TRC120038, a Novel Dual AT1/ETA Receptor Blocker for Control of Hypertension, Diabetic Nephropathy, and Cardiomyopathy in ob-ZSF1 Rats

In hypertensive subjects, angiotensin II and endothelin participate in a manner involving closely interwoven pathways in increasing blood pressure (BP) and inducing end organ damage. The primary objective of this study was to determine the effect of TRC120038, a novel dual AT1/ETA receptor blocker on BP, in obese Zucker spontaneously hypertensive fatty rats (ob-ZSF1), an animal model of moderate hypertension, diabetes with progressive renal and cardiac dysfunction. Ob-ZSF1 rats loaded with 0.5% salt were treated with TRC120038 (11.8 mg/kg bid.) or candesartan cilexetil (0.3 mg/kg od.) or vehicle control. Blood pressure (by radio-telemetry) and renal functional markers were monitored throughout the study. Cardiac function was assessed terminally by pressure volume catheter. Markers for renal dysfunction were measured and changes were evaluated histopathologically. TRC120038 showed greater fall in both systolic and diastolic BP in comparison to candesartan at its maximum antihypertensive dose. TRC120038 also reduced the severity of renal dysfunction and preserved cardiac function in ob-ZSF1 rat

TRC150094 attenuates progression of nontraditional cardiovascular risk factors associated with obesity and type 2 diabetes in obese ZSF1 rats

Chronic overnutrition and consequential visceral obesity is associated with a cluster of risk factors for cardiovascular disease and type 2 diabetes mellitus. Moreover, individuals who have a triad of hypertension, dysglycemia, and elevated triglycerides along with reduced high-density lipoprotein cholesterol have a greater residual cardiovascular risk even after factoring for the traditional risk factors such as age, smoking, diabetes, and elevated low-density lipoprotein cholesterol. In our previous study we demonstrated that TRC150094, when administered to rats receiving a high-fat diet, stimulated mitochondrial fatty acid oxidation (FAO) and reduced visceral adiposity, opening an interesting perspective for a possible clinical application. In the present study, oral administration of TRC150094 to obese Zucker spontaneously hypertensive fatty rats (obese ZSF1) improved glucose tolerance and glycemic profile as well as attenuated a rise in blood pressure. Obese ZSF1 rats treated with TRC150094 also showed reduced hepatic steatosis, reduced progression of nephropathy, and improved skeletal muscle function. At the cellular level, TRC150094 induced a significant increase in mitochondrial respiration as well as an increased FAO in liver and skeletal muscle, ultimately resulting in reduced hepatic as well as total body fat accumulation, as evaluated by magnetic resonance spectroscopy and magnetic resonance imaging, respectively. If reproduced in humans, these results could confirm that TRC150094 may represent an attractive therapeutic agent to counteract multiple residual cardiovascular risk components

The Effect of a Diiodothyronine Mimetic on Insulin Sensitivity in Male Cardiometabolic Patients: A Double-Blind Randomized Controlled Trial

<div><p>Background and aims</p><p>Obesity and its associated cardiometabolic co-morbidities are increasing worldwide. Since thyroid hormone mimetics are capable of uncoupling the beneficial metabolic effects of thyroid hormones from their deleterious effects on heart, bone and muscle, this class of drug is considered as adjacent therapeutics to weight-lowering strategies. This study investigated the safety and efficacy of TRC150094, a thyroid hormone mimetic.</p><p>Materials and Methods</p><p>This 4-week, randomized, placebo-controlled, double-blind trial was conducted in India and The Netherlands. Forty subjects were randomized at a 1∶1 ratio to receive either TRC150094 dosed at 50 mg or placebo once daily for 4 weeks. Hyperinsulinemic euglycemic clamp and ¹H-Magnetic Resonance Spectroscopy (MRS) were performed before and after treatment.</p><p>Results</p><p>At baseline, subjects were characterized by markedly impaired hepatic and peripheral insulin sensitivity. TRC150094 dosed 50 mg once daily was safe and well tolerated. Hepatic nor peripheral insulin sensitivity improved after TRC150094 treatment, expressed as the suppression of Endogenous Glucose Production from 59.5 to 62.1%; p = 0.477, and the rate of glucose disappearance from 28.8 to 26.4 µmol kg⁻¹min⁻¹, p = 0.185. TRC150094 administration did not result in differences in fasting plasma free fatty acids from 0.51 to 0.51 mmol/L, p = 0.887 or in insulin-mediated suppression of lipolysis from 57 to 54%, p = 0.102. Also, intrahepatic triglyceride content was unaltered.</p><p>Conclusion</p><p>Collectively, these data show that, in contrast to the potent metabolic effects in experimental models, TRC150094 at a dose of 50 mg daily does not improve the metabolic homeostasis in subjects at an increased cardiometabolic risk. Further studies are needed to evaluate whether TRC150094 has beneficial effects in patients with more severe metabolic derangement, such as overt diabetes mellitus and hypertriglyceridemia.</p><p>Trial Registration</p><p>clinicaltrials.gov <a href="http://clinicaltrials.gov/show/NCT01408667" target="_blank">NCT01408667</a></p></div

Flowdiagram.

<p>Screenfailures in specific; due to malignancy in history, ECG abnormalities at screening, too low fasting insulin or glucose, anemia, age and one withdrawing of consent after screening.</p

Efficacy data TRC150094 in males with increased cardiometabolic risk.

<p><b>A–D;</b> Box plots of hepatic insulin sensitivity (suppression of EGP %), peripheral insulin sensitivity (Rd umol*kg⁻¹min⁻¹), hepatic fat content (IHTG %) and insulin mediated suppression of lipolysis (suppression of lipolysis %) before after TRC administration. Blue background depicts reference values in healthy population, based on historical data <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0086890#pone.0086890-Soeters1" target="_blank">[16]</a>–<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0086890#pone.0086890-Hickner1" target="_blank">[19]</a>. <b>E</b>; Bar graph of lipid profile showing no improvement after TRC150094 administration.</p

Characteristics of Study Subjects at Baseline.

<p>NOTE. Values are expressed as mean ± standard deviation. No significant differences in clinical variables were found between TRC and Placebo group at baseline, p<0.05. The body mass index is the weight in kilograms divided by the square of the height in meters. HDLc, high-density lipoprotein cholesterol; LDLc, low-density lipoprotein cholesterol; TG, triglycerides.</p

Safety Analyses of Study Subjects at Baseline and After 4 Weeks.

<p>NOTE. Values are expressed as mean ± standard deviation.</p><p>*Nonparametric test showed a significant increase in FT4 after TRC150094 (p = 0.025). ALT, alanine aminotransferase; AST, aspartate aminotransferase; GGT, gamma glutamyltransferase; FT3, free trio-iodothyronine; FT4, free thyroxine; TSH, thyroid stimulating hormone (thyrotropin).</p