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Biomedical subjects

Michael H Davidson

Publications and source records attributed to Michael H Davidson.

At least 19 recordsLinked to original sources
PubMed2007

Squalene synthase inhibition: a novel target for the management of dyslipidemia.

A new class of compounds, known as squalene synthase inhibitors, has recently reached phase III clinical trials and may provide another therapeutic option for clinicians to improve risk management of low-density lipoprotein cholesterol (LDL-C). The clinical need for another LDL-C-lowering therapy is evident by the inability to achieve an LDL-C target of less than 70 mg/dL in the majority of very high-risk patients on statin monotherapy. Human clinical trial data with TAK-475, a novel and potent inhibitor of squalene synthase, have not yet been published.

Clinical Trials, Phase III as Topic↗
PubMed2006

Effect of pioglitazone compared with glimepiride on carotid intima-media thickness in type 2 diabetes: a randomized trial.

CONTEXT: Carotid artery intima-media thickness (CIMT) is a marker of coronary atherosclerosis and independently predicts cardiovascular events, which are increased in type 2 diabetes mellitus (DM). While studies of relatively short duration have suggested that thiazolidinediones such as pioglitazone might reduce progression of CIMT in persons with diabetes, the results of longer studies have been less clear. OBJECTIVE: To evaluate the effect of pioglitazone vs glimepiride on changes in CIMT of the common carotid artery in patients with type 2 DM. DESIGN, SETTING, AND PARTICIPANTS: Randomized, double-blind, comparator-controlled, multicenter trial in patients with type 2 DM conducted at 28 clinical sites in the multiracial/ethnic Chicago metropolitan area between October 2003 and May 2006. The treatment period was 72 weeks (1-week follow-up). CIMT images were captured by a single ultrasonographer at 1 center and read by a single treatment-blinded reader using automated edge-detection technology. Participants were 462 adults (mean age, 60 [SD, 8.1] years; mean body mass index, 32 [SD, 5.1]) with type 2 DM (mean duration, 7.7 [SD, 7.2] years; mean glycosylated hemoglobin [HbA1c] value, 7.4% [SD, 1.0%]), either newly diagnosed or currently treated with diet and exercise, sulfonylurea, metformin, insulin, or a combination thereof. INTERVENTIONS: Pioglitazone hydrochloride (15-45 mg/d) or glimepiride (1-4 mg/d) as an active comparator. MAIN OUTCOME MEASURE: Absolute change from baseline to final visit in mean posterior-wall CIMT of the left and right common carotid arteries. RESULTS: Mean change in CIMT was less with pioglitazone vs glimepiride at all time points (weeks 24, 48, 72). At week 72, the primary end point of progression of mean CIMT was less with pioglitazone vs glimepiride (-0.001 mm vs +0.012 mm, respectively; difference, -0.013 mm; 95% confidence interval, -0.024 to -0.002; P = .02). Pioglitazone also slowed progression of maximum CIMT compared with glimepiride (0.002 mm vs 0.026 mm, respectively, at 72 weeks; difference, -0.024 mm; 95% confidence interval, -0.042 to -0.006; P = .008). The beneficial effect of pioglitazone on mean CIMT was similar across prespecified subgroups based on age, sex, systolic blood pressure, duration of DM, body mass index, HbA(1c) value, and statin use. CONCLUSION: Over an 18-month treatment period in patients with type 2 DM, pioglitazone slowed progression of CIMT compared with glimepiride. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00225264

Adult↗
PubMed2006

Efficacy and safety of torcetrapib, a novel cholesteryl ester transfer protein inhibitor, in individuals with below-average high-density lipoprotein cholesterol levels on a background of atorvastatin.

