Статины

Источники

1. Регуляторное

   US Food and Drug Administration (labelling submitted by Organon LLC). ZOCOR (simvastatin) tablets, for oral use: full prescribing information US Food and Drug Administration approved prescribing information, via DailyMed; version 11, effective 28 March 2025, 2025.

   https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=8f55d5de-5a4f-4a39-8c84-c53976dd6af9

   Финансирование и результат

   Финансирование

   not stated; FDA-approved labelling carries no funding statement

   Результат

   Simvastatin is a lactone prodrug hydrolysed after administration to its active beta-hydroxyacid form, simvastatin acid; simvastatin acid and its metabolites inhibit HMG-CoA reductase, the rate-limiting enzyme that converts HMG-CoA to mevalonate. Inhibition of HMG-CoA reductase by simvastatin acid accelerates the expression of LDL receptors, followed by uptake of LDL cholesterol from blood into the liver and a fall in plasma LDL cholesterol. Because simvastatin undergoes extensive first-pass extraction in the liver, its availability to the general circulation is below 5%. Simvastatin is metabolised by CYP3A4, and simvastatin acid is a substrate of the transport protein OATP1B1. Contraindicated with strong CYP3A4 inhibitors and with ciclosporin, danazol or gemfibrozil. In clinical studies of 24,747 simvastatin-treated patients (median follow-up 4 years), myopathy (muscle symptoms with creatine kinase above 10 times the upper limit of normal) occurred in about 0.03%, 0.08% and 0.61% on 20, 40 and 80 mg daily; in a study of 12,064 patients with previous myocardial infarction (mean 6.7 years), in about 0.02% on 20 mg and 0.9% on 80 mg. Discontinue if markedly elevated creatine kinase occurs or myopathy is diagnosed or suspected.

2. Независимое

   Cholesterol Treatment Trialists' (CTT) Collaboration, Baigent C, Blackwell L, Emberson J, Holland LE, Reith C, 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.

   doi:10.1016/S0140-6736(10)61350-5PubMed 21067804

   Финансирование и результат

   Участники

   169 138

   Наблюдение

   median 4.8 years in trials of statin against control; 5.1 years in trials of more against less intensive statin

   Финансирование

   This work is supported at the CTSU by the UK Medical Research Council, British Heart Foundation, and, previously, the European Community Biomed Programme, and at the CTC by the Australian National Health and Medical Research Council and National Heart Foundation. The funding sources had no involvement in study design, data collection, analysis, interpretation, report writing or publication.

   Результат

   Across all 26 trials, haemorrhagic stroke occurred in 257 against 220 participants (rate ratio per 1.0 mmol/L LDL cholesterol reduction 1.12, 95% CI 0.93 to 1.35), while ischaemic stroke fell (1427 against 1751, 0.79, 0.74 to 0.85). First haemorrhagic strokes were fatal in 94 against 75; first non-fatal haemorrhagic strokes 163 against 145. In the more against less intensive trials haemorrhagic stroke occurred in 69 against 57 (1.21, 99% CI 0.76 to 1.91). SPARCL (55 against 33 haemorrhagic strokes) and CORONA (15 against 9) were not available; adding their published data gave a rate ratio of 1.21 (1.05 to 1.41) per 1.0 mmol/L, which the authors estimate at perhaps a few extra haemorrhagic strokes a year per 10,000 treated. Rhabdomyolysis was sought only as myopathy progressing to rhabdomyolysis: excess 1 (SE 1) per 10,000 in trials of statin against control (14 against 9 cases) and 4 (SE 2) per 10,000 in trials of more against less intensive therapy (14 against 6).

3. Регуляторное

   US Food and Drug Administration. FDA Drug Safety Communication: New restrictions, contraindications, and dose limitations for Zocor (simvastatin) to reduce the risk of muscle injury US Food and Drug Administration, Drug Safety Communication, 8 June 2011, 2011.

   http://web.archive.org/web/20110702013026/http://www.fda.gov:80/Drugs/DrugSafety/ucm256581.htm

   Финансирование и результат

   Финансирование

   US Food and Drug Administration

   Результат

   Simvastatin 80 mg is restricted to patients who have taken it for 12 months or more without muscle injury and is not to be started in new patients; about 2.1 million US patients were prescribed an 80 mg simvastatin product in 2010; 80 mg lowers LDL cholesterol by an additional 6% over 40 mg. In SEARCH (seven years, 80 mg against 20 mg in survivors of myocardial infarction) major vascular events occurred in 24.5% against 25.7%; myopathy (creatine kinase above 10 times the upper limit of normal) in 52 (0.9%) against 1 (0.02%) and rhabdomyolysis (above 40 times) in 22 (0.4%) against none, with no rhabdomyolysis deaths; rates were 5 and 2 per 1000 person-years in the first 12 months and 1 and 0.4 per 1000 person-years thereafter. Older age, female sex and calcium channel blockers (about double risk, particularly diltiazem) raised myopathy risk, and about 60% of cases were associated with a variant of the hepatic uptake transporter gene. Reporting of fatal rhabdomyolysis to the Adverse Event Reporting System was higher for 80 mg simvastatin than for lower doses or most other statins. Rhabdomyolysis can damage the kidneys and lead to fatal kidney failure; hospitalised rhabdomyolysis occurs in 4.9 per 100,000 people exposed to simvastatin for one year, and 4.4 per 100,000 on average for atorvastatin, pravastatin or simvastatin (Graham et al., JAMA 2004).

4. Регуляторное

   US Food and Drug Administration (labelling submitted by Viatris Specialty LLC). LIPITOR (atorvastatin calcium) tablets, for oral use: full prescribing information US Food and Drug Administration approved prescribing information, via DailyMed; version 8, effective 15 April 2024; sections 4 to 8 and 14, 2024.

   https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=a60cc18b-0631-4cf0-b021-9f52224ece65

   Финансирование и результат

   Финансирование

   not stated; FDA-approved labelling carries no funding statement

   Результат

   Contraindications: acute liver failure or decompensated cirrhosis; hypersensitivity, with anaphylaxis, angioneurotic oedema, erythema multiforme, Stevens-Johnson syndrome and toxic epidermal necrolysis reported. Warnings: atorvastatin may cause myopathy and rhabdomyolysis; acute kidney injury secondary to myoglobinuria and rare fatalities have occurred; risk factors are age 65 years or older, uncontrolled hypothyroidism, renal impairment, interacting drugs (CYP3A4, OATP1B1/1B3, P-gp and BCRP inhibitors, gemfibrozil, other fibrates, niacin 1 g/day or more, colchicine) and higher dose; muscle symptoms and creatine kinase rises may resolve on discontinuation. Rare immune-mediated necrotising myopathy with anti-HMG-CoA reductase antibodies, weakness and raised creatine kinase that persist after discontinuation, recurrence with the same or a different statin, and need for immunosuppressive treatment. Persistent transaminase rises above 3 times the upper limit of normal in 0.7% of patients in trials (0.2%, 0.2%, 0.6% and 2.3% on 10, 20, 40 and 80 mg); rare postmarketing fatal and non-fatal hepatic failure. Increases in HbA1c and fasting glucose. SPARCL post hoc analysis, 4731 patients with stroke or transient ischaemic attack in the previous 6 months, median 4.9 years: haemorrhagic stroke 55 (2.3%) on atorvastatin 80 mg against 33 (1.4%) on placebo (HR 1.68, 95% CI 1.09 to 2.59), non-fatal 38 against 16, fatal 17 against 18; with haemorrhagic stroke at entry 16% against 4%; ischaemic stroke 9.2% against 11.6%; diabetes reported as an adverse reaction in 6.1% against 3.8%. TNT, 10,001 patients with coronary heart disease after an 8-week open-label run-in on atorvastatin 10 mg, median 4.9 years, 80 mg against 10 mg: serious adverse reactions 1.8% against 1.4%, discontinuation for adverse reactions 9.9% against 8.1%, all-cause deaths 284 (5.7%) against 282 (5.6%), HR 1.01 (0.85 to 1.19), non-cardiovascular deaths 158 (3.2%) against 127 (2.5%), HR 1.25 (0.99 to 1.57). Postmarketing reports: pancreatitis, fatal and non-fatal hepatic failure, anaphylaxis, tendon rupture, rhabdomyolysis, myositis, peripheral neuropathy, depression, interstitial lung disease, angioneurotic oedema, bullous rashes including erythema multiforme, Stevens-Johnson syndrome and toxic epidermal necrolysis; rare cognitive impairment (memory loss, amnesia, confusion) reported with all statins, generally non-serious and reversible on discontinuation, onset 1 day to years, median resolution 3 weeks; rare new-onset or exacerbated myasthenia gravis, including ocular, with recurrence on the same or a different statin. Pregnancy: may cause fetal harm based on the mechanism of action, which decreases synthesis of cholesterol and possibly other biologically active substances derived from cholesterol; breastfeeding not recommended. Plasma concentrations about 40% (Cmax) and 30% (AUC) higher in healthy people aged 65 or older.

