Non-Statin Cholesterol Medications
For patients who cannot tolerate statins, ezetimibe 10 mg daily is the first-line alternative, followed by bempedoic acid 180 mg daily if LDL-C targets remain unmet, with PCSK9 inhibitors reserved for very high-risk patients who fail combination therapy. 1, 2
First-Line Therapy: Ezetimibe
Ezetimibe should be initiated at 10 mg once daily as the preferred initial non-statin agent, reducing LDL-C by approximately 15-20% with minimal side effects. 1, 2 The drug blocks intestinal cholesterol absorption via the NPC1L1 transporter and can be taken with or without food. 3 Both the American College of Cardiology and European Society of Cardiology provide Class I recommendations for ezetimibe as second-line therapy due to its established long-term safety, lower cost versus newer agents, and proven cardiovascular benefit in the IMPROVE-IT trial. 4, 1, 2
When combined with bile acid sequestrants, administer ezetimibe at least 2 hours before or 4 hours after the sequestrant to avoid binding interactions. 2
Second-Line Add-On: Bempedoic Acid
If LDL-C targets are not achieved with ezetimibe alone, add bempedoic acid 180 mg daily, which provides an additional 15-25% LDL-C reduction. 1, 2 The combination of ezetimibe plus bempedoic acid achieves approximately 35-38% total LDL-C reduction. 1, 2
Bempedoic acid acts upstream of HMG-CoA reductase but is inactive in skeletal muscle because it requires activation by very-long-chain acyl-CoA synthetase-1, an enzyme absent in muscle tissue—thereby avoiding muscle-related adverse effects. 1, 2 The CLEAR Outcomes trial demonstrated a 13% reduction in major adverse cardiovascular events in statin-intolerant patients, with a 17% reduction in those with diabetes. 4, 1, 2
Monitor baseline uric acid and liver function tests when initiating bempedoic acid. 1, 2 Treatment raises uric acid by an average of 0.8 mg/dL, with gout occurring in 1.5% versus 0.4% with placebo. 2 Tendon rupture occurred in 0.5% of patients; educate patients to report tendon pain promptly. 2
Third-Line Therapy: PCSK9 Inhibitors
For very high-risk patients (established ASCVD, recent acute coronary syndrome, or baseline LDL-C ≥190 mg/dL) who remain above target despite ezetimibe plus bempedoic acid, add a PCSK9 inhibitor (alirocumab, evolocumab, or inclisiran). 1, 2 These agents reduce LDL-C by approximately 50-60% and are well-tolerated in statin-intolerant patients with minimal muscle-related adverse effects. 4, 1, 2
The ODYSSEY ALTERNATIVE trial showed alirocumab reduced LDL-C by 54.8% in statin-intolerant patients with fewer skeletal muscle adverse events (32.5%) compared to ezetimibe (41.1%) or atorvastatin rechallenge (46%). 1, 2 Inclisiran offers semi-annual dosing (day 1, day 90, then every 6 months) with sustained 45% LDL-C reduction. 2
Target LDL-C <55 mg/dL with ≥50% reduction from baseline for very high-risk patients; <70 mg/dL for high-risk patients. 4, 1, 2
Alternative Options (Less Preferred)
Bile Acid Sequestrants
Bile acid sequestrants (colesevelam 3.8 g daily, cholestyramine, colestipol) can reduce LDL-C by 15-30% in patients with triglycerides <300 mg/dL who cannot tolerate bempedoic acid. 4, 1, 5 These agents bind bile acids in the intestinal lumen, depleting hepatic bile and upregulating LDL receptor activity. 1 Colesevelam has the added benefit of modestly improving glycemic control in patients with type 2 diabetes. 1
Common pitfall: Gastrointestinal complaints and drug interactions limit use; bile acid sequestrants are contraindicated when triglycerides are high due to risk of severe hypertriglyceridemia. 1, 5
Niacin
Niacin-based preparations (crystalline or extended-release) reduce LDL-C by 20-25%, significantly lower triglycerides, raise HDL-C, and lower lipoprotein(a) by up to 30%. 4, 1, 5 Niacin may be reasonable for statin-intolerant patients with low HDL-C or elevated lipoprotein(a). 4, 1, 5
Side effects include flushing, pruritus, gastrointestinal disturbances, and potential liver enzyme elevations. 1 Modest doses (750-2,000 mg/day) are generally manageable with adjustment of diabetes therapy. 5
Fibrates
Fibrates (fenofibrate preferred over gemfibrozil) should be initiated for triglycerides >500 mg/dL to prevent acute pancreatitis. 4, 2, 5 Fenofibrate reduces triglycerides by approximately 25-50% and decreases risk of nonfatal myocardial infarction. 5 However, randomized controlled trials do not support fibrates as add-on drugs for further LDL-C reduction. 2
When combining fenofibrate with any residual statin therapy, separate administration by at least 2 hours and monitor creatine kinase at baseline. 2
Lifestyle Modifications
Implement dietary changes targeting saturated fat <7% of total calories, trans fatty acids <1% of total calories, and dietary cholesterol <200 mg/day. 2, 5 This approach can reduce LDL-C by approximately 10%. 6, 7
Plant sterols/stanols (2 g/day) lower LDL-C by approximately 10%. 4, 8, 9, 10 Increased dietary fiber (10-25 g/day of soluble fiber) reduces LDL-C by 5-10%. 4, 6, 7 Nut consumption provides an additional 8% LDL-C reduction. 6
Daily physical activity (at least 30 minutes, 5-7 days per week) and weight management targeting BMI 18.5-24.9 kg/m² are strongly recommended. 2, 5
Monitoring Recommendations
Reassess lipid profile 4-8 weeks after initiating or adjusting therapy. 1, 2 For patients on PCSK9 inhibitors, assess LDL-C response every 3-6 months, then annually once at goal. 1, 2 Monitor liver enzymes (ALT/AST) at 8-12 weeks when using bempedoic acid or niacin. 2
Critical Pitfalls to Avoid
Do not label a patient as statin-intolerant without attempting at least 2-3 different statins, including one at the lowest FDA-approved dose. 1, 2 True statin intolerance occurs in <3% of patients; non-adherence is far more common. 2
Do not prescribe bempedoic acid alone (Nexletol) when the patient is not already on ezetimibe—this forfeits an additional 15-20% LDL-C reduction; start with the combination (Nexlizet) instead. 2
Refer to a lipid specialist when baseline LDL-C ≥190 mg/dL, when mixed dyslipidemia is complex, or when targets are not achieved despite combination therapy. 2