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Dorzagliatin monotherapy in Chinese patients with type 2 diabetes: a dose-ranging, randomised, double-blind, placebo-controlled, phase 2 study.
Zhu, D, Gan, S, Liu, Y, Ma, J, Dong, X, Song, W, Zeng, J, Wang, G, Zhao, W, Zhang, Q, et al
The lancet. Diabetes & endocrinology. 2018;(8):627-636
Abstract
BACKGROUND Glucokinase acts as a glucose sensor in the pancreas and a glucose processor in the liver, and has a central role in glucose homoeostasis. Dorzagliatin is a new, dual-acting, allosteric glucokinase activator that targets both pancreatic and hepatic glucokinases. Dorzagliatin has good pharmacokinetic and pharmacodynamic properties in humans, and provides effective 24-h glycaemic control and improves glucose sensitivity in patients with type 2 diabetes. We aimed to assess the efficacy and safety of dorzagliatin monotherapy at different doses in Chinese patients with type 2 diabetes. METHODS In this multicentre, randomised, double-blind, placebo-controlled, phase 2 study, we randomly assigned (1:1:1:1:1) patients to receive oral placebo or one of four doses of oral dorzagliatin (75 mg once a day, 100 mg once a day, 50 mg twice a day, or 75 mg twice a day) using permuted-block randomisation, with a block size of ten and without stratification. Eligible patients were men or non-fertile women (aged 40-75 years) with type 2 diabetes who had a BMI of 19·0-30·0 kg/m2, were on a diet and exercise regimen, and were previously untreated or treated with metformin or α-glucosidase inhibitor monotherapy. The study started with a 4-week placebo run-in period followed by a 12-week treatment period. The primary endpoint was the change in HbA1c from baseline to week 12, which was assessed in all patients who received at least one dose of study drug and had both baseline and at least one post-baseline HbA1c value. Safety was assessed in all patients who received at least one dose of study drug. This study is registered with ClinicalTrials.gov, number NCT02561338. FINDINGS Between Sept 29, 2015, and Aug 17, 2016, we randomly assigned 258 patients to one of the five study groups. At the end of 12 weeks, the least squares mean change in HbA1c from baseline was -0·35% (95% CI -0·60 to -0·10) in the placebo group, -0·39% (-0·64 to -0·14) in the 75 mg once daily group, -0·65% (-0·92 to -0·38) in the 100 mg once daily group, -0·79% (-1·06 to -0·52) in the 50 mg twice daily group, and -1·12% (-1·39 to -0·86) in the 75 mg twice daily group. Compared with the placebo group, the change in HbA1c between baseline and 12 weeks was significant in the 50 mg twice daily (p=0·0104) and the 75 mg twice daily (p<0·0001) groups. The number of adverse events was similar between the treatment groups and the placebo group. There were no reports of drug-related serious adverse events or severe hypoglycaemia. INTERPRETATION Dorzagliatin had a beneficial effect on glycaemic control and was safe and well tolerated over 12 weeks in Chinese patients with type 2 diabetes. FUNDING Hua Medicine, National Major Scientific and Technological Special Project for Significant New Drugs Development, Shanghai Science and Technology Innovation Action Project, Shanghai Pudong District Science and Technology Innovation Action Project, and Shanghai Municipal Commission of Economy and Informatisation Innovation Action Project.
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Effect of different loading doses of atorvastatin on percutaneous coronary intervention for acute coronary syndromes.
Sun, Y, Qi, G, Gao, Y, Zhang, H, Pang, X, Zhao, W, Zhang, Z
The Canadian journal of cardiology. 2010;(9):481-5
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Abstract
BACKGROUND Percutaneous coronary intervention (PCI)-induced myocardial damage is associated with late cardiovascular events. Treatment with atorvastatin before PCI can reduce myocardial damage during the peri-PCI period. OBJECTIVES To compare the safety and myocardial effects of different atorvastatin loading doses and dosing frequency before PCI in non-ST segment elevation acute coronary syndrome (NSTE-ACS) patients. METHODS Eighty NSTE-ACS patients were randomly divided into four groups (20 patients per group). The control group was given 40 mg atorvastatin each night. The three loading dose groups were treated the same as in the control group, but were given 80 mg atorvastatin 12 h before PCI (lowload group) in combination with 40 mg atorvastatin 2 h to 4 h before PCI (mid-load group) or 60 mg atorvastatin 2 h to 4 h before PCI (high-load group). All patients underwent PCI within 48 h to 72 h of admission, and received 40 mg atorvastatin for at least one month after PCI. Changes in myocardial markers and highly sensitive C-reactive protein were analyzed. Patients were followed up for 30 days to monitor the incidence of major adverse cardiac events (MACE). RESULTS No deaths or revascularizations were recorded. The incidences of MACE differed significantly between the four groups (40%, 25%, 10% and 0% for the control, low-load, mid-load and high-load groups, respectively; P<0.05). The incidence of MACE and cardiac troponin I level above the normal range, and post-PCI increases in creatine kinase-MB and highly sensitive C-reactive protein were significantly higher in the control group than in the high-load group (all P<0.007). The post-PCI alanine aminotransferase levels in all four groups were significantly higher than the pre-PCI levels, but were within normal ranges. No myalgia or myasthenia was observed. CONCLUSION The results of the present study show that short-term atorvastatin loading before PCI was well tolerated and had beneficial myocardial effects in patients with NSTE-ACS.