5. Регуляторное

   US Food and Drug Administration (labelling submitted by Organon LLC). ZOCOR (simvastatin) tablets, for oral use: full prescribing information US Food and Drug Administration approved prescribing information, via DailyMed; version 11, effective 28 March 2025; sections 4 to 8, 2025.

   https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=8f55d5de-5a4f-4a39-8c84-c53976dd6af9

   Финансирование и результат

   Финансирование

   not stated; FDA-approved labelling carries no funding statement

   Результат

   Contraindicated with strong CYP3A4 inhibitors, ciclosporin, danazol and gemfibrozil, in acute liver failure or decompensated cirrhosis, and in hypersensitivity, with anaphylaxis, angioedema and Stevens-Johnson syndrome reported. In a study of 12,064 survivors of myocardial infarction (mean 6.7 years), myopathy (creatine kinase above 10 times the upper limit of normal) occurred in about 0.02% on 20 mg and 0.9% on 80 mg, and rhabdomyolysis (creatine kinase above 40 times) in about 0% and 0.4%, highest in the first year. In a study of 10,269 patients on 40 mg (mean 5 years), myopathy or rhabdomyolysis below 0.1%. In patients at high cardiovascular risk on 40 mg (median 3.9 years), myopathy in about 0.05% of 7367 non-Chinese and 0.24% of 5468 Chinese patients, and 1.24% in Chinese patients given extended-release niacin 2 g/day in addition. Acute kidney injury secondary to myoglobinuria and rare fatalities have occurred. Rare immune-mediated necrotising myopathy. Persistent transaminases above 3 times the upper limit of normal in about 1% of patients in clinical studies; rare postmarketing fatal and non-fatal hepatic failure. In 4S (median 5.4 years) diabetes mellitus was reported in 4.2% on simvastatin against 3.6% on placebo. Postmarketing reports: anaemia, thrombocytopenia, leukopenia, haemolytic anaemia; pancreatitis; hepatitis, jaundice, fatal and non-fatal hepatic failure; hypersensitivity syndrome including anaphylaxis, angioedema, lupus erythematosus-like syndrome, dermatomyositis and vasculitis; immune-mediated necrotising myopathy, polymyalgia rheumatica; depression, paraesthesia, peripheral neuropathy; cognitive impairment, generally non-serious and reversible, onset 1 day to years, median resolution 3 weeks; new-onset or exacerbated myasthenia gravis; toxic epidermal necrolysis, erythema multiforme including Stevens-Johnson syndrome; interstitial lung disease; erectile dysfunction. Pregnancy: may cause fetal harm based on the mechanism of action; breastfeeding not recommended.

6. Независимое

   Khoo T, Tan E, Limaye V, Gunawardena H, Sadler R, Lamb JA, et al. The incidence of anti-HMGCR immune-mediated necrotizing myopathy: an Australian and UK retrospective multi-site cohort study Rheumatology (Oxford), 2025.

   doi:10.1093/rheumatology/keaf238PubMed 40347460

   Финансирование и результат

   Участники

   109

   Наблюдение

   median 2.3 years (IQR 1.5 to 4.2)

   Финансирование

   H.C., M.H.B. and M.T. are supported by the NIHR Manchester Biomedical Research Centre (NIHR203308). T.K. was supported by the Ken Muirden ARA Fellowship (Arthritis Australia National Research Program 2023), an Australian Government Postgraduate Research Training Program Scholarship, The Hospital Research Foundation-Arthritis/SA ARA Postgraduate Research Award and a 2024 Royal Australasian College of Physicians Research Entry Scholarship.

   Результат

   109 cases (51% female, median age 66). Mean annual incidence 2.9 cases per million person-years; among statin users 20.4 (UK) and 24.1 (Western and South Australia) cases per million statin users per year. 101 were statin-exposed, mostly to atorvastatin (77 of 101); median statin duration before diagnosis 3 years (1 month to 23 years). Median peak creatine kinase 7020 IU/L (964 to 39,076); 48 of 105 received intravenous immunoglobulin. At follow-up, 50 of 105 (47.6%) had normal creatine kinase and 48 of 104 (46.2%) normal muscle power. Eight (7.5%) were statin-naive.

7. Независимое

   Russo MW, Hoofnagle JH, Gu J, Fontana RJ, Barnhart H, Kleiner DE, et al. Spectrum of statin hepatotoxicity: experience of the drug-induced liver injury network Hepatology, 2014.

   doi:10.1002/hep.27157PubMed 24700436

   Финансирование и результат

   Участники

   22

   Наблюдение

   at least 6 months after onset

   Финансирование

   DILIN is supported by the National Institute of Diabetes and Digestive and Kidney Diseases under cooperative agreements 1UO1DK065201, 1UO1DK065193, 1UO1DKO65184, 1UO1DK065211, 1UO1DK065238 and 1UO1DK06F5176; supported in part by the Intramural Research Program of the NIH, National Cancer Institute.

   Результат

   22 of 1188 drug-induced liver injury cases were attributed to a statin; all commonly used statins were implicated. Median age 60 (41 to 80), 68% female; latency 34 days to 10 years (median 155 days); median peak ALT 892 U/L and bilirubin 6.1 mg/dL. Nine had cholestatic hepatitis and 12 hepatocellular injury, 6 of these with an autoimmune phenotype. Nine were hospitalised, 4 developed hepatic failure and 1 died; 4 (18%) developed chronic liver injury, 3 of them with an autoimmune phenotype. Mild aminotransferase rises occur in up to 3% of treated patients.

8. Регуляторное

   US Food and Drug Administration. FDA Drug Safety Communication: Important safety label changes to cholesterol-lowering statin drugs US Food and Drug Administration, Drug Safety Communication, 28 February 2012, 2012.

   http://web.archive.org/web/20120301154839/http://www.fda.gov:80/Drugs/DrugSafety/ucm293101.htm

   Финансирование и результат

   Финансирование

   US Food and Drug Administration

   Результат

   Labels of all statins were revised. Routine periodic liver enzyme monitoring was removed; testing is advised before starting and as clinically indicated. In the Adverse Event Reporting System the reporting rate of serious statin-associated liver injury was 2 or fewer per million patient-years; of 75 cases of severe liver injury, death or transplantation reported to 2009 (27 severe injury, 37 deaths, 11 transplants), 30 (14 deaths, 7 transplants, 9 severe injury) were assessed as possibly or probably associated with a statin and none as highly likely or definite. Of 133 patients with idiosyncratic drug-induced acute liver failure in the Acute Liver Failure Study Group, 15 were taking statins, and in 6 a statin was the only potential cause. Rare postmarketing reports of cognitive impairment (memory loss, forgetfulness, amnesia, confusion) were added: reports generally described people over 50 with ill-defined memory loss, onset 1 day to years after exposure, reversal on discontinuation with median resolution 3 weeks, and no association with fixed or progressive dementia, statin, age, dose or concomitant drugs; observational studies and trials did not suggest common or clinically significant cognitive decline. Increases in HbA1c and fasting glucose were added, based on a 27% increase in investigator-reported diabetes with rosuvastatin in JUPITER, the meta-analysis by Sattar et al. of 13 trials with 91,140 participants (odds ratio 1.09, 95% CI 1.02 to 1.17) and that by Rajpathak et al. of 6 trials with 57,593 participants (relative risk 1.13, 1.03 to 1.23). FDA stated that it continues to believe the cardiovascular benefits outweigh these small increased risks.

9. Регуляторное

   Medicines and Healthcare products Regulatory Agency. Statins: risk of hyperglycaemia and diabetes MHRA Drug Safety Update, January 2012, 2012.

   https://www.gov.uk/drug-safety-update/statins-risk-of-hyperglycaemia-and-diabetes

   Финансирование и результат

   Финансирование

   Medicines and Healthcare products Regulatory Agency

   Результат

   There is sufficient evidence to support an association between statin use and new-onset diabetes. In a 2010 trial meta-analysis (Sattar et al.) the odds ratio was 1.09 (95% CI 1.02 to 1.17), and treatment of 255 (150 to 852) patients for 4 years resulted in one extra case. The risk appears to lie mainly in patients already at increased risk: raised fasting glucose at baseline is a key factor, with history of hypertension, raised triglycerides and raised body mass index. Evidence is insufficient to confirm or exclude an increased risk for any member of the class. Between 2002 and 2008 statin prevalence in the UK doubled in people older than 40 and quadrupled in those older than 80. The MHRA concluded that reduced vascular risk outweighs the risk of diabetes.

