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Articles by Michael H. Davidson
Total Records ( 27 ) for Michael H. Davidson
  Christie M. Ballantyne , Michael H. Davidson , James M. McKenney , Laurence H. Keller , Daiva R. Bajorunas and Richard H. Karas
 

Background

The number of patients with multiple lipid abnormalities is increasing. Lipid treatment guidelines are established for low-density lipoprotein cholesterol (LDL-C) and non-high-density lipoprotein cholesterol (non-HDL-C). The importance of treating HDL-C and triglycerides is gaining recognition.

Objective

To determine, in patients who had been treated previously with simvastatin 40 mg/day, the efficacy, safety, and tolerability of two regimens of a combination of proprietary niacin, extended-release core, coated with 40 mg/day simvastatin (NER/S), compared to 80 mg/day simvastatin monotherapy (S80).

Methods

High-risk patients (n = 343) with dyslipidemia were treated for 24 weeks with NER/S (1000/40 mg/day or 2000/40 mg/day) or S80.

Results

Median percentage change from baseline to week 24 in non-HDL-C in either NER/S group was noninferior to S80 (−11.3%, −17.1%, and −10.1%, respectively). Changes in LDL-C were comparable (−8.6%, −11.6%, and −12.7%, respectively). Doubling the dose of simvastatin (S80) did not alter HDL-C, triglycerides, or lipoprotein(a); however, both NER/S doses resulted in significant improvements in all three parameters (+21.9%, −31.8%, and −21.0%, respectively, for NER/S 2000/40 mg/day). The safety of NER/S was consistent with the safety profile of each individual component. Treatment with both doses of NER/S was well tolerated; 59% of patients experienced flushing, 78% of flushing was mild or moderate in intensity, 49% of those who flushed during dose titration did not flush during weeks 13 to 24, and only 4.6% of patients discontinued because of flushing.

Conclusion

NER/S provides similar reductions in non-HDL-C and LDL-C compared to doubling the simvastatin dose to 80 mg; however, only NER/S resulted in improvements in HDL-C, triglycerides, and lipoprotein(a).

  Nicola Abate , Alberico L. Catapano , Christie M. Ballantyne , Michael H. Davidson , Adam Polis , Steven S. Smugar and Andrew M. Tershakovec
 

Background

Patients with diabetes mellitus (DM) and metabolic syndrome (MS) are at increased risk of developing coronary heart disease.

Objective

To compare the effects of ezetimibe/simvastatin (E/S) combination therapy, atorvastatin, and rosuvastatin in patients with DM, MS without DM, or neither disease.

Methods

Subgroup analysis of data from two 6-week, randomized, double-blind trials comparing E/S 10/10, 10/20, 10/40, or 10/80 mg with either atorvastatin 10, 20, 40, or 80 mg (Study 1), or rosuvastatin 10, 20, or 40 mg (Study 2). Treatments were compared by pooling across all doses for effects on low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), total cholesterol (TC), non-HDL-C, apolipoprotein B (ApoB), LDL-C:HDL-C, TC:HDL-C, and LDL-C goal attainment.

Results

E/S provided greater improvements than atorvastatin or rosuvastatin in LDL-C, TC, HDL-C (vs atorvastatin only), non-HDL-C, LDL-C:HDL-C, TC:HDL-C, and ApoB in all disease subgroups. There were no interactions of treatment by disease subgroup for these parameters, indicating a consistent treatment difference favoring E/S effect across the disease subgroups. A greater percentage of patients receiving E/S than atorvastatin or rosuvastatin attained their individual National Cholesterol Education Program Adult Treatment Panel III LDL-C goals, LDL-C <100 mg/dL, LDL-C <70 mg/dL, and non-HDL-C goals regardless of subgroup. All treatments were well-tolerated, with generally similar adverse experience rates.

Conclusions

Overall, E/S generally provided greater efficacy than either atorvastatin or rosuvastatin that was consistent across the subgroups of patients with DM, MS, or neither, in agreement with the results from the full study cohorts.

  William B. Borden and Michael H. Davidson
  not available
  Michael H. Davidson , Dawn M. Carlson , Robert M. Guthrie , Maureen T. Kelly , Aditya Lele , Carolyn M. Setze and Darryl J. Sleep
  not available
  Michael H. Davidson , Stacey L. Abby , Joanne M. Donovan and Michael R. Jones
  not available
  Peter H. Jones , Susan M. Buttler , Michael H. Davidson , Moti L. Kashyap , Maureen T. Kelly , Carolyn M. Setze , Darryl J. Sleep and James C. Stolzenbach
  not available
  Richard H. Karas , Daiva R. Bajorunas , Christie M. Ballantyne , Michael H. Davidson , Laurence H. Keller , James McKenney , Robert J. Padley and Roopal B. Thakkar
  not available
  Richard H. Karas , Daiva R. Bajorunas , Michael H. Davidson , Moti Kashyap , Laurence H. Keller , Robert H. Knopp , Robert J. Padley and Roopal B. Thakkar
  not available
  Michael H. Davidson , Nicola Abate , Christie M. Ballantyne , Alberico L. Catapano , Xia Xu , Jianxin Lin , Elizabeth Rosenberg and Andrew M. Tershakovec
 

Background

Recent evidence suggests that in addition to low-density lipoprotein cholesterol (LDL-C), apolipoprotein B (Apo-B), non-high-density lipoprotein cholesterol (non-HDL-C), some lipoprotein ratios, and C-reactive protein (CRP) are predictive of coronary heart disease (CHD) risk. This post-hoc analysis of two trials comparing single-tablet ezetimibe/simvastatin (EZE/SIMVA) to atorvastatin (ATORVA) or rosuvastatin (ROSUVA) evaluates the proportion of patients attaining LDL-C <70 mg/dL and specific levels of these emerging risk factors.

