Familial hypercholesterolemia (FH) — HeFH and HoFH
Autosomal codominant disorder of LDL receptor pathway → extreme LDL-C elevation → markedly accelerated atherosclerotic cardiovascular disease (ASCVD) → premature coronary heart disease + stroke + peripheral vascular disease. **GENETIC CAUSES**: **LDLR mutations 60-90%** (>2,000 variants); **APOB mutations 5-10%** (R3500Q most common); **PCSK9 gain-of-function ~5%**; **LDLRAP1 <1%** autosomal recessive. **HETEROZYGOUS FH (HeFH)**: one defective copy; **PREVALENCE ~1/250 GENERAL POPULATION** — much more common than previously appreciated; **~25 MILLION CASES GLOBALLY; ~80% CURRENTLY UNDIAGNOSED**; LDL-C 190-450 mg/dL untreated; men first coronary event median 40s pre-treatment; women 50s pre-treatment; ~50% men + ~30% women without treatment develop CHD by 50. **HOMOZYGOUS FH (HoFH)**: two defective copies (compound heterozygous or true homozygous); **PREVALENCE ~1/250,000-360,000**; LDL-C 400-1000+ mg/dL untreated; ASCVD ONSET CHILDHOOD/ADOLESCENCE; **CHILDREN CAN HAVE MI**; severe aortic stenosis; tendinous + tuberous xanthomas + xanthelasmas + corneal arcus; **HISTORICAL DEATH 20s-30s** pre-treatment + transplant. Clinical: cholesterol elevations + **TENDINOUS XANTHOMAS** (Achilles + finger extensors HIGHLY SPECIFIC) + xanthelasmas + corneal arcus <45y + premature CHD/stroke/PAD + family history premature CHD CRITICAL. Diagnostics: **DUTCH LIPID CLINIC NETWORK (DLCN) + Simon Broome + MEDPED CRITERIA**; high LDL-C + family history + xanthomas + premature CHD; **GENETIC TESTING** confirms ~80% with NGS panel; **CASCADE FAMILY SCREENING ONCE INDEX CASE IDENTIFIED CRITICAL** (each first-degree relative 50% risk). Standard of care: **HIGH-INTENSITY STATIN = FOUNDATION** atorvastatin 40-80mg or rosuvastatin 20-40mg + ezetimibe added often. Bile acid sequestrants + niacin historical. **LIPID APHERESIS** for HoFH + refractory HeFH. **TARGETS**: LDL-C <100 mg/dL primary prevention HeFH; <70 mg/dL with established ASCVD; <55 mg/dL very high risk. **PCSK9 INHIBITORS — MONOCLONAL ANTIBODIES (TRUE PEPTIDE/PROTEIN THERAPIES)**: **EVOLOCUMAB (REPATHA, Amgen) FDA AUGUST 2015** HeFH + HoFH + established ASCVD; SC Q2wk or monthly; ~60% LDL-C reduction; FOURIER mortality + MI + stroke reduction. **ALIROCUMAB (PRALUENT, Sanofi/Regeneron) FDA JULY 2015** HeFH + established ASCVD; SC Q2wk; ~60% LDL-C reduction; ODYSSEY OUTCOMES CV event reduction. Both bind circulating PCSK9 → blocks LDLR degradation → upregulated LDL clearance. **INCLISIRAN (LEQVIO, Novartis) = siRNA TARGETING HEPATIC PCSK9 mRNA FDA DECEMBER 2021** HeFH + established ASCVD; ~50% LDL-C reduction; SC Q6mo after loading; novel siRNA mechanism. **EVINACUMAB (EVKEEZA, Regeneron) = MONOCLONAL ANTIBODY targeting ANGPTL3 FDA FEBRUARY 2021** HoFH ≥12y (later ≥6mo); **EXPANDED MARCH 2024 ≥6 months**; ANGPTL3 inhibition LDLR-INDEPENDENT pathway crucial for HoFH where LDLR pathway broken; ELIPSE HoFH trial; ~50% LDL-C reduction (unprecedented for genetic LDLR-deficiency); IV Q4wk; transformative for HoFH. LOMITAPIDE (Juxtapid) MTP inhibitor FDA 2012 HoFH (complex hepatic + REMS). MIPOMERSEN (Kynamro) ASO ApoB FDA 2013 HoFH (WITHDRAWN 2019). **BEMPEDOIC ACID (NEXLETOL, Esperion) ATP-CITRATE LYASE INHIBITOR FDA 2020** non-statin oral; CLEAR Outcomes 2023 CV mortality reduction. **VERVE-101 / VERVE-102 (Verve Therapeutics) = IN VIVO CRISPR BASE EDITING of PCSK9** Phase 1; single-dose permanent. **FH FOUNDATION (US, thefhfoundation.org) + International FH Foundation + Heart UK + European Atherosclerosis Society FH Studies Collaboration**. AHA + ACC + ESC + IAS guidelines + Pediatric Lipid Working Group + FH Foundation Care Guideline. **Editorial**: **PCSK9 MONOCLONAL ANTIBODIES (evolocumab + alirocumab) + PCSK9 siRNA (inclisiran) + ANGPTL3 mAb (evinacumab HoFH) = TRUE PEPTIDE-CLASS DISEASE-MODIFYING THERAPIES** named explicitly as standard-of-care alongside statins. Community peptides Tier 3: BPC-157 pro-angiogenic concern in established atherosclerotic plaque; NMN cardiovascular framing doesn't map to LDL receptor pathway; GH-axis trio doesn't engage LDLR/APOB/PCSK9/ANGPTL3; semaglutide SELECT CV benefit COMPLEMENTARY to lipid therapy not substitute. Eightieth deliberate non-elevation of community peptides.
