Statins
BMJ 2024; 384 doi: https://doi.org/10.1136/bmj-2022-072584 (Published 24 January 2024) Cite this as: BMJ 2024;384:e072584
- Spoorthy Kulkarni, post CCT fellow in clinical pharmacology and therapeutics1,
- Michaela M Watts, senior research sister in cardiovascular trials12,
- Michalis Kostapanos, consultant in acute and general internal medicine with subspecialty expertise in cardiovascular risk management12
- 1Clinical Pharmacology Unit, Addenbrooke’s Hospital, Cambridge University Hospitals NHS Foundation Trust, Cambridge, UK
- 2Lipid clinic, Addenbrooke’s Hospital, Cambridge University Hospitals NHS Foundation Trust
- Correspondence to: M Kostapanos m.kostapanos{at}nhs.net
What you need to know
Statins are the first choice of therapy for hypercholesterolaemia and/or mixed dyslipidaemia for people with a moderate to high risk of cardiovascular disease
Evaluate cardiovascular disease risk for each patient and set individualised goals for serum levels of low density lipoprotein cholesterol
With shared decision making, select the appropriate statin intensity for treatment
Monitor safety and tolerability, as well as response to treatment, and escalate statin treatment as tolerated
Practical Prescribing is a series produced in conjunction with the Drug and Therapeutics Bulletin to highlight important issues for prescribers to consider and prompts for shared decision making between prescribers, patients, and their carers. Targeted at all medical and non-medical prescribers, particularly doctors in training, the series covers medicines commonly prescribed in primary and secondary care.
A 55 year old man without significant past medical history and who was not taking any regular medications has a transient ischaemic attack. His fasting lipid profile is total cholesterol 6.8 mmol/L (normal range <5 mmol/L), triglycerides 2.0 mmol/L (<1.7 mmol/L), high density lipoprotein cholesterol (HDL-C) 1.2 mmol/L (>1 mmol/L), low density lipoprotein cholesterol 4.6 mmol/L (<3.0 mmol/L), non-HDL-C 5.6 mmol/L (<4.0 mmol/L), and total-to-HDL cholesterol ratio 5.6 (<6). You are planning to discuss with the potential benefits and harms of treatment with a statin with him.
How often are statins prescribed and how do they work?
In 2018, across 83 countries covering 74% of the estimated global population, over 145 million people (2.6%) were taking a statin.1 In the UK, around 7.5 million (11.2%) people are prescribed a statin, with atorvastatin, simvastatin, and rosuvastatin being the most common. In England, over 80 million prescriptions for statins are dispensed at a cost of £116m yearly.2
Cardiovascular disease is the major contributor of mortality worldwide and accounts for approximately 30% of deaths globally.3 High cholesterol is one of the main modifiable risk factors for cardiovascular disease. Statins are efficacious in reducing serum levels of low density lipoprotein cholesterol (LDL-C) and cardiovascular disease risk, and their use is endorsed by most international guidelines, including American Heart Association, European Society of Cardiology, and the UK National Institute for Health and Care Excellence (NICE).456
Statins are the first choice of therapy for hypercholesterolaemia or mixed dyslipidaemia with inadequate response to lifestyle changes in (a) patients with a history of cardiovascular disease (secondary prevention), (b) for people with a moderate to high risk of cardiovascular disease based on risk prediction tools (such as a 10 year risk of cardiovascular disease ≥10%), and (c) in patients with certain comorbidities (diabetes and/or chronic kidney disease) (box 1).456 They are also indicated for the management of heterozygous or homozygous familial hypercholesterolaemia.7
Statin regimens, indications and treatment goals46
High intensity statins* for very high risk patients
Indicated for patients with
Established atherosclerotic cardiovascular disease (ASCVD)
Diabetes with target organ damage or ≥3 major risk factors, or early onset of type 1 diabetes of long duration (>20 years)
Severe chronic kidney disease (CKD) (eGFR <30 mL/min/1.73 m2)
