Lipid-Lowering Agents
One target, one signature lipid effect, and one classic toxicity per drug
The common pathway: the hepatic LDL receptor
One receptor, many drugs. The liver clears LDL through LDL receptors. When hepatocyte cholesterol falls, the sterol-sensing transcription factor SREBP-2 switches on receptor synthesis. Statins, bile acid sequestrants, ezetimibe, and bempedoic acid all deplete hepatocyte cholesterol and so increase receptors. PCSK9 inhibitors instead prevent receptor destruction. Triglyceride-lowering drugs act mainly on VLDL production and lipoprotein lipase.
| Class | Mechanism | Main lipid effect | Key adverse effects |
|---|---|---|---|
| Statins | Inhibit HMG-CoA reductase | LDL ↓↓↓ (20–60%) | Myopathy, rhabdomyolysis, ↑ transaminases |
| Bile acid resins | Bind intestinal bile acids | LDL ↓↓; TG may ↑ | GI upset; bind drugs and fat-soluble vitamins |
| Ezetimibe | Blocks NPC1L1 cholesterol uptake | LDL ↓ (~20%) | Rare ↑ transaminases, diarrhea |
| PCSK9 inhibitors | Antibody or siRNA against PCSK9 | LDL ↓↓↓ (50–60%) | Injection-site reactions |
| Bempedoic acid | Inhibits ATP-citrate lyase (liver only) | LDL ↓ (~20%) | ↑ Uric acid, gout, tendon rupture |
| Fibrates | PPAR-α agonists → ↑ LPL | TG ↓↓↓ (30–50%); HDL ↑ | Gallstones; myopathy with statins |
| Niacin | Inhibits adipose lipolysis → ↓ VLDL | HDL ↑↑↑ (15–35%); TG and LDL ↓ | Flushing, hyperglycemia, hyperuricemia, hepatotoxicity |
| Icosapent ethyl | Purified EPA; ↓ VLDL production | TG ↓ | Atrial fibrillation, bleeding |
| Lomitapide | Inhibits MTP (apoB lipoprotein assembly) | LDL ↓↓, receptor-independent | Hepatic steatosis, GI upset |
Statins
Mechanism. Statins competitively inhibit HMG-CoA reductase, the rate-limiting enzyme that converts HMG-CoA to mevalonate. The fall in hepatocyte cholesterol activates SREBP-2, which upregulates LDL receptors and increases LDL clearance. The result is the largest LDL reduction of any oral class (about 20–60%), with a modest fall in triglycerides and a small rise in HDL. (Terbinafine instead inhibits squalene epoxidase.) Short-half-life statins such as simvastatin and lovastatin are taken in the evening, when hepatic cholesterol synthesis peaks.
Outcomes. Statins are first-line lipid therapy because they reduce MI, stroke, and cardiovascular and all-cause mortality in both primary and secondary prevention. The benefit tracks the absolute LDL reduction, and statins also stabilize plaque and lower CRP.
Toxicity. Asymptomatic transaminase rises occur, but serious hepatotoxicity is rare; baseline LFTs are checked. Muscle toxicity runs from myalgia, to myositis with elevated CK, to rhabdomyolysis with myoglobinuric acute kidney injury. Risk rises with high doses, older age, hypothyroidism, renal impairment, and interacting drugs. Statins slightly increase the risk of new-onset diabetes and are usually stopped in pregnancy.
Interactions. Myopathy risk rises when statins are combined with fibrates (especially gemfibrozil), niacin, or CYP3A4 inhibitors. These inhibitors include clarithromycin, erythromycin, azole antifungals, HIV protease inhibitors, diltiazem, verapamil, cyclosporine, and grapefruit juice. Simvastatin, lovastatin, and atorvastatin depend on CYP3A4, so clarithromycin can push simvastatin into rhabdomyolysis. Pravastatin is not metabolized by CYP enzymes, and rosuvastatin only minimally (via CYP2C9), so they are preferred when an interacting drug is needed.
Other LDL-lowering drugs
Bile acid sequestrants. Cholestyramine, colestipol, and colesevelam are nonabsorbed anion-exchange resins that bind bile acids in the intestine and interrupt their enterohepatic recirculation. The liver upregulates cholesterol 7α-hydroxylase to replace the lost bile acids, depleting its own cholesterol and increasing LDL receptors, so LDL falls about 15–30%. Adverse effects include bloating, constipation, and a gritty taste. They can also raise triglycerides, so avoid them when triglycerides are high; they are contraindicated above about 500 mg/dL. Resins bind co-administered digoxin, warfarin, levothyroxine, and thiazides and reduce absorption of the fat-soluble vitamins A, D, E, and K. Other drugs are therefore given 1 hour before or 4–6 hours after. Colesevelam is better tolerated, binds fewer drugs, and also lowers HbA1c in type 2 diabetes.
