Step 2 CK · Internal Medicine · Endocrinology

Lipid & Metabolic Disorders

Name: Lipid & Metabolic Disorders
Creator: Veli Bakalov, MD

Statin benefit groups, the add-on ladder, and when triglycerides threaten the pancreas

Endocrinology·Diabetes & Metabolism·4 min read·9 high-yield points·Reviewed by Veli Bakalov, MD @HemeOncBuddy

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Four statin benefit groups: clinical ASCVD, LDL ≥190 mg/dL, diabetes at age 40–75, and 10-year PREVENT ASCVD risk ≥5% (2026 ACC/AHA: borderline 3 to <5%, intermediate 5 to <10%, high ≥10%); measure Lp(a) once in adulthood.
High-intensity statins (atorvastatin 40–80, rosuvastatin 20–40) lower LDL ≥50%; moderate-intensity (atorvastatin 10–20, rosuvastatin 5–10) lower it 30–49%.
Statins inhibit HMG-CoA reductase and upregulate hepatic LDL receptors; watch for myopathy (worse with gemfibrozil) and transaminitis, and avoid in pregnancy.
LDL ladder: maximal statin → ezetimibe (NPC1L1; IMPROVE-IT) → PCSK9 inhibitor (evolocumab, alirocumab) for FH or very-high-risk patients; LDL goals are <100 mg/dL (borderline or intermediate risk), <70 (high risk or ASCVD), and <55 (very-high-risk ASCVD); recheck lipids 4–12 weeks after any change.
Triglycerides above 500–1000 mg/dL cause acute pancreatitis → fibrate (PPAR-α, ↑ lipoprotein lipase), omega-3s, and control of diabetes and alcohol.
Metabolic syndrome = any 3 of 5: central obesity, TG ≥150, HDL <40 (men) or <50 (women), BP ≥130/85, fasting glucose ≥100.
Familial hypercholesterolemia: autosomal dominant LDL-receptor defect (~1 in 250) with very high LDL, tendon xanthomas, corneal arcus, and premature CAD → high-intensity statin + ezetimibe + PCSK9 inhibitor; offer genetic testing and screen relatives; children get universal lipid screening at 9 to 11 years, targeted from age 2.
Exclude secondary dyslipidemia before intensifying therapy: hypothyroidism, nephrotic syndrome, cholestasis, uncontrolled diabetes.
Obesity drugs at BMI ≥30 (≥27 with comorbidity; semaglutide and tirzepatide most effective); bariatric surgery at BMI ≥40 (≥35 with comorbidity), then monitor B12, iron, calcium, and vitamin D.

Who gets a statin

Four statin benefit groups. Lifestyle (diet, exercise, weight loss) underpins every lipid plan, and a statin is indicated for:

Clinical ASCVD (secondary prevention)
LDL ≥190 mg/dL
Diabetes at age 40–75
10-year PREVENT ASCVD risk ≥5% (primary prevention: intermediate 5 to <10%, high ≥10%; reasonable in borderline 3 to <5%)

The 2026 ACC/AHA dyslipidemia guideline replaced the Pooled Cohort Equations with the PREVENT equations (low risk <3%, borderline 3 to <5%, intermediate 5 to <10%, high ≥10%). In borderline or intermediate primary-prevention cases, risk enhancers (family history of premature ASCVD, CKD, metabolic syndrome, chronic inflammatory disease, Lp(a) ≥125 nmol/L) and a coronary artery calcium score help tip the decision. Measure Lp(a) once in every adult.

Statin intensity

Feature	High-intensity	Moderate-intensity
Regimens	Atorvastatin 40–80, rosuvastatin 20–40	Atorvastatin 10–20, rosuvastatin 5–10
LDL reduction	≥50%	30–49%
Typical patients	Clinical ASCVD, LDL ≥190, high-risk diabetes, PREVENT risk ≥10%	Diabetes age 40–75, PREVENT risk 5 to <10%

Mechanism and safety. Statins inhibit HMG-CoA reductase, the rate-limiting step of cholesterol synthesis. Lower hepatocyte cholesterol upregulates hepatic LDL receptors, so statins lower LDL the most of any class. Side effects are myalgias or myopathy (rarely rhabdomyolysis) and transaminitis. Check baseline liver enzymes, and check CK only if muscle symptoms appear. Interacting drugs such as macrolides, azole antifungals, and gemfibrozil raise myopathy risk. Statins are generally stopped in pregnancy, although the FDA removed the formal contraindication in 2021.

Beyond statins: the LDL ladder

Ezetimibe, then a PCSK9 inhibitor. If a maximally tolerated statin is insufficient, add ezetimibe, which blocks intestinal cholesterol absorption through NPC1L1; IMPROVE-IT showed added benefit on top of a statin. Next, add a PCSK9 inhibitor (evolocumab, alirocumab), which markedly lowers LDL, for familial hypercholesterolemia or very-high-risk patients not at goal.

