Medical Mythbusting Commentary for May 26, 2026
Source:
Experts have found a new type of cholesterol. And it could be the most dangerous
Reference: Source: openevidence.com
Remnant cholesterol — defined as total cholesterol minus LDL-C minus HDL-C — is an emerging and increasingly recognized causal risk factor for ASCVD. Management centers on lifestyle modification as first-line therapy, followed by pharmacotherapy targeting triglyceride-rich lipoproteins (TRLs), with non-HDL-C or apoB as the preferred treatment targets rather than remnant cholesterol itself.[1][2][3]
The following figure illustrates the lipoprotein spectrum and the calculation of remnant cholesterol:
Figure 1 Spectrum of Lipoproteins Indicating the Remnant TG-Rich Lipoproteins undefined
Definition and Clinical Significance
Remnant cholesterol represents the cholesterol content of VLDL, IDL, and chylomicron remnants.[1][2] It is calculated from a standard lipid panel as: total cholesterol − HDL-C − LDL-C.[2][5] Observational and Mendelian randomization studies consistently demonstrate that elevated remnant cholesterol is a causal risk factor for ASCVD, independent of LDL-C.[6][7][8] Individuals with remnant cholesterol ≥30 mg/dL have significantly higher cardiovascular risk regardless of LDL-C levels.[6] Lowering remnant cholesterol by approximately 32 mg/dL has been estimated to reduce recurrent MACE by 20% in secondary prevention.[6]
Lifestyle Management (First-Line)
The 2026 ACC/AHA Dyslipidemia Guidelines recommend lifestyle management as the first-line approach for hypertriglyceridemia and elevated remnant cholesterol:[3]
– Diet: Mediterranean, DASH, or predominantly plant-based dietary patterns; limit processed carbohydrates, added sugars, saturated fat, and alcohol[3][9]
– Weight loss: A 5%–10% reduction in body weight can lower TG by 20%–30%; each 1 kg of weight loss reduces TG by ~4 mg/dL[3]
– Exercise: ≥150 minutes/week of moderate-intensity or 75 minutes/week of vigorous-intensity aerobic activity, plus resistance training twice weekly[3]
– Address secondary causes: Uncontrolled diabetes, hypothyroidism, excessive alcohol, medications (e.g., certain antipsychotics, estrogens), and insulin resistance[3][9]
Pharmacotherapy
After 4–12 weeks of lifestyle optimization and management of secondary causes, persistent hypertriglyceridemia (fasting TG ≥150 mg/dL) may warrant pharmacotherapy.[9] The 2026 ACC/AHA guidelines provide a tiered approach:[3]
– Statins remain first-line pharmacotherapy for ASCVD risk reduction in patients with hypertriglyceridemia. They lower TG modestly (10%–30%) in a dose-dependent manner and reduce remnant cholesterol to a considerable degree. LDL-C lowering remains the priority in patients with clinical ASCVD.[10][3]
– Icosapent ethyl (IPE) 4 g/day may be reasonable (Class 2b) in adults ≥50 years with clinical ASCVD or diabetes plus ≥1 ASCVD risk factor, with persistent TG 150–499 mg/dL and LDL-C <100 mg/dL on maximally tolerated statin. In the REDUCE-IT trial, IPE reduced the primary composite endpoint by 25%, with roughly half of the benefit estimated to be attributable to remnant cholesterol reduction. However, the 2026 guidelines note that the mineral oil placebo may have exaggerated the treatment effect, and IPE carries small but significantly increased risks of atrial fibrillation and bleeding.[3][11]
– Fibrates (fenofibrate, fenofibric acid) have a more profound TG-lowering effect but do not provide incremental ASCVD risk reduction when added to statin therapy. They remain reasonable for severe hypertriglyceridemia (TG ≥500 mg/dL) to reduce pancreatitis risk.[6][12][3]
– Ezetimibe and PCSK9 inhibitors lower remnant cholesterol to a considerable degree and should be considered in patients who have not reached non-HDL-C goals after adequate LDL-C lowering.[10]
– Olezarsen (apoC-III inhibitor) is FDA-approved for familial chylomicronemia syndrome (FCS) with fasting TG ≥1000 mg/dL, reducing TG by ~43.5%.[3]
Emerging Therapies
Novel gene-silencing therapies targeting apolipoprotein C-III (olezarsen, plozasiran) and ANGPTL3 (evinacumab) can lower remnant cholesterol by 50%–80%.[7][13] Cardiovascular outcome trials are ongoing to determine whether these pronounced remnant cholesterol reductions translate into ASCVD event reduction.[7][14]
Monitoring and Treatment Targets
The 2026 ACC/AHA guidelines recommend using non-HDL-C or apoB rather than LDL-C alone to guide clinical decision-making in patients with hypertriglyceridemia, as these measures capture the atherogenic burden of both LDL and remnant particles.[3][15] Non-HDL-C is easily calculated (total cholesterol − HDL-C) from a nonfasting lipid panel at no additional cost.[16]
Would you like to explore the specific non-HDL-C and apoB treatment targets recommended by the 2026 ACC/AHA guidelines for different risk categories?
