Statins

Introduction

Based on extensive evidence, statins are recommended as first-line pharmacologic therapy for atherosclerotic cardiovascular disease (ASCVD) risk reduction by the 2018 multi-society cholesterol guidelines, as well as all other guidelines. Consistent evidence from over 24 trials shows that statins reduce the risk of ASCVD in proportion to the magnitude of low-density lipoprotein cholesterol (LDL-C) lowering across a range of ASCVD risk, as long as heart failure (NYHA Class II-IV) or end-stage renal disease/hemodialysis are not present. Each 39 mg/dL reduction in LDL-C reduces the risk of major ASCVD events by about 21% (Figure 18-1). The full relative risk reduction occurs within 2 years of initiating statin therapy. Statins reduce the risk of major ASCVD by a similar magnitude across all patient subgroups, risk factor levels, LDL-C levels and other characteristics, with the exception that there is some evidence of a slightly greater reduction in major ASCVD events in men than in women (Figures 18-2 and 18-3). Statins have also been shown to be safe and well-tolerated in properly selected patients, similar to those who participated in a broad range of primary and secondary prevention trials.

Clinical Highlight I

• Statins are first-line therapy for reducing ASCVD risk.
• Use the appropriate intensity of statin in patients most likely to benefit.
• Statins are very well tolerated in the large majority of patients who might benefit.

Enlarge 

Enlarge 

Enlarge 

Appropriate Uses

The 2018 multi-society cholesterol guideline strongly recommends statin therapy for four groups of patients most likely to experience a net ASCVD risk reduction benefit.

• Statins are recommended (Class of Recommendation [COR] I) for high-risk patients, such as those with:
• Clinical ASCVD (Figure 8-2)
• Primary prevention when LDL-C is ≥190 mg/dL (Figure 8-3)
• Diabetes in patients 40-75 years of age (Figure 8-3)
• Primary prevention in patients 40-75 years of age and LDL-C of 70-189 mg/dL with a high (≥20%) estimated 10-year ASCVD risk (Figure 8-3).

Statins can also be considered for primary prevention following a clinician-patient discussion about the risk estimate and risk enhancers (see Figure 8-3), for:

• Patients 40 to 75 years of age with intermediate (≥7.5% to 20%) 10-year ASCVD risk (COR I)
• Patients 40 to 75 years of age with borderline (≥5% to 7.5%) 10-year ASCVD risk (COR IIb).

High-intensity statins (Table 18-1) are recommended for high-risk patients without safety concerns and can be considered for those with intermediate 10-year ASCVD risk. Moderate-intensity statins are otherwise recommended. In patients unable to tolerate moderate- or high-intensity statin therapy, the maximally tolerated intensity should be used.

Enlarge 

Enlarge 

Enlarge 

Clinical Highlight II

• Use high-intensity statins to reduce ASCVD risk in high-risk patients (and consider them for intermediate-risk patients) unless there are safety concerns.
• Use moderate-intensity statins to reduce ASCVD risk if there are safety concerns with high-intensity statins and in intermediate- and borderline-risk patients.
• Use the maximally tolerated statin dose if unable to tolerate the recommended statin intensity.

Mechanism of Action

Statins block the rate-limiting enzyme in cholesterol synthesis 3-hydroxy-3-methyl-glutaryl-CoA (HMG-CoA) reductase. This enzyme catalyzes the conversion of HMG-CoA to mevalonic acid, which through a series of subsequent steps is converted to cholesterol. Inhibiting HMG-CoA reductase reduces intracellular and plasma cholesterol levels, resulting in upregulated expression of low-density lipoprotein (LDL) receptors in the liver and extrahepatic tissues. The increased number of LDL receptors can then remove more of the cholesterol-rich apolipoproteins: LDL, very low density lipoprotein (VLDL) and VLDL remnants from plasma. Reduced intracellular cholesterol levels also increase PCSK9 levels, which attenuates statin efficacy at higher doses.

There are seven statins available in the United States (Figure 18-4). In 2023, all seven are available as generics.

Enlarge 

Pleiotropic Effects of Statins

Statins have multiple “pleiotropic” or non–LDL-C effects including lowering high-sensitivity C-reative protein (hs-CRP). However, these effects do not appear to result in additional ASCVD risk reduction compared with other treatments that primarily lower LDL-C, including partial ileal bypass surgery, bile acid sequestrants, diet, or ezetimibe (Figure 18-5).

Enlarge 

LDL-C Efficacy

The 2018 multi-society cholesterol guideline grouped statin regimens as high-, moderate-, or low-intensity (Table 8-1) according to their use in randomized trials. High-intensity statins include the highest doses of atorvastatin (40-80 mg) and rosuvastatin (20-40 mg), or a statin used in combination with another LDL-C lowering agent such as ezetimibe.

High-intensity statin regimens reduce LDL-C by ≥50%, which is desirable for high-risk patients. High-intensity statins reduced ASCVD events more than moderate-intensity statins in three randomized trials (TNT, IDEAL, PROVE-IT). Moderate-intensity statin regimens lower LDL-C by approximately 30% to <50%. Starting doses of statins generally achieve this degree of LDL-C lowering (pitavastatin 2 mg, atorvastatin 10 mg, lovastatin or pravastatin 40 mg, rosuvastatin 10 mg, simvastatin 40 mg and fluvastatin 80 mg).

