Serious harms

Statins are prescribed to lower LDL cholesterol and the risk of heart attack and stroke 1.

ConditionHow oftenWho is at riskSource
Rhabdomyolysis, with kidney injury and rare deaths1 (SE 1) extra per 10,000 in trials; 4.4 admissions per 100,000 users a yearAge 65 or older, uncontrolled hypothyroidism, renal impairment, interacting drugs, higher dose234
Myopathy on simvastatin 80 mg0.9% against 0.02% on 20 mg, rhabdomyolysis 0.4% against none, of 12,064 over 6.7 yearsFirst year; a liver transporter variant associated with about 60% of cases35
Immune-mediated necrotising myopathy20.4 and 24.1 per million users a year in UK and Australian regionsAfter 1 month to 23 years of use (median 3 years)6
Liver injury and rare liver failure22 of 1188 cases in a US drug-induced liver injury registry; 4 became chronic, 1 with cirrhosis diedUnpredictable; latency 34 days to 10 years478
New-onset diabetes1 extra per 255 treated for 4 yearsRaised fasting glucose, triglycerides or body mass index; hypertension9
Haemorrhagic strokePerhaps a few extra per 10,000 a yearRecent stroke, above all haemorrhagic: 16% on atorvastatin 80 mg against 4% on placebo (post hoc)24
Admission for acute kidney injury1 extra per 1700 treated for 120 days, high against low potencyWithout chronic kidney disease10
Myasthenia gravis10 UK reports in 28 years; more than 9.5 million UK users in 2022With or without prior myasthenia11
Interstitial lung disease, anaphylaxis, Stevens-Johnson syndromeLung disease very rare; others not always reliably estimableNot stated124

The kidney injury is secondary to myoglobinuria, and muscle symptoms may resolve on stopping 4. Necrotising myopathy, with antibodies against HMG-CoA reductase, persists after stopping and has recurred with the same or another statin 4; creatine kinase had normalised in 50 of 105 patients at a median 2.3 years 6.

Other pathways it affects

The enzyme that statins block is found in every tissue and supplies more than cholesterol 16.

Mevalonate pathwayCytosol and endoplasmic reticulum
  1. Acetyl-CoA
  2. Acetyl-CoA acetyltransferase 2 (ACAT2)Condenses two acetyl-CoA and releases CoA
  3. Acetoacetyl-CoA
  4. HMG-CoA synthase 1 (HMGCS1)Acetyl-CoA, H2OAdds a third acetyl unit and releases CoA
  5. HMG-CoA
  6. HMG-CoA reductase (HMGCR)2 NADPHStatinsRate-limiting step; enzyme of the ER membrane; releases CoA
  7. Mevalonate
  8. Mevalonate kinase (MVK)ATP
  9. Mevalonate 5-phosphate
  10. Phosphomevalonate kinase (PMVK)ATP
  11. Mevalonate 5-diphosphate
  12. Diphosphomevalonate decarboxylase (MVD)ATPReleases CO2 and phosphate; product is the C5 isoprenoid unit
  13. Isopentenyl diphosphate
  14. Isopentenyl-diphosphate isomerase 1 (IDI1)
  15. Dimethylallyl diphosphate
  16. Farnesyl diphosphate synthase (FDPS)Isopentenyl diphosphateAdds one C5 unit and releases diphosphate
  17. Geranyl diphosphate
  18. Farnesyl diphosphate synthase (FDPS)Isopentenyl diphosphateBranch point to ubiquinone, dolichol, haem A and prenylated proteins
  19. Farnesyl diphosphate
  20. Squalene synthase (FDFT1)NADPHJoins two farnesyl diphosphates through presqualene diphosphate
  21. Squalene
  22. Squalene monooxygenase (SQLE)O2, NADPH through cytochrome P450 oxidoreductase (POR), FADAlso regarded as rate-limiting for sterol synthesis
  23. (S)-2,3-Epoxysqualene
  24. Lanosterol synthase (LSS)Cyclisation yields the first sterol
  25. Lanosterol
  26. several stepsBloch or modified Kandutsch-Russell route; CYP51A1 first, DHCR24 or DHCR7 last
  27. Cholesterol

Its downstream intermediates supply:

  • coenzyme Q10, which transports electrons in mitochondria and requires COQ2, expressed most in skeletal muscle, adrenal glands and heart 1716;
  • haem A of cytochrome c oxidase, through COX10 and COX15, the latter mainly in oxidative tissues such as muscle, heart and brain 16;
  • dolichol phosphate, to which sugars are attached for protein glycosylation 16;
  • farnesyl and geranylgeranyl groups attached to proteins 17;
  • a tRNA modification by TRIT1, which is required for selenoprotein expression 16.
Electron flow through the respiratory chainInner mitochondrial membrane; cytochrome c in the intermembrane space
  1. NADH
  2. Complex I, NADH:ubiquinone oxidoreductaseFMN, Iron-sulfur clusters4 H+ out of the matrix per NADH; complex II also reduces ubiquinone
  3. Ubiquinol
  4. Complex III, cytochrome bc1 complex2 haem b, Rieske [2Fe-2S] cluster, Haem c1Q cycle: 4 H+ released outside, 2 H+ taken from the matrix per ubiquinol
  5. Reduced cytochrome c
  6. Complex IV, cytochrome c oxidaseO2, CuA, Haem a, Haem a3 and CuBPer 2 electrons: 2 H+ pumped out; 2 matrix H+ and ½ O2 form H2O
  7. Water

