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Biomedical subjects

Michael H Davidson

Publications and source records attributed to Michael H Davidson.

At least 37 records · Page 2Linked to original sources
PubMed2006

Lipid-altering efficacy of the ezetimibe/simvastatin single tablet versus rosuvastatin in hypercholesterolemic patients.

OBJECTIVE: To assess the lipid-altering efficacy and safety of ezetimibe/simvastatin single tablet product compared with rosuvastatin at the approved usual starting, next highest, and maximum doses. RESEARCH DESIGN AND METHODS: Double-blind, multicenter, 6-week, parallel-group study in hypercholesterolemic patients (n = 2959). Patients were randomized based on stratification by low-density lipoprotein cholesterol (LDL-C) levels to ezetimibe/simvastatin or rosuvastatin, respectively, at the usual starting (10/20 or 10 mg/day), the next highest (10/40 or 20 mg/day), and maximum doses (10/80 or 40 mg/day). RESULTS: At all doses and across doses, ezetimibe/simvastatin reduced LDL-C levels significantly more (52-61%) than rosuvastatin (46-57%; p < or = 0.001). Significantly greater percentages of all patients (p < 0.001) and high risk patients (p < or = 0.005) attained LDL-C levels < 70 mg/dL (1.8 mmol/L) following ezetimibe/simvastatin treatment compared with rosuvastatin at the prespecified doses and across doses. Ezetimibe/simvastatin also produced significantly greater reductions in total cholesterol (p < 0.001), non-high-density lipoprotein cholesterol (p < 0.001), lipid ratios (p < or = 0.003), and apolipoprotein B (p < 0.05). Reductions in triglycerides were significantly greater with ezetimibe/simvastatin than rosuvastatin at the usual starting (p = 0.004) and next highest (p = 0.006) doses, and across all doses (p < 0.001). Increases in high-density lipoprotein cholesterol, and decreases in high sensitivity C reactive protein (hsCRP) were similar between treatment groups. Safety profiles were comparable for both treatments; however, the percent of patients with proteinuria was significantly higher following rosuvastatin treatment than ezetimibe/simvastatin, respectively at 10 mg versus 10/20 mg/day (p = 0.004) and 40 mg versus 10/80 mg/day (p < 0.001). CONCLUSION: Ezetimibe/simvastatin was more effective than rosuvastatin in LDL-C lowering, and provided greater or comparable improvements in other lipid measures and hsCRP at the approved usual starting, next highest, and maximum doses in hypercholesterolemic patients. Although the doses compared in this study were not equivalent on a milligram basis, the results provide clinically relevant information regarding the use of these drugs for initial therapy and for subsequent use at higher doses when appropriate. Both treatments were generally well-tolerated; however, this study was not powered nor of sufficient duration to assess the prevalence of rare clinical adverse effects. Overall, ezetimibe/simvastatin offers an effective and tolerable treatment option for lipid management. An assessment of its full clinical benefit awaits evaluation in longer-term clinical studies.

Anticholesteremic Agents↗
PubMed2006

Lipid-lowering effects of statins: a comparative review.

The pharmacological regulation of lipid metabolism in patients with dyslipidaemia is unequivocally associated with significant reductions in risk for cardiovascular morbidity and mortality. There is strong clinical trial data to support of the use of statin therapies in the settings of both primary and secondary prevention. This paper addresses: i) the mechanisms of action of antilipidaemic medications; ii) dosing regimens and the pharmacokinetic differences among drugs of the same class; iii) risk for drug interactions; and iv) reviews the clinical trial evidence used to support the use of particular antilipidaemic medications in specific physiological settings.

Cytochrome P-450 CYP3A↗
PubMed2006

Statin/fibrate combination in patients with metabolic syndrome or diabetes: evaluating the risks of pharmacokinetic drug interactions.

