Adverse effects of incretin-based therapies on major cardiovascular and arrhythmia events: meta-analysis of randomized trials

Diabetes/Metabolism Research and Reviews

Volumn 32, Issue 8, 2016, Pages 843-857

  Wang, Tiansheng ^a   Wang, Fei ^b   Zhou, Junwen ^a   Tang, Huilin ^c   Giovenale, Sharon ^b  

^a PEKING UNIVERSITY HEALTH SCIENCE CENTER   (China)

^b UNIVERSITY OF CONNECTICUT   (United States)

^c INDIANA UNIVERSITY   (United States)

Author keywords

cardiovascular risk; dipeptidylpeptidase 4 inhibitors; glucagon like peptide 1 receptor agonists; incretin drugs; meta analysis; randomized controlled trials

Indexed keywords

DIPEPTIDYL PEPTIDASE IV INHIBITOR; GLUCAGON LIKE PEPTIDE 1 RECEPTOR AGONIST; INCRETIN;

ARTICLE; CARDIOVASCULAR DISEASE; CARDIOVASCULAR RISK; DRUG SAFETY; HEART ARRHYTHMIA; HEART FAILURE; HUMAN; META ANALYSIS; MORTALITY; NON INSULIN DEPENDENT DIABETES MELLITUS; PRIORITY JOURNAL; RANDOMIZED CONTROLLED TRIAL (TOPIC); RISK REDUCTION; SYSTEMATIC REVIEW; CASE CONTROL STUDY; CHEMICALLY INDUCED; DIABETES MELLITUS, TYPE 2; PROGNOSIS;

ARRHYTHMIAS, CARDIAC; CARDIOVASCULAR DISEASES; CASE-CONTROL STUDIES; DIABETES MELLITUS, TYPE 2; HUMANS; INCRETINS; PROGNOSIS; RANDOMIZED CONTROLLED TRIALS AS TOPIC;

EID: 84965107617     PISSN: 15207552     EISSN: 15207560     Source Type: Journal    
DOI: 10.1002/dmrr.2804     Document Type: Article

References (146)

