Results from a Phase 1 Study Assessing the Pharmacokinetics of the Aldosterone Synthase Inhibitor Baxdrostat in Participants with Varying Degrees of Renal Function.

Baxdrostat is a selective small-molecule aldosterone synthase inhibitor in development for treatment of hypertension and chronic kidney disease. This phase 1, open-label, parallel-group study assessed the safety and pharmacokinetics (PK) of baxdrostat in participants with varying degrees of renal function. Participants were enrolled into control (estimated glomerular filtration rate [eGFR] ≥60 mL/min), moderate to severe renal impairment (eGFR 15-59 mL/min), or kidney failure (eGFR <15 mL/min) groups and received a single 10-mg baxdrostat dose followed by 7 days of inpatient PK blood and urine sampling.

Results From a Randomized, Open-Label, Crossover Study Evaluating the Effect of the Aldosterone Synthase Inhibitor Baxdrostat on the Pharmacokinetics of Metformin in Healthy Human Subjects.

Background: Due to the high comorbidity of diabetes and hypertension, co-administration of metformin with anti-hypertensive drugs is likely. Baxdrostat is an aldosterone synthase inhibitor in development for the potential treatment of hypertension. In vitro data indicated that baxdrostat inhibits the multidrug and toxin extrusion 1 (MATE1) and MATE2-K renal transporters.

Results from a phase 1, randomized, double-blind, multiple ascending dose study characterizing the pharmacokinetics and demonstrating the safety and selectivity of the aldosterone synthase inhibitor baxdrostat in healthy volunteers.

Baxdrostat is a selective inhibitor of aldosterone synthase designed for the treatment of disorders associated with elevated aldosterone. This study evaluated the safety, pharmacokinetics, and pharmacodynamics of multiple ascending doses of baxdrostat in healthy volunteers. Subjects were randomized to receive oral baxdrostat (0.

Efficacy and safety of eicosapentaenoic acid ethyl ester (AMR101) therapy in statin-treated patients with persistent high triglycerides (from the ANCHOR study).

AMR101 is an ω-3 fatty acid agent containing ≥96% pure icosapent-ethyl, the ethyl ester of eicosapentaenoic acid. The efficacy and safety of AMR101 were evaluated in this phase 3, multicenter, placebo-controlled, randomized, double-blinded, 12-week clinical trial (ANCHOR) in high-risk statin-treated patients with residually high triglyceride (TG) levels (≥200 and <500 mg/dl) despite low-density lipoprotein (LDL) cholesterol control (≥40 and <100 mg/dl). Patients (n = 702) on a stable diet were randomized to AMR101 4 or 2 g/day or placebo.

Eicosapentaenoic acid ethyl ester (AMR101) therapy in patients with very high triglyceride levels (from the Multi-center, plAcebo-controlled, Randomized, double-blINd, 12-week study with an open-label Extension [MARINE] trial).

AMR101 is an omega-3 fatty acid agent containing ≥96% eicosapentaenoic acid ethyl ester and no docosahexaenoic acid. Previous smaller studies suggested that highly purified eicosapentaenoic acid lowered triglyceride (TG) levels without increasing low-density lipoprotein (LDL) cholesterol levels. TG-lowering therapies such as fibrates, and fish oils containing both eicosapentaenoic acid and docosahexaenoic acid, can substantially increase LDL cholesterol levels when administered to patients with very high TG levels (≥500 mg/dl).

Carotid atherosclerosis progression in familial hypercholesterolemia patients: a pooled analysis of the ASAP, ENHANCE, RADIANCE 1, and CAPTIVATE studies.

Background: Until recently, patients with heterozygous familial hypercholesterolemia (HeFH) were considered the best subjects for the assessment of changes in carotid intima-media thickness (cIMT) in randomized intervention trials. Our aims were to investigate whether contemporary statin-treated HeFH patients still show accelerated cIMT increase and to assess the impact of statin treatment, before and after random assignment, on atherosclerosis progression.

Methods And Results: We retrospectively evaluated cIMT change, and prior statin treatment and postbaseline LDL-C change as predictors of cIMT change, in 1513 HeFH patients who were randomly assigned to the statin arms of the early ASAP and more recent RADIANCE 1, CAPTIVATE, and ENHANCE studies.

Risk reduction and tolerability of fluvastatin in patients with the metabolic syndrome: a pooled analysis of thirty clinical trials.

Objective: This pooled analysis of 30 completed clinical trials assessed the efficacy and safety profile in reducing cardiovascular disease (CVD) risk of fluvastatin in the treatment of dyslipidemia in patients with and without the metabolic syndrome (metS).

Methods: Data from 30 double-blind, randomized, placebo-controlled or fluvastatin-controlled trials with > or =6 weeks of active treatment and daily fluvastatin doses of 20, 40, and 80 mg were pooled. Patients received fluvastatin or placebo.

The renal safety profile of fluvastatin: results of a pooled analysis.

