Sustained reduction of serum cholesterol in low-dose 6-year simvastatin treatment with minimum side effects in 51,321 Japanese hypercholesterolemic patients.

The Japan Lipid Intervention Trial (J-LIT) study, a nationwide cohort study utilizing the clinical practice of general physicians, was designed to clarify the relationship between the incidence of coronary heart disease and serum lipid concentrations during simvastatin therapy, as well as the safety of the therapy, in a large number of Japanese hypercholesterolemic patients. All the enrolled patients were treated with simvastatin. The current study analyzed the lipid lowering effect and safety of the low-dose simvastatin therapy used in the J-LIT study. Open-labeled simvastatin was given to 51,321 patients at an initial dose of mostly 5 mg/day. After 6 months of the treatment, the average serum total cholesterol (TC) and low density lipoprotein-cholesterol concentrations in all the patients followed up were reduced by 18.3% and 26.0%, respectively, and that of high density lipoprotein-cholesterol increased 2.3% on average. These concentrations were well maintained throughout the 6-year treatment period. A minority of patients (1.4%) unexpectedly had a remarkable reduction in TC concentration by more than 40%. Hyper-responders, even to low-dose statin, were found for the first time in this large-scale and long-term investigation. Overall adverse drug reactions occurred in 3.3% of subjects during the 6-year treatment, the major events being hepatic and musculoskeletal disorders, of which the incidence was less than 1%. Low-dose simvastatin therapy of 5 mg/day effectively controlled the serum TC concentration by reducing it by approximately 20% on average in hypercholesterolemic Japanese patients, a reduction that corresponds to the effect of simvastatin 20 mg/day in Western studies. In addition, the low incidence of drug-related adverse events in this study may be also related to the low dosage of simvastatin.     

The risk of cardiovascular events in Japanese hypertensive patients with hypercholesterolemia: sub-analysis of the Japan Lipid Intervention Trial (J-LIT) Study, a large-scale observational cohort study.

Coronary events and stroke are leading causes of death in Japan. However, the effects of hypertension on the risk of coronary events and stroke have not been well established in Japanese hypercholesterolemic patients. This study aimed to determine the relationship between the risk of coronary events or stroke and blood pressure and cholesterol levels during low-dose simvastatin treatment using data from the Japan Lipid Intervention Trial (J-LIT) study (a large scale nationwide cohort study). In the present study, 47,294 hypercholesterolemic patients were treated with open-labeled simvastatin (5 to 10 mg/day) for 6 years by a large number of physicians in a clinical setting. The adjusted incidence rates of coronary events in males and females were 8.9 and 2.3 and those of stroke were 17.6 and 11.3/1000 patients during the 6-year period, respectively. The incidence rate of stroke was higher than that of coronary events in both males and females. An obvious sex difference was observed in terms of the incidence of coronary events. The risk of coronary events, stroke, and total cardiovascular events were increased, with elevations in blood pressure observed in patients treated for hypercholesterolemia. The risk of total cardiovascular events in the groups exhibiting less lipid control increased, with lower blood pressure levels than those of the well-controlled group. For patients with hypercholesterolemia and hypertension, blood pressure should be strictly controlled in order to prevent both coronary events and stroke, and the serum total cholesterol levels should be maintained at low levels as well.     

Large scale cohort study of the relationship between serum cholesterol concentration and coronary events with low-dose simvastatin therapy in Japanese patients with hypercholesterolemia.

Hyperlipidemia is a well-established risk factor for primary coronary heart disease (CHD). Although simvastatin is known to lower serum lipid concentrations, the protective effect of such lipid-lowering therapy against primary CHD has not been established in Japanese patients with hypercholesterolemia. The Japan Lipid Intervention Trial was a 6-year, nationwide cohort study of 47,294 patients treated with open-labeled simvastatin (5-10 mg/day) and monitored by physicians under standard clinical conditions. The aim of the study was to determine the relationship between the occurrence of CHD and the serum lipid concentrations during low-dose simvastatin treatment. Simvastatin reduced serum concentrations of total cholesterol (TC), low-density lipoprotein- cholesterol (LDL-C) and triglyceride (TG), by 18.4%, 26.8% and 16.1% on average, respectively, during the treatment period. The risk of coronary events was higher when the average TC concentration was > or =240 mg/dl and the average LDL-C concentration was > or =160 mg/dl. The incidence of coronary events increased in the patients with TG concentration > or =300 mg/dl compared with patients with TG concentration <150 mg/dl. The high-density lipoprotein cholesterol (HDL-C) inversely correlated with the risk of coronary events. The J-curve association was observed between average TC or LDL-C concentrations and total mortality. Malignancy was the most prevalent cause of death. The health of patients should be monitored closely when there is a remarkable decrease in TC and LDL-C concentrations with low-dose statin. A reasonable strategy to prevent coronary events in Japanese hypercholesterolemic patients without prior CHD under low-dose statin treatment might be regulating the serum lipid concentrations to at least <240 mg/dl for TC, <160 mg/dl for LDL-C, <300 mg/dl for TG, and >40 mg/dl for HDL-C.     

