SGLT2抑制剂的减重作用及机制的研究进展
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摘要
钠-葡萄糖共转运蛋白2(SGLT2)抑制剂可以抑制葡萄糖在近曲小管中的重吸收,从而降低血浆葡萄糖,是近年来2型糖尿病(T2DM)治疗领域研究的热点。SGLT2抑制剂在增加尿糖排泄的同时,通过渗透性利尿以及热量损失,产生减重的效果。本综述从SGLT2抑制剂的减重效果、作用机制、影响因素等方面进行阐述,并分析SGLT2抑制剂减重效果低于热量损失预期的原因,展望SGLT2抑制剂在肥胖症治疗领域的巨大前景。
引文
[1]CHEN L,MAGLIANO D J,ZIMMET P Z.The worldwide epidemiology of type 2 diabetes mellitus--present and future perspectives[J].Nat Rev Endocrinol,2011,8(4):228-236.
[2]WING R R,LANG W,WADDEN T A,et al.Benefits of modest weight loss in improving cardiovascular risk factors in overweight and obese individuals with type 2 diabetes[J].Diabetes Care,2011,34(7):1481-1486.
[3]ARROYO-JOHNSON C,MINCEY K D.Obesity epidemiology worldwide[J].Gastroenterol Clin North Am,2016,45(4):571-579.
[4]EHRENKRANZ J R L,LEWIS N G,RONALD KAHN C,et al.Phlorizin:a review[J].Diabetes/Metabolism Research and Reviews,2005,21(1):31-38.
[5]LEE Y J,LEE Y J,HAN H J.Regulatory mechanisms of Na(+)/glucose cotransporters in renal proximal tubule cells[J].Kidney Int Suppl,2007(106):S27-S35.
[6]NEAL B,PERKOVIC V,MAHAFFEY K W,et al.Canagliflozin and cardiovascular and renal events in type 2 diabetes[J].N Engl J Med,2017,377(7):644-657.
[7]ZINMAN B,WANNER C,LACHIN J M,et al.Empagliflozin,cardiovascular outcomes,and mortality in type 2 diabetes[J].N Engl J Med,2015,373(22):2117-2128.
[8]SHARMA R,WILKINSON L,VRAZIC H,et al.Comparative efficacy of once-weekly semaglutide and SGLT-2 inhibitors in type 2 diabetic patients inadequately controlled with metformin monotherapy:a systematic literature review and network metaanalysis[J].Curr Med Res Opin,2018,34(9):1595-1603.
[9]SHYANGDAN D S,UTHMAN O A,WAUGH N.SGLT-2 receptor inhibitors for treating patients with type 2 diabetes mellitus:a systematic review and network meta-analysis[J].BMJOpen,2016,6(2):e9417.
[10]NEAL B,PERKOVIC V,DE ZEEUW D,et al.Efficacy and safety of canagliflozin,an inhibitor of sodium-glucose cotransporter 2,when used in conjunction with insulin therapy in patients with type 2 diabetes[J].Diabetes Care,2015,38(3):403-411.
[11]LORENZI M,PLOUG U J,LANGER J,et al.Liraglutide versus sglt-2 inhibitors in people with type 2 diabetes:a network meta-analysis[J].Diabetes Ther,2017,8(1):85-99.
[12]CAI X,YANG W,GAO X,et al.The association between the dosage of sglt2 inhibitor and weight reduction in type 2 diabetes patients:a meta-analysis[J].Obesity(Silver Spring),2018,26(1):70-80.
[13]BLEVINS T.Combination therapy for patients with uncontrolled type 2 diabetes mellitus:adding empagliflozin to pioglitazone or pioglitazone plus metformin[J].Expert Opin Drug Saf,2015,14(5):789-793.
[14]JOHNSON JOHNSON PHARMACEUTICAL RESEARCH DE-VELOPMENT L L C.A study of the safety and effectiveness of canagliflozin(JNJ-28431754)in promoting weight loss in overweight and obese patients who do not have diabetes.clinicaltrials.gov[R].Johnson Johnson Pharmaceutical Research Development,L L C,2013.
