Utility of Saxagliptin in the Treatment of Type 2 Diabetes: Review of Efficacy and Safety

Advances in Therapy

Volumn 32, Issue 11, 2015, Pages 1065-1084

  Jain, Rajeev ^a  

^a Advanced Healthcare   (United States)

Author keywords

Antidiabetes drugs; Dipeptidyl peptidase 4 inhibitor; Saxagliptin; Type 2 diabetes mellitus

Indexed keywords

ANTIDIABETIC AGENT; DAPAGLIFLOZIN; DIPEPTIDYL PEPTIDASE IV INHIBITOR; METFORMIN; SAXAGLIPTIN; ADAMANTANE; DIPEPTIDE; GLUCAGON LIKE PEPTIDE 1; GLUCOSE BLOOD LEVEL;

ADD ON THERAPY; ANGIONEUROTIC EDEMA; CARDIOVASCULAR RISK; CEREBROVASCULAR ACCIDENT; CLINICAL TRIAL (TOPIC); CONTROLLED CLINICAL TRIAL (TOPIC); DIABETIC PATIENT; DIARRHEA; DISEASE EXACERBATION; DRUG EFFICACY; DRUG HYPERSENSITIVITY; DRUG SAFETY; DRUG TOLERABILITY; FRACTURE; GLYCEMIC CONTROL; HEADACHE; HEART FAILURE; HEART INFARCTION; HOSPITALIZATION; HUMAN; HYPOGLYCEMIA; INFECTION; KIDNEY DYSFUNCTION; LYMPHOCYTOPENIA; MONOTHERAPY; NEOPLASM; NON INSULIN DEPENDENT DIABETES MELLITUS; OPPORTUNISTIC INFECTION; PANCREATITIS; PHASE 3 CLINICAL TRIAL (TOPIC); REVIEW; RHINOPHARYNGITIS; RISK ASSESSMENT; SIDE EFFECT; SKIN DEFECT; THROMBOCYTOPENIA; TREATMENT OUTCOME; UPPER RESPIRATORY TRACT INFECTION; URINARY TRACT INFECTION; ANALOGS AND DERIVATIVES; CARDIOVASCULAR DISEASES; CHEMICALLY INDUCED; COMBINATION DRUG THERAPY; DIABETES MELLITUS, TYPE 2; GLUCOSE BLOOD LEVEL; METABOLISM;

ADAMANTANE; BLOOD GLUCOSE; CARDIOVASCULAR DISEASES; CLINICAL TRIALS AS TOPIC; DIABETES MELLITUS, TYPE 2; DIPEPTIDES; DIPEPTIDYL-PEPTIDASE IV INHIBITORS; DRUG THERAPY, COMBINATION; GLUCAGON-LIKE PEPTIDE 1; HUMANS; HYPOGLYCEMIA; HYPOGLYCEMIC AGENTS;

EID: 84948575892     PISSN: 0741238X     EISSN: 18658652     Source Type: Journal    
DOI: 10.1007/s12325-015-0262-9     Document Type: Review

References (64)

