Management of Severe Hyperlipidemia in a Patient with Statin-Induced Myopathy on Repatha
Add bempedoic acid 180 mg daily to the current Repatha regimen to achieve the LDL-cholesterol target of <70 mg/dL, while simultaneously initiating fenofibrate 54-160 mg daily to address the severe hypertriglyceridemia (607 mg/dL) and prevent acute pancreatitis. 1, 2
Immediate Priority: Address the Severe Hypertriglyceridemia
The triglyceride level of 607 mg/dL represents severe hypertriglyceridemia (≥500 mg/dL) and requires immediate pharmacologic intervention to prevent acute pancreatitis, which occurs in 14% of patients at this level. 2 This takes precedence over further LDL-lowering because the pancreatitis risk is immediate and life-threatening.
Fenofibrate as First-Line for Triglyceride Reduction
Initiate fenofibrate 54-160 mg daily immediately as first-line therapy for severe hypertriglyceridemia, regardless of LDL-cholesterol levels or cardiovascular risk. 2 Fenofibrate provides 30-50% triglyceride reduction and is the preferred fibrate because it does not inhibit statin glucuronidation (unlike gemfibrozil), making it safer if statins are ever reconsidered. 2
The primary goal is rapid reduction of triglycerides to <500 mg/dL to eliminate pancreatitis risk, followed by further reduction to <200 mg/dL (ideally <150 mg/dL) to reduce cardiovascular risk. 2
Critical Dietary Interventions for Severe Hypertriglyceridemia
Restrict total dietary fat to 20-25% of total daily calories for triglycerides in the 500-999 mg/dL range. 2 This is non-negotiable at this triglyceride level.
Completely eliminate all added sugars, as sugar intake directly increases hepatic triglyceride production. 2
Abstain completely from all alcohol consumption—even 1 ounce daily increases triglycerides by 5-10%, and alcohol can precipitate hypertriglyceridemic pancreatitis at this level. 2
Increase soluble fiber to >10 g/day from sources like oats, beans, and vegetables. 2
Optimize Glycemic Control
- Aggressively optimize glycemic control, as the HbA1c of 5.9% suggests good control, but uncontrolled diabetes is often the primary driver of severe hypertriglyceridemia. 2 Even modest improvements in glucose control can reduce triglycerides by 20-50% independent of lipid medications. 2
Addressing the Elevated LDL-Cholesterol
The LDL-cholesterol of 199 mg/dL is critically elevated for a patient with diabetes, hypertension, and hyperlipidemia—all high-risk features that mandate an LDL target of <70 mg/dL. 1 The current Repatha dose (140 mg every 2 weeks) is appropriate, but additional therapy is needed.
Why Not Increase Repatha Dose?
Repatha can be dosed at either 140 mg every 2 weeks or 420 mg monthly, but the every-2-week dosing already provides maximal LDL reduction (50-60% from baseline). 3, 4, 5 Increasing to monthly dosing would not provide additional benefit and might reduce consistency of effect.
Evolocumab (Repatha) reduces LDL-C by 66-75% when added to statin therapy, but in statin-intolerant patients receiving evolocumab monotherapy, the reduction is approximately 53-56%. 4, 6 This patient is likely not achieving the full 60-70% reduction because she cannot tolerate statins.
Add Bempedoic Acid as the Optimal Non-Statin LDL-Lowering Agent
Bempedoic acid 180 mg daily is the ideal addition because it provides 20-28% LDL-cholesterol reduction without causing myopathy (it is not activated in muscle tissue, only in the liver). 1 This is critical for a patient with documented statin-induced myopathy.
Bempedoic acid inhibits ATP citrate lyase in the liver, reducing cholesterol synthesis upstream of statins, and is well tolerated with no long-term safety concerns in early development. 1
Expected LDL reduction with Repatha + bempedoic acid: The combination should reduce LDL from 199 mg/dL to approximately 60-80 mg/dL, achieving the <70 mg/dL target. 1, 4
Why Not Ezetimibe?
Ezetimibe 10 mg daily provides only 13-20% additional LDL reduction when added to PCSK9 inhibitors, which may be insufficient to reach the <70 mg/dL target from a baseline of 199 mg/dL. 1 However, ezetimibe could be considered if bempedoic acid is unavailable or not tolerated.