[15]JANSSEN RESEARCH DEVELOPMENT L L C.Effects of coadministration of canagliflozin 300 mg and phentermine 15 mg with placebo in the treatment of non-diabetic overweight and obese participants.clinicaltrials.gov[R].Janssen Research Development,LLC,2016.
[16]HIROSE S,NAKAJIMA S,IWAHASHI Y,et al.Impact of the 8-week administration of tofogliflozin for glycemic control and body composition in japanese patients with type 2 diabetes mellitus[J].Intern Med,2016,55(22):3239-3245.
[17]KAWATA T,IIZUKA T,IEMITSU K,et al.Ipragliflozin improves glycemic control and decreases body fat in patients with type 2 diabetes mellitus[J].J Clin Med Res,2017,9(7):586-595.
[18]BOLINDER J,LJUNGGREN O,JOHANSSON L,et al.Dapagliflozin maintains glycaemic control while reducing weight and body fat mass over 2 years in patients with type 2 diabetes mellitus inadequately controlled on metformin[J].Diabetes Obes Metab,2014,16(2):159-169.
[19]SAKAI S,KAKU K,SEINO Y,et al.Efficacy and safety of the SGLT2 inhibitor luseogliflozin in japanese patients with type2 diabetes mellitus stratified according to baseline body mass index:pooled analysis of data from 52-week phase III trials[J].Clin Ther,2016,38(4):843-862.
[20]LEITER L A,YOON K H,ARIAS P,et al.Canagliflozin provides durable glycemic improvements and body weight reduction over 104 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.
[21]BONNER C,KERR-CONTE J,GMYR V,et al.Inhibition of the glucose transporter SGLT2 with dapagliflozin in pancreatic alpha cells triggers glucagon secretion[J].Nat Med,2015,21(5):512-517.
[22]FERRANNINI E,MUSCELLI E,FRASCERRA S,et al.Metabolic response to sodium-glucose cotransporter 2 inhibition in type 2 diabetic patients[J].J Clin Invest,2014,124(2):499-508.
[23]XU L,OTA T.Emerging roles of SGLT2 inhibitors in obesity and insulin resistance:Focus on fat browning and macrophage polarization[J].Adipocyte,2018,7(2):121-128.
[24]纪立农,郭立新,郭晓蕙,等.钠-葡萄糖共转运蛋白2(SGLT2)抑制剂临床合理应用中国专家建议[J].中国糖尿病杂志,2016,24(10):865-870.
[25]IEMITSU K,IIZUKA T,TAKIHATA M,et al.Factors influencing changes in hemoglobin a1c and body weight during treatment of type 2 diabetes with ipragliflozin:interim analysis of the ASSIGN-K study[J].J Clin Med Res,2016,8(5):373-378.
[26]ZHANG L,FENG Y,LIST J,et al.Dapagliflozin treatment in patients with different stages of type 2 diabetes mellitus:effects on glycaemic control and body weight[J].Diabetes Obes Metab,2010,12(6):510-516.
[27]BROWN R E,GUPTA N,ARONSON R.Effect of dapagliflozin on glycemic control,weight,and blood pressure in patients with type 2 diabetes attending a specialist endocrinology practice in canada:a retrospective cohort analysis[J].Diabetes Technol Ther,2017,19(11):685-691.
[28]PETRYKIV S,SJOSTROM C D,GREASLEY P J,et al.Differential effects of dapagliflozin on cardiovascular risk factors at varying degrees of renal function[J].Clin J Am Soc Nephrol,2017,12(5):751-759.
[29]ITO D,INOUE K,SUMITA T,et al.Long-term effects of ipragliflozin on diabetic nephropathy and blood pressure in patients with type 2 diabetes:104-week follow-up of an open-label study[J].J Clin Med Res,2018,10(9):679-687.
[30]TANG H,CUI W,LI D,et al.Sodium-glucose co-transporter2 inhibitors in addition to insulin therapy for management of type 2 diabetes mellitus:A meta-analysis of randomized controlled trials[J].Diabetes Obes Metab,2017,19(1):142-147.
