Low-dose Pravastatin Research Articles

Statins in Ischemic Stroke Prevention: What Have We Learned in the Post-SPARCL (The Stroke Prevention by Aggressive Reduction in Cholesterol Levels) Decade?

We describe the current status of lipid-lowering therapies for ischemic stroke prevention. The SPARCL trial published in 2006 has been a landmark study in vascular neurology. The trial demonstrated that high-dose atorvastatin prevents recurrent stroke, and led the AHA/ASA to recommend statin therapy for patients with stroke or TIA of atherosclerotic origin. Recently, the J-STARS study demonstrated that therapy with low-dose pravastatin reduced atherothrombotic infarction incidence among patients with prior ischemic stroke. Besides, several trials have shown improved stroke outcomes with non-statin lipid-lowering medications: IMPROVE-IT with ezetimibe on top of simvastatin and PCSK9 inhibitors-FOURIER with evocolumab and ODYSSEY-OUTCOMES with alirocumab-on top of statin therapy. LDL-cholesterol remains the primary lipid treatment target for reduction of stroke risk. Randomized trials have shown that each reduction of 40mg/dL in the level of LDL-cholesterol reduces the stroke risk by approximately one quarter, and further, reductions in LDL-cholesterol levels have shown to produce additional reductions in stroke risk. Currently, we have evidence of benefit for adding non-statin lipid-modifying therapies to statins to reduce stroke risk. Surely, these novel strategies to reduce residual lipidic risk will provide future benefits on stroke prevention.

Long-Term Effect of Pravastatin on Carotid Intima-Media Complex Thickness: The J-STARS Echo Study (Japan Statin Treatment Against Recurrent Stroke).

The effect of statins on progression of carotid intima-media complex thickness (IMT) has been shown exclusively in nonstroke Western patients. This study aimed to determine the effect of low-dose pravastatin on carotid IMT in Japanese patients with noncardioembolic ischemic stroke. This is a substudy of the J-STARS trial (Japan Statin Treatment Against Recurrent Stroke), a multicenter, randomized, open-label, parallel-group trial to examine whether pravastatin reduces stroke recurrence. Patients were randomized to receive pravastatin (10 mg daily, usual dose in Japan; pravastatin group) or not to receive any statins (control group). The primary outcome was IMT change of the common carotid artery for a 5-year observation period. IMT change was compared using mixed-effects models for repeated measures. Of 864 patients registered in this substudy, 71 without baseline ultrasonography were excluded, and 388 were randomly assigned to the pravastatin group and 405 to the control group. Baseline characteristics were not significantly different, except National Institutes of Health Stroke Scale scores (median, 0 [interquartile range, 0-2] versus 1 [interquartile range, 0-2]; P=0.019) between the 2 groups. Baseline IMT (mean±SD) was 0.887±0.155 mm in the pravastatin group and 0.887±0.152 mm in the control group (P=0.99). The annual change in the IMT at 5-year visit was significantly reduced in the pravastatin group as compared with that in the control group (0.021±0.116 versus 0.040±0.118 mm; P=0.010). The usual Japanese dose of pravastatin significantly reduced the progression of carotid IMT at 5 years in patients with noncardioembolic stroke. URL: http://www.clinicaltrials.gov. Unique identifier: NCT00361530.

Abstract TMP94: Treatment With Pravastatin Decreases the Level of Serum Hs-CRP in Ischemic Stroke Patients - Hs-CRP Sub-study of the Japan Statin Treatment Against Recurrent Stroke (J-STARS)

