required to increase CK levels in these FH patients.
SLCO1B1 C allele, which has been associated with statin-associated muscle symptoms in literature,11–13 did not show association with muscle symptoms in our study. A few explanations exist for this finding, with one of them being interaction with race in our study. Prior reports suggest that statin-associated muscle symptoms may affect African Americans differently compared to non-African Americans. African American men were reported to have nearly eightfold increased risk of statin-associated muscle symptoms (adjusted HR 7.87 95% CI 5.30 to 11.68) in a prospective cohort study.14 Furthermore, a large systematic review of genetic factors that could influence statin-associated muscle symptoms showed that African Americans have different genetic variants of cytochrome P450 enzymes and influx transporter SLCO1B1 that may affect statin concentrations and subsequent statin-associated muscle symptoms.15 In fact, in our study, lower BMI was associated with muscle symptoms only in non-African Americans but not African-Americans, and African Americans have lower percentage of the SLCO1B1 TC genotype compared to non-African Americans. Given a small sample size of our study, we may not be detecting independent increased risk of muscle symptoms in African Americans. These findings suggest that multiple factors contribute to statin-associated muscle symptoms, and some risk factors may not be clearly elucidated.
Most prior studies of SLCO1B1 rs4149056 focused on a specific statin (mostly simvastatin) and did not study a special subtype of population such as patients with FH.12,13 In one prior study of FH patients, Santos et al also did not find an association between SLCO1B1 haplotypes and statin-associated muscle symptoms. The study used high resolution melting analysis to determine haplotypes in 143 Brazilian patients with FH and studied atorvastatin-induced muscle symptoms and CK elevation.16 As genome-wide association studies and the candidate gene approach will potentially allow us to personalize treatment with regard to SLCO1B1 alleles,17 it may be appropriate to study at a larger scale of prevalence of such alleles in FH patients.
In our study, patients developed symptoms after 10 month of statin therapy; whereas in prior reports, most developed muscle symptoms within 2 weeks, up to 2 months.18 FH patients often start lipid lowering therapy at young ages and thus have longer exposure to statins when compared to statin users in the general population. Also, our data was collected retrospectively through chart review, while studies such as PRIMO obtained data through questionnaires in general medicine clinics in France.
Among patients who developed statin-associated muscle symptoms, ezetimibe was associated with muscle symptoms in 43% of those that never tolerated statins. Previously, similar findings have been documented only in case reports. In one case report, a patient with risk factors for coronary artery disease and statin-associated exercise-induced muscle pain developed muscle symptoms again when treated alone with ezetimibe. Her symptoms promptly resolved after stopping ezetimibe.19 Similarly, in another report, a patient with dyslipidemia, a strong family history of CHD, Raynaud’s phenomenon, and statin intolerance who was symptom-free after stopping statin developed muscle symptoms again after only 2 weeks of ezetimibe therapy.20 A few explanations exist for why non-statins monotherapy may cause muscle symptoms: lowering of circulating cholesterol (regardless of mechanism) may have detrimental effects on muscle metabolism; prior statin therapy may predispose muscles to injury from other drugs. Alternatively, muscle symptoms may be due to factors such as anxiety or psychogenic factors and may not truly be related to lipid lowering drugs. Muscle symptoms experienced during statin treatment are influenced by patient expectations of negative effects. Additionally, a phenomenon known as nocebo effect, defined as adverse reaction experienced by a patient who receives such a therapy, has been described in patients with statin intolerance.21
Few prior studies of statin-associated muscle symptoms include detailed descriptions of patients’ subsequent clinical course or focus on genetically-screened FH patients. Rather, prior reports – which have also been retrospective reviews of electronic medical records - include patients within entire health care systems. For example, Zhang et al queried medical records at practices affiliated with Brigham and Women’s Hospital and Massachusetts General Hospital in Boston, MA. They found that out of 11,124 patients whose statins were discontinued at least temporarily, 6579 were re-challenged, and 92. 2% of the re-challenged were still taking a statin 12 months after the statin-associated event.22 Mampuya et al queried 1,605 patients referred to the Cleveland Clinic Preventive Cardiology Section. They found that 72.5% of patients with prior statin intolerance were able to eventually tolerate a statin. Similar to our findings, eventually tolerant patients had a significantly greater LDL-C reduction (eventually tolerant 21.3% ± 4.0% vs never intolerant 8.3 ± 2.2%, P < .001).23
In our cohort, among those who reestablish statin therapy, the statins most tolerated were rosuvastatin followed by pravastatin. This may be partially be explained by the fact that rosuvastatin and pravastatin are not extensively metabolized by the CYP450 3A pathway, unlike other statins.7 Most patients who reestablished statin therapy could tolerate a moderate intensity statin and had LDL-C reductions similar to pre-muscle symptoms levels. FH patients who never tolerated statin therapy remained undertreated patients. LDL-C levels were found to be markedly elevated in never tolerant patients despite use of non-statin lipid lowering drugs. Such patients may benefit from newer therapies such as PCSK9 inhibitors, as the different mechanism that targets and inactivates a specific protein may spare these patients from muscle side effects.24 If, however, the act of cholesterol lowering is what causes muscle symptoms in these patients, alternative methods for cardiovascular protection of these patients are needed.