10 year risk of fatal cardiovascular disease ≥10% (based on a risk prediction tool such as SCORE)
Familial hypercholesterolaemia with ASCVD or with another major risk factor
Options for starting treatment:
Atorvastatin 40-80 mg/day, rosuvastatin 20-40 mg/day
Simvastatin 80 mg/day no longer recommended because of unfavourable risk-benefit ratio compared with atorvastatin and rosuvastatin
NICE recommendation for starting regimen:
For patients with established ASCVD: atorvastatin 80 mg/day (consider lower dose if potential drug interactions, high risk of adverse effects, or patient preference)
For patients with severe CKD: atorvastatin 20 mg/day or consult a renal physician
For familial hypercholesterolaemia: high intensity statin as above
For very high risk primary prevention patients: atorvastatin 20 mg/day
ESC/EAS treatment goals: Reduce LDL-C levels by >50% from baseline and LDL-C goal of <1.4 mmol/L
NICE treatment goals:
Reduce LDL-C levels by >50% from baseline in patients with established ASCVD or familial hypercholesterolaemia
Reduce non-HDL-C levels by >40% for patients with CKD, high risk primary prevention patients, and patients with diabetes
High intensity statins* for high risk patients
Indicated for patients with
Markedly elevated single risk factors, particularly total cholesterol >8 mmol/L, LDL-C >4.9 mmol/L, blood pressure >180/110 mm Hg
Familial hypercholesterolaemia without other major risk factor
Diabetes without target organ damage, with diabetes duration >10 years or with an additional risk factor
Moderate CKD (eGFR 30-59 mL/min/1.73 m2)
10 year risk of fatal cardiovascular disease >5% to <10%
Options for starting treatment:
Atorvastatin 40-80 mg/day, rosuvastatin 20-40 mg/day
NICE recommendation for starting regimen:
Atorvastatin 20 mg/day for type 1 diabetes, type 2 diabetes plus a Qrisk3 score ≥10%, and moderate CKD
For familial hypercholesterolaemia: high intensity statin as above
ESC/EAS treatment goals: Reduce LDL-C levels by >50% from baseline and LDL-C goal of <1.8 mmol/
NICE treatment goals:
Reduce LDL-C levels by >50% from baseline in patients with familial hypercholesterolaemia
Reduce non-HDL-C levels by >40%
Moderate intensity statins* for moderate risk patients
Indicated for patients with
Young patients with diabetes (<35 years old for type 1, <50 years old for type 2) with diabetes duration <10 years, without other risk factors
10 year risk of fatal cardiovascular disease >1% to <5%
Options for starting treatment: Atorvastatin 10-20 mg/day, rosuvastatin 5-10 mg/day, simvastatin 20-40 mg/day, pravastatin 40-80 mg/day, fluvastatin XL 80 mg/day, fluvastatin 40 mg (twice daily), lovastatin 40 mg (not in UK), pitavastatin 2-4 mg (not in UK)
NICE recommendation for starting regimen: Atorvastatin 20 mg/day (consider it for type 1 diabetes)
ESC/EAS treatment goals: LDL-C goal of <2.6 mmol/
NICE treatment goals: Reduce non-HDL-C levels by >40%
* High intensity statins reduce serum LDL-C levels by average >50%, moderate intensity statins by 30-50%.
ESC/EAS = European Society of Cardiology/European Atherosclerosis Society. eGFR = estimated glomerular filtration rate. LDL-C = low density lipoprotein cholesterol. non-HDL-C = non-high density lipoprotein cholesterol.
Statins inhibit cholesterol synthesis in hepatocytes by competitively inhibiting hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase (fig 1).8 This leads to an upregulation of hepatic low density lipoprotein (LDL) receptors, enhancing the clearance of circulating LDL and other atherogenic lipoproteins.8 Statins also exert various pleiotropic anti-atherosclerotic effects: endothelial function improvement, atherosclerotic plaque stabilisation, and anti-inflammatory and anti-thrombotic actions.9
Mechanism of statin action. Statins inhibit cholesterol synthesis in hepatocytes by competitively inhibiting hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase. This effect leads to an upregulation of hepatic low-density lipoprotein (LDL) receptors enhancing the clearance of the circulating LDLs and other atherogenic lipoproteins, including very low density lipoproteins (VLDL)
What should I discuss with patients before starting treatment?
