胰高血糖素样肽1受体激动剂治疗2型糖尿病合并非酒精性脂肪肝有效性的系统评价和Meta分析
|
摘要
目的系统地评价胰高血糖素样肽1受体激动剂(GLP-1 RA)对2型糖尿病患者合并非酒精性脂肪肝的有效性。方法检索截止2016年3月Cochrane Library、EMBASE,Pub Med、Web of Science、中国期刊全文数据库(CNKI)、万方数据库、维普数据库和中国生物医学文献数据库中关于GLP-1 RA对于2型糖尿病合并非酒精性脂肪肝的随机对照试验,对于符合纳入标准的文献进行质量评价及筛选,采用Rev Man 5.2软件对数据进行合并分析。结果共纳入4项随机对照试验,共计145例患者。Meta分析结果显示,GLP-1RA与对照组相比可以明显改善2型糖尿病合并非酒精性脂肪肝患者的肝酶ALT[MD:-8.36,95%CI(-13.41-3.31),P=0.001],糖代谢指标Hb A1c[MD:-0.43%,95%CI(-0.73-0.31),P=0.005]、FBG[MD:-0.71%,95%CI(-1.39-0.03),P=0.04],BMI[MD:-1.38%,95%CI(-2.18-0.58),P=0.000 8],脂代谢指标TG[MD:-0.49%,95%CI(-0.82-0.16),P=0.004]。结论 GLP-1RA可以明显改善2型糖尿病合并非酒精性脂肪肝的代谢指标,鉴于纳入文献的数量和质量,尚需大型的RCT进一步验证。
OBJECTIVE To evaluate the efficacy of glucagon-like peptide-1 receptor agonists( GLP-1RA) on nonalcoholic fatty liver disease( NAFLD) in patients with type 2 diabetes mellitus( T2DM). METHODS The randomized controlled trials( RCTs) of GLP-1 RA,placebo,and anti-diabetes drugs in the treatment of NAFLD in patients with T2 DM were collected from Pub Med,Embase,CNKI,Wangfang database,VIP,and CBM. The trials were evaluated for the quality and selected,and the results of the studies were reviewed and analyzed using Rev Man 5. 2 software. RESULTS Four RCTs were included,involving 154 patients. The Meta-analysis showed that compared with the control group,GLP-1RA could significantly improve the ALT [MD:-8. 36,95% CI(-13. 41-3. 31),P = 0. 001],Hb A1 c [MD:-0. 43%,95% CI(-0. 73-0. 31),P = 0. 005],FBG [MD:-0. 71%,95% CI(-1. 39-0. 03),P = 0. 04],BMI [MD:-1. 38%,95% CI(-2. 18-0. 58),P = 0. 000 8],TG [MD:-0. 49%,95% CI(-0. 82-0. 16),P = 0. 004]. CONCLUSION GLP-1 RA can obviously improve the metabolic index of patients with NAFLD and T2 DM. Given the quality and quantity of the literature,large RCTs are still needed in the future.
OBJECTIVE To evaluate the efficacy of glucagon-like peptide-1 receptor agonists( GLP-1RA) on nonalcoholic fatty liver disease( NAFLD) in patients with type 2 diabetes mellitus( T2DM). METHODS The randomized controlled trials( RCTs) of GLP-1 RA,placebo,and anti-diabetes drugs in the treatment of NAFLD in patients with T2 DM were collected from Pub Med,Embase,CNKI,Wangfang database,VIP,and CBM. The trials were evaluated for the quality and selected,and the results of the studies were reviewed and analyzed using Rev Man 5. 2 software. RESULTS Four RCTs were included,involving 154 patients. The Meta-analysis showed that compared with the control group,GLP-1RA could significantly improve the ALT [MD:-8. 36,95% CI(-13. 41-3. 31),P = 0. 001],Hb A1 c [MD:-0. 43%,95% CI(-0. 73-0. 31),P = 0. 005],FBG [MD:-0. 71%,95% CI(-1. 39-0. 03),P = 0. 04],BMI [MD:-1. 38%,95% CI(-2. 18-0. 58),P = 0. 000 8],TG [MD:-0. 49%,95% CI(-0. 82-0. 16),P = 0. 004]. CONCLUSION GLP-1 RA can obviously improve the metabolic index of patients with NAFLD and T2 DM. Given the quality and quantity of the literature,large RCTs are still needed in the future.
引文
[1]RATZIU V,BELLENTANI S,CORTEZ-PINTO H,et al.A position state-ment on NAFLD/NASH based on the EASL 2009 special conference[J].J Hepatol,2010,53(2):372-384.