Methods

These were double-blind, 6-week, parallel group trials of hypercholesterolemic patients randomized to milligram equivalent doses of ATORVA versus EZE 10 mg/SIMVA, or to usual starting, next higher, and maximum doses of ROSUVA versus EZE/SIMVA. This analysis examined the percent of patients in prespecified dose comparisons and overall achievement of LDL-C <70 mg/dL and/or Apo-B <90 mg/dL, total cholesterol (TC)/HDL-C <4.0, or Apo-B/Apo-A-I <0.7 among all treated patients, non-HDL-C <100 mg/dL among patients with baseline triglycerides ≥200 mg/dL, or CRP <2.0 mg/L among patients with baseline CRP ≥2.0 mg/L.

Results

Within each trial, baseline characteristics were similar among groups. At all dose comparisons, significantly more patients receiving EZE/SIMVA reached LDL-C <70 mg/dL and achieved both LDL-C <70 mg/dL and either Apo-B <90 mg/dL, TC/HDL-C <4.0, or Apo-B/Apo-A-I <0.7 (EZE/SIMVA versus ATORVA) compared to ATORVA and ROSUVA. For most dose comparisons, significantly more patients receiving EZE/SIMVA attained both LDL-C <70 mg/dL and either non-HDL-C <100 mg/dL or CRP <2 mg/L compared to ATORVA or ROSUVA.

Conclusion

The greater efficacy related to changes in blood lipids of EZE/SIMVA compared with both ATORVA and ROSUVA extends to changes in many emerging risk factors. Ultimate clinical implications of these findings still need to be defined.

  Eileen E. Ming , Michael H. Davidson , Sanjay K. Gandhi , Marcelo Marotti , Carolyn G. Miles , Xiongkan Ke and James M. McKenney
 

Background

Patients may experience increased risk of adverse drug interactions when statins are administered concomitantly with cytochrome P450 3A4 (CYP3A4) inhibitors.

Objective

To determine patient numbers in routine clinical practice with concomitant exposure to CYP3A4-metabolized statins and CYP3A4 inhibitors and highlight potential risk for adverse drug interaction.

Methods

Exposure to prescription medications over 1 year (2005-2006) was evaluated from patient records: US PharMetrics Integrated Patient-Centric administrative claims database and the US General Electric Medical System (GEMS) database. Rates of concomitant prescribing of statins with CYP3A4 inhibitors (listed in United States of America product labels and all identified potential inhibitors) were examined in the cohort overall, in those aged ≥65 years, and in those receiving higher doses of statins.

Results

Overall, 951,166 patient records were included (PharMetrics n = 650,825; GEMS, n = 300,341). Of these, 792,081 (83%) patients used a CYP3A4-metabolized statin as opposed to a non-CYP3A4-metabolized statin (17%). Findings from both databases were consistent. Overall, 25-30% of patients given a CYP3A4-metabolized statin were concomitantly exposed to a CYP3A4 inhibitor, including approximately 9% concomitantly exposed to a labeled inhibitor, findings consistent with those in patients aged ≥65 years, and patients on higher doses of statins.

Conclusions

Clinicians frequently co-prescribe CYP3A4-metabolized statins with CYP3A4 inhibitors. Physician education regarding the impact of these inhibitors on the metabolism of lovastatin, simvastatin, and atrovastatin is needed. Further studies are also needed to determine whether concomitant administration of a non-CYP3A4-metabolized statin (such as fluvastatin, pravastatin, or rosuvastatin) with a CYP3A4 inhibitor, may reduce adverse event rates in routine clinical practice.

  Peter H. Jones , Michael H. Davidson , Anne C. Goldberg , Carl J. Pepine , Maureen T. Kelly , Susan M. Buttler , Carolyn M. Setze , Aditya Lele , Darryl J. Sleep and James C. Stolzenbach
 

Background

Patients with mixed dyslipidemia often require combination therapy to manage multiple lipid abnormalities.

Objective

To evaluate fenofibric acid in combination with a statin across three studies of patients with mixed dyslipidemia.

Methods

As prospectively planned, data were pooled from three randomized, double-blind, phase 3 studies of patients with low-density lipoprotein cholesterol (LDL-C) ≥130 mg/dL, triglycerides (TG) ≥150 mg/dL, and high-density lipoprotein cholesterol (HDL-C) <40 mg/dL (men) or <50 mg/dL (women). A total of 2715 patients were randomly assigned to 12-week treatment with fenofibric acid 135 mg monotherapy; low-, moderate-, or high-dose statin (rosuvastatin, simvastatin, or atorvastatin, depending on study) monotherapy; or fenofibric acid + low- or moderate-dose statin. The primary efficacy comparisons were mean percent change in HDL-C and TG (combination therapy vs. statin) and LDL-C (combination therapy vs. fenofibric acid).

