(3S-5S-6E)-7-[3-(4-fluorophenyl)-1-(propan-2-yl)-1H-indol-2-yl]-3-5-dihydroxyhept-6-enoic-acid and Diabetes-Mellitus

The long-term event monitoring (LEM) study evaluated the lipid-lowering efficacy and safety of fluvastatin in Japanese patients with hypercholesterolemia. The present sub-analysis focused on the impact of risk factors on event prevention.. In the LEM study, patients (n=21,139) who started fluvastatin between 2000/4/1 and 2002/3/31 in Japan were prospectively registered and followed up for 3 years (secondary prevention cohort) or 5 years (primary prevention cohort).. Of the patients registered, 19,084 were included in this sub-analysis. The secondary prevention group, demonstrated 8.27- and 2.89-fold higher incidence in cardiac events and cerebral events, respectively compared with the primary prevention group (P < 0.001). Complications of cerebrovascular disease demonstrated a 2.22- and 5.29-fold higher incidence in cardiac events and cerebral events (P < 0.01 and P < 0.001, respectively). Presence of diabetes mellitus (DM) in patients without complication significantly increased the incidence in both cardiac events (2.37) and cerebral events (2.15) as compared with non-DM patients for primary prevention (P < 0.001 and P < 0.01, respectively). For the secondary prevention, DM patients with complication of cardiac disease showed a significantly higher incidence in both cardiac events (1.59) and cerebral events (3.79) compared with non-DM patients (P < 0.05 and P < 0.01, respectively). In contrast, DM patients with complications of cerebrovascular disease showed a significantly higher incidence in cerebral events (2.58, P < 0.05), but not cardiac events compared with non-DM patients. Similarly, the presence of hypertension significantly increased the incidence in both cardiac (1.64) and cerebral events (1.81) for primary prevention (P < 0.01 and P < 0.05, respectively). For secondary prevention, hypertension in patients with complication of cardiac or cerebrovascular disease did not affect incidence in both cardiac and cerebral events. In the patients without complication, high triglycerides and low high density lipoprotein cholesterol (HDL-C), but not low density lipoprotein cholesterol (LDL-C), increased cerebral events, while only LDL-C significantly increased cardiac events. For secondary prevention, high triglycerides or low HDL-C, but not LDL-C, significantly increased the relative risk of cardiac events in the patients with complication of cardiac disease.. The LEM study, a large-scale prospective study of long-term fluvastatin treatment for hypercholesterolemia in Japanese patients, demonstrated high impact of complications such as DM and hypertension as well as high triglycerides or low HDL-C on cardiac and cerebral events. After long-term statin treatment, the control of other factors rather than LDL-C alone might be important to avoid vascular events.

Topics: Aged; Anticholesteremic Agents; Cardiovascular Diseases; Cerebrovascular Disorders; Cohort Studies; Diabetes Mellitus; Drug Monitoring; Fatty Acids, Monounsaturated; Female; Fluvastatin; Follow-Up Studies; Humans; Hypercholesterolemia; Hypertension; Indoles; Japan; Male; Middle Aged; Primary Prevention; Prospective Studies; Risk Factors; Secondary Prevention; Time Factors; Treatment Outcome

It is well established that statins improve the prognosis of patients with coronary artery disease. However, it is still unclear whether the protective effects of statins relate to lipid lowering alone or whether other pleiotropic effects may contribute. Thus, we compared the endothelial function among two groups of diabetic patients treated with fluvastatin 60 mg (F60) or fluvastatin 20 mg combined with ezetimibe 10 mg (F20/E10). The endothelial function was evaluated by measuring flow-mediated vasodilatation (FMD) at baseline and follow-up at 10 weeks. Similar improvements in FMD were observed in the two groups. The reduction in low-density lipoprotein cholesterol (LDL-C) was less pronounced in the F60 group, compared with the F20/E10 group. A significant reduction in remnant-like lipoprotein particles cholesterol (RLP-C) was observed in the F20/E10 group, but not in the F60 group. A correlation between the observed reduction in LDL-C or RLP-C and the improvement in FMD was observed in F20/E10 group. These results suggest that high-dose fluvastatin might have pleiotropic effects of potential clinical benefit, and that the combination of ezetimibe with a reduced dose of fluvastatin may also significantly improve endothelial function with reduction of LDL-C and RLP-C.