1. International Diabetes Federation. IDF Diabetes Atlas. Available at: http://www.idf.org/sites/default/files/Atlas-poster-2014_EN.pdf. Accessed 6 Nov 2015.
2. Centers for Disease Control and Prevention. National diabetes statistics report: estimates of diabetes and its burden in the United States, 2014. Available at: http://www.cdc.gov/diabetes/pubs/statsreport14/national-diabetes-report-web.pdf. Accessed 6 Nov 2015.
3. American Diabetes Association. Standards of medical care in diabetes-2015. Diabetes Care. 2015;38:S88–9.
4. McCarthy MI. Genomics, type 2 diabetes, and obesity. N Engl J Med. 2010;363:2339–50.
5. Valdez R, Yoon PW, Liu T, Khoury MJ. Family history and prevalence of diabetes in the US population: the 6-year results from the National Health and Nutrition Examination Survey (1999–2004). Diabetes Care. 2007;30:2517–22.
6. Ali MK, Bullard KM, Saaddine JB, Cowie CC, Imperatore G, Gregg EW. Achievement of goals in US diabetes care, 1999–2010. N Engl J Med. 2013;368:1613–24.
7. Stark Casagrande S, Fradkin JE, Saydah SH, Rust KF, Cowie CC. The prevalence of meeting A1C, blood pressure, and LDL goals among people with diabetes, 1988–2010. Diabetes Care. 2013;36:2271–2279.
8. Fowler M. Microvascular and macrovascular complications of diabetes. Clin Diabetes. 2008;26:77–82.
9. Centers for Disease Control and Prevention. National diabetes fact sheet, 2011: national estimates and general information on diabetes and prediabetes in the United States. US Department of Health and Human Services, Centers for Disease Control and Prevention. Available at: http://www.cdc.gov/diabetes/pubs/pdf/ndfs_2011.pdf. Accessed 6 Nov 2015.
10. Kahn SE, Cooper ME, Del Prato S. Pathophysiology and treatment of type 2 diabetes: perspectives on the past, present, and future. Lancet. 2014;383:1068–83.
11. DeFronzo R. Banting lecture. From the triumvirate to the ominous octet: a new paradigm for the treatment of type 2 diabetes mellitus. Diabetes. 2009;58:773–95.
12. Elrick H, Stimmler L, Hlad CJ Jr, Arai Y. Plasma insulin response to oral and intravenous glucose administration. J Clin Endocrinol Metab. 1964;24:1076–82.
13. Drucker DJ. The biology of incretin hormones. Cell Metab. 2006;3:153–65.
14. Nauck MA, Baller B, Meier JJ. Gastric inhibitory polypeptide and glucagon-like peptide-1 in the pathogenesis of type 2 diabetes. Diabetes. 2004;53:S190–6.
15. Drucker DJ, Nauck MA. The incretin system: glucagon-like peptide-1 receptor agonists and dipeptidyl peptidase-4 inhibitors in type 2 diabetes. Lancet. 2006;368:1696–705.
16. Frederich R, McNeill R, Berglind N, Fleming D, Chen R. The efficacy and safety of the dipeptidyl peptidase-4 inhibitor saxagliptin in treatment-naive patients with type 2 diabetes mellitus: a randomized controlled trial. Diabetol Metab Syndr. 2012;4:36.
17. Kumar KMP, Jain SM, Tou C, Schützer K-M. Saxagliptin as initial therapy in treatment-naive Indian adults with type 2 diabetes mellitus inadequately controlled with diet and exercise alone: a randomized, double-blind, placebo-controlled, phase IIIb clinical study. Int J Diabetes Dev Ctries. 2014;34:201–9.
18. Pan CY, Yang W, Tou C, Gause-Nilsson I, Zhao J. Efficacy and safety of saxagliptin in drug-naive Asian patients with type 2 diabetes mellitus: a randomized controlled trial. Diabetes Metab Res Rev. 2012;28:268–75.
19. Rosenstock J, Aguilar-Salinas C, Klein E, et al. Effect of saxagliptin monotherapy in treatment-naive patients with type 2 diabetes. Curr Med Res Opin. 2009;25:2401–11.
20. Wallace TM, Levy JC, Matthews DR. Use and abuse of HOMA modeling. Diabetes Care. 2004;27:1487–95.
21. DeFronzo R, Hissa MN, Garber AJ, et al. Once-daily saxagliptin added to metformin provides sustained glycemic control and is well tolerated over 102 weeks in patients with type 2 diabetes. Diabetes. 2009;58:547-P.
