ezetimibe--simvastatin-drug-combination and Dyslipidemias

Patients with diabetes represent a population at higher risk for cardiovascular disease. Diabetic dyslipidemia is characterized by the so-called atherogenic lipid triad, consisting of an increase in small dense low density lipoprotein particles and in triglyceride-rich lipoproteins, and a decrease in high-density lipoprotein cholesterol, with an increase in non-HDL cholesterol. Numerous trials have investigated the efficacy of add-on ezetimibe therapy for patients with type 2 diabetes and not controlled by statin therapy. The published data highly suggest that patients with type 2 diabetes may be more likely to benefit from ezetimibe/statin combination therapy. However, evidence specifically addressing hard clinical endpoints and prospective trials addressing differences in response between patients with or without diabetes are still needed.

Topics: Azetidines; Biomarkers; Diabetes Mellitus, Type 2; Drug Combinations; Dyslipidemias; Ezetimibe, Simvastatin Drug Combination; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Lipids; Simvastatin; Treatment Outcome

Proprotein convertase subtilisin/kexin type 9 (PCSK9) plays a major role in the regulation of lipoprotein metabolism, mostly through control of low-density lipoprotein receptor degradation. Depletion of cellular cholesterol causes a compensatory increase in plasma PCSK9 levels, which can diminish the cholesterol-lowering power of statins and may lead to the overproduction of intestinal lipoproteins, mainly thorough the up regulation of microsomal triglyceride transfer protein and the Niemann-Pick C1-like 1 protein, the target of ezetimibe. Thus, ezetimibe therapy may counter this unwanted effect of statins, providing an additional theoretical rationale for combining the effect of ezetimibe on intestinal cholesterol absorption and that of statins on cholesterol synthesis.

Topics: Animals; Azetidines; Cholesterol; Drug Combinations; Drug Synergism; Dyslipidemias; Ezetimibe, Simvastatin Drug Combination; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Intestinal Absorption; Intestines; Lipoproteins; Proprotein Convertase 9; Proprotein Convertases; Receptors, LDL; Serine Endopeptidases; Simvastatin; Treatment Outcome

Atherosclerotic cardiovascular disease (ASCVD) is a leading cause of morbidity and mortality in developed countries. The management of blood cholesterol through use of 3-hydroxy-3-methyl-glutaryl-CoA (HMG-CoA) reductase inhibitors (statins) in at-risk patients is a pillar of medical therapy for the primary and secondary prevention of cardiovascular disease. The recent 2013 American College of Cardiology/American Heart Association guideline on managing blood cholesterol provides an important framework for the effective implementation of risk-reduction strategies. The guideline identifies four cohorts of patients with proven benefits from statin therapy and streamlines the dosing and monitoring recommendations based on evidence from published, randomized controlled trials. Primary care physicians and cardiologists play key roles in identifying populations at elevated ASCVD risk. In providing a practical management overview of the current blood cholesterol guideline, we facilitate more informed discussions on treatment options between healthcare providers and their patients.

Topics: American Heart Association; Azetidines; Biomarkers; Cardiology; Cardiovascular Diseases; Cholesterol; Drug Combinations; Dyslipidemias; Ezetimibe, Simvastatin Drug Combination; Guideline Adherence; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Practice Guidelines as Topic; Practice Patterns, Physicians'; Risk Assessment; Risk Factors; Simvastatin; Treatment Outcome; United States

Topics: Azetidines; Cardiovascular Diseases; Cholesterol; Disease Progression; Drug Combinations; Dyslipidemias; Ezetimibe, Simvastatin Drug Combination; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Kidney Glomerulus; Kidney Tubules; Lipoproteins; Renal Insufficiency, Chronic; Risk Factors; Simvastatin

Although cholesterol-lowering medications can reduce the risk of recurrent cardiovascular events, premature discontinuation limits effectiveness. Discontinuation rates have not been systematically reported for lipid-lowering trials.. We evaluated medication discontinuation in IMPROVE-IT (Improved Reduction of Outcomes: Vytorin Efficacy International Trial), which evaluated placebo+simvastatin versus ezetimibe+simvastatin in patients hospitalized with the acute coronary syndrome and followed longitudinally postdischarge. Reasons for discontinuation were evaluated from randomization through study end (median 71.9 [interquartile range 51.8-85.8] months). Kaplan-Meier (KM) discontinuation rates were evaluated at 30 days, 1 year, and through year 7, and compared by treatment arm and region, with Cox proportional hazards modeling used to evaluate predictors of discontinuation. Overall, 46.7% of subjects discontinued study medication (KM rate by study end 50.9% [95% CI, 50.1%-51.7%]). The risk of discontinuation was highest early in the trial but decreased with increasing time, with a terminal KM rate per 100 person-years of 8.4 (8.2-8.6) from years 1 to 7. Discontinuation was higher in the placebo+simvastatin versus ezetimibe+simvastatin arm (KM rate 52.0% versus 49.8%, P=0.049) and was highest in the United States (7-year KM rate 57.4%). In multivariable modeling, smoking, prior revascularization, hypertension, unstable angina, female sex, nonwhite race, and US location were associated with higher discontinuation rates.. Although discontinuation was highest early and stabilized to 8% per year, because of prolonged follow-up, most discontinuation occurred after year 1. Adding ezetimibe to statin therapy did not increase discontinuation risk. Geographic differences and patient-level factors should be considered in trial design and analysis.. URL: https://www.clinicaltrials.gov . Unique identifier: NCT00202878.

