Oral Apolipoprotein A-I Mimetic D-4F Lowers HDL-Inflammatory Index in High-Risk Patients: A First-in-Human Multiple-Dose, Randomized Controlled Trial.

A single dose of the apolipoprotein (apo)A-I mimetic peptide D-4F rendered high-density lipoprotein (HDL) less inflammatory, motivating the first multiple-dose study. We aimed to assess safety/tolerability, pharmacokinetics, and pharmacodynamics of daily, orally administered D-4F. High-risk coronary heart disease (CHD) subjects added double-blinded placebo or D-4F to statin for 13 days, randomly assigned 1:3 to ascending cohorts of 100, 300, then 500 mg (n = 62; 46 men/16 women). D-4F was safe and well-tolerated. Mean ± SD plasma D-4F area under the curve (AUC, 0-8h) was 6.9 ± 5.7 ng/mL*h (100 mg), 22.7 ± 19.6 ng/mL*h (300 mg), and 104.0 ± 60.9 ng/mL*h (500 mg) among men, higher among women. Whereas placebo dropped HDL inflammatory index (HII) 28% 8 h postdose (range, 1.25-0.86), 300-500 mg D-4F effectively halved HII: 1.35-0.57 and 1.22-0.63, respectively (P \u3c 0.03 vs. placebo). Oral D-4F peptide dose predicted HII suppression, whereas plasma D-4F exposure was dissociated, suggesting plasma penetration is unnecessary. In conclusion, oral D-4F dosing rendered HDL less inflammatory, affirming oral D-4F as a potential therapy to improve HDL function

Efficacy and safety of bempedoic acid in patients not receiving statins in phase 3 clinical trials

BACKGROUND: Despite the high incidence of patients with statin tolerance problems, randomized evaluations of nonstatin oral treatment options for lowering of low-density lipoprotein cholesterol (LDL-C) in this population are sparse. OBJECTIVE: To assess the LDL-C lowering effect of bempedoic acid in patients not taking statins. METHODS: This was a pooled analysis of data from patients enrolled in four phase 3 bempedoic acid studies (12 to 52 weeks in duration) who were not taking concomitant statins (Phase 3 No Statin Cohort) and a phase 3 bempedoic acid plus ezetimibe fixed-dose combination study (BA+EZE FDC No Statin Cohort). The primary endpoint for all studies was the percent change from baseline to week 12 in LDL-C levels. Safety and tolerability were assessed by laboratory values and adverse events. RESULTS: In the Phase 3 No Statin Cohort, bempedoic acid (n = 394) lowered LDL-C levels at week 12 significantly more than placebo (n = 192; -26.5% [95% CI, -29.7%, -23.2%]; P\u3c0.001). The fixed-dose combination of bempedoic acid with ezetimibe lowered LDL-C by 39.2% (95% CI, -51.7% to -26.7%; P\u3c0.001). Muscle-related disorders occurred at a rate of 26.4 and 28.6 per 100 person-years with bempedoic acid and placebo, respectively. CONCLUSIONS: In patients with hypercholesterolemia unable to take statins, bempedoic acid lowered LDL-C levels by a mean of 26.5% vs placebo and bempedoic acid + ezetimibe fixed-dose combination lowered LDL-C by 39.2%. The treatments were generally well tolerated, suggesting that bempedoic acid may be efficacious and well tolerated in this challenging-to-treat patient population

Long-term efficacy and safety of the microsomal triglyceride transfer protein inhibitor lomitapide in patients with homozygous familial hypercholesterolemia

Homozygous familial hypercholesterolemia is a genetic disorder characterized by low-density lipoprotein (LDL)-receptor dysfunction, markedly elevated levels of LDL-cholesterol (LDL-C) and premature atherosclerosis. Patients are often poorly responsive to conventional lipid-lowering therapies that upregulate LDL-receptor expression