[31]SINCLAIR A,BODE B,HARRIS S,et al.Efficacy and safety of canagliflozin compared with placebo in older patients with type 2 diabetes mellitus:a pooled analysis of clinical studies[J].BMC Endocr Disord,2014,14:37.
[32]LI D,WANG T,SHEN S,et al.Urinary tract and genital infections in patients with type 2 diabetes treated with sodium-glucose co-transporter 2 inhibitors:A meta-analysis of randomized controlled trials[J].Diabetes Obes Metab,2017,19(3):348-355.
[33]PUCKRIN R,SALTIEL M P,REYNIER P,et al.SGLT-2 inhibitors and the risk of infections:a systematic review and meta-analysis of randomized controlled trials[J].Acta Diabetol,2018,55(5):503-514.
[34]何志琼,王艳立,胡茂清,等.ipragliflozin治疗2型糖尿病有效性及安全性的Meta分析[J].实用医学杂志,2017,33(19):3299-3303.
[35]PETERS A L,HENRY R R,THAKKAR P,et al.Diabetic ketoacidosis with canagliflozin,a sodium-glucose cotransporter 2inhibitor,in patients with type 1 diabetes[J].Diabetes Care,2016,39(4):532-538.
[36]SFEIR J G,MONTORI V M.In insulin-treated type 1 diabetes,canagliflozin increased diabetic ketoacidosis[J].Ann Intern Med,2016,165(2):C2.
[37]RUANPENG D,UNGPRASERT P,SANGTIAN J,et al.Sodium-glucose cotransporter 2(SGLT2)inhibitors and fracture risk in patients with type 2 diabetes mellitus:A meta-analysis[J].Diabetes Metab Res Rev,2017,33(6).
[38]KOHLER S,KASPERS S,SALSALI A,et al.Analysis of fractures in patients with type 2 diabetes treated with empagliflozin in pooled data from placebo-controlled trials and a head-to-head study versus glimepiride[J].Diabetes Care,2018,41(8):1809-1816.
[39]RYAN P B,BUSE J B,SCHUEMIE M J,et al.Comparative effectiveness of canagliflozin,SGLT2 inhibitors and non-SGLT2inhibitors on the risk of hospitalization for heart failure and amputation in patients with type 2 diabetes mellitus:A real-world meta-analysis of 4 observational databases(OBSERVE-4D)[J].Diabetes Obes Metab,2018,20(11):2585-2597.
[40]LI D,YANG J Y,WANG T,et al.Risks of diabetic foot syndrome and amputation associated with sodium glucose co-transporter 2 inhibitors:A Meta-analysis of Randomized Controlled Trials[J].Diabetes Metab,2018,44(5):410-414.
[41]TANG H,DAI Q,SHI W,et al.SGLT2 inhibitors and risk of cancer in type 2 diabetes:a systematic review and meta-analysis of randomised controlled trials[J].Diabetologia,2017,60(10):1862-1872.
[42]ABDUL-GHANI M A,DEFRONZO R A,NORTON L.Novel hypothesis to explain why SGLT2 inhibitors inhibit only 30-50%of filtered glucose load in humans[J].Diabetes,2013,62(10):3324-3328.
[43]DEFRONZO R A.Combination therapy with GLP-1 receptor agonist and SGLT2 inhibitor[J].Diabetes Obes Metab,2017,19(10):1353-1362.
[44]POLIDORI D,SANGHVI A,SEELEY R J,et al.How strongly does appetite counter weight loss?quantification of the feedback control of human energy intake[J].Obesity(Silver Spring),2016,24(11):2289-2295.
[45]DEVENNY J J,GODONIS H E,HARVEY S J,et al.Weight loss induced by chronic dapagliflozin treatment is attenuated by compensatory hyperphagia in diet-induced obese(DIO)rats[J].Obesity(Silver Spring),2012,20(8):1645-1652.
[46]GARVEY W T,VAN GAAL L,LEITER L A,et al.Effects of canagliflozin versus glimepiride on adipokines and inflammatory biomarkers in type 2 diabetes[J].Metabolism,2018,85:32-37.
