Antilipidemic Drugs

Fibrates — including fenofibrate and gemfibrozil — activate peroxisome proliferator-activated receptor-alpha, a nuclear receptor found predominantly in the liver, skeletal muscle, and heart. Peroxisome proliferator-activated receptor-alpha activation produces a coordinated transcriptional program that simultaneously reduces triglyceride synthesis and increases triglyceride catabolism.

The key effects are: upregulation of lipoprotein lipase, which increases hydrolysis of triglyceride-rich very low-density lipoprotein and chylomicron particles; downregulation of apolipoprotein C-III, a natural inhibitor of lipoprotein lipase, which further enhances triglyceride clearance; and upregulation of apolipoprotein A-I and A-II, which increases high-density lipoprotein cholesterol synthesis. The net lipid result is triglyceride reduction of 20 to 50 percent and high-density lipoprotein cholesterol increase of 10 to 20 percent. The effect on low-density lipoprotein cholesterol is variable and can paradoxically increase in patients with severe hypertriglyceridemia as very low-density lipoprotein is converted to low-density lipoprotein after triglyceride hydrolysis.

Fenofibrate is strongly preferred over gemfibrozil in patients on statin therapy. Gemfibrozil markedly raises statin plasma concentrations by inhibiting the hepatic uptake transporter and blocking metabolic pathways that clear statins from the body, substantially increasing the risk of muscle toxicity including rhabdomyolysis. The gemfibrozil-statin combination should generally be avoided; when a fibrate is needed alongside statin therapy, fenofibrate is used because it carries substantially lower pharmacokinetic interaction risk. Fenofibrate does require dose reduction in patients with significant kidney disease due to renal excretion.

Large randomized trials of fibrates added to background statin therapy in patients with elevated triglycerides and low high-density lipoprotein cholesterol have not demonstrated cardiovascular event reduction. A selective peroxisome proliferator-activated receptor-alpha modulator (pemafibrate) also failed to reduce cardiovascular events despite robust triglyceride lowering in a large trial, effectively confirming that triglyceride lowering per se does not translate to cardiovascular benefit in the modern statin era.

The current role of fibrates is therefore limited primarily to severe hypertriglyceridemia — triglycerides above 500 milligrams per deciliter — where the immediate clinical priority is pancreatitis prevention rather than cardiovascular risk reduction. Fenofibrate is first-line for this indication. Fibrates are not recommended as routine add-on cardiovascular therapy in patients on statin therapy with moderately elevated triglycerides.

Bile acid sequestrants bind bile acids in the intestinal lumen and prevent their reabsorption into the enterohepatic circulation. Bile acids are synthesized in the liver from cholesterol, so their depletion forces the liver to convert more cholesterol into bile acids to replenish the pool. The resulting fall in hepatic cholesterol content activates the sterol regulatory element-binding protein 2 pathway — the same compensatory mechanism activated by statins and ezetimibe — upregulating low-density lipoprotein receptor expression and increasing plasma low-density lipoprotein clearance.

Bile acid sequestrants reduce low-density lipoprotein cholesterol by approximately 15 to 25 percent depending on dose and formulation. They have no systemic absorption and therefore no systemic adverse effects. However, they modestly increase triglycerides (typically five to ten percent) through compensatory upregulation of hepatic very low-density lipoprotein synthesis, which is a meaningful consideration in patients with pre-existing hypertriglyceridemia. They should not be used in patients with triglycerides above 300 milligrams per deciliter.

Cholestyramine and colestipol are older granular powder formulations taken dissolved in liquid. They are effective but poorly tolerated due to gritty texture and gastrointestinal adverse effects including constipation, bloating, flatulence, and nausea. Colesevelam is a newer tablet formulation with better tolerability. It also has a unique additional approved indication: modest reduction of hemoglobin A1c (approximately 0.5 percent) in type 2 diabetes, making it potentially useful in patients with combined hypercholesterolemia and diabetes who need low-density lipoprotein cholesterol lowering without systemic drug exposure.

Bile acid sequestrants non-specifically bind many co-ingested medications in the intestinal lumen, reducing their absorption. This affects a wide range of drugs including warfarin, thyroid hormone, digoxin, statins, fibrates, thiazide diuretics, beta-blockers, and fat-soluble vitamins. All other oral medications must be taken at least one hour before or four to six hours after the bile acid sequestrant dose to avoid significant absorption interference. This timing requirement substantially complicates use in polypharmacy patients and is a major practical limitation in the typical cardiovascular patient who may be on anticoagulation, thyroid replacement, or cardiac glycosides.

Bile acid sequestrants occupy a narrow but defined niche. They are appropriate as adjunctive low-density lipoprotein cholesterol lowering in patients who cannot tolerate systemic agents; as the only pregnancy-compatible low-density lipoprotein cholesterol-lowering option (not systemically absorbed, no fetal risk); for pediatric familial hypercholesterolemia where systemic drug exposure is undesirable; and for combined hypercholesterolemia plus type 2 diabetes where colesevelam's dual benefit is an advantage. They are not appropriate as first-line agents in typical patients who can tolerate statins or ezetimibe.

Bempedoic acid inhibits adenosine triphosphate-citrate lyase, an enzyme upstream of 3-hydroxy-3-methylglutaryl coenzyme A reductase in the cholesterol synthesis pathway. Because the enzyme that activates bempedoic acid is present in the liver but absent in skeletal muscle, bempedoic acid does not cause the muscle toxicity associated with statins. This makes it particularly attractive for statin-intolerant patients.

As monotherapy, bempedoic acid reduces low-density lipoprotein cholesterol by approximately 18 to 21 percent. A fixed-dose combination tablet with ezetimibe achieves approximately 38 percent reduction. A large cardiovascular outcomes trial in statin-intolerant patients with or at high risk for atherosclerotic cardiovascular disease demonstrated a significant 13 percent reduction in the primary cardiovascular composite endpoint, establishing bempedoic acid as the first oral non-statin low-density lipoprotein cholesterol-lowering agent with proven cardiovascular outcomes in statin-intolerant patients. The main adverse effects are gout and hyperuricemia (due to increased uric acid from the mechanism of action) and a small increase in tendon injury risk.

Severe hypertriglyceridemia above 500 milligrams per deciliter, particularly above 1,000 milligrams per deciliter, carries acute pancreatitis risk that is independent of its atherosclerotic cardiovascular disease implications. In this setting, triglyceride reduction for pancreatitis prevention takes immediate priority over cardiovascular risk reduction. First-line treatment is fenofibrate combined with a very-low-fat diet, alcohol cessation, and glucose optimization in diabetic patients. Icosapentaenoic acid ethyl ester may be added once triglycerides are below 500 milligrams per deciliter. Novel agents targeting apolipoprotein C-III are emerging options for the rare patients with genetic forms of severe hypertriglyceridemia.