Several limitations merit consideration. Our data may not be generalizable to all FH patients as our sample was primarily ascertained from north Texas and from lipid subspecialty clinics. Some of the variables did not differ statistically significantly because measurements may have been too infrequent to detect an effect. Further studies could pool patient data from multiple centers to detect subtle differences to further elucidate strategies in optimizing lipid levels in patients with statin-associated muscle symptoms. Referral bias may influence the high prevalence of statin-associated muscle symptoms in our study; experiencing muscle symptoms is a common referral reason seen in lipid specialty clinics. Additionally, follow-up time is variable given the nature of retrospective study. Variables such as age, BMI, and hypertension were established at the time of enrollment into this study. Because of the cross-sectional nature of our data, associations between various characteristics and statin-associated muscle symptoms are hypothesis-generating and do not establish causality. Although we evaluated association of SLCO1B1 rs4149056, our cohort had a very small number of patients on simvastatin, which is linked to SLCO1B1 rs4149056. Lastly, lipid management (e.g., alternate dosing strategy, choice of non-statin agents) following statin-associated muscle symptoms may largely depend on the preference of the particular treatment team.
Statin-associated muscle symptoms represent an added therapeutic challenge in patients with FH. Risk factors include increased age, lower BMI, less hypertension, and less premature CHD. After developing muscle symptoms, many patients reestablished statin therapy and achieved LDL-C reductions. Overall, 10% of all FH patients had statin-associated muscle symptoms and never re-established statin therapy. Such patients developed muscle symptoms even on non-statin lipid lowering therapies. Because they continued to have elevations in LDL-C, new therapeutic options, such as PCSK9 inhibitors, may be of particular benefit. Further insight is needed into the relationship of FH and statin-associated muscle symptoms so all FH patients can be adequately treated.
Table 4.
Non-statin muscle symptoms in Eventually Tolerant vs Never Tolerant familial hypercholesterolemia patients with statin-associated muscle symptoms
| Eventually Tolerant n=40 | Never Tolerant n=28 | p-value | |
|---|---|---|---|
| Nonstatin Muscle symptoms (%) | 6 (15.4%) | 14 (50%) | 0.003 |
| Non-statin lipid lowering drugs that are associated with muscle symptoms | |||
| Cholesytramine (%) | 1 (2.5%) | 1 (3.6%) | |
| Colesevelam (%) | 0 | 0 | |
| Colestipol (%) | 0 | 1 (2.5%) | |
| Ezetemibe (%) | 3 (7.5%) | 12 (42.9%) | 0.0008 |
| Fenofibrate (%) | 1 (2.5%) | 2 (7.1%) | |
| Fish oil (%) | 0 | 0 | |
| Gemfibrozil (%) | 1 (2.5%) | 0 | |
| Niacin (%) | 1 (2.5%) | 1 (3.6%) | |
Footnotes
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