Bempedoic acid safety analysis: Pooled data from four phase 3 clinical trials

Background An ongoing need exists for safe and effective lipid-lowering therapies (LLTs) for patients unable to achieve desired lipid levels with current treatment options. Objective The objective of this study was to describe the safety profile of bempedoic acid, an oral, first-in-class, adenosine triphosphate (ATP)–citrate lyase inhibitor that significantly reduces low-density lipoprotein cholesterol (LDL-C) levels by 17.4%–28.5% vs placebo. Methods This was a pooled analysis of four phase 3, randomized (2:1), double-blind, placebo-controlled studies in patients with hypercholesterolemia who required additional LDL-C lowering, despite stable maximally-tolerated LLT. Patients received 180 mg of bempedoic acid (n = 2424) or placebo (n = 1197) once daily for 12 to 52 weeks. Assessments included treatment-emergent adverse events (TEAEs) and clinical laboratory tests. Results Of 3621 patients (the median drug exposure: 363 days), exposure-adjusted TEAE rates were 87.1/100 and 82.9/100 person-years (PY) for bempedoic acid and placebo, respectively. No single TEAE influenced the difference in rates. TEAEs leading to discontinuation occurred at rates of 13.4/100 and 8.9/100 PY for bempedoic acid vs placebo, with the most common cause being myalgia, which occurred less frequently with bempedoic acid vs placebo (1.5/100 vs 2.0/100 PY). Rates of myalgia and muscle weakness were comparable vs placebo. Bempedoic acid was associated with mild increases in blood urea nitrogen, creatinine, and uric acid and decreases in hemoglobin. These laboratory abnormalities were apparent by week 4, stable over time, and reversible after treatment cessation. Gout incidence was 1.6/100 vs 0.5/100 PY in the bempedoic acid vs placebo groups. New-onset diabetes/hyperglycemia occurred less frequently with bempedoic acid vs placebo (4.7/100 vs 6.4/100 PY). The safety profile was consistent across subgroups. Conclusions Bempedoic acid is generally safe and well tolerated among patients with hypercholesterolemia who require additional LLT

Flaxseed supplementation improved insulin resistance in obese glucose intolerant people: a randomized crossover design

<p>Abstract</p> <p>Background</p> <p>Obesity leads to an increase in inflammation and insulin resistance. This study determined antioxidant activity of flaxseed and its role in inflammation and insulin resistance in obese glucose intolerant people.</p> <p>Methods</p> <p>Using a randomized crossover design, nine obese glucose intolerant people consumed 40 g ground flaxseed or 40 g wheat bran daily for 12 weeks with a 4-week washout period. Plasma inflammation biomarkers (CRP, TNF-α, and IL-6), glucose, insulin, and thiobaribituric acid reactive substance (TBARS) were measured before and after of each supplementation.</p> <p>Results</p> <p>Flaxseed supplementation decreased TBARS (p = 0.0215) and HOMA-IR (p = 0.0382). Flaxseed or wheat bran supplementation did not change plasma inflammatory biomarkers. A positive relationship was found between TBARS and HOMA-IR (r = 0.62, p = 0.0003).</p> <p>Conclusions</p> <p>The results of the study weakly support that decreased insulin resistance might have been secondary to antioxidant activity of flaxseed. However, the mechanism(s) of decreased insulin resistance by flaxseed should be further determined using flaxseed lignan.</p

Effects of a Flaxseed-Derived Lignan Supplement in Type 2 Diabetic Patients: A Randomized, Double-Blind, Cross-Over Trial

Flaxseed consumption has been shown to improve blood lipids in humans and flaxseed-derived lignan has been shown to enhance glycemic control in animals. The study aimed to investigate the effect of a flaxseed-derived lignan supplement on glycemic control, lipid profiles and insulin sensitivity in type 2 diabetic patients.This was a randomized, double-blind, placebo-controlled, cross-over trial and it was conducted between April and December 2006 in Shanghai, China. Seventy-three type 2 diabetic patients with mild hypercholesterolemia were enrolled into the study. Patients were randomized to supplementation with flaxseed-derived lignan capsules (360 mg lignan per day) or placebo for 12 weeks, separated by an 8-week wash-out period. HbA1c, lipid profiles, insulin resistance index and inflammatory factors were measured. Sixty-eight completed the study and were included in the analyses. The lignan supplement significantly improved glycemic control as measured by HbA(1c) (-0.10+/-0.65 % vs. 0.09+/-0.52 %, P = 0.001) compared to placebo; however, no significant changes were observed in fasting glucose and insulin concentrations, insulin resistance and blood lipid profiles. Urinary excretion of lignan metabolites (enterodiol and enterolactone) was significantly higher after the lignan supplement intervention compared to baseline (14.2+/-18.1 vs. 1.2+/-2.4 microg/mL, P<0.001). Data also suggested minimal competition between lignan and isoflavones for bioavailability when measured by the excretion concentrations.Daily lignan supplementation resulted in modest, yet statistically significant improvements in glycemic control in type 2 diabetic patients without apparently affecting fasting glucose, lipid profiles and insulin sensitivity. Further studies are needed to validate these findings and explore the efficacy of lignans on type 2 diabetes.ClinicalTrials.gov NCT00363233

An increase in dietary n-3 fatty acids decreases a marker of bone resorption in humans