Topics: Aged; Anticholesteremic Agents; Azetidines; Cholesterol, HDL; Cholesterol, LDL; Diabetes Mellitus; Dose-Response Relationship, Drug; Drug Therapy, Combination; Endothelium, Vascular; Ezetimibe; Fatty Acids, Monounsaturated; Female; Fluvastatin; Humans; Indoles; Male; Middle Aged; Treatment Outcome; Triglycerides; Vasodilation

The effect of a cholesterol-lowering diet and subsequent fluvastatin treatment (Lescol, Novartis; 20 mg/day) on serum lipids and lipoproteins was investigated in 21 diabetic patients (eight women, 13 men, age range 31-63 years, BMI 25.9 +/- 4.5 kg/m2) who had undergone successful kidney transplantation. A cholesterol-lowering diet followed for 8 weeks had apparently no effect on serum lipid concentrations. Fluvastatin applied afterwards for 12 months significantly decreased the total cholesterol, triglyceride and LDL cholesterol levels from 7.7 +/- 0.94, 2.84 +/- 0.85 and 4.87 +/- 1.05 mmol/l to 6.40 +/- 0.74, 2.64 +/- 0.86 and 3.52 +/- 0.69 mmol/l, P < 0.001, < 0.05 and < 0.001, respectively, while the level of HDL cholesterol increased from 1.12 +/- 0.28 to 1.52 +/- 0.39 mmol/l, P < 0.001. Serum concentration of lipoprotein(a) remained unchanged. The serum level of apolipoprotein-A1 increased from 1.52 +/- 0.28 to 1.83 +/- 0.29 mmol/l (P < 0.01) and that of lipoprotein-B decreased from 1.37 +/- 0.20 to 1.20 +/- 0.36 mmol/l (P < 0.05). These maximum changes were achieved by the 12th week of fluvastatin treatment, and no further significant change was observed in the remaining part of the year. The other parameters that could have influenced lipid metabolism (doses of diuretics and steroid, daily dose and serum level of cyclosporin, kidney function, degree of proteinuria, HbA1c, etc.) remained unchanged throughout the study. Thus, the improvement in lipid concentrations can be ascribed exclusively to fluvastatin. No side effects were observed during the 1-year follow up. Liver enzymes and CPK remained within the normal reference limits. Fluvastatin proved to be an effective and safe drug for treating the dyslipidaemia of transplanted patients receiving steroid cyclosporin immunosuppression.

Topics: Adult; Anticholesteremic Agents; Cholesterol; Diabetes Mellitus; Diet; Fatty Acids, Monounsaturated; Female; Fluvastatin; Follow-Up Studies; Humans; Indoles; Kidney Transplantation; Lipoproteins; Male; Middle Aged

Randomized control trials of statins have not demonstrated significant benefits in outcomes of heart failure (HF). However, randomized control trials may not always be generalizable. The aim was to determine whether statin and statin type-lipophilic or -hydrophilic improve long-term outcomes in Africans with HF.. This was a retrospective longitudinal study of HF patients aged ≥18 years hospitalized at a tertiary healthcare center between January 1, 2009 and December 31, 2013 in Ghana. Patients were eligible if they were discharged from first admission for HF (index admission) and followed up to time of all-cause, cardiovascular, and HF mortality or end of study. Multivariable time-dependent Cox model and inverse-probability-of-treatment weighting of marginal structural model were used to estimate associations between statin treatment and outcomes. Adjusted hazard ratios were also estimated for lipophilic and hydrophilic statin compared with no statin use. The study included 1488 patients (mean age 60.3±14.2 years) with 9306 person-years of observation. Using the time-dependent Cox model, the 5-year adjusted hazard ratios with 95% CI for statin treatment on all-cause, cardiovascular, and HF mortality were 0.68 (0.55-0.83), 0.67 (0.54-0.82), and 0.63 (0.51-0.79), respectively. Use of inverse-probability-of-treatment weighting resulted in estimates of 0.79 (0.65-0.96), 0.77 (0.63-0.96), and 0.77 (0.61-0.95) for statin treatment on all-cause, cardiovascular, and HF mortality, respectively, compared with no statin use.. Among Africans with HF, statin treatment was associated with significant reduction in mortality.

