Research · PMID 34637926
Reviewed by Neal Rouzier, MD, Preventive Medicine · Sep 2026
HDL cholesterol concentrations and risk of atherosclerotic cardiovascular disease - Insights from randomized clinical trials and human genetics.
Biochimica et biophysica acta. Molecular and cell biology of lipids · January 2022 · Emilie Westerlin Kjeldsen, Jesper Qvist Thomassen, Ruth Frikke-Schmidt
What this study found
Through seven decades the inverse association between HDL cholesterol concentrations and risk of atherosclerotic cardiovascular disease (ASCVD) has been observed in case-control and prospective cohort studies. This robust inverse association fuelled the enthusiasm towards development of HDL cholesterol increasing drugs, exemplified by the cholesteryl ester transfer protein (CETP) inhibitor trials and the extended-release niacin HPS2-THRIVE trial.
How RAGMD uses this study
Clinical questions this paper informs
Synthesis lives on the evidence question — this page shows where the study sits in that analysis.
Primary study
Do therapies that raise HDL reduce cardiovascular events?
Trials of niacin and CETP inhibitors raised HDL without consistent reduction in cardiovascular events when added to statins, challenging the hypothesis that raising HDL alone is protective.
Open evidence analysisCore study
Do omega-3 supplements prevent cardiovascular disease in the general population?
High-dose EPA (icosapent ethyl) reduced events in selected high-risk statin-treated patients in REDUCE-IT. General over-the-counter omega-3 supplements show inconsistent or null benefit in primary prevention populations.
Open evidence analysisSupporting literature
Is ApoB more useful than LDL-C for cardiovascular risk prediction?
Prospective cohorts and meta-analyses suggest ApoB may capture atherogenic particle burden better than LDL-C alone, particularly when triglycerides are elevated or LDL particles are discordant with LDL-C.
Open evidence analysisSupporting literature
Should adults take statins for primary cardiovascular prevention?
Meta-analyses of primary prevention trials show reduced major adverse cardiovascular events with statins in appropriately selected moderate-to-high-risk adults. Shared decision-making should weigh absolute risk reduction against side effects and patient preference.
Open evidence analysisSupporting literature
Does elevated lipoprotein(a) independently increase cardiovascular risk?
Mendelian randomization and epidemiologic data support Lp(a) as a causal cardiovascular risk factor. Specific Lp(a)-lowering therapies are emerging but routine treatment beyond standard risk factor control awaits outcome trial confirmation.
Open evidence analysisSupporting literature
Does hormone therapy improve metabolic syndrome markers?
Menopausal hormone therapy may favorably affect some metabolic markers in selected women but is not a primary treatment for metabolic syndrome. Lifestyle and cardiometabolic risk management remain foundational.
Open evidence analysisSupporting literature
Can hormone therapy help insulin resistance in peri- and postmenopausal women?
Some studies show improved insulin sensitivity with estrogen-based therapy in early postmenopause, but results are not uniform across regimens. HRT should not replace evidence-based diabetes prevention or treatment.
Open evidence analysisSupporting literature
Does testosterone therapy affect blood pressure?
Testosterone effects on blood pressure are modest and inconsistent across trials. Monitoring blood pressure remains part of routine TRT follow-up, especially with fluid retention or erythrocytosis.
Open evidence analysisSupporting literature
Should aspirin be used for primary cardiovascular prevention?
Current guidelines generally discourage routine aspirin for primary prevention in low-to-moderate-risk adults because bleeding harm offsets modest benefit. Select high-risk individuals may still be considered with shared decision-making.
Open evidence analysisSupporting literature
Should coronary artery calcium scoring guide statin decisions?
Coronary artery calcium can reclassify intermediate-risk patients and inform statin initiation when risk is uncertain. A score of zero may support deferring therapy in selected low-risk individuals with shared decision-making.
Open evidence analysisSupporting literature
Does vitamin D supplementation reduce mortality or major disease?
Meta-analyses show vitamin D supplementation does not significantly reduce all-cause mortality in unselected populations. Targeted repletion may benefit those with documented deficiency.
Open evidence analysisSupporting literature
Does magnesium supplementation improve metabolic health markers?
Trials in deficient or at-risk individuals show modest improvements in some glycemic and blood pressure markers, but routine supplementation for metabolic disease prevention is not strongly supported in general populations.
Open evidence analysisSupporting literature
Does DHEA supplementation improve health outcomes in aging adults?
DHEA raises circulating androgens and estrogens modestly but lacks robust outcome trial evidence for cardiovascular, cognitive, or mortality benefit in healthy aging adults without documented deficiency.
Open evidence analysisSupporting literature
When is growth hormone replacement appropriate in adults?
Growth hormone replacement is evidence-supported for adults with confirmed GH deficiency from pituitary disease, improving body composition and quality of life. Use in healthy aging or performance enhancement lacks safety and efficacy evidence.
Open evidence analysis