When to intubate in GCS?

GCS ≤ 8 requires intubation for airway protection. The patient cannot protect their own airway at this level of consciousness. Motor score is the most prognostically important component.

What is the best initial fluid for sepsis resuscitation?

Lactated Ringer's (LR) is the preferred resuscitation fluid. The SMART trial (2018) showed balanced crystalloids reduced death, new renal failure, and persistent renal dysfunction compared to normal saline.

When to start vasopressors in septic shock?

Start norepinephrine (first-line vasopressor) if MAP remains < 65 mmHg after initial 30 mL/kg crystalloid resuscitation, or earlier if patient is profoundly hypotensive. Do not delay pressors to complete full fluid resuscitation.

Why can serum uric acid be normal during acute gout?

During acute inflammation, IL-6 increases renal urate excretion and redistributes urate from plasma to tissues. Up to 40% of acute gout flares have normal serum uric acid. Joint aspiration with polarized microscopy is needed for definitive diagnosis.

How do you distinguish lupus flare from infection in SLE?

Key clues: CRP is low/normal in flare but elevated in infection. Complement (C3/C4) drops in flare but is normal/elevated in infection. Procalcitonin is elevated in bacterial infection but normal in flare. Anti-dsDNA rises in flare, stable in infection.

What is the difference between DKA and HHS?

DKA features acidosis (pH 600), hyperosmolality (> 320), and minimal ketosis -typically in Type 2 DM. DKA requires insulin drip; HHS requires aggressive fluid resuscitation first.

When to give tPA in acute ischemic stroke?

IV alteplase (tPA) can be given within 4.5 hours of last known well time in eligible patients. CT head must rule out hemorrhage first. For large vessel occlusion, mechanical thrombectomy can be performed up to 24 hours with favorable imaging.

What antibiotics for community-acquired pneumonia?

Inpatient non-ICU: ceftriaxone + azithromycin. ICU: ceftriaxone + azithromycin (add vancomycin if MRSA risk). Outpatient healthy: amoxicillin. Outpatient with comorbidities: augmentin + azithromycin or respiratory fluoroquinolone. Duration: 5 days if clinically stable for 48 hours.

How to interpret iron studies?

Iron deficiency: low ferritin (< 30), high TIBC, low iron, low transferrin saturation (< 20%). Anemia of chronic disease: normal/high ferritin (acute phase reactant), low TIBC, low iron. A ferritin of 50-100 in an inflamed patient may still represent iron deficiency.

What is the correction rate for hyponatremia?

Correct sodium no more than 8 mEq/L in 24 hours to avoid osmotic demyelination syndrome (ODS). For symptomatic severe hyponatremia with seizures, give 3% hypertonic saline 100-150 mL bolus over 10-20 minutes. If overcorrected, use D5W + DDAVP rescue protocol.

When to start antibiotics in meningitis?

Within 30-60 minutes. Do NOT delay antibiotics for LP or CT. Draw blood cultures, start empiric antibiotics (vancomycin + ceftriaxone ± ampicillin if > 50 or immunocompromised), then perform LP when possible. Dexamethasone should be given before or with the first antibiotic dose.

DOACs vs warfarin in antiphospholipid syndrome?

DOACs are contraindicated in APS. The TRAPS trial (2018) showed rivaroxaban was inferior to warfarin with more thrombotic events in triple-positive APS patients. Warfarin with INR target 2-3 is the standard for APS, indefinitely.

How to manage scleroderma renal crisis?

ACE inhibitors (captopril) are life-saving -start immediately and titrate aggressively. Do NOT hold for rising creatinine. Steroids > 15 mg prednisone per day precipitate scleroderma renal crisis. ARBs are NOT a substitute -evidence is only for ACEi.

What are the 4 pillars of heart failure treatment?

Guideline-directed medical therapy (GDMT) for HFrEF: (1) ARNI or ACEi/ARB, (2) beta-blocker (carvedilol, metoprolol succinate, or bisoprolol), (3) MRA (spironolactone or eplerenone), (4) SGLT2 inhibitor (dapagliflozin or empagliflozin). All four should be initiated and titrated to target doses.

Outpatient Lipid Management -2026 ACC/AHA Dyslipidemia Guideline -RoundsRx

🔍 Overview

🔴 2026 ACC/AHA Dyslipidemia Guideline (March 13, 2026) -Key Changes from 2018:

Domain	2018 Cholesterol Guideline	2026 Dyslipidemia Guideline
Risk Calculator	2013 Pooled Cohort Equation. Race input. Ages 40-79. 10-yr only.	PREVENT-ASCVD replaces PCE. Ages 30-79, race removed, adds CKD / HbA1c / SDI, 10- AND 30-year risk.
Risk Bands	<5 / 5-7.5 / 7.5-20 / ≥20%	<3 / 3-<5 / 5-<10 / ≥10%. Lowered to compensate for PREVENT producing lower scores.
Primary Prevention LDL Goal	"≥50% reduction" -no numeric goal.	NEW numeric goals: PREVENT ≥10% → LDL <55. PREVENT 5-<10% → LDL <70.
Secondary Prevention LDL Goal	<70 universally for clinical ASCVD.	Split: very-high-risk ASCVD <55 (apoB <55) vs standard-risk <70. Lp(a) ≥50 + ASCVD newly added to VHR definition.
Lp(a) and ApoB	Optional risk enhancers.	Lp(a) once per lifetime in all adults. ApoB routinely if TG >200, DM, low LDL on therapy. ApoB targets align with the LDL goal: <55 / <70 / <90.
Early Intervention	None formally.	NEW category: HeFH at diagnosis (incl. age 8-10), age ≤30 with LDL ≥160, strong family hx, high 30-yr PREVENT.
Non-Statin Add-Ons	Stepwise ladder: statin → ezetimibe → PCSK9i mAb.	Parallel options: ezetimibe / bempedoic acid (CLEAR Outcomes 2023) / PCSK9i mAb / inclisiran (siRNA, SC q6mo). Combination from start expected for VHR.
HIV Primary Prevention	Per general guidance.	Pitavastatin 4 mg recommended in HIV age 40-75 regardless of LDL threshold (REPRIEVE 2023: 35% MACE reduction).

→ Full 2018 vs 2026 Comparison · 2026 Dyslipidemia Guideline (Circulation) · See What's New

PREVENT-ASCVD Risk Categories (2026 Primary Prevention)

The PREVENT equations are now the recommended risk tool. Use the PREVENT calculator; new thresholds drive treatment.

10-yr PREVENT-ASCVD Risk	Category	2026 Recommendation	vs 2018 (Pooled Cohort Equation)
< 3%	Low	Lifestyle. Moderate-intensity statin may be considered if LDL 160-189 (severe hypercholesterolemia subgroup). Otherwise reassess in 4-6 yr.	2018 cutoff was <5% (low). Threshold tightened in 2026 because PREVENT scores run lower than PCE -keeps the same population on lifestyle-only.
3% to < 5%	Borderline	Lipid-lowering therapy may be considered after risk discussion. CAC scoring useful tiebreaker. Risk enhancers (FH, Lp(a) ≥ 50, CKD, premature family hx) tip toward starting.	2018 borderline was 5-7.5%. 2026 lowered the band to 3-<5% to compensate for PREVENT producing lower scores than PCE. Population qualifying is roughly similar.
5% to < 10%	Intermediate	Lipid-lowering should be considered. Moderate-intensity statin; LDL goal < 70 mg/dL. Add non-statin if not at goal.	2018 used 7.5-20% as "intermediate." 2026 added a numeric LDL goal here (<70) -2018 had none for primary prevention.
≥ 10%	High	Lipid-lowering recommended. High-intensity statin; LDL goal < 55 mg/dL. Combination therapy expected.	2018 high-risk was ≥20% (or 7.5-20% with enhancers → high-intensity). 2026 added <55 numeric LDL goal -2018 had no primary-prevention numeric goal at all.

Important calibration point: PREVENT generally produces lower 10-yr risk estimates than the 2013 PCE -especially in Black patients and the elderly -because it removes race and recalibrates to contemporary cohorts. Treatment thresholds were also lowered to compensate. The combination is roughly risk-neutral overall (similar populations qualify for statin), but the math is now more equitable.

Who Gets a Statin (2026 Indications)

The 2026 guideline reorganizes the old "4 statin benefit groups" into broader treatment indications. Same core decisions (ASCVD, severe LDL, DM, primary-prevention risk) but with new thresholds and a NEW "early intervention" category for young high-LDL patients.

▶ Two paths to LDL < 55 -don't mix them up (tap to expand)

The 2026 guideline uses different criteria for primary vs secondary prevention. The percentage-based rule (≥10%) only applies to primary prevention.

First question: Has the patient already had an ASCVD event (MI, stroke/TIA, coronary revasc, PAD with imaging)?

