SGLT2抑制剂治疗2型糖尿病肾脏安全性的Meta分析
|
摘要
目的评价钠-葡萄糖共转运蛋白2 (SGLT2)抑制剂治疗2型糖尿病(T2DM)对肾脏安全性的影响。方法通过检索PubMed、 Embase、 OVID、 Cochrane Library、 Web of Science、中国知网、万方、维普等数据库及临床试验注册网站,查找SGLT2抑制剂与安慰剂或其他类降血糖药比较治疗T2DM的随机对照试验(RCT),采用RevMan 5.3对肾小球滤过率(eGFR)、血肌酐(SCr)、尿白蛋白与肌酐比值(UACR)等肾功能指标以及肾功能损害、急性肾功能衰竭的发生率进行Meta分析。结果共纳入38个RCT,包括20 163例T2DM患者。当疗程≤26周时,与安慰剂组比较, SGLT2抑制剂高剂量组eGFR显著降低(WMD=-9.03, 95%CI:-1.56～-0.31, P=0.004, I~2=33%)、 SCr显著增高(WMD=0.70, 95%CI:0.09～1.30, P=0.02, I~2=0%);而两个剂量组与阳性对照组相比均无显著差异(P>0.05)。当疗程≥48周时, SGLT2抑制剂两个剂量组eGFR和SCr改变与安慰剂组均相似(P> 0.05);与阳性对照组比较,两个剂量组eGFR均显著增高、 SCr显著降低(P <0.05)。SGLT2抑制剂两个剂量组UACR与安慰剂组无显著差异(P> 0.05);疗程≥48周时,与阳性对照组比较,高剂量组UACR显著降低(WMD=-20.05, 95%CI:-37.79～-2.32, P=0.03, I2=0%)。SGLT2抑制剂组肾功能损害和急性肾功能衰竭发生率与安慰剂组和阳性对照组比较均无显著差异(P> 0.05)。结论 SGLT2抑制剂治疗T2DM患者引起肾功能损害、急性肾功能衰竭的风险与安慰剂或阳性药相当,在持续治疗中对肾脏的安全性较好。
AIM To evaluate the renal safety of sodium-glucose cotransporter 2(SGLT2) inhibitors in patients with type 2 diabetes mellitus( T2 DM). METHODS PubMed, Embase, OVID, Cochrane Library,Web of Science, CNKI, Wanfang and VIP database and clinical trial registration sites were searched to collect the literatures on rand omized controlled trials( RCTs) of SGLT2 inhibitors compared with placebo or positive control agents. The meta-analysis was conducted by RevMan 5.3 software about the outcomes of renal safety such as estimated in glomerular filtration rate(eGFR), serum creatinine(SCr), urinary albumin to creatinine ratio( UACR), the incidence of renal impairment and acute renal failure. RESULTS Thirty-eight RCTs were included, including 20 163 patients with T2DM. During less than 26 weeks, a greater reduction in eGFR( WMD =-9.03, 95% CI:-1.56--0.31, P = 0.004, I~2= 33%) and a greater increase in SCr( WMD =0.70, 95% CI: 0.09-1.30, P = 0.02, I~2= 0%) were observed in high dose group of SGLT2 inhibitors compared with placebo group, whereas no significant differences in eGFR and SCr between the two dose groups of SGLT2 inhibitors and positive control group( P > 0.05). During more than 48 weeks, there were no significant differences in e GFR and SCr between SGLT2 inhibitors groups and placebo group( P > 0.05).Compared with the positive control group, e GFR was significantly increased and SCr was significantly decreased in the two dose groups(P < 0.05). There were no significant differences in UACR between the two dose groups of SGLT2 inhibitors and placebo group( P > 0.05). Compared with the positive control group, UACR was significantly lower in the high dose group during more than 48 weeks(WMD =-20.05, 95% CI:-37.79--2.32,P = 0.03, I~2= 0%). In the incidence of renal impairment and acute renal failure, there were no significant differences between the SGLT2 inhibitors groups and the placebo group or the positive control group(P > 0.05).CONCLUSION The incidence of renal impairment and acute renal failure of SGLT2 inhibitors in treatment of patients with T2DM is similar with placebo or positive control agents, and the renal safety of SGLT2 is better in continuous treatment.