Topics: Acute Coronary Syndrome; Aged; Asia; Australia; Biomarkers; Double-Blind Method; Drug Administration Schedule; Drug Utilization; Dyslipidemias; Europe; Ezetimibe, Simvastatin Drug Combination; Female; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Lipids; Male; Middle Aged; New Zealand; North America; Practice Patterns, Physicians'; Risk Factors; South America; Time Factors; Treatment Outcome

Background In randomized trials (SHARP [Study of Heart and Renal Protection], IMPROVE -IT [Improved Reduction of Outcomes: Vytorin Efficacy International Trial]), combination of statin and ezetimibe resulted in additional reduction of cardiovascular events. The reduction was greater in patients with type 2 diabetes mellitus (T2 DM ), where elevated remnant cholesterol and high cardiovascular disease risk is characteristic. To evaluate possible causes behind these results, 40 patients eligible for cholecystectomy, randomized to simvastatin, ezetimibe, combined treatment (simvastatin+ezetimibe), or placebo treatment during 4 weeks before surgery, were studied. Methods and Results Fasting blood samples were taken before treatment start and at the end (just before surgery). Bile samples and liver biopsies were collected during surgery. Hepatic gene expression levels were assessed with qPCR . Lipoprotein, apolipoprotein levels, and content of cholesterol, cholesteryl ester, and triglycerides were measured after lipoprotein fractionation. Lipoprotein subclasses were analyzed by nuclear magnetic resonance. Apolipoprotein affinity for human arterial proteoglycans ( PG ) was measured. Biomarkers of cholesterol biosynthesis and intestinal absorption and bile lipid composition were analyzed using mass spectrometry. Combined treatment caused a statistically significant decrease in plasma remnant particles and apolipoprotein B (ApoB)/lipoprotein content of cholesterol, cholesteryl esters, and triglycerides. All treatments reduced ApoB-lipoprotein PG binding. Simvastatin and combined treatment modified the composition of lipoproteins. Changes in biomarkers of cholesterol synthesis and absorption and bile acid synthesis were as expected. No adverse events were found. Conclusions Combined treatment caused atheroprotective changes on ApoB-lipoproteins, remnant particles, bile components, and in ApoB-lipoprotein affinity for arterial PG . These effects might explain the decrease of cardiovascular events seen in the SHARP and IMPROVE - IT trials. Clinical Trial Registration URL : www.clinicaltrialsregister.eu . Unique identifier: 2006-004839-30).

Topics: Apolipoprotein B-100; Bile; Biomarkers; Cholecystectomy; Cholesterol; Chylomicron Remnants; Dyslipidemias; Ezetimibe, Simvastatin Drug Combination; Female; Gallstones; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Liver; Male; Membrane Proteins; Membrane Transport Proteins; Middle Aged; Single-Blind Method; Time Factors; Treatment Outcome