Results

Fenofibric acid + low-dose statin increased HDL-C (18.1% vs. 7.4%) and reduced TG (−43.9% vs. −16.8%) versus low-dose statin monotherapy and reduced LDL-C (−33.1% vs. −5.1%) versus fenofibric acid monotherapy (P <.001 for all). Fenofibric acid + moderate-dose statin increased HDL-C (17.5% vs. 8.7%) and reduced TG (−42.0% vs. −23.7%) versus moderate-dose statin monotherapy and reduced LDL-C (−34.6% vs. −5.1%) versus fenofibric acid monotherapy (P <.001 for all). Combination therapy was generally well tolerated, and safety profiles were similar to monotherapies. No rhabdomyolysis was reported.

Conclusion

In patients with mixed dyslipidemia, combination therapy simultaneously improved multiple lipid abnormalities more effectively than fenofibric acid or statin monotherapies.

  Michael H. Davidson , Kathleen M. Fox , Sanjay K. Gandhi , Robert L. Ohsfeldt and James M. McKenney
 

Objective

We sought to examine the diagnoses and medical management patterns of patients before the incidence of a cardiovascular (CV) event.

Methods

A retrospective study of claims data from a national managed care plan was conducted. Eligible patients had a myocardial infarction, stroke, or revascularization between January 1, 2004 and December 31, 2005, and at least 3 years of continuous enrollment before the CV event. Patients were stratified by whether or not they had a diagnosis of atherosclerosis in the 3 years before the CV event. Diagnostic testing, lipid monitoring, and statin treatment patterns were assessed during the 3-year period before the CV event.

Results

There were 16,543 patients with a CV event, and 65% had no previous diagnosis of atherosclerosis. For all patients, 58% were men, and mean age was 60 years. Angiography or cardiac imaging was performed in <3% of patients, and cardiac stress testing was performed in 13% of patients before the event. Only 19% of patients had ≥1 lipid test in the 12 months and 32% in the 3 years before the event, and their 12-month mean low-density lipoprotein cholesterol was 113 mg/dL. Thirty-four percent of patients were on statin therapy within the 3 years before event. The patient subgroup diagnosed with atherosclerosis had significantly more patients with cardiac testing, lipid monitoring, and statin therapy compared with patients with no previous diagnosis of atherosclerosis.

Conclusion

These results from an actual clinical practice dataset indicate opportunities for improved detection and management of underlying atherosclerotic heart disease to avoid future cardiovascular events.

  Michael H. Davidson , Kevin C. Maki , Harold Bays , Roderick Carter and Christie M. Ballantyne
 

Background

Prescription omega-3-acid ethyl esters (P-OM3) often are used for hypertriglyceridemic patients receiving statin therapy who have residual increases in atherogenic lipoprotein lipid levels. To date, limited information has been published regarding the effects of omega-3 fatty acid consumption on lipoprotein particle concentrations.

Objective

We evaluated the effects of adding P-OM3 4 g/d to an ongoing regimen of simvastatin 40 mg/d on lipoprotein particles (P) in subjects with hypertriglyceridemia.

Methods

Data were analyzed from the multicenter, randomized, double-blind, placebo-controlled Combination of Prescription Omega-3s with Simvastatin (COMBOS) study. After an 8-week simvastatin lead-in, 254 subjects received P-OM3 (n=122) or placebo (n=132) for an additional 8 weeks. Nuclear magnetic resonance spectroscopy was used to assess lipoprotein concentrations and sizes. Remnant-like particle cholesterol, apolipoprotein (Apo) CIII, Apo AI, and lipoprotein-associated phospholipase A2 (Lp-PLA2) levels also were measured.

Results

Compared with placebo, P-OM3 reduced mean very-low-density lipoprotein (VLDL-P) size and increased low-density lipoprotein particle (LDL-P) size (P < .006 for both) without altering high-density lipoprotein particle (HDL-P) size. P-OM3 did not significantly change total VLDL-P or LDL-P concentrations relative to placebo, but large VLDL-P and intermediate-density lipoprotein particle (IDL-P) concentrations were lowered (P < .01 for both), and the large LDL-P concentration was increased (P < .0001). HDL-P concentration was reduced (P < .0001) as the result of a decrease in medium HDL-P. Remnant-like particle cholesterol, Apo CIII, and Lp-PLA2 concentrations were reduced compared with placebo (all P < .003).

Conclusions

P-OM3 induces changes in sizes, concentrations, and compositions of lipoproteins that may have relevance for the atherothrombotic process.