AIM To evaluate the renal safety of sodium-glucose cotransporter 2(SGLT2) inhibitors in patients with type 2 diabetes mellitus( T2 DM). METHODS PubMed, Embase, OVID, Cochrane Library,Web of Science, CNKI, Wanfang and VIP database and clinical trial registration sites were searched to collect the literatures on rand omized controlled trials( RCTs) of SGLT2 inhibitors compared with placebo or positive control agents. The meta-analysis was conducted by RevMan 5.3 software about the outcomes of renal safety such as estimated in glomerular filtration rate(eGFR), serum creatinine(SCr), urinary albumin to creatinine ratio( UACR), the incidence of renal impairment and acute renal failure. RESULTS Thirty-eight RCTs were included, including 20 163 patients with T2DM. During less than 26 weeks, a greater reduction in eGFR( WMD =-9.03, 95% CI:-1.56--0.31, P = 0.004, I~2= 33%) and a greater increase in SCr( WMD =0.70, 95% CI: 0.09-1.30, P = 0.02, I~2= 0%) were observed in high dose group of SGLT2 inhibitors compared with placebo group, whereas no significant differences in eGFR and SCr between the two dose groups of SGLT2 inhibitors and positive control group( P > 0.05). During more than 48 weeks, there were no significant differences in e GFR and SCr between SGLT2 inhibitors groups and placebo group( P > 0.05).Compared with the positive control group, e GFR was significantly increased and SCr was significantly decreased in the two dose groups(P < 0.05). There were no significant differences in UACR between the two dose groups of SGLT2 inhibitors and placebo group( P > 0.05). Compared with the positive control group, UACR was significantly lower in the high dose group during more than 48 weeks(WMD =-20.05, 95% CI:-37.79--2.32,P = 0.03, I~2= 0%). In the incidence of renal impairment and acute renal failure, there were no significant differences between the SGLT2 inhibitors groups and the placebo group or the positive control group(P > 0.05).CONCLUSION The incidence of renal impairment and acute renal failure of SGLT2 inhibitors in treatment of patients with T2DM is similar with placebo or positive control agents, and the renal safety of SGLT2 is better in continuous treatment.
引文
[1]PACKHAM DK,ALVES TP,DWYER JP,et al.Relative incidence of ESRD versus cardiovascular mortality in proteinuric type 2 diabetes and nephropathy:results from the DIAMETRIC(Diabetes Mellitus Treatment for Renal Insufficiency Consortium)database[J].Am J Kidney Dis,2012,59(1):75-83.
[2]LIU XY,ZHANG N,CHEN R,et al.Efficacy and safety of sodium-glucose cotransporter 2 inhibitors in type 2 diabetes:a meta-analysis of randomized controlled trials for 1 to 2 years[J].JDiabetes Complications,2015,29(8):1295-1303.
[3]FDA.FDA Drug Safety Communication:FDA strengthens kidney warnings for diabetes medicines canagliflozin(Invokana,Invokamet)and dapagliflozin(Farxiga,Xigduo XR)[EB/OL].(2016-06-14)[2018-05].https://www.fda.gov/Drugs/DrugSafety/ucm505860.htm.
[4]JADAD AR,MOORE RA,CARROLL D,et al.Assessing the quality of reports of randomized clinical trials:is blinding necessary?[J].Control Clin Trials,1996,17(1):1-12.
[5]GUYATT GH,OXMAN AD,KUNZ R,et al.GRADE guidelines:7.Rating the quality of evidence-inconsistency[J].J Clin Epidemiol,2011,64(12):1294-1302.
[6]KOVACS CS,SESHIAH V,SWALLOW R,et al.Empagliflozin improves glycaemic and weight control as add-on therapy to pioglitazone or pioglitazone plus metformin in patients with type2 diabetes:a 24-week,randomized,placebo-controlled trial[J].Diabetes Obes Metab,2014,16(2):147-158.
[7]KOVACS CS,SESHIAH V,MERKER L,et al.Empagliflozin as add-on therapy to pioglitazone with or without metformin in patients with type 2 diabetes mellitus[J].Clin Ther,2015,37(8):1773-1788.
[8]HARING HU,MERKER L,SEEWALDT-BECKER E,et al.Empagliflozin as add-on to metformin in patients with type 2diabetes:a 24-week,randomize d,double-blind,placebocontrolled trial[J].Diabetes Care,2014,37(6):1650-1659.
[9]MERKER L,HARING HU,CHRISTIANSEN AV,et al.Empagliflozin as add-on to metformin in people with type 2diabetes[J].Diabet Med,2015,32(12):1555-1567.
[10]HARING HU,MERKER L,SEEWALDT-BECKER E,et al.Empagliflozin as add-on to metformin plus sulfonylurea in patients with type 2 diabetes:a 24-week,randomized,doubleblind,placebo-controlled trial[J].Diabetes Care,2013,36(11):3396-3404.
[11]HAERING HU,MERKER L,CHRISTIANSEN AV,et al.Empagliflozin as add-on to metformin plus sulphonylurea in patients with type 2 diabetes[J].Diabetes Res Clin Pract,2015,110(1):82-90.
[12]RODEN M,WENG J,EILBRACHT J,et al.Empagliflozin monotherapy with sitagliptin as an active comparator in patients with type 2 diabetes:a randomised,double-blind,placebocontrolled,phase 3 trial[J].Lancet Diabetes Endocrinol,2013,1(3):208-219.