Ask the patient about previous statin use. If they have previously taken a statin, review the indication, the effects of taking the medication, any adverse effects, and the reason it was stopped. Discuss with the patient the current indication of the statin, and potential benefits, risks of statin treatment, alternative options, and the effect of doing nothing.
Statins result in a greater absolute reduction in the risk of cardiovascular events in patients at higher baseline risk.4 Among those who receive a statin for primary prevention, the estimated numbers needed to treat to prevent a coronary event over five years are 146 and 53 for low risk and high risk individuals, respectively.10 The benefits of statins in preventing cardiovascular disease are proportional to their efficacy in lowering LDL-C levels.11 A meta-analysis of data from 14 randomised trials of statins concluded a proportional reduction in all-cause and coronary mortality by approximately 10% and 20%, respectively, per 1.0 mmol/L reduction in LDL-C.411 Therefore, high intensity statins (high potency statins at doses that can reduce LDL-C by ≥50%) provide greater reductions in LDL-C and in morbidity and mortality than moderate intensity statins,12 and are recommended for high risk patients by international guidelines (box 1).4
When asking patients about their understanding of why a statin may be indicated, it can be helpful to show the patient’s personalised information such as their 10-year cardiovascular disease risk score, heart age applications, and any relevant test results supporting the use of statin (such as carotid ultrasound to give a visual understanding of the patient’s atherosclerotic burden if available). Consider using online tools, such as decision aids offered by NICE, in which patients can visualise graphically the effect of statin treatment on preventing cardiovascular events over 10 years according to their cardiovascular disease risk category.13 If the patient would like to take longer to review the information before deciding whether to receive treatment, provide the option of a follow-up appointment and inform them that cardiovascular disease risk will be reassessed.6
Discuss non-pharmacologic options for the management of hypercholesterolaemia. Guidelines recommend adopting a balanced diet, taking regular exercise, maintaining normal body mass index, limiting alcohol and carbohydrate intake, especially if triglycerides are elevated, and smoking cessation.4
What are the important adverse effects to discuss?
Statin-associated muscle symptoms, including myalgia, arthralgia, and muscle stiffness or weakness are the most reported adverse effects and the commonest reason for stopping treatment and low adherence to treatment, which leads to poor cardiovascular outcomes.14 Rates of adverse events in real-world studies vary from 7% to 29%,14 whereas data from randomised placebo-controlled trials suggest a lower risk for these events.15 A meta-analysis of individual participant data from 19 randomised placebo-controlled trials of statins showed an excess rate of 11 adverse events per 1000 person-years with statins over placebo.16 Risk factors for developing statin-associated muscle symptoms include high dose treatment, frailty, age >70 years, hypothyroidism, liver or kidney dysfunction, vitamin D deficiency, and concomitant medications interacting with statins.14
Liver enzyme elevations occur in 0.5-2.0% of patients.17 These are mostly asymptomatic and present with mild to moderate elevations of mostly alanine transaminase (<3×upper limit of normal) which are dose-dependent and reversible with statin discontinuation. International reporting systems indicate that the incidence of severe liver injury associated with statins is ≤2 cases/1000 000 patient-years.17
Myopathy and rhabdomyolysis are rare, with incidences of about 1/10 000 and 1/100 000 people per year, respectively.14 Similarly rare is immune mediated necrotising myositis, characterised by elevated creatinine kinase and proximal muscle weakness, which can persist despite statin discontinuation.14
Statins induce a small but statistically significant increase in the risk of developing diabetes (defined as HbA1c ≥6.5%) by about 9-13%.18 It is estimated that 99 people need to be treated for five years with statins to cause one excess case of diabetes.19 This effect is more prominent in patients with increased body mass index, prediabetes, or metabolic syndrome. However, the benefits from effective LDL-C lowering by statins in non-diabetic hyperglycaemia or diabetes often exceed the risks from adverse glycaemia, and statin discontinuation is not recommended in these patients.18
Statin-induced proteinuria has been noted with high doses of potent statins.20 However, because of the long term benefits of statins on preservation of glomerular filtration rate and proteinuria,21 current guidelines do not recommend stopping statins in most of these instances.