Patients with the metabolic syndrome and/or Type 2 diabetes mellitus continue to have a high risk of coronary heart disease (CHD) and progression of atherosclerotic lesions despite aggressive statin therapy. Although the National Cholesterol Education Programme Adult Treatment Panel III guidelines recommend the use of fibrates in combination with statins in patients at very high risk of CHD (e.g., patients at the low-density lipoprotein cholesterol target with high triglycerides and low high-density lipoprotein cholesterol, many physicians remain reluctant to use these combinations due to concerns of myotoxicity. Recently conducted metabolic and pharmacokinetic drug-drug interaction studies using gemfibrozil or fenofibrate in combination with five commonly used statins demonstrated a widely different drug interaction potential for these two fibrates. Gemfibrozil causes a 2- to 6-fold increase in statin area under the curve and increases the exposure to many recently approved drugs for the treatment of diabetes. Alternatively, fenofibrate does not adversely affect either the metabolism or pharmacokinetics of the statins studied. These pharmacokinetic differences appear to translate into less potential for interactions with fenofibrate/statin combination therapy compared to gemfibrozil/statin co-administration. The Action to Control Cardiovascular Risk in Diabetes (ACCORD) study in 10,000 patients with Type 2 diabetes mellitus is testing the efficacy and safety of fenofibrate/statin combination.

Area Under Curve↗
PubMed2006

Combination therapy with ezetimibe and simvastatin to achieve aggressive LDL reduction.

A low-density lipoprotein (LDL) cholesterol goal of less than 100 mg/dl is recommended for patients at moderate to high risk of cardiovascular disease with an optional LDL goal of less than 70 mg/dl for patients at a very high risk of cardiovascular disease. Most patients will require reductions in LDL of more than 50% in order to achieve these more aggressive goals. Only a few agents will lower LDL by at least 50%. This review will focus on the efficacy and safety ezetimibe/simvastatin coadministered as a therapy with enhanced LDL-lowering efficacy, while minimizing the adverse effects of statins in a wide range of patients. Ezetimibe 10 mg/simvastatin 80 mg lowers LDL by approximately 60% and has been demonstrated to be superior to the highest doses of atorvastatin and rosuvastatin for lowering LDL and raising high-density lipoprotein.

Anticholesteremic Agents↗
PubMed2006

Differences between clinical trial efficacy and real-world effectiveness.

Aggressive lowering of low-density lipoprotein cholesterol (LDL-C) with statin therapy can reduce the incidence of morbidity and mortality from coronary heart disease (CHD) in primary and secondary prevention settings. Indeed, suboptimal statin treatment has been associated with an increased risk of CHD events. Surveys such as the Lipid Treatment Assessment Project (L-TAP) and National Cholesterol Education Program Evaluation Project Utilizing Novel E-Technology (NEPTUNE) II have demonstrated that patients in real-world clinical settings often fail to reach the target goals set forth by the National Cholesterol Education Program (NCEP) Adult Treatment Panel III (ATP III). This failure to reach target LDL-C levels in real-world clinical practice presents a therapeutic treatment gap. There may be multiple reasons for this discrepancy: lack of patient follow-up, absence of well-defined protocols (ie, use of low-potency statins in high-risk patients), adherence controls (eg, pill counts, refill records), cost, and lack of patient motivation are a few possibilities. Several large clinical trials since ATP III have shown that these goals are achievable through aggressive statin therapy. This review sets forth compelling data that starting patients on or switching to high-efficacy LDL-C-lowering therapy enhances achievement of NCEP ATP III guidelines outside of the controlled trial setting.

Clinical Trials as Topic↗
PubMed2005

Striated muscle safety of ezetimibe/simvastatin (Vytorin).