  Michael H. Davidson
  Should patients with diabetes with one additional risk factor have an LDL-C target <70 mg/dL? Dr. Gosmanov has raised the POINT that this guideline is premature and recommends caution because this target is not yet supported by the clinical trial evidence. As a member of the ADA and the American College of Cardiology Foundation Consensus Conference Report on Lipoprotein Management in Patients with Cardiometabolic Risk,1 this was an issue of heated debate among the consensus committee. Many panel members supported Dr.   
  Peter P. Toth and Michael H. Davidson
  The high-density lipoproteins (HDLs) are complex, polymolecular assemblies produced by the jejunum, liver, in serum, and on the surface of macrophages. HDL cholesterol (HDL-C) levels are an independent predictor of risk for cardiovascular events in both men and women. High serum levels of this lipoprotein are associated with reduced risk for atherosclerosis and its clinical sequelae, such as myocardial infarction, ischemic stroke, and death. The molecular basis for the apparent vasculoprotection afforded by elevated HDL-C is widely attributed to the ability of HDL particles to drive reverse cholesterol transport. The proteosome (protein cargo) of HDL also appears to endow this lipoprotein with a capacity to reduce oxidized lipids, promote endothelial cell nitric oxide production, reduce adhesion molecule expression, inhibit platelet activation, stimulate endothelial proliferation and inhibit apoptosis, and reduce inflammatory mediator expression, among other functions. Recent investigation suggests that among patients with coronary artery disease, HDL can also be dysfunctional, yielding a pro-inflammatory and pro-oxidative phenotype. Numerous drugs are currently in development in an effort to devise the means by which to optimally increase serum levels of functional, antiatherogenic HDL species. These drugs exploit a diverse range of mechanisms with potential for beneficially impacting the development and progression of atherosclerotic disease.
  Michael H. Davidson
  Cholesteryl ester transfer protein (CETP) plays an important role in reverse cholesterol transport and the maintenance of cholesterol homeostasis. The consequences of CETP activity are influenced by triglyceride (TG) levels. When TG levels are increased, CETP promotes transfer of cholesteryl esters to VLDL and the generation of atherogenic dyslipidemia. Combined activities of CETP and hepatic lipase in the presence of TG-rich lipoproteins generate small, dense HDL and LDL particles. Inhibition of CETP may reduce the risk of atherosclerosis in patients with dyslipidemia. Decreasing CETP activity has consistently inhibited atherosclerosis in animal models. Three small-molecule CETP inhibitors, dalcetrapib, torcetrapib, and anacetrapib, have been or are being tested in phase 3 clinical studies. All three demonstrated potentially beneficial effects on the lipid profile in patients with dyslipidemia. Imaging studies with torcetrapib failed to show an effect on atherosclerosis in humans, probably because of the off-target effect on the RAAS. Preclinical evidence suggests that dalcetrapib seems to lack the off-target adverse effects on the RAAS that potentially caused the clinical development of torcetrapib to be halted. The lack of adverse effects on the RAAS remains to be confirmed in phase 3 studies with dalcetrapib. CETP inhibition as a therapeutic strategy remains a valid option to be tested with a CETP inhibitor that does not share torcetrapib's off-target effects.
  Michael H. Davidson
  Familial hypercholesterolemia, which arises as a result of a mutation in the low-density lipoprotein (LDL) receptor gene, is characterized by elevated levels of low-density lipoprotein cholesterol (LDL-C), regardless of dietary and lifestyle modifications. Pharmacological therapy is often required to adequately control the elevated LDL-C levels associated with familial hypercholesterolemia. However, children with this genetic condition present many challenges for physicians, who must weigh the benefits of lipid-lowering therapy against the risks associated with the various treatment options. Furthermore, because familial hypercholesterolemia is a chronic condition, children will likely require long-term lipid-lowering therapy. As such, the potential effect of pharmacological treatment on development is of paramount importance in this population. Bile acid sequestrants represent a unique treatment option for children with familial hypercholesterolemia in that these agents are not systemically absorbed but rather exert their lipid-lowering effects via binding to bile acids within the gastrointestinal tract. A literature search was performed to identify clinical data related to the use of bile acid sequestrant therapy in children (<18 years of age) with familial hypercholesterolemia. Studies published in English between 1990 and December 2010 that were retrieved from MEDLINE and EMBASE were included in this systematic review. In total, five clinical studies were identified that evaluated bile acid sequestrant monotherapy, whereas two studies were identified that evaluated combination therapy with a bile acid sequestrant and low-dose statin. This review summarizes the clinical data regarding the efficacy and safety of bile acid sequestrants in this specialized population.
  Kevin C. Maki , Michael H. Davidson , Mary R. Dicklin , Marjorie Bell , MarySue Witchger and Steven B. Feinstein
 

Background

The rate of carotid intima media thickness (CIMT) progression has been widely used in clinical trials as a surrogate marker for subclinical atherosclerosis.

Objective

The aim of this study was to investigate relationships between coronary heart disease (CHD) risk markers and progression of CIMT in patients at moderate CHD risk.

Methods

Participants included men (45-75 years) and women (55-74 years) in the control arm of a clinical trial. All had at least one major CHD risk factor and baseline posterior wall CIMT 0.7-2.0 mm, without significant stenosis. Posterior (n = 134) and anterior wall (in a subset, n = 72) CIMT were assessed with B-mode ultrasound at baseline and 12 and ∼18 months. Fasting lipoprotein lipid, apolipoprotein (Apo), inflammatory, and oxidative stress markers were evaluated.