Large scale cohort study of the relationship between serum cholesterol concentration and coronary events with low-dose simvastatin therapy in Japanese patients with hypercholesterolemia and coronary heart disease: secondary prevention cohort study of the Japan Lipid Intervention Trial (J-LIT).

Hyperlipidemia is primarily implicated in the progression of coronary heart disease (CHD) and its treatment is essential for patients with a history of CHD. Statins such as simvastatin, the lipid-lowering agents, are well-known for their ability to normalize patient's serum lipid levels. The Japan Lipid Intervention Trial study of simvastatin is the first nationwide investigation of the relationship between serum lipid levels and the development of CHD in Japanese patients with hypercholesterolemia. Of 5,127 patients, exclusively with a history of documented CHD at enrollment, 4,673 were treated with open-labeled simvastatin at an initial dose of 5-10 mg/day and were monitored for 6 years. The risk of coronary events tended to be higher in patients with a serum total cholesterol (TC) > or =240 mg/dl compared with total cholesterol <240 mg/dl. The concentration of low-density lipoprotein cholesterol (LDL-C) positively correlated and that of high-density lipoprotein cholesterol (HDL-C) inversely correlated with the risk of CHD. Each 10 mg/dl decrease in LDL-C and each 10 mg/dl increase in HDL-C concentration reduced the risk of CHD by 8.0% (95% confidence interval 3.8-12.0) and 28.3% (95% CI 13.9-40.3), respectively. A reasonable therapeutic strategy to reduce CHD progression in patients with prior CHD under low-dose statin treatment might be regulating the serum LDL-C concentration to at least <120 mg/dl and HDL-C >40 mg/dl, respectively.     

Primary cardiovascular events and serum lipid levels in elderly Japanese with hypercholesterolemia undergoing 6-year simvastatin treatment: a subanalysis of the Japan lipid intervention trial

OBJECTIVES: To determine the relationship between serum lipid levels and the incidence of coronary events in older Japanese hypercholesterolemic patients without prior coronary heart disease (CHD). DESIGN: Post hoc subanalysis of the results in the Japan Lipid Intervention Trial. SETTING: A large-scale cohort observational study conducted throughout Japan. PARTICIPANTS: Men aged 35 to 70 and postmenopausal women younger than 70 with serum total cholesterol (TC) level of 220 mg/dL or greater treated for 6 years with low-dose simvastatin (52,421 total patients). After exclusion of 5,127 patients because of prior CHD and 4,934 patients because of incomplete data, 42,360 patients were divided into an older (9,860 patients, aged 65-70, mean age 67.1) and younger (32,500 patients, younger than 65, mean age 54.9) group and analyzed. MEASUREMENTS: Fasting serum lipid levels were measured every 6 months. Major coronary events, including fatal or nonfatal myocardial infarction, and sudden cardiac death as the primary endpoint and other cardiovascular diseases, including onset of angina pectoris, cerebrovascular events, and any causes of death, as the secondary endpoints were monitored. RESULTS: Simvastatin treatment in older patients was as safe and effective as in younger patients. Incident rates of major coronary events were 1.30 per 1,000 patient-years in the older group and 0.80 per 1,000 patient-years in the younger group. The incidence of a major coronary event was correlated to serum TC and low-density lipoprotein cholesterol (LDL-C) levels in both groups. The absolute risk of major coronary events in the older group was higher than in the younger group at any level of LDL-C, whereas the relative risk increased by 1.7% with an elevation of each 1 mg/dL LDL-C level in both groups. In the older group, the risk of major coronary events also increased as triglyceride level increased, whereas the risk decreased as high-density lipoprotein cholesterol level increased above 60 md/dL. CONCLUSION: The LDL-C level-dependent increase of relative risk of CHD was similar in elderly and younger patients, whereas the absolute risk at any LDL-C level in elderly patients was higher than in younger patients.     