1. Baggio LL, Drucker DJ. Biology of incretins: GLP-1 and GIP. Gastroenterology 2007; 132(6): 2131–2157.
2. Drucker DJ, Nauck MA. The incretin system: glucagon-like peptide-1 receptor agonists and dipeptidyl peptidase-4 inhibitors in type 2 diabetes. Lancet 2006; 368: 1696–1705.
3. Inzucchi SE, Bergenstal RM, Buse JB, et al. Management of hyperglycaemia in type 2 diabetes, 2015: a patient-centred approach. Update to a Position Statement of the American Diabetes Association and the European Association for the Study of Diabetes. Diabetologia 2015; 58: 429–442. doi:10.1007/s00125-014-3460-0.
4. Garber AJ, Abrahamson AJ, Barzilay JI, et al. American Association of Clinical Endocrinologists' Comprehensive Diabetes Management Algorithm 2013 Consensus Statement. Endocr Pract 2013; 19(Suppl 1): 1–48.
5. Rydén L, Grant PJ, Anker SD, et al. ESC guidelines on diabetes, pre-diabetes, and cardiovascular diseases developed in collaboration with the EASD: the Task Force on diabetes, pre-diabetes, and cardiovascular diseases of the European Society of Cardiology (ESC) and developed in collaboration with the European Association for the Study of Diabetes (EASD). Eur Heart J 2013; 34: 3035–3087.
6. Wannamethee SG, Shaper AG, Whincup PH, Lennon L, Sattar N. Impact of diabetes on cardiovascular disease risk and all-cause mortality in older men. Influence of age at onset, diabetes duration, and established and novel risk factors. Arch Intern Med 2013; 171: 404–410.
7. Sarwar N, Gao P, Seshasai SR, et al. Diabetes mellitus, fasting blood glucose concentration, and risk of vascular disease: a collaborative meta-analysis of 102 prospective studies. Lancet 2010; 375: 2215–2222.
8. Preis SR, Hwang S, Coady S, et al. Trends in all-cause and cardiovascular disease mortality among women and men with and without diabetes mellitus in the Framingham Heart Study, 1950 to 2005. Circulation 2009; 119: 1728–1735.
9. Taylor KS, Heneghan CJ, Farmer AJ, et al. All-cause and cardiovascular mortality in middle-aged people with type 2 diabetes compared with people without diabetes in a large U.K. primary care database. Diabetes Care 2013; 36: 2366–2371.
10. Haffner SM, Lehto S, Rönnemaa T, Pyörälä K, Laakso M. Mortality from coronary heart disease in subjects with type 2 diabetes and in nondiabetic subjects with and without prior myocardial infarction. N Engl J Med 1998; 339: 229–234.
11. Monami M, Genovese S, Mannucci E. Cardiovascular safety of sulfonylureas: a meta-analysis of randomized clinical trials. Diabetes Obes Metab 2013; 15: 938–953.
12. Morgan CL, Mukherjee J, Jenkins-Jones S, Holden SE, Currie CJ. Combination therapy with metformin plus sulfonylureas versus metformin plus DPP-4 inhibitors: association with major adverse cardiovascular events and all-cause mortality. Diabetes Obes Metab 2014; 16: 977–983. doi:10.1111/dom.12.
13. Nissen SE, Wolski K. Effect of rosiglitazone on the risk of myocardial infarction and death from cardiovascular causes. N Engl J Med 2007; 356: 2457–2471.
14. US Food and Drug Administration. Guidance for industry: diabetes mellitus – evaluating cardiovascular risk in new antidiabetic therapies to treat type 2 diabetes (2008) Available from: http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/ucm071627.pdf. Accessed February 17, 2015.
15. Holman RR, Sourij H, Califf RM. Cardiovascular outcome trials of glucose-lowering drugs or strategies in type 2 diabetes. Lancet 2014; 383: 2008–2017.
16. Kerr Saraiva F, Sposito AC. Cardiovascular effects of Glucagon-like peptide 1 (GLP-1) receptor agonists. Cardiovasc Diabetol 2014; 13: 142. doi:10.1186/s12933-014-0142-7.
17. Green JB. The dipeptidyl peptidase-4 inhibitors in type 2 diabetes mellitus: cardiovascular safety. Postgrad Med 2012; 124: 54–61.
18. Usser JR, Drucker DJ. Cardiovascular actions of incretin-based therapies. Circ Res 2014; 114: 1788–1803.
19. White WB, Cannon CP, Heller SR, et al. EXAMINE Investigators. Alogliptin after acute coronary syndrome in patients with type 2 diabetes. N Engl J Med 2013; 369: 1327–1335. doi:10.1056/NEJMoa1305889.
20. Scirica BM, Bhatt DI, Braunwald E, et al. SAVOR-TIMI 53 Steering Committee and Investigators. Saxagliptin and cardiovascular outcomes in patients with type 2 diabetes mellitus. N Engl J Med 2013; 369: 1317–1326. doi:10.1056/NEJMoa1307684.
21. Zannad F, Cannon CP, Cushman WC, et al. Heart failure and mortality outcomes in patients with type 2 diabetes taking alogliptin versus placebo in EXAMINE: a multicentre, randomised, double-blind trial. Lancet 2015; (published online March 10). doi:10.1016/S0140-6736(14)62225-X. Accessed March 20, 2015.
22. Green JB, Bethel MA, Amstrong PW, et al. Effect of sitagliptin on cardiovascular outcome in type 2 diabetes. N Engl J Med 2015; 356: 2457–2471. doi:10.1056/NEJMoa1501352. Accessed June 8, 2015.
23. Monami M, Cremasco F, Lamanna C, et al. Glucagon-like peptide-1 receptor agonists and cardiovascular events: a meta-analysis of randomized clinical trials. Exp Diabetes Res 2011; (published online Apr 26).Available from: http://www.hindawi.com/journals/jdr/2011/215764/ doi:10.1155/2011/215764, accessed December 6, 2014
