The Effects of Ezetimibe on Surrogate Markers of Cholesterol Absorption and Synthesis in Japanese Patients with Dyslipidemia

Abstract

Aim:To demonstrate the clinical benefit of inhibiting intestinal cholesterol absorption, we evaluated the effects of ezetimibe on surrogate markers of cholesterol absorption and synthesis, lipid and glucose metabolism, and markers of obesity and inflammation. Methods: A total of 120 patients with dyslipidemia (46 men; mean age 66.5 years), who had not achieved the low density lipoprotein cholesterol (LDL-C) goal recommended by the Japan Atherosclerosis Society Guideline despite diet and exercise or any statin therapy, were enrolled and additionally treated with ezetimibe (10 mg/day) for 12 weeks. . Recent studies have elucidated the molecular mechanisms underlying intestinal cholesterol absorption, another potential therapeutic target for hypercholesterolemia. In 2000, Niemann-Pick C1 like 1 (NPC1L1), a transporter protein important for intestinal cholesterol absorption, was cloned. NPC1L1 is composed of 1,359 amino acids, possesses 13 transmembrane spanning IntroductionElevated low density lipoprotein cholesterol (LDL-C) is a major risk factor for cardiovascular diseases and its two sources, i.e., de novo synthesis in the liver and the absorption of dietary and bilialy cholesterol in the intestine, have offered important targets for the treatment of hypercholesterolemia. HMGCoA reductase inhibitors (statins), which target choAddress for correspondence: Shinya Hiramitsu, Fujita Ezetimibe STudy Assembly (FESTA) investigators group, Shiroshita-cho 2-35, Minami-ku, Nagoya 457-0047, Japan E-mail: hirazy@fujita-hu.ac. , together with a growing body of evidence that relates cholesterol absorption to the risk of cardiovascular events 4,5) , has made investigators more aware of the importance of controlling cholesterol absorption for the prevention of these cardiovascular events. Some investigators have reported increased intestinal cholesterol absorption in US and/or European individuals with a history of coronary artery disease 6) , obesity 7) , or type 2 diabetes mellitus 8) , although the relevance of this alteration to these and other pathologies remains to be determined.Based on these considerations, we evaluated the clinical benefit of ezetimibe and its effect on surrogate markers of cholesterol absorption and synthesis in Japanese patients with hypercholesterolemia in order to establish more efficient lipid-lowering therapy. MaterialsBetween June and December 2007, patients who presented to the outpatient clinic of Fujita Ezetimibe Study Assembly were enrolled if they had not achieved the LDL-C goal levels recommended in the 2007 Guideline of the Japan Atherosclerosis Society (JAS) 9) despite diet and exercise without anti-dyslipidemic agents for at least 4 weeks (ezetimibe monotherapy group) or had not achieved the LDL-C management goal levels despite at least 4 weeks of statin therapy (co-administration with ezetimibe and any statin). The study protocol was approved by the Fujita Health University Ethics Committee and all patients gave written informed consent. MethodsAt enrollment, all patients were examined ...

Double-Blind Randomized Clinical Trial of the Effects of Ezetimibe on Postprandial Hyperlipidaemia and Hyperglycaemia

“…These results suggested that glucose tolerance was not exacerbated by ezetimibe. Several studies in humans 16,17,26) showed that HbA1c was decreased by ezetimibe. The results of our animal study 25) supported the concept that ezetimibe ameliorates hepatic insulin resistance as well as dyslipidaemia and hepatic steatosis in high-fat dietinduced obese subjects.…”

“…Clinically, the administration of ezetimibe has been shown to reduce fasting levels of total cholesterol (TC) and LDL-C in patients with primary hypercholesterolemia in both Japan and the United States 13,14) . In addition, ezetimibe has been reported to reduce postprandial hypertriglyceridaemia and inflammation and to improve insulin sensitivity 15,16) . In animals experiments, ezetimibe reversed dietinduced obesity 17,18) , liver steatosis [17][18][19][20] , and insulin resistance 19) .…”

Mutations inNPC1L1and Coronary Heart Disease

“…1 However, studies have also demonstrated an action of ezetimibe in the reduction of blood insulin and HbA1C levels. 2 Possible mechanisms include an increase in glucagon-like peptide-1 activity and in pancreatic beta cell mass, which have been observed in animal models. 3 This is consistent with the finding of increased insulin sensitivity in NPC1L1 knock out mice, or in mice treated with ezetimibe, when exposed to a diabetogenic diet.…”

“…This finding validates the concept that lifelong LDL cholesterol reduction has a greater impact on risk 1 than pharmacologic interventions, such as statin therapy, initiated later in life. 2 We have previously hypothesized that increased dietary sterol (cholesterol and xenosterol) absorption via NPC1L1 is associated with increased cardiovascular risk. 3,4 We further posit that there are sterol species in our diets (such as oxysterols, oxyphytosterols, etc.)…”

Ezetimibe in the Treatment of Patients with Metabolic Diseases

“…48,49 Ezetimibe monotherapy has also been observed to be associated with an improvement in visceral fat area, fasting insulin level, homeostasis model assessment of insulin resistance and hs-cRP level in patients with fatty liver. 50 hs-cRP is an important inflammatory biomarker related to adverse cardiovascular outcomes, 51,52 and studies have consistently shown a significant reduction in hs-cRP levels with ezetimibe-statin combination therapy.…”