NO → Primary prevention. Calculate PREVENT 10-yr risk:
- ≥ 10% → high risk → LDL < 55
- 5 to < 10% → intermediate → LDL < 70
- 3 to < 5% → borderline → SDM, optional therapy
- < 3% → lifestyle
YES → Secondary prevention. Do NOT use PREVENT -calculator is not validated post-event. Classify by clinical features:
- Very-high-risk ASCVD (multiple events / polyvascular / one event + multiple high-risk conditions / Lp(a) ≥ 50 + ASCVD) → LDL < 55
- Standard-risk ASCVD (clinical ASCVD without very-high-risk features) → LDL < 70

Bottom line: LDL < 55 = (PREVENT ≥ 10% AND no prior ASCVD) OR (very-high-risk ASCVD by clinical features). Secondary prevention has no percentage gate -it's a feature-based classification.

Indication	Definition	Statin Intensity / LDL Goal	vs 2018 Guideline
1. Clinical ASCVD (secondary prevention) + ASA 81 mg daily	Prior MI, stable angina, coronary revasc, stroke/TIA, PAD with imaging confirmation	High-intensity (atorvastatin 40-80 or rosuvastatin 20-40). Very-high-risk ASCVD [qualifies by ANY of: recurrent ASCVD events / polyvascular disease (≥2 of CAD, cerebrovascular, PAD) / one event + multiple high-risk conditions (age ≥65, HeFH, DM, CKD eGFR 15-59, HTN, smoking, prior CABG/PCI, persistent LDL ≥100 on max therapy, HF) / Lp(a) ≥50 + ASCVD]: LDL goal < 55 (apoB < 55). Standard ASCVD: LDL goal < 70. Evidence: 4S, 1994 · HPS, 2002 · PROVE-IT, 2004 · TNT, 2005 · SPARCL, 2006	2018 used <70 universally. CHANGED 2026 split into very-high-risk (<55) vs standard (<70). apoB <55 target is also new in 2026.
2. Severe hypercholesterolemia	LDL ≥ 190 mg/dL (often FH (familial hypercholesterolemia))	High-intensity regardless of risk. Goal LDL reduction ≥ 50%. Add ezetimibe / bempedoic acid → PCSK9i / inclisiran early. Treat all HeFH (heterozygous FH) starting at diagnosis (2026 emphasis: don't delay). Children with HeFH: consider statin from age 8-10.	Same indication as 2018. EARLIER START 2026 emphasizes treating HeFH at diagnosis (incl. children 8-10) rather than delaying to adulthood.
3. Primary prevention by PREVENT risk	Adult age 30-79 with LDL 70-189, no DM, no prior ASCVD event. Use this row only if rows 1-2 and 4-5 don't apply. The criteria are exclusion gates: age <30 → row 5, LDL ≥190 → row 2, DM → row 4, prior ASCVD → row 1, LDL <70 → no statin needed. PREVENT score then drives intensity.	See PREVENT category table above. ≥ 10% = high-intensity statin, LDL < 55. 5-<10% = moderate-intensity statin, LDL < 70. 3-<5% = SDM (shared decision-making) + risk enhancers / CAC (coronary artery calcium). Evidence: WOSCOPS, 1995 · JUPITER, 2008 · HOPE-3, 2016	CHANGED Major restructure: 2018 was age 40-75 with PCE thresholds (<5/5-7.5/7.5-20/≥20%). 2026 is age 30-79 with PREVENT thresholds (<3/3-<5/5-<10/≥10%). 2018 had no numeric primary-prev LDL goal; 2026 added <55 high / <70 intermediate.
4. Diabetes	DM age 40-75 with LDL 70-189; consider age 30-39 if LDL ≥ 160 or elevated 30-yr PREVENT risk	Moderate-intensity baseline. High-intensity if PREVENT risk ≥ 10%, multiple risk enhancers, or established ASCVD. Goal LDL < 70 if ASCVD; < 100 otherwise. Evidence: CARDS, 2004 · HPS-DM	2018 was age 40-75 only. EXPANDED 2026 added age 30-39 with LDL ≥ 160 or elevated 30-yr PREVENT. Intensification trigger now PREVENT ≥ 10% (was ASCVD ≥ 7.5% in 2018).
5. Early intervention NEW 2026	HeFH at any age, age ≤ 30 with LDL ≥ 160, strong family hx of premature ASCVD, high 30-yr PREVENT risk	Start statin earlier than the traditional age-40 cutoff. Rationale: cumulative LDL exposure ("LDL pack-years") drives lifetime ASCVD risk; delaying treatment in young high-LDL patients wastes the longest-yield treatment window.	NEW 2026 2018 had no formal "early intervention" category. Young patients with LDL 160-189 and no other risk factors mostly got lifestyle. 2026 enabled by PREVENT 30-yr risk estimation.

Lipid therapy is one piece of secondary prevention -don't forget aspirin. ASA 75-100 mg daily (typically 81 mg) is universally indicated for all secondary prevention of ASCVD: prior MI, ischemic stroke / TIA (non-cardioembolic), stable angina, PAD with imaging, post-CABG / PCI. Evidence: ATT, 2002 showed ~22% MACE reduction across all secondary-prevention subgroups. Exceptions: active major bleeding, severe thrombocytopenia, true ASA allergy. On full anticoagulation for AFib + stable ASCVD? Often drop ASA after 12 mo of triple therapy (AUGUSTUS, 2019; WOEST, 2013) -DOAC + clopidogrel monotherapy is the new standard for that combination. Primary prevention? ASA is no longer routinely recommended (ASPREE, 2018; ARRIVE, 2018).

"Very High-Risk ASCVD" (drives the <55 LDL goal)

2026 retains the very-high-risk ASCVD category from the 2018 framework / 2022 consensus. Defining it matters because it triggers the more aggressive LDL goal (<55 mg/dL with apoB <55) and earlier non-statin add-on.

Multiple major ASCVD events (e.g., recurrent MI, MI + stroke, MI + symptomatic PAD)
One major ASCVD event PLUS multiple high-risk conditions: age ≥ 65, HeFH, prior CABG/PCI outside the index event, DM, HTN, CKD (eGFR 15-59), smoking, persistent LDL ≥ 100 on max-tolerated statin + ezetimibe, history of HF
Polyvascular disease (≥ 2 of: CAD, cerebrovascular dz, PAD)
Lp(a) ≥ 50 mg/dL with established ASCVD (newly emphasized in 2026)

▶ Risk-Enhancing Factors (push borderline 3-<5% toward statin)

When PREVENT risk is borderline, these factors push toward statin treatment. Document at least one before starting therapy in this group. (Same list as 2018, with 2026 emphasis on Lp(a) and CKD.)

Family history of premature ASCVD (men < 55, women < 65 in first-degree relative)
Persistent LDL ≥ 160 (even before statin) or non-HDL ≥ 190
Chronic kidney disease (eGFR 15-59, or albuminuria)
Metabolic syndrome (≥ 3 of: waist, TG ≥ 150, HDL low, BP ≥ 130/85, fasting glucose ≥ 100)
Preeclampsia history or premature menopause (< 40)
Chronic inflammatory disease: RA, SLE, psoriasis, HIV / AIDS
South Asian ancestry (higher CV risk at any LDL)
Biomarkers: Lp(a) ≥ 50 mg/dL (≥ 125 nmol/L), hs-CRP ≥ 2 mg/L, ApoB ≥ 130, ABI < 0.9
CAC score ≥ 100 (or ≥ 75th percentile for age/sex)

Statin Intensity Definitions UNCHANGED FROM 2018

2026 retained the 2018 intensity classifications and dose tiers verbatim. No changes to high/moderate/low-intensity drug-and-dose mapping.

Intensity	Expected LDL Reduction	Drugs / Doses
High-intensity	≥ 50%	Atorvastatin 40-80 mg; rosuvastatin 20-40 mg
Moderate-intensity	30-49%	Atorvastatin 10-20 mg; rosuvastatin 5-10 mg; simvastatin 20-40 mg; pravastatin 40-80 mg; lovastatin 40 mg; fluvastatin 80 mg; pitavastatin 1-4 mg
Low-intensity	< 30%	Simvastatin 10 mg; pravastatin 10-20 mg; lovastatin 20 mg; fluvastatin 20-40 mg

Avoid simvastatin 80 mg. FDA black-box -higher rhabdomyolysis risk than other statins at equipotent doses. If a patient was at 80 mg before March 2010 without issues, they can stay; otherwise switch to atorvastatin or rosuvastatin.