Background and Purpose: Serum hs-CRP level has been shown as a reliable marker of vascular inflammation. One of the pleiotropic effect of statin could be anti-inflammation shown as decrease of hs-CRP level. However, it remains unclear whether statin decreases the hs-CRP level in ischemic stroke patients. This is a sub-study of J-STARS, and the primary outcome was change of hs-CRP after statin treatment. The secondary outcome was whether mean hs-CRP level during follow-up period is associated with recurrent stroke and transient ischemic attack (TIA), and all vascular event. Methods: Among 1578 patients enrolled in J-STARS, 1095 were included in Hs-CRP sub-study. Those were randomly assigned to pravastatin (n=545) or control group (n=550). The pravastatin group patients received 10 mg of pravastatin/day. Blood samples were obtained at baseline and 2, 6 months, 2 and 5 years after randomization. Hs-CRP levels were log-transformed for statistical analysis. Results: Baseline average hs-CRP level was 691 ng/L. Hs-CRP level was significantly decreased 2 months after pravastatin treatment, and remained significantly lower until the end of study. However, hs-CRP level did not show significant change in the control group. One SD increase of mean hs-CRP level during follow-up tended to increase the risk of stroke/TIA recurrence (HR 1.18, 95%CI 0.99-1.40, p=0.065) and significantly increased the risk of all vascular events (HR1.28, 95%CI 1.10-1.49, p<0.01). After adjustment with risk factors, the association between 1SD increase of hs-CRP and all vascular events remained significant. When cut-off level of hs-CRP level during follow-up was determined as 1000 ng/L, higher CRP level significantly increased the risk of stroke/TIA (HR 1.47, 95%CI 1.04-2.09, p=0.03) and all vascular events (HR 1.63, 95%CI 1.20-2.21, p<0.01). After adjustment, the association with stroke/TIA was of borderline significance (p=0.06) but remained significant with all vascular events (p=0.01). Conclusion: Low dose pravastatin significantly decreased the level of hs-CRP in ischemic stroke patients. High hs-CRP level during follow-up, particularly beyond 1000 ng/l, tended to increase the stroke/TIA recurrence and was significantly associated with the risk of all vascular events.

The Japan Statin Treatment Against Recurrent Stroke (J-STARS): A Multicenter, Randomized, Open-label, Parallel-group Study

BackgroundAlthough statin therapy is beneficial for the prevention of initial stroke, the benefit for recurrent stroke and its subtypes remains to be determined in Asian, in whom stroke profiles are different from Caucasian. This study examined whether treatment with low-dose pravastatin prevents stroke recurrence in ischemic stroke patients. MethodsThis is a multicenter, randomized, open-label, blinded-endpoint, parallel-group study of patients who experienced non-cardioembolic ischemic stroke. All patients had a total cholesterol level between 4.65 and 6.21mmol/L at enrollment, without the use of statins. The pravastatin group patients received 10mg of pravastatin/day; the control group patients received no statins. The primary endpoint was the occurrence of stroke and transient ischemic attack (TIA), with the onset of each stroke subtype set to be one of the secondary endpoints. FindingAlthough 3000 patients were targeted, 1578 patients (491 female, age 66.2years) were recruited and randomly assigned to pravastatin group or control group. During the follow-up of 4.9±1.4years, although total stroke and TIA similarly occurred in both groups (2.56 vs. 2.65%/year), onset of atherothrombotic infarction was less frequent in pravastatin group (0.21 vs. 0.64%/year, p=0.0047, adjusted hazard ratio 0.33 [95%CI 0.15 to 0.74]). No significant intergroup difference was found for the onset of other stroke subtypes, and for the occurrence of adverse events. InterpretationAlthough whether low-dose pravastatin prevents recurrence of total stroke or TIA still needs to be examined in Asian, this study has generated a hypothesis that it may reduce occurrence of stroke due to larger artery atherosclerosis. FundingThis study was initially supported by a grant from the Ministry of Health, Labour and Welfare, Japan. After the governmental support expired, it was conducted in collaboration between Hiroshima University and the Foundation for Biomedical Research and Innovation.

Risk reductions for cardiovascular disease with pravastatin treatment by dyslipidemia phenotype: A post hoc analysis of the MEGA Study

BackgroundThe beneficial effect of statins for cardiovascular disease (CVD) prevention has been well established. However, the effectiveness among different phenotypes of dyslipidemia has not been confirmed. ObjectiveWe evaluated the effect of pravastatin on the incidence of CVD in relation to the phenotype of dyslipidemia. MethodsThe MEGA Study evaluated the effect of low-dose pravastatin on primary prevention of CVD in 7832 Japanese patients, who were randomized to diet alone or diet plus pravastatin and followed for more than 5 years. These patients were classified into phenotype IIa (n=5589) and IIb (n=2041) based on the electrophoretic pattern for this post hoc analysis. ResultsIn the diet group there was no significant difference in the incidence of coronary heart disease (CHD), stroke, CVD, and total mortality between the two phenotypes. Phenotype IIb patients, compared to phenotype IIa, had lower levels of high-density lipoprotein cholesterol (HDL-C) and a significantly higher incidence of CVD in relation to a low HDL-C level (<47.5mg/dL; p=0.02). Furthermore, pravastatin decreased the relative risk for each major endpoint in both type IIa and type IIb dyslipidemia. Significant risk reductions were observed for CHD by 38% (p=0.04) and CVD by 31% (p=0.02) in type IIa dyslipidemia but not in phenotype IIb. ConclusionPravastatin therapy provided significant risk reductions for CHD and CVD in patients with phenotype IIa dyslipidemia, but not in those with phenotype IIb dyslipidemia.