[13]RODEN M,MERKER L,CHRISTIANSEN AV,et al.Safety,tolerability and effects on cardiometabolic risk factors of empagliflozin monotherapy in drug-naive patients with type 2diabetes:a double-blind extension of a phaseⅢrandomized controlled trial[J].Cardiovasc Diabetol,2015,14:154.
[14]ROSS S,THAMER C,CESCUTTI J,et al.Efficacy and safety of empagliflozin twice daily versus once daily in patients with type 2 diabetes inadequately controlled on metformin:a 16-week,randomized,placebo-controlled trial[J].Diabetes Obes Metab,2015,17(7):699-702.
[15]SOFTELAND E,MEIER JJ,VANGEN B,et al.Empagliflozin as add-on therapy in patients with type 2 diabetes inadequately controlled with linagliptin and metformin:a 24-week randomized,double-blind,parallel-group trial[J].Diabetes Care,2017,40(2):201-209.
[16]KADOWAKI T,HANEDA M,INAGAKI N,et al.Empagliflozin monotherapy in Japanese patients with type 2 diabetes mellitus:a randomized,12-week,double-blind,placebo-controlled,phaseⅡtrial[J].Adv Ther,2014,31(6):621-638.
[17]ROSENSTOCK J,JELASKA A,FRAPPIN G,et al.Improved glucose control with weight loss,lower insulin doses,and no increased hypoglycemia with empagliflozin added to titrated multiple daily injections of insulin in obese inadequately controlled type 2 diabetes[J].Diabetes Care,2014,37(7):1815-1823.
[18]ROSENSTOCK J,JELASKA A,ZELLER C,et al.Impact of empagliflozin added on to basal insulin in type 2 diabetes inadequately controlled on basal insulin:a 78-week randomized,double-blind,placebo-controlled trial[J].Diabetes Obes Metab,2015,17(10):936-948.
[19]LEWIN A,DEFRONZO RA,PATEL S,et al.Initial combination of empagliflozin and linagliptin in subjects with type 2 diabetes[J].Diabetes Care,2015,38(3):394-402.
[20]DeFRONZO RA,LEWIN A,PATEL S,et al.Combination of empagliflozin and linagliptin as second-line therapy in subjects with type 2 diabetes inadequately controlled on metformin[J].Diabetes Care,2015,38(3):384-393.
[21]RIDDERSTRALE M,ANDERSEN KR,ZELLER C,et al.Comparison of empagliflozin and glimepiride as add-on to metformin in patients with type 2 diabetes:a 104-week randomised active-controlled,double-blind,phase 3 trial[J].Lancet Diabetes Endocrinol,2014,2(9):691-700.
[22]BODE B,STENLOF K,SULLIVAN D,et al.Efficacy and safety of canagliflozin treatment in older subjects with type 2 diabetes mellitus:a randomized trial[J].Hosp Pract,2013,41(2):72-84.
[23]BODE B,STENLOF K,HARRIS S,et al.Long-term efficacy and safety of canagliflozin over 104 weeks in patients aged 55-80 years with type 2 diabetes[J].Diabetes Obes Metab,2015,17(3):294-303.
[24]JI L,HAN P,LIU Y,et al.Canagliflozin in Asian patients with type 2 diabetes on metformin alone or metformin in combination with sulphonylurea[J].Diabetes Obes Metab,2015,17(1):23-31.
[25]LAVALLE-GONZALEZ FJ,JANUSZEWICZ A,DAVIDSON J,et al.Efficacy and safety of canagliflozin compared with placebo and sitagliptin in patients with type 2 diabetes on background metformin monotherapy:a randomised trial[J].Diabetologia,2013,56(12):2582-2592.
[26]STENLOF K,CEFALU WT,KIM KA,et al.Efficacy and safety of canagliflozin monotherapy in subjects with type 2 diabetes mellitus inadequately controlled with diet and exercise[J].Diabetes Obes Metab,2013,15(4):372-382.
[27]INAGAKI N,KONDO K,YOSHINARI T,et al.Efficacy and safety of canagliflozin monotherapy in Japanese patients with type 2 diabetes inadequately controlled with diet and exercise:a24-week,randomized,double-blind,placebo-controlled,phaseⅢstudy[J].Expert Opin Pharmacother,2014,15(11):1501-1515.
[28]FULCHER G,MATTHEWS DR,PERKOVIC V,et al.Efficacy and safety of canagliflozin when used in conjunction with incretin-mimetic therapy in patients with type 2 diabetes[J].Diabetes Obes Metab,2016,18(1):82-91.
[29]ROSENSTOCK J,CHUCK L,GONZALEZ-ORTIZ M,et al.Initial combination therapy with canagliflozin plus metformin versus each component as monotherapy for drug-naive type 2diabetes[J].Diabetes Care,2016,39(3):353-362.
