Dyslipidemia & cholesterol management

What changes during this transition

Dyslipidemia is well-defined cardiovascular preventive medicine — the AHA/ACC 2018 cholesterol guideline and 2022 ACC ECDP frame management around ASCVD risk estimation, LDL-C as the dominant target with ApoB as the more accurate atherogenic burden measure, lipoprotein(a) screening once-in-a-lifetime, and triglycerides as a separate axis with its own intervention sequence. Standard-of-care is layered and well-evidenced. First-line: high-intensity statin therapy (atorvastatin 40-80 mg, rosuvastatin 20-40 mg) for established ASCVD or very-high-risk primary prevention; moderate-intensity for moderate-risk primary prevention. Add-on: ezetimibe (IMPROVE-IT 2015), PCSK9 inhibitors (evolocumab FOURIER 2017, alirocumab ODYSSEY OUTCOMES 2018), bempedoic acid (CLEAR Outcomes 2023 for statin-intolerant patients), and inclisiran (siRNA against PCSK9, FDA-approved December 2021). Triglycerides at ≥500 mg/dL warrant intervention to reduce pancreatitis risk; icosapent ethyl (Vascepa) carries the REDUCE-IT 2018 cardiovascular-event-reduction evidence at TG 150-499 mg/dL on optimized statin. Lipoprotein(a) is largely genetic with no FDA-approved Lp(a)-specific therapy yet — olpasiran and pelacarsen are in Phase 3. The peptide library's role on this axis is narrow and indirect. Semaglutide (Tier 2 surfaced) carries the SUSTAIN program signal on modest LDL-C and triglyceride reduction in the diabetic population, plus the SELECT 2023 NEJM cardiovascular-event-reduction result in non-diabetic adults with overweight or obesity plus established cardiovascular disease (20% MACE reduction over ~3.3 years) — substantial population overlap with the dyslipidemia conversation, but the editorial honesty is that the SELECT mechanism is largely weight loss + glycemic and inflammatory benefits, not direct LDL reduction. Tirzepatide (Tier 2 surfaced) is the strongest in-class triglyceride signal — SURPASS-4 and the SURMOUNT obesity trials showed greater TG reduction than semaglutide head-to-head, with SURMOUNT-MMO 2025 CV outcomes for the obesity population now available. Tesamorelin (Tier 3 surfaced) is the FDA-approved-for-HIV-associated-lipodystrophy peptide where Rule 6 non-propagation matters explicitly — the HIV-lipodystrophy TG and HDL signal does NOT propagate to general dyslipidemia, and surfacing it without that load-bearing caveat would mislead users. What is NOT surfaced and why. CJC-1295 is substrate-only because the GH-axis worsens insulin resistance and that downstream effect on lipid metabolism runs directionally wrong for users on a dyslipidemia axis (especially in the type-2-diabetes overlap subset that's common in this population). B12-methylcobalamin is substrate-only because homocysteine is not lipid — the VISP 2004 NEJM, HOPE-2 2006 NEJM, and Cochrane 2017 trials clearly demonstrated that B12+folate-driven homocysteine reduction does NOT translate to cardiovascular-event reduction; surfacing B12 as a 'cardiovascular peptide' would conflate a thoroughly-falsified hypothesis with the well-established dyslipidemia intervention sequence.