References
Non-High-Density Lipoprotein Cholesterol, Guideline Targets, and Population Percentiles for Secondary Prevention in 1.3 Million Adults: The VLDL-2 Study (Very Large Database of Lipids). Elshazly MB, Martin SS, Blaha MJ, et al. Journal of the American College of Cardiology. 2013;62(21):1960-1965. doi:10.1016/j.jacc.2013.07.045.
Elevated Remnant Cholesterol Reclassifies Risk of Ischemic Heart Disease and Myocardial Infarction. Doi T, Langsted A, Nordestgaard BG. Journal of the American College of Cardiology. 2022;79(24):2383-2397. doi:10.1016/j.jacc.2022.03.384.
Triglycerides and Cardiovascular Disease. Nordestgaard BG, Varbo A. Lancet (London, England). 2014;384(9943):626-635. doi:10.1016/S0140-6736(14)61177-6.
2026 ACC/AHA/AACVPR/ABC/ACPM/ADA/AGS/APhA/ASPC/NLA/PCNA Guideline on the Management of Dyslipidemia: A Report of the American College of Cardiology/American Heart Association Joint Committee on Clinical Practice Guidelines. Blumenthal RS, Morris PB, Gaudino M, et al. Journal of the American College of Cardiology. 2026;:S0735-1097(25)10254-4. doi:10.1016/j.jacc.2025.11.016.
Remnant Cholesterol and Atherosclerotic Cardiovascular Disease Risk. Burnett JR, Hooper AJ, Hegele RA. Journal of the American College of Cardiology. 2020;76(23):2736-2739. doi:10.1016/j.jacc.2020.10.029.
New Therapies for Lowering Triglyceride-Rich Lipoproteins: JACC Focus Seminar 3/4. Rosenson RS, Shaik A, Song W. Journal of the American College of Cardiology. 2021;78(18):1817-1830. doi:10.1016/j.jacc.2021.08.051.
Remnant Cholesterol, Not LDL Cholesterol, Is Associated With Incident Cardiovascular Disease. Castañer O, Pintó X, Subirana I, et al. Journal of the American College of Cardiology. 2020;76(23):2712-2724. doi:10.1016/j.jacc.2020.10.008.
Feasibility of Remnant Cholesterol as a Therapeutic Target for Atherosclerotic Cardio-Vascular Disease. Wulff AB, Varbo A, Nordestgaard AT, Nordestgaard BG. Expert Opinion on Therapeutic Targets. 2026;30(3):229-244. doi:10.1080/14728222.2026.2639678.
Remnant Cholesterol as a Causal Risk Factor for Ischemic Heart Disease. Varbo A, Benn M, Tybjærg-Hansen A, et al. Journal of the American College of Cardiology. 2013;61(4):427-436. doi:10.1016/j.jacc.2012.08.1026.
2026 ACC/AHA/AACVPR/ABC/ACPM/ADA/AGS/APhA/ASPC/NLA/PCNA Guideline on the Management of Dyslipidemia: A Report of the American College of Cardiology/American Heart Association Joint Committee on Clinical Practice Guidelines. Writing Committee Members, Blumenthal RS, Morris PB, et al. Circulation. 2026;. doi:10.1161/CIR.0000000000001423.
One in Five Atherosclerotic Cardiovascular Disease Events in Individuals With Diabetes Attributed to Elevated Remnant Cholesterol. Wadström BN, Pedersen KM, Wulff AB, Nordestgaard BG. Diabetes/Metabolism Research and Reviews. 2024;40(8):e70005. doi:10.1002/dmrr.70005.
VLDL Cholesterol Accounts for One-Half of the Risk of Myocardial Infarction Associated With apoB-Containing Lipoproteins. Balling M, Afzal S, Varbo A, et al. Journal of the American College of Cardiology. 2020;76(23):2725-2735. doi:10.1016/j.jacc.2020.09.610.
Triglyceride Lowering with Pemafibrate to Reduce Cardiovascular Risk. Das Pradhan A, Glynn RJ, Fruchart JC, et al. The New England Journal of Medicine. 2022;387(21):1923-1934. doi:10.1056/NEJMoa2210645.
Targeting Triglycerides for Cardiovascular Risk Reduction. Maiorca C, Tramontano D, Di Costanzo A, D’Erasmo L. Internal and Emergency Medicine. 2026;:10.1007/s11739-026-04383-1. doi:10.1007/s11739-026-04383-1.
Residual Lipid Risk in Atherosclerotic Cardiovascular Disease. Nordestgaard BG, Hegele RA. European Heart Journal. 2026;:ehag087. doi:10.1093/eurheartj/ehag087.
Non-HDL-Cholesterol in Dyslipidemia: Review of the State-of-the-Art Literature and Outlook. Raja V, Aguiar C, Alsayed N, et al. Atherosclerosis. 2023;383:117312. doi:10.1016/j.atherosclerosis.2023.117312.