10. Независимое

    Dormuth CR, Hemmelgarn BR, Paterson JM, James MT, Teare GF, Raymond CB, et al. Use of high potency statins and rates of admission for acute kidney injury: multicenter, retrospective observational analysis of administrative databases BMJ, 2013.

    doi:10.1136/bmj.f880PubMed 23511950

    Финансирование и результат

    Участники

    2 067 639

    Наблюдение

    up to two years after starting a statin

    Финансирование

    CNODES is funded by a grant from Health Canada, the Drug Safety and Effectiveness Network, and the Canadian Institutes for Health Research that oversaw the peer review and funding process.

    Результат

    High potency statins were defined as rosuvastatin 10 mg or more, atorvastatin 20 mg or more and simvastatin 40 mg or more. In patients without chronic kidney disease, current users of high potency statins were 34% more likely to be admitted with acute kidney injury in the first 120 days than users of low potency statins (rate ratio 1.34, 95% CI 1.25 to 1.43); in patients with chronic kidney disease 1.10 (0.99 to 1.23). The authors estimate that 1700 patients without chronic kidney disease treated with a high rather than a low potency statin for 120 days cause one additional admission for acute kidney injury. Six-month risk of admission on low potency statins was 1.0 to 4.0 per 1000 in patients without chronic kidney disease and 10 to 63 per 1000 in those with it.

11. Регуляторное

    Medicines and Healthcare products Regulatory Agency. Statins: very infrequent reports of myasthenia gravis MHRA Drug Safety Update, volume 17, issue 2, September 2023, 2023.

    https://www.gov.uk/drug-safety-update/statins-very-infrequent-reports-of-myasthenia-gravis

    Финансирование и результат

    Финансирование

    Medicines and Healthcare products Regulatory Agency

    Результат

    Following a European review (PRAC, January 2023), the product information of all statins is being updated to list myasthenia gravis and ocular myasthenia as adverse reactions of unknown frequency, with new warnings. Globally there has been a very small number of reports of new-onset or aggravated myasthenia gravis with atorvastatin, pravastatin, lovastatin, fluvastatin, simvastatin, rosuvastatin and pitavastatin. From 14 June 1995 to 19 June 2023 the MHRA received 10 UK Yellow Card reports (simvastatin, atorvastatin, pravastatin), against more than 9.5 million UK patients dispensed a statin in 2022 alone; median age 66 years (40 to 89); symptoms included double vision, difficulty with speech and swallowing, limb weakness and shortness of breath; onset a few days to three months after starting; three reports concerned recurrence or exacerbation in known myasthenia gravis, one a positive rechallenge; four patients were hospitalised; no fatal UK reports. Most UK reports note recovery after stopping, a minority continued to have symptoms, and recurrence has been reported on restarting the same or a different statin. Data are insufficient to determine whether statin, duration or dose alter the risk, or whether new-onset disease is transient or permanent.

12. Регуляторное

    Medicines and Healthcare products Regulatory Agency. Statins: updated adverse reaction information in patient leaflets MHRA Drug Safety Update, volume 3, issue 4, November 2009, 2009.

    https://www.gov.uk/drug-safety-update/statins-updated-adverse-reaction-information-in-patient-leaflets

    Финансирование и результат

    Финансирование

    Medicines and Healthcare products Regulatory Agency

    Результат

    A European-wide review of statins reported in February 2008 identified, from clinical trial and postmarketing data, sleep disturbance, memory loss, sexual disturbances, depression and interstitial pneumopathy, and concluded that the evidence supported a possible causal relationship with statin use. Summaries of Product Characteristics and patient leaflets of simvastatin, atorvastatin, pravastatin, fluvastatin and rosuvastatin were amended: any statin may be associated with depression, sleep disturbances, memory loss and sexual dysfunction, and statins may very rarely be associated with interstitial lung disease, presenting with dyspnoea, non-productive cough and deterioration in general health such as fatigue, weight loss and fever. The review stated that the balance of risks and benefits of statins as a class remains positive.

13. Независимое

    Cholesterol Treatment Trialists' Collaboration. Effect of statin therapy on muscle symptoms: an individual participant data meta-analysis of large-scale, randomised, double-blind trials Lancet, 2022.

    doi:10.1016/S0140-6736(22)01545-8PubMed 36049498

    Финансирование и результат

    Участники

    154 664

    Наблюдение

    weighted average median 4.3 years in the placebo-controlled trials

    Финансирование

    British Heart Foundation (PG/18/16/33570 and CH/1996001/9454), UK Medical Research Council (MC_UU_00017/4), and Australian National Health and Medical Research Council (GNT1037786 and GNT1150467). The Cholesterol Treatment Trialists' Collaboration has not received grant funding from industry; individual contributing trials were funded by the pharmaceutical industry, charities and government organisations. The funder of the study had no role in study design, data collection, data analysis, data interpretation, or writing of the report.

    Результат

    In post hoc subgroup analyses the relative risk of muscle pain or weakness in year 1 did not differ by whether trials had an active run-in, a placebo run-in or no run-in before randomisation, nor between hydrophilic and lipophilic statins; the authors report no evidence that run-in periods led to underestimation of statin-attributable muscle symptoms. For less intensive and moderate-intensity regimens the rate ratio for muscle pain or weakness was greater in women (1.09, 99% CI 1.03 to 1.16) than in men (1.00, 0.97 to 1.04). Data sharing statement: individual patient data from each contributing trial were provided to the collaboration on the understanding that they would be used only for its meta-analyses and would not be released to others; requests are to be made to the data custodians of each trial.

14. Финансирование не установлено

    Collins R, Reith C, Emberson J, Armitage J, Baigent C, Blackwell L, et al. Interpretation of the evidence for the efficacy and safety of statin therapy Lancet, 2016.

    doi:10.1016/S0140-6736(16)31357-5PubMed 27616593

    Финансирование и результат

    Финансирование

    not stated; the paper contains no funding statement

    Результат

    Narrative review by statin trialists. It states that about half of the large statin-against-control trials used a placebo run-in, which the authors argue would not lead to underestimates of side-effect rates, and that a few used an active-drug run-in, which may exclude some patients in whom treatment might cause adverse effects soon after starting. It states that any excesses of muscle-related symptoms due to statin therapy occurred in only about 0.1 to 0.2% of patients each year, that claims of statin intolerance in up to one-fifth of patients rest mainly on reports to regulators and observational studies, and that some reports on statin intolerance were funded by manufacturers of newer lipid-lowering agents.

15. Финансирование не установлено

    Parish E, Bloom T, Godlee F. Statins for people at low risk BMJ, 2015.

    doi:10.1136/bmj.h3908PubMed 26198025

    Финансирование и результат

    Финансирование

    not stated

    Результат

    Editorial. In August 2014 an expert panel convened by The BMJ called for anonymised individual patient data from the statin trials to be made available for independent scrutiny. In reply, the Cholesterol Treatment Trialists' Collaboration confirmed that its meta-analyses had been limited to patient-level data on cause-specific mortality, major vascular events and site-specific cancers, that other adverse events were not part of the original agreement, and that trialists agreed in 2013 to pool all adverse events. Of principal investigators of 32 major statin trials contacted by the journal, seven responded. The editors state that guideline producers had not had access to analyses by third parties independent of the trialists, that adverse event data remained the preserve of individual trialists and drug company sponsors, and that the trials were not designed specifically to measure harms. The journal acknowledged that it had published two articles that misrepresented rates of adverse events from statins.

16. Справочное издание

    UniProt Consortium. UniProt: the Universal Protein Knowledgebase in 2025 Nucleic Acids Research, 2025.

    doi:10.1093/nar/gkae1010PubMed 39552041

    Финансирование и результат

    Финансирование

    National Human Genome Research Institute [HG002273]; NIH Office of the Director [U24HG007822]; NIAID; NIA; NIGMS [R35GM141873]; NIDDK; NEI; NCI; NHLBI; BBSRC [BB/T015608/1]; National Science Foundation Directorate for Biological Sciences [BB/X002179/1]; Open Targets; Horizon 2020 [825575]; Swiss State Secretariat for Education, Research and Innovation; EMBL Australia.

