Table 1 Characteristics of included studies
Study (first author, year) | Country | Ethnicity | Study design | Definition of adverse drug reactions | Population disease | Source of participants |
|---|---|---|---|---|---|---|
Voora et al. (2009) | USA | Caucasian 86 %; African American 5 %; other 9 % | Cohort | A composite adverse event (CAE) of premature discontinuation for any side effect or myalgia/muscle cramps (irrespective of CK values) or CK > 3×ULN (irrespective of symptoms) | Hypercholesterolemia | Hospital |
Danik et al. (2013) | 26 countries | Caucasian 100 % | Cohort | Clinical myalgia or the broader categories of muscle weakness, stiffness, or pain and clinically severe myopathy (frank myopathy and rhabdomyolysis) | No disease | Population |
Donnelly et al. (2011) | UK (Scotland) | NA | Cohort | Intolerance defined as composite of abnormal CK measure 1–3 × ULN, with no abnormal recorded before statin commencement; or an abnormal ALT measure, with no abnormal before statin commencement (≥50 % increase in ALT from baseline also considered abnormal)and a relevant change in prescribing (switching statin to equivalent or lower dose, dose reduction of same statin, or discontinuation of statin prescribing) | Type 2 diabetes | Population |
Link et al. (2008) | UK | Caucasian 100 % | Case–control | “Definite” myopathy: muscle symptoms, with CK > 10 × ULN; “incipient” myopathy: CK > 3×ULN and 5 × baseline level, plus AAT > 1.7 × the baseline value without an elevated AAT level alone at any other visit irrespective of muscle symptoms | Myocardial infarction | Population |
de Keyser et al. (2014) | Netherlands | Caucasian 100 % | Cohort | The occurrence of either a dose decrease or a switch to another cholesterol-lowering drug or a too strong reduction in cholesterol level | NA | Population |
de Keyser et al. (2014) | Netherlands | Caucasian 100 % | Cohort | The occurrence of either a dose decrease or a switch to another cholesterol-lowering drug or a too strong reduction in cholesterol level | NA | Population |
de Keyser et al. (2014) | Netherlands | Caucasian 98 % | Cohort | The occurrence of either a dose decrease or a switch to another cholesterol-lowering drug or a too strong reduction in cholesterol level | Hypercholesterolemia and/or hypertension | Population |
de Keyser et al. (2014) | Netherlands | Caucasian 98 % | Cohort | The occurrence of either a dose decrease or a switch to another cholesterol-lowering drug or a too strong reduction in cholesterol level | Hypercholesterolemia and/or hypertension | Population |
Carr et al. (2013) | UK | Caucasians 100 % | Case–control | Myopathy: CK > 4×ULN; severe phenotype:denoted by CPK > 10 × ULN or rhabdomyolysis | Type2 diabetes, Alcohol dependence, Asthma, hypertention et al. | Population |
Santos et al. (2012) | Brazil | Caucasian 87 %; Mulatto 10 %; African 3 % | Cohort | Myalgia defined as muscle pain irrespective of CK values or CK > 3×ULN irrespective of symptoms | Familial hypercholesterolemia | Hospital |
Linde et al. (2010) | USA | NA | Cohort | Myalgias defined as muscular pain or weakness as reported by the patients, who graded their symptoms as mild, moderate or severe | Endocrine disorders | Hospital |
Marciante et al. (2011) | Case:US, Canada; control:US | Caucasian for case, control 1 (CHS), control 2 (HVH): 90.8, 84.5, 89.4 % | Case–control | Definite rhabdomyolysis defined as muscle pain or weakness associated with CK > 10 × ULN | Dyslipidemia | Population |
