The synergistic hypocholesterolemic activity of the potent cholesterol absorption inhibitor, ezetimibe, in combination with 3-hydroxy-3-methylglutaryl coenzyme a reductase inhibitors in dogs

Davis, Harry R.; Pula, Kathyrn K.; Alton, Kevin B.; Burrier, Robert E.; Watkins, Robert W.

doi:10.1053/meta.2001.26737

Cited by 97 publications

(77 citation statements)

References 18 publications

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“…5 An increased HMG CoA reductase activity has also been found in ezetimibe treated animals, whereby hepatic stores of cholesterol were reduced due to the inhibition of biliary cholesterol absorption and delivery back to the liver. 15 Whereas plasma and hepatic cholesterol levels increased significantly in wild-type and apoE Ϫ/Ϫ mice after 24 weeks on Western diet, plasma and hepatic cholesterol in male Npc1l1/apoE Ϫ/Ϫ and Npc1l1 Ϫ/Ϫ mice remained at levels comparable to chow-fed groups. Plasma cholesterol values doubled in female Npc1l1/apoE Ϫ/Ϫ and Npc1l1 Ϫ/Ϫ mice suggesting that they are not completely resistant to the effects of the high saturated fat, 0.15% cholesterolcontaining Western diet as male mice.…”

Section: Discussionmentioning

confidence: 92%

Deficiency of Niemann-Pick C1 Like 1 Prevents Atherosclerosis in ApoE ^−/− Mice

Davis¹,

Hoos²,

Tetzloff³

et al. 2007

ATVB

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118

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Objective-The objective of this study was to determine whether the deficiency of Niemann-Pick C1 Like 1 (Npc1l1) prevents atherosclerosis in apoE null mice. Methods and Results-Npc1l1Ϫ/Ϫ /apoE null Ϫ/Ϫ mice were generated and found to have a significant reduction in cholesterol absorption (Ϫ77%) compared with wild-type or apoE Ϫ/Ϫ mice. Npc1l1/apoE Ϫ/Ϫ mice were fed a chow or Western diet for 24 weeks, then lipoprotein, hepatic, and biliary cholesterol, and atherosclerosis development was compared with apoE Ϫ/Ϫ , Npc1l1 Ϫ/Ϫ , wild-type, and ezetimibe-treated apoE Ϫ/Ϫ mice. Chylomicron remnant/ VLDL cholesterol levels were reduced 80% to 90% in both chow and Western diet-fed Npc1l1/apoE Ϫ/Ϫ mice relative to apoE Ϫ/Ϫ mice. Male Npc1l1 Ϫ/Ϫ and Npc1l1/apoE Ϫ/Ϫ mice were completely resistant to diet induced hypercholesterolemia, and both male and female mice were completely resistant to increases in hepatic and biliary cholesterol levels. Atherosclerosis was reduced 99% in aortic lesion surface area, 94% to 97% in innominate artery intimal lesion area, and Ͼ90% in aortic root lesion area in both male and female Npc1l1/apoE Ϫ/Ϫ mice relative to apoE Ϫ/Ϫ mice. Conclusions-Lack of Npc1l1, the molecular target of the cholesterol absorption inhibitor ezetimibe, in apoE Ϫ/Ϫ mice results in a significant reduction in cholesterol absorption and plasma cholesterol levels, and causes a nearly complete protection from the development of atherosclerosis, under both cholesterol-fed and non-cholesterol-fed conditions.

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Section: Discussionmentioning

confidence: 92%

Deficiency of Niemann-Pick C1 Like 1 Prevents Atherosclerosis in ApoE ^−/− Mice

Davis¹,

Hoos²,

Tetzloff³

et al. 2007

ATVB

Self Cite

118

View full text Add to dashboard Cite

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“…10 On the basis of the current results and similar LDL-C reductions in primary hypercholesterolemia, [17][18][19][20][21][22] it would be anticipated that ezetimibe would exert comparable actions in other forms of severe hypercholesterolemia. The effect of statins in HoFH seems to be significantly limited by the inability of these patients to effectively upregulate the LDL receptor, 10 whereas the primary mechanism responsible for ezetimibe-induced LDL-C lowering, inhibition of cholesterol absorption at the intestinal brush border, 13,14,23 seems to be largely unaffected by the pathophysiological milieu of HoFH.…”

Section: Discussionmentioning

confidence: 99%

“…[17][18][19][20] Additionally, coadministration of ezetimibe with simvastatin or atorvastatin produced incremental LDL-C reductions and favorably affected total cholesterol, HDL cholesterol (HDL-C), and triglyceride levels. 17,19,[21][22][23] Because current pharmacological therapy of patients with HoFH fails to sufficiently reduce LDL-C concentrations, the present randomized, double-blind study evaluated the efficacy, safety, and tolerability of ezetimibe as an adjunct to diet and statins with or without LDL apheresis.…”

mentioning

confidence: 99%

Efficacy and Safety of Ezetimibe Coadministered With Atorvastatin or Simvastatin in Patients With Homozygous Familial Hypercholesterolemia

2002

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Background-Patients with homozygous familial hypercholesterolemia (HoFH) have a high incidence of cardiovascular morbidity and mortality from premature atherosclerosis, and the efficacy of pharmacological therapy has been limited. We evaluated the efficacy, safety, and tolerability of ezetimibe, a novel cholesterol absorption inhibitor, in a multicenter, double-blind, randomized trial of HoFH patients receiving atorvastatin or simvastatin.