    Результат

    Reviewed human UniProtKB entries, release 2026_03 (2 September 2026), read through rest.uniprot.org on 2026-10-22. COX10 (Q12887): heme O synthase, converts protoheme IX and farnesyl diphosphate to heme O; mitochondrial membrane; variants cause mitochondrial complex IV deficiency, nuclear type 3. COX15 (Q7KZN9): heme A synthase, converts heme O to heme A, the prosthetic group of cytochrome c oxidase; inner mitochondrial membrane; predominantly in tissues with high oxidative phosphorylation, including muscle, heart and brain; variants cause complex IV deficiency, nuclear type 6. TRIT1 (Q9H3H1): transfers a dimethylallyl group from dimethylallyl diphosphate to adenine 37 of a subset of cytosolic and mitochondrial tRNAs, with partial modification of the selenocysteine tRNA, and is required for selenoprotein expression; variants cause combined oxidative phosphorylation deficiency 35. COQ2 (Q96H96): prenylates 4-hydroxybenzoate with the decaprenyl chain to form coenzyme Q10, which carries electrons between respiratory chain complexes; highest expression in skeletal muscle, adrenal glands and heart; variants cause primary coenzyme Q10 deficiency 1. DHDDS (Q86SQ9): with NUS1 condenses isopentenyl diphosphate onto farnesyl diphosphate to form the precursor of dolichol phosphate, the sugar carrier for protein glycosylation in the endoplasmic reticulum; variants cause congenital disorder of glycosylation 1BB and retinitis pigmentosa 59. HMGCR (P04035): rate-limiting step in the synthesis of cholesterol and other isoprenoids; main target of statins; highest expression in cerebellum, fetal brain, testis, skin and adrenal gland; biallelic variants cause autosomal recessive limb-girdle muscular dystrophy 28, with progressive proximal and axial weakness, limited ambulation or wheelchair dependence within a few decades and frequent respiratory insufficiency (PubMed 36745799, 37167966).

17. Справочное издание

    UniProt Consortium. UniProt: the Universal Protein Knowledgebase in 2025 Nucleic Acids Research, 2025.

    doi:10.1093/nar/gkae1010PubMed 39552041

    Финансирование и результат

    Финансирование

    National Human Genome Research Institute [HG002273]; NIH Office of the Director [U24HG007822]; NIAID; NIA; NIGMS [R35GM141873]; NIDDK; NEI; NCI; NHLBI; BBSRC [BB/T015608/1]; National Science Foundation Directorate for Biological Sciences [BB/X002179/1]; Open Targets; Horizon 2020 [825575]; Swiss State Secretariat for Education, Research and Innovation; EMBL Australia.

    Результат

    Reviewed UniProtKB entries, release 2026_03, read through rest.uniprot.org. HMGCR (P04035): converts HMG-CoA to mevalonate, the rate-limiting step in the synthesis of cholesterol and other isoprenoids; ER membrane; main target of statins. FDFT1 (P37268): joins two farnesyl diphosphates through presqualene diphosphate with NADPH or NADH; first committed enzyme of sterol synthesis. SQLE (Q14534): oxidises squalene to (S)-2,3-epoxysqualene; considered a rate-limiting enzyme. FDPS (P14324): forms farnesyl diphosphate, precursor of sterols, dolichols and ubiquinones and substrate for protein farnesylation and geranylgeranylation. GGPS1 (O95749): forms geranylgeranyl diphosphate. PDSS1 (Q5T2R2) and PDSS2 (Q86YH6): extend farnesyl diphosphate with isopentenyl diphosphate to the decaprenyl side chain of ubiquinone-10; mitochondrion. COQ2 (Q96H96): prenylates 4-hydroxybenzoate with the polyprenyl chain; in humans the product is CoQ10, which transports electrons between respiratory chain complexes. DHDDS (Q86SQ9) and NUS1 (Q96E22): condense isopentenyl diphosphate onto farnesyl diphosphate to dehydrodolichyl diphosphate, mostly C95 and C100, precursor of dolichol phosphate, the sugar carrier for ER protein glycosylation. SRD5A3 (Q9H8P0): polyprenal reductase in the conversion of polyprenol to dolichol. FNTA (P49354), FNTB (P49356) and PGGT1B (P53609): transfer a farnesyl or geranylgeranyl group to the cysteine fourth from the C-terminus of proteins ending in Cys-aliphatic-aliphatic-X. LDLR (P01130): binds LDL, the major cholesterol-carrying lipoprotein of plasma, and transports it into cells by endocytosis; receptor-ligand complexes first cluster into clathrin-coated pits. PCSK9 (Q8NBP7): binds LDLR and promotes its degradation in intracellular acidic compartments by a non-proteolytic mechanism. NPC1L1 (Q9UHC9): critical for cholesterol uptake across the enterocyte plasma membrane; apical membrane. CYP7A1 (P22680): 7-alpha-hydroxylates cholesterol, a rate-limiting step of bile acid synthesis, with electrons from NADPH through cytochrome P450 reductase; ER membrane. FGF19 (O95750): suppresses bile acid synthesis by down-regulating CYP7A1; activity requires KLB and FGFR4. Gene-to-protein assignments of reviewed human entries: SREBF2 SREBP-2 (Q12772); SCAP (Q12770); INSIG1 (O15503); INSIG2 (Q9Y5U4); MBTPS1 site-1 protease (Q14703); MBTPS2 site-2 protease (O43462); LIPA lysosomal acid lipase (P38571); NPC1 (O15118); STAR (P49675); CYP11A1 cholesterol side-chain cleavage enzyme (P05108); CYP27B1 25-hydroxyvitamin D 1-alpha-hydroxylase (O15528); CYP27A1 sterol 27-hydroxylase (Q02318); CYP7B1 oxysterol 7-alpha-hydroxylase (O75881); NR1H4 farnesoid X receptor (Q96RI1); NR0B2 small heterodimer partner (Q15466); POR NADPH-cytochrome P450 reductase (P16435); APOA1 (P02647); ABCG1 (P45844); LIPG endothelial lipase (Q9Y5X9); DHCR24 (Q15392); DHCR7 (Q9UBM7).

18. Независимое

    Taylor BA, Lorson L, White CM, Thompson PD. A randomized trial of coenzyme Q10 in patients with confirmed statin myopathy Atherosclerosis, 2015.

    doi:10.1016/j.atherosclerosis.2014.12.016PubMed 25545331

    Финансирование и результат

    Регистрация

    NCT01140308

    Участники

    120

    Наблюдение

    8-week crossover confirmation phase, then 8 weeks of CoQ10 or placebo

    Финансирование

    Coenzyme Q10 in Statin Myopathy study is funded by NCCAM grant 1RC1AT005836 (P. Thompson).

    Результат

    In the double-blind crossover of simvastatin 20 mg against placebo in 120 people with prior statin myalgia, 35.8% had pain on simvastatin but not placebo (n=43), 29.2% on placebo but not simvastatin, 17.5% on both and 17.5% on neither. Serum CoQ10 fell from 1.3 to 0.8 µg/mL over 8 weeks on simvastatin with placebo and rose from 1.3 to 5.2 µg/mL with CoQ10 600 mg/day (ubiquinol). Pain severity and interference rose on simvastatin irrespective of CoQ10 (p = 0.53 and 0.56); muscle strength and VO2max did not change; pain was reported by 14 of 20 on CoQ10 against 7 of 18 on placebo (p = 0.05); time to pain onset 3.0 against 2.4 weeks (p = 0.55). Intramuscular CoQ10 was not measured.

19. Независимое

    Dohlmann TL, Kuhlman AB, Morville T, Dahl M, Asping M, Orlando P, et al. Coenzyme Q10 Supplementation in Statin Treated Patients: A Double-Blinded Randomized Placebo-Controlled Trial Antioxidants (Basel), 2022.

    doi:10.3390/antiox11091698PubMed 36139772

    Финансирование и результат

    Участники

    37

    Наблюдение

    8 weeks

    Финансирование

    This study was conducted at the University of Copenhagen and funded by the University of Copenhagen 2016 Center of Excellence grant, and by the Nordea Foundation. None of the funders had any influence on the study design, data collection, analysis or interpretation.

    Поддержка в натуральной форме

    CoQ10 and matched placebo tablets donated by PharmaNord (Vejle, Denmark).