[2]ORTIZ-LOPEZ C,LOMONACO R,ORSAK B,et al.Prevalence of prediabetes and dia-betes and metabolic profile of patients with nonalcoholic fatty liver disease(NAFLD)[J].Diabetes Care,2012,35(4):873-878.
[3]YANG W,LU J,WENG J,et al.Prevalence of diabetes among men and women in China[J].N Eng J Med,2010,362(12):1090-1101.
[4]GUARIGUATA L,WHITING D R,HAMBLETON I,et al.Global estimates of diabetes prevalence for 2013 and projections for 2035[J].Diabetes Res Clin Pract,2014,103(2):137-149.
[5]TARGHER G,BERTOLINI L,RODELLA S,et al.Non-alcoholic fatty liver disease is independently associated with an increased prevalence of chronic kidney disease and proliferative/laser-treated retinopathy in type 2 diabetic patients[J].Diabetologia,2008,51(3):444-450.
[6]LI R,LIU X Y,DU X L.Anti diabetes drugs-glucagon-like peptide-1 receptor agonists:liraglutide[J].Clin Pharm J,2011,46(8):637-638.
[7]DING X,SAXENA N,LIN S,et al.Exendin-4,a glucagon-like protein-1(GLP-1)receptor agonist,reverse hepatic steatosis in ob/ob mice[J].Hepatology,2006,43(1):178-181.
[8]MELLS J E,FU P P,SHARMA S,et al.Glp-1 analog,liraglutide,ameliorates hepatic steatosis and cardiac hypertrophy in C57BL/6J mice fed a Western diet[J].Am J Physiol Gastrointest Liver Physiol,2012,302(2):225-235.
[9]LIU Y,WEI R,HONG T P,et al.Potential roles of glucagonlike peptide-1-based therapies in treating non-alcoholic fatty liver disease[J].World J Gastroenterol,2014,20(27):9090-9097.
[10]ARMSTRONG M J,HULL D,GUO K,et al.Glucagon-like peptide 1 decreases lipotoxicity in non-alcoholic steatohepatitis[J].J Hepatology,2016,64(2):399-408.
[11]BERNSMEIER C,MEYER-GERSPACH A C,BLASER L S,et al.Glucose-induced glucagon-like Peptide 1 secretion is deficient in patients with non-alcoholic fatty liver disease[J].PLo S One,2014,9(1):e87488.
[12]JADAD A R,MOORE R A,CARROL D,et al.Assessing the quality of reports of randomized clinical trials:is blinding necessary[J].Control Clin Trials,1996,17(1):1-12.
[13]BI Y,ZHANG B,XU W,et al.Effects of exenatide,insulin,and pioglitazone on liver fat content and body fat distribu-tions in drug-naive subjects with type 2 diabetes[J].Acta Diabetol,2014,51(5):865-873.
[14]SATHYANARAYANA P,JOGI M,MUTHUPILLAI R,et al.Effects of combined exenatide and pioglitazone therapy on hepatic fat content in type 2 diabetes[J].Obesity(Silver Spring),2011,19(12):2310-2315.
[15]ARMSTRONG M J,GAUNT P,AITHAL G P,et al.Liraglutide safety and efficacy in patients with non-alcoholic steatohepatitis(LEAN):a multicentre,double-blind,randomised,placebocontrolled phase 2 study[J].Lancet,2016,387(10019):679-690.
[16]TANG A,RABASA-LHORET R,CASTEL H,et al.Effects of insulin glargine and liraglutide therapy on liver fat as measured by magnetic resonance in patients with type 2 diabetes:a randomized trial[J].Diabetes Care,2015,38(7):1339-1346.
[17]TRUJILLO J M,NUFFER W.GLP-1 receptor agonists for type 2diabetes mellitus:recent developments and emerging agents[J].Pharmacotherapy,2014,34(11):1174-1186.
[18]TELLA S H,RENDELL M S.Glucagon-like polypeptide agonists in type 2 diabetes mellitus:efficacy and tolerability,a balance[J].Ther Adv Endocrinol Metab,2015,6(3):109-134.
[19]TOMLINSON B,HU M,ZHANG Y,et al.An overview of new GLP-1 receptor agonists for type 2 diabetes.Expert Opin Investig[J].Drugs,2016,25(2):145-158.
[20]SHAO N,KUANG H Y,HAO M,et al.Benefits of exenatide on obesity and non-alcoholic fatty liver disease with elevated liver enzymes in patients with type 2 diabetes[J].Diabetes Metab Res Rev,2014,30(6):521-529.
