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Objectives Changes in cIMT have not been consistently correlated with cardiovascular risk reduction in clinical studies. The variability of carotid intima media thickness (cIMT) changes in published statin LDL-C-lowering studies in relation to various baseline and study characteristics was assessed. Methods This was an exploratory analysis of study-level data pooled from statin-treatment arms of 13 studies conducted during 1988–2006. Baseline mean common carotid artery (CCA)/cIMT, maximum mean CCA/cIMT and LDL-C levels, and annualized cIMT changes were estimated for the overall studies, those conducted before/after 2000, and in risk-based subgroups. Potential relationships between prespecified covariates and cIMT changes were assessed. Results Baseline mean CCA/cIMT and LDL-C levels were higher in the combined studies conducted before year 2000 (0.8521 mm) than after 2000 (0.7458 mm), and somewhat higher in study populations of patients with coronary heart disease risk and those with greater LDL-C reductions. Mean CCA/cIMT changes were also larger for the studies conducted before 2000 (−0.0119 mm/year) than after 2000 (−0.0013 mm/year). Notably, studies conducted before 2000 were of longer duration (≥2 years) than after 2000 (<2 years). Heterogeneity in cIMT change was attributed to baseline and study-design characteristics. Longer study duration and greater LDL-C reductions were significantly related to larger annualized cIMT changes. Maximum cIMT results were similar. Conclusion Baseline cIMT and LDL-C levels were lower, and cIMT changes were smaller in statin cIMT trials conducted after 2000 than those before 2000. These trends are consistent with increased treatment and control of high LDL-C levels over recent years in clinical practice, and may influence the results of cIMT studies. [ABSTRACT FROM AUTHOR]

Objective: Progression of carotid intima-media thickness (CIMT) is a surrogate indicator for the early stages of atherosclerosis. Methods: The study investigated relationships between baseline lipoprotein cholesterol, triglyceride (TG), and apolipoprotein (Apo) B levels assessed with density gradient ultracentrifugation (DGU) and progression of posterior wall common CIMT in men (45-75 years of age) and women (55-74 years of age) in the control arm of a clinical trial. Participants had baseline posterior wall CIMT 0.7-2.0 mm, without significant stenosis. CIMT was assessed using B-mode ultrasound at baseline, and 12 and ~18 months. A DGU cholesterol panel that assessed the major lipoprotein classes and subclasses, plus triglycerides, lipoprotein (a) cholesterol, low-density lipoprotein (LDL) peak time (inversely related to LDL particle density), and Apo B were performed on fasting baseline samples. Apo B was also measured using an enzyme linked immunosorbent assay. Results: Baseline CIMT was inversely associated (P < 0.001) with CIMT progression. After adjustment for baseline CIMT, significant predictors of posterior wall CIMT progression in linear regression analyses included LDL peak time (inverse, P = 0.045), total high-density lipoprotein cholesterol (HDL-C) (inverse, P = 0.001), HDL2-C (inverse, P = 0.005), HDL3-C (inverse, P = 0.003), very low-density lipoprotein (VLDL)-C (P = 0.037), and VLDL1+2-C (P = 0.016). Conclusion: These data indicate that DGU-derived indicators of the "atherogenic lipoprotein phenotype," including increased TG-rich lipoprotein cholesterol, lower HDL-C and HDL-C subfractions, and a greater proportion of LDL-C carried by more dense LDL particles, are associated with CIMT progression in men and women at moderate risk for coronary heart disease. [ABSTRACT FROM AUTHOR]