[47]MORAN T H.Hypothalamic nutrient sensing and energy balance[J].Forum Nutr,2010,63:94-101.
[48]HOLLANDER P,BAYS H E,ROSENSTOCK J,et al.Coadministration of canagliflozin and phentermine for weight management in overweight and obese individuals without diabetes:a randomized clinical trial[J].Diabetes Care,2017,40(5):632-639.
[2]WING R R,LANG W,WADDEN T A,et al.Benefits of modest weight loss in improving cardiovascular risk factors in overweight and obese individuals with type 2 diabetes[J].Diabetes Care,2011,34(7):1481-1486.
[3]ARROYO-JOHNSON C,MINCEY K D.Obesity epidemiology worldwide[J].Gastroenterol Clin North Am,2016,45(4):571-579.
[4]EHRENKRANZ J R L,LEWIS N G,RONALD KAHN C,et al.Phlorizin:a review[J].Diabetes/Metabolism Research and Reviews,2005,21(1):31-38.
[5]LEE Y J,LEE Y J,HAN H J.Regulatory mechanisms of Na(+)/glucose cotransporters in renal proximal tubule cells[J].Kidney Int Suppl,2007(106):S27-S35.
[6]NEAL B,PERKOVIC V,MAHAFFEY K W,et al.Canagliflozin and cardiovascular and renal events in type 2 diabetes[J].N Engl J Med,2017,377(7):644-657.
[7]ZINMAN B,WANNER C,LACHIN J M,et al.Empagliflozin,cardiovascular outcomes,and mortality in type 2 diabetes[J].N Engl J Med,2015,373(22):2117-2128.
[8]SHARMA R,WILKINSON L,VRAZIC H,et al.Comparative efficacy of once-weekly semaglutide and SGLT-2 inhibitors in type 2 diabetic patients inadequately controlled with metformin monotherapy:a systematic literature review and network metaanalysis[J].Curr Med Res Opin,2018,34(9):1595-1603.
[9]SHYANGDAN D S,UTHMAN O A,WAUGH N.SGLT-2 receptor inhibitors for treating patients with type 2 diabetes mellitus:a systematic review and network meta-analysis[J].BMJOpen,2016,6(2):e9417.
[10]NEAL B,PERKOVIC V,DE ZEEUW D,et al.Efficacy and safety of canagliflozin,an inhibitor of sodium-glucose cotransporter 2,when used in conjunction with insulin therapy in patients with type 2 diabetes[J].Diabetes Care,2015,38(3):403-411.
[11]LORENZI M,PLOUG U J,LANGER J,et al.Liraglutide versus sglt-2 inhibitors in people with type 2 diabetes:a network meta-analysis[J].Diabetes Ther,2017,8(1):85-99.
[12]CAI X,YANG W,GAO X,et al.The association between the dosage of sglt2 inhibitor and weight reduction in type 2 diabetes patients:a meta-analysis[J].Obesity(Silver Spring),2018,26(1):70-80.
[13]BLEVINS T.Combination therapy for patients with uncontrolled type 2 diabetes mellitus:adding empagliflozin to pioglitazone or pioglitazone plus metformin[J].Expert Opin Drug Saf,2015,14(5):789-793.
[14]JOHNSON JOHNSON PHARMACEUTICAL RESEARCH DE-VELOPMENT L L C.A study of the safety and effectiveness of canagliflozin(JNJ-28431754)in promoting weight loss in overweight and obese patients who do not have diabetes.clinicaltrials.gov[R].Johnson Johnson Pharmaceutical Research Development,L L C,2013.
[15]JANSSEN RESEARCH DEVELOPMENT L L C.Effects of coadministration of canagliflozin 300 mg and phentermine 15 mg with placebo in the treatment of non-diabetic overweight and obese participants.clinicaltrials.gov[R].Janssen Research Development,LLC,2016.
[16]HIROSE S,NAKAJIMA S,IWAHASHI Y,et al.Impact of the 8-week administration of tofogliflozin for glycemic control and body composition in japanese patients with type 2 diabetes mellitus[J].Intern Med,2016,55(22):3239-3245.