OBJECTIVES: This study sought to evaluate the efficacy and safety of torcetrapib in patients with low high-density lipoprotein cholesterol (HDL-C) levels receiving background atorvastatin. BACKGROUND: Elevating HDL-C levels may reduce the residual cardiovascular risk that is observed in patients treated with statin therapy. Torcetrapib (a cholesteryl ester transfer protein inhibitor) increases HDL-C and decreases low-density lipoprotein cholesterol (LDL-C). METHODS: This was a multicenter, double-blind, randomized trial. Patients with below-average HDL-C (men <44 mg/dl; women <54 mg/dl) who were eligible for statin therapy according to National Cholesterol Education Program Adult Treatment Panel III guidelines or who had LDL-C >130 mg/dl at screening entered an 8-week run-in period with atorvastatin 20 mg/day before randomization (n = 174) to torcetrapib 10, 30, 60, or 90 mg/day or placebo for 8 weeks. Atorvastatin was continued during treatment with torcetrapib. RESULTS: After 8 weeks, the percent change from baseline with torcetrapib (least-squares mean difference from placebo) ranged from 8.3% to 40.2% for HDL-C (p < or = 0.0001 for 30-mg and higher doses) and from 0.6% to -18.9% for LDL-C (p < 0.01 for 60-mg and 90-mg doses). Particle size for both HDL and LDL increased with torcetrapib. The incidence of all-causality and treatment-related adverse events was similar across placebo and torcetrapib treatment groups with no evidence of a dose-related response. In some treatment groups, small increases in systolic and diastolic blood pressures were noted. CONCLUSIONS: In statin-eligible patients, torcetrapib plus background atorvastatin resulted in substantial, dose-dependent increases in HDL-C, accompanied by additional decreases in LDL-C beyond those seen with atorvastatin alone. Torcetrapib plus atorvastatin was generally well tolerated.

Adult↗
PubMed2006

Efficacy and safety of torcetrapib, a novel cholesteryl ester transfer protein inhibitor, in individuals with below-average high-density lipoprotein cholesterol levels.

OBJECTIVES: This study was designed to evaluate the efficacy and safety of torcetrapib, a cholesteryl ester transfer protein (CETP) inhibitor, in subjects with low high-density lipoprotein cholesterol (HDL-C) levels. BACKGROUND: Evidence suggests HDL-C is atheroprotective. A proven mechanism for increasing the level of HDL-C is the inhibition of CETP. METHODS: A total of 162 subjects with below-average HDL-C (men <44 mg/dl; women <54 mg/dl) who were not taking lipid-modifying therapy were randomized to double-blind treatment with torcetrapib 10, 30, 60, or 90 mg/day or placebo ( approximately 30 subjects per group). RESULTS: The percent change from baseline to Week 8 with torcetrapib (least-squares mean difference from placebo) was dose-dependent and ranged from 9.0% to 54.5% for HDL-C (p < or = 0.0001 for 30 mg and higher doses) and from 3.0% to -16.5% for low-density lipoprotein cholesterol (LDL-C) (p < 0.01 for 90-mg dose). Low-density lipoprotein cholesterol lowering was less in subjects with higher (>150 mg/dl) versus lower levels of baseline triglycerides; at 60 mg, the change in LDL-C was 0.1% versus -22.2% (p < 0.0001), respectively. Particle size for both HDL and LDL increased with torcetrapib. There were no dose-related increases in the frequency of adverse events. Significant blood pressure increases were noted in 2 of 140 subjects. CONCLUSIONS: Torcetrapib resulted in substantial dose-dependent elevations in HDL-C, accompanied by moderate decreases in LDL-C at the higher doses. Torcetrapib was generally well tolerated.

Adult↗
PubMed2006

Mechanisms for the hypotriglyceridemic effect of marine omega-3 fatty acids.

A mechanism to explain the hypotriglyceridemic effects of marine omega-3 fatty acids in humans has not been clarified. A working model can be developed at the gene transcriptional level, which involves >or=4 metabolic nuclear receptors. These include liver X receptor, hepatocyte nuclear factor-4alpha (HNF-4alpha), farnesol X receptor, and peroxisome proliferator-activated receptors (PPARs). Each of these receptors is regulated by sterol receptor element binding protein-1c (SREBP-1c), the main genetic switch controlling lipogenesis. Omega-3 fatty acids elicit hypotriglyceridemic effects by coordinately suppressing hepatic lipogenesis through reducing levels of SREBP-1c, upregulating fatty oxidation in the liver and skeletal muscle through PPAR activation, and enhancing flux of glucose to glycogen through downregulation of HNF-4alpha. The net result is the repartitioning of metabolic fuel from triglyceride storage toward oxidation, thereby reducing the substrate available for very-low-density lipoprotein (VLDL) synthesis. By simultaneously downregulating genes encoding proteins that stimulate lipid synthesis and upregulating genes encoding proteins that stimulate fatty acid oxidation, omega-3 fatty acids are more potent hypotriglyceridemic agents than are omega-6 fatty acids, on a carbon-for-carbon basis. Additionally, peroxidation of omega-3 fatty acids may reduce VLDL secretion through stimulating apolipoprotein B degradation. Omega-3 fatty acids may act by enhancing postprandial chylomicron clearance through reduced VLDL secretion and by directly stimulating lipoprotein lipase activity. These combined effects support the use of omega-3 fatty acids as a valuable clinical tool for the treatment of hypertriglyceridemia.

