Lipid-Lowering Agents

Rapid Review·Cardiovascular

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PHARMACOLOGY

T2High yield

FA P324-325

Focus on

Six drugs sorted by what they move, and the point on the cholesterol pathway where each one intervenes.

Key takeaways

The seven drugs

Statins

inhibit HMG-CoA reductase, so cholesterol synthesis falls, intrahepatic cholesterol falls, LDL receptor recycling rises, and LDL catabolism increases; VLDL synthesis falls too. They reduce mortality in coronary artery disease. Adverse: hepatotoxicity with raised LFTs, and myopathy, especially with fibrates or niacin.

Bile acid resins (cholestyramine, colesevelam, colestipol)

disrupt enterohepatic bile acid circulation, so the liver converts more cholesterol into bile, intrahepatic cholesterol falls, and LDL receptor recycling rises. The liver also switches on HMG-CoA reductase to make up the loss, which a statin blocks, so the two are synergistic. Adverse: GI upset, and reduced absorption of other drugs and fat-soluble vitamins.

Ezetimibe

blocks cholesterol absorption at the small intestinal brush border. Adverse: rare raised LFTs, diarrhea.

Fibrates (fenofibrate, gemfibrozil)

activate PPAR-alpha (thiazolidinediones act on PPAR-gamma), upregulating lipoprotein lipase to clear triglycerides and lower VLDL production, and also raise HDL synthesis. Adverse: myopathy, worse with statins, and cholesterol gallstones via inhibition of cholesterol 7-alpha-hydroxylase.

Niacin

inhibits lipolysis in adipose tissue through hormone-sensitive lipase, and reduces hepatic VLDL synthesis. Adverse: facial flushing, which is prostaglandin-mediated and blunted by aspirin or by long-term use, plus hyperglycemia and hyperuricemia.

PCSK9 inhibitors (alirocumab, evolocumab)

block LDL receptor degradation in the lysosome, so more receptors recycle to the hepatocyte surface and hepatic LDL uptake rises. No CYP metabolism, so minimal drug interactions. Adverse: myalgias, and neurocognitive effects (delirium, dementia).

Fish oil and marine omega-3 fatty acids

reduce free fatty acid delivery to the liver and triglyceride-synthesising enzyme activity, lowering VLDL production and inhibiting ApoB synthesis. Adverse: nausea and a fishlike taste.

Every one of these sits at a distinct point on the pathway

laid out on the lipid pathway drug map.

Lipid-lowering agents by effect and mechanism
Drug	LDL	HDL	TG	Mechanism	Adverse effects
Statins	Falls most	Rises	Falls	Inhibit HMG-CoA reductase, raising LDL receptor recycling	Hepatotoxicity, myopathy (worse with fibrates or niacin)
Bile acid resins	Falls	Slight rise	Slight rise	Disrupt enterohepatic bile acid circulation	GI upset, reduced absorption of drugs and fat-soluble vitamins
Ezetimibe	Falls	Little change	Little change	Blocks cholesterol absorption at the brush border	Rare raised LFTs, diarrhea
Fibrates	Falls	Rises	Falls most	PPAR-alpha raises lipoprotein lipase	Myopathy with statins, cholesterol gallstones
Niacin	Falls	Rises most	Falls	Inhibits lipolysis; lowers hepatic VLDL synthesis	Flushing (prostaglandin-mediated), hyperglycemia, hyperuricemia
PCSK9 inhibitors	Falls most	Rises	Falls	Block LDL receptor degradation	No CYP metabolism; myalgias, neurocognitive effects
Fish oil (omega-3)	Slight rise	Slight rise	Falls at high doses	Lower VLDL production, inhibit ApoB	Nausea, fishlike taste

The two drugs that potentiate statin myopathy
Drug	Why it matters
Fibrates, especially gemfibrozil	Markedly raises myopathy risk with a statin
Niacin	Raises myopathy risk with a statin

Where each one acts on the pathway

What this shows

The lipid pathway with each drug at its point of action. Liver: statins block HMG-CoA reductase converting HMG-CoA to mevalonate; niacin reduces VLDL output; PCSK9 inhibitors block PCSK9-mediated LDL receptor degradation so more receptors recycle to the surface. Blood: lipoprotein lipase liberates free fatty acids from chylomicrons and VLDL, and fibrates upregulate it through PPAR-alpha. Adipose: niacin inhibits lipolysis. Intestine: ezetimibe blocks cholesterol absorption at the brush border and bile acid resins block bile acid reabsorption.

Cholesterol synthesis in the liver

acetyl-CoA to HMG-CoA to mevalonate by HMG-CoA reductase, then on to cholesterol. Statins block HMG-CoA reductase, the rate-limiting step. Trace the whole route on the figure.

