Differential Regulation of Lipoprotein Kinetics by Atorvastatin and Fenofibrate in Subjects With the Metabolic Syndrome

Watts, Gerald F.; Barrett, P. Hugh R.; Ji, Juying; Serone, Adrian; Chan, Dick C.; Croft, Kevin D.; Loehrer, F.; Johnson, A. G.

doi:10.2337/diabetes.52.3.803

Cited by 203 publications

(202 citation statements)

References 57 publications

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“…This contrasts with the concept that fenofibrate increases Apoa1 expression, as observed in mice [12]. Interestingly, fenofibrate has been reported to increase both the production and catabolism of apoA-I [32]. The Data are presented as median (IQR) and treatment effect as median difference (95% CI) of change (%) during the study.…”

Section: Discussioncontrasting

confidence: 45%

“…Thus, fenofibrate corrects the dominant defect in diabetic dyslipidaemia. Fenofibrate markedly increases the catabolism of VLDL1 particles and also the fractional transfer rate to VLDL2, while it has no effect on the production rates of VLDL1 triacylglycerol and apoB in patients with metabolic syndrome [32]. This increase in catabolism of VLDL particles occurs via PPARα activation, mediated by an increase in LPL activity together with a decrease in apoC-III synthesis.…”

Section: Discussionmentioning

confidence: 96%

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Long-term effects of fenofibrate on VLDL and HDL subspecies in participants with type 2 diabetes mellitus

et al. 2007

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Aims/hypothesis Low HDL-cholesterol (HDL-C) is frequently accompanied by high triacylglycerol levels in diabetic dyslipidaemia, increasing the risk of CHD. In the Fenofibrate Intervention and Event Lowering in Diabetes (FIELD) study, fenofibrate treatment lowered triacylglycerol levels, but the initial 5% increase in HDL-C attenuated over 5 years. We explored the changes in VLDL and HDL subspecies during fenofibrate treatment in a statin-free FIELD cohort. Methods We randomised 171 participants with type 2 diabetes mellitus, who had been recruited to the FIELD study in Helsinki, to micronised fenofibrate (200 mg/day) or placebo in double-blind study design. VLDL and HDL subspecies were separated by ultracentrifugation at baseline and at the second and fifth year. Apolipoprotein (apo)A-I and apoA-II were measured by immunoturbidometric methods and lipoprotein (Lp)A-I and LpAI-AII particles by differential immunoassay. Results Fenofibrate reduced plasma triacylglycerol levels by 26%, resulting from a marked reduction in VLDL1 triacylglycerol (0.62 vs 0.29 mmol/l, p<0.001). Fenofibrate caused an increase in LDL size (Δ0.80 nm, p<0.001). HDL-C was similar between the groups. HDL2-C was decreased by fenofibrate (−27.5% at 5th year, p<0.001) and HDL3-C increased (13.0% at 5th year, p<0.001). Fenofibrate had no effect on apoA-I, whereas apoA-II increased. Thus, LpA-I decreased while LpAI-AII increased. Activities of cholesteryl ester transfer protein, phospholipids transfer protein and lecithin:cholesterylacyl transferase were unchanged by fenofibrate. High homocysteine levels were associated with a slight decrease in HDL-C and apoA-I. Conclusions/interpretation Fenofibrate markedly reduced large VLDL particles and produced a clear shift in HDL subspecies towards smaller particles. The HDL3-C increase in conjunction with unchanged apoA-II levels is a dilemma with regard to cardiovascular disease.

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Section: Discussioncontrasting

confidence: 45%

Section: Discussionmentioning

confidence: 96%

Long-term effects of fenofibrate on VLDL and HDL subspecies in participants with type 2 diabetes mellitus

et al. 2007

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“…The first analysis used a previously described model 18 with a total VLDL tracer/tracee data set created by taking the weighted mean of the VLDL1 and VLDL2 tracer/tracee data. A confirmatory analysis was conducted 19 using the model shown in Figure 1.…”

Section: Kinetic Analysismentioning

confidence: 99%

Complete Deficiency of the Low-Density Lipoprotein Receptor Is Associated With Increased Apolipoprotein B-100 Production