Results

Baseline CIMT was inversely associated (P < .001) with CIMT progression. After adjustment for baseline CIMT, significant predictors of anterior wall CIMT progression in linear regression analyses included glucose (P = .044), high-density lipoprotein cholesterol (HDL-C, inverse, P = .006), triglycerides (TG, P = .006), and ratios of total cholesterol (TC)/HDL-C (P = .013), TG/HDL-C (P = .005), and Apo B/HDL-C (P = .021). Posterior wall CIMT progressed on average, whereas anterior wall CIMT regressed (0.0078 vs −0.0164 mm/year, P = .014). Significant baseline CIMT-adjusted predictors of posterior wall CIMT progression included TC (P = .028), low-density lipoprotein-C (P = .035), non-HDL-C (P = .004), TG (P = .016), Apo B (P = .005), and ratios of TC/HDL-C (P < .001), TG/HDL-C (P = .015), Apo B/Apo AI (P = .012) and Apo B/HDL-C (P = .004).

Conclusion

The strongest predictors for CIMT progression in anterior and posterior walls were lower baseline CIMT, increased TG, and elevated ratios, including TC/HDL-C, TG/HDL-C and Apo B/HDL-C.

  Michael H. Davidson , Christie M. Ballantyne , Terry A. Jacobson , Vera A. Bittner , Lynne T. Braun , Alan S. Brown , W. Virgil Brown , William C. Cromwell , Ronald B. Goldberg , James M. McKenney , Alan T. Remaley , Allan D. Sniderman , Peter P. Toth , Sotirios Tsimikas , Paul E. Ziajka , Kevin C. Maki and Mary R. Dicklin
  The National Cholesterol Education Program Adult Treatment Panel guidelines have established low-density lipoprotein cholesterol (LDL-C) treatment goals, and secondary non-high-density lipoprotein (HDL)-C treatment goals for persons with hypertriglyceridemia. The use of lipid-lowering therapies, particularly statins, to achieve these goals has reduced cardiovascular disease (CVD) morbidity and mortality; however, significant residual risk for events remains. This, combined with the rising prevalence of obesity, which has shifted the risk profile of the population toward patients in whom LDL-C is less predictive of CVD events (metabolic syndrome, low HDL-C, elevated triglycerides), has increased interest in the clinical use of inflammatory and lipid biomarker assessments. Furthermore, the cost effectiveness of pharmacological intervention for both the initiation of therapy and the intensification of therapy has been enhanced by the availability of a variety of generic statins. This report describes the consensus view of an expert panel convened by the National Lipid Association to evaluate the use of selected biomarkers [C-reactive protein, lipoprotein-associated phospholipase A2, apolipoprotein B, LDL particle concentration, lipoprotein(a), and LDL and HDL subfractions] to improve risk assessment, or to adjust therapy. These panel recommendations are intended to provide practical advice to clinicians who wrestle with the challenges of identifying the patients who are most likely to benefit from therapy, or intensification of therapy, to provide the optimum protection from CV risk.
  Christie M. Ballantyne , Michael H. Davidson , Carolyn M. Setze and Maureen T. Kelly
 

Background

Elevated levels of high-sensitivity C-reactive protein (hsCRP) correlate with an increased risk for cardiovascular events. Combination therapy with a statin and a fibrate may be more effective than statin monotherapy for reducing hsCRP, especially in patients with mixed dyslipidemia.

Objective

To characterize the treatment effects of rosuvastatin and fenofibric acid combination therapy compared with individual monotherapies in mixed dyslipidemic patients with baseline hsCRP ≥2 mg/L versus <2 mg/L and to determine the effects of long-term treatment with rosuvastatin and fenofibric acid combination therapy on hsCRP and other lipids for patients with hsCRP ≥2 mg/L after treatment with rosuvastatin monotherapy.

Methods

Data for the post hoc analysis were derived from two 12-week controlled studies and a 52-week extension study. Patients were treated with fenofibric acid 135 mg; rosuvastatin 5, 10, 20, or 40 mg; or rosuvastatin 5, 10, or 20 mg and fenofibric acid 135 mg in the controlled studies; and with rosuvastatin 20 mg and fenofibric acid 135 mg in the extension study.

Results

In this analysis, 65% (1416/2182) of patients had pretreatment baseline hsCRP ≥2 mg/L. Among all treatment groups, larger decreases in hsCRP were observed in patients with greater baseline hsCRP; however, improvements in other lipids/apolipoprotein were comparable between the baseline hsCRP categories. Among patients with high hsCRP (≥2 mg/L) remaining after 12 weeks of rosuvastatin 10, 20, or 40 mg monotherapy, hsCRP was reduced by ∼36% after switching to rosuvastatin 20 mg and fenofibric acid 135 mg for up to 52 weeks, and ∼36% of patients shifted from hsCRP ≥2 mg/L to <2 mg/L.