Apolipoprotein(a) size polymorphism is associated with coronary heart disease in polygenic hypercholesterolemia

BACKGROUND AND AIM: In addition to high serum cholesterol levels, various cardiovascular risk factors may be involved in the development of coronary heart disease (CHD) in hypercholesterolemic subjects. As the levels of lipoprotein(a) [Lp(a)], an important and independent cardiovascular risk factor, are high in polygenic hypercholesterolemia (PH), we investigated plasma Lp(a) levels and apolipoprotein(a) [apo(a)] phenotypes in relation to occurrence of CHD events in PH patients. METHODS AND RESULTS: Lp(a) levels and apo(a) isoforms were determined in 191 PH patients, 83 normocholesterolemic subjects with CHD, and 94 normocholesterolemic controls without CHD. Lp(a) levels were similar in the hypercholesterolemic subjects with (n=100) or without CHD (n=91): 21.4 (range 6.6-59.23) vs 18.5 (range 5.25-57.25) mg/dL (p=NS). Low molecular weight apo(a) isoforms were more prevalent (55%) in the PH patients with CHD, whereas high molecular weight apo(a) isoforms were more prevalent (62.6%) in those without CHD: this difference was significant (p<0.05). A stepwise multiple-discriminant analysis made in order to determine the independence of common cardiovascular risk factors, Lp(a) levels and low molecular weight apo(a) isoforms in predicting CHD among hypercholesterolemic subjects showed that the presence of a positive family history of CHD, smoking, age, and the presence of at least one apo(a) isoform of low molecular weight were independently associated with CHD. CONCLUSIONS: Despite high Lp(a) levels, our findings do not support the hypothesis that Lp(a) plays an independent role in determining clinical CHD in PH subjects. However, the presence of at least one low molecular weight apo(a) isoform is an independent genetic predictor of CHD in hypercholesterolemic subjects. Together with other cardiovascular risk factors, apo(a) phenotypes should be assessed to evaluate the overall CHD risk status of all subjects with high serum cholesterol levels.     

Reduced coronary events in simvastatin-treated patients with coronary heart disease and diabetes or impaired fasting glucose levels: subgroup analyses in the Scandinavian Simvastatin Survival Study

BACKGROUND: Patients with diabetes mellitus (DM) have a marked increase in coronary heart disease (CHD) events relative to those without DM. In a previous report from the Scandinavian Simvastatin Survival Study using a clinical case definition of DM (n = 202), simvastatin-treated patients had significantly fewer CHD events compared with placebo-treated control subjects. OBJECTIVE: To examine the effect of simvastatin therapy on CHD in patients with DM and impaired fasting glucose levels. METHODS: Using the 1997 American Diabetes Association diagnostic criteria, we assessed the effect of simvastatin therapy post hoc for an average of 5.4 years in Scandinavian Simvastatin Survival Study patients with normal fasting glucose (n = 3237), impaired fasting glucose (n = 678), and DM (n = 483). RESULTS: Simvastatin-treated patients with DM had significantly reduced numbers of major coronary events (relative risk [RR] = 0.58; P = .001) and revascularizations (RR = 0.52; P = .005). Total (RR = 0.79; P = .34) and coronary (RR = 0.72; P = .26) mortality were also reduced in DM, but not significantly, due to small sample size. In impaired fasting glucose (IFG) subjects, simvastatin use significantly reduced the number of major coronary events (RR = 0.62; P = .003), revascularizations (RR = 0.57; P = .009), and total (RR = 0.57; P = .02) and coronary (RR = 0.45; P = .007) mortality. CONCLUSION: Our results extend previous findings in patients with DM to a larger cohort, confirming the benefit of cholesterol lowering with simvastatin treatment on CHD events. In addition, significant decreases in total mortality, major coronary events, and revascularizations were observed in simvastatin-treated patients with impaired fasting glucose levels. These results strongly support the concept that cholesterol lowering with simvastatin therapy improves the prognosis of patients with elevated fasting glucose levels (> or =6.0 mmol/L [> or =110 mg/ dL]) or DM and known CHD.     

Implications of cardiovascular risk in patients with type 2 diabetes who have abnormal lipid profiles: is lower enough?

Patients with type 2 diabetes are at high risk for coronary heart disease (CHD); frequently, these patients have abnormal lipid profiles, placing them at even greater risk. A syndrome of insulin resistance, hyperinsulinaemia, hypertension, and high levels of fibrinogen and plasminogen activator inhibitor contributes to cardiovascular risk, which is not sufficiently decreased by glycaemic control alone. In several large interventional trials, CHD risk in patients with diabetes was substantially reduced by aggressive lipid-lowering therapy. In patients with diabetes, CHD, low high-density lipoprotein levels, and normal low-density lipoprotein levels, gemfibrozil reduced fatal and non-fatal CHD events. For lipid-lowering in patients with diabetes and CHD, pravastatin and simvastatin are the only HMG-CoA reductase inhibitors shown to reduce fatal and non-fatal CHD events. Of these, pravastatin has less potential for drug-drug interactions and may be safer to use, particularly for combination therapy with fibric acid derivatives, as may now be important for CHD prevention in mixed dyslipidaemias.     