Simvastatin 80 mg failed to reduce ASCVD events more than simvastatin 20 mg in two randomized trials in high-risk patients (SEARCH, A-to-Z), and also reduces LDL-C by <50% on average, so it is grouped with the moderate-intensity statins. Note, however, the FDA does not recommend initiating simvastatin 80 mg due to concerns about muscle safety; patients tolerating simvastatin 80 mg may remain on it.

Only patients who are intolerant to all available moderate-intensity statins should receive a low-intensity dose of statin or less than daily doses.

Each doubling of the statin dose will result in an additional 6% reduction in LDL-C and non– high-density lipoprotein cholesterol (HDL-C) (“rule of sixes”).

Enlarge 

Effects on Other Lipids

Statins reduce non–HDL-C to a similar degree as LDL-C. Statins and fibrates reduce coronary artery disease (CAD) risk in proportion to the magnitude of non–HDL-C lowering (Figure 18-6).

Moderate-intensity statins lower triglycerides by about 15% to 20%, while high-intensity statins can lower triglycerides by up to 30%. Statins modestly raise HDL-C (by 2% to 10%), regardless of intensity. Although HDL-C and triglyceride levels predict cardiovascular risk, the increases in HDL-C or decreases in triglyceride from statin or other pharmacologic therapy apparently do not contribute to further cardiovascular risk reduction in addition to that obtained from LDL-C lowering.

Enlarge 

Clinical Highlight III

• High-intensity statins reduce LDL-C by 50% or more on average.
• Moderate-intensity statins reduce LDL-C by 30-<50% on average.
• The magnitude of LDL-C lowering predicts the ASCVD risk reduction benefit from statin therapy.

Patient Selection to Enhance Safety

Statins were well tolerated in the randomized ASCVD outcomes trials. The participants in these trials were generally healthy and had no history of statin associated side effects. Women of childbearing potential or who were pregnant or breastfeeding were excluded from the statin trials due to the statin contraindication in pregnancy.

A number of characteristics are associated with an increased risk of statin myopathy, many of which may have precluded or reduced the likelihood of participation in the statin trials (Table 18-2). These characteristics may alter statin metabolism, and the risk of myopathy and rhabdomyolysis is often related to circulating drug levels (see Managing Adverse Effects During Statin Therapy for more information on the management of statin adverse effects).

Notably, moderate-intensity statins were generally well tolerated in the four trials that did include individuals with serious comorbidities (NYHA Class II-IV heart failure or undergoing maintenance hemodialysis: CORONA, GISSI-HF, AURORA, GDDS). However, very old patients, frail patients, or patients with other serious comorbidities were excluded from statin trials. Therefore, the potential for both adverse effects and an ASCVD risk reduction benefit is not known for groups of patients systematically excluded from the randomized trials.

Enlarge 

Clinical Highlight IV

• Individuals who do not have serious comorbidities or a history of statin-associated side effects are unlikely to have adverse effects related to statin therapy.

Metabolism

Statins are primarily metabolized in the liver by the hepatic cytochrome P450 enzyme (CYP) system, glucuronidation, or both (Table 18-2). Exposure to other drugs that are metabolized by these pathways may increase statin blood levels and thereby increase the potential for adverse effects (see below).

Renal Function

Some statins have relatively greater renal excretion: lovastatin, pitavastatin, pravastatin, rosuvastatin and simvastatin. Dose adjustment may be considered for patients with markedly impaired renal excretion.

All statins should be used with caution in patients with a glomerular filtration rate <30 mL/min/1.73m² since substantially impaired renal excretion is also a marker for other patient characteristics that may increase the potential for adverse muscle effects, including advanced age, frailty and polypharmacy.

Contraindications

Contraindications to statin therapy are few:

• Active liver disease, which may include unexplained persistent elevations in hepatic transaminase levels
• Women who are pregnant or may become pregnant
• Nursing mothers
• Hypersensitivity to any component of the medication.

Clinical Highlight V

• A woman of childbearing potential who is likely to experience a net benefit from statin therapy, and her partner, should be carefully counselled to practice effective contraception during statin therapy.

Potential Adverse Effects

Although patients taking statins commonly report adverse effects, few of these are attributable to statin therapy. In the randomized blinded statin trials, adverse effect rates were similar in the statin and placebo groups, with the exception of a slight excess of overt diabetes in statin-treated patients.

Muscle Symptoms

Rates of muscle symptoms and myopathy were similar in statin and control groups in the randomized trials. Serious myopathy and rhabdomyolysis occurred at a rate of about 0.01 excess case per 100 patients treated with a statin for 1 year. While 10%-15% of patients taking a statin report muscle symptoms, in the majority of patients they are unrelated to statin use.