Animals↗
PubMed2006

Effect of ACAT inhibition on the progression of coronary atherosclerosis.

BACKGROUND: The enzyme acyl-coenzyme A:cholesterol acyltransferase (ACAT) esterifies cholesterol in a variety of tissues. In some animal models, ACAT inhibitors have antiatherosclerotic effects. METHODS: We performed intravascular ultrasonography in 408 patients with angiographically documented coronary disease. All patients received usual care for secondary prevention, including statins, if indicated. Patients were randomly assigned to receive the ACAT inhibitor pactimibe (100 mg per day) or matching placebo. Ultrasonography was repeated after 18 months to measure the progression of atherosclerosis. RESULTS: The primary efficacy variable analyzing the progression of atherosclerosis--the change in percent atheroma volume--was similar in the pactimibe and placebo groups (0.69 percent and 0.59 percent, respectively; P=0.77). However, both secondary efficacy variables assessed by means of intravascular ultrasonography showed unfavorable effects of pactimibe treatment. As compared with baseline values, the normalized total atheroma volume showed significant regression in the placebo group (-5.6 mm3, P=0.001) but not in the pactimibe group (-1.3 mm3, P=0.39; P=0.03 for the comparison between groups). The atheroma volume in the most diseased 10-mm subsegment regressed by 3.2 mm3 in the placebo group, as compared with a decrease of 1.3 mm3 in the pactimibe group (P=0.01). The combined incidence of adverse cardiovascular outcomes was similar in the two groups (P=0.53). CONCLUSIONS: For patients with coronary disease, treatment with an ACAT inhibitor did not improve the primary efficacy variable (percent atheroma volume) and adversely affected two major secondary efficacy measures assessed by intravascular ultrasonography. ACAT inhibition is not an effective strategy for limiting atherosclerosis and may promote atherogenesis. (ClinicalTrials.gov number, NCT00268515.).

Cardiovascular Diseases↗
PubMed2006

A comparison of Canadian and American guidelines for lipid management using data from the National Cholesterol Education Program Evaluation ProjecT Utilizing Novel E-technology (NEPTUNE) II survey.

BACKGROUND: The United States' National Cholesterol Education Program (NCEP) Adult Treatment Panel III and the Canadian Working Group on Hypercholesterolemia and Other Dyslipidemias (CWG) have each issued guidelines for the treatment of dyslipidemia. OBJECTIVE: The present analysis compared the percentage of patients reaching target lipid levels according to NCEP and CWG guidelines among participants of the NCEP Evaluation ProjecT Utilizing Novel E-technology (NEPTUNE) II, a survey performed in the United States. METHODS: American physicians who were high prescribers of lipid-modifying medications (n=376) each enrolled 10 to 20 consecutive patients from February to September 2003. Medical information, laboratory measurements and treatment plans associated with a single office visit were entered into a personal digital assistant and uploaded to a central database via the Internet. RESULTS: Under both sets of guidelines, treatment success was strongly related to risk category (P<0.001). Treatment goal achievement in the low-risk (zero or one risk factor) and moderate-risk (two or more risk factors) categories was not substantially different between NCEP and CWG guidelines; however, in the high-risk category (coronary artery disease [CAD] and risk equivalents [RE]), CWG treatment goals were met less frequently than NCEP goals. NCEP combined low-density lipoprotein cholesterol and non-high-density lipoprotein cholesterol treatment goals were met by 39% of hypertriglyceridemic patients (27% in the CAD + CAD RE category). CWG combined low-density lipoprotein cholesterol and total cholesterol/high-density lipoprotein cholesterol ratio treatment goals were met by 38% of hypertriglyceridemic patients (19% in the CAD + CAD RE category). CONCLUSIONS: These data indicate substantial underachievement of treatment goals by patients at high risk under both the CWG and NCEP guidelines. The lower frequency of treatment success in high-risk patients according to the CWG definition indicates that more aggressive treatment is needed to reach CWG goals.

Anticholesteremic Agents↗
PubMed2006

Final conclusions and recommendations of the National Lipid Association Statin Safety Assessment Task Force.