24. Monami M, Dicembrini I, Nardini C, et al. Effects of glucagon-like peptide-1 receptor agonists on cardiovascular risk: a meta-analysis of randomized clinical trials. Diabetes Obes Metab 2014; 16: 38–47.
25. White W, Pratley R, Fleck P, et al. Cardiovascular safety of the dipeptidyl peptidase-4 inhibitor alogliptin in type 2 diabetes mellitus. Diabetes Obes Metab 2013; 15: 668–673.
26. Monami M, Ahren B, Dicembrini I, Mannucci E. Dipeptidyl peptidase-4 inhibitors and cardiovascular risk: a meta-analysis of randomized clinical trials. Diabetes Obes Metab 2013; 15: 112–120.
27. Agarwal S, Parashar A, Menon V. Meta-analysis of the cardiovascular outcomes with dipeptidyl peptidase-4 inhibitors: validation of the current FDA mandate. Am J Cardiovasc Drugs 2014; 14: 191–207. doi:10.1007/s40256-014-0070-7.
28. Wu S, Hopper I, Skiba M, Krum H. Dipeptidyl peptidase-4 inhibitors and cardiovascular outcomes: meta-analysis of randomized clinical trials with 55,141 participants. Cardiovasc Ther 2014; 32: 142–158.
29. Savarese G, Perrone-Filardi P, D'Amore C, et al. Cardiovascular effects of dipeptidyl peptidase-4 inhibitors in diabetic patients: a meta-analysis. Int J Cardiol 2015; 181: 239–244.
30. Nuesch E, Trelle S, Reichenbach S, et al. Small study effects in meta-analyses of osteoarthritis trials: meta-epidemiological study. BMJ 2010; 341: c3515. doi:10.1136/bmj.c3515.
31. Rosenstock J, Balas B, Charbonnel B, et al. The fate of taspoglutide, a weekly GLP-1 receptor agonist, versus twice-daily exenatide for type 2 diabetes. Diabetes Care 2013; 36: 498–504. doi:10.2337/dc12-0709/-/DC1.
32. Zhang J, Ding E, Song Y. Adverse effects of cyclooxygenase 2 inhibitors on renal and arrhythmia events. JAMA 2006; 296: 1619–1632.
33. Higgins JPT, Altman DG, Sterne JAC. Chapter 8: Assessing risk of bias in included studies. In Higgins JPT, Green S. Cochrane Handbook for Systematic Reviews of Interventions Version 5.1.0 [updated March 2011]. The Cochrane Collaboration, 2011. Available from www.cochrane-handbook.org. Accessed July 12, 2015.
34. ClinicalTrials.gov. An investigational drug study in patients with type 2 diabetes mellitus (MK0431-023). October 2004. https://www.clinicaltrials.gov/show/NCT00094757. (Accessed December 6, 2014).
35. Laakso M, Rosenstock J, Groop P-H, et al. Treatment with the dipeptidyl peptidase-4 inhibitor linagliptin or placebo followed by glimepiride in patients with Type 2 Diabetes with moderate to severe renal impairment: a 52-week, randomized, double-blind clinical trial. Diabetes Care 2015; 38(2): e15–e17. doi:10.2337/dc14-1684.
36. Lavalle-González 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. Diabetologia 2013; 56: 2582–2592. doi:10.1007/s00125-013-3039-1.
37. Araki E, Kawamori R, Inagaki N, et al. Long-term safety of linagliptin monotherapy in Japanese patients with type 2 diabetes. Diabetes Obes Metab 2013; 15: 364–371. doi:10.1111/dom.12039.
38. Sweeting MJ, Sutton AJ, Lambert PC. What to add to nothing? Use and avoidance of continuity corrections in meta-analysis of sparse data. Stat Med 2004; 23: 1351–1375.
39. Bradburn MJ, Deeks JJ, Berlin JA, Russell LA. Much ado about nothing: a comparison of the performance of meta-analytical methods with rare events. Stat Med 2007; 26: 53–77.
40. Higgins JPT, Deeks JJ, Altman DG. Chapter 16: Special topics in statistics. In Higgins JPT, Green S. Cochrane Handbook for Systematic Reviews of Interventions Version 5.1.0 (updated March 2011). The Cochrane Collaboration, 2011. Available from www.cochrane-handbook.org. Accessed July 12, 2015.
41. Deeks JJ, Higgins JPT, Altman DG. Chapter 9: Analysing data and undertaking meta-analyses. In Higgins JPT, Green S. Cochrane Handbook for Systematic Reviews of Interventions Version 5.1.0 (updated March 2011). The Cochrane Collaboration, 2011. Available from www.cochrane-handbook.org. Accessed July 12, 2015
42. Moher D, Liberati A, Tetzlaff J, Altman DG. The PRISMA group preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement. PLoS Med 2009; 6(7e1000097). doi:10.1371/journal.pmed.1000097.
43. DeFronzo RA, Hissa MN, Garber AJ, et al. The efficacy and safety of saxagliptin when added to metformin therapy in patients with inadequately controlled type 2 diabetes with metformin alone. Diabetes Care 2009; 32: 1649–1655.
44. Pfützner A, Paz-Pacheco E, Allen E, Frederich R, Chen R. Initial combination therapy with saxagliptin and metformin provides sustained glycaemic control and is well tolerated for up to 76 weeks. Diabetes Obes Metab 2011; 13: 567–576. doi:10.1111/j.1463-1326.2011.01385.x.
45. Strain WD, Lukashevich V, Kothny W, Hoellinger MJ, Paldánius PM. Individualized treatment targets for elderly patients with type 2 diabetes using vildagliptin add-on or lone therapy (INTERVAL): a 24 week, randomised, double-blind, placebo-controlled study. Lancet 2013; 382: 409–416. doi:10.1016/S0140-6736(13)60995-2.