Despite the excellent benefit/risk profile of statins, their use is limited by a dose-related risk of adverse events, particularly those related to muscle toxicity. Ezetimibe/simvastatin (Vytorin) is a cholesterol-lowering therapy that inhibits the intestinal absorption (ezetimibe) and synthesis (simvastatin) of cholesterol. This analysis compared the muscle safety profiles of ezetimibe/simvastatin and simvastatin monotherapy. We reviewed muscle-related adverse event (AE) data from 17 randomized, blinded clinical trials (13 base and 4 extension studies), in which ezetimibe and simvastatin were either co-administered as separate entities or given as a combination tablet to 4,558 patients. The following AE categories were summarized: incidence of musculoskeletal or connective-tissue AEs (all and drug related); discontinuations due to musculoskeletal or connective-tissue AEs (all and drug related); incidence of AEs reported under the term "myalgia" (all and drug related); discontinuation due to myalgia (all and drug related); incidence of "myopathy" (all and drug related); increases in creatine kinase to 3 to < 5, 5 to < 10, and > or = 10 times the upper limit of normal. For all AE categories examined, the incidence of muscle-related clinical and laboratory AEs or discontinuations due to muscle-related AEs was no more common in patients taking ezetimibe/simvastatin than in those taking simvastatin alone. Thus, the clinical trial experience with ezetimibe/simvastatin suggests that ezetimibe does not enhance or aggravate the muscle effects of simvastatin.

Azetidines↗
PubMed2005

Pharmacokinetic interactions between statins and fibrates.

Concomitant use of a fibrate and a statin may offer a therapeutic advantage to patients with dyslipidemia, especially in patients whose low-density lipoprotein cholesterol is controlled by statins but whose high-density lipoprotein cholesterol or triglycerides, or both, are not within goal. However, concern about drug-drug interactions may preclude optimal use of combination statin-fibrate therapy. This article reviews the pharmacokinetics between statins and fibrates, addressing risks associated with drug-drug interactions and combination therapy.

Area Under Curve↗
PubMed2005

Non-high-density lipoprotein cholesterol: the forgotten therapeutic target.

The National Cholesterol Education Program (NCEP) Adult Treatment Panel III (ATP III) has acknowledged mounting evidence of an independent association between hypertriglyceridemia and coronary artery disease risk by issuing guidelines that identify non-high-density lipoprotein (HDL) cholesterol as a secondary target for therapy in patients with elevated triglyceride levels. In 2003, a national survey of outpatient lipid management was conducted for patients undergoing treatment by physicians who were high prescribers of lipid-altering drugs. Results of the NCEP Evaluation Project Utilizing Novel E-Technology II (NEPTUNE II) survey indicated much higher frequencies of low-density lipoprotein (LDL) cholesterol goal achievement compared with frequencies observed in a similarly designed survey in 1997. However, non-HDL cholesterol treatment success in the NEPTUNE II survey was markedly lower than that for LDL cholesterol overall and across risk categories. More aggressive therapy is therefore needed to achieve non-HDL cholesterol goals than LDL cholesterol goals. After achievement of LDL cholesterol goals, non-HDL cholesterol can be managed more aggressively by lowering LDL cholesterol or by using strategies that target a reduction in very-low-density lipoprotein cholesterol. Because the prevalence of hypertriglyceridemia in the United States is high and increasing, enhanced efforts to improve non-HDL cholesterol goal achievement have the potential to produce a substantial effect on public health.

Cholesterol, HDL↗
PubMed2005

Reducing residual risk for patients on statin therapy: the potential role of combination therapy.

Cholesterol-lowering therapy with 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors, or statins, has been established as an effective method of reducing death and myocardial infarction among patients with coronary artery disease (CAD). However, a significant number of patients receiving statin therapy continue to have high residual risk. An important clinical challenge exists in reducing residual CAD risk with optimal therapies without increasing adverse effects. Combination therapy appears most appropriate for patients with a high rate of events of residual risk despite optimal statin therapy. This article discusses the role of combination therapy in managing CAD and in achieving optional targets in high-risk patient populations.

Atorvastatin↗
PubMed2005

Management of dyslipidemia in patients with complicated metabolic syndrome.

As the prevalence of the metabolic syndrome increases, 2 comorbid conditions--hepatic steatosis and human immunodeficiency virus (HIV) lipodystrophy--have become difficult clinical challenges. Dyslipidemia in patients with nonalcoholic fatty liver disease or nonalcoholic steatohepatitis may improve with use of statins, fibrates, niacin, and thiazolidinediones, but the data are presently very limited. HIV lipodystrophy is associated with a marked risk of coronary artery disease (CAD), and more aggressive management of the dyslipidemia is likely necessary to improve the prognosis.

