Nonstatin Hypolipidemic Agents

Primary indications include

• Hyperlipidemia: Hydroxymethylglutaryl coenzyme-A (HMG-CoA) reductase inhibitors (statins) are the major hypolipidemic drugs. Nonstatin drugs are used in pts with side-effects or those not responding well to statin therapy. Evolocumab also has an indication specifically for the treatment of homozygous familial hypercholesterolemia.

• Primary and secondary prevention of CV disease: CV benefits (reduction in myocardial infarction and stroke) in pts with hypercholesterolemia and mixed dyslipidemia.

Selective cholesterol absorption inhibitors: Ezetimibe

• Inhibits cholesterol absorption from the small intestine by blocking a critical mediator of cholesterol absorption, the Niemann-Pick C1–like 1 (NPC1L1) protein on the GI tract’s epithelial cells as well as in hepatocytes.

• Metabolized in the liver and small intestine via glucuronide conjugation with subsequent renal and biliary excretion. Half-life around 22 h. No significant inhibitor or inducer effects on cytochrome P-450 isoenzymes. Significant medication interactions with cyclosporine and fibrates other than fenofibrate.

• Common adverse drug reactions (≥1% of pts) include headache and/or diarrhea (steatorrhea). Infrequent adverse effects (0.1–1% of pts) include myalgia and/or raised liver function test (ALT/AST) results.

Niacin (also known as vitamin B3, or nicotinic acid)

• Decreases synthesis of apoB-containing lipoproteins via inhibition of DGAT2, a key enzyme for triglyceride synthesis, binding to HCAR2, thereby decreasing lipolysis and FFA flux to the liver for triglyceride synthesis and increased apoB catabolism. HDL levels are increased through direct and indirect pathways.

• Common adverse effects are flushing, headache, pain, abd pain, diarrhea, dyspepsia, nausea, vomiting, rhinitis, pruritus, and rash. High doses may reduce blood pressure as a result of acute vasodilation. Cardiac arrhythmias, increased PT and decreased platelet count have been reported.

• Contraindicated in active liver disease, persistent elevated serum transaminases, active peptic ulcer disease, or bleeding.

Fibrates (fibric acid derivatives): Gemfibrozil, fenofibrate, clofibrate

• Reduce insulin resistance when dyslipidemia is associated with other features of the metabolic syndrome

• Activate peroxisome proliferator-activated receptors (PPARs). Mechanism of action: Induction of lipoprotein lipolysis; increased hepatic FA uptake and reduction of TG production; induction of the β-oxidation pathway, causing a decrease in FA synthesis; increased removal of LDL particles; increase in HDL production; inhibition of cholesterol 7 alpha hydroxylase

• Adverse effects include gallstones, dyspepsia, and myopathy. Combination with statins increases risk of rhabdomyolysis (less lipophilic statins are probably safer). Substrate of CYP3A4.

• Caution with active liver disease, liver function test abnormalities

Bile acid sequestrants: Cholestyramine, colestipol, colesevelam HCl

• Bind bile acids and sequester them from the enterohepatic circulation, which reduces the amount of LDL in the blood.

• Not significantly absorbed from the gut. May bind drugs and fat-soluble vitamins (A, D, E, K) in the GI tract, preventing absorption; therefore should be administered several h apart from other drugs. No systemic side effects. GI tract effects include constipation, diarrhea, bloating, and flatulence.

Lomitapide

• Inhibits the microsomal triglyceride transfer protein (MTP or MTTP), which is necessary for VLDL assembly and secretion in the liver. Improves insulin sensitivity.

• Adverse effects: Elevated aminotransferase levels and hepatic steatosis; nausea, flatulence, and diarrhea.

• Extensively metabolized by CYP3A4 and a direct inhibitor of CYP3A4.

Mipomersen

• Antisense oligonucleotide that targets the messenger RNA for apolipoprotein B. Administered as a weekly injection for familial hypercholesterolemia.

• Adverse effects: Injection-site reactions, flu-like symptoms, elevated ALT and hepatic steatosis. No drug-drug interactions have been identified.

Proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors: Evolocumab, alirocumab

• Monoclonal antibodies that bind to and inhibit PCSK9 near the catalytic domain. PCSK9 binds to the LDL receptor so that it cannot remove LDL cholesterol from the blood. Inhibition allows more LDL receptors to be present on the surface of the liver and to remove more LDL-C from the blood. Therapeutic inhibition of HMG-CoA reductase by statins upregulates PCSK9, limiting the effectiveness of statins in lowering plasma LDL-C, so the indications are adjunct to diet and maximally tolerated statin therapy for the treatment of adults with heterozygous familial hypercholesterolemia or clinical atherosclerotic cardiovascular disease who require additional lowering of LDL.

• Administered subcutaneously every 15 or 30 d.

• Adverse effects include irritation at the injection site, possible neurocognitive effects (memory loss, amnesia, forgetfulness, dementia, or disorientation), nasopharyngitis. No renal or hepatic adverse effects and no apparent drug interactions.