Using RCT Data to Evaluate the Association of DPP-4 Inhibitors on Pancreatitis and/or Pancreatic Cancer Risk in T2DM: A Systematic Review and Meta-analysis
ZHAO Zi-nan, LIANG Liang, ZHU Yuan-chao, JI Li-wei, YANG Li-ping, HU Xin
Department of Pharmacy, National Center of Gerontology, Beijing Hospital, Beijing 100730, China
Abstract��OBJECTIVE To review systematically the association of dipeptidyl peptidase-4 inhibitors on pancreatitis and/or pancreatic cancer risk in type-2 diabetes mellitus. METHODS Databases including The Cochrane Library, PubMed, Embase, Clinical Trials.gov, CNKI, WanFang Data and CBM, were searched electronically for randomized controlled trials (RCTs) of DPP-4 inhibitors in pancreatitis and pancreatic cancer risk in T2DM patients up to June 2017. Two reviewers independently screened literatures according to the inclusion and exclusion criteria, extracted data, and assessed the methodological quality of the included studies. Then Meta-analysis was performed using Rev Man 5.3 software. RESULTS A total of 39 RCTs involving 65 189 patients were included. The results of Meta-analysis showed that there were no significant differences between the DPP-4 inhibitors group and the control group in the pancreatitis and/or pancreatic cancer adverse events (RR=0.92, 95%CI 0.69 to 1.23, P=0.59), pancreatitis (RR=1.05, 95%CI 0.76 to 1.4, P=0.79) and pancreatic cancer (RR=0.62, 95%CI (0.35, 1.08), P=0.09). Subgroup analyses showed there were no significant differences of acute pancreatitis events between DPP-4 inhibitors group and the control group (RR=1.42, 95%CI 0.82 to 2.47, P=0.21). CONCLUSION The present Meta-analysis of RCTs data does not suggest that DPP-4 inhibitors are associated with pancreatitis and/or pancreatic cancer. Long-term clinical studies are required to further prove this conclusion.
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ZHAO Zi-nan,LIANG Liang,ZHU Yuan-chao,JI Li-wei,YANG Li-ping,HU Xin. Using RCT Data to Evaluate the Association of DPP-4 Inhibitors on Pancreatitis and/or Pancreatic Cancer Risk in T2DM: A Systematic Review and Meta-analysis. Chinese Pharmaceutical Journal, 2018, 53(5): 397-404.
CHEN W W, DANG H Q, GENG T, et al. Study progress of DPP-4 inhibitors as novel antidiabic drugs[J]. Chin Hosp Pharm J (�й�ҽԺҩѧ��־), 2016, 3(6):511-517.
[2]
INZUCCHI S E, BERGENSTAL R M, BUSE J B, et al. Management of hyperglycemia in type 2 diabetes, 2015: a patient-centered approach: update to a position statement of the American diabetes association and the European association for the study of diabetes[J]. Diabetes Care, 2015, 38(1):140-149.
[3]
EGAN A G, BLIND E, DUNDER K, et al. Pancreatic safety of incretin-based drugs-FDA and EMA assessment[J]. N Engl J Med, 2014, 370(9):794-797.
[4]
ELASHOFF M, MATVEYENKO A V, GIER B, et al. Pancreatitis, pancreatic, and thyroid cancer with glucagon-like peptide-1-based therapies[J]. Gastroenterology, 2011, 141(1):150-156.
[5]
FDA Drug Safety Communication: FDA investigating reports of possible increased risk of pancreatitis and pre-cancerous findings of the pancreas from incretin mimetic drugs for type 2 diabetes [DB/OL]. US Food and Drug Administration, 2013 [2017-06-10]. https://www.fda.gov/drugs/drugsafety/ucm343187.htm.
[6]
ENGEL S S, ROUND E, GOLM G T, et al. Safety and tolerability of sitagliptin in type 2 diabetes: pooled analysis of 25 clinical studies[J]. Diabetes Ther, 2013, 4(2):119-145.
[7]
WHITE W B, CANNON C P, HELLER S R, et al. EXAMINE Investigators. Alogliptin after acute coronary syndrome in patients with type 2 diabetes[J]. N Engl Med, 2013,369(14):1327-1335.
[8]
HIGGINS J P T, GREEN S. Cochrane Handbook for Systematic Reviews of Interventions[M]. Vol.5. Wiley Online Library, 2008.