Clofibric Acid↗
PubMed2005

Results of the National Cholesterol Education (NCEP) Program Evaluation ProjecT Utilizing Novel E-Technology (NEPTUNE) II survey and implications for treatment under the recent NCEP Writing Group recommendations.

The most recent national survey of compliance with the National Cholesterol Education Program (NCEP) Adult Treatment Panel (ATP) guidelines was completed before ATP III and showed significant underachievement of low-density lipoprotein (LDL) cholesterol goals. The NCEP Evaluation ProjecT Utilizing Novel E-Technology (NEPTUNE) II was a national survey conducted in 2003. Of the 4,885 patients, 67% achieved their LDL cholesterol treatment goal, including 89%, 76%, and 57%, respectively, in the 0 or 1 risk factor, > or = 2 risk factors or coronary heart disease (CHD), and CHD risk equivalent categories. The percentage with triglyceride concentrations > or = 200 mg/dl (2.25 mmol/L) in each risk category who achieved their LDL cholesterol and non-high-density lipoprotein cholesterol goals was 64%, 52%, and 27%, respectively. Patients with diabetes (55%) and other CHD risk equivalents (40%) were less likely to have achieved their LDL cholesterol targets than those with CHD (62%). Of the 1,447 patients with cardiovascular disease, 75% could be classified as very high risk according to the new July 2004 NCEP Writing Group recommendations, and 17.8% of those at very high risk had an LDL cholesterol level of <70 mg/dl (<1.81 mmol/L). In conclusion, these results suggest improved lipid management compared with previous surveys. The largest treatment gaps were found for features new to ATP III as of July 2004, including goal achievement for patients with CHD risk equivalents and for non-high-density lipoprotein cholesterol targets. Most of those (75%) with cardiovascular disease in NEPTUNE II would be considered very high risk and candidates for aggressive therapy to reach the new optional treatment goals.

Anticholesteremic Agents↗
PubMed2005

Reporting rate of rhabdomyolysis with fenofibrate + statin versus gemfibrozil + any statin.

There is an increasing trend among physicians to use 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (statins) in combination with other antilipidemic agents. The complementary lipid-altering effects of statins and fibric acid derivatives (fibrates) have led to an increasing use of statin/fibrate combination therapy, particularly for patients who have mixed dyslipidemia. Clinical experience indicates that there may be an increased risk of myotoxicity associated with statin/fibrate combination therapy. However, it is not known whether there are differences in the rate of myotoxicity between the use of fenofibrate and gemfibrozil in combination with statins. To evaluate this question, data from the United States Food and Drug Administration's Adverse Event Reporting System was reviewed to determine how many adverse events were reported for patients who were being treated concomitantly with statins and fibrates. The findings suggest that the use of fenofibrate in combination with statins results in fewer reports of rhabdomyolysis per million prescriptions dispensed than does the use of gemfibrozil.

Adverse Drug Reaction Reporting Systems↗
PubMed2005

Efficacy and safety profile of fenofibrate-coated microgranules 130 mg, with and without food, in patients with hypertriglyceridemia and the metabolic syndrome: an 8-week, randomized, double-blind, placebo-controlled study.