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“…In hypercholesterolemic humans, ezetimibe alone significantly decreased LDL cholesterol (Ϫ18.5%) and increased HDL cholesterol (ϩ3.5%) (4). The combination of ezetimibe and the statins has shown significant synergy in lowering cholesterol in preclinical trials (10,11). Recent studies in hypercholesterolemic humans demonstrated that combining simvastatin (10 -20 mg/day) and ezetimibe (10 mg/day) led to a 50 -60% decrease in LDL cholesterol in 2 weeks of treatment (21,22).…”

Section: Discussionmentioning

confidence: 99%

“…During chronic preclinical studies, it was determined that ezetimibe inhibited the rise in plasma cholesterol normally observed with cholesterol feeding in the rhesus monkey with an ID 50 of 0.0005 mg/kg (1) and had comparable potency in dogs, rabbits, rats, and hamsters (10,11). However, no effect on plasma triglycerides was observed in these studies, most likely because all of the species exhibited normotriglyceridemia under the conditions studied.…”

mentioning

confidence: 99%

Ezetimibe, a Potent Cholesterol Absorption Inhibitor, Normalizes Combined Dyslipidemia in Obese Hyperinsulinemic Hamsters

Heek¹,

Austin²,

Farley³

et al. 2001

Diabetes

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Ezetimibe potently and selectively inhibits cholesterol absorption in the intestine, thereby reducing plasma cholesterol in preclinical models of hypercholesterolemia. Clinical trials have demonstrated that ezetimibe lowers LDL cholesterol and raises HDL cholesterol in humans. The effect of ezetimibe on other dyslipidemias, particularly hypertriglyceridemia, is not yet known. In the present studies, we assessed the effect of ezetimibe on combined hypercholesterolemia and hypertriglyceridemia in obese hyperinsulinemic hamsters. Hamsters were fed chow, chow with cholesterol (0.12%), or the same cholesterol diet containing different dietary triglycerides (15%) in the absence or presence of 1 mg/kg ezetimibe (in diet) for up to 84 days. Body weight, serum insulin, leptin, glucose, cholesterol, and triglyceride levels were analyzed. Cholesterol and triglyceride levels were also determined in VLDL؉IDL, LDL, and HDL. Hamsters maintained on high-fat diets became obese, hyperinsulinemic, hyperleptinemic, hypercholesterolemic, and hypertriglyceridemic. Ezetimibe did not affect body weight, insulin, or leptin, but ablated the combined hypercholesterolemia and hypertriglyceridemia induced by high-fat diets. Ezetimibe normalized VLDL؉IDL cholesterol and triglyceride and significantly decreased LDL cholesterol to below chow-fed levels. The ratio of HDL to LDL cholesterol increased significantly with the addition of ezetimibe. Ezetimibe completely eliminated the accumulation of cholesteryl ester and free cholesterol in liver that was induced under the various dietary conditions in the absence of drug. In conclusion, ezetimibe is very effective in correcting the combined dyslipidemia in diet-induced obese hyperinsulinemic hamsters and may be an effective therapy for ameliorating combined dyslipidemia in obese insulin-resistant and/or type 2 diabetic humans. Diabetes 50:1330 -1335, 2001 W e have previously described the discovery of a novel cholesterol absorption inhibitor, ezetimibe ( Fig. 1) (1-3), that lowers LDL cholesterol and raises HDL cholesterol in hypercholesterolemic humans (4). Evidence is mounting that reducing plasma cholesterol by dietary and/or pharmacological means leads to reductions in the incidence of death from vascular events (5-8). Ezetimibe is rapidly progressing through clinical trials, but it is not yet known what the effect of ezetimibe will be in the obese insulinresistant and/or type 2 human diabetic population, who often exhibit both hypercholesterolemia and hypertriglyceridemia. Management of combined dyslipidemia is of utmost importance in these populations because these conditions are associated with a much higher incidence of cardiovascular disease (9). Presently, there are very few pharmacological agents that significantly lower both plasma cholesterol and triglyceride levels.In acute preclinical studies, ezetimibe prevented the transport of 14 C-cholesterol from the intestinal lumen through the intestinal wall and into the plasma in rats (1). During chronic preclinical studies, it was determin...

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The synergistic hypocholesterolemic activity of the potent cholesterol absorption inhibitor, ezetimibe, in combination with 3-hydroxy-3-methylglutaryl coenzyme a reductase inhibitors in dogs

Cited by 97 publications

References 18 publications

Deficiency of Niemann-Pick C1 Like 1 Prevents Atherosclerosis in ApoE ^−/− Mice

Deficiency of Niemann-Pick C1 Like 1 Prevents Atherosclerosis in ApoE ^−/− Mice

Efficacy and Safety of Ezetimibe Coadministered With Atorvastatin or Simvastatin in Patients With Homozygous Familial Hypercholesterolemia

Ezetimibe, a Potent Cholesterol Absorption Inhibitor, Normalizes Combined Dyslipidemia in Obese Hyperinsulinemic Hamsters

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The synergistic hypocholesterolemic activity of the potent cholesterol absorption inhibitor, ezetimibe, in combination with 3-hydroxy-3-methylglutaryl coenzyme a reductase inhibitors in dogs

Cited by 97 publications

References 18 publications

Deficiency of Niemann-Pick C1 Like 1 Prevents Atherosclerosis in ApoE −/− Mice

Deficiency of Niemann-Pick C1 Like 1 Prevents Atherosclerosis in ApoE −/− Mice

Efficacy and Safety of Ezetimibe Coadministered With Atorvastatin or Simvastatin in Patients With Homozygous Familial Hypercholesterolemia

Ezetimibe, a Potent Cholesterol Absorption Inhibitor, Normalizes Combined Dyslipidemia in Obese Hyperinsulinemic Hamsters

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Deficiency of Niemann-Pick C1 Like 1 Prevents Atherosclerosis in ApoE ^−/− Mice

Deficiency of Niemann-Pick C1 Like 1 Prevents Atherosclerosis in ApoE ^−/− Mice