LDL Targets by Population (2026 ACC/AHA Dyslipidemia Guideline)

Population	2026 LDL Target	vs 2018 Cholesterol Guideline	ApoB Target / Trigger to intensify
Very high-risk ASCVD (recurrent event, polyvascular disease, ≥1 major event + multiple high-risk conditions, FH + ASCVD, or Lp(a) ≥ 50 + ASCVD)	< 55 mg/dL ≥ 50% reduction from baseline	2018 had <70. CHANGED AHA 2022 consensus first proposed <55 for this group; 2026 codified it. Lp(a) ≥ 50 + ASCVD newly added to definition in 2026.	apoB < 55 mg/dL. Add PCSK9i / inclisiran if LDL ≥ 70 on max statin + ezetimibe / bempedoic acid.
Standard-risk ASCVD (clinical ASCVD without very-high-risk features)	< 70 mg/dL ≥ 50% reduction	2018 also < 70. UNCHANGED	apoB < 70 (matches LDL goal). Add ezetimibe / bempedoic acid if > 70 on max statin; PCSK9i / inclisiran if still not at goal.
Primary prevention -high risk (PREVENT ≥ 10%)	< 55 mg/dL or ≥ 50% reduction	2018 had no numeric primary-prevention LDL goal (only "≥50% reduction"). NEW 2026	High-intensity statin baseline. Add non-statin if not at goal.
Primary prevention -intermediate risk (PREVENT 5 to < 10%)	< 70 mg/dL or ≥ 30-49% reduction	2018 had no numeric goal; just "30-49% reduction" with moderate statin. NEW 2026	Moderate-intensity statin baseline.
Primary prevention -borderline risk (PREVENT 3 to < 5%)	If treated: < 100 (or ≥ 30% reduction)	2018 borderline band was 5-7.5%; 2026 shifted to 3-<5% to compensate for PREVENT producing lower scores. CHANGED	Treatment optional / SDM. CAC scoring helpful tiebreaker.
Diabetes	< 70 if ASCVD or multiple risk factors; < 100 otherwise	2018 used "moderate-intensity for all DM 40-75"; 2026 added age 30-39 if LDL ≥ 160 or elevated 30-yr PREVENT. EXPANDED	ADA 2025. SGLT2i / GLP-1 RA also lower CV events independent of LDL.
FH (heterozygous)	< 100 (or < 70 if also ASCVD); ≥ 50% reduction	2018 same numeric goals. 2026 emphasizes "treat at diagnosis regardless of age"; supports statin in HeFH children from age 8-10. EARLIER START	PCSK9i / inclisiran often required to hit goal.
FH (homozygous, rare)	< 100 (treatment-intensive)	2018 same goal. UNCHANGED	Apheresis ± PCSK9i ± lomitapide ± evinacumab. Pediatric referral early.

"Lower for longer is better" -central principle of the 2026 guideline. Cumulative LDL exposure ("LDL pack-years") drives lifetime ASCVD risk. CTT meta-analysis showed each ~39 mg/dL LDL drop yields ~22% MACE reduction per year, compounding over time. FOURIER / ODYSSEY OUTCOMES confirmed safety down to LDL ~20-30 mg/dL. Implication: earlier and more aggressive LDL reduction yields more lifetime benefit -hence the 2026 emphasis on starting young high-LDL patients sooner and pushing primary-prevention targets lower.

🧪 Workup

When to Screen

2026 ACC/AHA Dyslipidemia Guideline: screen all adults starting at age 20 with a fasting or non-fasting lipid panel. Repeat every 4-6 yr if normal; more frequently if borderline or treated. NEW 2026: measure Lp(a) once per lifetime in all adults and apoB in patients with elevated TG, DM, low LDL on therapy, or borderline-risk decisions.
USPSTF 2022: statin initiation recommended for adults 40-75 with ≥ 1 CV risk factor and 10-yr ASCVD risk ≥ 10% (still in effect; 2026 ACC/AHA goes further with PREVENT-based thresholds).
Children (rare): universal screening once between ages 9-11 and again 17-21 (NHLBI 2011). Targeted earlier if family history of premature ASCVD or hypercholesterolemia. HeFH children: 2026 supports statin from age 8-10.
Special situations trigger earlier screening: family history of premature ASCVD, FH suspicion, xanthomas, premature CAD/stroke, pancreatitis (TG concern), DM, CKD, autoimmune disease, HIV.

Fasting vs Non-Fasting

Non-fasting lipid panel is acceptable for screening per the 2026 ACC/AHA Dyslipidemia Guideline (carried forward from 2018 ACC/AHA and ESC 2019). The exception: if non-fasting triglycerides > 400 mg/dL, repeat fasting for accurate LDL calculation (Friedewald equation fails at high TG).

Total cholesterol, HDL, direct LDL -minimally affected by fasting state
Triglycerides -increase 20-30% non-fasting; redraw fasting if > 400
Friedewald equation: LDL = TC - HDL - (TG / 5). Inaccurate when TG > 400 or LDL < 70 -use direct LDL or Martin-Hopkins method.
Children, post-MI acute, severe illness: fasting preferred for accuracy.

Initial Labs at Diagnosis

Test	Reason We Check	What It Changes
Fasting lipid panel (TC, LDL, HDL, TG, non-HDL)	Establish baseline + PREVENT calculator inputs	Drives statin initiation and intensity. Non-HDL = TC − HDL (more accurate than LDL when TG > 200; goal = LDL goal + 30).
Lp(a) ONCE per lifetime ROUTINE 2026	Genetic risk factor; doesn't change with lifestyle/statin. 2026 guideline upgraded this to routine adult measurement.	Lp(a) ≥ 50 mg/dL (or ≥ 125 nmol/L) is a major risk enhancer. Pushes borderline patients toward statin. Lp(a) ≥ 50 + ASCVD = "very high-risk" classification (LDL goal < 55). Cascade-screen family. PCSK9i and inclisiran modestly lower Lp(a) ~25%; apheresis for refractory.
ApoB ROUTINE 2026	Atherogenic particle count. 2026 emphasis: useful when LDL goal met (especially TG > 200, DM, or LDL < 70).	Targets: apoB < 55 in very-high-risk ASCVD; < 65 standard-risk ASCVD; < 80 primary prevention high risk; < 90 intermediate risk. ApoB > LDL goal even when LDL "looks OK" → intensify therapy (small dense LDL pattern).
BMP / eGFR	CKD is a risk enhancer + drug-safety baseline	eGFR < 60 = CKD = risk enhancer. Statin choice: pravastatin or atorvastatin OK without renal adjustment; rosuvastatin reduce dose at eGFR < 30.
HbA1c / fasting glucose	Diabetes is a major statin indication	If DM diagnosed, automatically falls into the moderate-to-high intensity statin group regardless of PREVENT score.
TSH	Hypothyroidism is the #1 reversible secondary cause of hypercholesterolemia	Untreated hypothyroidism → high LDL; treat thyroid before initiating statin (LDL often normalizes on levothyroxine alone).
LFTs (ALT, AST)	Baseline before statin (severe liver disease is a relative contraindication)	Mild elevation isn't a contraindication. NAFLD/MASLD is common and statins are generally safe (and may help). Avoid statin only if active hepatitis or cirrhosis with decompensation.
CK (only if myalgia or risk factors for myopathy)	Baseline before statin in select patients	Routine CK before statin not recommended. Check at baseline only if hx of myopathy, on multiple statins, or high-risk drug interactions.
UACR (selected)	Albuminuria suggests CKD risk enhancer	UACR ≥ 30 in a non-DM patient → CKD as risk enhancer; pushes toward statin.

Workup for Severe Hypercholesterolemia (LDL ≥ 190)

LDL ≥ 190 is presumed familial hypercholesterolemia (FH) until proven otherwise. Heterozygous FH affects ~1 in 200-500 -much more common than most providers realize.

Family history: premature ASCVD (M < 55, F < 65) in first-degree relatives, hypercholesterolemia in family
Physical exam: tendinous xanthomas (Achilles, knuckles), xanthelasma, corneal arcus < 45 yo (highly suggestive)
Genetic testing: LDLR (most common), APOB, PCSK9 gain-of-function. Positive in ~80% of FH cases. Confirms diagnosis and enables cascade family screening.
Cascade screening: test all first-degree relatives if FH confirmed -50% will be affected.
Secondary causes to rule out: hypothyroidism (TSH), nephrotic syndrome (UACR, albumin), cholestatic liver disease (LFTs, alk phos), drugs (steroids, retinoids, antipsychotics, calcineurin inhibitors).

Workup for Severe Hypertriglyceridemia (TG ≥ 500)

TG ≥ 1000 = pancreatitis risk. Triggers urgent treatment with fibrate, omega-3, and lifestyle. TG ≥ 500 is the threshold for pharmacologic treatment to prevent pancreatitis.