This article summarizes the final conclusions of the National Lipid Association (NLA) Statin Safety Task Force, based on a review and independent research of New Drug Application (NDA) information, US Food and Drug Administration (FDA) Adverse Event Reporting System (AERS) data, cohort and clinical trial results, and analysis of administrative claims database information and the assessment of its 4 Expert Panels, which focused on issues of statin safety with regard to liver, muscle, renal, and neurologic systems. Practical guidance in the form of recommendations to health professionals who manage the coronary artery disease risk of patients with statin therapy is provided.

Adverse Drug Reaction Reporting Systems↗
PubMed2006

Statin safety: an appraisal from the adverse event reporting system.

The adverse event (AE) profiles of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitor (statin) agents are of great interest, in particular the most recently approved statin, rosuvastatin. The forwarding of reports of AEs has been shown to be influenced by several reporting biases, including secular trend, the new drug reporting effect, product withdrawals, and publicity. Comparative assessments that use AE reporting rates are difficult to interpret under these circumstances, because such effects can themselves lead to marked increases in AE reporting. Consequently, many comparative reporting rate analyses are best carried out in conjunction with other metrics that put reporting burden into context, such as report proportion. All-AE reporting rates showed a temporal profile that resembled those of other statins when marketing cycle and secular trend were taken into account. A before-and-after cerivastatin withdrawal comparison showed a substantial increase in the reporting of AEs of interest for the statin class overall. Report proportion analyses indicated that the burden of rosuvastatin-associated AEs was similar to that for other statin agents. Analyses of monthly reporting rates showed that the reporting of rosuvastatin-associated rhabdomyolysis and renal failure have increased following AE-specific mass media publicity. Postrosuvastatin AE reporting patterns were comparable to those seen with other statins and did not resemble cerivastatin.

Adverse Drug Reaction Reporting Systems↗
PubMed2006

Statin safety: an assessment using an administrative claims database.

The large administrative databases of health plans contain information on drug-related medical adverse events (AE) and constitute an increasingly powerful tool for the assessment of drug safety. We conducted a retrospective observational study using an administrative managed care claims database covering 9 million members from diverse regions of the United States. Patients aged >or=18 years who received >or=2 prescriptions for lipid-lowering drugs between July 1, 2000 and December 1, 2004 were included in the study. Hospitalizations with diagnosis codes (International Classification of Diseases, 9th Revision, Clinical Modification [ICD-9]) related to muscle, kidney, and liver were determined for patients exposed to 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors (statins), fibrates, extended-release niacin, cholesterol absorption inhibitors, or statin combination therapy. A total of 473,343 patients contributed 490,988 person-years of monotherapy and 11,624 person-years of combination dyslipidemia therapy. Rates of hospitalization due to AEs in patients on monotherapy with currently available statins were similar, whereas the incidence of hospitalization for muscle disorders increased 6.7-fold with cerivastatin therapy. Patients who received a lipid-lowering medication with a concomitant cytochrome P450 3A4 (CYP3A4) inhibitor had a 6-fold increased rate of muscle disorders, including rhabdomyolysis. Hypertension was associated with a 5-fold increase in both muscle and renal events, whereas patients with diabetes mellitus had a 2.5-fold increased risk of renal events. No hospitalized cases of the index AEs were observed in study subjects during the 6-month period before initiation of the lipid-lowering drug. Statin monotherapy as currently prescribed is generally well tolerated and safe.

Chemical and Drug Induced Liver Injury↗
PubMed2006

Effects of fenofibrate on atherogenic dyslipidemia in hypertriglyceridemic subjects.