Conclusions

Combination therapy with rosuvastatin and fenofibric acid may be effective for improving the inflammatory biomarker, hsCRP as well as other lipid abnormalities in patients with mixed dyslipidemia and high hsCRP.

  Peter P. Toth , Christie M. Ballantyne , Michael H. Davidson , Joanne E. Tomassini , Dena Rosen Ramey , David Neff , Andrew M. Tershakovec , X. Henry Hu and Kaan Tunceli
 

Background

Recent trends suggest a decreased use of ezetimibe/simvastatin combination and coadministered ezetimibe plus statin therapies.

Objective

This analysis evaluated changes in prescription patterns for ezetimibe/simvastatin, ezetimibe plus statins, and statin therapies and expected effects on low-density lipoprotein cholesterol (LDL-C) lowering during 2007 to 2008.

Methods

Prescription pattern changes were assessed by the use of patient-level data from the IMS Health Longitudinal Rx database during two time periods, July 14, 2007 to January 13, 2008 (n = 8,813,674) and January 14, 2008 to July 13, 2008 (n = 9,131,030), 6 months before and after reporting of the results of The Ezetimibe and Simvastatin in Hypercholesterolemia Enhances Atherosclerosis Regression trial (ENHANCE) trial on January 14, 2008. Expected LDL-C reductions were estimated using data from previous controlled clinical trials.

Results

During 6 months post-ENHANCE, greater proportions of patients were switched from ezetimibe/simvastatin and ezetimibe plus statins to other lipid-lowering therapies by health care providers than 6 months pre-ENHANCE (21.1% vs 6.0% and 46.9% vs 38.5%, differences: −15.06% [95% confidence interval −15.14%, −14.97%] and −8.43% [95% confidence interval −8.70%, −8.17%], respectively). Greater proportions of these patients switched to statin monotherapy in the later than earlier period. Prescription patterns were similar for statins during both time periods, although fewer patients switched to ezetimibe/simvastatin and ezetimibe plus statin therapies post-ENHANCE. In both time periods, greater proportions of patients on ezetimibe/simvastatin and ezetimibe plus statins switched to less-than-equivalent LDL-C lowering efficacy doses of statins than those on statin therapy. On the basis of previous clinical data for these therapies, smaller LDL-C reductions would be expected in patients who switched from ezetimibe/simvastatin and ezetimibe plus statins to statins, despite a trend toward switching to greater statin doses in the later time period.

Conclusions

More patients switched from ezetimibe/simvastatin and ezetimibe plus statin to statin monotherapy 6 months after the reporting of the ENHANCE trial, the majority of which were prescribed less potent, LDL-C-lowering therapies. On the basis of the known LDL-C lowering efficacies for these therapies, such changes would be expected to increase LDL-C levels in these patients and may reduce the proportion of patients who achieve guideline-recommended LDL-C goals.

  Eli M. Roth , Robert S. Rosenson , Peter H. Jones , Michael H. Davidson , Maureen T. Kelly , Carolyn M. Setze , Aditya Lele and Kamlesh Thakker
 

Background

Goal/desirable lipid levels are underachieved in patients with mixed dyslipidemia. These patients may have substantial residual risk of cardiovascular disease even while receiving optimal LDL-C-lowering therapy and may require additional therapy to improve multiple lipid/lipoprotein levels.

Objective

To evaluate attainment of goal/desirable levels of lipids/lipoproteins after 12-week treatment with combination rosuvastatin + fenofibric acid versus rosuvastatin monotherapy.

Methods

This was a post hoc analysis of patients with mixed dyslipidemia who enrolled in one of two randomized controlled trials, and were treated (N = 2066) with rosuvastatin (5, 10, or 20 mg), fenofibric acid 135 mg, or rosuvastatin + fenofibric acid for 12 weeks. Data were pooled across doses of rosuvastatin as monotherapy and combination therapy.

Results

Compared with rosuvastatin monotherapy, combination therapy had comparable effects in achieving risk-stratified LDL-C goals; however, measures of total atherogenic burden were improved because significantly greater percentages of patients attained non-HDL-C goal in high- (62.9% vs 50.4%, P = .006) and moderate-risk groups (87.6% vs 80.4%, P = .016) and apolipoprotein B (ApoB) <90 mg/dL in high-risk group (59.8% vs 43.8%, P < .001). In the overall population, more patients treated with the combination therapy achieved desirable levels of HDL-C >40/50 mg/dL in men/women (P < .001), triglycerides <150 mg/dL (P < .001), and ApoB <90 mg/dL (P < .001), compared with rosuvastatin monotherapy. Furthermore, combination therapy resulted in significantly greater percentages of patients achieving simultaneous specified levels of LDL-C + non-HDL-C (P < .015); LDL-C + HDL-C + TG (P < .001); and LDL-C + HDL-C + triglycerides + non-HDL-C + ApoB (P < .001), compared with rosuvastatin monotherapy.

Conclusion

Rosuvastatin + fenofibric acid may be more efficacious than rosuvastatin alone in patients with mixed dyslipidemia.