[30]WILDING JP,CHARPENTIER G,HOLLANDER P,et al.Efficacy and safety of canagliflozin in patients with type 2diabetes mellitus inadequately controlled with metformin and sulphonylurea:a randomised trial[J].Int J Clin Pract,2013,67(12):1267-1282.
[31]SCHERNTHANER G,GROSS JL,ROSENSTOCK J,et al.Canagliflozin compared with sitagliptin for patients with type 2diabetes who do not have adequate glycemic control with metformin plus sulfonylurea:a 52-week randomized trial[J].Diabetes Care,2013,36(9):2508-2515.
[32]LEITER LA,YOON KH,ARIAS P,et al.Canagliflozin provides durable glycemic improvements and body weight reduction over104 weeks versus glimepiride in patients with type 2 diabetes on metformin:a randomized,double-blind,phase 3 study[J].Diabetes Care,2015,38(3):355-364.
[33]BOLINDER J,LJUNGGREN O,KULLBERG J,et al.Effects of dapagliflozin on body weight,total fat mass,and regional adipose tissue distribution in patients with type 2 diabetes mellitus with inadequate glycemic control on metformin[J].J Clin Endocrinol Metab,2012,97(3):1020-1031.
[34]BOLINDER J,LJUNGGREN O,JOHANSSON L,et al.Dapagliflozin maintains glycaemic control while reducing weight and bodyfat mass over 2 years in patients with type 2 diabetes mellitus inadequately controlled on metformin[J].Diabetes Obes Metab,2014,16(2):159-169.
[35]WILDING JP,WOO V,SOLER NG,et al.Long-term efficacy of dapagliflozin in patients with type 2 diabetes mellitus receiving high doses of insulin:a randomized trial[J].Ann Intern Med,2012,156(6):405-415.
[36]WILDING JP,WOO V,ROHWEDDER K,et al.Dapagliflozin in patients with type 2 diabetes receiving high doses of insulin:efficacy and safety over 2 years[J].Diabetes Obes Metab,2014,16(2):124-136.
[37]FERRANNINI E,RAMOS SJ,SALSALI A,et al.Dapagliflozin monotherapy in type 2 diabetic patients with inadequate glycemic control by diet and exercise:a randomized,double-blind,placebo-controlled,phase 3 trial[J].Diabetes Care,2010,33(10):2217-2224.
[38]BAILEY CJ,MORALES VILLEGAS EC,WOO V,et al.Efficacy and safety of dapagliflozin monotherapy in people with type 2diabetes:a randomized double-blind placebo-controlled 102-week trial[J].Diabet Med,2015,32(4):531-541.
[39]BAILEY CJ,GROSS JL,PIETERS A,et al.Effect of dapagliflozin in patients with type 2 diabetes who have inadequate glycaemic control with metformin:a randomised,double-blind,placebocontrolled trial[J].Lancet,2010,375(9733):2223-2233.
[40]BAILEY CJ,GROSS JL,HENNICKEN D,et al.Dapagliflozin add-on to metformin in type 2 diabetes inadequately controlled with metformin:a randomized,double-blind,placebo-controlled102-week trial[J].BMC Med,2013,11:43.
[41]NAUCK MA,del PRATO S,MEIER JJ,et al.Dapagliflozin versus glipizide as add-on therapy in patients with type 2diabetes who have inadequate glycemic control with metformin:a randomized,52-week,double-blind,active-controlled noninferiority trial[J].Diabetes Care,2011,34(9):2015-2022.
[42]NAUCK MA,del PRATO S,DURAN-GARCIA S,et al.Durability of glycaemic efficacy over 2 years with dapagliflozin versus glipizide as add-on therapies in patients whose type 2diabetes mellitus is inadequately controlled with metformin[J].Diabetes Obes Metab,2014,16(11):1111-1120.
[43]HENRY RR,MURRAY AV,MARMOLEJO MH,et al.Dapagliflozin,metformin XR,or both:initial pharmacotherapy for type 2 diabetes,a randomised controlled trial[J].Int J Clin Pract,2012,66(5):446-456.
[44]STROJEK K,YOON KH,HRUBA V,et al.Effect of dapagliflozin in patients with type 2 diabetes who have inadequate glycaemic control with glimepiride:a randomized,24-week,double-blind,placebo-controlled trial[J].Diabetes Obes Metab,2011,13(10):928-938.
[45]JI L,MA J,LI H,et al.Dapagliflozin as monotherapy in drugnaive Asian patients with type 2 diabetes mellitus:a randomized,blinded,prospective phaseⅢstudy[J].Clin Ther,2014,36(1):84-100.
[46]BAILEY CJ,IQBAL N,TJOEN C,et al.Dapagliflozin monotherapy in drug-naive patients with diabetes:a randomized-controlled trial of low-dose range[J].Diabetes Obes Metab,2012,14(10):951-959.
