RESUMEN
The coronavirus disease 2019 (COVID-19) pandemic challenges our collective understanding of transmission, prevention, complications, and clinical management of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. Risk factors for severe infection, morbidity, and mortality are associated with age, environment, socioeconomic status, comorbidities, and interventional timing. Clinical investigations report an intriguing association of COVID-19 with diabetes mellitus and malnutrition but incompletely describe the triphasic relationship, its mechanistic pathways, and potential therapeutic approaches to address each malady and their underlying metabolic disorders. This narrative review highlights common chronic disease states that interact epidemiologically and mechanistically with the COVID-19 to create a syndromic phenotype-the COVID-Related Cardiometabolic Syndrome-linking cardiometabolic-based chronic disease drivers with pre-, acute, and chronic/post-COVID-19 disease stages. Since the association of nutritional disorders with COVID-19 and cardiometabolic risk factors is well established, a syndromic triad of COVID-19, type 2 diabetes, and malnutrition is hypothesized that can direct, inform, and optimize care. In this review, each of the three edges of this network is uniquely summarized, nutritional therapies discussed, and a structure for early preventive care proposed. Concerted efforts to identify malnutrition in patients with COVID-19 and elevated metabolic risks are needed and can be followed by improved dietary management while simultaneously addressing dysglycemia-based chronic disease and malnutrition-based chronic disease.
RESUMEN
BACKGROUND: TRC150094, a novel mitochondrial modulator, reduces insulin resistance and is expected to improve the trinity of dysglycemia, dyslipidemia, and hypertension. In this multi-dose phase-2 study, we evaluated the safety and efficacy of TRC150094 in diabetic subjects with dyslipidemia receiving standard of care. METHODS: A randomized, multicenter, double-blind, placebo-controlled, parallel-group, Phase 2 study was conducted in 225 subjects from July 2013 to August 2015. The key inclusion criteria were body mass index of 23-35 kg/m2, age between 30 and 65 years, fasting glucose of ≥126 or glycated hemoglobin (HbA1c) of ≥6.4% stabilized on treatment with ≤2 oral hypoglycemic agents, apolipoprotein-B (apo-B) ≥100 mg/dL, serum triglyceride (TG) ≥150 mg/dL, systolic blood pressure (SBP) ≥130 mmHg, and diastolic blood pressure (DBP) ≥85 mmHg with/without antihypertensive treatment. The subjects were randomly assigned to one of three TRC150094 doses (25, 50, or 75 mg) or placebo for 24 weeks. The outcomes assessed included fasting plasma glucose (FPG), insulin, mean arterial blood pressure (MAP), and apoB. In addition, safety and tolerability were assessed. RESULTS: A reduction for dose up to 50 mg was noted for FPG in the range of 13.9 to 21.7 mg/dL (p < 0.05 for TRC150094 25 and 50 mg), fasting insulin reduction in the range 2.7 to 6.0 mU/L (all doses, p > 0.05), and improved HOMA-IR (-2.0 to -2.5) (all doses, p > 0.05) compared to placebo after 24 weeks of treatment. Furthermore, a significant reduction in MAP in the range 3.1 to 4.2 mmHg (p < 0.05 for TRC150094 25 and 75 mg) was noted. In addition, TRC150094 treatment was weight neutral, had a favorable effect on lowering atherogenic lipid fractions, including non-HDL cholesterol (-6.8 mg/dL at 50 mg dose). Adverse events were mild to moderate in nature and not dose-related. One adverse event not related to treatment led to the discontinuation of the study. Overall, TRC150094 was safe and well tolerated for up to 24 weeks. CONCLUSION: In this study, TRC150094 treatment in the dose range of 25 to 50 mg showed improvement in various components of CMBCD, ie, dysglycemia, dyslipidemia, and hypertension. TRIAL REGISTRATION: This study was registered in the Clinical Trial Registry of India. Trial registration number: CTRI/2013/03/003444. Date of registration: 4th March 2013.
RESUMEN
TRC150094, a novel mitochondrial modulator, can restore metabolic flexibility by improving insulin resistance in preclinical studies. This study primarily aims to evaluate the safety, tolerability, and pharmacokinetics (PK) of oral TRC150094 after conducting two double-blind, randomized, Phase-I studies, single ascending dose (SAD) and multiple ascending dose (MAD), with n = 46, in overweight/obese adult and elderly subjects. In addition, the effect of TRC150094 on pharmacodynamic (PD) efficacy markers was evaluated. PK assessments, including maximum concentration (Cmax), area under the plasma concentration (AUC), time to Cmax (Tmax), and elimination half-life (t½), were assessed at pre-specified time points. PD assessments included apolipoprotein B (ApoB), triglycerides, hepatic fat by magnetic resonance spectroscopy (MRS) and cardiopulmonary exercise testing (CPET) parameters. TRC150094 was rapidly absorbed, and the AUC of TRC150094 increased in a dose-dependent manner across all doses in non-elderly and elderly cohorts. Cmax was more than the dose-proportional for all doses in all cohorts. Tmax ranged from 0.25 to 4 h, and t½ ranged from 15 to 18 h, making TRC150094 suitable for once-daily dosing. Food did not interfere with the overall absorption of the drug. The metabolites of TRC150094 were glucuronide and sulfate conjugates, and 20% of the drug was excreted unchanged in the urine. TRC150094 at 50 mg showed an improving trend in triglycerides. A significant reduction in Apo B was observed after 50 mg dose (-2.34 vs. 13.24%, p = 0.008), which was, however, not the case after 150 mg (8.78 vs. 13.24%, p = 0.1221). Other parameters such as hepatic fat and insulin sensitivity indices (HOMA-IR, MATSUDA Index derived from OGTT) showed an improving trend for the dose of 50 mg. In terms of safety, all the AEs reported were mild to moderate in severity. None of the adverse events was considered definitely or probably related to treatment, and there were no abnormal laboratory findings. In conclusion, the PK of TRC150094 was linear with no clinically significant food effect. TRC150094 and its metabolites suggest a lesser likelihood of drug-drug interactions. Overall, TRC150094 ensured safety and exhibited suitability for all subjects. Clinical Trial Registration: EUDRA CT: 2009-014941-10 (SAD) and CTR-India registration: CTRI/2009/091/000601 (MAD).