The present multicenter, 6-week, randomized, double-blind, parallel-group, clinical trial evaluated the safety and efficacy of ezetimibe (10 mg) added to stable rosuvastatin therapy versus up-titration of rosuvastatin from 5 to 10 mg or from 10 to 20 mg. The study population included 440 subjects at moderately high/high risk of coronary heart disease with low-density lipoprotein (LDL) cholesterol levels higher than the National Cholesterol Education Program Adult Treatment Panel III recommendations (<100 mg/dl for moderately high/high-risk subjects without atherosclerotic vascular disease or <70 mg/dl for high-risk subjects with atherosclerotic vascular disease). Pooled data demonstrated that ezetimibe added to stable rosuvastatin 5 mg or 10 mg reduced LDL cholesterol by 21%. In contrast, doubling rosuvastatin to 10 mg or 20 mg reduced LDL cholesterol by 5.7% (between-group difference of 15.2%, p <0.001). Individually, ezetimibe plus rosuvastatin 5 mg reduced LDL cholesterol more than did rosuvastatin 10 mg (12.3% difference, p <0.001), and ezetimibe plus rosuvastatin 10 mg reduced LDL cholesterol more than did rosuvastatin 20 mg (17.5% difference, p <0.001). Compared to rosuvastatin up-titration, ezetimibe add-on achieved significantly greater attainment of LDL cholesterol levels of <70 or <100 mg/dl (59.4% vs 30.9%, p <0.001), and <70 mg/dl in all subjects (43.8% vs 17.5%, p <0.001); produced significantly greater reductions in total cholesterol, non–high-density lipoprotein cholesterol, and apolipoprotein B (p <0.001); and resulted in similar effects on other lipid parameters. Adverse experiences were generally comparable among the groups. In conclusion, compared to up-titration doubling of the rosuvastatin dose, ezetimibe 10 mg added to stable rosuvastatin 5 mg or 10 mg produced greater improvements in many lipid parameters and achieved greater attainment of the National Cholesterol Education Program Adult Treatment Panel III recommended LDL cholesterol targets in subjects with elevated LDL cholesterol and at moderately high/high coronary heart disease risk. [Copyright &y& Elsevier]

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. [ABSTRACT FROM AUTHOR]

Abstract: 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. [ABSTRACT FROM AUTHOR]

This randomized, double-blind, parallel trial assessed the influence of pomegranate juice consumption on anterior and posterior carotid intima–media thickness (CIMT) progression rates in subjects at moderate risk for coronary heart disease. Subjects were men (45 to 74 years old) and women (55 to 74 years old) with ≥1 major coronary heart disease risk factor and baseline posterior wall CIMT 0.7 to 2.0 mm, without significant stenosis. Participants consumed 240 ml/day of pomegranate juice (n = 146) or a control beverage (n = 143) for up to 18 months. No significant difference in overall CIMT progression rate was observed between pomegranate juice and control treatments. In exploratory analyses, in subjects in the most adverse tertiles for baseline serum lipid peroxides, triglycerides (TGs), high-density lipoprotein (HDL) cholesterol, TGs/HDL cholesterol, total cholesterol/HDL cholesterol, and apolipoprotein-B100, those in the pomegranate juice group had significantly less anterior wall and/or composite CIMT progression versus control subjects. In conclusion, these results suggest that in subjects at moderate coronary heart disease risk, pomegranate juice consumption had no significant effect on overall CIMT progression rate but may have slowed CIMT progression in subjects with increased oxidative stress and disturbances in the TG-rich lipoprotein/HDL axis. [Copyright &y& Elsevier]

OBJECTIVE: To compare changes in lipid levels (total cholesterol [total-C], low-density lipoprotein cholesterol [LDL-C], triglycerides [TG], and high-density lipoprotein cholesterol [HDL-C]) for patients who switched from standard fenofibrate 160 mg (requiring dosing with food) to fenofibrate 145 mg with no food effect (NFE). METHODS: The analyses were performed using an electronic medical records dataset from 1 January 2003 to 31 July 2005. Patients were eligible for the analysis if they had a diagnosis of hypertension, dyslipidaemia or diabetes mellitus, were written a prescription for standard fenofibrate 160 mg during the period 1 May 2004 to 30 April 2005, and were written a subsequent prescription for fenofibrate 145 mg NFE at least 60 days after first receiving the 160 mg dose. The outcomes measured were lipid levels: total-C, LDL-C, HDL-C and TG. RESULTS: 491 patients who switched from standard fenofibrate 160 mg to fenofibrate 145 mg NFE met all of the inclusion criteria. Patients who changed therapy to fenofibrate 145 mg NFE from standard fenofibrate 160 mg showed a beneficial response in lipid levels. Statistically significant patient-specific changes in lipid levels were observed for the change from baseline to standard fenofibrate 160 mg for three lipid levels (total-C, HDL-C and TG). Statistically significant changes were observed for the switch to fenofibrate 145 mg NFE for three lipid levels (total-C, LDL-C and TG). CONCLUSIONS: More patients treated in an outpatient clinical practice had better lipid results when prescribed fenofibrate 145 mg NFE than those prescribed standard fenofibrate 160 mg, suggesting that a less restrictive dosing regimen improves lipid outcomes. [ABSTRACT FROM AUTHOR]