[21]ARMSTRONG M J,HOULIHAN D D,ROWE I A,et al.Safety and efficacy of liraglutide in patients with type 2 diabetes with elevated liver enzymes:Individual patient data Meta-analysis of the LEAD programme[J].Aliment Pharmacol Ther,2013,37(2):234-242.
[22]POREPA L,RAY J G,SANCHEZ-ROMEU P,et al.Newly diagnosed diabetes mellitus as a risk factor for serious liver disease[J].CMAJ,2010,82(11):526-531.
[23]MUSSO G,CASSADER M,ROSINA F,et al.Impact of current treatments on liver disease,glucose metabolism and cardiovascular risk in non-alcoholic fatty liver disease(NAFLD):a systematic review and meta-analysis of randomised trials[J].Diabetologia,2012,55(4):885-904.
[24]CUTHBERTSON D J,IRWIN A,GARDNER C J,et al.Improved glycaemia correlates with liver fat reduction in obese,type2 diabetes,patients given glucagon-like peptide-1(GLP-1)receptor agonists[J].PLo S One,2012,7(12):e50117.
[25]CHATRATH H,VUPPALANCHI R,CHALASANI N.Dyslipidemia in patients with nonalco-holic fatty liver disease[J].Semin Liver Dis,2012,32(1):22-29.
[26]CHOI C S,SAVAGE D B,KULKARNI A,et al.Sup-pression of diacylglycerol acyltransferase-2(DGAT2),but not DGAT1,with antisense oligonucleotides reverses diet-induced he-patic steatosis and insulin resistance[J].J Biol Chem,2007,282(31):22678-22688.
[27]MUSSO G,CASSADER M,ROSINA F,et al.Impact of current treatments on liver disease,glucose metabolism and cardiovascular risk in non-alcoholic fatty liver disease(NAFLD):a systematic review and meta-analysis of randomised trials[J].Diabetologia,2012,55(4):885-904.
[28]ASRIH M,JORNAYVAZ F.Inflammation as a link between nonalcoholic fatty liver disease and insulin resistance[J].J Endocrinol,2013,218(3):25-36.
[29]DANIELE G,GUARDADO MENDOZA R,WINNIER D,et al.The inflammatory status score including IL-6,TNF-a,osteopontin,fractalkine,MCP-1 and adiponectin underlies whole-body insulin resistance and hyperglycemia in type 2 diabetes mellitus[J].Acta Diabetol,2014,51(1):123-131.
[30]LESMANA C R,HASAN I,BUDIHUSODO U,et al.Diagnostic value of a group of biochemical markers of liver fibrosis in patients with non-alcoholic steatohepatitis[J].J Did Dis,2009,10(3):201-206.
[31]SAVVIDOU S,KARATZIDOU K,TSAKIRI K,et al.Circulating adiponectin levels in type 2 diabetes mellitus patients with or without non-alcoholic fatty liver disease:results of a small,openlabel,randomized controlled intervention trial in a subgroup receiving short-term exenatide[J].Diabetes Res Clin Pract,2016,113:125-134.
[32]SATHYANARAYANA P,JOGI M,MUTHUPILLAI R,et al.Effects of combined exenatide and pi-oglitazone therapy on hepatic fat con-tent in type 2 diabetes[J].Obesity(Silver Spring),2011,19(12):2310-2315.
[33]JENDL E J,NAUCK M A,MATTHEWS D R,et al.Weight loss with liraglutide,a once-daily human glucagon-like peptide-1analogue for type 2 diabetes treatment as monotherapy or added to metformin,is primarily as a result of a reduction in fat tissue[J].Diabetes Obes Metab,2009,11(12):1163-1172.
[34]KENNY P R,BRADY D E,TORRES D M,et al.Exenatide in the treatment of diabetic pa-tients with non-alcoholic steatohepatitis:a case series[J].Am J Gastroenterol,2010,105(12):2707-2709.
[35]SUZUKI D,TOYODA M,KIMURA M,et al.Effects of liraglutide,a human glucagon-like peptide-1 analogue,on body weight,body fat area and body fat-related markers in patients with type 2diabetes mellitus[J].Intern Med,2013,52(10):1029-1034.
[36]CUTHBERTSON D J,IRWIN A,GARDNER C J,et al.Improved glycaemia correlates with liver fat reduction in obese,type2 diabetes,patients given glucagon-like peptide-1(GLP-1)receptor agonists[J].PLo S One,2012,7(12):e50117.