Secondary causes (most common): uncontrolled DM (insulin resistance), alcohol, obesity, hypothyroidism, nephrotic syndrome, drugs (estrogens, tamoxifen, beta-blockers, thiazides, isotretinoin, antipsychotics, protease inhibitors, glucocorticoids, immunosuppressants).
Treat the secondary cause first: tighten DM control, eliminate alcohol, replace thyroid hormone, switch offending drugs.
Familial hypertriglyceridemia / chylomicronemia syndrome: persistent TG > 1000 despite lifestyle, lipemic serum, eruptive xanthomas, lipemia retinalis, recurrent pancreatitis. Genetic testing (LPL, APOC2, APOA5, GPIHBP1, LMF1).
Acute pancreatitis triggered by hypertriglyceridemia: treat with insulin drip + heparin (if not bleeding) or apheresis for severe cases. Long-term: fibrate + icosapent ethyl + dietary fat restriction.

🚨 Management

▶ Lifestyle Interventions (always first or concurrent)

Intervention	Approximate LDL Reduction	Notes
Mediterranean diet	↓ 5-10%	PREDIMED, 2013 -reduced MACE 30%. Olive oil, nuts, fish, vegetables, whole grains. Limited red meat / processed food.
Saturated fat < 6% calories	↓ 5-15%	Replace with mono/polyunsaturated fats (olive oil, nuts, fish). Replacing with refined carbs does NOT help.
Soluble fiber 10-25 g/day	↓ 5-10%	Oats, beans, psyllium (Metamucil), fruit. Binds bile acids in the gut.
Plant sterols/stanols 2 g/day	↓ 6-15%	Available in fortified margarines, yogurts, supplements.
Aerobic exercise 150 min/week	Modest direct LDL effect; raises HDL	Larger benefit on TG (↓ 20-30%), HDL (↑ 5-10%), insulin sensitivity, weight.
Weight loss	↓ 5-8% per 10% weight loss	Especially helps TG, HDL, ApoB; mild LDL benefit.
Smoking cessation	Minimal LDL effect	HDL increases ~5 mg/dL within 3 weeks. Major MACE benefit independent of lipids.
Alcohol moderation	↓ TG significantly	Heavy alcohol drives TG; even modest reduction helps. Avoid completely if TG > 500.

Stacking lifestyle changes (Mediterranean + saturated fat reduction + fiber + exercise + weight loss) can drop LDL by 20-30% -comparable to a moderate-intensity statin.

2026 Statin Initiation Algorithm

Identify the indication: clinical ASCVD, severe LDL ≥ 190, DM, primary prevention by PREVENT, or 2026 early-intervention category (HeFH / age ≤ 30 with LDL ≥ 160 / strong family hx). If none → lifestyle, reassess in 4-6 yr.
Calculate PREVENT 10-yr risk (and 30-yr if young) using the PREVENT calculator. Categorize: low / borderline / intermediate / high.

Choose intensity by 2026 thresholds:

Intensity	2026 indication (any of)	Default drug + dose
High-intensity ≥ 50% LDL ↓	Clinical ASCVD (any: MI, stable angina, coronary revasc, stroke/TIA, PAD with imaging) -secondary prevention is always high-intensity LDL ≥ 190 (presumed FH; treat HeFH at diagnosis, age 8-10 in children) DM with high-risk features: established ASCVD, PREVENT ≥ 10%, or multiple risk enhancers Primary prevention with PREVENT ≥ 10% (high-risk band, LDL goal < 55) Early-intervention category (NEW 2026): HeFH at any age, age ≤ 30 with LDL ≥ 160, strong family hx of premature ASCVD, or high 30-yr PREVENT risk	Atorvastatin 40-80 mg Rosuvastatin 20-40 mg
Moderate-intensity 30-49% LDL ↓	Primary prevention with PREVENT 5-<10% (intermediate band, LDL goal < 70) DM age 40-75 without high-risk features (baseline DM indication) DM age 30-39 with LDL ≥ 160 or elevated 30-yr PREVENT (NEW 2026 expansion) Borderline PREVENT 3-<5% if SDM favors treatment (LDL goal < 100 if treated)	Atorvastatin 10-20 mg Rosuvastatin 5-10 mg (alt: pravastatin 40-80, simvastatin 20-40, pitavastatin 1-4, fluvastatin 80, lovastatin 40)
Lifestyle only	PREVENT < 3% AND no DM, no clinical ASCVD, LDL < 190. Reassess in 4-6 yr. Consider moderate-intensity if LDL 160-189 (severe hypercholesterolemia subgroup).	,

Start at the indicated intensity -don't titrate up. Each ~39 mg/dL LDL drop ≈ 22% MACE reduction per year (CTT meta-analysis); starting low and creeping up wastes treatment time. The 2026 "lower for longer" framing explicitly supports starting strong from day 1. Step down only for documented intolerance.

Modify drug choice (not intensity tier) for special populations:

Asian patients -more sensitive to rosuvastatin; start 5 mg per FDA labeling (esp. Japanese descent)
eGFR < 30 -rosuvastatin max 10 mg; pravastatin or atorvastatin preferred (no renal dose adjustment needed)
HIV on protease inhibitor -avoid simvastatin / lovastatin (severe CYP3A4 interactions); use pravastatin, pitavastatin, or rosuvastatin
Transplant on cyclosporine -pravastatin or pitavastatin at low dose; avoid simva / lova
Pregnancy -STOP all statins (teratogenic). Resume after delivery / breastfeeding.
Frail elderly with multiple comorbidities -consider one tier lower than the indicated intensity; weigh life expectancy and polypharmacy risk

Start atorvastatin or rosuvastatin -most potent, generic, well-tolerated. Atorvastatin 40-80 mg or rosuvastatin 20-40 mg for high-intensity; atorvastatin 10-20 or rosuvastatin 5-10 for moderate.
Counsel: lifelong therapy, myalgia possible (low rate), nocebo effect common. Frame around "lower for longer" -longer treatment = more benefit.
Recheck lipid panel in 4-12 weeks: measure LDL ± apoB ± non-HDL-C. Verify adherence and ≥ 30-50% LDL drop.
If not at LDL / apoB goal: confirm adherence and max-tolerated statin → add non-statin in parallel options (2026 reframing): ezetimibe (PO, cheap), bempedoic acid (PO, statin-intolerant alternative), PCSK9 mAb (SC q2-4 wk, fastest LDL drop), or inclisiran (SC q6mo, adherence advantage). Choice driven by cost, route preference, comorbidities.
Recheck in 4-12 weeks after each escalation. Combination therapy is the rule, not the exception, for very-high-risk ASCVD.

2026 framing shift: non-statin therapies are no longer a strict ladder (statin → ezetimibe → PCSK9i). They are parallel options. For a high-risk patient starting far from goal, jumping straight to statin + ezetimibe + PCSK9i / inclisiran (or initiating combination at start) is now explicitly supported -don't lose treatment time waiting for 6-week rechecks at each step.

Hypertriglyceridemia Management

Triglyceride Level	Action
< 150 mg/dL	Normal. Lifestyle continues.
150-499 (mild-moderate)	Statin first (also lowers TG modestly). Address secondary causes (DM, alcohol, weight). If clinical ASCVD, or DM with risk factors and TG persistently 150-499 on statin (high PREVENT risk): add icosapent ethyl 2 g BID (REDUCE-IT, 2019).
500-999	Fibrate first (fenofibrate 145 mg daily) to prevent pancreatitis. Statin still indicated for ASCVD risk if criteria met. Add icosapent ethyl. Aggressive lifestyle.
≥ 1000	Pancreatitis risk -urgent. Fibrate + icosapent ethyl + strict dietary fat restriction (< 15% calories temporarily). Eliminate alcohol. Treat secondary causes. Genetic workup if persistent.

Avoid gemfibrozil with statins -inhibits statin glucuronidation, increasing rhabdomyolysis risk significantly. Use fenofibrate instead when combining with a statin.

Fibrate-class skepticism (post-2022): PROMINENT, 2022 showed pemafibrate lowered TG ~26% but produced NO MACE reduction in DM patients on statin. Combined with prior negative ACCORD-Lipid, 2010, fibrate-class CV benefit beyond statin is largely disproven. Fenofibrate role today: pancreatitis prevention at TG ≥ 500, not ASCVD risk reduction. For ASCVD + residual TG-driven risk on statin, use icosapent ethyl (REDUCE-IT) instead.

Follow-up Cadence

After starting or changing therapy: recheck lipid panel in 4-12 weeks (sweet spot 6-8). This is when the ≥ 50% LDL-reduction goal is measured -drug reaches steady-state nadir by ~4 weeks, so don't recheck earlier (risk of falsely concluding non-response). Liver enzymes only if symptoms or hx of liver disease.
Stable on regimen at goal: annual lipid panel.
Don't routinely check CK unless myalgia. Don't routinely check LFTs unless symptoms or specific concern (FDA dropped routine LFT monitoring in 2012).
Adherence is key: ~50% of patients discontinue statins within 1 year. Re-engage with myalgia management, dose-adjustment, alternative regimens before declaring failure.