BACKGROUND: and objective: Atherogenic lipid parameters in patients with mixed dyslipidaemia have been demonstrated to increase atherosclerotic coronary heart disease (CHD) risk. Clinical studies have shown that HMG-CoA reductase inhibitor (statin) and fibric acid derivative (fibrate) combination therapy is effective at improving multiple lipid abnormalities in different patient populations at increased risk of CHD. However, inconsistencies with respect to trial designs and safety issues have limited the clinical use of this combination therapy. A comprehensive, controlled clinical trial programme was thus designed to evaluate three separate statins in combination with ABT-335, a new formulation of fenofibric acid. METHODS: Three separate 22-week, phase III, double-blind, active-controlled trials will evaluate combination therapy with ABT-335 135 mg/day and either rosuvastatin (10 mg/day and 20 mg/day), atorvastatin (20 mg/day and 40 mg/day) or simvastatin (20 mg/day and 40 mg/day) in comparison to either ABT-335 or the corresponding statin monotherapy. An approximate total of 2400 patients with elevated triglycerides (TG) [≥150 mg/dL], reduced high-density lipoprotein cholesterol (HDL-C) [<40 mg/dL for men and <50 mg/dL for women], and elevated low-density lipoprotein cholesterol (LDL-C) [≥130 mg/dL] will be randomized to one of six intervention arms per trial (two combination therapy and four monotherapy groups). The pre-specified primary efficacy endpoint is a composite of the mean percent changes in HDL-C and TG (comparing each combination therapy with the corresponding statin monotherapy dose) and LDL-C (comparing each combination therapy with ABT-335 monotherapy). Secondary endpoints include mean percent changes in non-HDL-C, very LDL-C, total cholesterol, apolipoprotein B and high sensitivity C-reactive protein levels. At study end, patients may enrol in a 12-month open-label extension study that will evaluate the long-term efficacy and safety of combination therapy. CONCLUSION: This is the largest phase III randomized, controlled clinical programme to date evaluating the efficacy and safety of the combined use of a new formulation of fenofibric acid (ABT-335) with three commonly prescribed statins in patients with mixed dyslipidaemia. [ABSTRACT FROM AUTHOR]

Abstract: Background: AGI-1067 (succinobucol) is a phenolic derivative of probucol that inhibits the vascular oxidative-inflammatory cascade and is intended to have an improved clinical profile. Objective: The Assessment of Lipoprotein Profiles (ALPS) study evaluated the effects of AGI-1067 on lipid, antioxidant, antiinflammatory and safety profiles in healthy subjects. Methods: This was a double-blind, placebo-controlled, 12-week, multicenter trial. Eligible subjects, aged 18 to 65 years, had low-density lipoprotein cholesterol (LDL-C) ≤ 190 mg/dL, triglyceride (TG) ≤ 600 mg/dL and Framingham risk <10%. Subjects were randomized 1:1 to oral 300 mg AGI-1067 (n = 127) or matching placebo (n = 127) once daily. Results: AGI-1067 and placebo treatment had small changes (mean) in: LDL-C (+2.98 vs −1.52 mg/dL, respectively; P = 0.057), apolipoprotein B (+1.48 vs −1.91 mg/dL; P = 0.267), high-density lipoprotein cholesterol (HDL-C) [−3.69 vs −0.29 mg/dL; P < 0.001], and apolipoprotein (Apo) A-I (−10.43 vs −6.14 mg/dL; P = 0.021). Subjects with baseline LDL-C > 130 mg/dL showed the largest decreases in HDL-C and ApoA-I, while subjects with LDL-C ≤130 mg/dL had insignificant changes in both parameters. Changes in cholesteryl ester transfer protein mass were significantly correlated (P < 0.0001) with LDL-C changes, but not HDL-C. Paraoxonase activity increased with AGI-1067 vs little change in placebo (+1.78 vs +0.15 U/L, respectively; P = 0.077). HDL particles isolated from AGI-1067 treated subjects showed significant antioxidant potency vs HDL particles from placebo subjects (thiobarbituric acid reactive substances in a LDL oxidation assay decreased −25.88% vs +7.88, respectively; P = 0.011). Conclusion: The ALPS study demonstrated that AGI-1067 had minor effects on LDL and HDL cholesterol. More dramatic effects were observed for HDL-associated paraoxonase and thiobarbituric acid reactive substances activity, suggesting that the antiatherosclerotic properties of AGI-1067 may involve an HDL antioxidant mechanism consistent with inhibition of the oxidative-inflammatory cascade, rather than involving a lipid regulating pathway. [Copyright &y& Elsevier]