What changes during this transition
Familial hypercholesterolemia (FH) is an autosomal codominant disorder of the LDL receptor pathway — LDLR mutations (60-90% of cases), APOB defects (5-10%, R3500Q most common), PCSK9 gain-of-function mutations (~5%), and rare autosomal recessive LDLRAP1 — causing markedly impaired hepatic LDL clearance and accelerated atherosclerotic cardiovascular disease. Heterozygous FH (HeFH) affects ~1 in 250 globally (~25 million cases, ~80% currently undiagnosed) with untreated LDL-C 190-450 mg/dL and median first coronary event in the 40s for men and 50s for women without treatment. Homozygous FH (HoFH) is rarer (~1 in 250,000 to 1 in 360,000) but devastating: untreated LDL-C 400-1000+ mg/dL, myocardial infarction in childhood or adolescence, severe aortic stenosis, characteristic tendinous and tuberous xanthomas, historically fatal in the 20s-30s before modern therapy. Standard of care has been transformed over the past decade by peptide and protein-class disease-modifying therapies. Statins remain foundational (high-intensity atorvastatin 40-80mg or rosuvastatin 20-40mg, with ezetimibe added). **EVOLOCUMAB (Repatha, Amgen) — FDA-approved August 2015** as a PCSK9 monoclonal antibody for HeFH, HoFH, and established ASCVD; subcutaneous every 2 weeks or monthly; ~60% LDL-C reduction; FOURIER demonstrated mortality, MI, and stroke reduction. **ALIROCUMAB (Praluent, Sanofi/Regeneron) — FDA-approved July 2015** as a PCSK9 monoclonal antibody for HeFH and established ASCVD; subcutaneous every 2 weeks; ~60% LDL-C reduction; ODYSSEY OUTCOMES showed cardiovascular event reduction. **INCLISIRAN (Leqvio, Novartis) — FDA-approved December 2021** as a small interfering RNA targeting hepatic PCSK9 mRNA; ~50% LDL-C reduction with subcutaneous dosing every 6 months after initial loading; ORION-4 cardiovascular outcomes trial ongoing. **EVINACUMAB (Evkeeza, Regeneron) — FDA-approved February 2021, expanded March 2024 to age ≥6 months** as a monoclonal antibody targeting ANGPTL3, transformative for HoFH because it lowers LDL-C ~50% via an LDLR-independent pathway — critical when the LDLR pathway is genetically broken; IV every 4 weeks. Lipid apheresis remains in use for refractory HeFH and many HoFH patients. Lomitapide (Juxtapid, MTP inhibitor) is FDA-approved for HoFH with a complex hepatic safety profile and REMS; mipomersen (Kynamro, ApoB ASO) was approved 2013 and withdrawn 2019. Bempedoic acid (Nexletol, ATP-citrate lyase inhibitor, FDA 2020) offers a non-statin oral option with CV benefit shown in CLEAR Outcomes 2023. Emerging: VERVE-101 and VERVE-102 (Verve Therapeutics) are in-vivo CRISPR base-editing approaches to permanently silence PCSK9 in a single dose — Phase 1. Cascade family screening is load-bearing — 50% transmission of the affected allele means each first-degree relative warrants screening, and childhood identification with timely treatment changes life trajectory dramatically. The FH Foundation (US, thefhfoundation.org), Heart UK, the International FH Foundation, and the European Atherosclerosis Society FH Studies Collaboration coordinate patient advocacy and research internationally. The community peptide catalog does not engage FH biology — BPC-157 has pro-angiogenic concerns in atherosclerotic populations, NMN's 'cardiovascular' framing doesn't map to LDL receptor pathway defects, GH-axis peptides affect triglycerides and HDL modestly but don't lower the LDL-C that defines FH, and semaglutide has complementary ASCVD-risk-reduction evidence (SELECT trial) but does not substitute for PCSK9 inhibition or evinacumab. Substrate exists for honest /ask answers when users probe; community peptides aren't elevated as discovery options because the FDA-approved peptide- and protein-class therapies — evolocumab, alirocumab, inclisiran, evinacumab — alongside statins, are the standard of care. Eightieth deliberate non-elevation of community peptides.