💊 Medications

Statins (foundation)

Drug	Dose	Notes
Atorvastatin (Lipitor) PREFERRED	10-80 mg PO daily (any time of day)	Most-prescribed statin. Hepatic clearance (CYP3A4) -watch interactions with macrolides, azoles, amiodarone, diltiazem, verapamil, grapefruit. Safe in CKD (no renal dose adjustment).
Rosuvastatin (Crestor) PREFERRED	5-40 mg PO daily	Most potent per mg. Minimal CYP3A4 metabolism -fewer drug interactions. Reduce dose at eGFR < 30 (max 10 mg). Asian patients more sensitive (start 5 mg).
Pravastatin (Pravachol)	10-80 mg PO daily	Hydrophilic, minimally metabolized by CYP -safest interaction profile. Useful in HIV (PI interactions), transplant patients on cyclosporine. Less potent.
Simvastatin (Zocor) AVOID 80 mg	10-40 mg PO at bedtime	Avoid 80 mg dose -FDA black-box for rhabdomyolysis. Many drug interactions (CYP3A4). Cheap.
Pitavastatin (Livalo)	1-4 mg PO daily	Newer, minimal CYP3A4 metabolism, preferred in HIV (lopinavir/ritonavir). More expensive.
Lovastatin, Fluvastatin	20-80 mg daily	Older, less commonly used.

▶ Choosing within high-intensity: atorvastatin 40 vs 80 mg (or rosuvastatin 20 vs 40)

Default to atorvastatin 40 mg (or rosuvastatin 20 mg) for high-intensity start. Reserve 80 mg (or rosuva 40 mg) for ACS/post-MI, very-high-risk ASCVD, or LDL not at goal on the lower dose at 4-12 weeks.

Scenario	Atorva dose	Why / Evidence
ACS / post-MI (within 30 days)	80 mg	PROVE-IT, 2004 -atorva 80 cut MACE 16% vs prava 40 post-ACS (LDL 62 vs 95). MIRACL, 2001 supported in-hospital initiation. Standard post-ACS protocol = atorva 80.
Very-high-risk ASCVD (recurrent events, polyvascular dz, ≥1 event + multiple high-risk conditions, Lp(a) ≥ 50 + ASCVD)	80 mg	2026 LDL goal < 55 (apoB < 55). 80 mg is needed to drive LDL low enough before adding ezetimibe / PCSK9i.
Not at LDL goal on 40 mg at 4-12 wk	Escalate to 80 mg first	Intensify within the same drug before adding a second agent. 40 → 80 adds ~6% more LDL reduction; cheaper and simpler than starting ezetimibe.
HeFH with very high baseline LDL	80 mg	When you need a reliable ≥ 50% drop from LDL 200-300+, 80 outperforms 40 at the margin.
Primary prevention with PREVENT ≥ 10%	40 mg	40 mg already delivers ≥ 50% LDL ↓ -enough for the high-risk band's < 55 goal in most patients. Reassess at 4-12 wk and escalate if needed.
Stable CAD without recent event	40 mg	40 is fine; reserve 80 if not at < 70 after 4-12 wk.
Older adults / polypharmacy / frail	Start 40 mg	Better tolerated. Escalate only if not at goal. Frail elderly -consider one tier down even when high-intensity is otherwise indicated.
Drug-interaction risk (macrolides, azoles, amiodarone, dilt/verapamil, grapefruit, protease inhibitors)	40 mg (or switch to rosuvastatin)	80 mg amplifies CYP3A4 interactions. Rosuvastatin has minimal CYP3A4 metabolism -safer choice if interactions are unavoidable.

Why not always 80? The atorva dose-response curve flattens at the top. 40 → 80 only adds ~6% more LDL reduction, but myalgia rate roughly doubles and adherence drops. Most landmark primary-prevention trials used moderate doses (CARDS atorva 10, ASCOT-LLA atorva 10, JUPITER rosuva 20). The 80 mg evidence base comes specifically from post-ACS / stable CAD secondary prevention trials (PROVE-IT, TNT, IDEAL).

Rosuvastatin 20 vs 40: rosuva 20 mg is the high-intensity default (potency ≈ atorva 40-80). Rosuva 40 reserved for the same scenarios as atorva 80 -more albuminuria / myalgia signal at 40 than 20. Many clinicians stop at rosuva 20 and add ezetimibe rather than push to 40 (better tolerated). Asian patients (esp. Japanese descent) -start rosuva 5 mg per FDA labeling.

▶ Choosing within moderate-intensity: which statin and which dose

Default to atorvastatin 10-20 mg or rosuvastatin 5-10 mg. The other moderate-intensity options exist for specific reasons -drug interactions, transplant patients, HIV on protease inhibitors, or cost. Use them when the default has a problem; don't use them by habit.

Scenario	Preferred drug + dose	Why
Default starting choice (most patients)	Atorvastatin 10-20 mg or rosuvastatin 5-10 mg	Most potent per mg, both generic, well-tolerated, atorva any time of day. Atorva 20 → ~38% LDL drop; rosuva 10 → ~43%.
HIV on protease inhibitor (lopinavir, ritonavir, atazanavir + ritonavir)	Pravastatin 40-80 mg or pitavastatin 1-4 mg	Avoid simvastatin / lovastatin (severe CYP3A4 interactions → rhabdo risk). Pravastatin is hydrophilic, minimally CYP-metabolized. Pitavastatin similar profile, more expensive. Rosuva is also acceptable.
Transplant on cyclosporine	Pravastatin 20-40 mg or pitavastatin 1-2 mg (low-dose)	Cyclosporine raises statin levels; pravastatin / pitavastatin minimize this. Avoid simvastatin and lovastatin. Atorva/rosuva can be used at reduced doses.
Drug interactions limit options (chronic macrolide, azole, amiodarone, dilt/verapamil, grapefruit-heavy diet)	Rosuvastatin 5-10 mg or pravastatin 40-80 mg	Both have minimal CYP3A4 metabolism. Switch from atorva/simva when interactions are unavoidable.
Asian patients (esp. Japanese descent)	Rosuvastatin 5 mg start (per FDA labeling)	Polymorphisms in OATP1B1 / SLCO1B1 increase rosuvastatin exposure. Start 5 mg and titrate; full 10 mg may behave like 20 mg in this population.
eGFR < 30 / dialysis	Atorvastatin 10-20 mg or pravastatin 40-80 mg	Atorva and prava don't need renal adjustment. Rosuvastatin: max 10 mg if eGFR < 30. Avoid statin in dialysis primary prevention (4D, AURORA showed no benefit); continue if already on it for ASCVD.
Pure cost-sensitive patient (no insurance, no comorbidities)	Simvastatin 20-40 mg at bedtime	Cheapest generic. Watch CYP3A4 interactions. Avoid 80 mg (FDA black-box for rhabdo). Atorva is now generic and similarly priced -prefer it when available.
Cannot tolerate atorva or rosuva at any dose	Pravastatin 40-80 mg	Hydrophilic statin with the lowest myalgia rate in head-to-head data. Less potent than atorva/rosuva (mid-moderate intensity at max), but a real option in true intolerance before declaring "non-statin only."
Pregnancy	STOP all statins	Teratogenic (FDA category X historically; 2021 FDA softened wording but pregnancy is still a contraindication for moderate or high doses). Bile acid sequestrants are the only acceptable lipid agent in pregnancy. Resume after delivery / breastfeeding.

2026 framework calls for moderate-intensity in: primary prevention with PREVENT 5-<10% (intermediate, LDL goal < 70), DM age 40-75 without high-risk features (LDL < 100), DM age 30-39 with LDL ≥ 160 or elevated 30-yr PREVENT, and borderline 3-<5% if SDM favors treatment. Don't drop to moderate-intensity from a high-intensity indication out of habit -if the patient has ASCVD or PREVENT ≥ 10%, the indication is high-intensity, even if you're choosing a low-CYP3A4 drug.

▶ Low-intensity statin: when (rarely) it's the right answer

Low-intensity statin is rarely a first choice in 2026. The "lower for longer" framing pushes toward at least moderate-intensity from day 1. Low-intensity (< 30% LDL ↓) is mostly a tolerability fallback, not a primary indication. Drugs: simvastatin 10 mg, pravastatin 10-20 mg, lovastatin 20 mg, fluvastatin 20-40 mg.