[2]ORTIZ-LOPEZ C,LOMONACO R,ORSAK B,et al.Prevalence of prediabetes and dia-betes and metabolic profile of patients with nonalcoholic fatty liver disease(NAFLD)[J].Diabetes Care,2012,35(4):873-878.
[3]YANG W,LU J,WENG J,et al.Prevalence of diabetes among men and women in China[J].N Eng J Med,2010,362(12):1090-1101.
[4]GUARIGUATA L,WHITING D R,HAMBLETON I,et al.Global estimates of diabetes prevalence for 2013 and projections for 2035[J].Diabetes Res Clin Pract,2014,103(2):137-149.
[5]TARGHER G,BERTOLINI L,RODELLA S,et al.Non-alcoholic fatty liver disease is independently associated with an increased prevalence of chronic kidney disease and proliferative/laser-treated retinopathy in type 2 diabetic patients[J].Diabetologia,2008,51(3):444-450.
[6]LI R,LIU X Y,DU X L.Anti diabetes drugs-glucagon-like peptide-1 receptor agonists:liraglutide[J].Clin Pharm J,2011,46(8):637-638.
[7]DING X,SAXENA N,LIN S,et al.Exendin-4,a glucagon-like protein-1(GLP-1)receptor agonist,reverse hepatic steatosis in ob/ob mice[J].Hepatology,2006,43(1):178-181.
[8]MELLS J E,FU P P,SHARMA S,et al.Glp-1 analog,liraglutide,ameliorates hepatic steatosis and cardiac hypertrophy in C57BL/6J mice fed a Western diet[J].Am J Physiol Gastrointest Liver Physiol,2012,302(2):225-235.
[9]LIU Y,WEI R,HONG T P,et al.Potential roles of glucagonlike peptide-1-based therapies in treating non-alcoholic fatty liver disease[J].World J Gastroenterol,2014,20(27):9090-9097.
[10]ARMSTRONG M J,HULL D,GUO K,et al.Glucagon-like peptide 1 decreases lipotoxicity in non-alcoholic steatohepatitis[J].J Hepatology,2016,64(2):399-408.
[11]BERNSMEIER C,MEYER-GERSPACH A C,BLASER L S,et al.Glucose-induced glucagon-like Peptide 1 secretion is deficient in patients with non-alcoholic fatty liver disease[J].PLo S One,2014,9(1):e87488.
[12]JADAD A R,MOORE R A,CARROL D,et al.Assessing the quality of reports of randomized clinical trials:is blinding necessary[J].Control Clin Trials,1996,17(1):1-12.
[13]BI Y,ZHANG B,XU W,et al.Effects of exenatide,insulin,and pioglitazone on liver fat content and body fat distribu-tions in drug-naive subjects with type 2 diabetes[J].Acta Diabetol,2014,51(5):865-873.
[14]SATHYANARAYANA P,JOGI M,MUTHUPILLAI R,et al.Effects of combined exenatide and pioglitazone therapy on hepatic fat content in type 2 diabetes[J].Obesity(Silver Spring),2011,19(12):2310-2315.
[15]ARMSTRONG M J,GAUNT P,AITHAL G P,et al.Liraglutide safety and efficacy in patients with non-alcoholic steatohepatitis(LEAN):a multicentre,double-blind,randomised,placebocontrolled phase 2 study[J].Lancet,2016,387(10019):679-690.
[16]TANG A,RABASA-LHORET R,CASTEL H,et al.Effects of insulin glargine and liraglutide therapy on liver fat as measured by magnetic resonance in patients with type 2 diabetes:a randomized trial[J].Diabetes Care,2015,38(7):1339-1346.
[17]TRUJILLO J M,NUFFER W.GLP-1 receptor agonists for type 2diabetes mellitus:recent developments and emerging agents[J].Pharmacotherapy,2014,34(11):1174-1186.
[18]TELLA S H,RENDELL M S.Glucagon-like polypeptide agonists in type 2 diabetes mellitus:efficacy and tolerability,a balance[J].Ther Adv Endocrinol Metab,2015,6(3):109-134.
[19]TOMLINSON B,HU M,ZHANG Y,et al.An overview of new GLP-1 receptor agonists for type 2 diabetes.Expert Opin Investig[J].Drugs,2016,25(2):145-158.
[20]SHAO N,KUANG H Y,HAO M,et al.Benefits of exenatide on obesity and non-alcoholic fatty liver disease with elevated liver enzymes in patients with type 2 diabetes[J].Diabetes Metab Res Rev,2014,30(6):521-529.