[47]ROSENSTOCK J,VICO M,WEI L,et al.Effects of dapagliflozin,an SGLT2 inhibitor,on HbA1c,body weight,and hypoglycemia risk in patients with type 2 diabetes inadequately controlled on pioglitazone monotherapy[J].Diabetes Care,2012,35(7):1473-1478.
[48]KAKU K,KIYOSUE A,INOUE S,et al.Efficacy and safety of dapagliflozin monotherapy in Japanese patients with type 2diabetes inadequately controlled by diet and exercise[J].Diabetes Obes Metab,2014,16(11):1102-1110.
[49]WEBER MA,MANSFIELD TA,CAIN VA,et al.Blood pressure and glycaemic effects of dapagliflozin versus placebo in patients with type 2 diabetes on combination antihypertensive therapy:a randomised,double-blind,placebo-controlled,phase 3 study[J].Lancet Diabetes Endocrinol,2016,4(3):211-220.
[50]ISHIHARA H,YAMAGUCHI S,NAKAO I,et al.Efficacy and safety of ipragliflozin as add-on therapy to insulin in Japanese patients with type 2 diabetes mellitus(IOLITE):a multi-centre,randomized,placebo-controlled,double-blind study[J].Diabetes Obes Metab,2016,18(12):1207-1216.
[51]WILDING JP,FERRANNINI E,FONSECA VA,et al.Efficacy and safety of ipragliflozin in patients with type 2 diabetes inadequately controlled on metformin:a dose-finding study[J].Diabetes Obes Metab,2013,15(5):403-409.
[52]LU CH,MIN KW,CHUANG LM,et al.Efficacy,safety,and tolerability of ipragliflozin in Asian patients with type 2 diabetes mellitus and inadequate glycemic control with metformin:results of a phase 3 randomized,place-controlled,double-blind,multicenter trial[J].J Diabetes Investig,2016,7(3):366-373.
[53]KAKU K,WATADA H,IWAMOTO Y,et al.Efficacy and safety of monotherapy with the novel sodium/glucose cotransporter-2inhibitor tofogliflozin in Japanese patients with type 2 diabetes mellitus:a combined phase 2 and 3 randomized,placebocontrolled,double-blind,parallel-group comparative study[J].Cardiovasc Diabetol,2014,13:65.
[54]WANNER C,INZUCCHI SE,LACHIN JM,et al.Empagliflozin and progression of kidney disease in type 2 diabetes[J].N Engl JMed,2016,375(4):323-334.
[55]NADKARNI GN,FERRANDINO R,CHANG A,et al.Acute kidney injury in patients on SGLT2 inhibitors:a propensitymatched analysis[J].Diabetes Care,2017,40(11):1479-1485.
[56]LYTVYN Y,PERKINS BA,CHERNEY DZ.Uric acid as a biomarker and a therapeutic target in diabetes[J].Can J Diabetes,2015,39(3):239-246.
[57]CHERNEY DZ,PERKINS BA,SOLEYMANLOU N,et al.Renal hemodynamic effect of sodium-glucose cotransporter 2inhibition in patients with type 1 diabetes mellitus[J].Circulation,2014,129(5):587-597.
[58]TAHARA A,KUROSAKI E,YOKONO M,et al.Effects of sodium-glucose cotransporter 2 selective inhibitor ipragliflozin on hyperglycaemia,oxidative stress,inflammation and liver injury in streptozotocin-induced type 1 diabetic rats[J].J Pharm Pharmacol,2014,66(7):975-987.
[2]LIU XY,ZHANG N,CHEN R,et al.Efficacy and safety of sodium-glucose cotransporter 2 inhibitors in type 2 diabetes:a meta-analysis of randomized controlled trials for 1 to 2 years[J].JDiabetes Complications,2015,29(8):1295-1303.
[3]FDA.FDA Drug Safety Communication:FDA strengthens kidney warnings for diabetes medicines canagliflozin(Invokana,Invokamet)and dapagliflozin(Farxiga,Xigduo XR)[EB/OL].(2016-06-14)[2018-05].https://www.fda.gov/Drugs/DrugSafety/ucm505860.htm.
[4]JADAD AR,MOORE RA,CARROLL D,et al.Assessing the quality of reports of randomized clinical trials:is blinding necessary?[J].Control Clin Trials,1996,17(1):1-12.
[5]GUYATT GH,OXMAN AD,KUNZ R,et al.GRADE guidelines:7.Rating the quality of evidence-inconsistency[J].J Clin Epidemiol,2011,64(12):1294-1302.
[6]KOVACS CS,SESHIAH V,SWALLOW R,et al.Empagliflozin improves glycaemic and weight control as add-on therapy to pioglitazone or pioglitazone plus metformin in patients with type2 diabetes:a 24-week,randomized,placebo-controlled trial[J].Diabetes Obes Metab,2014,16(2):147-158.
