← Master Index· Section 2 · Cardiovascular Disorders · Chapter 8

Dyslipidemia

Primary & secondary preventionStatin intensitySAMSDiPiro Ch 8 + IDT II 753

30-Second Snapshot

What it is:Elevated total cholesterol, LDL-C, or triglycerides; low HDL-C; or some combination. Silent for years until it shows up as an MI or a stroke.

Why we treat it:LDL particles migrate into vessel walls, get oxidized, get eaten by macrophages, and turn into foam cells and plaque. The goal is preventing ASCVD events, not fixing a number on a lab report.

The whole decision tree:Does the patient already have ASCVD? → high-intensity statin, done. No ASCVD? → check four boxes in order: LDL ≥190, diabetes age 40–75, age 40–75 with LDL 70–189 (calculate 10-year risk), everyone else.

The single biggest conceptual shift

This is nottreat-to-target anymore. You don't pick a drug to chase an LDL number. You identify which risk group the patient falls into, then assign a statin intensity. LDL levels come back in later only to decide whether to add a non-statin on top.

Pathophysiology - How a Plaque Forms

Infiltration.LDL-C and remnant lipoprotein particles migrate into the vessel wall.
Oxidation.Those particles get oxidized and taken up by macrophages.
Endothelial dysfunction.The artery loses its ability to dilate and shifts into a prothrombotic state.
Foam cells.Unregulated cholesterol uptake by macrophages creates foam cells, which build into atherosclerotic plaque.
Destabilization.Macrophages secrete matrix metalloproteinases that degrade the plaque's collagen matrix, making it unstable.
Fibrous cap.Repeated injury and repair builds a cap over a core of lipid, collagen, calcium, and inflammatory cells. Keeping that cap intact is what prevents rupture and thrombosis.

Clinical outcomes when it fails:angina, MI, arrhythmias, stroke, peripheral arterial disease, abdominal aortic aneurysm, sudden death.

Primary vs secondary dyslipidemia

Primary (genetic):hypercholesterolemia, hypertriglyceridemia, combined hyperlipidemia, HDL metabolism disorders. In familial hypercholesterolemia the defect is inability to bind LDL to LDL receptors, so LDL isn't degraded and cholesterol biosynthesis runs unregulated.
Secondary (acquired):diet (excess alcohol, anorexia, weight gain, high carbohydrate or saturated fat), comorbidities (nephrotic syndrome, renal failure, hypothyroidism, obesity, diabetes), and drugs.

Drugs that worsen lipids - check the list before escalating

Progestins · thiazide diuretics · glucocorticoids · β-blockers · isotretinoin · protease inhibitors · cyclosporine · mirtazapine · sirolimus. Also rule out hypothyroidism, which is a classic reversible cause.

The Lipid Panel - Know These Cutoffs

Lipid	Value (mg/dL)	Category
Total cholesterol
TC	<200	Desirable
	200–239	Borderline high
	≥240	High
LDL-C
LDL	<100	Optimal
	100–129	Near or above optimal
	130–159	Borderline high
	160–189	High
	≥190	Very high- automatic statin, no risk calc needed
HDL-C
HDL	<40 (men) · <50 (women)	Low
Triglycerides
TG	<150	Normal
	150–199	Borderline high
	200–499	High
	≥500	Very high- pancreatitis risk, TG becomes the target

Other baseline testing:AST/ALT, TSH, glucose, serum creatinine, BUN, urinalysis. Physical signs to look for: eruptive xanthomas, peripheral polyneuropathy, elevated BP, abdominal obesity.

Two numbers that end the conversation early

LDL ≥190→ high-intensity statin, no risk calculator needed, and suspect familial hypercholesterolemia.
TG ≥500→ stop worrying about LDL for a moment. Now you're preventing pancreatitis, and fibrates or omega-3 move to first line.

1⃣ Primary Prevention - No Established ASCVD

Work down this list in order. The first box the patient fits determines the answer.