Ezetimibe is safe and well-tolerated, with proven cardiovascular benefit when added to statins (IMPROVE-IT trial), but data on ezetimibe + PCSK9 inhibitor combinations are limited. 1
Why Not Bile Acid Sequestrants?
- Bile acid sequestrants (cholestyramine, colestipol, colesevelam) are relatively contraindicated when triglycerides are >200 mg/dL because they can paradoxically increase triglyceride levels. 1, 2 With triglycerides at 607 mg/dL, sequestrants are absolutely contraindicated.
Combination Therapy Safety Considerations
Repatha + Fenofibrate Safety
PCSK9 inhibitors (Repatha) do not increase myopathy risk when combined with fibrates, unlike statins. 2 This combination is safe and appropriate for this patient.
Monitor for muscle symptoms and obtain baseline creatine kinase (CPK) levels when initiating fenofibrate, particularly given the history of statin-induced myopathy. 2
Repatha + Bempedoic Acid Safety
Bempedoic acid does not cause myopathy because it is not activated in muscle tissue (lacks the enzyme ATP citrate lyase in skeletal muscle). 1 This makes it uniquely suited for patients with statin intolerance.
The combination of PCSK9 inhibitor + bempedoic acid has not been extensively studied in large trials, but mechanistically there are no safety concerns, as they work through different pathways. 1
Monitoring Strategy
Reassess fasting lipid panel in 4-8 weeks after initiating fenofibrate and bempedoic acid to evaluate triglyceride and LDL response. 2
Monitor renal function within 3 months after fenofibrate initiation and every 6 months thereafter, as fenofibrate is substantially excreted by the kidney. 2 Adjust fenofibrate dose if eGFR is 30-59 mL/min/1.73 m² (maximum 54 mg daily); discontinue if eGFR <30 mL/min/1.73 m². 2
Monitor for muscle symptoms and CPK levels at baseline and periodically, given the history of statin-induced myopathy. 2
Calculate non-HDL cholesterol (total cholesterol minus HDL cholesterol) with a target goal of <100 mg/dL for very high-risk patients. 1, 2
Treatment Goals and Expected Outcomes
Primary goal: Reduce triglycerides to <500 mg/dL within 4-8 weeks to eliminate pancreatitis risk, then to <200 mg/dL (ideally <150 mg/dL) to reduce cardiovascular risk. 2
Secondary goal: Achieve LDL-cholesterol <70 mg/dL for this very high-risk patient (diabetes, hypertension, hyperlipidemia). 1
Expected outcomes with fenofibrate + Repatha + bempedoic acid:
Critical Pitfalls to Avoid
Do not delay fenofibrate initiation while attempting lifestyle modifications alone—triglycerides ≥500 mg/dL require immediate pharmacologic intervention. 2
Do not use gemfibrozil instead of fenofibrate—gemfibrozil has significantly higher myopathy risk and should be avoided, especially in patients with statin intolerance. 2
Do not add bile acid sequestrants when triglycerides are >200 mg/dL, as they can worsen hypertriglyceridemia. 1, 2
Do not overlook secondary causes of hypertriglyceridemia: check TSH (hypothyroidism), review medications (thiazides, beta-blockers, estrogen), and assess alcohol intake. 2
Do not attempt to restart statins in this patient—the history of statin-induced myopathy is a contraindication, and alternative therapies (PCSK9 inhibitors, bempedoic acid) are available. 1, 6
Alternative Strategy if Bempedoic Acid is Unavailable
If bempedoic acid is not available or not covered by insurance, add ezetimibe 10 mg daily to Repatha, which provides an additional 13-20% LDL reduction. 1 This combination should reduce LDL from 199 mg/dL to approximately 80-100 mg/dL, which may still fall short of the <70 mg/dL target but represents significant improvement. 1
If LDL remains ≥70 mg/dL on Repatha + ezetimibe after 3 months, consider increasing Repatha to 420 mg monthly (though this is unlikely to provide additional benefit) or adding icosapent ethyl 2 g twice daily if triglycerides remain ≥150 mg/dL after fenofibrate therapy. 2 Icosapent ethyl provides cardiovascular benefit beyond lipid lowering in high-risk patients. 2