[7]KOVACS CS,SESHIAH V,MERKER L,et al.Empagliflozin as add-on therapy to pioglitazone with or without metformin in patients with type 2 diabetes mellitus[J].Clin Ther,2015,37(8):1773-1788.
[8]HARING HU,MERKER L,SEEWALDT-BECKER E,et al.Empagliflozin as add-on to metformin in patients with type 2diabetes:a 24-week,randomize d,double-blind,placebocontrolled trial[J].Diabetes Care,2014,37(6):1650-1659.
[9]MERKER L,HARING HU,CHRISTIANSEN AV,et al.Empagliflozin as add-on to metformin in people with type 2diabetes[J].Diabet Med,2015,32(12):1555-1567.
[10]HARING HU,MERKER L,SEEWALDT-BECKER E,et al.Empagliflozin as add-on to metformin plus sulfonylurea in patients with type 2 diabetes:a 24-week,randomized,doubleblind,placebo-controlled trial[J].Diabetes Care,2013,36(11):3396-3404.
[11]HAERING HU,MERKER L,CHRISTIANSEN AV,et al.Empagliflozin as add-on to metformin plus sulphonylurea in patients with type 2 diabetes[J].Diabetes Res Clin Pract,2015,110(1):82-90.
[12]RODEN M,WENG J,EILBRACHT J,et al.Empagliflozin monotherapy with sitagliptin as an active comparator in patients with type 2 diabetes:a randomised,double-blind,placebocontrolled,phase 3 trial[J].Lancet Diabetes Endocrinol,2013,1(3):208-219.
[13]RODEN M,MERKER L,CHRISTIANSEN AV,et al.Safety,tolerability and effects on cardiometabolic risk factors of empagliflozin monotherapy in drug-naive patients with type 2diabetes:a double-blind extension of a phaseⅢrandomized controlled trial[J].Cardiovasc Diabetol,2015,14:154.
[14]ROSS S,THAMER C,CESCUTTI J,et al.Efficacy and safety of empagliflozin twice daily versus once daily in patients with type 2 diabetes inadequately controlled on metformin:a 16-week,randomized,placebo-controlled trial[J].Diabetes Obes Metab,2015,17(7):699-702.
[15]SOFTELAND E,MEIER JJ,VANGEN B,et al.Empagliflozin as add-on therapy in patients with type 2 diabetes inadequately controlled with linagliptin and metformin:a 24-week randomized,double-blind,parallel-group trial[J].Diabetes Care,2017,40(2):201-209.
[16]KADOWAKI T,HANEDA M,INAGAKI N,et al.Empagliflozin monotherapy in Japanese patients with type 2 diabetes mellitus:a randomized,12-week,double-blind,placebo-controlled,phaseⅡtrial[J].Adv Ther,2014,31(6):621-638.
[17]ROSENSTOCK J,JELASKA A,FRAPPIN G,et al.Improved glucose control with weight loss,lower insulin doses,and no increased hypoglycemia with empagliflozin added to titrated multiple daily injections of insulin in obese inadequately controlled type 2 diabetes[J].Diabetes Care,2014,37(7):1815-1823.
[18]ROSENSTOCK J,JELASKA A,ZELLER C,et al.Impact of empagliflozin added on to basal insulin in type 2 diabetes inadequately controlled on basal insulin:a 78-week randomized,double-blind,placebo-controlled trial[J].Diabetes Obes Metab,2015,17(10):936-948.
[19]LEWIN A,DEFRONZO RA,PATEL S,et al.Initial combination of empagliflozin and linagliptin in subjects with type 2 diabetes[J].Diabetes Care,2015,38(3):394-402.
[20]DeFRONZO RA,LEWIN A,PATEL S,et al.Combination of empagliflozin and linagliptin as second-line therapy in subjects with type 2 diabetes inadequately controlled on metformin[J].Diabetes Care,2015,38(3):384-393.
[21]RIDDERSTRALE M,ANDERSEN KR,ZELLER C,et al.Comparison of empagliflozin and glimepiride as add-on to metformin in patients with type 2 diabetes:a 104-week randomised active-controlled,double-blind,phase 3 trial[J].Lancet Diabetes Endocrinol,2014,2(9):691-700.
[22]BODE B,STENLOF K,SULLIVAN D,et al.Efficacy and safety of canagliflozin treatment in older subjects with type 2 diabetes mellitus:a randomized trial[J].Hosp Pract,2013,41(2):72-84.
[23]BODE B,STENLOF K,HARRIS S,et al.Long-term efficacy and safety of canagliflozin over 104 weeks in patients aged 55-80 years with type 2 diabetes[J].Diabetes Obes Metab,2015,17(3):294-303.
[24]JI L,HAN P,LIU Y,et al.Canagliflozin in Asian patients with type 2 diabetes on metformin alone or metformin in combination with sulphonylurea[J].Diabetes Obes Metab,2015,17(1):23-31.