Exercise-induced silent myocardial ischemia and coronary morbidity and mortality in middle-aged men.

OBJECTIVES: We investigated the prognostic significance of exercise-induced silent myocardial ischemia in both high and low risk men with no prior coronary heart disease (CHD). BACKGROUND: Silent ischemia predicts future coronary events in patients with CHD, but there is little evidence of its prognostic significance in subjects free of CHD. METHODS: We investigated the association of silent ischemia, as defined by ST depression during and after maximal symptom-limited exercise test, with coronary risk in a population-based sample of men with no prior CHD followed for 10 years on average. RESULTS: Silent ischemia during exercise was associated with a 5.9-fold (95% CI 2.3 to 11.8) CHD mortality in smokers, 3.8-fold (95% CI 1.9 to 7.9) in hypercholesterolemic men and 4.7-fold (95% CI 2.4 to 9.1) in hypertensive men adjusting for other risk factors. The respective relative risks (RRs) of any acute coronary event were 3.0 (95% CI 1.7 to 5.1), 1.9 (95% CI 1.2 to 3.1) and 2.2 (95% CI 1.4 to 3.5). These associations were weaker in men without these risk factors. Furthermore, silent ischemia after exercise was a stronger predictor for the risk of acute coronary events and CHD death in smokers and in hypercholesterolemic and hypertensive men than in men without risk factors. CONCLUSIONS: Exercise-induced silent myocardial ischemia was a strong predictor of CHD in men with any conventional risk factor, emphasizing the importance of exercise testing to identify asymptomatic high risk men who could benefit from risk reduction and preventive measures.     

停用辛伐他汀对冠心病及冠心病危险因素患者血管内皮功能的影响

目的 观察在冠心病及冠心病危险因素患者中,停用辛伐他汀治疗对血管内皮功能的影响,并探讨相应作用机制。方法 入选33例血清胆固醇（Tc）水平未达标的冠心病及冠心病危险因素患者,分别于基线水平、停药前（即辛伐他汀20mg治疗4周后）及停用辛伐他汀1周时,采用高分辨超声技术检测肱动脉血流介导性扩张（FMD）评估血管内皮依赖性舒张功能,并测定一氧化氮（NO）、血浆内皮素（ET）、6-酮-前列腺素F1α（6-keto-PGF1α）和血栓素B2（TXB2）的水平及主要血脂参数的变化。结果 辛伐他汀治疗4周后可有效降低冠心病及冠心病危险因素患者TC、低密度脂蛋白胆固醇（LDL-C）水平,并明显改善患者肱动脉内皮依赖性舒张功能（FMD）。然而,停用辛伐他汀治疗1周后,所有患者肱动脉内皮依赖性舒张功能均较停药前明显下降（4．82士0．71）％与11．51±0．87％,P〈0．01）,甚至低于未服用辛伐他汀时的基线水平（4．82±0．71％与5．89±0．65％,P〈0．01）,其中冠心病患者停药后FMD下降幅度较仅有冠心病危险因素患者更显著（65．6％与56．3％,P〈0．01）。停药1周后,患者血清NO水平较停药前及基础值均明显降低,而血浆ET水平升高。血浆TXB,水平在停药前后无明显变化。此外,停药后患者血清LDL-C水平虽较治疗4周时有所升高,但仍未恢复至基线水平。停药后肱动脉FMD的变化仅与血清NO降低幅度呈正相关关系（r=0．674。P=0．004）,而与血清LDL-C水平变化无明显相关性（r=-0．414,P=0．083）。结论 在TC水平未达标的冠心病及冠心病危险因素患者中突然终止辛伐他汀治疗可在1周内完全逆转该药对血管内皮功能的改善作用,甚至还可能导致血管内皮功能进一步恶化。并且这种撤药反应随基础疾病的严重性增加。停药所致血管内皮功能损害可能与血管内皮源性的NO减少有关,是非胆固醇依赖性作用。     

Time course of C-reactive protein reduction with simvastatin therapy in patients with type 2 diabetes mellitus