46. Frederich R, McNeill R, Berglind N, Fleming D, Chen R. The efficacy and safety of the dipeptidyl peptidase-4 inhibitor saxagliptin in treatment-naïve patients with type 2 diabetes mellitus: a randomized controlled trial. Diabetol Metab Syndr 2012; 4(1): 36. doi:10.1186/1758-5996-4-36.
47. Borenstein M, Hedges LV, Higgins JPT, Rothstein HR. Chapter 42. Cumulative meta-analysis. In Introduction to Meta-Analysis. John Wiley & Sons, Ltd: Chichester, UK, 2009; 371–376. doi:10.1002/9780470743386.refs.
48. Nainggolan L. No CV benefit with lixisentide in ELIXA but results reassure. Medscape. Published and accessed June 8, 2015. http://www.medscape.com/viewarticle/846074
49. Davies MJ, Donnelly R, Barnett AH, Jones S, Nicolay C, Kilcoyne A. Exenatide compared with long-acting insulin to achieve glycaemic control with minimal weight gain in patients with type 2 diabetes: results of the Helping Evaluate Exenatide in patients with diabetes compared with Long-Acting insulin (HEELA) study. Diabetes Obes Metab 2009; 11: 1153–1162. doi:10.1111/j.1463-1326.2009.01154.x.
50. Bergenstal R, Lewin A, Bailey T, Chang D, Gylvin T, Roberts V. NovoLog Mix-vs.-Exenatide Study Group. Efficacy and safety of biphasic insulin aspart 70/30 versus exenatide in subjects with type 2 diabetes failing to achieve glycemic control with metformin and a sulfonylurea. Curr Med Res Opin 2009; 25: 65–75.
51. Buse JB, Henry RR, Han J, et al. Effects of exenatide (exendin-4) on glycemic control over 30 weeks in sulfonylurea-treated patients with type 2 diabetes. Diabetes Care 2004; 27: 2628–2635.
52. Buse JB, Bergenstal RM, Glass LC, Heilmann CR, Lewis MS, Kwan AY. Use of twice-daily exenatide in basal insulin-treated patients with type 2 diabetes: a randomized, controlled trial. Ann Intern Med 2011; 154: 103–112. doi:10.7326/0003-4819-154-2-201101180-00300.
53. Diamant M, Nauck MA, Shaginian R, et al. Glucagon-like peptide 1 receptor agonist or bolus insulin with optimized basal insulin in type 2 diabetes. Diabetes Care 2014; 37: 2763–2773. doi:10.2337/dc14-0876.
54. Diamant M, Van Gaal L, Guerci B, et al. Exenatide once weekly versus insulin glargine for type 2 diabetes (DURATION-3): 3-year results of an open-label randomized trial. Lancet Diabetes Endocrinol 2014; 2: 464–473.
55. Gallwitz B, Böhmer M, Segiet T, et al. Exenatide twice daily versus premixed insulin aspart 70/30 in metformin-treated patients with type 2 diabetes: a randomized 26-week study on glycemic control and hypoglycemia. Diabetes Care 2011; 34: 604–606. doi:10.2337/dc10-1900.
56. Gallwitz B, Guzman J, Dotta F, et al. Exenatide twice daily versus glimepiride for prevention of glycaemic deterioration in patients with type 2 diabetes with metformin failure (EUREXA): an open-label, randomised controlled trial. Lancet 2012; 379: 2270–2278. doi:10.1016/S0140-6736(12)60479-6.
57. Heine RJ, Van Gaal LF, Johns D, et al. Exenatide versus insulin glargine in patients with suboptimally controlled type 2 diabetes: a randomized trial. Ann Intern Med 2005; 143: 559–569.
58. Nauck MA, Duran S, Kim D, et al. A comparison of twice-daily exenatide and biphasic insulin aspart in patients with type 2 diabetes who were suboptimally controlled with sulfonylurea and metformin: a non-inferiority study. Diabetologia 2007; 50: 259–267.
59. Inagaki N, Atsumi Y, Oura T, Saito H, Imaoka T. Efficacy and safety profile of exenatide once weekly compared with insulin once daily in Japanese patients with type 2 diabetes treated with oral antidiabetes drug(s): results from a 26-week, randomized, open-label, parallel-group, multicenter, noninferiority study. Clin Ther 2012; 34: 1892–1908. doi:10.1016/j.clinthera.2012.07.007.
60. D'Alessio D, Haring HU, Charbonnel B, et al. Comparison of insulin glargine and liraglutide added to oral agents in patients with poorly controlled type 2 diabetes. Diabetes Obes Metab 2014; 17: 170–178. doi:10.1111/dom.12406.
61. Garber A, Henry RR, Ratner R, Hale P, Chang CT, Bode B. Liraglutide, a once-daily human glucagon-like peptide 1 analogue, provides sustained improvements in glycaemic control and weight for 2 years as monotherapy compared with glimepiride in patients with type 2 diabetes. Diabetes Obes Metab 2011; 13: 348–356. doi:10.1111/j.1463-1326.2010.01356.x.
62. Nauck M, Frid A, Hermansen K, et al. Efficacy and safety comparison of liraglutide, glimepiride, and placebo, all in combination with metformin, in type 2 diabetes: the LEAD (liraglutide effect and action in diabetes)-2 study. Diabetes Care 2009; 32: 84–90. doi:10.2337/dc08-1355.
63. Seino Y, Rasmussen MF, Nishida T, Kaku K. Efficacy and safety of the once-daily human GLP-1 analogue, liraglutide, vs glibenclamide monotherapy in Japanese patients with type 2 diabetes. Curr Med Res Opin 2010; 26: 1013–1022. doi:10.1185/03007991003672551.
64. ClinicalTrials.gov. Efficacy and safety of liraglutide in combination with insulin therapy compared to insulin alone in Japanese subjects with type 2 diabetes. April 2012. https://www.clinicaltrials.gov/show/NCT01572740. (accessed December 4, 2014).