Important caveat
FH is managed by lipid specialist + preventive cardiology + genetics + (for HoFH) lipid apheresis center + (Verve trial enrollment) clinical research. **PREVALENCE ~1/250 HeFH GLOBALLY — ~25M CASES ~80% UNDIAGNOSED**: major public health issue; cascade family screening + childhood screening change life trajectories dramatically. **HoFH ~1/250,000-360,000**: childhood/adolescent MI possible; historical death 20s-30s pre-treatment; aggressive intervention essential. **TENDINOUS XANTHOMAS** (Achilles + finger extensors) HIGHLY SPECIFIC but NOT universal — absence doesn't rule out FH. **CASCADE FAMILY SCREENING LOAD-BEARING**: each first-degree relative 50% risk; childhood identification + early statin treatment near-normal life expectancy. **DUTCH LIPID CLINIC NETWORK CRITERIA + Simon Broome + MEDPED**: points-based diagnostic; **GENETIC TESTING NGS PANEL ~80% identify**. **TARGETS**: LDL-C <100 mg/dL primary prevention HeFH; <70 mg/dL with established ASCVD; <55 mg/dL very high risk; HoFH often unable reach standard targets. **HIGH-INTENSITY STATIN FOUNDATION** + ezetimibe. **PCSK9 INHIBITORS PEPTIDE/PROTEIN THERAPIES STANDARD-OF-CARE**: **EVOLOCUMAB (Repatha, Amgen) FDA AUG 2015** HeFH + HoFH + ASCVD; SC Q2wk/monthly; ~60% LDL-C reduction; FOURIER mortality + MI + stroke. **ALIROCUMAB (Praluent, Sanofi/Regeneron) FDA JULY 2015** HeFH + ASCVD; SC Q2wk; ~60%; ODYSSEY OUTCOMES. **INCLISIRAN (Leqvio, Novartis) siRNA PCSK9 mRNA FDA DEC 2021** HeFH + ASCVD; ~50%; SC Q6mo after loading. **EVINACUMAB (Evkeeza, Regeneron) ANGPTL3 mAb FDA FEB 2021** HoFH ≥12y; **EXPANDED MARCH 2024 ≥6mo**; LDLR-INDEPENDENT pathway crucial when LDLR broken; ~50% LDL-C reduction HoFH (unprecedented). **LIPID APHERESIS**: weekly/biweekly LDL extraction for HoFH + refractory; significant lifestyle burden. **LOMITAPIDE (Juxtapid)** MTP inhibitor HoFH; REMS + hepatic safety. **BEMPEDOIC ACID (Nexletol) FDA 2020** non-statin oral; CLEAR Outcomes 2023. **VERVE-101/VERVE-102 CRISPR BASE EDITING** Phase 1; single-dose permanent PCSK9 reduction emerging. **COMMUNITY PEPTIDES**: BPC-157 + NMN + GH-axis trio + semaglutide Tier 3. **BPC-157**: pro-angiogenic VEGFR2 concern in established atherosclerotic plaque (plaque neovascularization implicated vulnerable plaque + intraplaque hemorrhage); no FH characterization. **NMN**: 'cardiovascular health' framing doesn't map to LDL receptor pathway defects. **GH-AXIS TRIO**: tesamorelin modest triglyceride effects (HIV-LD) ≠ LDL therapy in genetic dyslipidemia; CJC + ipa lipid effects inconsistent; IGF-1 atherosclerosis effects uncharacterized FH. **SEMAGLUTIDE**: SELECT 2023 trial showed 20% MACE reduction overweight/obese established ASCVD without diabetes ON TOP guideline-directed lipid therapy — COMPLEMENTARY adjunct not substitute for PCSK9 inhibition/evinacumab; modest LDL-C reduction ~5-10% not primary mechanism. **STATIN INTOLERANCE**: real issue for subset; alternatives bempedoic acid + ezetimibe + PCSK9 inhibitors. **PEDIATRIC FH MANAGEMENT**: increasingly aggressive; statin therapy often started age 8-10y in classic HeFH; evinacumab now ≥6mo for HoFH transformative. **HoFH SPECIFIC**: apheresis lifestyle burden real; transplant historical; evinacumab + apheresis combination + emerging gene editing possibilities. **REPRODUCTIVE DECISIONS**: affected couples need genetic counseling; HoFH child possible if both parents HeFH (25% risk); pre-conception screening + PGT options. **ACCESS BARRIERS**: PCSK9 inhibitors initially $14k/year (now substantially reduced); evinacumab + inclisiran specialized; copay assistance programs important; insurance prior auth common. **LP(A)**: independent atherogenic marker often elevated in FH families; baseline check; emerging therapies (pelacarsen, olpasiran) for high Lp(a) cardiovascular risk in trials. **STATIN CV SAFETY** in pregnancy: traditionally contraindicated; updated guidance emerging; coordinate lipid specialist + MFM. FH Foundation (thefhfoundation.org) + Heart UK + International FH Foundation + European Atherosclerosis Society + AHA + ACC + ESC + IAS reference standards. WADA athletes: PCSK9 inhibitors + inclisiran + evinacumab require TUE; community GH secretagogues prohibited.
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