The aim of this study was to investigate the time course of C-reactive protein (CRP) reduction with simvastatin in patients with type 2 diabetes mellitus. Thirty-five subjects (mean +/- SEM body mass index 32.8 +/- 1 kg/m(2), mean +/- SEM glycated hemoglobin 7.3 +/- 0.2%) were studied using a randomized, crossover, double-blind design. Patients were treated with simvastatin 40 mg or placebo for 28 days, with a minimum 28-day intervening washout. On entry, all subjects had low-density lipoprotein cholesterol >100 mg/dl and/or non-high-density lipoprotein cholesterol >130 mg/dl. High-sensitivity CRP (hs-CRP) was measured on days 0, 1, 3, 7, 14, 21, and 28 of each phase; fasting lipids were measured weekly. The mean hs-CRP level was 4.2 +/- 0.6 mg/L at baseline (>3.0 mg/L represents high risk). After simvastatin administration, there was a significant reduction in levels of log(hs-CRP) (p = 0.001). This effect of simvastatin was seen by day 7 (p = 0.008), with maximal reduction seen at day 14 (p = 0.004; hs-CRP in original units 3.1 +/- 0.5 mg/L with simvastatin and 4.1 +/- 0.6 mg/L with placebo). As expected, the change in hs-CRP was not related to low-density lipoprotein cholesterol reduction. By day 28 with simvastatin, hs-CRP had returned to near baseline levels. In conclusion, in patients with type 2 diabetes mellitus, simvastatin reduced hs-CRP within 7 days. However, this potentially beneficial effect was lost within 28 days.     

Vascular effects of simvastatin combined with ramipril in hypercholesterolemic patients with coronary artery disease, compared with simvastatin alone: a randomized, double-blind, placebo-controlled, crossover study

Because the mechanisms of the biological effects of statin and angiotensin converting enzyme inhibitor therapies differ, we studied the vascular responses to these therapies in hypercholesterolemic patients with coronary artery disease. We administered simvastatin 20 mg and placebo or ramipril 10 mg daily during 2 months with washout 2 months to 32 hypercholesterolemic patients with coronary artery disease. This study was randomized, double-blind, placebo-controlled, crossover in design. Simvastatin alone or combined with ramipril significantly changed lipoproteins, and improved the percent flow-mediated dilator response to hyperemia relative to baseline measurements by 33 +/- 6% and by 50 +/- 14%, respectively (both P <0.001) and reduced plasma levels of nitrate relative to baseline measurements (P=0.413 and 0.037, respectively), the plasma MDA levels relative to baseline measurements by 8 +/- 8% and by 18 +/- 9% (P=0.039 and P <0.001, respectively) and MCP-1 relative to baseline measurements by 7 +/- 4% and by 13 +/- 3%, respectively (P=0.019 and P <0.001, respectively), and CRP from 0.22 to 0.14 mg/dl and from 0.22 to 0.15 mg/dl, respectively (P=0.124 and 0.002, respectively), and PAI-1 antigen relative to baseline measurements (P=0.690 and 0.018, respectively). However, simvastatin combined with ramipril changed to greater but statistically insignificant extent the percent flow-mediated dilator response to hyperemia and plasma levels of nitrate, MDA, MCP-1, and PAI-1 antigen than simvastatin alone. Simvastatin alone or combined with ramipril showed significant beneficial effects on endothelial function in hypercholesterolemic patients with coronary artery disease. However, simvastatin combined with ramipril did not significantly change, compared with simvastatin alone.     

Impact of the Thr789Ala variant of the von Willebrand factor levels, on ristocetin co-factor and collagen binding capacity and its association with coronary heart disease in patients with diabetes mellitus type 2.

A Thr789Ala variant in the von Willebrand Factor (vWF) gene is associated with increased vWF plasma concentrations and might therefore affect the risk of coronary heart disease (CHD) in the general population. Patients with type 2 diabetes have an increased risk for premature atherosclerosis and are characterized by alterations of the coagulation system. However, it is not known whether the Thr789Ala variant in the vWF gene contributes to the increased CHD risk in patients with type 2 diabetes. We therefore investigated the potential relationship between the Thr789Ala variant in the vWF gene and the occurrence of CHD in 356 patients with type 2 diabetes, either with (DM+/CHD+, n = 204) or without evidence for CHD (DM+/CHD-, n = 152). In addition, two control groups without type 2 diabetes, with (DM-/CHD+, n = 22) or without CHD (DM-/CHD-, n = 100), were investigated. Individuals with the vWF Thr789Ala variant have significantly higher von Willebrand factor plasma concentrations (p < 0.001). In addition, ristocetin co-factor was significantly increased in vWF Thr789Ala variant carriers (p < 0.05). Ristocetin co-factor levels and collagen binding capacity were also increased in individuals affected with either type 2 diabetes, CHD or both (DM+/CHD+, DM+/CHD-, DM-/CHD+) as compared to healthy controls (DM-/CHD-) (p < 0.001). However, we did not find an association between the vWF Thr789Ala variant and the occurrence of CHD in patient with type 2 diabetes (p = 0.34). In conclusion, although the Thr789Ala vWF gene variant is associated with increased plasma concentrations of vWF, ristocetin co factor levels and collagen binding capacity in patients with type 2 diabetes and CHD, a direct effect of this variant on the occurrence of CHD in patients with type 2 diabetes, could not be detected.     