Check interactions with medications commonly coprescribed with statins. An example is simvastatin >20 mg/day co-administered with amlodipine >5 mg/day, in which selection of a different statin with no drug-drug interaction potential (such as atorvastatin) can allow dose titration of both medications. Different statins exert their effect through varying metabolic pathways, including the cytochrome P450 pathway and, for simvastatin, cytochrome P450 3A4.22 Consider interactions of statins with non-prescribed over-the-counter medications such as St John’s wort or certain foods and beverages such as grapefruit and pomegranate juice.23
What to consider when prescribing?
Before starting treatment with a statin, stratify patients into one of the cardiovascular risk categories and set a treatment target. Consider using risk prediction tools, and select a starting regimen based on the LDL-C reduction target relevant to baseline cardiovascular disease risk and the anticipated LDL-C-lowering effect (box 1).46 Consider conditions enhancing the risk of statin toxicity (such as history of myopathy).
Ask about the patient’s expectations and factors affecting adherence. Up to a third of high risk patients discontinued statins in randomised clinical trials, while data from registries indicate that in real world use, adherence to treatment declines to less than 50% and 30% at one and two years after treatment initiation, respectively.24 Factors leading to non-adherence include anticipation of adverse effects, imperceptible benefits, and statin regimen characteristics (dose and dosing complexity, such as timings of dosing and polypharmacy).25
Although the dosing instructions for simvastatin and pravastatin suggest that they should be taken at night, there is no such recommendation for atorvastatin and rosuvastatin.7 The difference in efficacy between daily and nightly administration, especially with the long acting statins (atorvastatin, rosuvastatin), is not clinically meaningful.26 These statins can be taken any time throughout the day if this is expected to improve adherence.
When considering the benefit-risk balance of statin treatment, inform women of childbearing potential that statins have not been approved for use in pregnancy and breastfeeding. In the UK, current NICE guidelines recommend stopping statins at least three months before any planned pregnancy and during gestation and breastfeeding.6
What should I monitor during the course of the prescription?
Before starting statin treatment, check baseline kidney, thyroid, and liver function and screen for secondary causes of dyslipidaemia including but not limited to poor glycaemic status, hypothyroidism, cholestasis, and albuminuria (fig 2).4 An abnormal urine albumin:creatinine ratio is an independent risk factor for cardiovascular disease, while nephrotic range albuminuria may be indicative of secondary hypercholesterolaemia.46 Figures 2-4 provide details for assessment of patients who are prescribed statins.46
Ask about unexplained muscle symptoms and whether these were associated with any previous lipid-lowering treatment. If so, assess creatine kinase levels. NICE guidelines recommend avoiding starting statin treatment if creatine kinase level is greater than five times the upper limit of normal and to check the level again in seven days (fig 5). If the level remains greater than five times the upper limit of normal do not start statins, but if the level is less than five times greater then start statins with lower than the intended dose.6
What other concerns might my patient have while taking treatment?
Most patients are concerned about adverse effects of statins, especially ones that may present daily and affect quality of life. Statin-associated muscle symptoms, liver injury, memory loss, and the risk of developing diabetes are common reasons given by patients who decline statin treatment.27 It is debated how much statin-associated muscle symptoms represent toxicity and how much they are a a nocebo effect (patients experiencing symptoms in anticipation of side effects). Most double-blind placebo-controlled trials of statins show no difference in prevalence of statin-associated muscle symptoms between statins and placebo.16 However, these trials may underestimate the prevalence of symptoms, either by exclusion of populations at risk for developing myopathy or by dropouts of patients with muscle symptoms in their run-in phase.
