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February 11, 2020 e67 Masanari Kuwabara, MD, PhD Jun Sasaki, MD, PhD Tetsunori Saikawa, MD, PhD Yasuyoshi Ouchi, MD, PhD In Response: We thank Dr Weingärtner et al for their valuable comments to our article, “Ezetimibe Lipid-Lowering Trial on Prevention of Atherosclerotic Cardiovascular Disease in 75 or Older (EWTOPIA 75): A Randomized, Controlled Trial.”1 As they mentioned, cholesterol synthesis deteriorates with aging. We agree with their comments; cholesterol metabolism, including cholesterol absorption and synthesis, is closely associated with the occurrence of cardiovascular diseases. The analysis of cholesterol metabolism in elderly subjects could explain why ezetimibe therapy is more effective in elderly subjects than younger subjects in the EWTOPIA 75 and IMPROVE-IT trials (Improved Reduction of Outcomes: Vytorin Efficacy International Trial).2 Campesterol is a marker of fractional cholesterol absorption. Ezetimibe therapy is expected to reduce campesterol levels. In contrast, lathosterol is a marker for endogenous cholesterol synthesis, and lathosterol levels correlate with cardiovascular events and all-cause mortality. In general, statin therapy reduces lathosterol levels,3 but ezetimibe therapy increases lathosterol levels as a result of reducing cholesterol absorption in the intestine.4 We are conducting a substudy of EWTOPIA 75, which is named KEEP (Kyushu Elderly Ezetimibe Phytosterol study; https://www.umin.ac.jp. Unique identifier: UMIN000017769). The primary outcome of KEEP included the change in cholesterol absorption and synthesis over 24 weeks. Here, we can show the preliminary data. We compared the change in campesterol and lathosterol levels between 390 subjects in the ezetimibe group and 458 subjects in the control group. The baseline levels of campesterol and lathosterol showed no significant difference between both groups. The decrease in campesterol levels (in terms of ×100 μg/mg of cholesterol) over 24 weeks was greater in the ezetimibe group than that in the control group (mean±SD; −108±111 versus −4.15±94.6, P<0.0001). In contrast, the increase in lathosterol levels (in terms of ×100 μg/mg of cholesterol) over 24 weeks was greater in the ezetimibe group than in the control group (37.9±52.0 versus 3.77±44.5, P<0.0001). These results suggest that ezetimibe therapy not only decreases cholesterol absorption but also increases cholesterol synthesis. Okada et al compared the change in campesterol and lathosterol levels between ezetimibe plus statin and a double dose of statin for 12 weeks.5 They showed that campesterol levels increased in the statin group but decreased in the ezetimibe/ statin group. In contrast, lathosterol levels decreased in the statin group but increased in the ezetimibe/statin group.5 The results by Okada et al are similar to our results in the ezetimibe group although their study design is different. KEEP showed that there is little change in campesterol and lathosterol levels in the control group. However, these results suggest that the effects of ezetimibe beyond lowering lowdensity lipoprotein cholesterol could explain the mechanisms by which ezetimibe © 2020 American Heart Association, Inc. RESPONSE TO LETTER TO THE EDITOR