Patients with diabetes mellitus and cardiovascular disease may not achieve adequate low-density lipoprotein cholesterol (LDL-C) lowering on statin monotherapy, attributed partly to atherogenic dyslipidemia. More intensive LDL-C-lowering therapy can be considered for these patients. A previous randomized, controlled study demonstrated greater LDL-C lowering in diabetic patients with symptomatic cardiovascular disease who switched from simvastatin 20 mg (S20) or atorvastatin 10 mg (A10) to combination ezetimibe/simvastatin 10/20 mg (ES10/20) therapy, compared with statin dose-doubling (to S40 or A20) or switching to rosuvastatin 10 mg (R10). The effect of these regimens on novel biomarkers of atherogenic dyslipidemia (low- and high-density lipoprotein particle number and lipoprotein-associated phospholipase A2 [Lp-PLA2]) was assessed.. Treatment effects on low- and high-density lipoprotein particle number (by NMR) and Lp-PLA2 (by ELISA) were evaluated using plasma samples available from 358 subjects in the study. Switching to ES10/20 reduced low-density lipoprotein-particle number numerically more than did statin dose-doubling and was comparable with R10 (-133.3, -94.4, and -56.3 nmol/L, respectively; P>0.05). Increases in high-density lipoprotein particle number were significantly greater with switches to ES10/20 versus statin dose-doubling (1.5 and -0.5 μmol/L; P<0.05) and comparable with R10 (0.7 μmol/L; P>0.05). Percentages of patients attaining low-density lipoprotein particle number levels <990 nmol/L were 62.4% for ES10/20, 54.1% for statin dose-doubling, and 57.0% for R10. Switching to ES10/20 reduced Lp-PLA2 activity significantly more than did statin dose-doubling (-28.0 versus -3.8 nmol/min per mL, P<0.05) and was comparable with R10 (-28.0 versus -18.6 nmol/min per mL; P>0.05); effects on Lp-PLA2 concentration were modest.. In diabetic patients with dyslipidemia, switching from statins to combination ES10/20 therapy generally improved lipoprotein subclass profile and Lp-PLA2 activity more than did statin dose-doubling and was comparable with R10, consistent with its lipid effects.. URL: http://www.clinicaltrials.gov. Unique identifier: NCT00862251.

Topics: 1-Alkyl-2-acetylglycerophosphocholine Esterase; Aged; Biomarkers; Cardiovascular Diseases; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Double-Blind Method; Drug Substitution; Dyslipidemias; Europe; Ezetimibe, Simvastatin Drug Combination; Female; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Lipoproteins; Male; Middle Aged; Risk Factors; South America; Time Factors; Treatment Outcome; United States

Although the efficacy of ezetimibe/simvastatin and atorvastatin on traditional lipid parameters has been studied extensively, the apolipoprotein B/apolipoprotein A1 (ApoB/ApoA1) ratio, which has a better predictive value for cardiovascular events, has not previously been used as a primary endpoint in these two treatment groups.. Our objective was to compare the efficacy and safety of ezetimibe/simvastatin 10/20 mg versus atorvastatin 20 mg once daily in Korean patients with type 2 diabetes mellitus.. This study was an open-label, randomized, controlled study. Type 2 diabetes patients with high levels of low-density lipoprotein (LDL) cholesterol (>100 mg/dL) were randomized to receive ezetimibe/simvastatin or atorvastatin.. The primary endpoint was the difference in the percent change of ApoB/ApoA1 at 12 weeks, and secondary endpoints were changes in lipid profiles, glycosylated hemoglobin (HbA1c), homeostatic model assessment (HOMA) index, and C-reactive protein.. In total, 132 patients (66 for each group) were enrolled and randomized. After 12 weeks of treatment, the ApoB/ApoA1 ratio was significantly reduced in both groups; however, the difference of changes between the two groups was not statistically significant (ezetimibe/simvastatin -38.6 ± 18.0 % vs. atorvastatin -34.4 ± 15.5 %; p = 0.059). There were no significant differences in changes to total cholesterol, LDL cholesterol, high-density lipoprotein cholesterol, triglycerides, ApoB, and ApoB48 between the two groups. However, the increments of ApoA1 were significantly greater in the ezetimibe/simvastatin group than in the atorvastatin group (2.8 ± 10.0 vs. -1.8 ± 9.8 %; p = 0.002). In the per-protocol analysis, improvement in ApoB/ApoA1 was significantly greater in the ezetimibe/simvastatin group (-42.8 ± 11.8 vs. -36.7 ± 13.2 %; p = 0.019). The changes in HbA1c, HOMA index, and C-reactive protein were comparable between the two groups. The adverse reaction rate was similar between the two groups (24.2 vs. 34.9 %; p = 0.180).. Ezetimibe/simvastatin 10/20 mg is comparable to atorvastatin 20 mg for the management of dyslipidemia, and may have more favorable effects on apolipoprotein profiles than atorvastatin 20 mg in Korean patients with type 2 diabetes mellitus.