BACKGROUND: The limited bioavailability of certain fenofibrate formulations necessitates administration with food, raising concerns about efficacy and compliance. There is a need for new formulations that have improved bioavailability and eliminate the requirement for administration with food. OBJECTIVE: The aim of this study was to assess the food-related efficacy of a new formulation of micronized fenofibrate coated on inert microgranules (FF-muG) for the treatment of hypertriglyceridemia in patients exhibiting the metabolic syndrome. METHODS: This was a randomized, double-blind, placebo-controlled, double-dummy, parallel-group study in patients who had fasting triglyceride (TG) concentrations > or =300 mg/dL and <1000 mg/dL and met National Cholesterol Education Program Adult Treatment Panel III criteria for the metabolic syndrome. A 6-week washout and diet lead-in period was followed by an 8-week treatment period. Eligible patients were randomized to receive either FF-muG 130 mg with food, FF-muG 130 mg without food, or placebo every day for 8 weeks. The primary end point was the mean percent change in TG levels from baseline to the end of treatment; changes in other lipid end points were also assessed. Safety profiles were assessed based on adverse-event reports, changes in clinical laboratory values and vital signs (including electrocardiography), and the findings of physical examinations. RESULTS: One hundred forty-six patients took part in the study: 54 received FF-muG 130 mg with food, 42 received FF-muG 130 mg without food, and 50 received placebo. The groups were similar in terms of mean age (56 years), sex (59.5%-63.0% men; 37.0%-40.5% women), race (83.3%-100% white), mean body weight (92 kg), mean height (172 cm), mean fasting baseline TG concentrations (480 mg/dL), and other components of the metabolic syndrome. The 2 FF-muG groups (with and without food) showed similar improvements in the dyslipidemia associated with the metabolic syndrome: TG levels decreased a mean of 36.7% and 36.6%, respectively (P < 0.001 vs placebo). The overall frequency of adverse events was similar in the 2 FF-muG groups and did not differ significantly from placebo (63.0%, 61.9%, and 52.0%, respectively). Gastrointestinal disturbances (eg, diarrhea, dyspepsia) occurred more frequently in the 2 FF-muG groups compared with the placebo group (31.5%, 26.2%, and 12.0%; P = NS). Significant increases from baseline in alanine aminotransferase were seen in both FF-muG groups (mean [SEM], 3.77 [2.60] and 11.69 [7.42] U/L, respectively; P < or = 0.05 vs placebo); however, these increases were considered clinically significant in only 5 cases, none of them requiring discontinuation of study drug. CONCLUSIONS: This study found no inequivalence in the TG-lowering effects of the 2 fenofibrate regimens compared with placebo. Both regimens were well tolerated. Thus, FF-muG 130 mg administered without regard to meals appears to be efficacious and well tolerated for the treatment of hypertriglyceridemia in patients exhibiting the metabolic syndrome.

Capsules↗
PubMed2005

Effects of raloxifene and low-dose simvastatin coadministration on plasma lipids in postmenopausal women with primary hypercholesterolemia.

Abstract Raloxifene and low-dose simvastatin can each reduce low-density lipoprotein (LDL) cholesterol without affecting high-density lipoprotein (HDL) cholesterol and triglycerides. The objective of this double-blind, 12-week study is to determine whether raloxifene and simvastatin coadministration gives added benefit beyond either monotherapy in affecting fasting lipoproteins and apolipoproteins. Ninety-five postmenopausal women with moderately elevated LDL cholesterol (mean, 146 mg/dL) were randomized to placebo, raloxifene 60 mg/d, simvastatin 10 mg/d, or raloxifene 60 mg/d coadministered with simvastatin 10 mg/d. Raloxifene, simvastatin, and coadministration therapy reduced mean LDL cholesterol by 10.5%, 23.3%, and 31.0% from baseline, respectively ( P < .003 vs baseline; P < .02 vs placebo), and mean apolipoprotein B by 10.4%, 24.2%, and 30.0% from baseline, respectively ( P < .003 vs baseline; P < .02 vs placebo). Each active treatment decreased non-HDL cholesterol compared with placebo ( P < .01). Coadministration treatment was more effective than either monotherapy in reducing LDL cholesterol ( P < .05). Coadministration treatment reduced mean apolipoprotein B ( P < .001) and non-HDL cholesterol ( P < .001) when compared with raloxifene, but was not significantly different when compared with simvastatin. Coadministration therapy increased HDL cholesterol and apolipoprotein A1 levels compared with placebo ( P < .02). No significant effect on triglycerides, very low density lipoprotein cholesterol, and lipoprotein (a) occurred with any active treatment. Raloxifene, simvastatin, and the coadministration therapy were generally well tolerated with clinical adverse effects similar to placebo. No woman had clinically significant elevated liver function tests requiring drug discontinuation. Further data on safety and lipid-lowering effects are needed before raloxifene and statin coadministration may be considered as therapeutic interventions for treating postmenopausal women to achieve National Cholesterol Education Program-Adult Treatment Panel III treatment guidelines.