Scenario	Drug + dose	Why
True statin intolerance, working up the ladder	Rosuvastatin 5 mg every other day or atorvastatin 10 mg every 3 days	Alternative-day regimens count as "low-intensity" by total weekly exposure. Many "intolerant" patients tolerate these (n-of-1 rechallenge after SAMSON, 2020). Better than declaring "non-statin only."
Frail elderly with severe polypharmacy	Pravastatin 10-20 mg or simvastatin 10 mg	When the goal is "any statin exposure" rather than achieving an LDL target, and the patient won't tolerate higher doses. Individualize -frailty, life expectancy, falls risk, drug burden all weigh in.
Drug-interaction forced floor (e.g., HIV on PI plus other CYP3A4 inhibitors)	Pravastatin 10-20 mg or pitavastatin 1 mg	When even moderate-intensity at standard dose isn't safe due to overlapping inhibitors. Combine with ezetimibe to recover some LDL drop without raising statin dose.
Borderline 3-<5% PREVENT with patient hesitance	Lifestyle first; if statin chosen via SDM: pravastatin 10-20 mg	Some patients in the borderline band insist on a "lowest possible" exposure. Defensible compromise: low-intensity statin + lifestyle + reassessment in 6-12 mo. CAC scoring is more useful here than dose-titration.

Don't confuse "low-intensity" with "low dose of a high-intensity drug": rosuvastatin 5 mg DAILY = moderate-intensity (≥ 30% LDL ↓). Rosuvastatin 5 mg EVERY OTHER DAY ≈ low-intensity. Atorvastatin 10 mg DAILY = moderate-intensity. The distinction is total weekly exposure, not the drug name.

Avoid: Simvastatin 10 mg "to start, then titrate" in a young patient with a clear high-intensity indication -that's wasted treatment time. Either commit to moderate-intensity (atorva 20 / rosuva 10) or work up the intolerance ladder explicitly. Don't drift on subtherapeutic dosing.

Statin side effects: myalgia (~5-10%, often nocebo on rechallenge), rhabdomyolysis (rare, < 0.1%), liver enzyme elevation (rarely clinically significant), small absolute increase in DM diagnosis (~1 case per 1000 patient-years -CV benefit far outweighs), cognitive symptoms (controversial, not borne out in trials). Avoid in pregnancy (teratogenic).

▶ When to stop a statin: LFT, CK, and clinical thresholds

Framing first: the FDA dropped routine LFT monitoring in 2012, and routine CK was never recommended. Don't recheck unless the patient has symptoms. Serial screening generated false alarms without catching the cases that mattered. Use clinical judgment + symptoms, not isolated lab numbers.

LFT-driven decisions

ALT or AST level	Action
< 3× ULN, asymptomatic	Continue. Don't stop, don't even recheck unless symptoms develop. Most mild transaminitis on statin is unrelated (NAFLD/MASLD, alcohol, viral hepatitis).
3-5× ULN, asymptomatic	Repeat in 1-2 weeks. Transient → continue. Persistent → work up other causes (NAFLD, alcohol, viral, autoimmune) before blaming the statin.
> 3× ULN WITH symptoms (fatigue, jaundice, RUQ pain, dark urine)	Hold the statin. Evaluate for clinical hepatitis. Rechallenge later with a different statin (pravastatin or pitavastatin -lowest hepatic burden) if no other cause is identified.
> 10× ULN OR clinical hepatitis (jaundice + INR rise + symptoms)	Permanent discontinuation. Work up acute liver failure. Switch to non-statin LDL-lowering: ezetimibe, bempedoic acid, PCSK9i, or inclisiran.

Non-contraindications -don't withhold a statin for these:

NAFLD / MASLD -statins are safe and may IMPROVE liver outcomes (don't withhold)
Compensated cirrhosis (Child-Pugh A) -generally safe; benefit usually outweighs risk
Stable mild ALT elevation (e.g., chronic 1.5× ULN from fatty liver) -continue

Genuine contraindications:

Active acute hepatitis (viral, drug-induced, autoimmune) -hold until resolved
Decompensated cirrhosis (Child-Pugh B or C with ascites / encephalopathy / variceal bleeding) -relative contraindication
Acute liver failure -absolute contraindication

CK-driven decisions

CK level	Action
< 5× ULN, asymptomatic	Continue. Common with exercise, IM injection, sex/race normal variation.
< 5× ULN WITH myalgia	Trial off, confirm symptoms resolve, rechallenge. Most "intolerance" is nocebo (SAMSON, 2020 -90% rechallenge tolerance).
5-10× ULN with myalgia	Hold statin, monitor CK trend. Rule out hypothyroidism (#1 reversible mimic), vitamin D deficiency, drug interaction (CYP3A4 inhibitors). Rechallenge with low-dose alternative regimen (rosuva 5 mg every other day, atorva 10 mg every 3 days).
> 10× ULN OR myoglobinuria / AKI	Stop immediately. Treat as rhabdomyolysis -IV fluids, monitor for AKI, evaluate for trigger (drug interaction, exercise, viral). Permanent discontinuation of that statin. Switch to bempedoic acid (no muscle effects) or ezetimibe-based regimen ± PCSK9i.

Routine baseline and monitoring rules:

LFTs at baseline -yes (identifies pre-existing liver disease that affects regimen choice). Do NOT recheck routinely -only if symptoms (FDA 2012 update).
CK at baseline -only in selected patients: prior myopathy, multi-statin exposure, high-risk drug interactions, severe renal/hepatic disease. Routine CK is not recommended.
TSH -check at baseline AND if myalgia develops. Hypothyroidism is the #1 reversible cause of statin-mimicking myalgia and the #1 reversible cause of secondary hypercholesterolemia.

Non-Statin LDL-Lowering Agents

Drug	Dose	LDL Reduction	Key Use / Trial
Ezetimibe (Zetia) 2ND LINE	10 mg PO daily	~20-25%	First add-on after maxed statin. IMPROVE-IT, 2015 -reduced MACE post-ACS. Cheap, well-tolerated, no major interactions.
Evolocumab (Repatha) PCSK9i	140 mg SC q2 weeks OR 420 mg monthly	~50-60%	FOURIER, 2017. GLAGOV, 2016: plaque regression on IVUS. EBBINGHAUS, 2017: no cognitive harm. For ASCVD or FH not at goal on max statin + ezetimibe. Expensive (~$5,800/yr but coverage often available with prior auth).
Alirocumab (Praluent) PCSK9i	75 or 150 mg SC q2 weeks	~50-60%	ODYSSEY OUTCOMES, 2018. Same indications as evolocumab.
Inclisiran (Leqvio) siRNA	284 mg SC at 0, 3 months, then q6 months	~50%	ORION 9/10/11. Twice-yearly injection -excellent adherence advantage. Same indications as PCSK9 mAbs. CV outcome trial pending.
Bempedoic acid (Nexletol)	180 mg PO daily	~17-25%	ATP-citrate lyase inhibitor (acts upstream of HMG-CoA reductase). Useful in statin intolerance -no muscle effects. CLEAR Outcomes, 2023: 13% MACE reduction. Watch hyperuricemia, gout flare.
Bempedoic + ezetimibe (Nexlizet)	180 mg / 10 mg PO daily	~38%	Combination pill, useful for statin-intolerant patients needing more LDL drop than either alone.
Cholestyramine, colestipol, colesevelam (Welchol) RARELY USED	Cholestyramine 4 g BID; colesevelam 3.75 g daily	~15-30%	Bile acid sequestrants. GI side effects (constipation), interfere with absorption of other drugs (separate by 4 h). Niche use. Colesevelam also lowers A1c modestly.

Triglyceride-Lowering Agents

Drug	Dose	Notes
Fenofibrate (Tricor, Trilipix) PREFERRED FIBRATE	145 mg PO daily (with food)	Reduces TG ~30-50%. Safe to combine with statins. Watch Cr (mild reversible rise common -don't reflexively discontinue), myopathy when combined with statin (low rate). Indication: TG ≥ 500.
Gemfibrozil (Lopid) AVOID WITH STATIN	600 mg PO BID	Inhibits statin glucuronidation -markedly increases rhabdomyolysis risk. Use only as monotherapy, not combined with statin. Otherwise effective for TG.
Icosapent ethyl (Vascepa) CV BENEFIT	2 g PO BID with meals	Pure EPA (not mixed omega-3). REDUCE-IT, 2019: 25% MACE reduction in patients with ASCVD or DM + TG 150-499 on statin. Mixed omega-3 (Lovaza, fish oil supplements) does NOT show this benefit -don't substitute.
Omega-3 (Lovaza, OTC fish oil) TG ONLY	4 g daily	Lowers TG ~20-30%. STRENGTH 2020 was negative for CV outcomes. Use only if pure EPA (Vascepa) not available; inferior choice.
Niacin (Niaspan) RARELY USED	500-2000 mg PO daily	AIM-HIGH 2011 and HPS2-THRIVE 2014 were negative for CV outcomes when added to statin. Side effects: flushing (worsened by alcohol/spicy food, reduced by ASA pretreatment), hyperglycemia, hyperuricemia/gout, hepatotoxicity. Largely abandoned.