Topics: Aged; Atorvastatin; Atrial Fibrillation; Black People; Cardiomyopathy, Dilated; Cardiovascular Diseases; Cause of Death; Comorbidity; Coronary Artery Disease; Diabetes Mellitus; Fatty Acids, Monounsaturated; Fluvastatin; Ghana; Heart Failure; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Hypertension; Indoles; Kaplan-Meier Estimate; Longitudinal Studies; Middle Aged; Mortality; Multivariate Analysis; Probability; Proportional Hazards Models; Renal Insufficiency, Chronic; Retrospective Studies; Rosuvastatin Calcium; Simvastatin; Treatment Outcome

Statins have been reported to prevent adverse cardiovascular events in patients with myocardial infarction (MI). However, the association of statin use and the risk of pneumonia requiring hospitalization in MI patients remains unclear.. A nested case-control study was conducted by using data from the National Health Insurance Research Database of Taiwan. Among 24,975 patients with MI, 2686 case patients with pneumonia requiring hospitalization were age- and sex-matched with 10,726 control patients using the incidence density sampling approach. Duration and dosage of statin use were obtained from pharmaceutical claims. Conditional logistic regression analyses were used to estimate the risk of hospitalization for pneumonia associated with statin use adjusted for patient's demographics, medical conditions and prescribed medications.. Statin use was associated with a 15% reduced risk of pneumonia requiring hospitalization among MI patients (adjusted odds ratio [aOR] = 0.85, 95% confidence interval [CI] = 0.77-0.95, P = 0.004). The association was more significant for MI patients unexposed to statin pretreatment (aOR = 0.76, 95% CI = 0.64-0.90, P = 0.001). Statins also exhibited favorable benefits in a time- and dose-dependent manner. The results were consistent in various subgroup analysis of the patients who were female, age ≥ 65 years, a low CHADS2 (i.e. congestive heart failure, hypertension, diabetes mellitus, previous stroke and age > 75 years old) score, and fewer comorbidities. Atorvastatin, fluvastatin and simvastatin were the most common prescribed statins and had similar effects.. Statins might be considered as an adjunctive therapy to reduce the risk of hospitalization for pneumonia for MI patients under thorough evaluation of individual comorbidities, previous statin use and optimal dosage.

Topics: Aged; Atorvastatin; Case-Control Studies; Comorbidity; Diabetes Mellitus; Fatty Acids, Monounsaturated; Female; Fluvastatin; Heart Failure; Hospitalization; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Hypertension; Incidence; Indoles; Logistic Models; Male; Middle Aged; Myocardial Infarction; Odds Ratio; Pneumonia; Protective Factors; Retrospective Studies; Risk Factors; Simvastatin; Stroke; Taiwan

Dysglycemia and dyslipidemia are important metabolic complications of organ transplantation. Statins are widely used to control dyslipidemia; however, long-term use of statins is related to diabetes mellitus (DM) and impaired fasting glucose (IFG). The aim of this study was to evaluate the influence of statins on the development of dysglycemia (IFG and/or DM) in renal allograft recipients.. A total of 394 patients without previously known DM or IFG who underwent kidney transplantation were enrolled. Patients were grouped into the two groups according to the use of statin (control, n=149; statin, n=245). The major statins used were fluvastatin (80 mg/d, n=134) and atorvastatin (20 mg/d, n=111). We compared the incidence of IFG or DM during the follow-up period.. The incidence of IFG was higher in the statin group than that in the control group (28.6% vs. 8.7%, P<0.001). The incidence of dysglycemia was significantly higher in the statin group (40.0% vs. 15.4%, P=0.001). Time to development of dysglycemia after transplantation was shorter in the statin group than in the control group (38.8±29.7 vs. 47.2±23.3 months, P=0.002). Statin use was associated with an increased risk for dysglycemia after adjustment for age, sex, body mass index, hypertension, cholesterol levels, hepatitis C infection, and type of immunosuppressant (hazard ratio=3.08, 95% confidence interval=1.91-4.98). The dysglycemic effect was more profound in the patients who used atorvastatin than in those who used fluvastatin (hazard ratio=2.21, 95% confidence interval=1.02-4.76).. Statin treatment is associated with an elevation in fasting plasma glucose and in the development of dysglycemia in renal allograft recipients.