Adult↗
PubMed2005

Lipid responses to a dietary docosahexaenoic acid supplement in men and women with below average levels of high density lipoprotein cholesterol.

OBJECTIVE: To assess fasting lipid responses to a docosahexaenoic acid (DHA) supplement in men and women with below-average levels of high-density lipoprotein (HDL) cholesterol. METHODS: This randomized, double-blind, controlled clinical trial included 57 subjects, 21-80 years of age, with fasting HDL cholesterol concentrations < or =44 mg/dL (men) and < or =54 mg/dL (women), but > or =35 mg/dL. Subjects were randomly assigned to receive either 1.52 g/day DHA from capsules containing DHA-rich algal triglycerides or olive oil (control) for six weeks. RESULTS: There were no significant differences between groups in baseline lipid values. The DHA supplemented group showed significant changes [-43 (DHA) vs. -14 (controls) mg/dL, p = 0.015] and percent changes [-21% (DHA) vs. -7% (controls), p = 0.009] in triglycerides, total (12 vs. 3 mg/dL; p = 0.021 and 6% vs. 2%; p = 0.018) and low-density lipoprotein (17 vs. 3 mg/dL; p = 0.001 and 12% vs. 3%; p = 0.001) cholesterol concentrations, and in the triglyceride to HDL cholesterol ratio (-1.33 vs. -0.50, p = 0.010), compared with controls. In addition, there was a significant reduction in the percentage of LDL cholesterol carried by small, dense particles in the DHA supplemented group (changes = -10% vs. -3%, p = 0.025). CONCLUSIONS: Supplementation with 1.52 g/d of DHA in men and women with below-average HDL cholesterol concentrations raised the LDL cholesterol level, but had favorable effects on triglycerides, the triglyceride/HDL cholesterol ratio and the fraction of LDL cholesterol carried by small, dense particles. Further research is warranted to evaluate the net impact of these alterations on cardiovascular risk.

Adult↗
PubMed2005

Use of a treatment algorithm to achieve NCEP ATP III goals with atorvastatin.

This multicenter, 8-week, single-step titration, open-label study sought to assess the percentage of subjects who achieved their National Cholesterol Education Program Adult Treatment Panel (NCEP ATP) III low-density lipoprotein (LDL)-cholesterol target when assigned a starting dose of atorvastatin (10 mg, 20 mg, 40 mg, or 80 mg) selected using an algorithm based on their 10-year CHD risk and the magnitude of LDL-cholesterol lowering necessary to reach goal. Following an 8-week washout period, 1298 subjects, categorized as low, medium, or high risk, were assigned to 4 weeks of treatment with a starting dose of atorvastatin selected by the algorithm. At week 4, subjects who did not achieve goal (15.8%) were titrated to the next-higher dose. The primary endpoint was the percentage of subjects in each risk group who achieved LDL-cholesterol goal at week 8. At 8 weeks, 84.8% of subjects (low risk 92.9%; moderate risk 84.0%; high risk 81.1%) achieved LDL-cholesterol target. The majority of patients (84.2%) achieved their lipid target through the use of the algorithm-based starting dose (10-80 mg) without the need for titration. No patient had elevations in creatine phosphokinase >10 times the upper limit of normal. Elevations in alanine aminotransaminase or aspartate aminotransaminase were observed in <1% of study subjects and were unrelated to dose. Selecting the starting dose of atorvastatin using a treatment algorithm achieves NCEP ATP III LDL-cholesterol goals in the majority of patients and minimizes the need for dose titration.

Adolescent↗