65. ClinicalTrials.gov. The effect of liraglutide versus placebo when added to basal insulin analogues with or without metformin in subjects with type 2 diabetes. June 2012. https://www.clinicaltrials.gov/show/NCT01617434. (accessed December 4, 2014).
66. ClinicalTrials.gov. Efficacy and safety of liraglutide versus placebo as add-on to existing diabetes medication in subjects with type 2 diabetes and moderate renal impairment. June 2012. https://www.clinicaltrials.gov/show/NCT01620489. (accessed December 4, 2014).
67. Pan CY, Han P, Liu X, et al. Lixisenatide treatment improves glycaemic control in Asian patients with type 2 diabetes mellitus inadequately controlled on metformin with or without sulfonylurea: a randomized, double-blind, placebo-controlled, 24-week trial (GetGoal-M-Asia). Diabetes Metab Res Rev 2014; 30: 726–735. doi:10.1002/dmrr.2541.
68. Pinget M, Goldenberg R, Niemoeller E, Muehlen-Bartmer I, Guo H, Aronson R. Efficacy and safety of lixisenatide once daily versus placebo in type 2 diabetes insufficiently controlled on pioglitazone (GetGoal-P). Diabetes Obes Metab 2013; 15: 1000–1007. doi:10.1111/dom.12121.
69. Riddle MC, Aronson R, Home P, et al. Adding once-daily lixisenatide for type 2 diabetes inadequately controlled by established basal insulin: a 24-week, randomized, placebo-controlled comparison (GetGoal-L). Diabetes Care 2013; 36: 2489–2496. doi:10.2337/dc12-2454.
70. Rosenstock J, Hanefeld M, Shamanna P, et al. Beneficial effects of once-daily lixisenatide on overall and postprandial glycemic levels without significant excess of hypoglycemia in type 2 diabetes inadequately controlled on a sulfonylurea with or without metformin (GetGoal-S). J Diabetes Complications 2014; 28: 386–392. doi:10.1016/j.jdiacomp.2014.01.012.
71. Seino Y, Min KW, Niemoeller E, Takami A. GETGOAL-L Asia Study Investigators. Randomized, double-blind, placebo-controlled trial of the once-daily GLP-1 receptor agonist lixisenatide in Asian patients with type 2 diabetes insufficiently controlled on basal insulin with or without a sulfonylurea (GetGoal-L-Asia). Diabetes Obes Metab 2012; 14: 910–917. doi:10.1111/j.1463-1326.2012.01618.x.
72. Home P, Shamanna P, Stewart M, et al. Efficacy and tolerability of albiglutide versus placebo and versus pioglitazone over 1 year in people with type 2 diabetes currently taking metformin and glimepiride: HARMONY 5. Diabetes Obes Metab 2014; 17: 179–187. doi:10.1111/dom.12414.
73. ClinicalTrials.gov. Safety and efficacy study of albiglutide in type 2 diabetes. February 2009. https://www.clinicaltrials.gov/show/NCT00849017. (accessed November 13, 2014).
74. Reusch J, Stewart MW, Perkins CM, et al. Efficacy and safety of once-weekly glucagon-like peptide 1 receptor agonist albiglutide (HARMONY 1 trial): 52-week primary endpoint results from a randomized, double-blind, placebo-controlled trial in patients with type 2 diabetes mellitus not controlled on pioglitazone, with or without metformin. Diabetes Obes Metab 2014; 16: 1257–1264.
75. Rosenstock J, Fonseca VA, Gross JL, et al. Advancing basal insulin replacement in type 2 diabetes inadequately controlled with insulin glargine plus oral agents: a comparison of adding albiglutide, a weekly GLP-1 receptor agonist, versus thrice-daily prandial insulin lispro. Diabetes Care 2014; 37: 2317–2325. doi:10.2337/dc14-0001.
76. Weissman PN, Carr MC, Ye J, et al. HARMONY 4: randomized clinical trial comparing once-weekly albiglutide and insulin glargine in patients with type 2 diabetes inadequately controlled with metformin with or without sulfonylurea. Diabetologia 2014; 57: 2475–2484. doi:10.1007/s00125-014-3360-3.
77. Umpierrez G, Tofé Povedano S, Pérez Manghi F, Shurzinske L, Pechtner V. Efficacy and safety of dulaglutide monotherapy versus metformin in type 2 diabetes in a randomized controlled trial (AWARD-3). Diabetes Care 2014; 37: 2168–2176. doi:10.2337/dc13-2759.
78. Blonde L, Jendle J, Gross J, et al. Once-weekly dulaglutide versus bedtime insulin glargine, both in combination with prandial insulin lispro, in patients with type 2 diabetes (AWARD-4): a randomised, open-label, phase 3, non-inferiority study. Lancet 2015; 385(9982): 2057–2066. doi:10.1016/S0140-6736(15)60936-9.
79. ClinicalTrials.gov. A study of dulaglutide in Japanese participants with type 2 diabetes mellitus. April 2012. https://www.clinicaltrials.gov/show/NCT01584232. (accessed November 13, 2014).
80. 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. Diabetes Obes Metab 2011; 13: 160–168. doi:10.1111/j.1463-1326.2010.01334.x.
81. Aschner P, Katzeff HL, Guo H, et al. Efficacy and safety of monotherapy of sitagliptin compared with metformin in patients with type 2 diabetes. Diabetes Obes Metab 2010; 12: 252–261. doi:10.1111/j.1463-1326.2009.01187.x.
82. Aschner P, Chan J, Owens DR, 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. Lancet 2012; 379: 2262–2269. doi:10.1016/S0140-6736(12)60439-5.