[25]LAVALLE-GONZALEZ FJ,JANUSZEWICZ A,DAVIDSON J,et al.Efficacy and safety of canagliflozin compared with placebo and sitagliptin in patients with type 2 diabetes on background metformin monotherapy:a randomised trial[J].Diabetologia,2013,56(12):2582-2592.
[26]STENLOF K,CEFALU WT,KIM KA,et al.Efficacy and safety of canagliflozin monotherapy in subjects with type 2 diabetes mellitus inadequately controlled with diet and exercise[J].Diabetes Obes Metab,2013,15(4):372-382.
[27]INAGAKI N,KONDO K,YOSHINARI T,et al.Efficacy and safety of canagliflozin monotherapy in Japanese patients with type 2 diabetes inadequately controlled with diet and exercise:a24-week,randomized,double-blind,placebo-controlled,phaseⅢstudy[J].Expert Opin Pharmacother,2014,15(11):1501-1515.
[28]FULCHER G,MATTHEWS DR,PERKOVIC V,et al.Efficacy and safety of canagliflozin when used in conjunction with incretin-mimetic therapy in patients with type 2 diabetes[J].Diabetes Obes Metab,2016,18(1):82-91.
[29]ROSENSTOCK J,CHUCK L,GONZALEZ-ORTIZ M,et al.Initial combination therapy with canagliflozin plus metformin versus each component as monotherapy for drug-naive type 2diabetes[J].Diabetes Care,2016,39(3):353-362.
[30]WILDING JP,CHARPENTIER G,HOLLANDER P,et al.Efficacy and safety of canagliflozin in patients with type 2diabetes mellitus inadequately controlled with metformin and sulphonylurea:a randomised trial[J].Int J Clin Pract,2013,67(12):1267-1282.
[31]SCHERNTHANER G,GROSS JL,ROSENSTOCK J,et al.Canagliflozin compared with sitagliptin for patients with type 2diabetes who do not have adequate glycemic control with metformin plus sulfonylurea:a 52-week randomized trial[J].Diabetes Care,2013,36(9):2508-2515.
[32]LEITER LA,YOON KH,ARIAS P,et al.Canagliflozin provides durable glycemic improvements and body weight reduction over104 weeks versus glimepiride in patients with type 2 diabetes on metformin:a randomized,double-blind,phase 3 study[J].Diabetes Care,2015,38(3):355-364.
[33]BOLINDER J,LJUNGGREN O,KULLBERG J,et al.Effects of dapagliflozin on body weight,total fat mass,and regional adipose tissue distribution in patients with type 2 diabetes mellitus with inadequate glycemic control on metformin[J].J Clin Endocrinol Metab,2012,97(3):1020-1031.
[34]BOLINDER J,LJUNGGREN O,JOHANSSON L,et al.Dapagliflozin maintains glycaemic control while reducing weight and bodyfat mass over 2 years in patients with type 2 diabetes mellitus inadequately controlled on metformin[J].Diabetes Obes Metab,2014,16(2):159-169.
[35]WILDING JP,WOO V,SOLER NG,et al.Long-term efficacy of dapagliflozin in patients with type 2 diabetes mellitus receiving high doses of insulin:a randomized trial[J].Ann Intern Med,2012,156(6):405-415.
[36]WILDING JP,WOO V,ROHWEDDER K,et al.Dapagliflozin in patients with type 2 diabetes receiving high doses of insulin:efficacy and safety over 2 years[J].Diabetes Obes Metab,2014,16(2):124-136.
[37]FERRANNINI E,RAMOS SJ,SALSALI A,et al.Dapagliflozin monotherapy in type 2 diabetic patients with inadequate glycemic control by diet and exercise:a randomized,double-blind,placebo-controlled,phase 3 trial[J].Diabetes Care,2010,33(10):2217-2224.
[38]BAILEY CJ,MORALES VILLEGAS EC,WOO V,et al.Efficacy and safety of dapagliflozin monotherapy in people with type 2diabetes:a randomized double-blind placebo-controlled 102-week trial[J].Diabet Med,2015,32(4):531-541.
[39]BAILEY CJ,GROSS JL,PIETERS A,et al.Effect of dapagliflozin in patients with type 2 diabetes who have inadequate glycaemic control with metformin:a randomised,double-blind,placebocontrolled trial[J].Lancet,2010,375(9733):2223-2233.
[40]BAILEY CJ,GROSS JL,HENNICKEN D,et al.Dapagliflozin add-on to metformin in type 2 diabetes inadequately controlled with metformin:a randomized,double-blind,placebo-controlled102-week trial[J].BMC Med,2013,11:43.
[41]NAUCK MA,del PRATO S,MEIER JJ,et al.Dapagliflozin versus glipizide as add-on therapy in patients with type 2diabetes who have inadequate glycemic control with metformin:a randomized,52-week,double-blind,active-controlled noninferiority trial[J].Diabetes Care,2011,34(9):2015-2022.