    Результат

    CoQ10 400 mg daily or placebo for eight weeks did not change muscle CoQ10 content, mitochondrial respiratory capacity, mitochondrial content or reactive oxygen species production, and did not affect myalgia intensity on a 10 cm visual analogue scale; individual changes in muscle CoQ10 did not correlate with changes in myalgia.

20. Независимое

    Yogev Y, Shorer Z, Koifman A, Wormser O, Drabkin M, Halperin D, et al. Limb girdle muscular disease caused by HMGCR mutation and statin myopathy treatable with mevalonolactone Proceedings of the National Academy of Sciences of the United States of America, 2023.

    doi:10.1073/pnas.2217831120PubMed 36745799

    Финансирование и результат

    Участники

    6

    Финансирование

    Israel Science Foundation (grant 2034/18) to O.S.B.; scholarship to Y.Y. from the Foulkes Foundation; National Knowledge Center for Rare/Orphan Diseases of the Israel Ministry of Science, Technology and Space, Ben-Gurion University of the Negev.

    Результат

    A homozygous loss-of-function missense mutation in HMGCR caused autosomal recessive limb-girdle muscle disease in six individuals of one kindred: onset in the fourth decade with pain on exertion, then fatigue and weakness of proximal and axial muscles, culminating in respiratory muscle involvement; the three oldest (aged 49, 58 and 51) were wheelchair-bound or bedridden with respiratory insufficiency, one ventilated by tracheostomy. Imaging showed fatty replacement of proximal and axial muscles that the authors describe as highly reminiscent of end-stage statin myopathy and immune-mediated necrotising myopathy. Oral mevalonolactone, the product of the enzyme, was given to one patient without significant adverse effects and resolved statin-induced myopathy in mice. The paper states that up to 30% of statin users report muscle symptoms, while reports differ.

21. Независимое

    Lotta LA, Sharp SJ, Burgess S, Perry JRB, Stewart ID, Willems SM, et al. Association Between Low-Density Lipoprotein Cholesterol-Lowering Genetic Variants and Risk of Type 2 Diabetes: A Meta-analysis JAMA, 2016.

    doi:10.1001/jama.2016.14568PubMed 27701660

    Финансирование и результат

    Участники

    321 044

    Финансирование

    United Kingdom Medical Research Council (MC_UU_12015/1, MC_PC_13046, MC_PC_13048, MR/L00002/1); EU FP6 programme for EPIC-InterAct (LSHM_CT_2006_037197); Wellcome Trust grants to individual authors. The funding bodies had no role in the design or conduct of the study; collection, management, analysis or interpretation of the data; preparation, review or approval of the manuscript or the decision to submit the manuscript for publication.

    Результат

    LDL-lowering alleles at HMGCR were associated with type 2 diabetes and coronary artery disease in opposite directions; per LDL-lowering T allele of rs12916 the odds ratio for type 2 diabetes was 1.029 (95% CI 1.012 to 1.046), and HMGCR alleles were associated with higher body mass index and waist-to-hip ratio. Per genetically predicted 1 mmol/L lower LDL cholesterol, the odds ratio for type 2 diabetes was 2.42 (1.70 to 3.43) for NPC1L1 variants and 1.19 (1.02 to 1.38) for PCSK9 variants, while coronary risk fell similarly for each gene. Associations with diabetes were heterogeneous across genes (I-squared 77.2%).

22. Независимое

    Dietschy JM, Turley SD. Thematic review series: brain Lipids. Cholesterol metabolism in the central nervous system during early development and in the mature animal Journal of Lipid Research, 2004.

    doi:10.1194/jlr.R400004-JLR200PubMed 15254070

    Финансирование и результат

    Финансирование

    The original research from this laboratory reviewed in the paper was supported by Grants R37 HL-09610 and T32 DK-07745 from the National Institutes of Health and by a grant from the Moss Heart Fund.

    Результат

    Review. In humans the mean concentration of unesterified cholesterol in the central nervous system (about 23 mg/g) is higher than in any other tissue, mostly in compact myelin; the CNS is 2.1% of body weight but contains 23% of the whole-body sterol pool. The cholesterol for CNS growth apparently comes exclusively from synthesis within it, and there is no evidence of net transfer of sterol from blood into brain or spinal cord; in adults synthesis exceeds need and cholesterol leaves the CNS, partly as 24(S)-hydroxycholesterol. Turnover of the CNS sterol pool is about 0.03% a day in the human brain against 0.7% a day for the whole body. The authors state that there is no evidence that plasma cholesterol directly influences CNS cholesterol metabolism, that all orally given statins partially inhibit cholesterol synthesis in the CNS, and that small changes in plasma 24(S)-hydroxycholesterol after statins cannot be proven to reflect changes in its CNS production; whether plasma cholesterol changes affect cognition or dementia remained uncertain.

23. Независимое

    Zoungas S, Wolfe R, Moran C, Nicholls SJ, Cloud GC, Reid CM, et al. Atorvastatin, Cardiovascular Events, and Disability-free Survival in Older Adults New England Journal of Medicine, 2026.

    doi:10.1056/NEJMoa2607314PubMed 42670961

    Финансирование и результат

    Регистрация

    NCT02099123

    Участники

    9 971

    Наблюдение

    median 5.9 years

    Финансирование

    Abstract: Funded by the National Health and Medical Research Council and others. Registry NCT02099123: sponsor Monash University; collaborators National Health and Medical Research Council, Australia, and National Heart Foundation, Australia. Protocol (BMJ Open 2023) and baseline (JAHA 2024) papers: funding from NHMRC (APP1068146, APP1161503) and the Heart Foundation of Australia; the funders have had no role in the study design, collection, management, analysis, and interpretation of data or in writing or submission of reports or publications. The full NEJM text was not readable.

    Результат

    Atorvastatin 40 mg daily (n=4984) against identical placebo (n=4987). Primary cardiovascular composite (cardiovascular death, non-fatal myocardial infarction or stroke, or coronary revascularisation): 297 participants (10.9 per 1000 person-years) against 412 (15.5 per 1000 person-years), HR 0.70 (95% CI 0.61 to 0.82). Death from any cause, dementia or persistent physical disability: 637 (21.6 per 1000 person-years) against 676 (23.0), HR 0.94 (0.84 to 1.05), P = 0.25. Serious adverse events 131 (2.7%) against 129 (2.7%); musculoskeletal, hepatobiliary and diabetes-related adverse events were more common with atorvastatin. The authors conclude that atorvastatin lowered major cardiovascular events but did not lengthen disability-free survival.

24. Финансировано индустрией

    Nohria A, Prsic A, Liu PY, Okamoto R, Creager MA, Selwyn A, et al. Statins inhibit Rho kinase activity in patients with atherosclerosis Atherosclerosis, 2009.

    doi:10.1016/j.atherosclerosis.2008.12.023PubMed 19167712

    Финансирование и результат

    Участники

    35

    Наблюдение

    28 days

    Финансирование

    This work was supported by grants from the National Institutes of Health (HL052233, PO1 HL-48743); Doris Duke Charitable Foundation; and Pfizer, Inc. (Morristown, NJ). One author received a National Health Research Institute grant from Taiwan.

    Результат

    Atorvastatin 80 mg reduced leukocyte Rho kinase (ROCK) activity against placebo (p = 0.002), significantly within 2 weeks, and the reduction remained after controlling for changes in LDL cholesterol and triglycerides (p = 0.01); changes in ROCK activity did not correlate with changes in LDL cholesterol (r = 0.2, p = 0.25). Rho activation requires isoprenoid intermediates of the mevalonate pathway. The authors describe these as first-in-man findings.

25. Финансирование не установлено

    Schooling CM, Au Yeung SL, Freeman G, Cowling BJ. The effect of statins on testosterone in men and women, a systematic review and meta-analysis of randomized controlled trials BMC Medicine, 2013.

    doi:10.1186/1741-7015-11-57PubMed 23448151

    Финансирование и результат

    Участники

    869

    Наблюдение

    trials of 2 weeks or more

    Финансирование

    not stated

    Результат

    Statins lowered testosterone by 0.66 nmol/L (95% CI 0.14 to 1.18) in men and by 0.40 nmol/L (0.05 to 0.75) in women with polycystic ovary syndrome; overall by 0.44 nmol/L (0.13 to 0.75). Most included trials were carried out by teams affiliated with or funded by pharmaceutical companies. The authors state that whether this is a detrimental side effect or a mode of action warrants investigation.