Effects of Pravastatin and Atorvastatin on HDL Cholesterol and Glucose Metabolism in Patients with Dyslipidemia and Glucose Intolerance: The PRAT Study

While statins have the property of increasing high-density lipoprotein cholesterol (HDL-C) in addition to lowering low-density lipoprotein cholesterol (LDL-C), a potential adverse effect on glucose metabolism has raised a concern over statin therapy. In a comparative trial, we investigated the effects of low-dose pravastatin and atorvastatin on HDL-C and glucose metabolism in patients with elevated LDL-C levels and glucose intolerance. Eligible patients were men aged ≥20 years or postmenopausal women who had LDL-C ≥140 mg/dL, HDL-C <80 mg/dL, and triglycerides <500 mg/dL and who had glucose intolerance. The patients were randomly allocated to either pravastatin (10 mg/day) or atorvastatin (10 mg/day) treatment for 12 months in an unblinded fashion. The percent changes from the baseline were compared between the treatments. Of 202 patients who were randomized to either of the two treatments, 195 patients started the study medication, and 187 patients underwent the follow-up measurements at 6 or 12 months (pravastatin, n= 93; atorvastatin, n= 94). HDL-C increased by 4.3% (p= 0.03) in the pravastatin group and by 5.8% (p=0.0005) in the atorvastatin group and showed no between-group difference (p= 0.38). LDL-C decreased substantially in both groups (pravastatin, 21.5%; atorvastatin, 35.5%), and the decrease was much greater in the atorvastain group (p<0.0001). HbA1c slightly increased in both groups, but showed no measurable difference in the increase between the two treatments (p=0.30). Pravastatin and atorvastatin of 10 mg per day each increased HDL-C by almost the same extent. These two statins did not show a differential effect on glucose metabolism.

Double-Dose Pravastatin Versus Add-On Ezetimibe with Low-Dose Pravastatin -Effects on LDL Cholesterol, Cholesterol Absorption, and Cholesterol Synthesis in Japanese Patients with Hypercholesterolemia (PEAS study)

This study compared the effect of doubling the dose of pravastatin with that of adding ezetimibe to low-dose pravastatin on the LDL cholesterol (LDL-C) level and on cholesterol absorption and synthesis markers. The tolerability of the 2 regimens was also compared. This was a multicenter, open-label, parallel-group trial. Subjects were aged from 20 to 74 years and had an LDL-C ≥ 120 mg/dL despite pravastatin therapy at 5-10 mg/day. They were randomly allocated to receive either add-on ezetimibe (10 mg/day) or double-dose pravastatin, and follow-up was performed for 12 weeks. The primary endpoints were the changes of LDL-C and apolipoprotein (apo) B levels after 12 weeks of treatment. Cholesterol absorption and synthesis markers were also determined. LDL-C and apo B decreased by 16% and 14% in the ezetimibe add-on group versus 5.9% and 4.4%, respectively, in the pravastatin double-dose group. The between-group differences of these decreases were highly significant. Cholesterol absorption markers (sitosterol, campesterol, and cholestanol) were reduced by 48%, 36%, and 10%, respectively, in the ezetimibe add-on group, and were increased by 17%, 14%, and 6%, respectively, in the pravastatin double-dose group. Lathosterol (a cholesterol synthesis marker) increased by 76% in the ezetimibe add-on group and by 24% in the pravastatin double-dose group. The difference was statistically significant. No serious adverse effect was observed in either group. Adding ezetimibe to low-dose pravastatin achieves greater decreases in LDL-C, apo B, and cholesterol absorption markers than doubling the dose of pravastatin.