Effect of co-administering ezetimibe with on-going simvastatin treatment on LDL-C goal attainment in hypercholesterolemic patients with coronary heart disease

OBJECTIVE: To determine whether co-administering ezetimibe with on-going simvastatin treatment was more effective than placebo plus on-going simvastatin in achieving an LDL-C treatment target of < or = 2.60 mmol/l (100 mg/dl) in hypercholesterolemic patients with coronary heart disease (CHD). METHODS: Men and women (age > or = 18 years) with documented CHD and on a stable dose of simvastatin 10 mg or 20 mg for at least 6 weeks were recruited for this study. After a 4-week simvastatin 10 or 20 mg plus placebo and diet run-in period, patients were eligible for randomization if LDL-C > 2.60 and < or = 4.20 mmol/l and triglycerides (TG) < or = 4.00 mmol/l. Eligible patients were randomized to a double-blind comparative study with ezetimibe 10 mg co-administered with on-going simvastatin 10 mg or 20 mg (n=181) versus placebo to match ezetimibe co-administered with simvastatin 10 mg or 20 mg (n=191) for 6 weeks. RESULTS: At baseline, mean LDL-C was comparable between the ezetimibe (3.14 mmol/l) and placebo (3.19 mmol/l) groups. With the addition of ezetimibe or placebo to on-going simvastatin therapy, the percentage of patients achieving the LDL-C goal of < or = 2.60 mmol/l after 6 weeks of treatment was significantly (p < or = 0.001) greater in the ezetimibe group (74.3%) than in the placebo group (16.7%). The addition of ezetimibe to on-going simvastatin treatment also resulted in a significantly (p < or = 0.001) larger mean percent reduction in LDL-C from baseline (25.2%) compared with placebo (0.9%). Ezetimibe was generally well tolerated compared to placebo when added to on-going simvastatin treatment. CONCLUSIONS: Co-administering ezetimibe with on-going simvastatin 10 or 20 mg treatment allowed more hypercholesterolemic patients with CHD to reach the LDL-C treatment target of < or = 2.60 mmol/l.     

Effect of Low‐Density Lipoprotein Cholesterol Lowering by Ezetimibe/Simvastatin on Outcome Incidence: Overview,Meta‐Analyses,and Meta‐Regression Analyses of Randomized Trials

This analysis investigated the extent of different outcome reductions from low‐density lipoprotein cholesterol (LDL‐C) lowering following ezetimibe/simvastatin treatment and the proportionality of outcome to LDL‐C reductions. The authors searched PubMed between 1997 and mid‐June 2015 (any language) and the Cochrane Library to identify all randomized controlled trials comparing ezetimibe/simvastatin with placebo or less intensive LDL‐C lowering. Risk ratios (RR) and 95% confidence intervals (CIs), standardized to 20 mg/dL LDL‐C reduction, were calculated for 5 primary outcomes (fatal and nonfatal) and 4 secondary outcomes (non‐cardiovascular [CV] death, cancer, myopathy, and hepatopathy). Five ezetimibe/simvastatin RCTs (30 051 individuals) were eligible, 2 comparing ezetimibe/simvastatin vs placebo and 3 vs less intensive treatment. Outcomes reduced almost to the same extent were stroke (RR: ?13%, 95% CI: ?21% to ?3%), coronary heart disease (CHD; RR: ?12%, 95% CI: ?19% to ?5%), and composite of stroke and CHD (RR: ?14%, 95% CI: ?20% to ?8%). Absolute risk reductions: 5 strokes, 10 CHD events, and 16 stroke and CHD events prevented for every 1000 patients treated for 5 years. Residual risk was almost 7× higher than absolute risk reduction for all the above outcomes. All death outcomes were not reduced, and secondary outcomes did not differ between groups. Logarithmic risk ratios were not associated with LDL‐C lowering. Our meta‐analysis provides evidence that, in patients with different CV disease burden, major CV events are safely reduced by LDL‐C lowering with ezetimibe/simvastatin, while raising the hypothesis that the extent of LDL‐C lowering might not be accompanied by incremental clinical‐event reduction.     

