Efficacy and Safety of Avandamet or Uptitrated Metformin Treatment in Patients with Type 2 Diabetes Inadequately Controlled with Metformin Alone： A Multicenter, Randomized,Controlled Trial

Background：At present,China has listed the compound tablet containing a fixed dose ofrosiglitazone and metformin,Avandamet,which may improve patient compliance.The aim of this study was to evaluate the efficacy and safety of Avandamet or uptitrated metformin treatment in patients with type 2 diabetes inadequately controlled with metformin alone.Methods：This study was a 48-week,multicenter,randomized,open-labeled,active-controlled trial.Patients with inadequate glycaemic control （glycated hemoglobin [HbA1c] 7.5-9.5%） receiving a stable dose of metformin （≥1500 mg） were recruited from 21 centers in China （from 19 November,2009 to 15 March,2011）.The primary objective was to compare the proportion of patients who reached the target of HbA1c ≤7% between Avandamet and metformin treatment.Results：At week 48,83.33% of patients reached the target of HbA 1 c ≤7% in Avandamet treatment and 70.00% in uptitrated metformin treatment,with significantly difference between groups.The target of HbAlc ≤6.5% was reached in 66.03% of patients in Avandamet treatment and 46.88% in uptitrated metformin treatment.The target of fasting plasma glucose （FPG） ≤6.1 mmol/L was reached in 26.97% of patients in Avandamet treatment and 19.33% in uptitrated metformin treatment.The target of FPG ≤7.0 mmol/L was reached in 63.16% of patients in Avandamet treatment and 43.33% in uptitrated metformin treatment.Fasting insulin decreased 3.24 ±0.98 μU/ml from baseline in Avandamet treatment and 0.72 ＆#177; 1.10 μU/ml in uptitrated metformin treatment.Overall adverse event （AE） rates and serious AE rates were similar between groups.Hypoglycaemia occurred rarely in both groups.Conclusions：Compared with uptitrated metformin,Avandamet treatment provided significant improvements in key parameters ofglycemic control and was generally well tolerated.Registration number：ChiCTR-TRC-13003776.

Cathepsin L plays a key role in SARS-CoV-2 infection in humans and humanized mice and is a promising target for new drug development

To discover new drugs to combat COVID-19,an understanding of the molecular basis of SARS-CoV-2 infection is urgently needed.Here,for the first time,we report the crucial role of cathepsin L(CTSL)in patients with COVID-19.The circulating level of CTSL was elevated after SARS-CoV-2 infection and was positively correlated with disease course and severity.Correspondingly,SARS-CoV-2 pseudovirus infection increased CTSL expression in human cells in vitro and human ACE2 transgenic mice in vivo,while CTSL overexpression,in turn,enhanced pseudovirus infection in human cells.CTSL functionally cleaved the SARS-CoV-2 spike protein and enhanced virus entry,as evidenced by CTSL overexpression and knockdown in vitro and application of CTSL inhibitor drugs in vivo.Furthermore,amantadine,a licensed anti-influenza drug,significantly inhibited CTSL activity after SARS-CoV-2 pseudovirus infection and prevented infection both in vitro and in vivo.Therefore,CTSL is a promising target for new anti-COVID-19 drug development.