Ezetimibe. Ezetimibe blocks the Niemann-Pick C1-Like 1 (NPC1L1) sterol transporter on the jejunal brush border, reducing absorption of dietary and biliary cholesterol. The liver responds with more LDL receptors, and LDL falls about 20%. It is usually added to a statin and is well tolerated, with rare transaminase elevation or diarrhea. It is also the treatment for sitosterolemia (ABCG5/ABCG8 defects), in which plant sterols are overabsorbed.
PCSK9 inhibitors. PCSK9 is a circulating protein that binds hepatic LDL receptors and routes them to lysosomes for destruction. Blocking it lets receptors recycle to the cell surface; LDL falls about 50–60%, and cardiovascular events decline. Alirocumab and evolocumab are monoclonal antibodies against PCSK9, injected subcutaneously every 2–4 weeks; injection-site reactions are the main side effect. Inclisiran is a GalNAc-conjugated small interfering RNA that hepatocytes take up. It degrades PCSK9 mRNA and is injected at 0 and 3 months and then twice yearly. SREBP-2 also drives PCSK9 production, so statins raise PCSK9 and partly blunt their own effect, which is why the combination is synergistic.
Bempedoic acid. This prodrug is activated by very-long-chain acyl-CoA synthetase-1, an enzyme present in liver but not skeletal muscle. It inhibits ATP-citrate lyase, which supplies cytosolic acetyl-CoA upstream of HMG-CoA reductase. LDL receptors increase and LDL falls about 20%. Because it is inactive in muscle, it causes little myopathy and is used for statin intolerance. It raises uric acid (gout) and rarely causes tendon rupture.
Lomitapide. Lomitapide inhibits microsomal triglyceride transfer protein (MTP), blocking assembly of apoB lipoproteins: VLDL in the liver and chylomicrons in the gut. It therefore lowers LDL without functional LDL receptors and is used in homozygous familial hypercholesterolemia. Retained triglyceride causes hepatic steatosis and transaminase elevation, and patients need a very low-fat diet to limit GI upset and steatorrhea; fat-soluble vitamin deficiency can occur.
When both LDL-receptor alleles are null, drugs that work through the receptor (statins, PCSK9 inhibitors) have little effect. Receptor-independent agents such as lomitapide and evinacumab, an antibody against ANGPTL3, fill the gap.
Triglyceride and HDL drugs
Fibrates. Gemfibrozil and fenofibrate activate the nuclear receptor PPAR-α. This increases lipoprotein lipase synthesis and decreases apoC-III, an LPL inhibitor, so VLDL and chylomicron triglyceride is hydrolyzed faster. Fibrates produce the largest triglyceride fall (about 30–50%) and raise HDL through apoA-I. Their main use is severe hypertriglyceridemia, to prevent pancreatitis. (PPAR-γ, by contrast, is the target of thiazolidinediones.) Fibrates inhibit cholesterol 7α-hydroxylase, so fewer bile acids are made while more cholesterol is secreted into bile, causing cholesterol gallstones. They increase statin myopathy, most with gemfibrozil, which blocks statin glucuronidation and hepatic uptake; fenofibrate is the safer partner. Fibrates also potentiate warfarin.
Niacin. Niacin (vitamin B3) inhibits lipolysis in adipose tissue by reducing hormone-sensitive lipase activity, so less free fatty acid reaches the liver and hepatic VLDL synthesis falls. Triglycerides and LDL fall, lipoprotein(a) falls, and HDL rises the most of any drug (about 15–35%). The adverse effects are distinctive:
- Flushing and pruritus mediated by prostaglandins (PGD2), blunted by aspirin taken 30 minutes before the dose.
- Insulin resistance with hyperglycemia.
- Hyperuricemia with gout.
- Hepatotoxicity, especially with sustained-release forms.
Added to a statin, niacin did not reduce cardiovascular events (AIM-HIGH, HPS2-THRIVE), so it is now rarely used.
Icosapent ethyl. This highly purified ethyl ester of eicosapentaenoic acid (EPA) lowers triglycerides by reducing hepatic VLDL production. It reduced cardiovascular events in statin-treated patients with persistently high triglycerides (REDUCE-IT). It modestly increases atrial fibrillation and bleeding tendency.