83. Arjona Ferreira JC, Marre M, Barzilai N, et al. Efficacy and safety of sitagliptin versus glipizide in patients with type 2 diabetes and moderate-to-severe chronic renal insufficiency. Diabetes Care 2013; 36: 1067–1073. doi:10.2337/dc12-1365.
84. Fonseca V, Staels B, Morgan JD 2nd, et al. Efficacy and safety of sitagliptin added to ongoing metformin and pioglitazone combination therapy in a randomized, placebo-controlled, 26-week trial in patients with type 2 diabetes. J Diabetes Complications 2013; 27: 177–183. doi:10.1016/j.jdiacomp.2012.09.007.
85. Henry RR, Staels B, Fonseca VA, et al. Efficacy and safety of initial combination treatment with sitagliptin and pioglitazone—a factorial study. Diabetes Obes Metab 2014; 16: 223–230. doi:10.1111/dom.12194.
86. ClinicalTrials.gov. A study to evaluate the safety and efficacy of sitagliptin 100 mg in participants with type 2 diabetes mellitus who have inadequate glycemic control (MK-0431-229). February 2010. https://clinicaltrials.gov/ct2/show/NCT01076075 (accessed November 25, 2014).
87. ClinicalTrials.gov. Safety and efficacy of co-administration of sitagliptin and metformin in China (MK-0431-121). February 2010. https://www.clinicaltrials.gov/show/NCT01076088 (accessed November 25, 2014)
88. ClinicalTrials.gov. Clinical trial to evaluate the safety and efficacy of the addition of sitagliptin in participants with type 2 diabetes mellitus receiving acarbose monotherapy (MK-0431-130). June 2010. https://www.clinicaltrials.gov/show/NCT01177384 (accessed November 25, 2014).
89. ClinicalTrials.gov. Safety and efficacy of sitagliptin compared with glimepiride in elderly participants with type 2 diabetes mellitus (MK-0431-251). August 2010. https://www.clinicaltrials.gov/show/NCT01189890 (accessed November 25, 2014).
90. ClinicalTrials.gov. Study of sitagliptin for the treatment of type 2 diabetes mellitus with inadequate glycemic control on insulin (MK-0431-260). October 2011. https://www.clinicaltrials.gov/show/NCT01462266 (accessed November 25, 2014).
91. Philis-Tsimikas A, Del Prato S, Satman I, et al. Effect of insulin degludec versus sitagliptin in patients with type 2 diabetes uncontrolled on oral antidiabetic agents. Diabetes Obes Metab 2013; 15: 760–766. doi:10.1111/dom.12115.
92. Reasner C, Olansky L, Seck TL, et al. The effect of initial therapy with the fixed-dose combination of sitagliptin and metformin compared with metformin monotherapy in patients with type 2 diabetes mellitus. Diabetes Obes Metab 2011; 13: 644–652. doi:10.1111/j.1463-1326.2011.01390.x.
93. 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, placebo-controlled, phase 3 trial. Lancet Diabetes Endocrinol 2013; 1: 208–219. doi:10.1016/S2213-8587(13)70084-6.
94. Schernthaner G, Gross JL, Rosenstock J, et al. Canagliflozin compared with sitagliptin for patients with type 2 diabetes who do not have adequate glycemic control with metformin plus sulfonylurea: a 52-week randomized trial. Diabetes Care 2013; 36: 2508–2515. doi:10.2337/dc12-2491.
95. 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. Int J Clin Pract 2010; 64: 562–576. doi:10.1111/j.1742-1241.2010.02353.x.
96. Vilsbøll T, Rosenstock J, Yki-Järvinen H, et al. Efficacy and safety of sitagliptin when added to insulin therapy in patients with type 2 diabetes. Diabetes Obes Metab 2010; 12: 167–177. doi:10.1111/j.1463-1326.2009.01173.x.
97. 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. Diabetes Obes Metab 2010; 12: 442–451.
98. Yang W, Guan Y, Shentu Y, et al. The addition of sitagliptin to ongoing metformin therapy significantly improves glycemic control in Chinese patients with type 2 diabetes. J Diabetes 2012; 4: 227–237. doi:10.1111/j.1753-0407.2012.00213.x.
99. Yoon KH, Shockey GR, Teng R, et al. Effect of initial combination therapy with sitagliptin, a dipeptidyl peptidase-4 inhibitor, and pioglitazone on glycemic control and measures of β-cell function in patients with type 2 diabetes. Int J Clin Pract 2011; 65: 154–164. doi:10.1111/j.1742-1241.2010.02589.x.
100. Yoon KH, Steinberg H, Teng R, et al. Efficacy and safety of initial combination therapy with sitagliptin and pioglitazone in patients with type 2 diabetes: a 54-week study. Diabetes Obes Metab 2012; 14: 745–752. doi:10.1111/j.1463-1326.2012.01594.x.
101. DeFronzo RA, Burant CF, Fleck P, Wilson C, Mekki Q, Pratley RE. Efficacy and tolerability of the DPP-4 inhibitor alogliptin combined with pioglitazone, in metformin-treated patients with type 2 diabetes. J Clin Endocrinol Metab 2012; 97(5): 1615–1622. doi:10.1210/jc.2011-2243.
102. Del Prato S, Camisasca R, Wilson C, Fleck P. Durability of the efficacy and safety of alogliptin compared with glipizide in type 2 diabetes mellitus: a 2-year study. Diabetes Obes Metab 2014; 16: 1239–1246. doi:10.1111/dom.12377.
103. Nauck MA, Ellis GC, Fleck PR, Wilson CA, Mekki Q. Alogliptin Study 008 Group. Efficacy and safety of adding the dipeptidyl peptidase-4 inhibitor alogliptin to metformin therapy in patients with type 2 diabetes inadequately controlled with metformin monotherapy: a multicentre, randomised, double-blind, placebo-controlled study. Int J Clin Pract 2009; 63: 46–55. doi:10.1111/j.1742-1241.2008.01933.x.