In confirmed statin myalgia, serum coenzyme Q10 fell from 1.3 to 0.8 µg/mL in 8 weeks on simvastatin 20 mg; supplements of 400 or 600 mg/day did not reduce myalgia in independent trials 1819. Biallelic HMGCR variants cause limb-girdle muscular dystrophy 28; in the first family, the authors describe the muscle imaging as highly reminiscent of end-stage statin myopathy 1620. LDL-lowering HMGCR alleles were associated with type 2 diabetes (odds ratio 1.029 per allele) 21.

The central nervous system, 2.1% of body weight, holds 23% of the body’s sterol; the cholesterol for its growth apparently comes exclusively from local synthesis 22. In rare reports, memory loss reversed on stopping (median 3 weeks) 8; in 9971 people aged 70 or older, atorvastatin 40 mg did not change the composite of death, dementia or persistent physical disability (HR 0.94, 0.84 to 1.05) 23.

What it is for and how it works

People who inherit lower LDL cholesterol develop less coronary heart disease 26.

Statins competitively inhibit HMG-CoA reductase 27. In cells and animals, lower cholesterol in the endoplasmic reticulum releases SREBP-2, which activates the LDL receptor gene, so liver cells remove more LDL 2829.

In the body

Atorvastatin, rosuvastatin and simvastatin are taken up into the liver by a transporter protein, OATP1B1 27130.

CYP3A4 metabolises atorvastatin and simvastatin, but not rosuvastatin to a clinically significant extent 27130. Simvastatin is contraindicated with strong CYP3A4 inhibitors, ciclosporin, danazol and gemfibrozil 5. The MHRA advises against systemic fusidic acid with statins after suspected fatal rhabdomyolysis 31.

Genetic variation

Ancestry and inherited variants alter blood statin levels and muscle risk 323.

In pharmacokinetic studies, Asian subjects had about twice the median rosuvastatin exposure of White controls 32. On simvastatin 40 mg over a median 3.9 years, myopathy occurred in about 0.24% of 5468 Chinese and 0.05% of 7367 non-Chinese patients 5.

Benefit against harm

In a review of trials in people without cardiovascular disease, one death was avoided per 286 treated for up to 6 years 33.

GroupBenefitSerious harm
21 trials, median 4.8 yearsMajor vascular events 2.8% against 3.6% a year 34Rhabdomyolysis 1 extra per 10,000 2
Recent stroke or transient ischaemic attack, atorvastatin 80 mg (2365) against placebo (2366), median 4.9 yearsIschaemic stroke 9.2% against 11.6% (post hoc) 4Haemorrhagic stroke 2.3% against 1.4% (post hoc); diabetes 6.1% against 3.8% 4
Aged 70 or older without cardiovascular disease, diabetes or dementia, median 5.9 yearsCardiovascular events 10.9 against 15.5 per 1000 person-years 23Serious adverse events 2.7% in both groups; more musculoskeletal, hepatobiliary and diabetes-related events 23

Only 3 of its 22 trials reported no industry funding; the reviewers had no individual data 33. In 46,864 Catalans aged 75 or older without diabetes, new statin use was not associated with fewer cardiovascular events (HR 0.94 at 75 to 84, 0.93 from 85) 35.

Without the medicine

In 7447 Spanish adults at high risk, a Mediterranean diet with extra virgin olive oil or nuts lowered heart attack, stroke or cardiovascular death from 4.4% to 3.8% and 3.4% over a median 4.8 years, without a difference in all-cause mortality 36. The first report was retracted for randomisation irregularities; this reanalysis gave similar results 36.

How the recommendations were set

Of 288 members of 14 US and Canadian lipid and diabetes guideline panels from 2000 to 2010, 52% had financial conflicts of interest 37.

Stopping

In an open-label trial in people aged 75 or older taking a statin to prevent a first heart attack or stroke, 35 of 484 (7.2%) died within 3 years after stopping and 48 of 604 (7.9%) with continuation 39.

In an unblinded trial in people with a life expectancy of 1 month to 1 year, 60-day mortality was 45 of 189 (23.8%) after stopping and 39 of 192 (20.3%) with continuation, so non-inferiority was not shown 40.

A prescription is changed only together with the prescriber.