Data from recent clinical trials of high- versus moderate-dose statin therapy support the recommendation to achieve a low-density lipoprotein (LDL) <100 mg/dl in high-risk patients and reveal that many patients will require a high-dose statin to achieve this goal. Overall, low rates of serious musculoskeletal (<0.6%) and hepatic (<1.3%) toxicity have been observed with high-dose statin therapy. In the long-term trials, atorvastatin 80 mg had higher rates of persistent transaminase elevations but rates of myopathy and rhabdomyolysis similar to lower doses of statins. The rate of myopathy and rhabdomyolysis for simvastatin 80 mg, although still low, was about 4× higher than for atorvastatin 80 mg and lower doses of statin. A similar margin of safety would be expected in properly selected patients with characteristics similar to those who participated in the clinical trials. High-dose statin therapy or combination therapy will be required for the large majority of very high-risk patients to achieve the optional LDL goal of <70 mg/dl. While the combination of ezetimibe, bile-acid sequestering agents, niacin, and fenofibrate with moderate dose statins appears to be reasonably safe, the long-term safety of combination with high-dose statins remains to be established. In order to optimize patient outcomes, clinicians should be aware of specific patient characteristics, such as advancing age, gender, body mass index, or glomerular filtration rate, which predict muscle and hepatic statin toxicity. [Copyright &y& Elsevier]

The article presents a randomized, double-blind, controlled trial comparing the effect of pioglitazone and glimepiride on carotid artery intima-media thickness in patients with type 2 diabetes mellitus. The trial was conducted at clinical sites in the Chicago, Illinois metropolitan area. The study found that over an 18-month treatment period for patients with type 2 diabetes mellitus, pioglitazone slowed the progression of carotid artery intima-media thickness to a greater degree than glimepiride.

Biological therapies involve the utilization of proteins, DNA, antibodies, or other substances derived or synthesized from living tissue for therapeutic effects. There are several biological therapies in clinical development for the prevention and treatment of atherosclerosis. The most advanced in human trials are apolipoprotein mimetics, which include apolipoprotein A-1Milano and phospholipid complexes. Infusions of these apolipoprotein mimetics have been demonstrated to reduce atherosclerotic development in both animal models and humans over a relatively short period of time. Autoimmunization to create neutralizing antibodies to CETP is also in human trials. [Copyright &y& Elsevier]

Advancing age is an independent risk factor for the development of coronary heart disease. However, the significance of hypercholesterolemia as a cardiovascular risk factor in the elderly, has been widely debated. While no large-scale, randomized clinical trial has been conducted to evaluate cholesterol lowering solely in the elderly, evidence from older subgroups in several intervention trials supports the efficacy of lowering elevated low-density lipoprotein cholesterol for reducing cardiovascular risk in the elderly. Furthermore, although the relative risk of hypercholesterolemia for coronary heart disease incidence may be attenuated with advancing age, the population-wide impact of treating elevated cholesterol levels in the elderly would be large, due to the high frequency of coronary heart disease in the elderly. This article reviews key issues in the management of hypercholesterolemia with respect to coronary heart disease risk reduction in the elderly. [ABSTRACT FROM AUTHOR]

Obicetrapib is a selective cholesteryl ester transfer protein (CETP) inhibitor. Previous research has demonstrated similar pharmacokinetic (PK) responses to single doses of obicetrapib between Japanese and White males, but the PK responses have not been established in Chinese individuals. The purpose of this randomized, parallel, open‐label trial was to characterize the PK and pharmacodynamic (PD; CETP activity and plasma lipids) responses and safety of single doses (5, 10, or 25 mg; N = 36) and multiple doses (10 mg for 14 days; N = 12) of obicetrapib in healthy Chinese individuals. The maximum concentration and area under the drug concentration‐time curve of obicetrapib from 0 h to infinity increased with dose after all single doses of obicetrapib. After 7 consecutive days of dosing, low‐density lipoprotein cholesterol and high‐density lipoprotein cholesterol reached their minimum and maximum changes of 42% reduction and 108% increase, respectively. Primary PK and PD parameters after single‐ and multiple‐dose administration of obicetrapib were similar to those in healthy white participants in previous studies. One participant in the 5 mg dose group experienced a treatment‐emergent adverse event of decreased white blood cell and neutrophil counts, which resolved without intervention. In conclusion, these findings support the inclusion of Chinese individuals in the ongoing phase 3 clinical development program of obicetrapib. [ABSTRACT FROM AUTHOR]