104. Pratley RE, Fleck P, Wilson C. Efficacy and safety of initial combination therapy with alogliptin plus metformin versus either as monotherapy in drug-naïve patients with type 2 diabetes: a randomized, double-blind, 6-month study. Diabetes Obes Metab 2014; 16: 613–621. doi:10.1111/dom.12258.
105. Rosenstock J, Rendell MS, Gross JL, Fleck PR, Wilson CA, Mekki Q. Alogliptin added to insulin therapy in patients with type 2 diabetes reduces HbA(1C) without causing weight gain or increased hypoglycaemia. Diabetes Obes Metab 2009; 11: 1145–1152. doi:10.1111/j.1463-1326.2009.01124.x.
106. Rosenstock J, Inzucchi SE, Seufert J, Fleck PR, Wilson CA, Mekki Q. Initial combination therapy with alogliptin and pioglitazone in drug-naïve patients with type 2 diabetes. Diabetes Care 2010; 33: 2406–2408. doi:10.2337/dc10-0159.
107. Rosenstock J, Wilson C, Fleck P. Alogliptin versus glipizide monotherapy in elderly type 2 diabetes mellitus patients with mild hyperglycaemia: a prospective, double-blind, randomized, 1-year study. Diabetes Obes Metab 2013; 15: 906–914. doi:10.1111/dom.12102.
108. Del Prato S, Barnett AH, Huisman H, Neubacher D, Woerle HJ, Dugi KA. Effect of linagliptin monotherapy on glycaemic control and markers of β-cell function in patients with inadequately controlled type 2 diabetes: a randomized controlled trial. Diabetes Obes Metab 2011; 13: 258–267. doi:10.1111/j.1463-1326.2010.01350.x.
109. 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. Lancet 2012; 380: 475–483. doi:10.1016/S0140-6736(12)60691-6.
110. Haak T, Meinicke T, Jones R, et al. Initial combination of linagliptin and metformin improves glycaemic control in type 2 diabetes: a randomized, double-blind, placebo-controlled study. Diabetes Obes Metab 2012; 14: 565–574.
111. Inagaki N, Watada H, Murai M, et al. Linagliptin provides effective, well-tolerated add-on therapy to pre-existing oral antidiabetic therapy over 1 year in Japanese patients with type 2 diabetes. Diabetes Obes Metab 2013; 15: 833–843. doi:10.1111/dom.12110.
112. ClinicalTrials.gov. Treatment of type 2 diabetes with linagliptin 2.5 mg bid + metformin 500 or 1000 mg bid and metformin 1000 mg bid. June 2009. https://www.clinicaltrials.gov/show/NCT00915772 (accessed November 22, 2014).
113. ClinicalTrials.gov. 30 week parallel group comparison study of linagliptin + pioglitazone (5 + 15, 5 + 30 and 5 + 45 mg) qd versus respective monotherapies, followed by a comparison of 5 mg + 30 mg and 5 mg + 45 mg versus respective monotherapies in type 2 diabetes for up to 54 weeks. August 2010. https://www.clinicaltrials.gov/show/NCT01183013 (accessed November 22, 2014).
114. ClinicalTrials.gov. Efficacy and safety study of linagliptin (5 mg administered orally once daily) over 24 weeks in type 2 diabetic patients with insufficient glycaemic control despite metformin therapy. September 2010. https://www.clinicaltrials.gov/show/NCT01215097 (accessed November 22, 2014).
115. Owens DR, Swallow R, Dugi KA, Woerle HJ. Efficacy and safety of linagliptin in persons with type 2 diabetes inadequately controlled by a combination of metformin and sulphonylurea: a 24-week randomized study. Diabet Med 2011; 28: 1352–1361. doi:10.1111/j.1464-5491.2011.03387.x.
116. Taskinen MR, Rosenstock J, Tamminen I, et al. Safety and efficacy of linagliptin as add-on therapy to metformin in patients with type 2 diabetes: a randomized, double-blind, placebo-controlled study. Diabetes Obes Metab 2011; 13: 65–74. doi:10.1111/j.1463-1326.2010.01326.x.
117. Thrasher J, Daniels K, Patel S, Whetteckey J. Black/African American patients with type 2 diabetes mellitus: study design and baseline patient characteristics from a randomized clinical trial of linagliptin. Expert Opin Pharmacother 2012; 13: 2443–2452. doi:10.1517/14656566.2012.740459.
118. 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. Diabetes Care 2013; 36: 3875–3881. doi:10.2337/dc12-2718.
119. Barnett AH, Charbonnel B, Li J, Donovan M, Fleming D, Iqbal N. Saxagliptin add-on therapy to insulin with or without metformin for type 2 diabetes mellitus: 52-week safety and efficacy. Clin Drug Investig 2013; 33: 707–717. doi:10.1007/s40261-013-0107-8.
120. Chacra AR, Tan GH, Ravichandran S, List J, Chen R. CV181040 Investigators. Safety and efficacy of saxagliptin in combination with submaximal sulphonylurea versus up-titrated sulphonylurea over 76 weeks. Diab Vasc Dis Res 2011; 8: 150–159. doi:10.1177/1479164111404574.
121. Göke B, Gallwitz B, Eriksson JG, Hellqvist Å, Gause-Nilsson I. 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. Int J Clin Pract 2013; 67: 307–316.
122. Hollander PL, Li J, Frederich R, Allen E, Chen R. CV181013 Investigators. Safety and efficacy of saxagliptin added to thiazolidinedione over 76 weeks in patients with type 2 diabetes mellitus. Diab Vasc Dis Res 2011; 8: 125–135. doi:10.1177/1479164111404575.
