What are the alternatives to HMG-CoA (3-hydroxy-3-methylglutaryl-coenzyme A) reductase inhibitors, commonly referred to as statins?

From the Guidelines

Alternatives to statins, such as bempedoic acid, PCSK9 inhibitors, ezetimibe, bile acid sequestrants, fibrates, and niacin, should be considered for patients who cannot tolerate statins or have not achieved target LDL cholesterol levels with statin therapy, as they can help reduce cardiovascular risk, although their effectiveness may vary. When considering alternatives to statins, it's essential to evaluate the patient's specific lipid abnormality, side effect profile, cost considerations, and individual cardiovascular risk factors 1. Some key alternatives include:

• Bempedoic acid, which inhibits ATP-citrate lyase and can reduce LDL-C levels by approximately 24.5% compared to placebo, making it a potential option for patients with statin-associated muscle symptoms 1
• PCSK9 inhibitors, such as evolocumab and alirocumab, which are powerful injectable medications that can lower LDL by 50-70%
• Ezetimibe, which blocks cholesterol absorption in the intestine and is often the first alternative to statins, with a typical dose of 10mg daily
• Bile acid sequestrants, such as cholestyramine and colesevelam, which bind to cholesterol-containing bile acids
• Fibrates, such as fenofibrate and gemfibrozil, which primarily reduce triglycerides but have modest effects on LDL
• Niacin, which can improve multiple lipid parameters but has significant side effects, including flushing. It's crucial to weigh the benefits and risks of each alternative and consider the most recent and highest-quality evidence when making treatment decisions, prioritizing the reduction of morbidity, mortality, and improvement of quality of life 1.

From the FDA Drug Label

Effect of REPATHA on Lipid Parameters in Patients with HeFH (Mean % Change from Baseline to Week 12 in RUTHERFORD-2)

• 140 mg every 2 weeks or 420 mg once monthly yield similar reductions in LDL-C

Study 6 (HAUSER-RCT, NCT02392559) was a randomized, multicenter, placebo-controlled, double-blind, 24-week trial in 157 pediatric patients aged 10 to 17 years with HeFH

The difference between REPATHA and placebo in mean percent change in LDL-C from baseline to Week 24 was −38% (95% CI: −45%, −31%; p < 0. 0001).

Study 7 (TESLA, NCT01588496) was a multicenter, double-blind, randomized, placebo-controlled, 12-week trial in 49 patients (not on lipid-apheresis therapy) with HoFH

The difference between REPATHA and placebo in mean percent change in LDL-C from baseline to Week 12 was −31% (95% CI: −44%, −18%; p < 0. 0001).

Alternatives to statin may include evolocumab (REPATHA), as it has been shown to reduce LDL-C levels in patients with HeFH and HoFH.

• Evolocumab can be administered as an adjunct to other lipid-lowering therapies, such as statins and ezetimibe.
• The recommended dosage of evolocumab is 140 mg every 2 weeks or 420 mg once monthly. 2

From the Research

Alternatives to Statin Therapy

Alternatives to statin therapy are considered when patients experience statin intolerance, which is fairly common 3. The following alternatives are available:

• Ezetimibe: a non-statin lipid-lowering medication that can be used alone or in combination with statins 3, 4
• Bile acid sequestrants: can be used individually or in combination with statins to lower low-density lipoprotein cholesterol (LDL-C) levels 4
• PCSK9 inhibitors: monoclonal antibodies that can achieve LDL cholesterol reductions of 50% to 70% across various patient populations and background lipid-lowering therapies 5
• Lipoprotein apheresis: a treatment option for high-risk patients with multiple cardio-vascular events and sub-optimal LDL cholesterol despite lipid-lowering drug therapy 3
• Fibrates: may improve cardiovascular outcomes as monotherapy, but trials in combination with statins have failed to show a benefit, except in those with elevated triglycerides or low HDL-C 6
• Niacin: may reduce cardiovascular events as monotherapy, but recent trials in combination with statins have failed to show a benefit 6

Non-Statin Therapies

Non-statin therapies have a limited role in reducing cardiovascular events in those maintained on guideline-directed statin therapy 6. However, in certain clinical situations, such as patients who are unable to tolerate statin therapy or recommended intensities of statin therapy, non-statin therapies may be useful in reducing cardiovascular events. These situations include:

• Patients with persistent severe elevations in triglycerides
• Patients with high cardiovascular risk
• Patients who cannot tolerate statin therapy due to muscle-related symptoms or other adverse events 7

Management of Statin-Intolerant Patients

The management of statin-intolerant patients involves:

• Statin cessation or dose reduction
• Evaluation of alternative causes for muscle-related symptoms
• Re-challenge with the same statin at a lower dose or an alternative statin
• Consideration of non-statin lipid-lowering therapies 3, 7