Heart disease is the leading cause of death in women (El Khoudary et al., 2020). Most women who die from it may have had a 'normal' LDL. The standard lipid panel was designed and validated on male populations in the 1960s - and it can systematically underestimate risk in women, particularly during and after the menopause transition.
ApoB, Lipoprotein(a), and hs-CRP are the three markers that may have the strongest evidence for reclassifying cardiovascular risk in women. None of them are on a standard lipid panel. All three require a specific order - and the conversation to ask for them.
Why LDL-C may not be enough
LDL-cholesterol measures the cholesterol content carried inside LDL particles. ApoB measures the number of particles themselves - one ApoB protein per atherogenic particle (Sniderman et al., 2019). Two women can have identical LDL-C but very different particle counts: one with large, buoyant particles (may mean lower risk), one with small, dense particles (may mean higher risk). ApoB can see the difference. LDL-C may not (Mora et al., 2014).
The ACC/AHA now endorse ApoB as a preferred risk marker and a secondary treatment target. For women, particularly those who are insulin resistant or have high triglycerides with borderline LDL, ApoB can provide information that may change clinical decisions.
The ApoB-LDL discordance in women
Insulin resistance - more common in perimenopausal women than at any other life stage - can produce exactly the pattern where LDL-C is borderline but ApoB is elevated. A normal LDL in this context may be false reassurance (Mora et al., 2014).
Lipoprotein(a): the genetic wild card
Lp(a) is structurally similar to LDL but carries an additional protein - apolipoprotein(a) - that can make it particularly atherogenic and thrombogenic (Reyes-Soffer et al., 2022). Approximately one in five people carry elevated Lp(a) (above 50 mg/dL or 125 nmol/L), and this can be almost entirely genetically determined (Miramontes González, 2026). Diet and statins may not meaningfully lower it (Miramontes González, 2026).
Elevated Lp(a) can roughly double the risk of coronary artery disease and aortic stenosis, independently of other risk factors. Because it's genetic and stable over a lifetime, you may only need to test it once. But most people have never heard of it and have never had it checked.
hs-CRP: vascular inflammation
High-sensitivity CRP measures low-grade systemic inflammation - the kind that can predict cardiovascular events over years, not the kind an acute infection can raise. Persistent hs-CRP above 2 mg/L can roughly double cardiovascular risk independently of lipids. In the landmark JUPITER trial, statin therapy reduced major cardiovascular events by 44% in nearly 18,000 participants with normal LDL but elevated hs-CRP (Ridker et al., 2008).
In women, hs-CRP may be a stronger predictor of cardiovascular events than LDL-C (Ridker et al., 2002). The Women's Health Study may support this: hs-CRP outperformed LDL-C, total cholesterol, and homocysteine for predicting first cardiovascular events in a cohort of nearly 28,000 women.
When menopause can change everything
Estrogen can be cardioprotective. It can raise HDL, lower LDL and ApoB, keep arterial walls flexible, and suppress vascular inflammation. As estrogen withdraws through perimenopause, the lipid profile can shift substantially - sometimes within a single year (Matthews et al., 2009). ApoB and LDL-C can rise; HDL may fall; hs-CRP can climb alongside visceral fat.
The window of highest change - and the highest opportunity for preventive intervention - may be the early transition. Baselining ApoB, Lp(a), and hs-CRP in the early 40s, before the inflection, allows you to track the trajectory rather than reacting to it a decade later.
References
- El Khoudary, S. R., et al. (2020). Menopause Transition and Cardiovascular Disease Risk: Implications for Timing of Early Prevention: A Scientific Statement From the American Heart Association. Circulation, 142(25), e506-e532. PMID 33251828
- Sniderman, A. D., et al. (2019). Apolipoprotein B Particles and Cardiovascular Disease: A Narrative Review. JAMA Cardiology, 4(12), 1287-1295. PMID 31642874
- Mora, S., et al. (2014). Discordance of low-density lipoprotein (LDL) cholesterol with alternative LDL-related measures and future coronary events. Circulation, 129(5), 553-561. PMID 24345402
- Reyes-Soffer, G., et al. (2022). Lipoprotein(a): A Genetically Determined, Causal, and Prevalent Risk Factor for Atherosclerotic Cardiovascular Disease: A Scientific Statement From the American Heart Association. Arteriosclerosis, Thrombosis, and Vascular Biology, 42(1), e48-e60. PMID 34647487
- Miramontes González, J. P. (2026). Lipoprotein(a): Cardiovascular Risk and Emerging Targeted Therapies. American Journal of Cardiovascular Drugs, doi:10.1007/s40256-026-00825-5. PMID 42675370
- Ridker, P. M., et al. (2008). Rosuvastatin to prevent vascular events in men and women with elevated C-reactive protein. New England Journal of Medicine, 359(21), 2195-2207. PMID 18997196
- Ridker, P. M., et al. (2002). Comparison of C-reactive protein and low-density lipoprotein cholesterol levels in the prediction of first cardiovascular events. New England Journal of Medicine, 347(20), 1557-1565. PMID 12432042
- Matthews, K. A., et al. (2009). Are changes in cardiovascular disease risk factors in midlife women due to chronological aging or to the menopausal transition? Journal of the American College of Cardiology, 54(25), 2366-2373. PMID 20082925