Topics: Adult; Anticholesteremic Agents; Atorvastatin; Blood Glucose; Diabetes Complications; Diabetes Mellitus; Dyslipidemias; Fasting; Fatty Acids, Monounsaturated; Female; Fluvastatin; Follow-Up Studies; Glomerular Filtration Rate; Heptanoic Acids; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Hyperglycemia; Immunosuppressive Agents; Incidence; Indoles; Kidney Transplantation; Male; Middle Aged; Pyrroles; Renal Insufficiency

The French National Health Insurance and the Ministry of Health have introduced multiple reforms in recent years to increase prescribing efficiency. These include guidelines, academic detailing, financial incentives for the prescribing and dispensing of generics drugs as well as a voluntary pay-for-performance programme. However, the quality and efficiency of prescribing could be enhanced potentially if there was better understanding of the dynamics of prescribing behaviour in France.. To analyse the patient and general practitioner characteristics that influence patented versus multiple-sourced statin prescribing in France.. Statistical analysis was performed on the statin prescribing habits from 341 general practitioners (GPs) that were included in the IMS-Health Permanent Survey on Medical Prescription in France, which was conducted between 2009 and 2010 and involved 14,360 patients. Patient characteristics included their age and gender as well as five medical profiles that were constructed from the diagnoses obtained during consultations. These were (1) disorders of lipoprotein metabolism, (2) heart disease, (3) diabetes, (4) complex profiles and (5) profiles based on other diagnoses. Physician characteristics included their age, gender, solo or group practice, weekly workload and payment scheme.. Patient age had a statistically significant impact on statin prescribing for patients in profile 1 (disorders of lipoprotein metabolism) and profile 3 (complex profiles) with a greater number of patented statins being prescribed for the youngest patients. For instance, patients older than 76 years with a complex profile were prescribed fewer patented statins than patients aged 68-76 years old with the same medical profile (coefficient: -0.225; p = 0.0008). By contrast, regardless of the patient's age, the medical profile did not affect the probability of prescribing a patented statin except in young patients with heart diseases who were prescribed a greater number of patented statins (coefficient: 0.3992; p = 0.0007). Prescribing was also statistically influenced by physician features, e.g., older male physicians were more likely to prescribe patented statins (coefficient: 0.245; p = 0.0417) and GPs practicing in groups were more likely to prescribe multiple sourced statins (coefficient: -0.178; p = 0.0338), which is an important finding of the study. GPs with a lower workload prescribed a greater number of patented statins.. There is significant variability in the prescribing of different statins among patient and physician profiles as well as between solo and group practices. Consequently, there are opportunities to target demand-side measures to enhance the prescribing of multiple-sourced statins. Further studies are warranted, in particular in other therapeutic classes, to provide a counter-balance to the considerable marketing activities of pharmaceutical companies.

Topics: Adult; Age Factors; Aged; Aged, 80 and over; Atorvastatin; Diabetes Mellitus; Drug Prescriptions; Drugs, Generic; Fatty Acids, Monounsaturated; Female; Fluorobenzenes; Fluvastatin; France; General Practitioners; Heart Diseases; Heptanoic Acids; Humans; Indoles; Lipid Metabolism Disorders; Male; Middle Aged; Models, Statistical; Practice Patterns, Physicians'; Pravastatin; Prescription Drugs; Pyrimidines; Pyrroles; Rosuvastatin Calcium; Simvastatin; Sulfonamides

Renal transplantation is associated with an increased risk for premature cardiovascular disease. We analyzed the data in the placebo arm of Assessment of Lescol in Renal Transplantation (ALERT) to improve our understanding of the relationship between cardiovascular risk factors and outcomes in this unique population.. We performed Cox survival analysis for myocardial infarction, cardiac death, and noncardiac death in 1,052 patients recruited to the placebo arm of ALERT. These subjects were aged 30 to 75 years, had stable graft function at least 6 months after transplantation, had a serum total cholesterol level between 155 and 348 mg/dL (4 and 9 mmol/L), and were receiving cyclosporine-based immunosuppression.. The results confirm previous studies. In multivariate analysis, preexisting coronary heart disease (hazard ratio [HR], 3.69; P < 0.001), total cholesterol level (HR, 1.55 per 50 mg/dL; P = 0.0045), and prior acute rejection (HR, 2.36; P = 0.0023) were independent risk factors. Conversely, independent risk factors for cardiac death were age (HR, 1.58 per decade; P = 0.0033), diabetes (HR, 3.35; P = 0.0002), ST-T changes on the ECG (HR, 3.17; P = 0.0004), and serum creatinine level (HR, 2.65 per milligram per deciliter; P < 0.0001).. This analysis confirms that renal transplant recipients share risk factors for myocardial infarction and cardiac death with the general population. However, the pattern of risk factors and their relationship with outcomes is atypical, highlighting the unique nature of cardiovascular risk in transplant recipients.