When should I stop the prescription?
Guidelines on deprescribing statins vary, and this decision should be on a case-by-case basis.28 Permanent deprescribing is generally reserved for patients with an extremely reduced life expectancy or on an end-of-life care pathway.28 Statins should be also discontinued in cases when an absolute contraindication to their use arises, and when they are not tolerated (side effects) to the extent that the benefit-risk balance is in favour of statin discontinuation. Choosing to not pursue treatment for hypercholesterolaemia should be a shared decision with an informed benefit-risk discussion relevant to the clinical context.
Non-statin drugs for lowering low density lipoprotein cholesterol
Under the direction of a specialist, non-statin drugs can be used when statins are contraindicated or not tolerated. Examples include ezetimibe, bile acid sequestrants (such as cholestyramine), and bempedoic acid. Combination treatment may result in more substantial LDL-C reductions than monotherapy,429 and fixed combinations of statins with ezetimibe may be safer and more tolerable than high dose statin regimens alone.30 Drugs inhibiting proprotein convertase subtilisin/kexin type 9 (PCSK9) include the monoclonal antibodies alirocumab and evolocumab and the small interfing RNA inclisiran. They are effective in lowering LDL-C levels as monotherapies and in combination with statins.43132
Summary characteristics of statins33
Mechanism of action
Inhibition of hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase, resulting in reduced cholesterol biosynthesis in hepatocytes and lowering of serum low density lipoprotein cholesterol (LDL-C) by an upregulation of hepatic LDL receptors
Indications
Management of dyslipidaemias and prevention of cardiovascular disease events in secondary prevention and in selected moderate to high risk patients in primary prevention
Familial hypercholesterolaemia
Common adverse effects
Class-specific—Statin-associated muscle symptoms (SAMS) such as myalgia, arthralgia, and muscle weakness; liver enzyme elevations (mainly alanine transaminase); creatine kinase elevations; increased risk of diabetes or worsening of glycaemia; proteinuria
Rare class-specific—Myopathy and myositis, drug-induced liver injury, peripheral neuropathy
Non-specific—Gastrointestinal disorders, headache, nightmares and insomnia, nasopharyngitis, sexual dysfunction
Most important drug-drug interactions
Variable interactions in the class due to differences in metabolism and elimination. Simvastatin, predominantly, and atorvastatin are metabolised by cytochrome P450 3A4 (CYP3A4), hence several interactions with potent and moderate CYP3A4 inhibitors such as ketoconazole, clarithromycin, HIV protease inhibitors. In co-administration with CYP3A4 inhibitors, the lowest statin dose that is likely to produce the desirable therapeutic benefit should be used. CYP3A4 inducers such as rifampicin, St John’s wort, and efavirenz may reduce plasma levels of these statins. CYP interactions are less relevant to rosuvastatin because of limited metabolism by CYP. Fibrates may increase the levels of most statins and increase adverse events related to statin intake. Gemfibrozil co-administration with statins should be avoided. Digoxin levels may be increased by atorvastatin and simvastatin, but not by rosuvastatin. Warfarin monitoring is desirable when statin treatment is initiated.
Cautions
Increased alcohol intake, age >70 years, frailty, hypothyroidism, concomitant medications interacting with statins, history of underlying myopathy, and kidney or liver function impairment increase the risk of statin-induced myopathy
Prescribing in renal or hepatic impairment
Hepatic impairment—Contraindicated with active liver disease or unexplained persistent elevations of serum transaminases exceeding three times the upper limit of normal
Renal impairment—Adjustment of dose is required, which varies by statin in relation to their extent of renal elimination. For patients with severe renal insufficiency (creatinine clearance <30 mL/min), avoid doses above the lowest starting doses. Dose adjustments may not be required for atorvastatin based on the kidney function.