Group	Risk assessment	Treatment
LDL-C ≥190	Not necessary	High-intensity statin
Diabetes, age 40–75	Optional - only to help pick intensity	Moderate-intensity statinminimum; high-intensity if higher risk
Age 40–75, LDL-C 70–189	Calculate 10-year ASCVD risk(Pooled Cohort Equations / ASCVD Risk Estimator Plus)	See risk tiers below
Age >75	Clinical assessment + risk discussion	Moderate-intensity statin is reasonable
Age 20–39	Estimate lifetimerisk	Lifestyle only, unless family history of premature ASCVD andLDL ≥160 → statin
Age 0–19	Not necessary	Lifestyle only unless familial hypercholesterolemia

The 10-year risk tiers (age 40–75, LDL 70–189)

10-yr ASCVD risk	Tier	Action
<5%	Low	Lifestyle only
5 to <7.5%	Borderline	Lifestyle; moderate-intensity statin if risk enhancers present
7.5 to <20%	Intermediate	Moderate-intensity statin if risk enhancers present. Consider coronary artery calcium if the decision is uncertain
≥20%	High	High-intensity statin

Where the exam lives

7.5%is the number that triggers a real clinician–patient risk discussion about starting a statin. 20%is where you jump to high intensity. And a lifetime risk estimate in a 20–39 year old onlyjustifies lifestyle change, never drug initiation.

2⃣ Secondary Prevention - Established ASCVD

Anyone with clinical ASCVD gets a high-intensity statin. Moderate intensity only if they're over 75 or can't tolerate high intensity. Lifestyle alone is never appropriate here.

Then decide: is this "very high-risk" ASCVD?

Very high-risk means ≥2 major ASCVD events, OR 1 major event plus ≥2 high-risk conditions.

Major ASCVD events	High-risk conditions
• Recent ACS (within past year) • History of MI other than ACS • History of ischemic stroke • Symptomatic peripheral arterial disease	• Age ≥65 • Heterozygous familial hypercholesterolemia • Prior CABG or PCI outside an ACS event • Diabetes mellitus · Hypertension · Current smoking • CKD (eGFR 15–59) • LDL-C ≥100 despite maximally tolerated statin + ezetimibe • History of heart failure

The add-on ladder

High-intensity statin.
If LDL-C remains ≥70→ adding ezetimibeis reasonable.
In very high-risk patients, if LDL-C is still ≥70after ezetimibe → adding a PCSK9 inhibitoris reasonable.

Remember the threshold as 70 / 70 / 100

70= add ezetimibe in ASCVD. 70= add PCSK9i in very high-risk ASCVD. 100= the FH threshold for adding non-statins in patients without an ASCVD event, and also the LDL value that itself counts as a high-risk condition.

Statin Intensity - Memorize This Table

High intensity ↓ LDL ≥50%	Moderate intensity ↓ LDL 30 to <50%	Low intensity ↓ LDL <30%
Atorvastatin 40–80 mg Rosuvastatin 20–40 mg	Atorvastatin 10–20 mg Rosuvastatin 5–10 mg Simvastatin 20–40 mg Pravastatin 40–80 mg Lovastatin 40 mg Fluvastatin XL 80 mg · Fluvastatin 40 mg BID Pitavastatin 2–4 mg	Simvastatin 10 mg Pravastatin 10–20 mg Lovastatin 20 mg Fluvastatin 20–40 mg Pitavastatin 1 mg

Only two drugs reach high intensity

Atorvastatin and rosuvastatin.Nothing else gets there at any dose. If a question asks for high-intensity therapy and the options include simvastatin 80 mg, that's the distractor - and the FDA specifically recommends against starting simvastatin at 80 mg because of myopathy and rhabdomyolysis risk.

Potency ranking(most to least LDL lowering): rosuvastatin → atorvastatin → pitavastatin → simvastatin → lovastatin → pravastatin → fluvastatin.

Statins - Mechanism, Effects, Interactions

Mechanism:Inhibit HMG-CoA reductase, blocking conversion of HMG-CoA to mevalonate - the rate-limiting step in cholesterol synthesis. Less intracellular cholesterol means the liver upregulates LDL receptors, which pulls LDL out of the blood. That upregulation, not the synthesis block itself, is the main driver.

Effect	Magnitude
↓ LDL-C	20–60%
↑ HDL-C	6–12%
↓ Triglycerides	10–29%

The dose-response reality:every 38 mg/dL reduction in LDL-C produces roughly a 21% reduction in ASCVD events over 5 years. The relationship is log-linear, and lower is better.

Drug interactions - which statins are risky and why

All statins except pravastatin undergo some CYP metabolism.