Maximal statinFirst-line; blocks synthesis
Add ezetimibeBlocks intestinal absorption
Add PCSK9 inhibitorEvolocumab or alirocumab

LDL-lowering ladder

PCSK9 normally degrades LDL receptors; blocking it keeps more receptors on the hepatocyte surface clearing LDL from the blood.

Chase lower LDL in the highest risk. The 2026 guideline restored LDL goals: below 100 mg/dL for borderline or intermediate risk, below 70 mg/dL for high risk or ASCVD, and below 55 mg/dL for very-high-risk ASCVD (non-HDL goals are 30 mg/dL higher), escalating from statin to ezetimibe to PCSK9 inhibitor. Recheck a lipid panel 4–12 weeks after starting or changing therapy to gauge response and adherence.

Lipid-lowering drugs

Drug	Mechanism	Main effect	Adverse effects
Statins	Inhibit HMG-CoA reductase	↓↓ LDL	Myopathy, transaminitis; usually stopped in pregnancy
Ezetimibe	Blocks NPC1L1 absorption	↓ LDL	Well tolerated
PCSK9 inhibitors	Preserve LDL receptors	↓↓ LDL	Injection-site reactions
Fibrates	PPAR-α → ↑ lipoprotein lipase	↓↓ Triglycerides	Myopathy with statins, gallstones, transaminitis
Bile acid sequestrants (cholestyramine)	Bind bile acids in the gut	↓ LDL	↑ Triglycerides, GI upset, bind other drugs
Niacin	↓ Hepatic VLDL output	↑ HDL	Flushing, hyperglycemia, hyperuricemia; largely abandoned

Triglycerides and metabolic syndrome

Very high triglycerides threaten the pancreas. Triglycerides above 500–1000 mg/dL risk acute pancreatitis, and marked chylomicronemia can also cause eruptive xanthomas and lipemia retinalis. Treat with a fibrate (fenofibrate, gemfibrozil), omega-3 fatty acids, and control of diabetes and alcohol; oral estrogens, hypothyroidism, and nephrotic syndrome also push triglycerides up. Statins primarily target LDL, not marked hypertriglyceridemia. In triglyceride-induced pancreatitis, an insulin infusion activates lipoprotein lipase and lowers triglycerides quickly.

Fibrates activate PPAR-α, upregulating lipoprotein lipase, and lower triglycerides most effectively. Myopathy is worse when they are combined with statins, especially gemfibrozil. For high-risk patients already on a statin, icosapent ethyl (purified EPA) reduces cardiovascular events.

REDUCE-IT showed icosapent ethyl (4 g/day) cut cardiovascular events in high-triglyceride patients already on statins.

Metabolic syndrome requires at least 3 of 5 criteria, all rooted in insulin resistance, which raises the risk of diabetes and ASCVD:

3 of 5criteria needed for metabolic syndrome

Central obesity: increased waist circumference (>40 inches in men, >35 inches in women)
Triglycerides ≥150 mg/dL
HDL <40 mg/dL in men or <50 mg/dL in women
Blood pressure ≥130/85
Fasting glucose ≥100 mg/dL

Familial hypercholesterolemia and secondary causes

FH: broken LDL receptor, early CAD. Familial hypercholesterolemia is autosomal dominant, usually a defective LDL receptor (also ApoB or gain-of-function PCSK9). It causes very high LDL, tendon xanthomas, corneal arcus, and premature coronary disease. The heterozygous form affects about 1 in 250; homozygotes develop coronary disease in childhood. Treat aggressively with a high-intensity statin plus ezetimibe plus a PCSK9 inhibitor, offer genetic testing when FH is suspected, and screen first-degree relatives (cascade screening).

Screen children too. Universal lipid screening is done once at age 9 to 11; targeted screening starts as early as age 2 when a parent has FH or there is a family history of premature ASCVD.

Tendon xanthomas (Achilles, extensor tendons) and premature CAD in a first-degree relative are red flags for FH.

Rule out secondary dyslipidemia before intensifying therapy: hypothyroidism, nephrotic syndrome, cholestasis, and uncontrolled diabetes.

Obesity: drugs and surgery

Pharmacotherapy is added to lifestyle change. The most effective agents are the GLP-1 agonist semaglutide and the GLP-1/GIP agent tirzepatide; others are phentermine-topiramate, naltrexone-bupropion, and orlistat, a lipase inhibitor that causes oily stools and fat-soluble vitamin loss.

Bariatric surgery. Roux-en-Y gastric bypass and sleeve gastrectomy give durable weight loss and diabetes remission. Bypass also risks dumping syndrome and marginal ulcers, and persistent postoperative vomiting can precipitate thiamine deficiency.

Obesity treatment thresholds

Feature	Pharmacotherapy	Bariatric surgery
BMI threshold	≥30, or ≥27 with a weight-related comorbidity	≥40, or ≥35 with a significant comorbidity; increasingly 30–34.9 with poorly controlled type 2 diabetes
Main options	Semaglutide, tirzepatide	Roux-en-Y gastric bypass, sleeve gastrectomy
Monitor	Drug-specific effects (nausea with GLP-1 agents)	B12, iron, calcium, and vitamin D deficiencies