The Effect of Low-Dose Pravastatin in Metabolic Syndrome for Primary Prevention of Cardiovascular Disease in Japan

The Management of Elevated Cholesterol in the Primary Prevention Group of Adult Japanese (MEGA) Study demonstrated the beneficial effect of low-dose pravastatin treatment (10-20 mg/d) on cardiovascular disease (CVD) in Japanese patients with mild-to-moderate hypercholesterolemia. However, it is not known whether mild lipid modification is effective even for patients at high risk. In this study, we evaluated low-dose pravastatin treatment in patients with metabolic syndrome in the MEGA Study. Metabolic syndrome (MetSyn) was defined according to the modified US National Cholesterol Education Program criteria. There were 72 coronary heart disease (CHD) events and 130 CVD events in 2636 patients with MetSyn, and 70 CHD events and 125 CVD events in 5196 patients without MetSyn (hazard ratios 1.85 and 1.90, respectively). No significant risk reduction in CHD was found in the diet plus pravastatin group compared with the diet group patients with MetSyn (hazard ratio .78, P = .29). On the other hand, there was a significant 36% CVD risk reduction (P = .01) in the diet plus pravastatin group compared with the diet group patients with MetSyn, with a small number needed to treat (45). These results indicate that low-dose pravastatin provides a substantial beneficial effect for the prevention of CVD in Japanese patients with MetSyn without known CVD, a population at proportionally high risk in primary prevention.

Low-Dose Pravastatin and Age-Related Differences in Risk Factors for Cardiovascular Disease in Hypercholesterolaemic Japanese

Limited data are available regarding the relationship between age and the effect of HMG-CoA reductase inhibitor (statin) treatment. The aim of the present analysis was to evaluate the relationships between age, baseline patient characteristics, and pravastatin treatment with respect to the development of cardiovascular disease (CVD) in the Management of Elevated Cholesterol in the Primary Prevention Group of Adult Japanese (MEGA) study, a large-scale clinical study conducted in Japanese patients with mild or moderate hyperlipidaemia to evaluate the primary preventive effect of pravastatin against coronary heart disease. To compare the prevalence of CVD risk factors, the incidence of CVD in relation to each risk factor, and final values and changes in lipid parameters, the 7832 patients were classified into six age groups: <45, 45-49, 50-54, 55-59, 60-64 and ≥65 years. The relationship between pravastatin (10-20 mg/day) treatment efficacy and aging and the incidence of events in relation to the age groups were compared using the multivariable Cox proportional hazards model. The prevalences of diabetes mellitus and hypertension were higher in older men than in younger men, while the prevalences of smoking and obesity were higher in younger men. However, a similar difference in risk factors was not seen in women. High-density lipoprotein cholesterol was higher in women than in men across all age groups. Triglycerides were higher in younger men than in older men and all groups of women. The mean follow-up levels of total cholesterol and low-density lipoprotein cholesterol were lower in older patients than in younger patients. Pravastatin (10-20 mg/day) reduced the risk of CVD by about 30-40% across all age groups, and there was no difference between men and women. Of particular note in this analysis, CVD risk was markedly reduced in older women compared with younger women (53% vs 30% in women aged ≥65 vs ≥45 years). A similar satisfactory risk reduction for CVD was achieved with low-dose pravastatin in all men and in older women in particular, despite differences in the prevalence of risk factors. ClinicalTrials.gov Identifier: NCT00211705.

Management of Elevated Cholesterol in the primary prevention Group of Adult Japanese (MEGA) Study assists the view that a fasting plasma glucose level ≥100 mg/dL increases cardiovascular risk.

Aims/Introduction: To evaluate the relationship between fasting plasma glucose (FPG) level and cardiovascular disease in patients with hypercholesterolemia, and to evaluate the effect of pravastatin on risk reduction in a post-hoc analysis of the large-scale Management of Elevated Cholesterol in the primary prevention Group of Adult Japanese (MEGA) Study. A total of 7832 patients were randomized to diet alone or diet plus low-dose pravastatin (10-20 mg/day, average 8.3 mg during follow-up periods) and followed for >5 years. In this analysis, the relationship between FPG and risk of cardiovascular disease events over 5 years were studied in 6673 patients with recorded baseline FPG levels by using the multivariable Cox proportional hazards model with the restricted quadratic spline based on three knots for FPG quartiles. The spline curve showed an obvious sharp increased risk from a FPG of ≥100 mg/dL. The spline curve in the diet plus pravastatin group was consistently lower than in the diet group, regardless of the FPG level. The risk of cardiovascular disease appears to increase when FPG is ≥100 mg/dL, with a sharp increased risk found above this level in patients with hypercholesterolemia. Statin treatment seems to be beneficial to reduce cardiovascular disease risk in this population. This trial was registered with ClinicalTrials.gov (no. NCT00211705). (J Diabetes Invest, doi: 10.1111/j.2040-1124.2011.00121.x, 2011).