26. Независимое

    Cohen JC, Boerwinkle E, Mosley TH, Hobbs HH. Sequence variations in PCSK9, low LDL, and protection against coronary heart disease New England Journal of Medicine, 2006.

    doi:10.1056/NEJMoa054013PubMed 16554528

    Финансирование и результат

    Участники

    12 887

    Наблюдение

    15 years

    Финансирование

    Supported by the Donald W. Reynolds Foundation, the W.M. Keck Foundation, and the Le Ducq Foundation; by a grant (HL 20948) from the National Institutes of Health; and as a collaborative study by contracts (N01-HC-55015, N01-HC-55016, N01-HC-55018, N01-HC-55019, N01-HC-55020, N01-HC-55021, and N01-HC-55022) with the National Heart, Lung, and Blood Institute.

    Результат

    Of 3363 Black participants, 2.6% carried the PCSK9 nonsense mutation Y142X or C679X (allele frequencies 0.8% and 1.8%), and their mean LDL cholesterol was 28% lower than in non-carriers. Over the 15-year follow-up, coronary heart disease (myocardial infarction, fatal coronary heart disease or coronary revascularisation) occurred in 1 of 85 carriers (1.2%) against 9.7% of non-carriers (P = 0.008); the age- and sex-adjusted hazard ratio was 0.11 (95% CI 0.02 to 0.81; P = 0.03). Of 9524 White participants, 3.2% carried PCSK9 R46L, which was associated with 15% lower LDL cholesterol and coronary events in 6.3% against 11.8% (hazard ratio 0.50, 95% CI 0.32 to 0.79; P = 0.003).

27. Регуляторное

    US Food and Drug Administration (labelling submitted by Viatris Specialty LLC). LIPITOR (atorvastatin calcium) tablets, for oral use: full prescribing information US Food and Drug Administration approved prescribing information, via DailyMed; version 8, effective 15 April 2024, 2024.

    https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=a60cc18b-0631-4cf0-b021-9f52224ece65

    Финансирование и результат

    Финансирование

    not stated; FDA-approved labelling carries no funding statement

    Результат

    Mechanism of action: atorvastatin is a selective, competitive inhibitor of HMG-CoA reductase, the rate-limiting enzyme that converts HMG-CoA to mevalonate, a precursor of sterols including cholesterol; in animal models it lowers plasma cholesterol by inhibiting hepatic HMG-CoA reductase and cholesterol synthesis and by increasing hepatic cell-surface LDL receptors. Absorption: absolute bioavailability of the parent drug about 14% and systemic availability of HMG-CoA reductase inhibitory activity about 30%, the low systemic availability being attributed to presystemic clearance in gastrointestinal mucosa and/or hepatic first-pass metabolism. Atorvastatin is extensively metabolised to ortho- and parahydroxylated derivatives that inhibit HMG-CoA reductase equivalently, and about 70% of circulating inhibitory activity is attributed to active metabolites; in vitro studies suggest the importance of metabolism by CYP3A4. Elimination is primarily biliary; plasma half-life about 14 hours, half-life of inhibitory activity 20 to 30 hours; less than 2% of a dose appears in urine. Atorvastatin is a substrate of the hepatic transporters OATP1B1 and OATP1B3 and of the efflux transporter BCRP. Ciclosporin raised atorvastatin AUC 8.69-fold and Cmax 10.66-fold.

28. Независимое

    Brown MS, Radhakrishnan A, Goldstein JL. Retrospective on Cholesterol Homeostasis: The Central Role of Scap Annual Review of Biochemistry, 2018.

    doi:10.1146/annurev-biochem-062917-011852PubMed 28841344

    Финансирование и результат

    Финансирование

    National Institutes of Health (HL20948 to J.L.G., M.S.B. and A.R.) and The Welch Foundation (I-1793 to A.R.).

    Результат

    Review. SREBPs are ER membrane proteins with an NH2-terminal bHLH-Zip domain, two transmembrane helices and a COOH-terminal domain that binds Scap; SREBP-2 is specialised for cholesterol homeostasis. In cholesterol-deprived cells the MELADL sequence in cytosolic Loop 6 of Scap binds Sec23-Sec24 of COPII and Scap carries SREBPs to the Golgi, where S1P cleaves the luminal loop and S2P cleaves within the transmembrane helix, releasing the bHLH-Zip domain to the nucleus. Cholesterol binds luminal Loop 1 of Scap (apparent Kd 67 nM for the purified loop); Scap then binds Insig-1 or Insig-2 and MELADL becomes inaccessible to COPII. 25-Hydroxycholesterol binds Insig, not Scap. Insig-1 and Insig-2 also bind the membrane domain of HMG CoA reductase, the rate-controlling enzyme of cholesterol biosynthesis, and trigger its ubiquitination and degradation. Sterol-sensing domains occur in Scap, HMG CoA reductase, 7-dehydrocholesterol reductase (last step of cholesterol synthesis), NPC1 (export of LDL-derived cholesterol from lysosomes) and NPC1L1 (intestinal cholesterol absorption).

29. Независимое

    Goldstein JL, Brown MS. A century of cholesterol and coronaries: from plaques to genes to statins Cell, 2015.

    doi:10.1016/j.cell.2015.01.036PubMed 25815993

    Финансирование и результат

    Финансирование

    The authors' experimental work over 40 years was supported by grants from the NIH (HL-20948), the Perot Foundation, the Moss Heart Foundation and the O'Donnell Foundation.

    Результат

    Narrative review. Cholesterol is a 27-carbon, four-ring molecule synthesised from acetate, a two-carbon unit attached to CoA; HMG-CoA reductase catalyses the rate-controlling step. An LDL particle contains about 1500 cholesteryl ester molecules in its core and a coat of about 800 phospholipid molecules, about 500 unesterified cholesterol molecules and one 500-kDa apoB. LDL receptors cluster in coated pits; internalised LDL reaches lysosomes, where cholesteryl esters are hydrolysed. The LDLR gene on the short arm of chromosome 19 has 18 exons and encodes a mature protein of 839 amino acids with seven cysteine-rich LDL-binding repeats and a 50-amino-acid cytoplasmic tail that directs it to coated pits. FH heterozygotes have half the functional receptors and about twofold LDL. Nuclear SREBP-2 activates the LDL receptor gene and the cholesterol biosynthetic genes; statins lower ER cholesterol, activate SREBP-2, raise hepatic LDL receptors and lower plasma LDL. Most LDL is removed by hepatic LDL receptors. PCSK9 binds hepatic LDL receptors and disrupts their recycling. African-Americans heterozygous for PCSK9 nonsense mutations Y142X or C679X had 28% lower LDL and 88% fewer heart attacks. Conclusions on human liver are extrapolated from rats, mice, hamsters and dogs.

30. Регуляторное

    US Food and Drug Administration (labelling submitted by AstraZeneca Pharmaceuticals LP). CRESTOR (rosuvastatin) tablets, for oral use: full prescribing information US Food and Drug Administration approved prescribing information, via DailyMed; version 19, effective 23 September 2026, 2026.

    https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=325a5d0e-9a72-4015-9fcd-1655fb504cee

    Финансирование и результат

    Финансирование

    not stated; FDA-approved labelling carries no funding statement

    Результат

    Rosuvastatin clearance is not dependent on metabolism by cytochrome P450 3A4 to a clinically significant extent. Rosuvastatin is a substrate of CYP2C9 and of transporter proteins including the hepatic uptake transporter organic anion-transporting polypeptide 1B1 (OATP1B1) and the efflux transporter breast cancer resistance protein (BCRP); coadministration of inhibitors of these transporters, such as ciclosporin, certain HIV protease inhibitors and ticagrelor, may raise rosuvastatin plasma concentrations and the risk of myopathy and rhabdomyolysis. Disposition involves OATP1B1 and other transporter proteins, and higher plasma concentrations have been reported in very small groups of patients (n = 3 to 5) who carry two reduced-function alleles of the gene encoding OATP1B1 (SLCO1B1 521T>C). The frequency of the SLCO1B1 521 C/C genotype is generally lower than 5% in most racial and ethnic groups, and the effect of this polymorphism on the efficacy or safety of rosuvastatin has not been clearly established.

31. Регуляторное

    Medicines and Healthcare products Regulatory Agency. Systemic fusidic acid and interaction with statins MHRA Drug Safety Update, volume 5, issue 2, September 2011, 2011.

    https://www.gov.uk/drug-safety-update/systemic-fusidic-acid-and-interaction-with-statins

    Финансирование и результат

    Финансирование

    Medicines and Healthcare products Regulatory Agency

    Результат

    The number and severity of case reports of rhabdomyolysis, including fatal cases, suspected to be due to an interaction between systemic fusidic acid and a statin had increased; the mechanism is unknown and could apply to some or all statins. Systemic fusidic acid should not be given with statins; where it is essential, statin treatment should be stopped for its duration and reintroduced 7 days after the last dose.