[21]ARMSTRONG M J,HOULIHAN D D,ROWE I A,et al.Safety and efficacy of liraglutide in patients with type 2 diabetes with elevated liver enzymes:Individual patient data Meta-analysis of the LEAD programme[J].Aliment Pharmacol Ther,2013,37(2):234-242.
[22]POREPA L,RAY J G,SANCHEZ-ROMEU P,et al.Newly diagnosed diabetes mellitus as a risk factor for serious liver disease[J].CMAJ,2010,82(11):526-531.
[23]MUSSO G,CASSADER M,ROSINA F,et al.Impact of current treatments on liver disease,glucose metabolism and cardiovascular risk in non-alcoholic fatty liver disease(NAFLD):a systematic review and meta-analysis of randomised trials[J].Diabetologia,2012,55(4):885-904.
[24]CUTHBERTSON D J,IRWIN A,GARDNER C J,et al.Improved glycaemia correlates with liver fat reduction in obese,type2 diabetes,patients given glucagon-like peptide-1(GLP-1)receptor agonists[J].PLo S One,2012,7(12):e50117.
[25]CHATRATH H,VUPPALANCHI R,CHALASANI N.Dyslipidemia in patients with nonalco-holic fatty liver disease[J].Semin Liver Dis,2012,32(1):22-29.
[26]CHOI C S,SAVAGE D B,KULKARNI A,et al.Sup-pression of diacylglycerol acyltransferase-2(DGAT2),but not DGAT1,with antisense oligonucleotides reverses diet-induced he-patic steatosis and insulin resistance[J].J Biol Chem,2007,282(31):22678-22688.
[27]MUSSO G,CASSADER M,ROSINA F,et al.Impact of current treatments on liver disease,glucose metabolism and cardiovascular risk in non-alcoholic fatty liver disease(NAFLD):a systematic review and meta-analysis of randomised trials[J].Diabetologia,2012,55(4):885-904.
[28]ASRIH M,JORNAYVAZ F.Inflammation as a link between nonalcoholic fatty liver disease and insulin resistance[J].J Endocrinol,2013,218(3):25-36.
[29]DANIELE G,GUARDADO MENDOZA R,WINNIER D,et al.The inflammatory status score including IL-6,TNF-a,osteopontin,fractalkine,MCP-1 and adiponectin underlies whole-body insulin resistance and hyperglycemia in type 2 diabetes mellitus[J].Acta Diabetol,2014,51(1):123-131.
[30]LESMANA C R,HASAN I,BUDIHUSODO U,et al.Diagnostic value of a group of biochemical markers of liver fibrosis in patients with non-alcoholic steatohepatitis[J].J Did Dis,2009,10(3):201-206.
[31]SAVVIDOU S,KARATZIDOU K,TSAKIRI K,et al.Circulating adiponectin levels in type 2 diabetes mellitus patients with or without non-alcoholic fatty liver disease:results of a small,openlabel,randomized controlled intervention trial in a subgroup receiving short-term exenatide[J].Diabetes Res Clin Pract,2016,113:125-134.
[32]SATHYANARAYANA P,JOGI M,MUTHUPILLAI R,et al.Effects of combined exenatide and pi-oglitazone therapy on hepatic fat con-tent in type 2 diabetes[J].Obesity(Silver Spring),2011,19(12):2310-2315.
[33]JENDL E J,NAUCK M A,MATTHEWS D R,et al.Weight loss with liraglutide,a once-daily human glucagon-like peptide-1analogue for type 2 diabetes treatment as monotherapy or added to metformin,is primarily as a result of a reduction in fat tissue[J].Diabetes Obes Metab,2009,11(12):1163-1172.
[34]KENNY P R,BRADY D E,TORRES D M,et al.Exenatide in the treatment of diabetic pa-tients with non-alcoholic steatohepatitis:a case series[J].Am J Gastroenterol,2010,105(12):2707-2709.
[35]SUZUKI D,TOYODA M,KIMURA M,et al.Effects of liraglutide,a human glucagon-like peptide-1 analogue,on body weight,body fat area and body fat-related markers in patients with type 2diabetes mellitus[J].Intern Med,2013,52(10):1029-1034.
[36]CUTHBERTSON D J,IRWIN A,GARDNER C J,et al.Improved glycaemia correlates with liver fat reduction in obese,type2 diabetes,patients given glucagon-like peptide-1(GLP-1)receptor agonists[J].PLo S One,2012,7(12):e50117.