[9]
ROSENSTOCK J, RENDELL M S, GROSS J L, et al. Alogliptin added to insulin therapy in patients with type 2 diabetes reduces HbA(1C) without causing weight gain or increased hypoglycaemia[J]. Diabetes Obes Metab, 2009, 11(12):1145-1152.
[10]
ROSENSTOCK J, INZUCCHI S E, SEUFERT J, et al. Initial combination therapy with alogliptin and pioglitazone in drug-naïve patients with type 2 diabetes[J]. Diabetes Care, 2010, 33(11):2406-2408.
[11]
DEFRONZO R A, BURANT C F, FLECK P, et al. Efficacy and tolerability of the DPP-4 inhibitor alogliptin combined with pioglitazone, in metformin-treated patients with type 2 diabetes[J]. J Clin Endocrinol Metab, 2012, 97(5):1615-1622.
[12]
DEL PRATO S, CAMISASCA R, WILSON C, et al. Durability of the efficacy and safety of alogliptin compared with glipizide in type 2 diabetes mellitus: a 2-year study[J]. Diabetes Obes Metab, 2014, 16(12):1239-1246.
[13]
GALLWITZ B, ROSENSTOCK J, RAUCH T, et al. 2-Year efficacy and safety of linagliptin compared with glimepiride in patients with type 2 diabetes inadequately controlled on metformin: a randomised, double-blind, non-inferiority trial[J]. Lancet, 2012, 380(9840):475-483.
[14]
YKI-JÄRVINEN H, ROSENSTOCK J, DURÁN-GARCIA S, et al. Effects of adding linagliptin to basal insulin regimen for inadequately controlled type 2 diabetes: a ��52-week randomized, double-blind study[J]. Diabetes Care, 2013, 36(12):3875-3881.
CHARBONNEL B, KARASIK A, LIU J, et al. Efficacy and safety of the dipeptidyl peptidase-4 inhibitor sitagliptin added to ongoing metformin therapy in patients with type 2 diabetes inadequately controlled with metformin alone[J]. Diabetes Care, 2006, 29(12):2638-2643.
[17]
PFÜTZNER A, PAZ-PACHECO E, ALLEN E, et al. Initial combination therapy with saxagliptin and metformin provides sustained glycaemic control and is well tolerated for up to 76 weeks[J]. Diabetes Obes Metab, 2011, 13(6):567-576.
[18]
NOWICKI M, RYCHLIK I, HALLER H, et al. Saxagliptin improves glycaemic control and is well tolerated in patients with type 2 diabetes mellitus and renal impairment[J]. Diabetes Obes Metab, 2011, 13(6):523-532.
[19]
HOLLANDER PL, LI J, FREDERICH R, et al. Safety and efficacy of saxagliptin added to thiazolidinedione over 76 weeks in patients with type 2 diabetes mellitus[J]. Diab Vasc Dis Res, 2011, 8(2):125-135.
[20]
FREDERICH R, MCNEILL R, BERGLIND N, et al. The efficacy and safety of the dipeptidyl peptidase-4 inhibitor saxagliptin in treatment-naïve patients with type 2 diabetes mellitus: a randomized controlled trial[J]. Diabetol Metab Syndr, 2012, 4(1):36.
[21]
BARNETT A H, CHARBONNEL B, DONOVAN M, et al. Effect of saxagliptin as add-on therapy in patients with poorly controlled type 2 diabetes on insulin alone or insulin combined with metformin[J]. Curr Med Res Opin, 2012, 28(4):513-523.
[22]
GÖKE B, GALLWITZ B, ERIKSSON J G, et al. Saxagliptin vs. glipizide as add-on therapy in patients with type 2 diabetes mellitus inadequately controlled on metformin alone: long-term(52-week) extension of a 52-week randomised controlled trial[J]. Int J Clin Pract, 2013, 67(4):307-316.
[23]
RAZ I, BHATT D L, HIRSHBERG B, et al. Incidence of pancreatitis and pancreatic cancer in a randomized controlled multicenter trial(SAVOR-TIMI 53) of the dipeptidyl peptidase-4 inhibitor saxagliptin[J]. Diabetes Care, 2014, 37(9):2435-2441.
[24]
RAZ I, HANEFELD M, XU L, et al. Efficacy and safety of the dipeptidyl peptidase-4 inhibitor sitagliptin as monotherapy in patients with type 2 diabetes mellitus[J]. Diabetologia, 2006, 49(11):2564-2571.