22. Hermans MP, Delibasi T, Farmer I, et al. Effects of saxagliptin added to sub-maximal doses of metformin compared with uptitration of metformin in type 2 diabetes: the PROMPT study. Curr Med Res Opin. 2012;28:1635–45.
23. 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;94:217–24.
24. Jadzinsky M, Pfutzner A, Paz-Pacheco E, Xu Z, Allen E, Chen R. Saxagliptin given in combination with metformin as initial therapy improves glycaemic control in patients with type 2 diabetes compared with either monotherapy: a randomized controlled trial. Diabetes Obes Metab. 2009;11:611–22.
25. Hollander P, Li J, Allen E, Chen R. CV181-013 Investigators. Saxagliptin added to a thiazolidinedione improves glycemic control in patients with type 2 diabetes and inadequate control on thiazolidinedione alone. J Clin Endocrinol Metab. 2009;94:4810–9.
26. Chacra AR, Tan GH, Apanovitch A, et al. Saxagliptin added to a submaximal dose of sulphonylurea improves glycaemic control compared with uptitration of sulphonylurea in patients with type 2 diabetes: a randomised controlled trial. Int J Clin Pract. 2009;63:1395–406.
27. Barnett AH, Charbonnel B, Donovan M, Fleming D, Chen R. Effect of saxagliptin as add-on therapy in patients with poorly controlled type 2 diabetes on insulin alone or insulin combined with metformin. Curr Med Res Opin. 2012;28:513–23.
28. Moses RG, Kalra S, Brook D, et al. A randomized controlled trial of the efficacy and safety of saxagliptin as add-on therapy in patients with type 2 diabetes and inadequate glycaemic control on metformin plus a sulphonylurea. Diabetes Obes Metab. 2014;16:443–50.
29. Göke B, Gallwitz B, Eriksson J, Hellqvist A, Gause-Nilsson I. Saxagliptin is non-inferior to glipizide in patients with type 2 diabetes mellitus inadequately controlled on metformin alone: a 52-week randomised controlled trial. Int J Clin Pract. 2010;64:1619–31.
30. Rosenstock J, Hansen L, Zee P, et al. Dual add-on therapy in type 2 diabetes poorly controlled with metformin monotherapy: a randomized double-blind trial of saxagliptin plus dapagliflozin addition vs single addition of saxagliptin or dapagliflozin to metformin. Diabetes Care. 2015;38:376–83.
31. 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;16:1239–46.
32. 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;380:475–83.
33. Matthews DR, Dejager S, Ahren B, et al. Vildagliptin add-on to metformin produces similar efficacy and reduced hypoglycaemic risk compared with glimepiride, with no weight gain: results from a 2-year study. Diabetes Obes Metab. 2010;12:780–9.
34. 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;64:562–76.
35. Rosenstock J, Gross JL, Aguilar-Salinas C, et al. Long-term 4-year safety of saxagliptin in drug-naive and metformin-treated patients with type 2 diabetes. Diabet Med. 2013;30:1472–6.
36. Pfützner A, Paz-Pacheco E, Allen E, Frederich B, Chen R, for the CV181039 Investigators. Initial combination therapy with saxagliptin and metformin provides sustained glycaemic control and is well tolerated for up to 76 weeks. Diabetes Obes Metab. 2011;13:567–76.
37. Hollander PL, Li J, Frederich R, Allen E, Chen R. CV 181013 Investigators. Safety and efficacy of saxagliptin added to thiazolidinedione over 76 weeks in patients with type 2 diabetes mellitus. Diab Vasc Dis Res. 2011;8:125–35.
38. Chacra AR, Tan GH, Ravichandran S, List J, Chen R. CV181040 Investigators. Safety and efficacy of saxagliptin in combination with submaximal sulphonylurea vs up-titrated sulphonylurea over 76 weeks. Diab Vasc Dis Res. 2011;8:150–9.
39. Goke B, Gallwitz B, Eriksson JG, Hellqvist A, 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;67:307–16.
40. International Diabetes Federation. Managing older people with type 2 diabetes. Available at: http://www.idf.org/guidelines/managing-older-people-type-2-diabetes. Accessed 6 Nov 2015.
