Efficacy Of HMG-CoA Reductase Inhibitors Research Articles

Efficacy of HMG-CoA reductase inhibitors in the prevention of cerebrovascular attack in 1016 patients older than 75 years among 4014 type 2 diabetic individuals

Background/objectivesHMG-CoA reductase inhibitors (statins) reduce ischemic heart disease (IHD) in middle-aged diabetic individuals, and LDL-cholesterol (LDL-C) is a risk factor. However, their preventive effects on cerebrovascular attack (CVA) have not been identified in elderly, especially in elderly ≥75years (late elderly), who account for approximately 30% of diabetic individuals in Japan. Randomized controlled studies of statins for late elderly are difficult to carry out, because many co-morbidities in elderly disrupt randomized controlled conditions. MethodsWe performed a prospective cohort study (Japan Cholesterol and Diabetes Mellitus Study) with 5.5years of follow-up since 2004. A total of 4014 type 2 diabetic patients without previous IHD or CVA (n=1936 women; age=67.4±9.5years; ≥75years: n=1016) were enrolled, while 405 patients were registered as sub-cohort patients. We recorded detailed information on medications and laboratory data after every change in medication in patients of sub-cohort and suffered from IHD or CVA. We subdivided statin-users into prevalent, new and non-users. ResultsA total of 104 CVAs occurred during 5.5-years. Plasma HDL-C level was inversely correlated with CVA in patients ≥65years. In case–control study, among patients who were not prescribed statins, CVA increased in age-dependent manner. CVA incidence was lower in prevalent and new statin-users than in non-users (hazard ratio [HR]:0.46, 0.523), especially in late elderly (HR: 0.51, 0.21). Statins reduced CVAs mainly due to a direct effect and partially due to the effects of HDL-C and glucose metabolism. No significant differences were observed between statins. ConclusionStatins prevented CVA in middle-aged, elderly and late elderly diabetic patients via a direct effect. This study is the first to demonstrate the usefulness of observational studies for statistically analyzing agents' effects on late elderly.

Evaluation of short-term safety and efficacy of HMG-CoA reductase inhibitors in hypercholesterolemic patients with elevated serum alanine transaminase concentrations: PITCH study (PITavastatin versus atorvastatin to evaluate the effect on patients with hypercholesterolemia and mild to moderate hepatic damage)

We evaluated the safety and efficacy of the 3-hydroxyl-3-methylglutaryl coenzyme A reductase inhibitors atorvastatin and pitavastatin in patients with mild-to-moderate increased levels of hepatic enzymes. In this 12-week, prospective, randomized, open-label, active drug-controlled, and dose-titration study, 189 subjects with elevated low-density lipoprotein cholesterol (≥3.36 mmol/L) and alanine transaminase (ALT; ×1.25≥ and ≤×2.5 ULN; 50-100 IU/L) concentrations, but nonalcoholic and serologically negative for viral hepatitis markers at screening, were randomized to 12 weeks of treatment with pitavastatin 2-4 mg/day (PITA, n= 97) or atorvastatin 10-20 mg/day (ATOR, n= 92). Pitavastatin and atorvastatin equally reduced low-density lipoprotein cholesterol concentrations (-34.6 ± 16.0% and -38.1 ± 16.2%, respectively, P < .0001 each by analysis of variance). Seven (n= 4 PITA, n= 3 ATOR) and 10 (n= 5 PITA, n= 5 ATOR) patients experienced episodes of ALT >100 IU/L at weeks 4 and 12, respectively, with one patient in each group excluded because of severe ALT elevation >3× ULN (>120 IU/L) at week 4. The 135 patients with persistently increased ALT concentrations at screening and randomization showed significant reductions in ALT after 12 weeks of treatment with PITA (n= 68, -8.4%) or ATOR (n= 67, -8.9%; P < .05, analysis of variance). Serial nonenhanced computed tomography in 38 subjects (n= 18 PITA, n= 20 ATOR) showed that both statins reduced the severity of hepatic steatosis, especially in subjects with clear hepatic steatosis at baseline (n= 9 PITA, n= 10 ATOR). Statin treatment of another 38 subjects with spontaneous normalization of ALT at randomization had little effect on ALT levels but did not induce severe ALT elevation (>100 IU/L). Conventional doses of pitavastatin and atorvastatin effectively and safely reduce elevated hepatic enzyme concentrations.