  Michael H. Davidson , Judith Johnson , Michael W. Rooney , Michael L. Kyle and Douglas F. Kling
 

Background

Omega-3 (OM-3) fatty acid products are indicated for the treatment of severe hypertriglyceridemia; however, the omega-3-acid ethyl ester (OM-3 EE) formulations require significant pancreatic lipase stimulation with high-fat meals for adequate intestinal absorption of the metabolites eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA). A novel omega-3 free fatty acid (OM-3 FFA) formulation (Epanova®, Omthera Pharmaceuticals Inc., Princeton, NJ) was developed to maximize EPA and DHA bioavailability during a low-fat diet.

Objective

To compare the relative bioavailability of EPA and DHA from single 4-gram doses of OM-3 FFA and a prescription OM-3 EE (Lovaza®, GlaxoSmithKline, Research Triangle Park, NC).

Methods

This was a randomized, open-label, single dose, 4-way crossover, bioavailability study of OM-3 FFA and OM-3 EE administered during periods of low-fat and high-fat consumption to 54 overweight adults. Bioavailability was determined by the ln-transformed area under the plasma concentration versus time curve (AUC0-t) during a 24-hour interval for EPA and DHA (baseline-adjusted).

Results

The baseline-adjusted AUC0-t for total EPA + DHA during the low-fat period was 4.0-fold greater with OM-3 FFA compared with OM-3 EE (2650.2 vs 662.0 nmol.h/mL, respectively; P < .0001). During the high-fat period, AUC0-t for OM-3 FFA was approximately 1.3-fold greater than OM-3 EE (P < .0001). During the low-fat period, 30 of 51 (58.8%) subjects dosed with OM-3 FFA maintained an AUC0-t that was ≥50% of the respective high-fat AUC0-t in contrast to only 3 of 50 (6.0%) subjects dosed with OM-3 EE.

Conclusions

During a low-fat consumption period, the OM-3 FFA formulation provided dramatically improved bioavailability over the OM-3 EE formulation in overweight subjects. These findings offer a potential therapeutic advantage of the OM-3 FFA formulation for the treatment of severe hypertriglyceridemia as these patients are expected to adhere to a low-fat diet.

  Mark J. Cziraky , Vincent J. Willey , James M. McKenney , Siddhesh A. Kamat , Maxine D. Fisher , John R. Guyton , Terry A. Jacobson and Michael H. Davidson
 

Background

The occurrence of low rates of rhabdomyolysis among patients receiving lipid-lowering drugs (LLDs) in randomized clinical trials may be elucidated with population-based studies.

Objective

To determine the risk of hospitalized rhabdomyolysis associated with LLD therapy.

Methods

This observational study used claims data from 9 million members of five United States health plans to identify patients (≥18 years) who received >2 statin and nonstatin LLDs during July 2000 to December 2004. Inpatient International Classification of Diseases, Ninth Revision, Clinical Modification, codes for rhabdomyolysis (791.3, 728.89, and 728.88) were observed during the follow-up period; cases were confirmed with patients' medical records. Rhabdomyolysis events were reported per 10,000 person-years of LLD exposure; multivariate analysis was conducted.

Results

The study cohort (N = 473,343) received 490,988 and 11,624 person-years of LLD, and combination therapy, respectively. Medical charts were obtained for 104 of 144 eligible patients with rhabdomyolysis claims; 42 cases were confirmed. With atorvastatin as reference, rhabdomyolysis rates (95% confidence interval) were greatest for cerivastatin, 8.4 (2.3-21.7); no difference among available statins was observed. Rates for other LLD monotherapies were: niacin, 2.1 (0.3−7.7), ezetimibe, 2.1 (0.3−7.8), fenofibrate, 0 (0−1.7), and gemfibrozil, 2.0 (0.5−5.2). Multivariate analysis showed only cerivastatin with a significantly greater risk of rhabdomyolysis (odds ratio 4.74, 95% confidence interval 1.1-21.2, P = .041) versus atorvastatin among the statins. Combination therapies had increased rhabdomyolysis risk (OR 7.1, 1.6-31.6, P = .010) versus LLDs alone.

Conclusion

The risk of habdomyolysis among hospitalized patients receiving statins was low; no difference among the available statins was evident. Further data are needed to establish the risk profile but current findings already offer guidance to physicians.

  Michael H. Davidson , Michael Rooney , Elisabeth Pollock , Joan Drucker and Young Choy
 

Background

Niacin monotherapy in patients with dyslipidemia and impaired fasting glucose (IFG) may result in hyperglycemia. Colesevelam has the unique dual approvals to lower low-density lipoprotein cholesterol (LDL-C) and to improve glycemic control in type 2 diabetes mellitus.

Objectives

The aim of our study was to evaluate the effect of combined colesevelam and niacin treatment on LDL-C–lowering and glycemic control in subjects with IFG and dyslipidemia.

Methods

Men or women ≥ 18 years of age, with dyslipidemia (non-high-density lipoprotein cholesterol ≥ 100 mg/dL and ≤ 220 mg/dL; high-density lipoprotein cholesterol < 60 mg/dL) and fasting plasma glucose (FPG) ≥ 90 mg/dL and ≤ 145 mg/dL were randomly assigned 1:1 to colesevelam (3750 mg/d) with niacin titration (n = 70) or placebo with niacin titration (n = 70) over 12 weeks. Niacin was titrated from 500 mg/d up to a maximum of 2000 mg/d as tolerated, and all subjects took enteric-coated aspirin daily. Lipid and glycemic efficacy parameters were assessed as well as safety evaluations of adverse events, vital signs, alanine aminotransferase, aspartate aminotransferase, hematology, and urinalysis.

