Statin Intolerance
If a patient can't tolerate a statin
1. Confirm TRUE statin intolerance first
Nocebo dominates — most statin-associated muscle symptoms reproduce on placebo (SAMSON, StatinWISE). Screen reversible causes: hypothyroidism, vitamin D deficiency, strenuous exercise, drug interactions (CYP3A4, gemfibrozil). Check CK only if severe/objective symptoms; most SAMS have normal CK. NLA definition: symptoms with ≥2 statins, one at the lowest approved dose, resolving off and recurring on rechallenge.
2. Statin-modification strategies (exhaust before abandoning statins)
Stop, let symptoms resolve 2–4 wk, then rechallenge — same statin at lower dose or a different statin. Switch to a hydrophilic statin (pravastatin, rosuvastatin, fluvastatin — less muscle penetration). Try intermittent/alternate-day dosing of a long-half-life statin (rosuvastatin, atorvastatin). Remove interacting drugs.
3. Add / substitute non-statins (in order)
Ezetimibe first (oral, cheap, safe; IMPROVE-IT). Then bempedoic acid — muscle-sparing prodrug, favored in intolerance (CLEAR Outcomes). Then PCSK9i mAb (evolocumab/alirocumab, ~50–60% LDL; FOURIER, ODYSSEY) or inclisiran (siRNA, q6-month dosing) for high-risk patients not at goal.
4. Refer to lipid specialist
Suspected familial hypercholesterolemia, LDL persistently ≥190 despite therapy, or statin intolerance with high residual risk needing PCSK9i/inclisiran with access barriers.
How each class affects your lipids
Search by drug, brand, mechanism, or side effect.
Showing 9 of 9 classes
Statins (HMG-CoA reductase inhibitors)
e.g. atorvastatin, Lipitor, rosuvastatin, Crestor
Inhibit HMG-CoA reductase → ↓ hepatic cholesterol synthesis → upregulate hepatic LDL receptors, clearing LDL from the blood. The reference mechanism the other classes are contrasted against.
Myalgia (mostly nocebo — reproduces on placebo in SAMSON/StatinWISE), transaminitis (rare), small ↑ in new-onset diabetes, rare rhabdomyolysis.
First-line, strongest outcome data. Exhaust dose/switch/alternate-day strategies before abandoning.
Source: ACC/AHA 2018 cholesterol; SAMSON 2020; StatinWISE
Ezetimibe
e.g. ezetimibe, Zetia
Blocks NPC1L1 → ↓ intestinal cholesterol absorption. Works in the gut, upstream of hepatic synthesis — complementary to statins rather than redundant.
Very well tolerated; rare diarrhea and arthralgia. No muscle or liver toxicity as monotherapy.
First non-statin add-on or monotherapy if fully statin-intolerant. Oral, generic, cheap. IMPROVE-IT.
Source: ACC 2022 non-statin pathway; IMPROVE-IT
Bempedoic acid
e.g. bempedoic acid, Nexletol, Nexlizet
ATP-citrate lyase inhibitor, one step upstream of HMG-CoA in the same synthesis pathway. A prodrug activated in liver but NOT in skeletal muscle → less myalgia than statins — the reason it is favored in statin intolerance.
Hyperuricemia/gout, tendon rupture, ↑ transaminases, benign ↑ creatinine.
Favored in statin intolerance (muscle-sparing). CLEAR Outcomes showed CV benefit in statin-intolerant patients.
Source: ACC 2022 non-statin pathway; CLEAR Outcomes 2023
PCSK9 inhibitor — monoclonal antibody
e.g. evolocumab, Repatha, alirocumab, Praluent
Monoclonal antibody binds circulating PCSK9 → less LDL-receptor degradation → more receptor recycling → greater LDL clearance. Largest LDL drop of the injectables.
Injection-site reactions; otherwise very well tolerated. SubQ every 2 weeks.
High/very-high risk not at goal on statin ± ezetimibe. FOURIER, ODYSSEY OUTCOMES. Cost/PA barrier.
Source: ACC 2022 non-statin pathway; FOURIER; ODYSSEY OUTCOMES
Inclisiran (siRNA PCSK9)
e.g. inclisiran, Leqvio
Small interfering RNA silences hepatic PCSK9 mRNA — same PCSK9 target as the antibodies but acting on the message, upstream of protein production.
Injection-site reactions. Dosed at 0 and 3 months, then every 6 months — adherence advantage.
Alternative to PCSK9i mAb when q6-month dosing aids adherence. Outcome trials ongoing.
Source: ACC 2022 non-statin pathway; ORION program
Bile-acid sequestrant
e.g. colesevelam, Welchol, cholestyramine, Questran
Binds bile acids in the gut and is not absorbed → the liver diverts cholesterol to make new bile acids → upregulates LDL receptors. Colesevelam also lowers A1c ~0.5%.
Constipation, ↑ triglycerides, ↓ absorption of other drugs and fat-soluble vitamins (separate dosing).
Niche add-on; useful when a modest LDL drop plus A1c benefit is wanted. Avoid with high triglycerides.
Source: ACC/AHA 2018 cholesterol; colesevelam A1c data
Fibrate
e.g. fenofibrate, Tricor, gemfibrozil, Lopid
PPAR-α agonist → ↑ lipoprotein lipase and ↓ hepatic VLDL. A triglyceride tool, not an LDL tool — different target than the LDL-lowering classes.
Myopathy — gemfibrozil + statin markedly raises risk; prefer fenofibrate with a statin. ↑ creatinine, gallstones.
Not for statin intolerance per se — a TG agent. Fenofibrate over gemfibrozil when combined with a statin.
Source: ACC/AHA 2018 cholesterol; ACCORD-Lipid
Icosapent ethyl (IPE)
e.g. icosapent ethyl, Vascepa
Purified EPA → ↓ hepatic VLDL-triglyceride production plus membrane and anti-inflammatory effects. Distinct from mixed omega-3 preparations, which lack the outcome data.
Atrial fibrillation, ↑ bleeding risk.
TG agent with CV-outcome data (REDUCE-IT) in high-risk patients with TG 135–499 on a statin. Not an LDL tool.
Source: REDUCE-IT
Niacin
e.g. niacin, nicotinic acid, Niaspan
↓ hepatic VLDL/apoB synthesis. The best HDL-raiser of any class — but raising HDL did not translate into fewer events, the cautionary tale for HDL as a target.
No CV benefit and net harm added to a statin (AIM-HIGH, HPS2-THRIVE): flushing, hyperglycemia, hepatotoxicity, gout.
NOT recommended for CV risk reduction. Shown for teaching — explains why HDL-raising was abandoned.
Source: AIM-HIGH; HPS2-THRIVE
Pathway per ACC 2022 Expert Consensus Decision Pathway on non-statin therapies and the NLA statin-intolerance definition. Educational reference — clinical decisions remain yours.