Metabolism	Statins	Interaction risk
CYP3A4	Lovastatin, simvastatin, atorvastatin	Highest.3A4 inhibitors (verapamil, diltiazem, azoles, macrolides, protease inhibitors, grapefruit) raise statin levels and SAMS risk
Other CYPs (2C9, 2C8, 2C19)	Fluvastatin, pitavastatin, rosuvastatin	Lower
Minimal CYP	Pravastatin	Lowest - the go-to when interactions are the problem

Gemfibrozilis a separate mechanism: it interferes with statin glucuronidation, which is how statins are cleared. That raises SAMS risk regardless of CYP pathway. This is why fenofibrate is preferred over gemfibrozilwhen combining with a statin.

Liver, diabetes, and other safety

Transaminases:mild ALT elevations can occur. Routine liver enzyme monitoring is not required.Get a baseline before starting so you have something to compare against later. Statins can be started in chronic liver disease, compensated cirrhosis, and NAFLD, but are contraindicated in decompensated cirrhosis or acute liver failure.

New-onset diabetes:small risk, under 1%. Concentrated in patients on higher doses who already have risk factors - obesity, impaired fasting glucose, A1C >6%, metabolic syndrome. The CV benefit still outweighs it.

Statin-Associated Muscle Symptoms (SAMS)

Reported by 10–25%of statin users and a leading reason for discontinuation.

Presentation	Features
Myalgia(most common)	Bilateral achiness, weakness, or cramps in large muscle groups - thighs, back
Rhabdomyolysis(rare, serious)	CK >10× upper limit of normal, potential AKI. Dark "tea-colored" urine, nausea, vomiting, confusion, coma, arrhythmias, electrolyte disturbance, death. Incidence 0.1% vs 0.04% placebo

Risk factors:advanced age · female sex · low BMI · frequent heavy exercise · kidney disease · hypothyroidism · elevated statin concentrations from drug interactions. Start lower in patients with several of these, then titrate up once tolerated.

How to work up and manage SAMS

Stop the statinif symptoms are intolerable.
If symptoms resolve→ restart a differentstatin at a lower dose. Hydrophilic statins like rosuvastatin may be better tolerated than lipophilic ones like simvastatin.
If symptoms don't resolve→ the statin probably wasn't the cause. Look for hypothyroidism or severe vitamin D deficiency before rechallenging.
Alternative strategy:every-other-day dosing with a long half-life statin (atorvastatin, rosuvastatin).
Failed multiple statins→ move to non-statin therapy.

CK monitoring

Routine CK monitoring is not recommended.Check CK only in a symptomatic patient, to rule out rhabdomyolysis and support a myalgia diagnosis. Same logic as liver enzymes - baseline for reference, not routine surveillance.

Non-Statin Agents

Drug	Mechanism	LDL effect	Dose
Ezetimibe(Zetia)	Inhibits NPC1L1 cholesterol transporter in small intestine and hepatocytes	↓ 15–24%	10 mg daily
Evolocumab(Repatha)	PCSK9 monoclonal antibody	Large ↓	140 mg SC q2wk or 420 mg SC monthly
Alirocumab(Praluent)	PCSK9 monoclonal antibody	Large ↓	75 mg SC q2wk, max 150 mg
Colesevelam(Welchol)	Bile acid sequestrant	Modest ↓	6 tabs daily or 3 tabs BID; max 3750 mg
Cholestyramine(Questran)	Bile acid sequestrant	Modest ↓	4 g once or twice daily; max 24 g
Colestipol(Colestid)	Bile acid sequestrant	Modest ↓	2 g once or twice daily (tabs)

Ezetimibe - the preferred first add-on

Preferred adjunct because it modestly reduces recurrent CV eventswhen combined with a statin - that outcome data is what puts it ahead of other non-statins in the ladder.

Well tolerated. Mild GI complaints like diarrhea, myalgia, and ALT elevations when combined with a statin. No CYP450 effects, which makes it a clean add-on. One exception: with cyclosporine, exposure to both drugs increases.

PCSK9 inhibitors, bile acid sequestrants, niacin, omega-3

PCSK9 inhibitors:injectable monoclonal antibodies. Reserved for very high-risk ASCVD with LDL ≥70 despite statin plus ezetimibe, and for familial hypercholesterolemia. Adding one is "reasonable," not automatic - cost and access matter.

Bile acid sequestrants:bind bile acids in the gut, forcing the liver to pull cholesterol to make more. Main problems are GI: constipation and bloating. They also bind other drugs, so separate administration. Phytosterol supplements need 2–4 hours of separation to avoid being bound.