BACKGROUND: The metabolic syndrome (MS) is often accompanied by atherogenic dyslipidemia, which is characterized by elevated triglycerides (TG), reduced high-density lipoprotein cholesterol (HDL-C), and elevated numbers of small, dense low-density lipoprotein (LDL) particles. HYPOTHESIS: It was hypothesized that a threshold exists for the circulating TG level needed to produce changes in LDL subclass distribution. METHODS: Hypertriglyceridemic (TG > or =300 and <1000 mg/dl) subjects with the MS were randomly assigned to placebo (n=50) or 130 mg/day of micronized fenofibrate-coated microgranules (n=96) for 8 weeks. RESULTS: In the overall analysis, fenofibrate treatment resulted in significant (p < 0.05) changes versus placebo in TG (-36.6%), non-HDL-C (-7.5%), very low-density lipoprotein-C (-32.7%), LDL-C (15.0%), HDL-C (14.0%), remnant lipoprotein-C (-35.1%), apolipoprotein B (-6.0%), apolipoprotein A-I (5.3%), and apolipoprotein C-III--29.7%). Changes in LDL particle diameter in the fenofibrate group were significantly inversely associated with the TG level achieved on treatment (p = 0.019). When individually matched for percent change in TG, subjects with on-treatment TG < 200 mg/dl, in contrast to those with on-treatment values > or =200 mg/dl, had significantly different median responses (p < 0.05) in LDL size (0.79 vs. -0.06 nm) and cholesterol carried by small (-35 vs. 21 mg/dl) and large (31 vs. 11 mg/dl) particles. CONCLUSION: These data support the view that a threshold exists below which the TG level must be lowered to produce shifts in LDL particle size.

Adult↗
PubMed2006

Reduced treatment success in lipid management among women with coronary heart disease or risk equivalents: results of a national survey.

BACKGROUND: This survey assessed and compared National Cholesterol Education Program (NCEP) Third Adult Treatment Panel lipid treatment goal achievement for men versus women undergoing treatment of dyslipidemia. METHODS: Patients receiving treatment for dyslipidemia from physicians (N = 376) in the United States who were high prescribers of lipid medications were enrolled in the NCEP Evaluation Project Utilizing Novel E-Technology (NEPTUNE) II. Data from a single office visit were collected and entered into the NEPTUNE software on a personal digital assistant and uploaded to a central database via the Internet. RESULTS: Of the 4885 patients evaluated, 2103 (43%) were women. NCEP Third Adult Treatment Panel low-density lipoprotein cholesterol (LDL-C) goal achievement was similar between women and men with 0 or 1 risk factor (89% and 88%, respectively) and 2 or more risk factors (75% and 76%, respectively). However, fewer women than men achieved goal in the coronary heart disease and risk equivalents (CHD + CHD RE) category (50% vs 60%, respectively; P < .001). Logistic regression analyses examining the association between sex and LDL-C treatment goal achievement, and evaluating potential confounding by other predictors of treatment success, indicated an age-adjusted odds ratio of 0.66 (95% confidence interval, 0.56-0.77; P < .001) and a multivariate odds ratio of 0.76 (95% confidence interval, 0.62-0.93; P = .009) for women compared with men in the CHD + CHD RE category. CONCLUSIONS: Female sex was associated with lower likelihood of LDL-C goal achievement among patients with CHD + CHD RE. This relationship remained significant after adjustment for other significant predictors of treatment success.

Anticholesteremic Agents↗
PubMed2006

Ethnic differences in achievement of cholesterol treatment goals. Results from the National Cholesterol Education Program Evaluation Project Utilizing Novel E-Technology II.

BACKGROUND: African Americans (AA) have the highest coronary heart disease mortality rate of any ethnic group in the United States. Data from the National Cholesterol Education Program Evaluation ProjecT Utilizing Novel E-Technology (NEPTUNE) II survey were used to assess ethnic differences in low-density lipoprotein cholesterol (LDL-C) goal achievement. METHODS: NEPTUNE II surveyed patients with treated dyslipidemia to assess achievement of treatment goals established by the Adult Treatment Panel III of the National Cholesterol Education Program. United States physicians working in primary care or relevant subspecialties enrolled 10 to 20 consecutive patients (May to September 2003), and patient data were recorded in Personal Digital Assistants and uploaded to a central database via the internet. RESULTS: Among 4,885 patients receiving treatment for dyslipidemia, 79.7% were non-Hispanic white (NHW) and 8.4% were AA. Non-Hispanic white and AA patients had significantly different frequencies of treatment success, with 69.0% and 53.7%, respectively, having achieved their LDL-C goal (P<.001). African-American patients were more likely to be in the highest risk category, and less likely to be using lipid drug therapy, taking high-efficacy statins, and receiving care from a subspecialist, but the difference in goal achievement remained significant (P<.001) after adjustment for these and other predictors of treatment success. CONCLUSIONS: The frequency of treatment success in dyslipidemia management was significantly lower in AA than NHW patients. Additional research is needed to elucidate reasons for this disparity and to evaluate strategies for improving goal achievement among AA patients receiving therapy for dyslipidemia.

Black or African American↗