A pooled analysis was designed to evaluate the effects of fluvastatin on the kidney, in terms of renal adverse events, laboratory abnormalities, and renal function over time. An analysis of adverse events was performed on data from 30 completed clinical trials of fluvastatin in 11,815 patients. An analysis of renal function was also performed on data from patients who participated in long-term studies >6 months in treatment duration.

The effect of fluvastatin on cardiac outcomes in patients with moderate to severe renal insufficiency: a pooled analysis of double-blind, randomized trials.

Background: Individuals with chronic kidney disease are at high risk for cardiovascular disease and have a high prevalence of hyperlipidemia. Lipid-lowering therapy may help patients with renal disease reduce their risk for cardiovascular events.

Methods: A pooled analysis of 30 completed clinical trials compared the efficacy and safety profiles of fluvastatin in subgroups of patients with moderate to severe renal insufficiency (creatinine clearance < 50 ml/min) and patients with normal renal function or mild renal insufficiency (creatinine clearance > or = 50 ml/min).

Comparison of efficacy and safety of rosuvastatin versus atorvastatin in African-American patients in a six-week trial.

The lipid-modifying effects of statin therapy in hypercholesterolemic African-Americans have not been well characterized. This study compared the efficacy and safety of rosuvastatin and atorvastatin treatment for 6 weeks in hypercholesterolemic African-American adults. In the African American Rosuvastatin Investigation of Efficacy and Safety (ARIES) trial (4522US/0002), 774 adult African-Americans with low-density lipoprotein cholesterol > or = 160 and < or = 300 mg/dl and triglycerides < 400 mg/dl were randomized to receive open-label rosuvastatin 10 or 20 mg or atorvastatin 10 or 20 mg for 6 weeks.

Comparison of efficacy and safety assessment of fluvastatin in patients <65 years versus > or =65 years of age.

This pooled analysis of 30 completed clinical trials assessed the efficacy and safety of fluvastatin in patients <65 (n = 8,037) and patients > or =65 years of age (n = 3,717). The results demonstrated that in patients > or =65 years of age, lipid changes with fluvastatin therapy are equivalent to or slightly better than those observed in patients <65 years of age. Treatment with fluvastatin produced a significantly lower incidence of major cardiovascular clinical end points (major adverse cardiac events [MACEs]) and an increase in the time to a first MACE in the older population.

Effects of baseline level of triglycerides on changes in lipid levels from combined fluvastatin + fibrate (bezafibrate, fenofibrate, or gemfibrozil).

This analysis was conducted to evaluate the effect of baseline triglyceride levels on lipid and lipoprotein changes after treatment with the combination of fluvastatin and fibrates. The analysis involved pooling data from 10 studies that included 1,018 patients with either mixed hyperlipidemia or primary hypercholesterolemia. Patients received a combination of fluvastatin and a fibrate (bezafibrate, fenofibrate, or gemfibrozil) from 16 to 108 weeks.

Comparison of treatment with fluvastatin extended-release 80-mg tablets and immediate-release 40-mg capsules in patients with primary hypercholesterolemia.

Background: According to the National Cholesterol Education Program (NCEP) Adult Treatment Panel (ATP) III guidelines, hypercholesterolemic patients with greater risk for cardiovascular heart disease require more aggressive lowering of low-density lipoprotein cholesterol (LDL-C) levels. Numerous studies have demonstrated that despite these guidelines, patients often do not reach their target levels, and that physicians frequently do not titrate the drug beyond the starting dose. For these patients, it may be more suitable to initiate treatment with a higher starting dose of statin.

The challenges of conducting clinical endpoint studies.

In order to evaluate the effects of a particular treatment strategy on mortality and major morbidity within a disease entity, large, multinational, relatively long-term clinical endpoint studies are often conducted. The primary challenge of conducting these studies is to maintain consistency in the interpretation of the clinical endpoints across different geographic areas and over the long time course of the study. The success of a clinical endpoint study depends on understanding the challenges and incorporating the special requirements of these studies into the protocol design and operational procedures throughout the study.

Effects of simvastatin, an HMG-CoA reductase inhibitor, in patients with hypertriglyceridemia.

Background: Patients with elevated levels of serum triglycerides (TG) often have other associated lipid abnormalities (e.g., low levels of high-density lipoprotein cholesterol [HDL-C]) and are at increased risk of developing coronary heart disease.

The impact of the National Cholesterol Education Program Adult Treatment Panel III guidelines on drug development.

In the newest guidelines of the National Cholesterol Education Program (NCEP) Adult Treatment Panel (ATP) III, more intensive low-density lipoprotein cholesterol-lowering therapy, together with more attention to other lipid and lipoprotein parameters, are recommended for a larger group of dyslipidemic patients than was covered under ATP I and ATP II. A discussion to evaluate how future drug development might be affected by these new guidelines took place at the 14th International Symposium on Drugs Affecting Lipid Metabolism (DALM) conference, held in New York in September 2001. These discussions involved how to develop new lipid-lowering drugs in an era in which so much compelling evidence demonstrates the benefits of statins.