[17]KAWATA T,IIZUKA T,IEMITSU K,et al.Ipragliflozin improves glycemic control and decreases body fat in patients with type 2 diabetes mellitus[J].J Clin Med Res,2017,9(7):586-595.
[18]BOLINDER J,LJUNGGREN O,JOHANSSON L,et al.Dapagliflozin maintains glycaemic control while reducing weight and body fat mass over 2 years in patients with type 2 diabetes mellitus inadequately controlled on metformin[J].Diabetes Obes Metab,2014,16(2):159-169.
[19]SAKAI S,KAKU K,SEINO Y,et al.Efficacy and safety of the SGLT2 inhibitor luseogliflozin in japanese patients with type2 diabetes mellitus stratified according to baseline body mass index:pooled analysis of data from 52-week phase III trials[J].Clin Ther,2016,38(4):843-862.
[20]LEITER L A,YOON K H,ARIAS P,et al.Canagliflozin provides durable glycemic improvements and body weight reduction over 104 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.
[21]BONNER C,KERR-CONTE J,GMYR V,et al.Inhibition of the glucose transporter SGLT2 with dapagliflozin in pancreatic alpha cells triggers glucagon secretion[J].Nat Med,2015,21(5):512-517.
[22]FERRANNINI E,MUSCELLI E,FRASCERRA S,et al.Metabolic response to sodium-glucose cotransporter 2 inhibition in type 2 diabetic patients[J].J Clin Invest,2014,124(2):499-508.
[23]XU L,OTA T.Emerging roles of SGLT2 inhibitors in obesity and insulin resistance:Focus on fat browning and macrophage polarization[J].Adipocyte,2018,7(2):121-128.
[24]纪立农,郭立新,郭晓蕙,等.钠-葡萄糖共转运蛋白2(SGLT2)抑制剂临床合理应用中国专家建议[J].中国糖尿病杂志,2016,24(10):865-870.
[25]IEMITSU K,IIZUKA T,TAKIHATA M,et al.Factors influencing changes in hemoglobin a1c and body weight during treatment of type 2 diabetes with ipragliflozin:interim analysis of the ASSIGN-K study[J].J Clin Med Res,2016,8(5):373-378.
[26]ZHANG L,FENG Y,LIST J,et al.Dapagliflozin treatment in patients with different stages of type 2 diabetes mellitus:effects on glycaemic control and body weight[J].Diabetes Obes Metab,2010,12(6):510-516.
[27]BROWN R E,GUPTA N,ARONSON R.Effect of dapagliflozin on glycemic control,weight,and blood pressure in patients with type 2 diabetes attending a specialist endocrinology practice in canada:a retrospective cohort analysis[J].Diabetes Technol Ther,2017,19(11):685-691.
[28]PETRYKIV S,SJOSTROM C D,GREASLEY P J,et al.Differential effects of dapagliflozin on cardiovascular risk factors at varying degrees of renal function[J].Clin J Am Soc Nephrol,2017,12(5):751-759.
[29]ITO D,INOUE K,SUMITA T,et al.Long-term effects of ipragliflozin on diabetic nephropathy and blood pressure in patients with type 2 diabetes:104-week follow-up of an open-label study[J].J Clin Med Res,2018,10(9):679-687.
[30]TANG H,CUI W,LI D,et al.Sodium-glucose co-transporter2 inhibitors in addition to insulin therapy for management of type 2 diabetes mellitus:A meta-analysis of randomized controlled trials[J].Diabetes Obes Metab,2017,19(1):142-147.
[31]SINCLAIR A,BODE B,HARRIS S,et al.Efficacy and safety of canagliflozin compared with placebo in older patients with type 2 diabetes mellitus:a pooled analysis of clinical studies[J].BMC Endocr Disord,2014,14:37.
[32]LI D,WANG T,SHEN S,et al.Urinary tract and genital infections in patients with type 2 diabetes treated with sodium-glucose co-transporter 2 inhibitors:A meta-analysis of randomized controlled trials[J].Diabetes Obes Metab,2017,19(3):348-355.