Brunham et al. (2012) | Netherlands | Caucasian100 % | Case–control | Plasma CK > 10 × ULN. | Dyslipidemia | Hospital |
Study (first author, year) | Statin type | Dose/regimen [mean (SD)] (mg/d) | SNP | Case/(control or cohort size) | Case | Control | ||||
|---|---|---|---|---|---|---|---|---|---|---|
TT | TC | CC | TT | TC | CC | |||||
Voora et al. (2009) | Mixed | Multiple doses | rs4149056 | 97/351 | 62 | 31 | 4 | 263 | 84 | 4 |
Simvastatin | 20.0 for 8 weeks + 80.0 for 8 weeks | 34/124 | 17 | 17b | 91 | 33b | ||||
Atorvastatin | 10.0 for 8 weeks + 80.0 for 8 weeks | 31/115 | 21 | 10b | 88 | 27b | ||||
Pravastatin | 10.0 for 8 weeks + 40.0 for 8 weeks | 31/111 | 23 | 8b | 83 | 28b | ||||
Danik et al. (2013) | Rosuvastatin | 20.0 | rs4149056 | 471/4404a | NA | NA | NA | NA | NA | NA |
Donnelly et al. (2011) | Mixed (simvastatin major) | Multiple doses | rs4149056 | 816/1275 | 565 | 227 | 24 | 905 | 348 | 22 |
rs2306283 | 816/1275 | 316 | 399 | 101 | 471 | 606 | 198 | |||
Link et al. (2008) | Simvastatin | 80.0 | rs4149056 | 85/90 | 29 | 35 | 21 | 70 | 17 | 3 |
de Keyser et al. (2014) | Simvastatin | Starting dose:20.0(11.4) | rs4149056 | 319/1462a | NA | NA | NA | NA | NA | NA |
de Keyser et al. (2014) | Atorvastatin | Starting dose:17.8(13.2) | rs4149056 | 110/367a | NA | NA | NA | NA | NA | NA |
de Keyser et al. (2014) | Simvastatin | Starting dose:41.7(18.9) | rs4149056 | 88/393a | NA | NA | NA | NA | NA | NA |
de Keyser et al. (2014) | Atorvastatin | Starting dose:45.0(34.8) | rs4149056 | 42/244a | NA | NA | NA | NA | NA | NA |
Carr et al. (2013) | Mixed | Case:33.2 (15.7), contro:30.6(15.7) | rs4149056 | 76/372 | 40 | 30 | 6 | 260 | 101 | 11 |
Simvastatin | NA | 59/222 | 29 | 25 | 5 | 147 | 71 | 4 | ||
Atorvastatin | NA | 11/110 | 7 | 4 | 0 | 86 | 22 | 2 | ||
Santos et al. (2012) | Atorvastatin | Case:62.9(20.5) control:61.0(22.7) | rs4149056 | 14/129 | 12 | 2b | 94 | 35b | ||
rs2306283 | 14/129 | 10 | 4b | 70 | 59b | |||||
Linde et al. (2010) | Mixed | Multiple doses | rs4149056 | 27/19 | 14 | 12 | 1 | 15 | 4 | 0 |
Marciante et al. (2011) | Cerivastatin | Case:0.6(0.2) | rs4149056 | 65/716 | NA | NA | NA | NA | NA | NA |
rs2306283 | 185/732 | NA | NA | NA | NA | NA | NA | |||
Brunham et al. (2012) | Mixed | Case:31.0 (23.0) control:36.0 (25.0) | rs4149056 | 25/83 | 15 | 8 | 2 | 57 | 20 | 6 |
Simvastatin | NA | 12/39 | 5 | 6 | 1 | 27 | 10 | 2 | ||
Atorvastatin | NA | 10/34 | 7 | 2 | 1 | 24 | 7 | 3 | ||
Study (first author, year) | Effect estimate (95 % CI) | ||||||
|---|---|---|---|---|---|---|---|
CC vs. TT | TC vs. TT | TC/CC vs. TT | CC vs. TT/TC | Additive | C vs. T | Adjusting factors | |
Voora et al. (2009) | 4.24 (1.03–17.43)c | 1.57 (0.95–2.57)c | 1.70 (1.04–2.80)e | 3.73 (0.92–15.20)c | 1.70 (1.11–2.61)c | 1.67 (1.10–2.52)c | Race, gender |
NA | NA | 2.76 (1.26–6.02)c | NA | NA | NA | – | |
NA | NA | 1.55 (0.65–3.70)c | NA | NA | NA | – | |
NA | NA | 1.03 (0.41–2.57)c | NA | NA | NA | – | |
Danik et al. (2013) | 1.13 (0.65–1.97)d | 0.90 (0.72–1.12)d | NA | NA | 0.95 (0.79–1.15)d | NA | – |
Donnelly et al. (2011) | 1.75 (0.97–3.15)c | 1.04 (0.86–1.27)c | 1.09 (0.90–1.32)c | 2.05 (1.02,4.09)e | 1.12 (0.94–1.33)c | 1.12 (0.94–1.32)c | Statin adherence, study duration, maximum dose, prescription for other lipid–regulating drugs, cyp3a4 inhibiting drugs, age, and rs2306283 |