[25]
RAZ I, CHEN Y, WU M, et al. Efficacy and safety of sitagliptin added to ongoing metformin therapy in patients with type 2 diabetes[J]. Curr Med Res Opin, 2008, 24(2):537-550.
[26]
CHAN J C, SCOTT R, ARJONA FERREIRA J C, et al. Safety and efficacy of sitagliptin in patients with type 2 diabetes and chronic renal insufficiency[J]. Diabetes Obes Metab, 2008, 10(7):545-555.
[27]
WILLIAMS-HERMAN D, JOHNSON J, TENG R, et al. Efficacy and safety of sitagliptin and metformin as initial combination therapy and as monotherapy over 2 years in patients with type 2 diabetes[J]. Diabetes Obes Metab, 2010, 12(5):442-451.
[28]
SECK T, NAUCK M, SHENG D, et al. Safety and efficacy of treatment with sitagliptin or glipizide in patients with type 2 diabetes inadequately controlled on metformin: a 2-year study[J]. Int J Clin Pract, 2010, 64(5):562-576.
[29]
BERGENSTAL R M, WYSHAM C, MACCONELL L, et al. Efficacy and safety of exenatide once weekly versus sitagliptin or pioglitazone as an adjunct to metformin for treatment of type 2 diabetes(DURATION-2):a randomised trial[J]. Lancet, 2010, 376(9739):431-439.
[30]
ARECHAVALETA R, SECK T, CHEN Y, et al. Efficacy and safety of treatment with sitagliptin or glimepiride in patients with type 2 diabetes inadequately controlled on metformin monotherapy: a randomized, double-blind, non-inferiority trial[J]. Diabetes Obes Metab, 2011, 13(2):160-168.
[31]
ASCHNER P, CHAN J, OWENS D R, et al. Insulin glargine versus sitagliptin in insulin-naive patients with type 2 diabetes mellitus uncontrolled on metformin(EASIE):a multicentre, randomised open-label trial[J]. Lancet, 2012, 379(9833):2262-2269.
[32]
VIOLANTE R, OLIVEIRA J H, YOON K H, et al. A randomized non-inferiority study comparing the addition of exenatide twice daily to sitagliptin or switching from sitagliptin to exenatide twice daily in patients with type 2 diabetes experiencing inadequate glycaemic control on metformin and sitagliptin[J]. Diabet Med, 2012, 29(11):417-424.
[33]
WAINSTEIN J, KATZ L, ENGEL S S, et al. Initial therapy with the fixed-dose combination of sitagliptin and metformin results in greater improvement in glycaemic control compared with pioglitazone monotherapy in patients with type 2 diabetes[J]. Diabetes Obes Metab, 2012, 14(5):409-418.
[34]
RUSSELL-JONES D, CUDDIHY R M, HANEFELD M, et al. Efficacy and safety of exenatide once weekly versus metformin, pioglitazone, and sitagliptin used as monotherapy in drug-naive patients with type 2 diabetes(DURATION-4):a 26-week double-blind study[J]. Diabetes Care, 2012, 35(2):252-258.
[35]
BAJAJ M, GILMAN R, PATEL S, et al. Linagliptin improved glycaemic control without weight gain or hypoglycaemia in patients with type 2 diabetes inadequately controlled by a combination of metformin and pioglitazone: a 24-week randomized, double-blind study[J]. Diabet Med, 2014, 31(12):1505-1514.
[36]
AHRÉN B, JOHNSON S L, STEWART M, et al. HARMONY 3: 104-week randomized, double-blind, placebo- and active-controlled trial assessing the efficacy and safety of albiglutide compared with placebo, sitagliptin, and glimepiride in patients with type 2 diabetes taking metformin[J]. Diabetes Care, 2014, 37(8):2141-2148.
[37]
BETHEL M A, ENGEL S S, GREEN J B, et al. Assessing the safety of sitagliptin in older participants in the trial evaluating cardiovascular outcomes with sitagliptin(TECOS)[J]. Diabetes Care, 2017, 40(4):494-501.
[38]
GARBER A J, SCHWEIZER A, BARON M A, et al. Vildagliptin in combination with pioglitazone improves glycaemic control in patients with type 2 diabetes failing thiazolidinedione monotherapy: a randomized, placebo-controlled study[J]. Diabetes Obes Metab, 2007, 9(2):166-174.