Topics: Adult; Aged; Cardiovascular Diseases; Creatinine; Death, Sudden, Cardiac; Diabetes Mellitus; Double-Blind Method; Fatty Acids, Monounsaturated; Female; Fluvastatin; Follow-Up Studies; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Hypercholesterolemia; Immunosuppressive Agents; Indoles; Kidney Failure, Chronic; Kidney Transplantation; Male; Middle Aged; Mortality; Myocardial Infarction; Obesity; Proportional Hazards Models; Randomized Controlled Trials as Topic; Risk Factors; Smoking; Survival Analysis

To investigate the direct anti-atherosclerotic properties of statins.. Using in vitro and ex vivo models, the effect of different statins on key events involved in atherogenesis has been investigated. We studied the ability of statins to modulate modified LDL-induced cholesterol esterification, metalloproteinase secretion by macrophages, and arterial myocyte migration and proliferation. The mechanisms underlying the inhibitory effect of statins have also been explored. Finally, the antiproliferative effect of sera from statin-treated patients has been confirmed in a cell culture system.. Fluvastatin, simvastatin, lovastatin, atorvastatin, and cerivastatin, but not pravastatin, dose-dependently decrease smooth muscle cell (SMC) migration and proliferation. Moreover, statins are able to reduce cholesterol accumulation in macrophages in vitro by blocking cholesterol esterification and endocytosis of modified lipoproteins and matrix-degrading enzyme secretion. This in vitro inhibition was completely prevented by mevalonate and partially by all-trans farnesol and all-trans geranylgeraniol, confirming the specific role of isoprenoid metabolites (probably through prenylated protein[s]) in regulating these cellular events. The inhibitory effect of statins on SMC proliferation has been shown in different models of proliferating cells, such as cultured arterial myocytes and rapidly proliferating carotid and femoral intimal lesions in rabbits, independently of their ability to reduce plasma cholesterol. Finally, ex vivo studies showed that sera from fluvastatin-treated patients interfere with SMC proliferation.. These results suggest that 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors exert a direct anti-atherosclerotic effect in the arterial wall, beyond their effects on plasma lipids that could translate into a more significant prevention of cardiovascular disease. These findings provide a basis for the beneficial effect of statins in clinical trials also involving diabetic patients--a population with a higher absolute risk of recurrent cardiovascular events.

Topics: Animals; Arteriosclerosis; Atorvastatin; Cell Division; Cell Movement; Cells, Cultured; Cholesterol; Cholesterol Esters; Diabetes Complications; Diabetes Mellitus; Diabetic Angiopathies; Endocytosis; Fatty Acids, Monounsaturated; Fluvastatin; Heptanoic Acids; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Indoles; Lipoproteins; Lovastatin; Macrophages; Macrophages, Peritoneal; Mice; Mice, Inbred BALB C; Muscle, Smooth; Pyridines; Pyrroles; Simvastatin

Currently available data and clinical observations which suggest that there is a pathogenetic relationship between hypertension, diabetes mellitus, and atherosclerosis have provided a concept of the X syndrome, by which hypertensive patients, mainly males, have impaired insulin tolerance along with hyperinsulinemia and concurrent atherogenic disorders of lipid metabolism. The paper discussed the specific pathogenetic mechanisms, clinical manifestations, and prospects for drug correction of the metabolic syndrome. The treatment of arterial hypertension with the calcium antagonist Lomir has indicated there are no negative changes as a control of non-insulin-dependent diabetes mellitus in the presence of effective correction of arterial hypertension and atherogenic dyslipidemias. With the monotherapy of essential hypertension concurrent with hypercholesterolemia with the alpha 1-adrenoblocker Doxazosin, in addition to the agent's high antihypertensive effects, the authors noted its favourable action on lipid spectral parameters and platelet functional activity. There is abundant evidence for the use of specific hypolipidemic agents in patients with essential hypertensive refractory to current antihypertensive drugs. The data obtained with the use of Lescol (fluvastatin) in patients with hypertensive disease and hypercholesterolemia suggest that by substantially reducing the levels of total cholesterol, triglycerides, low density lipoprotein cholesterol and its transport protein apo B does not deteriorate the quality of correction of arterial hypertension in this group of patients.

Topics: Anticholesteremic Agents; Arteriosclerosis; Diabetes Mellitus; Diabetes Mellitus, Type 2; Doxazosin; Enzyme Inhibitors; Fatty Acids, Monounsaturated; Female; Fluvastatin; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Hypercholesterolemia; Hypertension; Indoles; Insulin Resistance; Isradipine; Lipid Metabolism; Male; Middle Aged; Syndrome