Effect of olmesartan and pravastatin on experimental cerebral aneurysms in rats

The major initiation process of intracranial aneurysms is thought to involve endothelial dysfunction due to hemodynamic stress. Angiotensin II type 1 receptor blockers and statins improve vascular endothelium function. The effects of olmesartan and pravastatin were investigated on the development of experimental aneurysms in rats. Eighty-three rats underwent aneurysm induction. Seven groups of 10–14 rats were treated with low or high dose olmesartan, low or high dose pravastatin, low doses of olmesartan and pravastatin, hydralazine, or no drug (control) for 12 weeks, when rats were sacrificed for vascular corrosion casting and scanning electron microscopy. Aneurysmal changes at the anterior cerebral–olfactory artery bifurcation were divided into stages 0 (no abnormality) to III (saccular aneurysm). Systolic arterial blood pressure was elevated over 170 mm Hg in the control, low dose pravastatin, and high dose pravastatin groups, but not in the other groups. The control group demonstrated aneurysmal changes in 100% and stage III in 50% of rats. Aneurysmal changes were observed in most rats in the other groups, but the incidence of stage III was 10% or less. The staging pattern showed significant differences between the groups ( P = 0.028). Pravastatin reduced both stages III and II + III and olmesartan ameliorated stage III, implying that these may prevent aneurysmal formation through acting on different steps. (209 words)

Pravastatin and cardiovascular risk in moderate chronic kidney disease

Objectives To investigate the relation between chronic kidney disease (CKD) and cardiovascular disease (CVD) and retrospectively to evaluate the effect of low dose of pravastatin in Japanese hypercholesterolemic patients with CKD enrolled in the large-scale randomized MEGA Study. Methods In this post hoc analysis, effect of low dose pravastatin treatment (10–20 mg daily) on the primary prevention of the cardiovascular disease and renal function after 5 years was evaluated in 7196 patients with normal kidney function/mild CKD or moderate CKD. Patients were classified based on an estimated glomerular filtration rate (eGFR) ≥60 or 30–<60 mL/min/1.73 m 2 as having normal renal function/mild CKD or moderate CKD, respectively. Since Japanese guidelines do not allow statin use in patients with severe kidney disease, such individuals were excluded. Results The incidence of CVD events was 35–49% higher in patients with moderate CKD than in those with normal renal function/mild CKD. Notably, in the moderate CKD group pravastatin significantly reduced CHD by 48% ( P = 0.02), stroke by 73% ( P < 0.01), CVD by 55% ( P < 0.01), and total mortality by 51% ( P = 0.02). Moreover, the change in eGFR during follow-up in patients with moderate CKD was significantly ( P = 0.03) higher in those assigned to receive diet plus pravastatin (+6.3%) compared with those on diet alone (+5.1%). Conclusions Risk of CVD is higher in patients with moderate CKD compared with those with normal renal function/mild CKD, and was significantly reduced by treatment with pravastatin. Pravastatin also exerted beneficial effects on renal function in patients with moderate CKD.

Metabolic syndrome abating the beneficial effect of pravastatin treatment on adhesion of endothelium by monocytes in subjects with hypercholesterolemia

Statin, a potent lipid-lowering agent, ameliorates the interaction of monocytes and endothelium, a critical step in the atherosclerotic process. However, it remains unclear whether this effect of statin depends on different doses or the presence of metabolic syndrome. In this prospectively double-blind study, 21 hypercholesterolemia subjects, with low-density lipoprotein cholesterol between 130 and 170 mg/dL, received low-dose (10 mg/d) or high-dose (40 mg/d) pravastatin treatment for 8 weeks. We assessed the reduction of monocyte adhesion to cultured endothelium between different-dose groups and the relationship to metabolic syndrome. Total cholesterol and low-density lipoprotein cholesterol were significantly decreased after 40-mg pravastatin treatment (−23.3% ± 3.7%, P < .001 and −28.8% ± 3.0%, P < .001), and the reductions were greater than those in the 10-mg group ( P = .041 and P = .045, respectively). There was no significant difference in monocyte adhesion between high-dose and low-dose pravastatin treatment. When all subjects were divided into an improvement group and a no improvement group, according to the median of change percentage of monocyte adhesion after pravastatin treatment, there were significantly more subjects with metabolic syndrome in the no improvement than the improvement group (6 vs 1 person, P =.024). Using logistic regression analysis, metabolic syndrome, rather than dose effect of pravastatin, was an independent predictor of interaction between monocytes and endothelium (95% confidence interval = 0.001-0.865, P = .041). Attenuating adhesion between monocytes and endothelium is altered by the presence of metabolic syndrome when hypercholesterolemia subjects receive pravastatin treatment.