Interactions between the single nucleotide polymorphisms in the homocysteine pathway (MTHFR 677C&gt;T, MTHFR 1298 A&gt;C, and CBSins) and the efficacy of HMG-CoA reductase inhibitors in preventing cardiovascular disease in high-risk patients of hypertension: the GenHAT study

High homocysteine blood concentrations predispose to coronary artery disease and statins influence homocysteine levels. To study whether genes that regulate homocysteine metabolism interact with statins to modify the risk of coronary heart disease (CHD) and other cardiovascular outcomes. The Genetics of Hypertension Associated Treatment is an ancillary study of the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT). The genotyped population in the Lipid-Lowering Trial of Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial included 9624 participants randomly assigned to pravastatin or to usual care. The efficacy of pravastatin in reducing risk of all-cause mortality and CHD was compared among genotype strata (MTHFR 677 CC, CT, and TT, MTHFR 1298 AA, AC, and CC, CBSins DD and I) by examining an interaction term in a proportional hazards model. No evidence existed of a pharmacogenetic effect on statins with the MTHFR 1298 A>C genotype for CHD risk. However, in persons with the CC variant for the MTHFR 677 C>T genotype, a significantly protective effect against CHD [0.71 (95% CI 0.58-0.87)] was shown, although in the CT [1.25 (95% CI 0.97-1.61)] and TT groups [0.80 (95% CI 0.50-1.28)] there were no such effects (interaction hazard ratio P=0.004). The CBSins, I+ variant was associated with a significantly reduced risk for CHD among those on statin treatment [0.58 (95% CI 0.44-0.78)] whereas the DD genotype showed no effect of statin therapy [1.01 (95% CI 0.84-1.20; P=0.002 for interaction]. For the endpoint all-cause mortality, no significant differences in efficacy were noted. Polymorphisms in genes in the homocysteine pathway (MTHFR 677 C>T and CBSins) appear to modify the efficacy of pravastatin in reducing risk of cardiovascular events.

Impact of Genetic Polymorphisms on the Efficacy of HMG-CoA Reductase Inhibitors

Although pharmacologic treatment for cholesterol reduction represents an advance in cardiovascular and atherosclerosis treatment, the benefits of such therapy are still limited because of interindividual variability in the response to these drugs. Disease severity, treatment adherence, physiologic conditions, biologic conditions, and the patient's genetic profile could be cited as important factors in the evaluation of interindividual variability. In regard to the latter consideration, three large groups of genes could be investigated: (i) genes that code for proteins involved in metabolism and/or drug transport, thereby influencing the pharmacokinetics of these compounds; (ii) genes that code for proteins involved in the mechanism of action and/or in the metabolic pathway of drug action, and which therefore influence pharmacodynamics; and (iii) genes that code for proteins involved in direct development of the disease or in intermediate phenotypes. In this review we discuss pharmacogenetic studies of the HMG-CoA reductase inhibitors (statins) and the implications of pharmacogenetic considerations for predicting treatment efficacy and reducing the adverse effects of these drugs. Once new studies have been performed and most of the genetic variability associated with drug action has been revealed, the great challenge will be to apply this knowledge in clinical medicine.