[33]PUCKRIN R,SALTIEL M P,REYNIER P,et al.SGLT-2 inhibitors and the risk of infections:a systematic review and meta-analysis of randomized controlled trials[J].Acta Diabetol,2018,55(5):503-514.
[34]何志琼,王艳立,胡茂清,等.ipragliflozin治疗2型糖尿病有效性及安全性的Meta分析[J].实用医学杂志,2017,33(19):3299-3303.
[35]PETERS A L,HENRY R R,THAKKAR P,et al.Diabetic ketoacidosis with canagliflozin,a sodium-glucose cotransporter 2inhibitor,in patients with type 1 diabetes[J].Diabetes Care,2016,39(4):532-538.
[36]SFEIR J G,MONTORI V M.In insulin-treated type 1 diabetes,canagliflozin increased diabetic ketoacidosis[J].Ann Intern Med,2016,165(2):C2.
[37]RUANPENG D,UNGPRASERT P,SANGTIAN J,et al.Sodium-glucose cotransporter 2(SGLT2)inhibitors and fracture risk in patients with type 2 diabetes mellitus:A meta-analysis[J].Diabetes Metab Res Rev,2017,33(6).
[38]KOHLER S,KASPERS S,SALSALI A,et al.Analysis of fractures in patients with type 2 diabetes treated with empagliflozin in pooled data from placebo-controlled trials and a head-to-head study versus glimepiride[J].Diabetes Care,2018,41(8):1809-1816.
[39]RYAN P B,BUSE J B,SCHUEMIE M J,et al.Comparative effectiveness of canagliflozin,SGLT2 inhibitors and non-SGLT2inhibitors on the risk of hospitalization for heart failure and amputation in patients with type 2 diabetes mellitus:A real-world meta-analysis of 4 observational databases(OBSERVE-4D)[J].Diabetes Obes Metab,2018,20(11):2585-2597.
[40]LI D,YANG J Y,WANG T,et al.Risks of diabetic foot syndrome and amputation associated with sodium glucose co-transporter 2 inhibitors:A Meta-analysis of Randomized Controlled Trials[J].Diabetes Metab,2018,44(5):410-414.
[41]TANG H,DAI Q,SHI W,et al.SGLT2 inhibitors and risk of cancer in type 2 diabetes:a systematic review and meta-analysis of randomised controlled trials[J].Diabetologia,2017,60(10):1862-1872.
[42]ABDUL-GHANI M A,DEFRONZO R A,NORTON L.Novel hypothesis to explain why SGLT2 inhibitors inhibit only 30-50%of filtered glucose load in humans[J].Diabetes,2013,62(10):3324-3328.
[43]DEFRONZO R A.Combination therapy with GLP-1 receptor agonist and SGLT2 inhibitor[J].Diabetes Obes Metab,2017,19(10):1353-1362.
[44]POLIDORI D,SANGHVI A,SEELEY R J,et al.How strongly does appetite counter weight loss?quantification of the feedback control of human energy intake[J].Obesity(Silver Spring),2016,24(11):2289-2295.
[45]DEVENNY J J,GODONIS H E,HARVEY S J,et al.Weight loss induced by chronic dapagliflozin treatment is attenuated by compensatory hyperphagia in diet-induced obese(DIO)rats[J].Obesity(Silver Spring),2012,20(8):1645-1652.
[46]GARVEY W T,VAN GAAL L,LEITER L A,et al.Effects of canagliflozin versus glimepiride on adipokines and inflammatory biomarkers in type 2 diabetes[J].Metabolism,2018,85:32-37.
[47]MORAN T H.Hypothalamic nutrient sensing and energy balance[J].Forum Nutr,2010,63:94-101.
[48]HOLLANDER P,BAYS H E,ROSENSTOCK J,et al.Coadministration of canagliflozin and phentermine for weight management in overweight and obese individuals without diabetes:a randomized clinical trial[J].Diabetes Care,2017,40(5):632-639.