32. Регуляторное

    US Food and Drug Administration (labelling submitted by AstraZeneca Pharmaceuticals LP). CRESTOR (rosuvastatin) tablets, for oral use: full prescribing information US Food and Drug Administration approved prescribing information, via DailyMed; version 19, effective 23 September 2026; sections 4 to 8, 2026.

    https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=325a5d0e-9a72-4015-9fcd-1655fb504cee

    Финансирование и результат

    Финансирование

    not stated; FDA-approved labelling carries no funding statement

    Результат

    Warnings: myopathy and rhabdomyolysis, with acute kidney injury secondary to myoglobinuria and rare fatalities; risk factors are age 65 years or older, uncontrolled hypothyroidism, renal impairment, interacting drugs and higher dose; myopathy risk greater on 40 mg; Asian patients may be at higher risk, with about 2-fold median exposure against White controls; exposure raised to a clinically significant extent in severe renal impairment (creatinine clearance below 30 mL/min/1.73 m2) without haemodialysis. Rare immune-mediated necrotising myopathy. Transaminases above 3 times the upper limit of normal in 1.1% on rosuvastatin against 0.5% on placebo in pooled placebo-controlled trials; rare postmarketing fatal and non-fatal hepatic failure. Dipstick-positive proteinuria and microscopic haematuria, more frequent on 40 mg, generally transient, clinical significance unknown. Increases in HbA1c and fasting glucose that in some instances exceed the threshold for diagnosis of diabetes; in JUPITER (8901 per group, mean 2 years) diabetes was reported in 2.8% on rosuvastatin 20 mg against 2.3% on placebo and mean HbA1c rose by 0.1%. METEOR (rosuvastatin 40 mg, n=700, against placebo, n=281, mean 1.7 years): ALT above 3 times the upper limit of normal 2.2% against 0.7%, increased creatine phosphokinase 2.6% against 0.7%. Children aged 10 to 17 with heterozygous familial hypercholesterolaemia: creatine kinase above 10 times the upper limit of normal in 4 of 130 on rosuvastatin against 0 of 46 on placebo. Postmarketing reports: thrombocytopenia; hepatitis, jaundice, fatal and non-fatal hepatic failure; immune-mediated necrotising myopathy; peripheral neuropathy; cognitive impairment, generally non-serious and reversible, onset 1 day to years, median resolution 3 weeks; new-onset or exacerbated myasthenia gravis with recurrence on rechallenge; depression; sleep disorders including insomnia and nightmares; gynaecomastia; interstitial lung disease; drug reaction with eosinophilia and systemic symptoms (DRESS); lichenoid drug eruption. Pregnancy: may cause fetal harm based on the mechanism of action; breastfeeding not recommended; limited case reports show rosuvastatin in human milk.

33. Независимое

    Chou R, Cantor A, Dana T, Wagner J, Ahmed AY, Fu R, et al. Statin Use for the Primary Prevention of Cardiovascular Disease in Adults: Updated Evidence Report and Systematic Review for the US Preventive Services Task Force JAMA, 2022.

    doi:10.1001/jama.2022.12138PubMed 35997724

    Финансирование и результат

    Участники

    90 624

    Наблюдение

    6 months to 6 years

    Финансирование

    This research was funded under contract HHSA290201500007i; Group A, Task Order 75Q80119F32009, from the Agency for Healthcare Research and Quality (AHRQ), US Department of Health and Human Services, under a contract to support the US Preventive Services Task Force (USPSTF). Investigators worked with USPSTF members and AHRQ staff to develop the scope, analytic framework, and key questions; AHRQ had no role in study selection, quality assessment, or synthesis.

    Результат

    Statins were associated with lower all-cause mortality (RR 0.92, 95% CI 0.87 to 0.98; absolute risk difference -0.35%, -0.57% to -0.14%), stroke (RR 0.78; ARD -0.39%), myocardial infarction (RR 0.67; ARD -0.85%) and composite cardiovascular outcomes (RR 0.72; ARD -1.28%); cardiovascular mortality RR 0.91 (0.81 to 1.02; ARD -0.13%). Data for people older than 75 were sparse; mean age was 52 to 66 in all trials except PROSPER (70 to 82), and ten trials restricted enrolment to age 75 or younger. Pooled harms: serious adverse events RR 0.97 (0.93 to 1.01), myalgia 0.98 (0.86 to 1.11), raised ALT 0.94 (0.78 to 1.13), diabetes 1.04 (0.92 to 1.19), with one trial of high-intensity therapy showing 1.25 (1.05 to 1.49). Three trials reported no industry funding; the rest were fully or partially industry funded. Reviewers did not have access to individual patient data. Mortality benefit was smaller than in the 2016 review after adding primary prevention data from ALLHAT-LLT and PROSPER, which found no reduction in all-cause or cardiovascular mortality.

34. Независимое

    Cholesterol Treatment Trialists' (CTT) Collaboration, Baigent C, Blackwell L, Emberson J, Holland LE, Reith C, 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.

    doi:10.1016/S0140-6736(10)61350-5PubMed 21067804

    Финансирование и результат

    Участники

    169 138

    Наблюдение

    median 4.8 years in trials of statin against control; 5.1 years in trials of more against less intensive statin

    Финансирование

    This work is supported at the CTSU by the UK Medical Research Council, British Heart Foundation, and, previously, the European Community Biomed Programme, and at the CTC by the Australian National Health and Medical Research Council and National Heart Foundation. The funding sources had no involvement in study design, data collection, analysis, interpretation, report writing or publication.

    Результат

    In the 21 trials of statin against control, first major vascular events (major coronary event, coronary revascularisation or stroke) occurred in 7136 (2.8% per annum) of 64,744 participants allocated statin against 8934 (3.6% per annum) of 64,782 allocated control, a 22% (95% CI 19 to 24) reduction with a weighted mean LDL cholesterol difference of 1.07 mmol/L at 1 year; 21% (19 to 23) per 1.0 mmol/L. Across all 26 trials, per 1.0 mmol/L LDL cholesterol reduction: major vascular events rate ratio 0.78 (0.76 to 0.80); all-cause mortality 0.90 (0.87 to 0.93); cancer incidence 1.00 (0.96 to 1.04). Excess rhabdomyolysis 1 (SE 1) per 10,000 in the trials of statin against control.

35. Независимое

    Ramos R, Comas-Cufí M, Martí-Lluch R, Balló E, Ponjoan A, Alves-Cabratosa L, et al. Statins for primary prevention of cardiovascular events and mortality in old and very old adults with and without type 2 diabetes: retrospective cohort study BMJ, 2018.

    doi:10.1136/bmj.k3359PubMed 30185425

    Финансирование и результат

    Участники

    46 864

    Наблюдение

    median 5.6 years

    Финансирование

    Ministerio de Salud (EC11-267); Carlos III Health Institute, co-financed with European Union ERDF funds (RedIAPP RD16/0007/0004; Red de Investigación Cardiovascular RD12/0042/0061, RD12/0042/0013; Miguel Servet Contract CP12/03287); Departament de Salut, Generalitat de Catalunya (2014 SGR 240; 2017 SGR 1146). The sponsors had no role in the design and conduct of the study; the collection, management, analysis, or interpretation of the data; or the preparation, review, or approval of the manuscript.

    Результат

    Propensity-adjusted hazard ratios for new statin use. Without diabetes, aged 75 to 84: atherosclerotic cardiovascular disease 0.94 (95% CI 0.86 to 1.04), all-cause mortality 0.98 (0.91 to 1.05); aged 85 or older: 0.93 (0.82 to 1.06) and 0.97 (0.90 to 1.05). With diabetes, aged 75 to 84: 0.76 (0.65 to 0.89) and 0.84 (0.75 to 0.94); aged 85 or older: 0.82 (0.53 to 1.26) and 1.05 (0.86 to 1.28). In people without diabetes older than 74, statins were not associated with lower cardiovascular disease or mortality even when incidence exceeded proposed treatment thresholds.