Simvastatin protection against acute immune-mediated glomerulonephritis in mice

In addition to cholesterol lowering, 3-hydroxy-3-nethylglutaryl coenzyme A (HMG-CoA) reductase inhibitors limit inflammatory changes associated with atherosclerosis. There is also support for their use as inhibitors of progression in chronic renal disease, irrespective of cause. In this study, their capacity to limit acute renal inflammation was evaluated. For this purpose, mice were treated with Simvastatin either prior to, at the time of, or shortly after induction of nephrotoxic nephritis. The severity of disease was determined by evaluation of blood urea nitrogen (BUN), proteinuria, and renal histologic changes. The reversibility of benefit was evaluated by the administration of mevalonic acid along with nephrotoxic serum (NTS) and Simvastatin The severity of the acute nephritis, including proteinuria, elevated BUN, and histologic changes, was ameliorated in a dose-dependent manner, when Simvastatin was administered either prior to NTS injection or at the time of NTS injection. By contrast, Simvastatin did not alter the course of established nephritis. Coadministration of mevalonic acid, the immediate substrate following HMG-CoA reductase, abolished Simvastatin's renoprotective effect, indicating that the benefit is, at least in part, due to interference with HMG-CoA reductase and biosynthetic substrates downstream from the enzyme. These findings provide the rationale for the evaluation of the efficacy of HMG-CoA reductase inhibitors in patients with recurrent forms of renal inflammation, to limit the severity of acute exacerbations of disease, prevent renal scarring and slow the rate of progression.

Cost-Effectiveness Analysis of Cholesterol-Lowering Therapies in Spain

To assess the cost efficacy of atorvastatin, simvastatin, lovastatin, fluvastatin, pravastatin, and colestyramine in the reduction of low-density lipoprotein-cholesterol (LDL-C) levels and the cost per patient to achieve the National Cholesterol Education Program Adult Treatment Panel III (NCEP ATP III) therapeutic objectives in Spain. The following treatments were evaluated: atorvastatin, simvastatin, and pravastatin 10-40 mg/day; lovastatin and fluvastatin 20-80 mg/day; and colestyramine 12-24 g/day. The cost effectiveness of these treatments was evaluated, in terms of cost per percentage of LDL-C reduction, by comparing annual treatment costs versus the efficacy of LDL-C reduction. Treatment costs included medication costs (2003 wholesale prices), control measures, and the treatment of adverse affects. The efficacy of HMG-CoA reductase inhibitors (statins) was obtained from a meta-analysis of results obtained from clinical trials published between 1993 and 2003 that met the following criteria: monotherapy; >16 weeks of treatment; randomized allocation of individuals to the intervention and comparator groups; dietary treatment for > or =3 months before administration of medication; and double-blind measurement of outcomes. Average and incremental cost-effectiveness ratios were calculated to assess the efficiency of cholesterol-lowering treatments. Efficacy, in terms of percentage of LDL-C reduction, ranged from 10% for colestyramine 12 g/day to 49% for atorvastatin 40 mg/day. Total annual treatment costs ranged from euro 321 for fluvastatin 20 mg/day to euro 1151 for atorvastatin 40 mg/day. Cost-effectiveness ratios, in terms of cost per percentage of LDL-C reduced, were: euro 11-23 for atorvastatin; euro 12-21 for simvastatin; euro 14-22 for lovastatin; euro 15-24 for fluvastatin; euro 21-42 for pravastatin; and euro 35-46 for colestyramine. Atorvastatin 10 mg/day was the most cost-effective treatment, followed by simvastatin 10 mg/day, lovastatin 20 mg/day, and fluvastatin 20 mg/day. Atorvastatin was the most cost-effective treatment in the achievement of the NCEP ATP III LDL-C reduction objectives in patients with high (<100 mg/dL) and moderate (<130 mg/dL) risk of coronary heart disease (CHD), with a cost per patient of euro 747 and euro 405 per year, respectively. Fluvastatin was the most cost-effective treatment in the achievement of the NCEP ATPIII therapeutic objective in patients with low-risk of CHD (LDL-C <160 mg/dL), with a cost per patient of euro 321. Atorvastatin 10 mg/day was the most cost-effective cholesterol-lowering drug, followed by simvastatin 10 mg/day, lovastatin 20 mg/day, and fluvastatin 20 mg/day. The preferred statin should be atorvastatin in patients with moderate-to-high CHD risk and fluvastatin in patients with low risk for CHD.