Prevalence of urinary tract infection and renal scars in patients with diabetes mellitus

Insulin resistance is known as an important risk factor for coronary artery disease (CAD). However, CAD-related mortality in Japanese type 2 diabetics is lower than in Caucasians. To investigate whether insulin resistance is related to CAD in Japanese type 2 diabetics, we measured insulin sensitivity and several coronary risk factors in Japanese patients with type 2 diabetes with and without CAD. Thirty-three patients with definite CAD and 33 age- and sex-matched patients without CAD (control) were studied. Insulin sensitivity was assessed by the K index of insulin tolerance test (KITT). Clinical characteristics, classical risk factors, lipoprotein (a), and insulin sensitivity were compared between the two groups. Patients with CAD had a significantly longer duration of diabetes (9.0 +/- 1.4 vs. 5.5 +/- 0.9 years, P < 0.05, respectively), were mostly hypertensive (69.7 vs. 39.4%, P < 0.05), and more likely to be treated with insulin (45.5 vs. 18.2%, P < 0.05) compared with the control. Concerning the metabolic parameters, patients with CAD had a significantly higher insulin resistance than control (2.40 +/- 0.15 vs. 3.23 +/- 0.17%/min, P < 0.01, respectively), higher triglyceride (1.39 +/- 0.10 vs. 1.05 +/- 0.05 mmol/l, P < 0.05), lower HDL cholesterol (1.05 +/- 0.05 vs. 1.28 +/- 0.06 mmol/l, P < 0.05), and higher lipoprotein (a) (27.5 +/- 4.3 vs. 17.4 +/- 2.0 mg/dl, P < 0.05). Multiple logistic regression analysis indicated that hypertension, insulin resistance, high lipoprotein (a) and triglyceride, and low HDL cholesterol were independently related to CAD. Our results suggest that insulin resistance per se is a significant risk factor for CAD in Japanese patients with type 2 diabetes.     

Effect of pravastatin-induced LDL-cholesterol reduction on coronary heart disease and cerebrovascular disease in Japanese: Hokuriku lipid coronary heart disease study-pravastatin atherosclerosis trial (Holicos-PAT)

The purpose of Holicos-PAT was to investigate the efficacy of serum lipid lowering by pravastatin against coronary heart disease (CHD) and cerebrovascular disease (CVD) in the Japanese population.Hypercholesterolemic men and women (n = 2,232), aged 40-70 years, were followed up for 5 years, while they were receiving pravastatin (group P, n = 1,422) or only diet therapy (group C, n = 810).The primary endpoint was CHD (a composite of onset or worsening of angina pectoris, performing CABG or PTCA, non-fatal myocardial infarction, death from CHD including heart death or sudden death).The secondary endpoints were comprised of CVD, total mortality, variation of serum lipid and apoprotein levels, and a relationship between the LDL-C level and occurrence of CHD.For several reasons (proving to meet the exclusion criteria after registration, etc.), 1,290 cases of group P and 749 cases of group C were used as subjects for the primary analysis.The mean follow-up period was 4.5 years in group P and 4.2 years in group C for events of CHD.The mean LDL-C level (SD) in group P was 176 (29) mg/dl and decreased to 134 (29) mg/dl one year later.This effect continued during the follow-up period.CHD events occurred in 9.2/1000 patient-years for men and 2.4/1000 patient-years for women without a history of CHD.CHD events occurred in 55.3/1000 patient-years for men and 23.6/1000 patient-years for women with a history of CHD, which was 6 times higher in men and 10 times higher in women than in those without a history of CHD, respectively.The adjusted relative risk ratio of group P to group C for CHD events was 0.74 (95%CI: 0.47-1.19).In the patients with a history of CHD, the ratio was 0.55 (95%CI: 0.30-1.00).The effect was apparent in the patients with a history of CHD.The incidence of myocardial infarction in Japanese patients with hypercholesterolemia living in the Hokuriku district was apparently lower, than the worldwide incidence, indicative that pravastatin may have a tendency to inhibit the occurrence of events of arteriosclerotic disease.     

