Study On Biological Activity And Clinical Application Of SGLT-2 Inhibitors

BACKGROUNDSince the beginning of reform and opening up,diabetes has become one of the most serious chronic noncommunicable diseases in China.Cardiovascular disease is the leading cause of death in type 2 diabetes.Current guidelines for diabetes prevention and treatment in China suggest early and aggressive combination therapy for newly diagnosed obese diabetes patients to reduce the risk of cardiovascular disease.Based on a new hypoglycemic mechanism,SGLT-2 inhibitors,a novel oral hypoglycemic drug,can effectively reduce blood sugar,reduce weight,reduce blood pressure,and have cardiovascular and renal protective effects by reducing the reabsorption of glucose by proximal renal tubules and increasing the excretion of urinary glucose.Therefore,it is necessary to further develop SGLT-2 inhibitors and discover their clinical efficacy.This thesis consists of two parts:1.Study on biological activity of a novel SGLT-2 inhibitor.2.Effects of dapagliflozin combined with metformin on blood lipids and blood vessels in newly diagnosed obese type 2 diabetes patients.PART1 Study on biological activity of a novel SGLT-2 inhibitor.OBJECTIVETo evaluate the in vitro and in vivo pharmacological activities of SGLT-2 inhibitor SU-011.METHODSThe in vitro activities of SU-011 were investigated in cell-based AMG uptake assays.The urinary glucose excretion,glucose tolerance and the risk of hypoglycemia were evaluated in normal mice.Moreover,the dose-response relationship and chronic pharmacological studies of SU-011 were explored in STZ-induced diabetic mice,a streptozotocin-treated model with impaired insulin secretion.KEY FINDINGSSU-011 is a highly potent and selective SGLT2 inhibitor with an IC50 value of 5.6 nM and 1137-fold selectivity for SGLT1.In healthy mice,SU-011 improves the tolerance to glucose load and promotes the urinary glucose excretion.Besides,SU-011,even at the dose of 10 mg/kg,exhibited a low risk of hypoglycemia.During chronic treatment in STZ-induced diabetic mice,SU-011 exhibited sustained glucose-lowering effect without the side effect of weight gain.The levels of non-fasting and fasting plasma glucose,food consumption,water intake,and HbAlc were significantly decreased in SU-011-treated group.Moreover,SU-011 decreases the plasma levels of IL-1β,TNF-α,and CRP even better than that of dapagliflozin.CONCLUSIONSThese results suggest that su-011 can significantly reduce blood glucose levels and inflammatory cytokines without the risk of weight gain and hypoglycemia.PART2 Effects of dapagliflozin combined with metformin on blood lipids and blood vessels in newly diagnosed obese type 2 diabetes patients.OBJECTIVEAmong the newly diagnosed obese patients with type 2 diabetes,saxagliptin combined with metformin was used as the control group to observe the changes of glucose metabolism,lipid metabolism,uric acid and other metabolic indicators,as well as the changes of carotid intima-media thickness(CIMT)and ankle brachial index(ABI)in the patients after 36 weeks of treatment with dapagliflozin combined with metformin.METHODSWe followed 94 newly diagnosed obese type 2 diabetes patients for 36 weeks using an open prospective randomized controlled study.A newly designed questionnaire was used to collect the patients’ basic information,including personal history,family history of diabetes,smoking and drinking.The previous history and medication history of hypertension,coronary heart disease and other related diseases were all collected.Physical examination indicators such as height,weight,waist circumference and blood pressure were measured.Biochemical indexes such as liver and kidney function and blood lipids were also measured.Each patient received oral glucose tolerance test(OGTT)for simple steamed bun,and the fasting and 2-hour insulin levels were measured.In addition,CIMT and ABI were measured in each patient.KEY FINDINGS1、Baseline Comparison.There were no significant differences between two groups in gender,age,BMI,waist circumference,systolic blood pressure(SBP),diastolic blood pressure(DBP),glucose metabolism index(HbA1C,FPG,2hPG,FINS),blood lipid spectrum(serum TC,TG,HDL-C,LDL-C,apo B and apo A-1,apoB/apo A-1 ratio),uric acid.There were no differences in CIMT and ABI between the two treating groups.2、Comparison of indicators before and after treatment in dapagliflozin treating group.BMI,WC,SBP and DBP、HbA1c、HOMA-IR、TG,LDL-C,apo B and apoB/apoA-1 ratios、uric acid were decreased after 36 weeks of treatment(P<.05),while HDL-C and apo A-1 levels increased from baseline(P<.05).The total serum cholesterol was 5.45 ±1.31mmol/L after treatment,which was slightly lower than that at baseline,but the difference was not statistically significant(P=0.284).CIMT was 1.05±0.26mm at baseline and 0.82±0.10mm after treatment in the dapagliflozin group,with a statistically significant decrease(P=0.032).ABI was 1.09 ± 0.28 higher than that at baseline(0.85 ±0.20)(P=0.045).3、Comparison of indicators before and after treatment in saxagliptin treating group.BMI,WC,SBP,DBP,fasting blood glucose,2hPG,HbA1C,HOMA-IR,TG,and apo B were all significantly lower than before treatment(P<.05).The fasting insulin level was 79.64±30.20um/L,which was lower than that before treatment,but the difference was not statistically significant(P=0.328).After treatment,TC,LDL-C and apoB/apoA-1 ratio all decreased from baseline,while HDL and apo A-1 levels increased from baseline,but the differences were not statistically significant.The mean value of uric acid after treatment was 338.8±27.2 umol/L,which was lower than the baseline level,but the difference was not statistically significant(P=0.296).The mean value of CIMT after treatment was 1.08 ±0.20mm,which was slightly decreased(P=0.585),while ABI after treatment was 0.92 ±0.21 higher than that of the baseline(0.89±0.18),with no statistically significant differences(P=0.463).4、Comparison of the improvement of each index between the two treating groups.The reduction of HbA1C,BMI,TG,LDL-C,apo B,and apo B/apo A-1 ratio in dapagliflozin treating group was greater than that of saxagliptin.CIMT was reduced in both groups,and the net reduction of CIMT in dapagliflozin treating group was stronger than that in saxagliptin(P<.05).The increase of ABI in dapagliflozin treating group was better than that in saxagliptin treating group,and the difference was statistically significant(P<.05).CONCLUSIONSIn the study,we found that dapagliflozin could effectively reduce HbA1C、weight、blood pressure、uric acid,improve lipid metabolism and insulin resistance in patients with type 2 diabetes.In addition,we found that dapagliflozin reduced serum apo B levels and the apo B/apo A-1 ratio,suggesting that dapagliflozin may be early involved in anti-atherosclerosis because apolipoproteins could better reflects atherosclerosis.The extent of reduction of CIMT and increase of ABI in the dapagliflozin treating group was better than that in the saxagliptin treating group.Since CIMT and ABI are good indicators for evaluating the risk of cardiovascular disease,the results of this study suggest that dapagliflozin has more advantages in reducing the risk of cardiovascular disease.