Higher Cholesterol Absorption Marker at Baseline Predicts Fewer Cardiovascular Events in Elderly Patients Receiving Hypercholesterolemia Treatment: The KEEP Study

J Am Heart Assoc. 2024 Feb 6;13(3):e031865. doi: 10.1161/JAHA.123.031865. Epub 2024 Jan 19.


Background: Higher cholesterol absorption has been reported to be related to a higher incidence of cardiovascular events (CVEs). The KEEP (Kyushu Elderly Ezetimibe Phytosterol) study, a substudy of the EWTOPIA 75 (Ezetimibe Lipid-Lowering Trial on Prevention of Atherosclerotic Cardiovascular Disease in 75 or Older) study, investigated the relationships of cholesterol absorption and synthesis markers with CVEs in older old individuals with hypercholesterolemia, particularly in relation to ezetimibe treatment.

Methods and results: Eligible patients were those aged ≥75 years who had low-density lipoprotein cholesterol ≥140 mg/dL, no history of coronary artery disease, and no recent use of lipid-lowering drugs. Participants were randomly assigned into a diet-only or diet-plus-ezetimibe group. Baseline and 24-week follow-up blood samples were analyzed for cholesterol absorption (eg, campesterol) and synthesis markers (eg, lathosterol). Of 1287 patients, 1061 patients with baseline measurement were analyzed. Over a median follow-up of 4.0 years, 64 CVEs occurred. Higher campesterol levels at baseline were significantly associated with a lower risk of CVEs. After adjustment for sex, age, and treatment, the hazard ratios for the lowest to highest quartile categories of baseline campesterol were 1.00 (reference), 0.59 (95% CI, 0.30-1.17), 0.44 (95% CI, 0.21-0.94), and 0.44 (95% CI, 0.21-0.93), respectively (trend P=0.01). This association persisted after further adjustment for hypertension, diabetes, and other cardiovascular risk factors. Neither interactions with ezetimibe treatment nor mediating effects of the changes in cholesterol absorption markers were observed.

Conclusions: The KEEP study indicated that higher campesterol levels without lipid-lowering drugs were associated with a lower incidence of CVEs in older old individuals with hypercholesterolemia who were subsequently treated with diet or ezetimibe.

Registration: URL: https://www.umin.ac.jp; unique identifier: UMIN000017769.

Keywords: atherosclerotic cardiovascular disease; cholesterol absorption marker; elderly; ezetimibe; primary prevention.

Publication types

  • Randomized Controlled Trial

MeSH terms

  • Aged
  • Anticholesteremic Agents* / adverse effects
  • Cholesterol
  • Coronary Artery Disease* / drug therapy
  • Drug Therapy, Combination
  • Ezetimibe / therapeutic use
  • Humans
  • Hydroxymethylglutaryl-CoA Reductase Inhibitors* / therapeutic use
  • Hypercholesterolemia* / drug therapy
  • Hypercholesterolemia* / epidemiology
  • Hypolipidemic Agents / therapeutic use


  • Anticholesteremic Agents
  • Hydroxymethylglutaryl-CoA Reductase Inhibitors
  • Cholesterol
  • Ezetimibe
  • Hypolipidemic Agents