123. Schernthaner G, Durán-Garcia S, Hanefeld M, et al. Efficacy and tolerability of saxagliptin compared with glimepiride in elderly patients with type 2 diabetes: a randomized, controlled study (GENERATION). Diabetes Obes Metab 2015; 17(7): 630–648. doi:10.1111/dom.12461.
124. Pan CY, Yang W, Tou C, Gause-Nilsson I, Zhao J. Efficacy and safety of saxagliptin in drug-naïve Asian patients with type 2 diabetes mellitus: a randomized controlled trial. Diabetes Metab Res Rev 2012; 28: 268–275. doi:10.1002/dmrr.1306.
125. Yang W, Pan CY, Tou C, Zhao J, Gause-Nilsson I. Efficacy and safety of saxagliptin added to metformin in Asian people with type 2 diabetes mellitus: a randomized controlled trial. Diabetes Res Clin Pract 2011; 94: 217–224. doi:10.1016/j.diabres.2011.07.035.
126. Bolli G, Dotta F, Colin L, Minic B, Goodman M. Comparison of vildagliptin and pioglitazone in patients with type 2 diabetes inadequately controlled with metformin. Diabetes Obes Metab 2009; 11: 589–595. doi:10.1111/j.1463-1326.2008.01023.x.
127. Bosi E, Camisasca RP, Collober C, Rochotte E, Garber AJ. Effects of vildagliptin on glucose control over 24 weeks in patients with type 2 diabetes inadequately controlled with metformin. Diabetes Care 2007; 30: 890–895.
128. Bosi E, Dotta F, Jia Y, Goodman M. Vildagliptin plus metformin combination therapy provides superior glycaemic control to individual monotherapy in treatment-naive patients with type 2 diabetes mellitus. Diabetes Obes Metab 2009; 11: 506–515. doi:10.1111/j.1463-1326.2009.01040.x.
129. 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. Diabetes Obes Metab 2009; 11: 157–166.
130. Garber AJ, Schweizer A, Baron MA, Rochotte E, Dejager S. Vildagliptin in combination with pioglitazone improves glycaemic control in patients with type 2 diabetes failing thiazolidinedione monotherapy: a randomized, placebo-controlled study. Diabetes Obes Metab 2007; 9: 166–174.
131. 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. Diabetes Obes Metab 2009; 11: 571–578. doi:10.1111/j.1463-1326.2008.01021.x.
132. 1c over 1 year in drug-naïve patients with Type 2 diabetes. Diabet Med 2007; 24: 955–961. doi:10.1111/j.1464-5491.2007.02191.x.
133. Schweizer A, Dejager S, Bosi E. Comparison of vildagliptin and metformin monotherapy in elderly patients with type 2 diabetes: a 24-week, double-blind, randomized trial. Diabetes Obes Metab 2009; 11: 804–812. doi:10.1111/j.1463-1326.2009.01051.x.
134. Ahrén B, Johnson SL, 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. Diabetes Care 2014; 37: 2141–2148. doi:10.2337/dc14-0024.
135. Bergenstal RM, 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. Lancet 2010; 376: 431–439. doi:10.1016/S0140-6736(10)60590-9.
136. Russell-Jones D, Cuddihy RM, 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. Diabetes Care 2012; 35: 252–258. doi:10.2337/dc11-1107.
137. Borenstein M, Hedges LV, Higgins JPT, Rothstein HR. Chapter 37. Further methods for dichotomous data. Introduction to Meta-Analysis. John Wiley & Sons, Ltd: Chichester, UK, 2009; 331–339. doi:10.1002/9780470743386.refs.
138. Stahn A, Pistrosch F, Ganz X, et al. Relationship between hypoglycemic episodes and ventricular arrhythmias in patients with type 2 diabetes and cardiovascular diseases: silent hypoglycemias and silent arrhythmias. Diabetes Care 2014; 37: 516–520. doi:10.2337/dc13-0600.
139. Chow E, Bernjak A, Williams S, et al. Risk of cardiac arrhythmias during hypoglycemia in patients with type 2 diabetes and cardiovascular risk. Diabetes 2014; 63: 1738–1747. doi:10.2337/db13-0468.
140. Lindström T, Jorfeldt L, Tegler L, et al. Hypoglycaemia and cardiac arrhythmias in patients with type 2 diabetes mellitus. Diabetic Med 1992; 9: 536–541. doi:10.1111/j.1464-5491.1992.tb01834.x.
141. Mischke K, Knackstedt C, Marx N, et al. Insights into atrial fibrillation. Minerva Med 2013; 104: 119–130.
142. Robinson LE, Holt TA, Rees K, et al. Effects of exenatide and liraglutide on heart rate, blood pressure and body weight: systematic review and meta-analysis. BMJ Open 2013; 3 e001986. doi:10.1136/bmjopen-2012-001986.
143. Ferdinand KC, While WB, Calhoun DA, et al. Effects of the once-weekly glucagon-like peptide-1 receptor agonist dulaglutide on ambulatory blood pressure and heart rate in patients with type 2 diabetes mellitus. Hypertension 2014; 64: 731–737.
144. Pyke C, Heller RS, Kirk RK, et al. GLP-1-receptor localization in monkey and human tissue: novel distribution revealed with extensively validated monoclonal antibody. Endocrinology 2014; 155(4): 1280–1290. doi:10.1210/en.2013-1934.
145. Christensen M, Knop FK. Once-weekly GLP-1 agonists: how do they differ from exenatide and liraglutide? Curr Diab Rep 2010; 10: 124–132. doi:10.1007/s11892-010-0102-x.
146. Kim SC, Glynn RJ, Liu J, et al. Dipeptidyl peptidase-4 inhibitors do not increase the risk of cardiovascular events in type 2 diabetes: a cohort study. Acta Diabetol 2014; 51(6): 1015–1023. doi:10.1007/s00592-014-0663-2.