[42]NAUCK MA,del PRATO S,DURAN-GARCIA S,et al.Durability of glycaemic efficacy over 2 years with dapagliflozin versus glipizide as add-on therapies in patients whose type 2diabetes mellitus is inadequately controlled with metformin[J].Diabetes Obes Metab,2014,16(11):1111-1120.
[43]HENRY RR,MURRAY AV,MARMOLEJO MH,et al.Dapagliflozin,metformin XR,or both:initial pharmacotherapy for type 2 diabetes,a randomised controlled trial[J].Int J Clin Pract,2012,66(5):446-456.
[44]STROJEK K,YOON KH,HRUBA V,et al.Effect of dapagliflozin in patients with type 2 diabetes who have inadequate glycaemic control with glimepiride:a randomized,24-week,double-blind,placebo-controlled trial[J].Diabetes Obes Metab,2011,13(10):928-938.
[45]JI L,MA J,LI H,et al.Dapagliflozin as monotherapy in drugnaive Asian patients with type 2 diabetes mellitus:a randomized,blinded,prospective phaseⅢstudy[J].Clin Ther,2014,36(1):84-100.
[46]BAILEY CJ,IQBAL N,TJOEN C,et al.Dapagliflozin monotherapy in drug-naive patients with diabetes:a randomized-controlled trial of low-dose range[J].Diabetes Obes Metab,2012,14(10):951-959.
[47]ROSENSTOCK J,VICO M,WEI L,et al.Effects of dapagliflozin,an SGLT2 inhibitor,on HbA1c,body weight,and hypoglycemia risk in patients with type 2 diabetes inadequately controlled on pioglitazone monotherapy[J].Diabetes Care,2012,35(7):1473-1478.
[48]KAKU K,KIYOSUE A,INOUE S,et al.Efficacy and safety of dapagliflozin monotherapy in Japanese patients with type 2diabetes inadequately controlled by diet and exercise[J].Diabetes Obes Metab,2014,16(11):1102-1110.
[49]WEBER MA,MANSFIELD TA,CAIN VA,et al.Blood pressure and glycaemic effects of dapagliflozin versus placebo in patients with type 2 diabetes on combination antihypertensive therapy:a randomised,double-blind,placebo-controlled,phase 3 study[J].Lancet Diabetes Endocrinol,2016,4(3):211-220.
[50]ISHIHARA H,YAMAGUCHI S,NAKAO I,et al.Efficacy and safety of ipragliflozin as add-on therapy to insulin in Japanese patients with type 2 diabetes mellitus(IOLITE):a multi-centre,randomized,placebo-controlled,double-blind study[J].Diabetes Obes Metab,2016,18(12):1207-1216.
[51]WILDING JP,FERRANNINI E,FONSECA VA,et al.Efficacy and safety of ipragliflozin in patients with type 2 diabetes inadequately controlled on metformin:a dose-finding study[J].Diabetes Obes Metab,2013,15(5):403-409.
[52]LU CH,MIN KW,CHUANG LM,et al.Efficacy,safety,and tolerability of ipragliflozin in Asian patients with type 2 diabetes mellitus and inadequate glycemic control with metformin:results of a phase 3 randomized,place-controlled,double-blind,multicenter trial[J].J Diabetes Investig,2016,7(3):366-373.
[53]KAKU K,WATADA H,IWAMOTO Y,et al.Efficacy and safety of monotherapy with the novel sodium/glucose cotransporter-2inhibitor tofogliflozin in Japanese patients with type 2 diabetes mellitus:a combined phase 2 and 3 randomized,placebocontrolled,double-blind,parallel-group comparative study[J].Cardiovasc Diabetol,2014,13:65.
[54]WANNER C,INZUCCHI SE,LACHIN JM,et al.Empagliflozin and progression of kidney disease in type 2 diabetes[J].N Engl JMed,2016,375(4):323-334.
[55]NADKARNI GN,FERRANDINO R,CHANG A,et al.Acute kidney injury in patients on SGLT2 inhibitors:a propensitymatched analysis[J].Diabetes Care,2017,40(11):1479-1485.
[56]LYTVYN Y,PERKINS BA,CHERNEY DZ.Uric acid as a biomarker and a therapeutic target in diabetes[J].Can J Diabetes,2015,39(3):239-246.
[57]CHERNEY DZ,PERKINS BA,SOLEYMANLOU N,et al.Renal hemodynamic effect of sodium-glucose cotransporter 2inhibition in patients with type 1 diabetes mellitus[J].Circulation,2014,129(5):587-597.
[58]TAHARA A,KUROSAKI E,YOKONO M,et al.Effects of sodium-glucose cotransporter 2 selective inhibitor ipragliflozin on hyperglycaemia,oxidative stress,inflammation and liver injury in streptozotocin-induced type 1 diabetic rats[J].J Pharm Pharmacol,2014,66(7):975-987.