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Chuang Li,&ast; Kuizheng He,&ast; Yixing Yang, Kuibao Li, Mulei Chen, Lefeng Wang, Xiaorong Xu,&ast; Weiming Li&ast; Heart Center and Beijing Key Laboratory of Hypertension, Beijing Chaoyang Hospital, Capital Medical University, Beijing, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Weiming Li; Xiaorong Xu, Heart Center and Beijing Key Laboratory of Hypertension, Beijing Chao-Yang Hospital, Capital Medical University, 8&num; Gong-Ti South Road, Beijing, 10020, People’s Republic of China, Email liweiming@sina.com; medicinexxr@163.comIntroduction: Non-high-density-lipoprotein cholesterol (non-HDL-C) is a secondary therapeutic target in cardiovascular diseases and is used for residual risk assessment in patients with coronary artery syndrome (ACS). This study was designed to determine the association between non-HDL-C in patients with prior coronary artery bypass graft (CABG) with ACS and clinical outcomes.Methods: We retrospectively analyzed 468 patients with prior CABG with ACS and categorized them into two groups based on the median non-HDL-C level. The primary endpoints were major adverse cardiovascular events (MACEs), including cardiovascular death and recurrent myocardial infarction. Kaplan–Meier curves, Cox proportional-hazard regressions, and restricted cubic splines were used to determine the association between non-HDL-C and MACEs. The discrimination and reclassification of the nomogram based on non-HDL-C were assessed using time-dependent receiver operating characteristic (ROC) curves and net reclassification improvement (NRI).Results: During the average follow-up time of 744.5 days, non-HDL-C was independently associated with the occurrence of MACEs (hazard ratio [HR] = 5.01, 95% confidence interval [CI] = 1.65– 15.24; p = 0.005) after adjusting for other lipid parameters. The spline curves indicated a linear relationship between non-HDL-C and MACEs (p-nonlinear: 0.863). The time-dependent areas under the ROC curves of prior-CABG-ACS nomograms containing non-HDL regarding MACEs in two consecutive years were 91.7 (95% CI: 85.5– 97.9) and 91.5 (95% CI: 87.3– 95.7), respectively. The NRI analysis indicated that the prior-CABG-ACS model improved the reclassification ability for 1- and 2-year MACEs (22.4% and 7%, p < 0.05, respectively).Discussion: Non-HDL is independently associated with the risk of MACEs in patients with prior CABG with ACS. The prior-CABG-ACS nomogram based on non-HDL-C and five convenient variables generates valid and stable predictions of MACE occurrence.Keywords: non-HDL cholesterol, major adverse cardiovascular events, prior coronary artery bypass grafting, GRACE score

Deepa Joshi,1 Prashant GJ,1 Shohini Ghosh,1 Anookh Mohanan,1 Shashank Joshi,2 Viswanathan Mohan,3 Subhankar Chowdhury,4 Chaitanya Dutt,1 Nikhil Tandon5 1Torrent Pharmaceuticals Ltd., Ahmedabad, Gujarat, India; 2Lilavati Hospital, Mumbai, India; 3Dr. Mohan’s Diabetes Specialities Centre (Madras Diabetes Research Foundation), Tamil Nadu, India; 4Department of Endocrinology, Institute of Post-Graduate Medical Education and Research and Seth Sukhlal Karnani Memorial Hospital, Kolkata, India; 5Department of Endocrinology, All India Institute of Medical Sciences, New Delhi, IndiaCorrespondence: Deepa Joshi, Research & Development, Torrent Pharmaceuticals Ltd., Ahmedabad, Gujarat, India, Tel + 91 7971315571, Email deepajoshi@torrentpharma.comBackground: 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.Keywords: cardiometabolic-based chronic disease, mitochondrial modulator, type 2 diabetes, non-HDL cholesterol, hypertension, dyslipidemia

Obesity, metabolic syndrome and diabetes are conditions with increasing prevalence around the world. Cardiovascular risk in diabetics is often so high as to overlap with event rates observed in those with established coronary disease and this has lead to diabetes being classified as a coronary risk equivalent. However, despite the elevated risk of cardiovascular events associated with diabetes and the metabolic syndrome, these patients often have normal low density lipoprotein (LDL) cholesterol despite frequent increases in apolipoprotein B, triglycerides and nonhigh density lipoprotein (HDL) cholesterol. In contrast to LDL cholesterol, non-HDL cholesterol represents cardiovascular risk across all patient populations but is currently only recommended as a secondary target of therapy by the ATP III report for patients with hypertriglyceridemia. This article provides an overview of the studies that shown non-HDL cholesterol to be superior to LDL cholesterol in predicting cardiovascular events and presents the case for non-HDL cholesterol being the more appropriate primary target of therapy in the context of the obesity pandemic. Adopting non-HDL cholesterol as the primary therapeutic target for all patients will conceivably lead to an appropriate intensification of therapy for high risk patients with low LDL cholesterol.