Pravastatin reduces the risk for cardiovascular disease in Japanese hypercholesterolemic patients with impaired fasting glucose or diabetes: Diabetes subanalysis of the Management of Elevated Cholesterol in the Primary Prevention Group of Adult Japanese (MEGA) Study

Diabetes mellitus (DM) is a major risk factor for cardiovascular disease (CVD) in patients with no history of CVD. Evidence for the effect of statins on CVD in the diabetic population in low-risk populations (e.g., Japanese) is limited. We evaluated the effect of pravastatin on risk reduction of CVD related to baseline glucose status in a primary prevention setting. The Management of Elevated Cholesterol in the Primary Prevention Group of Adult Japanese (MEGA) Study, in patients with mild-to-moderate hypercholesterolemia (220–270 mg/dL), showed that low-dose pravastatin significantly reduced the risk for CVD by 26%. This exploratory subanalyses examined the efficacy of diet plus pravastatin on CVD in 2210 patients with abnormal fasting glucose (AFG, including 1746 patients with DM and 464 patients with impaired fasting glucose (IFG) at 5 years in the MEGA Study. CVD was threefold higher in AFG patients (threefold higher in DM, and twofold higher in IFG) compared with normal fasting glucose (NFG) patients in the diet group. Diet plus pravastatin treatment significantly reduced the risk of CVD by 32% (hazard ratio 0.68, 95% CI 0.48–0.96, number needed to treat, 42) in the AFG group compared with the diet alone group, and no significant interaction between AFG and NFG (interaction P = 0.85) was found. Safety problems were not observed during long-term treatment with pravastatin. In conclusion, pravastatin reduces the risk of CVD in subjects with hypercholesterolemia and abnormal fasting glucose in the primary prevention setting in Japan.

Effects of pravastatin in prevention of diabetes and mechanism thereof: experiment with non-obese diabetic mice

To explore the effects of pravastatin in prevention of diabetes and mechanisms thereof. 1183 to 4-week-old female non-obese diabetic (NOD) mice were randomly divided into 4 groups: control group (n = 30), fed with regular diet, low-dose pravastatin group (n = 29), fed with 1 mg kg(-1) d(-1) pravastatin via the diet, medium-dose pravastatin group (n =29) fed with 10 mg kg(-1) d(-1) pravastatin via the diet, and high-dose pravastatin group (n = 30), fed with 40 mg kg(-1) d(-1) pravastatin via the diet. The mice were followed up till they were 30-week old. Urine glucose was measured every week. Eight 12-week old mice without onset of DM from each group were killed with the pancreas taken out to undergo insulitis scoring via microscopy. Another 8 12-week old mice without onset of DM from each group were killed with their spleens taken out. Suspension of splenocytes was made, put into a 96-well plate, and stimulated by rGAD65; and [3SH]-thymidine was incorporated. The stimulation index (SI) of the splenocytes was calculated. Flow cytometry was used to observe the population of CD4 CD25+ regulatory T cells. ELISA was used to detect the interferon (IFN)-gamma and interleukin (IL)-4 levels in the supernatants of splenocytes. RT-PCR was used to detect the mRNA expression of IFN-gamma and IL4 in the spleen. At 30 weeks of age, the incidence rate of DM onset of the high-dose pravastatin group was significantly lower than that of the control group (P = 0.003), and the incidence rates of DM onset of the medium and low dose groups were not significantly different from that of the control group (both P >0.05). The severity of insulitis at 12 weeks of age of the high-dose pravastatin group was significantly lower than that of the controls group (P <0.001). There were no significant difference in the SI level and in the percentage of CD4+ CD25+ regulatory T cells among the four groups (all P >0.05). The IFN-gamma level in the supernatant of splenocytes of the high-dose pravastatin group was (42 + 20) pg/ml, significantly lower than that of the control group [(157 + 32) pg/ml, P = 0.000]. The IFN-gamma mRNA expression level in the spleen of the high-dose pravastatin group was 0.24 +/- 0.10, significantly lower than that of the control group (0.81 +/- 0.18, P =0.000). The IL-4 level in the supernatants of splenocytes of the high-dose pravastatin group was S (91 +/- 22) pg/m, significantly higher than that of the control group [(44 +/- 20) pg/ml, P=0.000)]. The IL4 mRNA expression level in spleen of the high-dose pravastatin group was 0.39 +/- 0.18, significantly higher than that of the control group (0.20 +/- 0.08, P = 0.002). However, there were not significant differences in the IFN-gamma and IL-4 levels in the supernatant and the IFN-gamma and IL-4 mRNA expression in spleen among the medium dose, low dose, and control groups (all P >0.05). High-dose pravastatin therapy at early time decreases the IFN-gamma level and increases the IL-4 level, shifts the immune response to the direction of Th2, and subsequently lessens insulitis and prevents DM.