⚠️ Refractory & Special Populations

Statin Intolerance

Most "statin intolerance" is nocebo or unrelated myalgia. SAMSON 2020 and similar n-of-1 trials show 90% of "statin-intolerant" patients tolerate the same statin on blinded rechallenge. Always rechallenge before labeling intolerant.

Confirm: stop statin, confirm symptoms resolve, restart same or different statin -if symptoms recur reproducibly, label intolerant.
Rule out alternatives: hypothyroidism (TSH), vitamin D deficiency, polymyalgia rheumatica, drug interaction (CYP3A4 inhibitors).
Switch statin: try a hydrophilic statin (pravastatin) or low-dose alternative (rosuvastatin 5 mg every other day, atorvastatin 10 mg q3 days). Many patients tolerate alternative regimens.
Add non-statin agents: ezetimibe + bempedoic acid + PCSK9i / inclisiran can replicate statin LDL-lowering without statin exposure.
CoQ10 supplementation -modest evidence; some patients report benefit, low harm. 100-200 mg daily.

Familial Hypercholesterolemia (FH)

Heterozygous FH: ~1 in 200-500. Untreated LDL typically 200-400, with premature CAD often by age 40 men / 50 women.
Homozygous FH: rare (~1 in 1 million), LDL often > 500, CAD in childhood, requires apheresis ± PCSK9i ± lomitapide / evinacumab.
Diagnosis: LDL ≥ 190 + family hx of premature CAD, or genetic confirmation. Dutch Lipid Clinic Network or Simon Broome criteria.
Treatment: high-intensity statin + ezetimibe early. PCSK9i / inclisiran often needed -insurance approval is reasonable for FH. Goal: LDL reduction ≥ 50%, < 100 (or < 70 if also ASCVD).
Cascade family screening: test all first-degree relatives. Children of an affected parent have 50% risk.
Lipoprotein(a): often elevated in FH; check once. PCSK9i and inclisiran modestly lower Lp(a); apheresis for very high Lp(a) refractory to drugs.

Lp(a) -Targeted Therapies (emerging, 2024-2025)

Lp(a) is a strong, genetically-determined ASCVD risk factor with no approved Lp(a)-specific therapy yet. PCSK9i and inclisiran lower Lp(a) ~20-25% as a side effect; apheresis is the only intervention with proven Lp(a) reduction > 50%. Several agents in late-stage trials are expected to change practice 2025-2027.

Agent (Class)	Mechanism	Lp(a) Reduction	Status
Pelacarsen (TQJ230) PHASE 3	Antisense oligonucleotide (ASO) -hepatic LPA mRNA, monthly SC injection	~80%	Lp(a)HORIZON outcome trial enrolling. Results expected 2025.
Olpasiran PHASE 3	siRNA -hepatic LPA mRNA, q12-week SC injection	~95%	OCEAN(a)-Outcomes Phase 3 enrolling. PALM-1 / Phase 2 (NEJM 2022) showed durable 95% Lp(a) reduction.
Lepodisiran PHASE 2	siRNA -single-dose hepatic LPA silencing, durable	~94% at 1 year off single dose	Phase 2 ALPACA published 2024 (NEJM). Outcome trial in development. Single-dose durability is the differentiator.
Muvalaplin PHASE 2	Oral small molecule -disrupts apo(a)-apoB-100 assembly, blocks Lp(a) particle formation	~65-85%	Phase 2 (JAMA 2024) -first oral Lp(a)-lowering agent. Pill-form advantage if outcome trials confirm benefit.
Lipoprotein apheresis FDA-APPROVED	Selective Lp(a) and LDL removal via column, weekly or biweekly	~50-75% per session	FDA-approved for Lp(a) ≥ 60 mg/dL with progressive ASCVD despite max therapy. Burdensome (4-6 hour sessions q1-2 weeks). Reserved for refractory disease until drugs approved.

Key knowledge gap: all four investigational agents lower Lp(a) dramatically, but none has yet shown CV outcome benefit. The field assumes Lp(a) reduction reduces ASCVD events (Mendelian randomization supports this), but ongoing Phase 3 trials will define if and how much. Until then, focus on optimizing standard ASCVD risk factors aggressively in elevated-Lp(a) patients (lower LDL goal, BP control, statin + ezetimibe ± PCSK9i).

Special Populations

Population	Considerations
Pregnancy	STOP all statins, ezetimibe, fibrates, niacin, PCSK9i -teratogenic or insufficient data. Bile acid sequestrants safe. Resume after delivery / breastfeeding.
Elderly (> 75)	Continue statin if life expectancy > 1 year and tolerating. Initiate based on individualized risk-benefit. ASPREE 2018: aspirin in elderly without prior CV disease no benefit + harm. Statins still beneficial for secondary prevention.
HIV / on protease inhibitors	Avoid simvastatin and lovastatin (severe CYP3A4 interactions). Use pravastatin, pitavastatin, or rosuvastatin. PCSK9i safe. REPRIEVE, 2023: pitavastatin 4 mg reduced MACE 35% in HIV patients age 40-75 even at low-moderate ASCVD risk and LDL below standard treatment threshold -statin recommended for primary prevention in HIV regardless of LDL.
CKD (eGFR < 60)	CKD itself is a risk enhancer -lowers threshold for statin. Pravastatin or atorvastatin OK without renal adjustment. Rosuvastatin reduce dose at eGFR < 30 (max 10 mg). SHARP, 2011: simva + ezetimibe reduced MACE 17% in CKD pre-dialysis. Avoid statin if on dialysis without prior ASCVD (4D, AURORA negative).
Liver disease	Statins safe in NAFLD/MASLD (often help). Avoid in active hepatitis or decompensated cirrhosis. Mild ALT elevation alone is not a contraindication.
Transplant on calcineurin inhibitors	Cyclosporine increases statin levels. Use pravastatin or pitavastatin at low dose. Avoid simvastatin/lovastatin.

📋 On Rounds

Pimp Questions

What changed in the 2026 ACC/AHA Dyslipidemia Guideline?

Released March 13, 2026; replaces the 2018 Cholesterol Guideline. Six big changes: (1) PREVENT-ASCVD calculator replaces 2013 PCE -no race input, includes CKD, ages 30-79. (2) New risk categories: low <3%, borderline 3-<5%, intermediate 5-<10%, high ≥10%. (3) Lower numeric LDL goals in primary prevention: <55 if PREVENT ≥10%, <70 if 5-<10%. (4) Earlier statin starts: all HeFH at diagnosis, age ≤30 with LDL ≥160, strong family hx, high 30-yr PREVENT. (5) Routine apoB and Lp(a) testing. (6) Non-statin add-ons reframed as parallel options (ezetimibe / bempedoic acid / PCSK9i / inclisiran) -not a strict ladder. Core principle: "lower LDL for longer is better" -cumulative-exposure framing.

What are the 2026 statin indications?

(1) Clinical ASCVD -high-intensity statin; LDL < 55 if very-high-risk, < 70 otherwise. (2) LDL ≥ 190 -high-intensity regardless of risk; treat HeFH at diagnosis. (3) Primary prevention by PREVENT: ≥10% high-intensity, <55 goal; 5-<10% moderate-intensity, <70 goal; 3-<5% SDM. (4) Diabetes -moderate-intensity baseline, high-intensity if PREVENT ≥10% or ASCVD. (5) NEW: early intervention -age ≤30 with LDL ≥160, strong family hx, high 30-yr PREVENT. Rationale: cumulative LDL exposure ("LDL pack-years") drives lifetime risk.

Why did 2026 introduce numeric LDL goals in primary prevention when 2018 didn't have them?

2018 used "≥50% reduction" as the only target -no absolute number for primary prevention. 2026 added <55 for high-risk and <70 for intermediate-risk primary prevention based on accumulated CTT meta-analytic evidence and FOURIER / ODYSSEY OUTCOMES safety data showing benefit continues to LDL ~20-30 with no floor. Combined with PREVENT producing lower 10-yr risk estimates, lower numeric goals keep treatment intensity calibrated to actual risk. The framing is "lower for longer is better" -cumulative LDL exposure drives lifetime ASCVD, so push targets lower in primary prevention.

A 55F with LDL 220, no symptoms, family history of MI in father at 48. What's the diagnosis and management?

Familial hypercholesterolemia (heterozygous) until proven otherwise. LDL ≥ 190 + premature CAD in first-degree relative meets clinical criteria. Workup: rule out secondary causes (TSH, UACR, LFTs), genetic testing (LDLR most common), exam for xanthomas / xanthelasma. Management: high-intensity statin (atorvastatin 40-80 or rosuvastatin 20-40) + ezetimibe early; add PCSK9i / inclisiran if LDL not at goal. Goal ≥ 50% LDL reduction, < 100 (or < 70 if also ASCVD). Cascade family screening -test all first-degree relatives (50% affected).