Hepatic Transaminase Elevations

In the randomized trials, statins did not increase hepatic transaminases and did not cause serious hepatotoxicity or liver failure. As a result, the FDA and the 2018 multi-society cholesterol guideline do not recommend routine monitoring liver function tests.

Hemorrhagic Stroke

Hemorrhagic stroke was very uncommon in the statin trials with a rate of about 0.01 excess cases per 100 patients treated for 1 year. The risk of hemorrhagic stroke may be higher in patients with a history of hemorrhagic stroke receiving a high-intensity statin and in Asian patients. The reduction in ischemic stroke with statins outweighs any excess risk of hemorrhagic stroke, resulting in a reduction in total stroke.

Diabetes

Statins are associated with a modest excess risk of diabetes, which is related to intensity. Moderate-intensity statins increase the excess risk of diabetes by 0.1 excess case of diabetes per 100 patients treated for 1 year; high-intensity statins increase the excess risk to 0.3 excess case per 100 patients per year. This rate occurs in addition to the background risk of diabetes, which is often relatively high in candidates for statin therapy on the basis of their ASCVD risk. Statins are associated with increased risk of diabetes only in patients who have risk factors for diabetes. Diabetes diagnosis occurs 2 to 4 months earlier in statin-treated patients than in those not receiving a statin, making it unlikely to have any sequelae.

Cognitive Function

The statin trials have not reported an excess of cognitive impairment. In those trials that formally assessed cognitive function, moderate intensity statins had no effect on cognitive function in the trials overall (HPS, PROSPER), with some suggestion of a benefit in clinical trial participants >70 years of age (HPS). In patients with dementia, statins had a neutral effect on cognition in randomized trials.

However, postmarketing reports have associated cognitive impairment (e.g., memory loss, forgetfulness, amnesia, memory impairment, confusion) with statin use. Symptoms were generally mild and reversible upon statin discontinuation, with variable times to symptom onset (1 day to years) and symptom resolution (median of 3 weeks). As a result, the FDA has issued a warning that statins could cause ill-defined memory loss or impairment, which is reversible upon statin discontinuation.

The general approach to statin withdrawal/rechallenge used for the management of muscle symptoms during statin therapy may help clarify the relationship of the cognitive symptoms to statin use.

Mood

A meta-analysis of randomized trials found no negative effects from statins on psychological outcomes and evidence of mood-related benefits.

Neuropathy

Rates of neuropathy and other neurologic conditions are similar in statin and control groups in randomized trials. Rarely, idiosyncratic peripheral neuropathy may develop that resolves with statin discontinuation.

Renal

Statins have no adverse renal effects and may prevent decline in renal function with time.

Cancer

Cancer rates are similar in statin and control groups in individual and meta-analyses of randomized trials. Cancer rates have remained similar in the two treatment groups in long-term follow-up of several statin trials. In large population studies, statin use is associated with lower cancer mortality. Figure 18-7 shows the incidence of cancer in statin trials.

Enlarge 

Drug-Drug Interactions

Statins have interactions with various drugs depending on their primary pathway for metabolism. Healthcare professionals should refer to the drug labels for the latest recommendations.

Metabolized by CYP 3A4

The three statins that are metabolized by hepatic cytochrome P450 enzyme (CYP) 3A4 have the greatest potential for drug interactions—atorvastatin, lovastatin and simvastatin (remember as “A, L, S”) (Table 18-3).

Avoid concomitant use of these agents with potent inhibitors of CYP3A4, including azole antifungals, macrolide antibiotics, rifampin and protease inhibitors (Table 18-4).

Lower doses of simvastatin and lovastatin are recommended for patients receiving weaker CYP3A4 inhibitors such as amiodarone and the calcium channel blockers diltiazem and verapamil (alternatives include amlodipine and nifedipine). Interactions with some antidepressants have also been reported; paroxetine and venlafaxine may be alternatives for some patients.

Enlarge 

Enlarge 

Not Metabolized by CYP3A4

Alternatives to CYP3A4 metabolized statins include:

• Rosuvastatin, which is minimally metabolized
• Pravastatin, which has no cytochrome P450 metabolism
• Fluvastatin, which is metabolized by the 2C9 pathway
• Pitavastatin, which has no significant CYP3A4, 2C9, or 2C8 metabolism.

Glucuronidation

All statins are glucuronidated, increasing the potential for interaction with gemfibrozil. Fenofibrate has minimal effects on glucuronidation.

Cyclosporine

Cyclosporine raises blood levels of virtually all statins by both cytochrome P450 and other pathways, and low doses of statins (preferably other than atorvastatin, lovastatin and simvastatin) should be titrated carefully if needed. See Special Clinical Populations for further discussion of other immunosuppressant drugs.

Clinical Highlight VI

• The vast majority of patients tolerate statins well.
• Rarely, idiosyncratic adverse events may occur; establish statin causality by withdrawing and rechallenging with the statin or statins.
• Atorvastatin and simvastatin are appropriate for most patients; avoid concomitant use with CYP3A4 inhibitors.
• Rosuvastatin, pitavastatin and fluvastatin are alternatives with fewer drug-drug interactions.
• Avoid concomitant use of gemfibrozil and statins.