Prediction of the therapeutic response to simvastatin by pretreatment lipid concentrations in 2082 subjects

Miserez, André R.; Rossi, F. A.; Keller, Ulrich

doi:10.1007/bf00199871

Cited by 20 publications

(6 citation statements)

References 31 publications

(30 reference statements)

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“…Thus, subjects with the highest LDL apoB concentrations and the lowest catabolic rates experienced the most pronounced increase in LDL apoB catabolism during atorvastatin treatment. This suggests that the extent of increase in LDL catabolism secondary to statins is dependent on the baseline metabolic state and offers an explanation for the previous observation of a correlation between baseline LDL cholesterol concentrations and the extent of their decrease during simvastatin therapy (41). However, two additional mechanisms contributed to the lipid-lowering mechanism of atorvastatin in our study.…”

Section: Discussionsupporting

confidence: 73%

Effects of atorvastatin versus fenofibrate on apoB-100 and apoA-I kinetics in mixed hyperlipidemia

Bilz

Wagner

Schmitz

et al. 2004

Journal of Lipid Research

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Kinetics of apo B and apo AI were assessed in 8 patients with mixed hyperlipidemia at baseline and after 8 weeks of atorvastatin 80 mg q.d. and micronised fenofibrate 200 mg q.d. in a cross-over study. Both increased hepatic production and decreased catabolism of VLDL accounted for elevated cholesterol and triglyceride concentrations at baseline. Atorvastatin significantly decreased triglyceride, total, VLDL and LDL cholesterol and apo B concentrations ( ؊ 65%, ؊ 36%, ؊ 57%, ؊ 40% and ؊ 33%, respectively, P Ͻ 0.05). Kinetic analysis revealed that atorvastatin stimulated the catabolism of apo B containing lipoproteins, enhanced the delipidation of VLDL 1 and decreased VLDL 1 production. Fenofibrate lowered triglycerides and VLDL cholesterol ( ؊ 57% and ؊ 64%, respectively, P Ͻ 0.05) due to enhanced delipidation of VLDL 1 and VLDL 2 and increased VLDL 1 catabolism. Changes of HDL particle composition accounted for the increase of HDL cholesterol during atorvastatin and fenofibrate (18% and 23%, P Ͻ 0.01). Only fenofibrate increased apo AI concentrations through enhanced apo AI synthesis (45%, P Ͻ 0.05). We conclude that atorvastatin exerts additional beneficial effects on the metabolism of apo B containing lipoproteins unrelated to an increase in LDL receptor activity. Fenofibrate but not atorvastatin increases apo AI production and plasma turnover.

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Section: Discussionsupporting

confidence: 73%

Effects of atorvastatin versus fenofibrate on apoB-100 and apoA-I kinetics in mixed hyperlipidemia

Bilz

Wagner

Schmitz

et al. 2004

Journal of Lipid Research

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“…In contrast, TAK‐475 did not affect plasma HDL cholesterol in beagle dogs (Table 1). In studies using patients with a relatively high HDL cholesterol level, HMG‐CoA reductase inhibitors have been reported as reducing or tending to reduce HDL cholesterol, although in patients with a low HDL cholesterol level some HMG‐CoA reductase inhibitors increase the level of this lipoprotein (Miserez et al ., 1994; Narita et al ., 1997).…”

Section: Discussionmentioning

confidence: 99%

Lipid‐lowering properties of TAK‐475, a squalene synthase inhibitor, in vivo and in vitro