Effect of Early Use of Low-Dose Pravastatin on Major Adverse Cardiac Events in Patients With Acute Myocardial Infarction

It is unclear whether early initiation of low-dose pravastatin therapy can reduce the occurrence of major adverse cardiac events after acute myocardial infarction (AMI). The study group comprised 353 patients with AMI who had plasma total cholesterol levels of 200-250 mg/dl and triglyceride levels <300 mg/dl. The patients were randomly assigned to either receive pravastatin (10 mg/daily, n=176) or not (n=177). The primary endpoint was a composite of death, nonfatal myocardial infarction (MI), unstable angina (UA), stroke, revascularization, and rehospitalization because of other cardiovascular disease. The follow-up period was 9 months. The primary endpoint occurred in 31 patients (17.9%) in the pravastatin group and 55 patients (31.4%) in the non-pravastatin group (relative risk, 0.56; 95% confidence interval, 0.36-0.87). There were no significant differences in the risk of death, nonfatal MI, UA, and stroke between the 2 groups, although the pravastatin group had a lower risk of need for revascularization. For patients with AMI, early and low-dose pravastatin therapy (10 mg/daily) reduces recurrent major adverse cardiac events, mostly the requirement for revascularization.

Phytosterols dissolved in diacylglycerol oil reinforce the cholesterol-lowering effect of low-dose pravastatin treatment

Background and aims Dietary therapy using phytosterols can reinforce statin treatment; however the value of a low-dose combination of those agents remains to be investigated. Plant sterols (PS), dissolved in diacylglycerol (DAG) oil, (PS/DAG) can be effective at a relatively low dose. The objective of the present study was to examine the effect of PS/DAG oil on blood cholesterol concentrations in hypercholesterolemic outpatients on low-dose pravastatin (10 mg/day). Methods and results The patients ( n = 61) were randomly assigned to one of three groups, who consumed TAG (control), DAG or PS/DAG oil. The average intake of PS from the PS/DAG oil during the test period was significantly higher than that for TAG and DAG oils (502 vs. 49 and 38 mg/day, P < 0.05). Significant cholesterol-lowering effects from the baseline were observed in the case of the PS/DAG oil treatment alone. Changes in low-density lipoprotein (LDL) cholesterol were inversely correlated with baseline serum campesterol concentrations ( r = −0.560, P < 0.05), but not baseline LDL cholesterol concentrations. In addition, serum apolipoprotein B concentrations were reduced to a greater extent in subjects with high versus low levels of baseline campesterol (−13.2 mg/dL vs. −3.1 mg/dL, P < 0.05). Furthermore, there was a mild, but significant reduction in serum lipoprotein (a) concentration from the baseline (−5.9 mg/dL), which was correlated with the reduction in serum apolipoprotein B concentration ( r = 0.596, P < 0.05). Conclusion A low-dose combination of PS/DAG oil and pravastatin may be a useful strategy for further ameliorating blood cholesterol and lipoprotein (a) concentrations for hypercholesterolemic patients with a low response to pravastatin.

The Effects of High Dose Pravastatin and Low Dose Pravastatin and Ezetimibe Combination Therapy on Lipid, Glucose Metabolism and Inflammation

