The Study On Efficacy And Safety Of Benfluorex In Treatment Of Type 2 Diabetes Mellitus

Background:Benfluorex,as an amphetamine-type drug,since came out in 1976,had been widespread in clinical application,after the late 80's to early 90's,at a large number of basic and clinical research to confirm its hypoglycemic effect,indications have been extended to glucose and lipid metabolism disorders,diabetes,obesity and so on.The capacity of benfluorex to enhance insulin action has led to much speculation regarding its mechanism of action.Chronic benfluorex treatment,in a variety of genetic and dietary animal models of diabetes and insulin resistance,has been shown to diminish circulating insulin levels and to decrease blood glucose,triglycerides,and cholesterol concentrations.From these studies,it is possible to postulate a multifactorial mode of action of this drug that involves three independent but interactive processes:(1) a direct effect on insulin target tissues,mediated by mechanisms distal to the binding of insulin to its receptor,(2) modulation of the glucoregulatory hormone balance,including a diminution in both adrenal and sympathetic tone,leading to improved hepatic sensitivity to insulin,and(3) reduced hepatic and muscle lipid availability,leading to improved glucose utilization in skeletal muscle.The multiplicity of the neuroendocrine and biochemical effects of benfluorex cannot be explained by a single cellular or molecular action.It has been suggested that insulin sensitizers may act on key molecules involved in the sequence of biochemical events involving the insulin signal transduction process.Objective The aim of this study is to observe the efficacy and safety of benfluorex in treatment of type 2 diabetes mellitus compared with metfomin.Research Design and Methods Protocol of the study was approved by the Ethics Committee of Xijing Hospital of Fourth Military Medical University.The trial was conducted in accordance with the ethical principles stated in the Declaration of Helsinki 1964,as revised in Edinburgh,U.K.,in October 2000.All subjects provided written informed consent before entering the trial.Design:A stratified randomized double-blind controlled trial.Medicine:Benfluorex was from Shandong Xinghua Pharmaceutical Co Ltd.(150 mg/tab,Batch No. 0706077).Metformin was from Beijing Sihuan Pharmaceutical Co.Ltd(250mg/tab,Batch No.20070407).Eligibility criteria were type 2 diabetes with age 18-70 years,BMI of 23-40 kg/m~2,FPG of 7-13 mmol/L,and GHbA1_c of 7-10%despite monotherapy with a diet or insulinotropic agent treatment for at least 1 month.Exclusion criteria were severe complications of diabetes,an alanine aminotransferase plasma level two times above the upper limit of normal,active proliferative retinopathy,uncontrolled high blood pressure(≥160/95 mmHg),or any disorder that could interfere with the study conduct or end point evaluation.Patients were withdrawn for lack of efficacy,which was defined as two fasting plasma glucose(FPG) measurements≥10.8 mmol/l at the maximum tolerated dose for 4 weeks.After a 1-2 week of run-in period,56 type 2 diabetes mellitus visiting 2nd hospitals of Jilin University in Changchun were randomly divided into two equal groups,study group (n=28)treated with benfluorex150 mg bid / tid for 16 weeks,and control group(n=28) treated with metformin 500 mg bid/tid for 16 weeks.The primary efficacy end point was GHbAlc.The secondary end points were FPG, fasting serum insulin(FSI),and lipid profile(TG,TC,HDL-C,LDL-C),each assessed at baseline and week 16.Meanwhile,safety was assessed by adverse event spontaneous reporting,physical examination,recording of vital signs,fundus examination,laboratory tests, and 12-lead electrocardiogram at baseline and at week 16.Hypoglycemic events were recorded from the patient diary and were based on suggestive clinical symptoms only.Results Both groups were similar at baseline.Completed study data had been obtained from 53 patients.Three withdrawals(5.4%) occurred,1 for patients receiving benfluorex and 2 for patients receiving the metformin.1 patient in control group withdrew because of lost.2 patients withdrew because of lack of efficacy(1 in each group).1.Improving glycemic control:16 weeks after treatment there was significant difference in the GHbA1c level,FPG level and PPG level contrast with pretherapy.A1c significantly decreased with benfluorex from 7.89±1.37 to 6.59±0.89(p＜0.05) and diminish with metformin from 7.95±1.39 to 6.49±0.81.while there was no obvious difference between these two groups(P＞0.05).The reaching-standard-rate(≤6.5%) of GHbA1c in the contrast group and study group respectively was 50.8%and 49.2%.The fasting and postprandial blood glucose level significantly decreased in study groups with 1.67±2.11mmol/L and 3.17±2.86mmol/L.2.Improving insulin resistance:The fasting and postprandial serum insulin level significantly decreased in study groups,however,the two target above-mentioned did not changed significantly in the contrast group,the levels of serum insulin 2 hours after meal in both groups did not changed significantly(P＞0.05).3.Improving the lipid profile:Compared with the metformin,benfluorex was better in decreacing lipid,statistically significant difference was shown in the level of TG and LDL-C.But insignificant difference was shown in the contrast group. 4.Safty:The adverse event rates of the study and control groups were 10.7%and 7.1% respectively(P＞0.05),and the main adverse events were gastrointestinal side effects,hypodynamia and dizziness.No serious adverse events were found in both groups, and only one patient was withdrawn due to adverse events of medication.Conclusion Benfluorex have the effects of reducing the levels of HbA1c,FBG,PPG,INS and TG,LDL-C.No serious adverse reactions were shown during the short-term treatment. The efficacy and safety of benfluorex within 16 week treatment for type 2 diabetes mellitus is comparable to those of Metfomin treatment with mild adverse side effects.In addition,we also found that benfluorex can improve insulin resistance and lipid profile.But further confirmation with clinical randomized controlled trials of high quality,large sample and long-term follow-up is needed.