Niacin:↓ TG 20–50%, ↑ HDL 5–30% (the biggest HDL rise of any agent), ↓ LDL 5–20%. But it has not improved CV outcomesin patients already on a statin, which is why it's fallen out of favor. Flushing and itching are prostaglandin-mediated - take aspirin 325 mg shortly beforethe dose, take with meals, titrate slowly, and avoid alcohol and hot drinks around dosing. Associated with elevated hepatic enzymes, hyperuricemia, and hyperglycemia. Contraindicated in active liver disease and active peptic ulcer disease. Niaspan is the only prescription (extended-release) form and has fewer skin reactions and lower hepatotoxicity risk than OTC sustained-release products. Nicotinamide is not a substitute- it doesn't lower lipids.

Omega-3 PUFA:low doses (<2 g/day) did notreduce ASCVD events and aren't recommended for primary prevention. Icosapent ethyl(EPA only) is FDA approved to reduce CV events in adults with TG ≥150 who have established CV disease, or diabetes plus ≥2 other risk factors, and are already on maximally tolerated statin. GI complaints and "fishy burps" are common with OTC products - refrigerating capsules helps. Caution with fish or shellfish allergy, and with antiplatelets or anticoagulants since bleeding time may be prolonged.

Red yeast rice is not a statin substitute

It contains monacolin K, chemically identical to lovastatin. But content varies over 120-foldbetween OTC products - some have essentially none, others have more than the label claims. There are documented cases of rhabdomyolysis, liver toxicity, and renal failure. If a patient insists, tell them to buy a reputable product and never combine it with a prescription statin.

Hypertriglyceridemia

TG 150–499

Lifestyle first:5–10% weight loss, cut sugar and refined carbs, increase activity, quit smoking, restrict alcohol.
Find secondary causes:uncontrolled diabetes, CKD, protease inhibitors, atypical antipsychotics.
Statins are first-lineafter lifestyle. They lower TG up to 30% at higher doses while also handling the LDL.
Fibrates lower TG effectively but aren't routine here- no evidence they reduce ASCVD risk at borderline-high TG.
Icosapent ethylis the only omega-3 product indicated for borderline-high TG andASCVD risk reduction.

TG ≥500 - different game

Now you're preventing pancreatitis

Dietary fat restriction is essential because it cuts synthesis and entry of new chylomicrons. Fibrates and omega-3 PUFA become first-linebecause they primarily lower TG. Statins may still be reasonable first-line if 10-year ASCVD risk is ≥7.5%. Success = getting TG below 500 and preventing pancreatitis, not hitting an LDL goal.

Low HDL-C

Defined as <40 mg/dL in men, <50 in women. It's a strong independent risk predictor, but there is no HDL target. The primary target stays LDL-C. Lifestyle (smoking cessation, physical activity) is the preferred approach. Niacin raises HDL the most of any agent, but no trial has shown that raising HDL reduces ASCVD risk.

Familial Hypercholesterolemia & Diabetes

Familial hypercholesterolemia

Suspect itin adults with untreated LDL-C ≥190 or non-HDL-C ≥220 plus a family history of high cholesterol or ASCVD in first-degree relatives.

No prior ASCVD event:high-intensity statin. If LDL remains ≥100on max tolerated statin → add ezetimibe, bempedoic acid, and/or a PCSK9 inhibitor.
Prior ASCVD event:the non-statin threshold drops to ≥70.
Specialty options:mipomersen (apo B-100 synthesis inhibitor, ~25% further LDL reduction) and lomitapide (MTP inhibitor, ~40%). Both carry black box warnings for severe hepatotoxicityand are REMS-restricted. Evinacumab (ANGPTL3 inhibitor) is IV every 4 weeks for homozygous FH age 12+, lowering LDL ~50% and TG ~55%. LDL apheresis and liver transplant are last resorts.

Diabetes

Diabetic dyslipidemia is a characteristic pattern: high TG, low HDL, and modestly elevated but small dense LDLthat is highly atherogenic.

Statins are first-line based on trial evidence of reduced ASCVD events and mortality.
Age 40–75 with diabetes qualifies for a statin without a risk calculation. Use the risk score to pick intensity.
High-intensity statin preferred with a history of ASCVD.
Ezetimibe and evolocumab both improved outcomes added to statin. Fenofibrate plus simvastatin did not reduce CV events versus simvastatin alonein type 2 diabetes - a notable negative result.

Therapeutic Lifestyle Changes

First-line for any lipoprotein disorder, and continued even in patients on drug therapy. Lifestyle aloneis never appropriate in established ASCVD.

