Abstract
Background and aimsObesity 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.Materials and MethodsThis 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.ResultsAt 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.ConclusionCollectively, 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.Trial Registrationclinicaltrials.gov NCT01408667
Highlights
Obesity and its associated co-morbidities have a detrimental impact on global health, representing the leading cause of disability and premature death worldwide. [1]
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 mmol kg21min21, 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
Summary
Obesity and its associated co-morbidities have a detrimental impact on global health, representing the leading cause of disability and premature death worldwide. [1]. Analogs of TH with a 22-fold higher affinity for the hepatic thyroid hormone receptor beta (TRb) than the ‘ubiquitous’ TRa isoform were reported to lower low density lipoprotein cholesterol (LDLc) by approximately 30% without significant heart, muscle or bone toxicity. [8,9] In phase I clinical studies, once daily oral administration of TRC150094 at doses of 50 mg and 150 mg for 28 days were well tolerated without any adverse safety signals in the obese subjects. This study investigated the safety and efficacy of TRC150094, a thyroid hormone mimetic
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