Topics: Aged; Anticholesteremic Agents; Apolipoprotein A-I; Apolipoproteins B; Asian People; Atorvastatin; Azetidines; Cholesterol, LDL; Diabetes Mellitus, Type 2; Drug Combinations; Dyslipidemias; Ezetimibe, Simvastatin Drug Combination; Female; Heptanoic Acids; Humans; Lipids; Male; Middle Aged; Pyrroles; Republic of Korea; Simvastatin; Treatment Outcome

The dyslipidemia control through lipid lowering therapy is one of the targets for the treatment of CKD. By this pilot study we aimed to evaluate the effect of hypolipidemic drugs on the levels of low molecular weight (LMW) thiols bound to LDL in nephropatic patients. We enrolled thirty CKD randomized to receive three different hypolipidemic regimens: simvastatin alone (40 mg/day) or ezetimibe/simvastatin combined therapy (10/20 or 10/40 mg/day). LMW thiols in their reduced and total form, oxidative stress indices as malondialdehyde and allantoin/uric acid ratio were evaluated. LDL thiolation decreased in all treated patients, but a greater efficacy was attained from a combined therapy with a higher simvastatin dose, by which a 31% decrease of all S-bound thiols was reached after 1 year of therapy. In particular, in this patients group the reduction of apoB-Hcy was greater than 40%. The concomitant decrease of the oxidative stress indices during the therapy brings to the hypothesis that decreased levels of protein bound thiols may be a consequence of oxidative stress improvement. Therefore lipid lowering therapy may have beneficial effects also through the reduction of LDL-S-homocysteinylation that has been reported to have antiangiogenic and proatherogenic effect on endothelial vascular cells.

Topics: Allantoin; Apolipoproteins B; Azetidines; Cholesterol, LDL; Drug Combinations; Dyslipidemias; Ezetimibe, Simvastatin Drug Combination; Female; Homocystine; Humans; Hypolipidemic Agents; Lipid Metabolism; Male; Malondialdehyde; Middle Aged; Oxidative Stress; Pilot Projects; Renal Insufficiency, Chronic; Simvastatin; Sulfhydryl Compounds; Uric Acid

STUDY OBJECTIVE. To evaluate the effectiveness of switching statin therapy using a therapeutic conversion program versus usual care conversion among patients enrolled in the Colorado Indigent Care Program when atorvastatin was removed from the formulary.. Prospective cohort study.. Family medicine center and other ambulatory care clinics of a university-based health care system.. One hundred seventeen ambulatory care patients with dyslipidemia who were treated with atorvastatin.. Clinical pharmacists in the family medicine center implemented a therapeutic conversion program (30 patients), switching atorvastatin to a new formulary regimen of simvastatin, rosuvastatin, or ezetimibe-simvastatin, using an algorithm designed to achieve patient-specific goals for low-density lipoprotein cholesterol (LDL). Usual care occurred in the other ambulatory care clinics without clinical pharmacists (87 patients), where medical providers switched atorvastatin to a formulary regimen based on a suggested (but optional) equipotency conversion algorithm.. Primary end points were LDL concentration and LDL goal attainment before and after conversion. Before and after conversion, respectively, mean LDL concentrations were 86.7 and 82.3 mg/dl in the therapeutic conversion group (p=0.44) versus 78.3 and 85.2 mg/dl in the usual care group (p=0.01). Percentages of patients attaining LDL goal were 80% before and 97% after conversion in the therapeutic conversion group (p=0.04) compared with 90% before and 75% after conversion in the usual care group (p=0.01).. Use of a prospective, therapeutic statin conversion program was associated with increased control of dyslipidemia, whereas usual care statin conversion was associated with decreased control. These data suggest that proactive involvement of clinical pharmacists in converting lipid-lowering drugs results in superior patient care outcomes compared with a less aggressive approach.

Topics: Adult; Aged; Azetidines; Cholesterol, LDL; Colorado; Drug Combinations; Dyslipidemias; Ezetimibe, Simvastatin Drug Combination; Female; Fluorobenzenes; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Hypolipidemic Agents; Male; Pharmacists; Poverty; Pyrimidines; Rosuvastatin Calcium; Simvastatin; Sulfonamides

Triglyceride-rich lipoproteins may contribute to the high cardiovascular risk of patients with CKD. This study evaluated associations of apo-B and markers of triglyceride-rich lipoproteins with cardiovascular events in people with CKD.. Analyses were conducted in 9270 participants with CKD in the Study of Heart and Renal Protection (SHARP): 6245 not on dialysis (mean eGFR 26.5 ml/min per 1.73 m. During a median follow-up of 4.9 years (interquartile range, 4.0-5.5 years), 1406 participants experienced at least one atherosclerotic vascular event. In multivariable adjusted models, positive associations with atherosclerotic vascular events were observed for apo-B (HR per 1 SD, 1.19; 95% confidence interval, 1.12 to 1.27), triglycerides (1.06; 1.00 to 1.13), the ratio of triglyceride to HDL cholesterol (1.10; 1.03 to 1.18), and triglyceride-rich lipoprotein cholesterol (1.14; 1.05 to 1.25). By contrast, inverse associations with nonatherosclerotic vascular events were observed for each of these lipid markers: apo-B (HR per 1 SD, 0.92; 0.85 to 0.98), triglycerides (0.86; 0.81 to 0.92), the ratio of triglyceride to HDL cholesterol (0.88; 0.82 to 0.94), and triglyceride-rich lipoprotein cholesterol (0.85; 0.77 to 0.94).. Higher apo-B, triglycerides, ratio of triglyceride to HDL cholesterol, and triglyceride-rich lipoprotein cholesterol concentrations were associated with increased risk of atherosclerotic vascular events in CKD. Reducing triglyceride-rich lipoproteins using novel therapeutic agents could potentially lower the risk of atherosclerotic cardiovascular disease risk in the CKD population.