Pregnancy and breastfeeding
Contraindicated
Table of equivalence
Cost effectiveness
Secondary prevention—Based on the unit cost with of generic pricing (approximately £13.44/year for atorvastatin 20 mg), and healthcare cost of a cardiovascular event, statins are considered cost effective in secondary prevention patients3536
Primary prevention—Statins are likely cost effective in patients with risk of cardiovascular disease >3.0%/year (new NICE pharmacoeconomic models awaited). Despite the 10% Qrisk3 threshold that has been maintained in the updated NICE recommendation, a more personalised patient-centred approach is now recommended regarding offering statin treatment even in patients with Qrisk3 score <10%
Further information resources for clinicians
Toxbase. Clinical toxicology database of the National Poisons Information Service. https://www.toxbase.org/
British National Formulary (BNF). https://bnf.nice.org.uk/
Drugs and Lactation Database (LactMed). https://www.ncbi.nlm.nih.gov/books/NBK501922/
BUMPS; best use of medicines in pregnancy. https://www.medicinesinpregnancy.org/
Mach F, Baigent C, Catapano AL, et al; ESC Scientific Document Group. 2019 ESC/EAS guidelines for the management of dyslipidaemias: lipid modification to reduce cardiovascular risk. Eur Heart J 2020;41:111-88. doi:10.1093/eurheartj/ehz455
National Institute for Health and Care Excellence. Cardiovascular disease: risk assessment and reduction, including lipid modification (clinical guideline CG181). 2014. https://www.nice.org.uk/guidance/cg181
Reputable patient information leaflets and decision aids
NHS. Overview: Statins. https://www.nhs.uk/conditions/statins/
Heart UK. Statins. https://www.heartuk.org.uk/getting-treatment/statins
Heart UK. Cholesterol. https://www.heartuk.org.uk/?gclid=EAIaIQobChMI0JvEj5XI9wIVEoFQBh3IwwYBEAMYASAAEgJqIPD_BwE
NICE. Cardiovascular disease: risk assessment and reduction, including lipid modification (NICE guideline NG238). Patient decision aid. https://www.nice.org.uk/guidance/ng238/resources/patient-decision-aid-information-243780160
NICE. CKS. Lipid modification - CVD prevention: Statins. https://cks.nice.org.uk/topics/lipid-modification-cvd-prevention/prescribing-information/statins/
How patients were involved in the creation of this article
There was no patient or public involvement in the writing of this article
Education into practice
Do you know which statin to start, at what dose, and in whom?
How you monitor safety and response to treatment in patients newly started on statin treatment?
How this article was created
This article was created after thorough review of the current practice guidelines for the management of dyslipidaemia with emphasis on the 2019 ESC/EAS Guidelines for the management of dyslipidaemias and the 2014 NICE clinical guidelines on cardiovascular disease (CG181). Other sources, including Toxbase; British National Formulary; Lactmed and BUMPS for pregnant women, were also consulted.
Literature on statin side effects, red flags controversies, practical tips, and non-statin options for lowering LDL-C levels was also critically reviewed and discussed in this manuscript.
Footnotes
Advisers to this series are Fraz Mir, consultant physician at Addenbrooke’s Hospital, Cambridge, and David Phizackerley, deputy editor of Drug and Therapeutics Bulletin.
Contributors: SK, MW and MK have all contributed to the literature search, drafting considerable parts of the manuscript and critically reviewing it. The content of the final version of the manuscript was reviewed and approved by all authors, who agree to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.
Competing interests: The BMJ has judged that the authors have no disqualifying financial ties to commercial companies that are relevant to this paper. The authors declare the following other interests: MK is an NHS employee (Consultant Physician) with a secondment in the GlaxoSmithKline (GSK) Research and Development Clinical Unit Cambridge (by 50%). MK also receives Consultancy fee from GSK and has a Consultancy agreement with Amarin Pharmaceuticals. SK is a trainee in Clinical Pharmacology and Therapeutics and is currently funded by UKRI-MRC Secondment Award (MR/W003538/1) to work part-time (50%) with AstraZeneca. MW conducts as a Lead Clinical Research Nurse Practitioner the ORION-4 study in the Cambridge University Hospitals, co-sponsored by the University of Oxford and Novartis.