Weight:measure weight and BMI every visit; target 5–10% loss if overweight or obese.
Activity:moderate-to-vigorous intensity, 3–4 times weekly, averaging 40 minutes per session.
Diet:cut saturated and trans fats. Emphasize vegetables, fruits, whole grains, low-fat dairy, poultry, fish, legumes, nuts. Limit sweets, sugary drinks, red meat. Adapt to the patient's caloric needs and cultural food preferences, and involve whoever actually cooks.
Soluble fiber:oat bran, pectins, gums, psyllium. Target about 25 g/daytotal fiber. Lowers TC and LDL; little effect on HDL or TG. Bonus: helps the constipation from bile acid sequestrants.
Plant sterols and stanols:2–3 g daily lowers LDL 5–15%. Give 2–4 hours apart from bile acid sequestrants.
Smoking cessationfor every patient.

Monitoring

Parameter	When	Notes
Lipid panel	Baseline, then 4–12 weeks after starting or changing therapy, then every 3–12 months	Confirms adherence and expected percent reduction
ALT/AST	Baseline only	Routine monitoring not required. Baseline exists for comparison if enzymes rise later
Creatine kinase	Only if symptomatic	Routine monitoring not recommended. Used to exclude rhabdomyolysis
A1C / glucose	Periodically in at-risk patients	Small new-onset diabetes signal on higher-dose statins
Weight and BMI	Every visit	Anchors the lifestyle conversation
Muscle symptoms	Every visit - ask directly	Patients often stop the statin silently rather than report it

Patient Counseling

"This won't make you feel different."Same problem as blood pressure. The benefit is invisible and years out. Say it plainly at the first fill.
Muscle aches: call, don't quit.Frame it as "if your thighs or back get achy on both sides, call me - there are five things we can try before giving up on statins."
Dark or tea-colored urine with muscle pain = go in now.That's the rhabdomyolysis signal.
Grapefruitmatters for simvastatin, lovastatin, and atorvastatin. It does not matter for pravastatin or rosuvastatin.
Timing:short half-life statins (simvastatin, lovastatin, fluvastatin) work better dosed in the evening since cholesterol synthesis peaks overnight. Lovastatin specifically with the evening meal. Atorvastatin and rosuvastatin have long half-lives and can go any time.
Niacin flushing:aspirin 325 mg about 30 minutes before, take with food, skip alcohol and hot beverages around the dose. Warn them it's uncomfortable but harmless and fades with continued use.
Bile acid sequestrants bind other drugs.Separate other medications by several hours and expect constipation - fiber helps.
Fish oil burpsimprove if you keep the capsules in the freezer or fridge.
Red yeast rice is not a safer statin.Never stack it on top of a prescription statin.

High-Yield Recall Sheet

Only atorvastatin 40–80 and rosuvastatin 20–40 are high intensity.High = ↓LDL ≥50%, moderate = 30 to <50%, low = <30%.
LDL ≥190 → high-intensity statin, no risk calculation.
Diabetes age 40–75 → statin, no risk calculation needed(risk score only picks intensity).
10-yr risk tiers:<5% low · 5–7.5% borderline · 7.5–20% intermediate · ≥20% high → high-intensity.
Established ASCVD → high-intensity statin.Moderate only if >75 or intolerant.
Add-on ladder:statin → ezetimibe if LDL ≥70 → PCSK9i if still ≥70 in very high-risk.
Very high-risk = ≥2 major events, or 1 major event + ≥2 high-risk conditions.
SAMS in 10–25%.Rhabdo is rare (0.1%), CK >10× ULN, tea-colored urine.
No routine CK or LFT monitoring.Baseline LFT only; CK only if symptomatic.
CYP3A4 statins= lovastatin, simvastatin, atorvastatin. Pravastatin= least interaction-prone.
Gemfibrozil + statin = bad(glucuronidation). Use fenofibrateinstead.
Simvastatin 80 mg should not be started- FDA myopathy warning.
TG ≥500 → fibrate or omega-3 first, target is pancreatitis prevention.
No HDL target exists.LDL stays the target.
Niacin raises HDL the most but doesn't improve outcomes on top of a statin.
Statins contraindicated in decompensated cirrhosis / acute liver failure, but fine in compensated cirrhosis and NAFLD.
Every 38 mg/dL LDL drop ≈ 21% fewer ASCVD events over 5 years.