Topics: Aged; Anticholesteremic Agents; Apolipoprotein B-100; Biomarkers; Cardiovascular Diseases; Dyslipidemias; Ezetimibe, Simvastatin Drug Combination; Female; Glomerular Filtration Rate; Heart Disease Risk Factors; Humans; Kidney; Lipoproteins; Male; Middle Aged; Prognosis; Randomized Controlled Trials as Topic; Renal Dialysis; Renal Insufficiency, Chronic; Risk Assessment; Time Factors; Triglycerides

Markers of inflammation, including plasma C-reactive protein (CRP), are associated with an increased risk of cardiovascular disease, and it has been suggested that this association is causal. However, the relationship between inflammation and cardiovascular disease has not been extensively studied in patients with chronic kidney disease. To evaluate this, we used data from the Study of Heart and Renal Protection (SHARP) to assess associations between circulating CRP and LDL cholesterol levels and the risk of vascular and non-vascular outcomes. Major vascular events were defined as nonfatal myocardial infarction, cardiac death, stroke or arterial revascularization, with an expanded outcome of vascular events of any type. Higher baseline CRP was associated with an increased risk of major vascular events (hazard ratio per 3x increase 1.28; 95% confidence interval 1.19-1.38). Higher baseline LDL cholesterol was also associated with an increased risk of major vascular events (hazard ratio per 0.6 mmol/L higher LDL cholesterol; 1.14, 1.06-1.22). Higher baseline CRP was associated with an increased risk of a range of non-vascular events (1.16, 1.12-1.21), but there was a weak inverse association between baseline LDL cholesterol and non-vascular events (0.96, 0.92-0.99). The efficacy of lowering LDL cholesterol with simvastatin/ezetimibe on major vascular events, in the randomized comparison, was similar irrespective of CRP concentration at baseline. Thus, decisions to offer statin-based therapy to patients with chronic kidney disease should continue to be guided by their absolute risk of atherosclerotic events. Estimation of such risk may include plasma biomarkers of inflammation, but there is no evidence that the relative beneficial effects of reducing LDL cholesterol depends on plasma CRP concentration.

Topics: Aged; Anticholesteremic Agents; Biomarkers; C-Reactive Protein; Cardiovascular Diseases; Cholesterol, LDL; Down-Regulation; Dyslipidemias; Ezetimibe, Simvastatin Drug Combination; Female; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Inflammation; Inflammation Mediators; Male; Middle Aged; Randomized Controlled Trials as Topic; Renal Insufficiency, Chronic; Risk Factors; Severity of Illness Index; Time Factors; Treatment Outcome

After an acute coronary syndrome, the 6-year results of the "IMPROVE-IT" randomized trial showed a 1.6% reduction in the number of nonfatal myocardial infarctions with the ezetimibe + simvastatin combination compared with simvastatin alone, but no reduction in mortality.

Topics: Acute Coronary Syndrome; Anticholesteremic Agents; Biomarkers; Cholesterol, LDL; Dyslipidemias; Ezetimibe, Simvastatin Drug Combination; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Randomized Controlled Trials as Topic; Risk Assessment; Risk Factors; Time Factors; Treatment Outcome

Topics: Anticholesteremic Agents; Biomarkers; Cardiovascular Diseases; Cholesterol, LDL; Dyslipidemias; Evidence-Based Medicine; Ezetimibe; Ezetimibe, Simvastatin Drug Combination; Genetic Predisposition to Disease; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Membrane Proteins; Membrane Transport Proteins; Mutation; Phenotype; Polymorphism, Single Nucleotide; Randomized Controlled Trials as Topic; Risk Factors; Treatment Outcome

Topics: Anticholesteremic Agents; Azetidines; Drug Combinations; Dyslipidemias; Ezetimibe; Ezetimibe, Simvastatin Drug Combination; Fatty Liver; Humans; Insulin Resistance; Simvastatin