Effect of Genetic Polymorphism of OATP-C (SLCO1B1) on Lipid-Lowering Response to HMG-CoA Reductase Inhibitors

The effect of genetic polymorphism of human organic anion transporting polypeptide C (OATP-C) on the lipid-lowering response to 3-hydroxy-3-methylglutaryl-CoA (HMG-CoA) reductase inhibitors was assessed. A retrospective study was conducted on 66 patients who underwent treatment of hyperlipidemia with HMG-CoA reductase inhibitors in a municipal hospital in a community-based cohort of Ehime prefecture in the southern part of Japan. Plasma lipid concentrations before and after administration were analyzed in patients in relation to the 521T/C (Val-174-->Ala) polymorphism in the OATP-C gene (TT: n=44 (66.7%), TC: n=20 (30.3%), CC: n=0 (0.0%), undetermined: n=2 (3.0%)). Total cholesterol level was significantly lowered after treatment with HMG-CoA reductase inhibitors in all patients (p<0.001); moreover, subjects with the 521C allele showed an attenuated total-cholesterol-lowering effect compared with those homozygous for the 521T allele (-22.3+/-8.7% vs. -16.5+/-10.5%, p<0.05). These data suggest that the 521T/C polymorphism of the OATP-C gene modulates the lipid-lowering efficacy of HMG-CoA reductase inhibitors.

2P-0359 Gender-specific efficacy of HMG-CoA reductase inhibitors on the prevention of stroke: A meta-analysis of randomized, placebo-controlled, double-blind trials by gender

2P-0359 Gender-specific efficacy of HMG-CoA reductase inhibitors on the prevention of stroke: A meta-analysis of randomized, placebo-controlled, double-blind trials by gender

2P-0589 Influence of apolipoprotein E polymorphisms on coronary artery disease and on the efficacy of HMG-CoA reductase inhibitors in men

2P-0589 Influence of apolipoprotein E polymorphisms on coronary artery disease and on the efficacy of HMG-CoA reductase inhibitors in men

Efficacy of HMG-CoA reductase inhibitors in treating osteoporosis.

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Lipid-lowering activity of atorvastatin and lovastatin in rodent species: triglyceride-lowering in rats correlates with efficacy in LDL animal models

Since inhibitors of HMG-CoA reductase lower plasma triglycerides rather than cholesterol in rats, we compared the triglyceride-lowering activity of lovastatin in rats to that of atorvastatin, a more potent synthetic inhibitor, prior to evaluating these drugs in established animal models in which low density lipoproteins (LDL) rather than high density lipoproteins (HDL) are the major transporters of plasma cholesterol. Atorvastatin was more efficacious than lovastatin in normal, chow-fed rats, and more potent in rats with endogenous hypertriglyceridemia (sucrose-fed). In hypertriglyceridemic rats plasma apoB concentrations decreased only with atorvastatin (30 mg/kg), and VLDL-triglyceride secretion (Triton method) was also decreased more by atorvastatin. The inactive enantiomer of atorvastatin did not lower plasma triglycerides. Thus, triglyceride-lowering was dependent upon inhibition of HMG-CoA reductase. Liver unesterified cholesterol and cholesteryl esters (mg/g) were increased by both drugs in normal rats but remained unchanged in hypertriglyceridemic rats. In normal, chow-fed guinea pigs atorvastatin was a more potent cholesterol-lowering drug, and unlike lovastatin, lowered plasma triglycerides and VLDL-cholesterol. In casein-fed rabbits with endogenous hypercholesterolemia and in chow-fed rabbits atorvastatin lowered LDL-cholesterol more potently than lovastatin, but in chow-fed rabbits neither drug had an effect on the in vivo rate of VLDL-lipid secretion, suggesting that efficacy was due to inhibition of direct LDL production and/or enhanced LDL clearance. We conclude that normal rats can be used as a preclinical tool to assess the efficacy of HMG-CoA reductase inhibitors since triglyceride-lowering correlates with cholesterol-lowering in LDL animal models. In this regard atorvastatin is a more potent hypolipidemic agent than lovastatin in animals. A common but not sole mechanism for these drugs may be direct inhibition of the hepatic production of the major apoB-containing lipoprotein in a given species, e.g. VLDL in rats and LDL in guinea pigs and rabbits.