What are the risks and benefits of statin therapy in patients at high risk of cardiovascular events?

From the Guidelines

Statin therapy is recommended for patients at high risk of cardiovascular events as the benefits generally outweigh the risks. The primary benefit of statins is significant reduction in cardiovascular events and mortality by lowering LDL cholesterol levels, with risk reductions of 20-30% for major cardiovascular events 1. Common statins include atorvastatin (10-80mg daily), rosuvastatin (5-40mg daily), and simvastatin (10-40mg daily), with higher doses providing greater LDL reduction. Potential risks include muscle-related side effects ranging from mild myalgia (5-10% of patients) to rare but serious rhabdomyolysis (<0.1%), mild liver enzyme elevations, slightly increased risk of new-onset diabetes (especially in those with pre-existing risk factors), and rare cognitive effects. Most side effects are reversible upon discontinuation.

Key Considerations

• Patients should be monitored with baseline liver function tests and as clinically indicated, with CPK measurement reserved for symptomatic patients.
• The risk-benefit ratio is most favorable for secondary prevention (those with established cardiovascular disease) and primary prevention patients with multiple risk factors or very high LDL levels.
• Starting with a moderate-intensity statin and titrating as needed while monitoring for side effects is a practical approach for most high-risk patients.
• The USPSTF recommends using the ACC/AHA Pooled Cohort Equations to calculate 10-year risk of CVD events, and initiating use of low- to moderate-dose statins in adults aged 40 to 75 years without a history of CVD who have 1 or more CVD risk factors and a calculated 10-year CVD event risk of 7.5% to 10% 1.
• High-intensity statin therapy appears to confer incremental clinical benefit compared with less intensive therapy, and is recommended for patients ≤75 years of age who have clinical atherosclerotic cardiovascular disease (including those with MI) 1.

From the FDA Drug Label

The JUPITER study was stopped early by the Data Safety Monitoring Board due to meeting predefined stopping rules for efficacy in rosuvastatin tablets-treated subjects The primary end point was a composite end point consisting of the time-to-first occurrence of any of the following major CV events: CV death, nonfatal myocardial infarction, nonfatal stroke, hospitalization for unstable angina or an arterial revascularization procedure. Rosuvastatin tablets significantly reduced the risk of major CV events (252 events in the placebo group vs. 142 events in the rosuvastatin group) with a statistically significant (p<0. 001) relative risk reduction of 44% and absolute risk reduction of 1. 2%

The benefits of statin therapy in patients at high risk of cardiovascular events include:

• Reduced risk of major CV events, such as CV death, nonfatal myocardial infarction, and nonfatal stroke
• Reduced risk of arterial revascularization procedures
• Increased HDL-C and reduced LDL-C, hsCRP, total cholesterol, and serum triglyceride levels

The risks of statin therapy in patients at high risk of cardiovascular events include:

• Potential increased risk of uterine stromal polyps and hepatocellular adenoma/carcinoma at high doses
• Potential adverse effects on fertility, although no adverse effect on fertility was observed at 50 mg/kg/day in rat fertility studies
• Potential for increased plasma concentrations in patients with reduced function alleles of the gene that encodes OATP1B1 (SLCO1B1 521T > C) 2, 2, 2

From the Research

Risks of Statin Therapy

• The risk of statin-induced serious muscle injury, including rhabdomyolysis, is <0.1% 3
• The risk of serious hepatotoxicity is ≈0.001% 3
• The risk of statin-induced newly diagnosed diabetes mellitus is ≈0.2% per year of treatment, depending on the underlying risk of diabetes mellitus in the population studied 3
• Statins possibly increase the risk of hemorrhagic stroke in patients with cerebrovascular disease, but they clearly produce a greater reduction in the risk of atherothrombotic stroke and thus total stroke, as well as other cardiovascular events 3
• There is no convincing evidence for a causal relationship between statins and cancer, cataracts, cognitive dysfunction, peripheral neuropathy, erectile dysfunction, or tendonitis 3

Benefits of Statin Therapy

• Statins inhibit cholesterol biosynthesis and decrease circulating levels of LDL cholesterol, which translates into a ~ 20% relative reduction of major vascular events and coronary mortality per mmol/L LDL reduction achieved 4
• Statins are efficient in preventing first cardiovascular events 4
• The benefits of statins in primary prevention outweigh the risks, particularly among high-risk patients 5
• High-intensity statins are recommended for patients at high risk for atherosclerotic cardiovascular disease (ASCVD) and can benefit by the addition of nonstatin drugs 6
• Statins significantly reduce cardiovascular morbidity and mortality in patients with and without coronary heart disease 7
• Statins effectively lower atherogenic lipoproteins and result in clinically significant reductions in cardiovascular morbidity and mortality 7

Patient-Specific Considerations

• The pros and cons of statin therapy should be weighted by considering patient-specific life circumstances and assessing the individual cardiovascular risk, as provided by risk calculators 4
• Statin treatment is generally indicated in patients with diabetes mellitus, as it poses a high risk even in the absence of known coronary artery disease 4
• In patients who will not tolerate a statin dose necessary to achieve their LDL target level, ezetimibe may be added 4
• Restarting statin therapy in patients who have stopped taking a statin due to subjective complaints can be challenging, but it is important, especially in patients at high risk of cardiovascular events 3