0.76 (0.58–1.01)c | 0.98 (0.81–1.19)c | 0.93 (0.77–1.11)c | 0.71 (0.52,0.96)e | 0.90 (0.79–1.02)c | 0.90 (0.79–1.02)c | Statin adherence, study duration, maximum dose, prescription for other lipid–regulating drugs, cyp3a4 inhibiting drugs, age, and rs4149056 | |
Link et al. (2008) | 16.90 (4.70–61.10) | 4.97 (2.41–10.24)c | 6.76 (3.46–13.20)c | 9.52 (2.72–33.28)c | 4.50 (2.60–7.70) | 5.65 (3.32–9.62)c | – |
de Keyser et al. (2014) | 1.74 (1.05–2.88)d,e | 0.77 (0.58–1.02)d,e | NA | NA | NA | NA | Age, sex, and starting dose |
de Keyser et al. (2014) | 1.49 (0.54–4.10)d,e | 1.17 (0.77–1.79)d,e | NA | NA | NA | NA | Age, sex, and starting dose |
de Keyser et al. (2014) | 1.38 (0.34–5.71)d,e | 0.74 (0.45–1.24)d,e | NA | NA | NA | NA | Age, sex, and starting dose |
de Keyser et al. (2014) | NA | NA | 0.97 (0.68–1.40)d,e | NA | NA | NA | Age, sex, and starting dose |
Carr et al. (2013) | 4.32 (1.82–10.43)e | 1.93 (1.14–3.27)c | 2.09 (1.27–3.45)c | 2.81 (1.01–7.86)c | 2.08 (1.35–3.23)e | 1.93 (1.29–2.89)c | Statin type,previous history of type 2 diabetes, asthma,hypertension |
6.33 (1.60–25.02)c | 1.78 (0.97–3.27)c | 2.03 (1.13–3.63)c | 5.05 (1.31–19.43)c | 2.13 (1.29–3.54)e | 1.95 (1.23–3.10)c | ||
2.31 (0.10–52.59)c | 2.23 (0.60–8.32)c | 2.05 (0.55–7.58)c | 1.89 (0.09–41.74)c | 1.91 (0.56–6.54)e | 1.66 (0.52–5.28)c | ||
Santos et al. (2012) | NA | NA | 2.24 (0.47–10.72)e | NA | NA | NA | NA |
NA | NA | 2.08 (0.62–7.00)e | NA | NA | NA | NA | |
Linde et al. (2010) | 3.21 (0.12–85.20)c | 3.21 (0.84–12.35)c | 3.48 (0.92–13.25)c | 2.21 (0.09–57.14)c | 3.44 (0.95–12.53)c | 2.98 (0.90–9.89)c | – |
Marciante et al. (2011) | NA | NA | NA | NA | 2.45 (1.61–3.75)e | NA | Age at statin use, sex, and race |
NA | NA | NA | NA | 0.96 (0.75,1.24)e | NA | ||
Brunham et al. (2012) | 1.27 (0.23–6.92)c | 1.52 (0.56–4.12)c | 1.50 (0.58–3.69) | 1.12 (0.21–5.91)c | 1.26 (0.63–2.51)c | 1.32 (0.62–2.81)c | – |
2.70 (0.20–35.75)c | 3.24 (0.81–13.02)c | 4.50 (0.73–27.59) | 1.68 (0.14–20.35)c | 2.19 (0.79–6.12)c | 2.29 (0.82–6.38)c | – | |
1.14 (0.10–12.79)c | 0.98 (0.17–5.83)c | 1.06 (0.22–4.80) | 1.15 (0.11,12.43)c | 1.04 (0.36–3.07)c | 1.06 (0.30–3.70)c | – | |
Study (first author, year) | Statin type | Genotyping methods | Deviation from HWE |
|---|---|---|---|
Voora et al. (2009) | Mixed | NA | No |
Simvastatin | NA | ||
Atorvastatin | NA | ||
Pravastatin | NA | ||
Danik et al. (2013) | Rosuvastatin | NA | NA |
Donnelly et al. (2011) | Mixed (simvastatin major) | TAQMAN assays | No |
No | |||
Link et al. (2008) | Simvastatin | PCR-fluorescence | No |
de Keyser et al. (2014) | Simvastatin | Microarray genotyping procedures | NA |
de Keyser et al. (2014) | Atorvastatin | Microarray genotyping procedures | NA |
de Keyser et al. (2014) | Simvastatin | TaqMan allelic discrimination | NA |
de Keyser et al. (2014) | Atorvastatin | TaqMan allelic discrimination | NA |
Carr et al. (2013) | Mixed | TaqMan real-time PCR SNP genotyping assays | No |
Simvastatin | No | ||
Atorvastatin | No | ||
Santos et al. (2012) | Atorvastatin | PCR-HRM | No |
No | |||
Linde et al. (2010) | Mixed | PCR and DNA sequencing | No |
Marciante et al. (2011) | Cerivastatin | Illumina Goldengate custom panel; Taqman 5′ nuclease discrimination assay; pyrosequencing on the PyroMark Q96MD platform. | NA |
NA | |||
Brunham et al. (2012) | Mixed | Illumina Goldengate genotyping assay | Yes |
Simvastatin | No | ||
Atorvastatin | No |