PC-1 (ENPP1) K121Q polymorphism in overweight and obese type 2 diabetic coronary heart disease patients

AIM: The aim of the present study was to investigate the prevalence of the PC-1 121Q allele and to test its association to cardiovascular risk factors in type 2 diabetes mellitus (DM) patients. METHODS: A total of 103 unrelated Caucasians from Serbia, including 71 DM patients without CHD (aged 59.4 +/- 8.9 years, with a mean body mass index (BMI) of 33.3 +/- 4.8 kg/m2) and 32 DM patients who suffered from coronary heart disease (DM+CHD) (aged 59.3 +/- 8.0 years, with a mean BMI of 30.37 +/- 3.71 kg/m2), were genotyped for PC-1 K121Q using a mutagenic separated PCR assay. RESULTS: The prevalence of the PC-1 121Q allele was significantly higher in DM+CHD, compared to DM (P < 0.001) and control (P < 0.001) groups, since it was found in 10 (14%) DM patients, 13 (41%) DM+CHD patients and 10 (17%) control subjects.When the association of PC-1 121Q allele and the risk of suffering from CHD were assessed within the DM group in a binary logistic regression model adjusting for age and sex, PC-1 121Q allele carriers had a 76% lower risk (OR 0.24; 95% CI: 0.08-0.67, P = 0.006) for developing CHD compared to subjects who exhibited PC-1 wild-type. CONCLUSION: The prevalence of the PC-1 121Q allele was significantly higher in type 2 diabetic patients who suffered from CHD, compared to type 2 diabetic patients without CHD. However, after a binary logistic regression model analysis, adjusting for age and sex., PC-1 121Q allele carriers had a 76% lower risk (OR 0.24; 95% CI: 0.08-0.67, P = 0.006) for developing CHD compared to subjects who exhibited PC-1 wild-type. Since these data were cross-sectional, the potential patient selection and survival bias, as well as community underdiagnosis of DM and CHD, could most likely substantially underestimate the genetic influence.     

Efficacy of cholesterol-lowering treatment in Japanese elderly patients with coronary artery disease and normal cholesterol level using 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor

The clinical benefit of cholesterol-lowering treatment is unknown in the Japanese elderly in whom the prevalence of morbidity and mortality related to coronary artery disease are known to be low. To evaluate the efficacy of cholesterol-lowering treatment with 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitor in Japanese elderly patients with documented coronary artery disease, 121 patients with serum cholesterol > or = 150 mg/dl prospectively received HMG-CoA reductase inhibitor, and 271 patients undergoing cholesterol-lowering treatment based on dietary therapy alone served as historical controls. The 143 elderly patients age > or = 65 years in the 2 groups had similar baseline serum total cholesterol level (201 +/- 30 vs 202 +/- 31 mg/dl), age (71 +/- 4 vs 70 +/- 4 years), proportion of men (37/53 vs 64/90), number of diseased vessels (1.7 +/- 0.9 vs 1.5 +/- 1.0), and incidences of other classical coronary risk factors, including hypertension, diabetes mellitus, smoking, obesity and family history of coronary artery disease. In all 392 patients, similar trends were observed, including serum total cholesterol level (208 +/- 33 vs 201 +/- 34 mg/dl). With HMG-CoA reductase inhibitors, serum total cholesterol level was reduced by 14% in the elderly subjects and by 13% in all patients. During the follow-up of approximately 3 years, cardiac events occurred in 5 patients (one elderly) in the treatment group and 38 patients (12 elderly) in the control group. Kaplan-Meier survival estimates revealed a higher event-free survival rate with HMG-CoA reductase inhibitors in the elderly subjects (98% vs 85%, p < 0.05) and in all patients (94% vs 86%, p < 0.05). Cox proportional hazard modeling also demonstrated a significant reduction in risk for cardiac events with drug therapy (relative risk 0.32, p < 0.05), in addition to the number of diseased vessels (relative risk 1.8, p < 0.01). In contrast, no additional risk was observed with advancing age. Cholesterol-lowering treatment with HMG-CoA reductase inhibitors is effective to improve the prognosis of Japanese elderly patients, including those with normal serum cholesterol level.     

Coronary artery calcium and cardiovascular risk in diabetes

Measurement of coronary artery calcium score (CACS) by electron beam tomography has been shown to a powerful predictor of coronary heart disease events in asymptomatic non-diabetic subjects. In type 2 diabetes, measurement of CACS was found to be a powerful predictor of cardiovascular events which could enhance prediction provided by established risk models. 23% of type 2 diabetic subjects with low CACS were found to be at low risk for cardiovascular events. Moreover mortality was similar for type 2 diabetic and non-diabetic subjects with undetectable coronary artery calcification. Conversely type 2 diabetic subjects with high CACS were identified who were at high cardiovascular risk. Thus not all those with type 2 diabetes are at similar cardiovascular risk. Measurement of CACS enables cardiovascular risk in type 2 diabetes to be stratified so that the level of preventive therapy could be reduced in some and intensified in others. Although prospective data for the power of CACS to predict CHD events in type 1 diabetes are lacking, measurement of CACS could help in deciding on preventive therapy in type 1 diabetes.