Coronary artery disease (CAD) is presently the major cause of mortality and morbidity. Anti-hyperlipidemic treatment is one of the main treatment steps in the management of CAD. Statins are the cornerstones in this treatment. Ezetimibe can be reliably used, when statins prove ineffective in treatment, or to reduce their side effects. In the present study we examined the effects of high-dose pravastatin (40 mg) and low-dose pravastatin (10 mg) + ezetimibe (10 mg) combination therapy on lipid and glucose mechanism, as well as inflammation. This study registered 100 cases. Of the cases, 50 [57.1 +/- 11.1 years (24 (48%) females and 26 (52%) males)] were administered 40 mg/day pravastatin (group 1) and 50 [53.2 +/- 12.2 years (27 (54%) females and 23 (46%) males)] were administered 10 mg pravastatin + 10 mg ezetimibe (group 2). In group 1, total cholesterol fell from 231.1 +/- 83.5 mg/dl to 211.3 +/- 37.2 mg/dl (p = 0.03), triglyceride from 243.5 +/- 96.8 mg/dl to 190.9 +/- 55.2 mg/dl (p = 0.003), and LDL cholesterol from 165.7 +/- 29.7 mg/dl to 133.4 +/- 26.6 mg/dl (p = 0.02). In group 2, total cholesterol dropped from 250.9 +/- 51.8 mg/dl to 187.9 +/- 34.9 mg/dl (p = 0.001), triglyceride from 270.3 +/- 158.9 mg/dl to 154.6 +/- 60.7 mg/dl (p = 0.001), and LDL cholesterol from 158.1 +/- 47.5 mg/dl to 116.9 +/- 26.4 mg/dl (p = 0.001). Insulin resistance decreased from 4.05 +/- 2.31 to 3.16 +/- 1.90 (p = 0.07) in group 1 and from 2.96 +/- 1.50 to 2.05 +/- 0.55 (p = 0.009) in group 2. High sensitive C-reactive protein fell from 6.69 +/- 6.11 mg/l to 3.02 +/- 1.70 mg/l (p = 0.01) in group 1 and from 6.36 +/- 2.06 mg/l to 2.68 +/- 1.69 mg/l (p = 0.001) in group 2. Both therapy regimes are effective. However, we found that low-dose pravastatin and ezetimibe combination therapy is more effective than high-dose pravastatin therapy on lipid metabolism, glucose metabolism and inflammation.

Primary prevention of cardiovascular diseases among hypercholesterolemic Japanese with a low dose of pravastatin

The MEGA Study was Japan's first primary prevention trial of cardiovascular disease (CVD) by cholesterol lowering with low-dose pravastatin. Included were postmenopausal women aged < or =70 years and men aged 40-70 years with mildly elevated total cholesterol (TC) level 220-270 mg/dL. In all, 8214 outpatients were randomly assigned to receive diet alone or diet plus pravastatin 10-20mg/day for an average follow-up of 5.3 years. The primary endpoint was a composite of fatal and nonfatal MI, angina, cardiac and sudden death, and coronary revascularization. TC was reduced by 11.5% in the diet plus pravastatin group versus 2.1% in the diet alone group. LDL-C was reduced by 18% and 3.2% in the two groups, respectively. TC was reduced to <220 mg/dL and LDL-C to <130 mg/dL in patients in the diet plus pravastatin group. There was a significant 33% reduction of the primary endpoint in the diet plus pravastatin group compared with the diet alone group. Notable findings of the MEGA Study included the observation that despite pravastatin's modest LDL-C reductions in this low-risk population, a 33% reduction of CHD events was achieved. Even though 68% of patients were women, who have been traditionally considered at less risk than men, significant CHD risk reduction was observed across all groups.

Cardiovascular complications of HIV: an overview of risk and a novel approach to prevention ??? the HIV polypill study

To review the risk of cardiovascular complications in HIV-infected patients receiving combination antiretroviral treatment. Recent data suggest that patients with chronic HIV infection will require continuous lifelong combination antiretroviral treatment, which may increase the risk of cardiovascular disease in all populations by substantial amounts. Simple, safe and effective interventions to reduce cardiovascular complications in HIV-infected patients will be required. Studies in the general population suggest that the primary prevention of cardiovascular disease with a pill combining blood-pressure-lowering, cholesterol-lowering and antiplatelet treatments (a polypill) might decrease cardiovascular events. An HIV polypill study with 8000 HIV-infected patients with a moderate risk of cardiovascular disease randomized to either a polypill of low-dose pravastatin, aspirin, hydrochlorothiazide and lisinopril or to placebo is described. The primary clinical endpoint would be a composite of cardiovascular mortality, non-fatal myocardial infarction and stroke. A vanguard study of 400 patients could assess changes in cholesterol, blood pressure and other risk factors. The clinical endpoint study described would have 80% power to detect a 23% reduction in the rate of cardiovascular events in the polypill arm. A study of a polypill like that proposed for the general population will provide crucial information on the risks and benefits of primary cardiovascular prevention in HIV-infected patients.