[39]
PAN C, YANG W, BARONA J P, et al. Comparison of vildagliptin and acarbose monotherapy in patients with type 2 diabetes: a 24-week, double-blind, randomized trial[J]. Diabet Med, 2008, 25(4):435-441.
[40]
SCHERBAUM W A, SCHWEIZER A, MARI A, et al. Evidence that vildagliptin attenuates deterioration of glycaemic control during 2-year treatment of patients with type 2 diabetes and mild hyperglycaemia[J]. Diabetes Obes Metab, 2008, 10(11):1114-1124.
[41]
FERRANNINI E, FONSECA V, ZINMAN B, et al. Fifty-two-week efficacy and safety of vildagliptin vs. glimepiride in patients with type 2 diabetes mellitus inadequately controlled on metformin monotherapy[J]. Diabetes Obes Metab, 2009, 11(2):157-166.
[42]
ROSENSTOCK J, NIGGLI M, MALDONADO-LUTOMIRSKY M. Long-term 2-year safety and efficacy of vildagliptin compared with rosiglitazone in drug-naïve patients with type 2 diabetes mellitus[J]. Diabetes Obes Metab, 2009, 11(6):571-578.
[43]
WANG T, WANG F, GOU Z, et al. Using real-world data to evaluate the association of incretin-based therapies with risk of acute pancreatitis: a meta-analysis of 1 324 515 patients from observational studies[J]. Diabetes Obes Metab, 2015, 17(1):32-41.
[35]
BAJAJ M, GILMAN R, PATEL S, et al. Linagliptin improved glycaemic control without weight gain or hypoglycaemia in patients with type 2 diabetes inadequately controlled by a combination of metformin and pioglitazone: a 24-week randomized, double-blind study[J]. Diabet Med, 2014, 31(12):1505-1514.
[36]
AHRÉN B, JOHNSON S L, STEWART M, et al. HARMONY 3: 104-week randomized, double-blind, placebo- and active-controlled trial assessing the efficacy and safety of albiglutide compared with placebo, sitagliptin, and glimepiride in patients with type 2 diabetes taking metformin[J]. Diabetes Care, 2014, 37(8):2141-2148.
[37]
BETHEL M A, ENGEL S S, GREEN J B, et al. Assessing the safety of sitagliptin in older participants in the trial evaluating cardiovascular outcomes with sitagliptin(TECOS)[J]. Diabetes Care, 2017, 40(4):494-501.
[38]
GARBER A J, SCHWEIZER A, BARON M A, et al. Vildagliptin in combination with pioglitazone improves glycaemic control in patients with type 2 diabetes failing thiazolidinedione monotherapy: a randomized, placebo-controlled study[J]. Diabetes Obes Metab, 2007, 9(2):166-174.
[39]
PAN C, YANG W, BARONA J P, et al. Comparison of vildagliptin and acarbose monotherapy in patients with type 2 diabetes: a 24-week, double-blind, randomized trial[J]. Diabet Med, 2008, 25(4):435-441.
[40]
SCHERBAUM W A, SCHWEIZER A, MARI A, et al. Evidence that vildagliptin attenuates deterioration of glycaemic control during 2-year treatment of patients with type 2 diabetes and mild hyperglycaemia[J]. Diabetes Obes Metab, 2008, 10(11):1114-1124.
[41]
FERRANNINI E, FONSECA V, ZINMAN B, et al. Fifty-two-week efficacy and safety of vildagliptin vs. glimepiride in patients with type 2 diabetes mellitus inadequately controlled on metformin monotherapy[J]. Diabetes Obes Metab, 2009, 11(2):157-166.
[42]
ROSENSTOCK J, NIGGLI M, MALDONADO-LUTOMIRSKY M. Long-term 2-year safety and efficacy of vildagliptin compared with rosiglitazone in drug-naïve patients with type 2 diabetes mellitus[J]. Diabetes Obes Metab, 2009, 11(6):571-578.
[43]
WANG T, WANG F, GOU Z, et al. Using real-world data to evaluate the association of incretin-based therapies with risk of acute pancreatitis: a meta-analysis of 1 324 515 patients from observational studies[J]. Diabetes Obes Metab, 2015, 17(1):32-41.
2018, Vol. 53 