PCSK9

normally binds the LDL receptor and tags it for degradation, so blocking PCSK9 lets more receptors recycle to the surface and hepatic LDL uptake rises.

Intestinal lumen

ezetimibe blocks cholesterol absorption at the brush border, and bile acid resins block bile acid reabsorption.

Chylomicrons

carry dietary lipid through the lymphatics; lipoprotein lipase liberates free fatty acids at the capillary bed; chylomicron remnants return to the liver via the ApoE receptor.

Adipose lipolysis

inhibited by niacin through hormone-sensitive lipase, so less free fatty acid reaches the liver and VLDL synthesis falls.

Lipoprotein lipase upregulation

the fibrate mechanism, acting through PPAR-alpha, which clears triglyceride from VLDL and chylomicrons.

Where each drug acts along the pathway
Site	Drug	Molecular target
Hepatic cholesterol synthesis	Statins	HMG-CoA reductase, the rate-limiting step
LDL receptor degradation	PCSK9 inhibitors (alirocumab, evolocumab)	PCSK9
Intestinal cholesterol absorption	Ezetimibe	The brush border transporter
Bile acid reabsorption	Bile acid resins	Enterohepatic circulation
Adipose lipolysis	Niacin	Hormone-sensitive lipase
Lipoprotein lipase upregulation	Fibrates	PPAR-alpha

The LDL receptor loop, the unifying theme

Three routes, one endpoint

statins, bile acid resins, and PCSK9 inhibitors all end at the same place, more LDL receptors on the hepatocyte.

Statins: less synthesis, so less intrahepatic cholesterol.
Bile acid resins: cholesterol diverted into bile, so less intrahepatic cholesterol.
PCSK9 inhibitors: less receptor destruction.

Three routes to the same endpoint, more LDL receptors
Drug	How it raises LDL receptors
Statins	Less cholesterol synthesis, so less intrahepatic cholesterol and more receptor recycling
Bile acid resins	More cholesterol converted to bile, so less intrahepatic cholesterol and more receptor recycling
PCSK9 inhibitors	Less receptor degradation, so more receptor recycling

Two side effects with a mechanism

Why fibrates cause gallstones

they inhibit cholesterol 7-alpha-hydroxylase, the rate-limiting enzyme of bile acid synthesis, so less cholesterol becomes bile acid and the bile becomes supersaturated with cholesterol.

Why bile acid resins raise triglycerides slightly

diverting cholesterol into bile acid synthesis drives compensatory hepatic VLDL production.

The two enzymes that sound alike but are not
Enzyme	Pathway	Inhibited by	Consequence
HMG-CoA reductase	Cholesterol synthesis	Statins	LDL falls
Cholesterol 7-alpha-hydroxylase	Bile acid synthesis	Fibrates	Cholesterol gallstones

A patient flushes after every dose of niacin. What is the mechanism, and what do you tell them to take beforehand?

The flush is prostaglandin-mediated, so aspirin taken beforehand prevents it (and it fades with long-term use).

How it's tested

Niacin's flushing is prostaglandin-mediated, which is why aspirin taken beforehand prevents it, and that mechanism is the question rather than the side effect itself. For the myopathy question, the drug to name alongside a statin is a fibrate.

Statins, bile acid resins, and PCSK9 inhibitors converge on the same endpoint, more LDL receptors on the hepatocyte surface, but arrive by three different routes, and the question is usually whether you can name the route rather than the endpoint. Fibrates cause gallstones by inhibiting cholesterol 7-alpha-hydroxylase, which blocks conversion of cholesterol into bile acids and leaves the bile supersaturated. Keep that enzyme distinct from HMG-CoA reductase, which is the statin target in a different pathway entirely.

Go deeper

First Aid 2026 — CV/Pharmacology (p.324-325) · B&B — Statins; cholesterol-lowering drugs · Mehlman — HY Cardio (statins, niacin flushing, fibrates, PCSK9); familial dyslipidemias cross-ref Biochemistry

High-yield images2

The lipid pathway with each drug at its point of action. Liver: statins block HMG-CoA reductase converting HMG-CoA to mevalonate; niacin reduces VLDL output; PCSK9 inhibitors block PCSK9-mediated LDL receptor degradation so more receptors recycle to the surface. Blood: lipoprotein lipase liberates free fatty acids from chylomicrons and VLDL, and fibrates upregulate it through PPAR-alpha. Adipose: niacin inhibits lipolysis. Intestine: ezetimibe blocks cholesterol absorption at the brush border and bile acid resins block bile acid reabsorption.

Flashcards for this page

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How do bile acid resins lower lipid levels?

Prevents intestinal (...) of bile acids → Liver synthesizes more from (...) stores

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