Millar

Maugeais

Ikewaki

et al. 2005

ATVB

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Objective-We addressed the role of the low-density lipoprotein (LDL) receptor in determining clearance rates and production rate (PR) of apolipoprotein B (apoB) in humans. Methods and Results-Kinetic studies using endogenous labeling of apoB with deuterated leucine were performed in 7 genetically defined patients with homozygous familial hypercholesterolemia (FH) and compared with 4 controls. The fractional catabolic rates (FCR) and PRs for apoB were determined by multicompartmental modeling. In addition to the role of mediating clearance of apoBcontaining lipoproteins, a role for the LDL receptor in regulating the hepatic production rate (PR) of VLDL apoB has been proposed. 4,5 Williams et al 4 observed that blocking LDL receptor on the surface of the HepG2 cells affected apoB secretion. This led them to conclude that there can be reuptake of newly secreted apoB from hepatocytes by the LDL receptor. Twisk et al 5 studied apoB secretion in vitro using primary hepatocyte cultures from Ldlr Ϫ/Ϫ and wild-type mice. They found that hepatocytes from Ldlr Ϫ/Ϫ mice had reduced intracellular degradation resulting in an increased PR of apoB, which led to their hypothesis that the LDL receptor targets apoB for degradation within the secretory pathway. 5 In vivo studies using the Watanabe heritable hyperlipidemic (WHHL) rabbit showed no effect of LDL receptor Original

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“…LPL activity in postheparin plasma was not affected by the treatment. Additionally, it has been shown (31,32) that atorvastatin treatment resulted in an increase in fractional catabolic rate of apoB-containing lipoproteins but no change in the apoB production rate.…”

mentioning

confidence: 99%

Atorvastatin Decreases Apolipoprotein C-III in Apolipoprotein B-Containing Lipoprotein and HDL in Type 2 Diabetes

Dallinga‐Thie

Berk-Planken²,

Bootsma³

et al. 2004

Diabetes Care

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OBJECTIVE -Apolipoprotein (apo)C-III is a constituent of HDL (HDL apoC-III) and of apoB-containing lipoproteins (LpB:C-III). It slows the clearance of triglyceride-rich lipoproteins (TRLs) by inhibition of the activity of the enzyme lipoprotein lipase (LPL) and by interference with lipoprotein binding to cell-surface receptors. Elevated plasma LpB:C-III is an independent risk factor for cardiovascular disease. We studied the effect of atorvastatin on plasma LpB:C-III and HDL apoC-III. RESEARCH DESIGN AND METHODS-We studied the effect of 30 weeks' treatment with 10 and 80 mg atorvastatin on plasma apoC-III levels in a randomized, double-blind, placebo-controlled trial involving 217 patients with type 2 diabetes and fasting plasma triglycerides between 1.5 and 6.0 mmol/l.RESULTS -Baseline levels of total plasma apoC-III, HDL apoC-III, and LpB:C-III were 41.5 Ϯ 10.0, 17.7 Ϯ 5.5, and 23.8 Ϯ 7.7 mg/l, respectively. Plasma apoC-III was strongly correlated with plasma triglycerides (r ϭ 0.74, P Ͻ 0.001). Atorvastatin 10-and 80-mg treatment significantly decreased plasma apoC-III (atorvastatin 10 mg, 21%, and 80 mg, 27%), HDL apoC-III (atorvastatin 10 mg, 22%, and 80 mg, 28%) and LpB:C-III (atorvastatin 10 mg, 23%, and 80 mg, 28%; all P Ͻ 0.001). The decrease in plasma apoC-III, mainly in LpB:C-III, strongly correlated with a decrease in triglycerides (atorvastatin 10 mg, r ϭ 0.70, and 80 mg, r ϭ 0.78; P Ͻ 0.001). Atorvastatin treatment also leads to a reduction in the HDL apoC-III-to-HDL cholesterol and HDL apoC-III-to-apoA-I ratios, indicating a change in the number of apoC-III per HDL particle (atorvastatin 10 mg, Ϫ21%, and 80 mg, Ϫ31%; P Ͻ 0.001).CONCLUSIONS -Atorvastatin treatment resulted in a significant dose-dependent reduction in plasma apoC-III, HDL apoC-III, and LpB:C-III levels in patients with type 2 diabetes. These data indicate a potentially important antiatherogenic effect of statin treatment and may explain (part of) the triglyceride-lowering effect of atorvastatin.

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Differential Regulation of Lipoprotein Kinetics by Atorvastatin and Fenofibrate in Subjects With the Metabolic Syndrome

Cited by 203 publications

References 57 publications

Long-term effects of fenofibrate on VLDL and HDL subspecies in participants with type 2 diabetes mellitus

Long-term effects of fenofibrate on VLDL and HDL subspecies in participants with type 2 diabetes mellitus

Complete Deficiency of the Low-Density Lipoprotein Receptor Is Associated With Increased Apolipoprotein B-100 Production

Atorvastatin Decreases Apolipoprotein C-III in Apolipoprotein B-Containing Lipoprotein and HDL in Type 2 Diabetes

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