Results

Adjunct colesevelam had significantly greater LDL-C-lowering effect than niacin alone (placebo); -20.67% vs −12.86%, respectively (P = .0088). Niacin-mediated increases in FPG were significantly less with adjunct colesevelam (1.8 mg/dL vs 6.7 mg/dL; P = .0046), and fewer colesevelam subjects had increases of ≥10 mg/dL in FPG (8 vs 17, respectively). Adjunct colesevelam resulted in significantly smaller increases in hemoglobin A1c than placebo (0.06% vs 0.18%, respectively; P = .005). Consistent with hemoglobin A1c and FPG changes, fructosamine levels significantly decreased with colesevelam treatment (−5.0 μmol/L) but increased with placebo (3.0 μmol/L; P =.0255).

Conclusions

Colesevelam as an adjunct to niacin therapy further lowers LDL-C while obviating the adverse effects of niacin on glucose metabolism in patients with dyslipidemia and IFG.

  Scott M. Grundyemail , Hidenori Arai , Philip Barter , Thomas P. Bersot , D. John Betteridge , Rafael Carmena , Ada Cuevas , Michael H. Davidson , Jacques Genest , Y. Antero Kesaniemi , Shaukat Sadikot , Raul D. Santos , Andrey V. Susekov , Rody G. Sy , S. LaleTokgozoglu , Gerald F. Watts and Dong Zhao
  An international panel of the International Atherosclerosis Society has developed a new set of recommendations for the management of dyslipidemia. The panel identifies non-high-density lipoprotein cholesterol as the major atherogenic lipoprotein. Primary and secondary prevention are considered separately. Optimal levels for atherogenic lipoproteins are derived for the two forms of prevention. For primary prevention, the recommendations emphasize lifestyle therapies to reduce atherogenic lipoproteins; drug therapy is reserved for subjects at greater risk. Risk assessment is based on estimation of lifetime risk according to differences in baseline population risk in different nations or regions. Secondary prevention emphasizes use of cholesterol-lowering drugs to attain optimal levels of atherogenic lipoproteins.
  John J.P. Kastelein , Kevin C. Maki , Andrey Susekov , Marat Ezhov , Borge G. Nordestgaard , Ben N. Machielse , Douglas Kling and Michael H. Davidson
 

Background

Omega-3 fatty acids in free fatty acid form have enhanced bioavailability, and plasma levels are less influenced by food than for ethyl ester forms.

Objective

The aim was to evaluate the safety and lipid-altering efficacy in subjects with severe hypertriglyceridemia of an investigational pharmaceutical omega-3 free fatty acid (OM3-FFA) containing eicosapentaenoic acid and docosahexaenoic acid.

Methods

This was a multinational, double-blind, randomized, out-patient study. Men and women with triglycerides (TGs) ≥500 mg/dL, but <2000 mg/dL, took control (olive oil [OO] 4 g/d; n = 99), OM3-FFA 2 g/d (plus OO 2 g/d; n = 100), OM3-FFA 3 g/d (plus OO 1 g/d; n = 101), or OM3-FFA 4 g/d (n = 99) capsules for 12 weeks in combination with the National Cholesterol Education Program Therapeutic Lifestyle Changes diet.

Results

Fasting serum TGs changed from baseline by −25.9% (P < .01 vs OO), −25.5% (P < .01 vs OO), and −30.9% (P < .001 vs OO) with 2, 3, and 4 g/d OM3-FFA, respectively, compared with −4.3% with OO. Non-high-density lipoprotein cholesterol (non-HDL-C), total cholesterol-to-HDL-C ratio, very low-density lipoprotein cholesterol, remnant-like particle cholesterol, apolipoprotein CIII, lipoprotein-associated phospholipase A2, and arachidonic acid were significantly lowered (P < .05 at each OM3-FFA dosage vs OO); and plasma eicosapentaenoic acid and docosahexaenoic acid were significantly elevated (P < .001 at each OM3-FFA dosage vs OO). With OM3-FFA 2 and 4 g/d (but not 3 g/d), low-density lipoprotein cholesterol was significantly increased compared with OO (P < .05 vs OO). High-sensitivity C-reactive protein responses with OM3-FFA did not differ significantly from the OO response at any dosage. Fewer subjects reported any adverse event with OO vs OM3-FFA, but frequencies across dosage groups were similar. Discontinuation due to adverse event, primarily gastrointestinal, ranged from 5% to 7% across OM3-FFA dosage groups vs 0% for OO.

Conclusions

OM3-FFA achieved the primary end point for TG lowering and secondary end point of non-HDL-C lowering at 2, 3, and 4 g/d in persons with severe hypertriglyceridemia. This trial was registered at www.clinicaltrials.gov as NCT01242527.

 
 
 
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