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

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

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