From the Guidelines
When statins are not tolerated for hypercholesterolemia treatment, ezetimibe is typically the first alternative, followed by consideration of PCSK9 inhibitors, bempedoic acid, or bile acid sequestrants, depending on the degree of LDL reduction needed and patient preferences. The most recent guidelines from the European Heart Journal in 2024 1 recommend a high-intensity statin up to the highest tolerated dose to reach the LDL-C goals, and if the goal is not achieved, combination with ezetimibe is recommended. For patients who are statin intolerant and do not achieve their goal on ezetimibe, combination with bempedoic acid is recommended, and for those who do not achieve their goal on a maximum tolerated dose of statin and ezetimibe, combination with a PCSK9 inhibitor is recommended.
Some key points to consider when choosing an alternative medication include:
- Ezetimibe (10 mg daily) can lower LDL cholesterol by 15-20% with minimal side effects 1
- PCSK9 inhibitors like evolocumab (140 mg subcutaneously every 2 weeks) or alirocumab (75-150 mg subcutaneously every 2 weeks) can reduce LDL by 50-60%, though they require injections and are more expensive 1
- Bempedoic acid (180 mg daily) works earlier in the same pathway as statins but with fewer muscle-related side effects 1
- Bile acid sequestrants such as cholestyramine (4 g 1-2 times daily) or colesevelam (625 mg tablets, 6 tablets daily) can reduce LDL by 15-30% but may cause gastrointestinal side effects and drug interactions 1
The choice among these alternatives depends on the degree of LDL reduction needed, cost considerations, side effect profiles, and patient preferences. Combination therapy using multiple non-statin medications may be necessary to achieve target lipid levels in high-risk patients. According to the 2024 ESC guidelines 1, lipid-lowering treatment with an LDL-C goal of <1.4 mmol/L (55 mg/dL) and a ≥50% reduction in LDL-C vs. baseline is recommended, and a high-intensity statin up to the highest tolerated dose to reach the LDL-C goals is recommended for all patients with chronic coronary syndrome.
From the FDA Drug Label
Effect of REPATHA on LDL-C in Patients with Hyperlipidemia when Combined with Statins The difference between REPATHA 420 mg once monthly and placebo in mean percent change in LDL-C from baseline to Week 52 was −55% (95% CI: −60%, −50%; p < 0. 0001) Study 4 (MENDEL-2, NCT01763827) was a multicenter, double-blind, randomized, placebo- and active-controlled, 12-week trial that included 614 patients with hyperlipidemia who were not taking lipid-lowering therapy at baseline. The difference between REPATHA and placebo in mean percent change in LDL-C from baseline to Week 12 was −55% (95% CI: −60%, −50%; p < 0. 0001) and −57% (95% CI: −61%, −52%; p < 0.0001) for the 140 mg every 2 weeks and 420 mg once monthly dosages, respectively.
Evolocumab (REPATHA) is a potential medication for hypercholesterolemia when statins are not tolerated.
- The medication has been shown to significantly reduce LDL-C levels in patients with hyperlipidemia.
- In the MENDEL-2 study, evolocumab reduced LDL-C levels by −55% and −57% compared to placebo for the 140 mg every 2 weeks and 420 mg once monthly dosages, respectively 2.
- The medication can be used as an alternative to statins in patients who are intolerant to statin therapy.
From the Research
Alternatives to Statins for Hypercholesterolemia
When statins are not tolerated, several alternative medications can be considered for the treatment of hypercholesterolemia. These include:
- Ezetimibe, a cholesterol absorption inhibitor
- PCSK9 inhibitors, such as evolocumab and alirocumab
- Bempedoic acid, a recently approved medication
- Bile acid sequestrants
Mechanism of Action and Efficacy
These alternative medications work through different mechanisms to lower LDL cholesterol levels. For example:
- Ezetimibe inhibits cholesterol absorption in the intestines, reducing LDL cholesterol levels by approximately 18% when used alone and by an additional 25% when combined with statin therapy 3
- PCSK9 inhibitors, such as evolocumab, reduce LDL cholesterol levels by 53% to 56% by targeting the PCSK9 protein and increasing the liver's ability to remove LDL cholesterol 3
- Bempedoic acid has been shown to lower LDL cholesterol levels, although its exact mechanism of action is not fully understood 4
Safety and Tolerability
The safety and tolerability of these alternative medications have been evaluated in several studies. For example:
- Ezetimibe has been shown to be well-tolerated, with side effects similar to those of placebo 5
- PCSK9 inhibitors have been associated with a small increase in injection site reactions, but are generally considered safe and effective 4, 6
- Bempedoic acid has been associated with a small increase in plasma uric acid and slightly increased frequency of episodes of gout in susceptible subjects 4
Treatment Strategies
When statins are not tolerated, treatment strategies may involve:
- Trying alternative statins, such as pravastatin or fluvastatin, which may be better tolerated 7
- Using ezetimibe or PCSK9 inhibitors as monotherapy or in combination with a statin 7, 6
- Considering bile acid sequestrants or other alternative medications 7
- In high-risk patients, lipoprotein apheresis may be considered if LDL cholesterol targets are not reached with lipid-lowering therapy 7