This study was designed to determine whether a soluble dietary fiber supplement containing gum arabic and pectin in apple juice would lower serum lipids in 110 hypercholesterolemic men and women. Subjects were stabilized on an American Heart Association Phase I Diet for 8 wk. Those with elevated low density lipoprotein cholesterol levels, despite dietary modification, continued to follow the diet and were randomly assigned to receive 720 mL/d of apple juice containing 0 (control), 5, 9 or 15 g of gum arabic and pectin (4:1 ratio) for 12 wk, followed by a 6-wk apple juice-only washout phase. Serum lipid profiles, body weight and 3-day diet records were collected at 3-wk intervals. No significant differences among groups were observed in serum lipid responses during treatment or washout. During the treatment phase, mean serum total cholesterol and triglyceride concentrations increased by 3.5 and 28.5%, respectively (all groups combined, P < 0.0001). The high density lipoprotein cholesterol level did not change significantly from baseline in any group. During washout, mean total cholesterol concentration rose by an additional 2.4% (P < 0.05) compared with the value at the end of the treatment period, suggesting that the apple juice used to deliver the fiber supplement may have contributed to the adverse changes observed in the serum lipid profile. These findings do not support the hypothesized hypocholesterolemic effect of the gum arabic/pectin (4:1) mixture studied, but do underline the importance of selecting appropriate vehicles for delivery of dietary fiber mixtures. [ABSTRACT FROM AUTHOR]

The author comments on a meta-analysis of clinical trials that examined the association between high-dose statin therapy and increased risk of new-onset diabetes mellitus. According to the author, one possible explanation for statin-induced insulin resistance is inhibition of isoprenoid biosynthesis. He contends that statin monotherapy is effective in reducing low density lipoprotein regardless of the dosage. He points out that high-dose statin therapy is associated with toxicity risk.

Presents a clinical trial on the efficacy of the concurrent administration of marine oil and simvastatin therapy in patients with hyperlipidemia. Profile of patients; Serum lipid concentrations and responses to treatment; Compliance to the treatment regimen.

Fibrates are an important class of drugs for the management of dyslipidemia. This class of drugs is generally well tolerated but is infrequently associated with several safety issues. Fibrates, most likely by an effect mediated by peroxisome proliferator-activated receptor–α, may reversibly increase creatinine and homocysteine but are not associated with an increased risk for renal failure in clinical trials. Fibrates are associated with a slightly increased risk (<1.0%) for myopathy, cholelithiasis, and venous thrombosis. In clinical trials, patients without elevated triglycerides and/or low high-density lipoprotein cholesterol (HDL) levels, fibrates are associated with an increase in noncardiovascular mortality. In combination with statins, gemfibrozil generally should be avoided. The preferred option is fenofibrate, which is not associated with an inhibition of statin metabolism. Clinicians are advised to measure serum creatinine before fibrate use and adjust the dose accordingly for renal impairment. Routine monitoring of creatinine is not required, but if a patient has a clinically important increase in creatinine, and other potential causes of creatinine increase have been excluded, consideration should be given to discontinuing fibrate therapy or reducing the dose. [Copyright &y& Elsevier]

It is well established that low high-density lipoprotein (HDL) cholesterol is a risk factor for coronary artery disease (CAD). Growing evidence from epidemiologic as well as intervention studies have identified that a low level of HDL cholesterol contributes to cardiovascular disease risk. In addition, a number of clinical trials have substantiated that an inverse association between HDL cholesterol concentrations and cardiovascular risk exists. Decreasing low-density lipoprotein cholesterol levels with statins has a major impact on cardiovascular risk reduction, and statin therapy plays a significant role in the management of CAD. However, low levels of HDL cholesterol remain as a cardiovascular risk factor despite statin therapy. This article presents an overview of statin clinical trials and discusses implications for the clinical management of patients with low HDL cholesterol levels and increased cardiovascular risk. [Copyright &y& Elsevier]