When do you check Lp(a)?

Once per lifetime in adults (it's genetically determined and doesn't change). Especially in: family history of premature ASCVD, FH, recurrent ASCVD events despite optimal statin, or borderline ASCVD risk needing tiebreaker. Lp(a) ≥ 50 mg/dL (or ≥ 125 nmol/L) is a major risk enhancer -pushes borderline patients toward statin and intensifies treatment in established disease. Statins do NOT lower Lp(a) (sometimes raise it). PCSK9i and inclisiran modestly lower it (~25%). Apheresis for very high refractory levels.

Why avoid gemfibrozil with a statin?

Gemfibrozil inhibits glucuronidation of statins, increasing statin plasma levels and the risk of severe rhabdomyolysis. Cerivastatin (withdrawn) caused multiple fatal rhabdo cases when combined with gemfibrozil. Use fenofibrate instead when combining with a statin -it doesn't have the same interaction. If gemfibrozil is necessary, use as monotherapy.

A patient with ASCVD on atorvastatin 80 and ezetimibe 10 still has LDL 95. Goal < 70. Next step?

Add a PCSK9 inhibitor -evolocumab 140 mg SC q2 weeks or alirocumab 75-150 mg SC q2 weeks. Will reduce LDL another 50-60%, easily getting below 70 (often below 30). Alternative: inclisiran 284 mg SC at 0, 3 months, then q6 months for adherence advantage. Both are FDA-approved for ASCVD or FH not at goal on max-tolerated statin + ezetimibe. Insurance often covers with prior authorization. Bempedoic acid is an oral alternative if injection is unacceptable, but smaller LDL effect.

Clinical Examples

📋 Case 1, Primary prevention with intermediate risk

Patient: 52F, BP 128/82, LDL 145, HDL 48, TG 150, A1c 5.7%, no DM, no ASCVD, non-smoker, mother had MI at 58. PREVENT 10-yr risk = 6.8%.

Key findings: 2026 intermediate-risk band (PREVENT 5 to <10%). Risk enhancer present (premature ASCVD in mother < 65). LDL above 130 also an enhancer.

Management:

Start moderate-intensity statin per 2026 guideline (intermediate-risk band): atorvastatin 20 mg or rosuvastatin 10 mg.
LDL goal < 70 mg/dL (2026 added a numeric goal for the intermediate band; 2018 had none for primary prevention).
Risk enhancers (mother MI < 65, LDL ≥ 130) reinforce the indication; CAC score is optional now -more useful as a tiebreaker in the borderline 3-<5% band, less needed at PREVENT 6.8%.
Lifestyle: Mediterranean diet, exercise 150 min/week, smoking cessation if applicable.
Recheck lipid panel in 4-12 weeks; intensify to high-intensity or add ezetimibe if not at < 70.

Teaching point: The 2026 framework relabels 5-7.5% (an old PCE borderline tier) as intermediate risk (PREVENT 5-<10%), with a numeric LDL goal of < 70. CAC scoring is most useful in the new borderline 3-<5% band, where SDM dominates -CAC = 0 reasonably defers statin; CAC > 100 supports starting.

📋 Case 2, Very-high-risk secondary prevention not at goal

Patient: 65M with prior MI 2 years ago, hypertension on lisinopril. On atorvastatin 80 mg, aspirin 81 mg, metoprolol. LDL 92, HDL 42, TG 180, apoB 78.

Key findings: Very-high-risk ASCVD per 2026 (one major event + multiple high-risk conditions: age ≥ 65 AND HTN). LDL goal is therefore < 55 mg/dL (apoB < 55), not < 70. He's far from goal at LDL 92 despite max-intensity statin -needs combination therapy.

Management:

Continue atorvastatin 80 mg (already at maximum-intensity).
Add ezetimibe 10 mg daily -expected ~20% further LDL drop → ~LDL 73 (IMPROVE-IT, 2015). Still won't hit < 55.
Add PCSK9i (evolocumab 140 mg SC q2 wk or alirocumab 75-150 mg SC q2 wk) -another ~50-60% drop → LDL ~30, comfortably below 55. Alternative: inclisiran 284 mg SC at 0, 3 months, then q6 mo for adherence advantage. FOURIER, 2017 · ODYSSEY OUTCOMES, 2018.
Consider adding icosapent ethyl 2 g BID for residual TG-driven ASCVD risk at TG 180 (REDUCE-IT, 2019).
Reinforce lifestyle, adherence, and aspirin.

Teaching point: The 2026 guideline split ASCVD into very-high-risk (LDL < 55, apoB < 55) and standard-risk (< 70). One MI + age ≥ 65 + HTN = very-high-risk → triple therapy (statin + ezetimibe + PCSK9i / inclisiran) is often the rule, not the exception. Ezetimibe alone won't get this patient to goal -don't stop there.

📋 Case 3, Severe hypertriglyceridemia

Patient: 45M, recurrent epigastric pain. Lipid panel: TG 1,840, LDL incalculable, HDL 28. A1c 8.4%, drinks 4-5 beers nightly. Lipase 320 (mildly elevated).

Key findings: Severe hypertriglyceridemia with pancreatitis. Multiple secondary causes (uncontrolled DM, alcohol).

Management:

Acute: NPO, IV fluids, treat pancreatitis. Insulin drip ± heparin for severe hypertriglyceridemia. Apheresis if persistent > 1000 with worsening pancreatitis.
Long-term: fenofibrate 145 mg daily (TG ≥ 500 → pancreatitis prevention).
Strict alcohol cessation. Tighten DM control (likely needs insulin or GLP-1 RA).
Dietary fat restriction (< 15% calories temporarily).
Add icosapent ethyl 2 g BID -25% MACE reduction in DM/ASCVD with persistent TG 150-499 on statin (REDUCE-IT 2019). Distinct from generic OTC fish oil (mixed EPA/DHA, no CV benefit).
Once TG < 500 and stable: start moderate-intensity statin (atorvastatin 20 mg or rosuvastatin 10 mg) -DM is an automatic 2026 statin indication. LDL goal < 100 (or < 70 if PREVENT ≥ 10% or other ASCVD risk emerges). Recheck PREVENT once DM is controlled; uncontrolled A1c inflates the score.

Teaching point: TG ≥ 1000 = pancreatitis emergency. Treat secondary causes aggressively (DM, alcohol). Fibrate first-line for prevention -statin doesn't address pancreatitis risk (that's a fibrate / EPA / dietary fat target). But once TG settles, the patient still needs a statin: DM is one of the 5 standalone 2026 statin indications, regardless of his LDL number.

⚡ Summary

Summary

2026 Framework

PREVENT-ASCVD calc; categories: low <3%, borderline 3-<5%, intermediate 5-<10%, high ≥10%. "Lower for longer is better."

2026 LDL Goals

Very-high-risk ASCVD <55 (apoB <55). Standard ASCVD <70. Primary prev high <55. Intermediate <70.

Indications

ASCVD, LDL ≥190, DM, PREVENT ≥10% (high-intensity), 5-<10% (moderate). NEW: early intervention age ≤30 LDL ≥160 / HeFH / high 30-yr PREVENT.

Intensity

High = atorva 40-80 / rosuva 20-40 (≥50% LDL ↓). Moderate = atorva 10-20 / rosuva 5-10 (30-49%).

Routine 2026 Labs

Lp(a) once per lifetime; apoB when LDL goal met or TG >200, DM, low LDL.

Add-On (parallel)

Statin → ezetimibe / bempedoic acid / PCSK9i mAb / inclisiran. Choose by cost, route, route preference. Combo therapy expected for very-high-risk.

FH

LDL ≥ 190 = FH until proven otherwise. High-intensity statin + ezetimibe + PCSK9i. Treat at diagnosis (2026). Cascade screen family.

High TG

≥ 500: fenofibrate (NOT gemfibrozil with statin). ≥ 1000: pancreatitis. ASCVD + TG 150-499: icosapent ethyl (REDUCE-IT). PROMINENT 2022 closed door on fibrate ASCVD benefit.

Statin Intolerance

Mostly nocebo (SAMSON). Rechallenge before labeling. Bempedoic acid (CLEAR Outcomes) + ezetimibe + PCSK9i if true intolerance.

Pregnancy

STOP statins, ezetimibe, fibrates, niacin, PCSK9i. Bile acid sequestrants only.

Lp(a)-Targeted

Pelacarsen, olpasiran, lepodisiran, muvalaplin in Phase 2-3. Apheresis only currently approved. CV outcome trials pending.

HIV (REPRIEVE 2023)

Pitavastatin 4 mg cut MACE 35% in HIV age 40-75 below traditional LDL threshold. Statin recommended regardless of LDL.