36. Независимое

    Estruch R, Ros E, Salas-Salvadó J, Covas MI, Corella D, Arós F, et al. Primary Prevention of Cardiovascular Disease with a Mediterranean Diet Supplemented with Extra-Virgin Olive Oil or Nuts New England Journal of Medicine, 2018.

    doi:10.1056/NEJMoa1800389PubMed 29897866

    Финансирование и результат

    Регистрация

    ISRCTN35739639

    Участники

    7 447

    Наблюдение

    median 4.8 years (interquartile range 2.8 to 5.8); stopped at the fourth prespecified interim analysis

    Финансирование

    Instituto de Salud Carlos III, Spanish Ministry of Health (RTIC G03/140, RTIC RD 06/0045, CIBEROBN); Centro Nacional de Investigaciones Cardiovasculares; Fondo de Investigación Sanitaria–Fondo Europeo de Desarrollo Regional; Ministerio de Ciencia e Innovación; Fundación Mapfre 2010; Consejería de Salud de la Junta de Andalucía; Public Health Division of the Department of Health of the Autonomous Government of Catalonia; Generalitat Valenciana; Regional Government of Navarra; Patient-Centered Outcomes Research Institute grant to one author. None of the sponsors had any role in the study design, data analysis, or reporting of the results.

    Поддержка в натуральной форме

    Extra virgin olive oil donated by Hojiblanca and Patrimonio Comunal Olivarero; walnuts by the California Walnut Commission; almonds by Borges; hazelnuts by Morella Nuts.

    Результат

    Mediterranean diet with extra virgin olive oil (1 litre per week per household, goal at least 4 tablespoons a day), Mediterranean diet with 30 g mixed nuts a day, or control diet (advice to reduce dietary fat), with quarterly dietary sessions. Primary end point (myocardial infarction, stroke or cardiovascular death): 96 of 2543 (3.8%), 83 of 2454 (3.4%) and 109 of 2450 (4.4%); 8.1, 8.0 and 11.2 per 1000 person-years; 5-year absolute risks 3.6%, 4.0% and 5.7%; adjusted hazard ratios 0.69 (95% CI 0.53 to 0.91) for olive oil and 0.72 (0.54 to 0.95) for nuts. The authors report an absolute difference of 1.7 to 2.1 percentage points over 5 years; the reciprocal of 2.1 points gives a number needed to treat of 48 for 5 years for the olive oil diet. Death from any cause 118, 116 and 114 (hazard ratios 0.90, 0.69 to 1.18, and 1.12, 0.86 to 1.47). Stroke 0.65 (0.44 to 0.95) and 0.54 (0.35 to 0.82); myocardial infarction 0.82 (0.52 to 1.30) and 0.76 (0.47 to 1.25). Protocol deviations not described in the 2013 report: 425 household members assigned without randomisation to the group of the member already enrolled; 467 participants at site D assigned by clinic; inconsistent use of randomisation tables at site B (593 participants). The original report was withdrawn; estimates were adjusted for baseline characteristics and propensity scores and do not rely exclusively on the assumption that all participants were randomly assigned. Excluding all 1588 participants with known or suspected deviations (5859 analysed): hazard ratios 0.71 (0.52 to 0.97) and 0.68 (0.49 to 0.95). Urinary hydroxytyrosol was measured as the adherence biomarker of the olive oil group. The oil supplied was polyphenol-rich, unlike the ordinary refined variety, which is poor in polyphenols. Fish and legume intake rose by 0.3 and 0.4 weekly servings in the Mediterranean groups against control; the authors state that the major between-group differences involved the supplemental items, extra virgin olive oil and nuts.

37. Независимое

    Neuman J, Korenstein D, Ross JS, Keyhani S. Prevalence of financial conflicts of interest among panel members producing clinical practice guidelines in Canada and United States: cross sectional study BMJ, 2011.

    doi:10.1136/bmj.d5621PubMed 21990257

    Финансирование и результат

    Участники

    288

    Финансирование

    This project was not directly supported by any research funds. One author is funded by a Veterans' Administration HSR&D career development award; one is supported by the National Institute on Aging (K08 AG032886) and by the American Federation of Aging Research through the Paul B Beeson Career Development Award Program.

    Результат

    Five of the 14 guidelines had no accompanying declaration of conflicts of interest. Of 288 panel members, 138 (48%) declared conflicts at publication; among 73 who declared none, 8 (11%) were found to have one or more; overall 150 (52%) had conflicts, 12 undeclared. Of members declaring conflicts, 93% reported honoraria, speakers' fees, consultancy or stock ownership from manufacturers of relevant drugs. Six of 12 identified chairs had conflicts. Government-sponsored panels had fewer conflicts than others (15 of 92, 16%, against 135 of 196, 69%). Among hyperlipidaemia panels, 44 of 99 members (44%) had conflicts, and 40 of 61 (66%) in the hyperlipidaemia guidelines with declarations.

38. Консенсус

    Grundy SM, Cleeman JI, Merz CN, Brewer HB Jr, Clark LT, Hunninghake DB, et al. Implications of recent clinical trials for the National Cholesterol Education Program Adult Treatment Panel III guidelines Circulation, 2004.

    doi:10.1161/01.CIR.0000133317.49796.0EPubMed 15249516

    Финансирование и результат

    Финансирование

    not stated; approved by the National Heart, Lung, and Blood Institute, the American Heart Association and the American College of Cardiology Foundation

    Результат

    Based on five statin trials published after 2001 (including HPS and PROVE IT), the update kept an LDL cholesterol goal below 100 mg/dL for high-risk people but made a goal below 70 mg/dL a therapeutic option for very high risk, including people with baseline LDL below 100 mg/dL; for moderately high-risk people (2 or more risk factors, 10-year risk 10 to 20%) the goal stayed below 130 mg/dL with below 100 mg/dL as an option; drug therapy should lower LDL cholesterol by at least 30 to 40%. The authors state that HPS and PROVE IT cannot be taken as the final word on lowering LDL well below 100 mg/dL.

39. Независимое

    Bonnet F, Poulizac P, Rousselot N, Couffinhal T, Galli G, Berdaï D, et al. Discontinuation of statins for primary prevention of atherosclerotic cardiovascular disease in adults aged 75 years or older (SAGA/SITE): a multicentre, open-label, pragmatic, non-inferiority randomised trial Lancet Healthy Longevity, 2026.

    doi:10.1016/j.lanhl.2026.100884PubMed 42580354

    Финансирование и результат

    Регистрация

    NCT02547883

    Участники

    1 180

    Наблюдение

    36 months

    Финансирование

    French Ministry of Health within the framework of the Medico Economical Research Program (PRME) 2014. Registry: sponsor University Hospital, Bordeaux; grant PRME 14-0037 from the French Ministry of Health.

    Результат

    Open-label randomisation 5:4 to continue (639) or stop (521) statins; 1160 analysed for the primary estimand. Death at 36 months: 48 of 604 (7.9%) continuing against 35 of 484 (7.2%) stopping; absolute difference -0.68% (95% CI -3.95 to 2.60), within the prespecified non-inferiority margin of 5%. Adverse events in 461 of 631 (73.1%) continuing and 390 of 527 (74.0%) stopping; non-cardiovascular adverse events 72.3% against 72.7%. The authors conclude that discontinuation was non-inferior to continuation for 3-year all-cause mortality.

40. Независимое

    Kutner JS, Blatchford PJ, Taylor DH, Ritchie CS, Bull JH, Fairclough DL, et al. Safety and benefit of discontinuing statin therapy in the setting of advanced, life-limiting illness: a randomized clinical trial JAMA Internal Medicine, 2015.

    doi:10.1001/jamainternmed.2015.0289PubMed 25798575

    Финансирование и результат

    Регистрация

    NCT01415934

    Участники

    381

    Наблюдение

    up to 1 year; primary end point at 60 days

    Финансирование

    This study received funding from the National Institute of Nursing Research (grants UC4-NR012584 and U24-NR014637), with resources and facilities of the Veterans Affairs Health Care System. The National Institute of Nursing Research had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.

    Результат

    Unblinded pragmatic trial: 189 participants were randomised to discontinue and 192 to continue statins. Death within 60 days: 45 (23.8%) after discontinuation against 39 (20.3%) with continuation (90% CI of the difference -3.5% to 10.5%; P = 0.36); non-inferiority was not achieved because the upper limit exceeded the prespecified margin of 5%. Median time to death 229 against 190 days (P = 0.60). Cardiovascular events in 13 against 11 participants. Mean total McGill quality-of-life score (0 to 10, area under the curve) 7.11 against 6.85 (P = 0.04). The primary end point was changed from survival to death within 60 days partway through the trial on the advice of the data and safety monitoring board.