Nishimoto

Amano

Tozawa

et al. 2003

British J Pharmacology

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1 Squalene synthase is the enzyme that converts farnesyl pyrophosphate to squalene in the cholesterol biosynthesis pathway. We examined the lipid-lowering properties of 1-[[(3R,5S)-1-(3-acetoxy-2,2-dimethylpropyl)-7-chloro-5-(2,3-dimethoxyphenyl)-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-yl]acetyl]piperidine-4-acetic acid (TAK-475), a novel squalene synthase inhibitor. 2 TAK-475 inhibited hepatic cholesterol biosynthesis in rats (ED 50 , 2.9 mg kg À1 ) and showed lipidlowering effects in beagle dogs, marmosets, cynomolgus monkeys and Wistar fatty rats. 3 In marmosets, TAK-475 (30, 100 mg kg À1 , p.o., for 4 days) lowered both plasma non-high-density lipoprotein (HDL) cholesterol and triglyceride, but did not affect plasma HDL cholesterol. On the other hand, atorvastatin (10, 30 mg kg À1 , p.o., for 4 days) lowered the levels of all these lipids. A correlation between decrease in triglyceride and increase in HDL cholesterol was observed, and TAK-475 increased HDL cholesterol with a smaller decrease in triglyceride than did atorvastatin. 4 TAK-475 (60 mg kg À1 , p.o., for 15 days) suppressed the rate of triglyceride secretion from the liver in hypertriglyceridemic Wistar fatty rats, which show an enhanced triglyceride secretion rate from the liver compared with their lean littermates. 5 In HepG2 cells, TAK-475 and its pharmacologically active metabolite, T-91485, increased the binding of 125 I-low-density lipoprotein (LDL) to LDL receptors. 6 These results suggest that TAK-475 has clear hypolipidemic effects in animals via inhibition of hepatic triglyceride secretion and upregulation of LDL receptors, and that TAK-475 might increase HDL cholesterol by decreasing triglyceride. Thus, TAK-475 is expected to be useful for the treatment of dyslipidemia.

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“…In two cases (0.1%), serum CK increased to slightly above the upper limit of normal. No cases of myopathy were observed in this trial 65 …”

Section: Data From Large‐scale Clinical Trialsmentioning

confidence: 56%

“…Dose Dependency. The incidence of myotoxic adverse reactions related to HMG‐CoA reductase inhibitor therapy is dose‐dependent—or, more appropriately, plasma concentration‐related 65,69,70 . For example, in a recently concluded clinical trial 69 in which simvastatin was given in doses of 40, 80, and 160 mg, myopathy, elevated CK levels, and muscle aches were more common at the 160‐mg dose level.…”

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confidence: 99%

Rhabdomyolysis and Satin Therapy: Relevance to the Elderly

Sica

Gehr

2002

American J Geri Cardiology

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A recent debate has emerged as to the risk-benefit ratio of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors (statins). This debate has centered on the withdrawal of the HMG-CoA reductase inhibitor cerivastatin (Baycol). Its withdrawal was prompted by an unacceptably high rate of rhabdomyolysis associated with its use. The development of rhabdomyolysis in cerivastatin-treated patients surprised few, since myotoxicity is a class effect with HMG-CoA reductase inhibitors. What has sprung from the cerivastatin experience, though, is the concept of "guilt by association"; thus, other members of this class are now viewed in a similarly negative light. Such misgivings are understandable, but to a degree may be ill-advised, since differences exist in the risk and therefore the rate of rhabdomyolysis occurrence among the various HMG-CoA reductase inhibitors. In this regard, pravastatin and fluvastatin are least likely to provoke muscle cell damage, which, at least in part, relates to their not being metabolized by the cytochrome P-450 (CYP) 3A4 pathway. When muscle damage does occur with HMG-CoA reductase inhibitors, it is commonly the result of drug-drug interactions rather than a specific adverse response to HMG-CoA reductase inhibitor monotherapy. Such drug-drug interactions inevitably result in higher plasma concentrations of an HMG-CoA reductase inhibitor and thereby an increased risk of myotoxicity. A growing consensus supports an expanded use of HMG-CoA reductase inhibitors in elderly patients. Polypharmacy and altered drug metabolism both put the elderly patient at increased risk of myotoxicity when drugs in the HMG-CoA reductase inhibitor class are administered. Physicians must take many factors into account when selecting a member of the HMG-CoA reductase inhibitor class, particularly as relates to their use in the multiply medicated elderly patient.

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Prediction of the therapeutic response to simvastatin by pretreatment lipid concentrations in 2082 subjects

Cited by 20 publications

References 31 publications

Effects of atorvastatin versus fenofibrate on apoB-100 and apoA-I kinetics in mixed hyperlipidemia

Effects of atorvastatin versus fenofibrate on apoB-100 and apoA-I kinetics in mixed hyperlipidemia

Lipid‐lowering properties of TAK‐475, a squalene synthase inhibitor, in vivo and in vitro

Rhabdomyolysis and Satin Therapy: Relevance to the Elderly

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