Human, animal, and in vitro research indicates a beneficial effect of appropriate amounts of omega-3 (n-3) polyunsaturated fatty acids (PUFA) on bone health. This is the first controlled feeding study in humans to evaluate the effect of dietary plant-derived n-3 PUFA on bone turnover, assessed by serum concentrations of N-telopeptides (NTx) and bone-specific alkaline phosphatase (BSAP). Subjects (n = 23) consumed each diet for 6 weeks in a randomized, 3-period crossover design: 1) Average American Diet (AAD; [34% total fat, 13% saturated fatty acids (SFA), 13% monounsaturated fatty acids (MUFA), 9% PUFA (7.7% LA, 0.8% ALA)]), 2) Linoleic Acid Diet (LA; [37% total fat, 9% SFA, 12% MUFA, 16% PUFA (12.6% LA, 3.6% ALA)]), and 3) α-Linolenic Acid Diet (ALA; [38% total fat, 8% SFA, 12% MUFA, 17% PUFA (10.5% LA, 6.5% ALA)]). Walnuts and flaxseed oil were the predominant sources of ALA. NTx levels were significantly lower following the ALA diet (13.20 ± 1.21 nM BCE), relative to the AAD (15.59 ± 1.21 nM BCE) (p < 0.05). Mean NTx level following the LA diet was 13.80 ± 1.21 nM BCE. There was no change in levels of BSAP across the three diets. Concentrations of NTx were positively correlated with the pro-inflammatory cytokine TNFα for all three diets. The results indicate that plant sources of dietary n-3 PUFA may have a protective effect on bone metabolism via a decrease in bone resorption in the presence of consistent levels of bone formation

Inhibition of cancer cell invasion and metastasis by genistein

Genistein is a small, biologically active flavonoid that is found in high amounts in soy. This important compound possesses a wide variety of biological activities, but it is best known for its ability to inhibit cancer progression. In particular, genistein has emerged as an important inhibitor of cancer metastasis. Consumption of genistein in the diet has been linked to decreased rates of metastatic cancer in a number of population-based studies. Extensive investigations have been performed to determine the molecular mechanisms underlying genistein’s antimetastatic activity, with results indicating that this small molecule has significant inhibitory activity at nearly every step of the metastatic cascade. Reports have demonstrated that, at high concentrations, genistein can inhibit several proteins involved with primary tumor growth and apoptosis, including the cyclin class of cell cycle regulators and the Akt family of proteins. At lower concentrations that are similar to those achieved through dietary consumption, genistein can inhibit the prometastatic processes of cancer cell detachment, migration, and invasion through a variety of mechanisms, including the transforming growth factor (TGF)-β signaling pathway. Several in vitro findings have been corroborated in both in vivo animal studies and in early-phase human clinical trials, demonstrating that genistein can both inhibit human cancer metastasis and also modulate markers of metastatic potential in humans, respectively. Herein, we discuss the variety of mechanisms by which genistein regulates individual steps of the metastatic cascade and highlight the potential of this natural product as a promising therapeutic inhibitor of metastasis

Iyengar Yoga versus Enhanced Usual Care on Blood Pressure in Patients with Prehypertension to Stage I Hypertension: a Randomized Controlled Trial

The prevalence of prehypertension and Stage 1 hypertension continues to increase despite being amenable to non-pharmacologic interventions. Iyengar yoga (IY) has been purported to reduce blood pressure (BP) though evidence from randomized trials is lacking. We conducted a randomized controlled trial to assess the effects of 12 weeks of IY versus enhanced usual care (EUC) (based on individual dietary adjustment) on 24-h ambulatory BP in yoga-naïve adults with untreated prehypertension or Stage 1 hypertension. In total, 26 and 31 subjects in the IY and EUC arms, respectively, completed the study. There were no differences in BP between the groups at 6 and 12 weeks. In the EUC group, 24-h systolic BP (SBP), diastolic BP (DBP) and mean arterial pressure (MAP) significantly decreased by 5, 3 and 3 mmHg, respectively, from baseline at 6 weeks (P < .05), but were no longer significant at 12 weeks. In the IY group, 24 h SBP was reduced by 6 mmHg at 12 weeks compared to baseline (P = .05). 24 h DBP (P < .01) and MAP (P < .05) decreased significantly each by 5 mmHg. No differences were observed in catecholamine or cortisol metabolism to explain the decrease in BP in the IY group at 12 weeks. Twelve weeks of IY produces clinically meaningful improvements in 24 h SBP and DBP. Larger studies are needed to establish the long term efficacy, acceptability, utility and potential mechanisms of IY to control BP