Hypercholesterolemia

From: 5 minutes Consult

Medication (Drugs)
Treatment initiation depends on LDL, HDL, and triglyceride levels as modified by risk factors and history of previous CHD or risk equivalents (2,3)[A]:
Risk factors:
Cigarette smoking
Hypertension (BP >140/90 or on antihypertensive medication)
Age (male >45 years, female >55 years)
HDL <40 mg/dL
MI or stroke in 1st-degree relative (male <55 years or female <65 years)
CHD or CHD risk equivalent (major coronary events >20% per 10 years):
Coronary, carotid, aortic, or peripheral vascular disease
Diabetes mellitus (although it is not clear that younger type 2 diabetics have the same risk as older type 2s; less aggressive targets may be appropriate in younger individuals)

Primary goal: LDL lowering for patients refractory to exercise, diet treatment (2,3)[A]:
CHD or CHD risk equivalent: <100 mg/dL
2+ risk factors: <130 mg/dL
0–1 risk factor: <160 mg/dL
Clinical trial evidence supports an optional goal of LDL <70 mg/dL for very high-risk patients (4,5)[A].

Further stratification of patients with 2+ risk factors can employ Framingham scoring (6) [A].

Secondary goal: In patients with triglycerides >200 mg/dL, non-HDL cholesterol (total cholesterol-HDL), <130 mg/dL (CHD or CHD risk equivalent), <160 mg/dL (2+ risk factors), and <190 mg/dL (0–1 risk factor) (2,3)[A]
Pharmacologic therapy considered when LDL is refractory to lifestyle intervention or levels exceed therapeutic goal by >30 mg/dL.
Pharmacologic measures to increase HDL are not supported by current clinical trials (2,3).

First Line
HMG-CoA reductase inhibitors (statins):
Fluvastatin (Lescol), lovastatin (Mevacor), pravastatin (Pravachol), or simvastatin (Zocor): 20–80 mg/d
Atorvastatin (Lipitor): 10–80 mg/d
Rosuvastatin (Crestor): 10–40 mg/d

Contraindications:
HMG-CoA reductase inhibitors: Active or chronic liver disease, pregnancy, breast-feeding
Precautions from ACC/AHA/NHLBI recommendations (7):
Severe myopathy rare: ~0.1% (Studied with lovastatin and simvastatin but all statins believed to carry similar potential):
Evaluate muscle symptoms and CK before therapy to establish baseline, 12 weeks after the initiation of therapy, and with follow-up if muscle symptoms are present.
Educate patient to report muscle discomfort/weakness or brown urine.
CK measurement 3–10× upper normal limit: Evaluate symptoms and CK weekly until resolved.
CK measurement >10× upper normal limit: Discontinue statin.
Liver function tests (ALT, AST) before therapy to establish baseline, 12 weeks after the initiation of therapy, and then annually.

Significant possible interactions:
Fibric acid derivatives, niacin, cyclosporine, azole antifungals, or macrolide antibiotics may increase the possibility of myositis. Combination therapy (2 or more medications) also increases risk of myositis.
Statins reduce major coronary events, CHD deaths, need for coronary procedures, stroke, and all-cause mortality, although number needed to treat to prevent a single event varies widely and may be in the 300–500 range per year for primary prevention (less for secondary prevention) (2)[A]. As an example, some studies such as WOSCOPS (n = 6,495) show primary prevention benefits at 6 years in nonfatal MI or CHD death (NNT = 33) and all-cause mortality (NNT = 146).

Composite data from 6 large clinical trials (4S, WOSCOPS, CARE, AFCAPS/TexCAPS, LIPID, HPS; n >44,000 total) with a varied population suggest following reduction with statins (8):
All CHD: NNT = 30 (95% CI: 25–35)
All stroke: NNT = 47 (95% CI: 39–58)
All CHD and stroke: NNT = 23 (95% CI: 20–27)
All-cause mortality: NNT = 59 (95% CI: 45–86)

Statins most probably have beneficial pleiotrophic effects beyond lipid lowering as risk reduction does not parallel lipid lowering.
24% reduction in LDL was sufficient to provide full pravastatin benefit in WOSCOPS trial despite greater achieved reductions.

ALERT
Avoid grapefruit juice.
Take statins late in day as majority of liver cholesterol synthesis occurs at night:
Exception due to longer t1/2 (14–19 hours): Atorvastatin and rosuvastatin

Second Line
Ezetimibe (Zetia), 10 mg/d:
Selectively inhibits intestinal absorption of cholesterol and related phytosterols
No clinically relevant outcome data demonstrates benefit
Ezetimibe/simvastatin (10/10, 10/20, 10/40, 10/80 mg) combined formulation (Vytorin) enhances LDL lowering in FH patients; however, it fails to confer additional cardiovascular benefit seen with statin alone (9,10) [A].

Cholestyramine (Questran) or colestipol (Colestid) bile acid–binding resins: 1–6 packets per day taken b.i.d. or t.i.d., or colesevelam (Welchol) 6 tablets daily:
Effect: 15–20% fall in LDL

Niacin (nicotinic acid): Target dose of 1.5–6 g/d in 3 divided doses with meals for regular release formulation (Niacor) or 375 mg–2 g once daily at bedtime for extended release formulation (Niaspan):
Effect: 15–30% LDL lowering, decreases triglycerides, increases HDL
Hepatic dysfunction more common in patients who take immediate-release niacin

Fibric acid derivatives:
Gemfibrozil (Lopid) and fenofibrate (Antara, Lofibra, Tricor, Triglide) are effective for reducing triglycerides with modest elevation of HDL and variable effect on LDL, but should be used only with caution with a statin due to risk of rhabdomyolysis.

Contraindications:
Cholestyramine: Complete biliary obstruction, bowel obstruction, TG >200 mg/dL, TG >400 mg/dL (absolute), dysbetalipoproteinemia (absolute)
Nicotinic acid: Acute peptic ulcer, diabetes mellitus, hyperuricemia, severe gout (absolute), chronic liver disease (absolute)
Fibric acid derivatives: Hepatic or renal dysfunction, gallbladder disease
Precautions:
Cholestyramine: Gradually increase dose on weekly basis to minimize GI side effects (particularly constipation, flatulence).
Nicotinic acid: Titrate dose according to package insert to minimize side effects (e.g., cutaneous flushing). Caution with diabetes mellitus, renal disease, gout, active gallbladder disease.

Significant possible interactions:
Cholestyramine: Other drugs taken <1 hour before or within 6 hours after may be bound and not absorbed as well. Fat-soluble vitamins A, D, E, and K absorption may be impeded.
Fibric acid derivatives: May potentiate effects of warfarin and oral hypoglycemic agents. Avoid with statins.

Complementary and Alternative Therapies

Beta-sitosterols and red yeast rice can reduce total cholesterol and LDL. Niacin and polidocanol can reduce total cholesterol and LDL while increasing HDL (5,6,7,8).
Omega-3 fatty acids and fish oil may be used for concomitant hypertriglyceridemia.