41. Karyekar CS, Ravichandran S, Allen E, Fleming D, Frederich R. Tolerability and efficacy of glycemic control with saxagliptin in older patients (aged ≥65 years) with inadequately controlled type 2 diabetes mellitus. Clin Interv Aging. 2013;8:419–30.
42. Laakso M. Cardiovascular disease in type 2 diabetes from population to man to mechanisms: the Kelly West Award Lecture 2008. Diabetes Care. 2010;33:442–9.
43. Cook W, Bryzinski B, Slater J, Frederich R, Allen E. Saxagliptin efficacy and safety in patients with type 2 diabetes mellitus and cardiovascular disease history or cardiovascular risk factors: results of a pooled analysis of phase 3 clinical trials. Postgrad Med. 2013;125:145–54.
44. Hirshberg B, Leibowitz G, Iqbal N, Cook W, Wei C, Sjostrand M. Saxagliptin responder analysis: a pooled analysis of 5 clinical trials (abstract). Endocr Pract. 2014;20:1A–44A.
45. Hirshberg B, Parker A, Edelberg H, Donovan M, Iqbal N. Safety of saxagliptin: events of special interest in 9156 patients with type 2 diabetes mellitus. Diabetes Metab Res Rev. 2014;30:556–69.
46. Scirica BM, Bhatt DL, Braunwald E, et al. Saxagliptin and cardiovascular outcomes in patients with type 2 diabetes mellitus. N Engl J Med. 2013;369:1317–26.
47. Scirica BM, Braunwald E, Raz I, et al. Heart failure, saxagliptin, and diabetes mellitus: observations from the SAVOR-TIMI 53 randomized trial. Circulation. 2014;130:1579–88.
48. Udell JA, Bhatt DL, Braunwald E, et al. Saxagliptin and cardiovascular outcomes in patients with type 2 diabetes and moderate or severe renal impairment: observations from the SAVOR-TIMI 53 trial. Diabetes Care. 2015;38:696–705.
49. Monami M, Dicembrini I, Mannucci E. Dipeptidyl peptidase-4 inhibitors and heart failure: a meta-analysis of randomized clinical trials. Nutr Metab Cardiovasc Dis. 2014;24:689–97.
50. Weir DL, McAlister FA, Senthilselvan A, Minhas-Sandhu JK, Eurich DT. Sitagliptin use in patients with diabetes and heart failure: a population-based retrospective cohort study. JACC Heart Fail. 2014;2:573–82.
51. Fu AZ, Johnston S, Sheehan J, et al. Risk of hospitalization for heart failure with dipeptidyl peptidase-4 inhibitors vs sulfonylureas and with saxagliptin vs sitagliptin in a US claims database. Diabetes. 2015;64:LB42.
52. Giorda CB, Picariello R, Tartaglino B, et al. Hospitalisation for heart failure and mortality associated with dipeptidyl peptidase 4 (DPP-4) inhibitor use in an unselected population of subjects with type 2 diabetes: a nested case-control study. BMJ Open. 2015;5:e007959.
53. White WB, Cannon CP, Heller SR, et al. Alogliptin after acute coronary syndrome in patients with type 2 diabetes. N Engl J Med. 2013;369:1327–35.
54. Zannad F, Cannon C, Cushman WC, et al. Heart failure and mortality outcomes in patients with type 2 diabetes taking alogliptin vs placebo in EXAMINE: a multicentre, randomised, double-blind trial. Lancet. 2015;385:2067–76.
55. Green JB, Bethel MA, Armstrong PW, et al. Effect of sitagliptin on cardiovascular outcomes in type 2 diabetes. N Engl J Med. 2015;373:232–42.
56. Rosenstock J, Marx N, Kahn SE, et al. Cardiovascular outcome trials in type 2 diabetes and the sulphonylurea controversy: rationale for the active-comparator CAROLINA trial. Diab Vasc Dis Res. 2013;10:289–301.
57. Butler PC, Elashoff M, Elashoff R, Gale EA. A critical analysis of the clinical use of incretin-based therapies: are the GLP-1 therapies safe? Diabetes Care. 2013;36:2118–25.
58. Nauck MA. A critical analysis of the clinical use of incretin-based therapies: the benefits by far outweigh the potential risks. Diabetes Care. 2013;36:2126–32.
59. Egan AG, Blind E, Dunder K, et al. Pancreatic safety of incretin-based drugs–FDA and EMA assessment. N Engl J Med. 2014;370:794–7.
60. Elashoff M, Matveyenko AV, Gier B, Elashoff R, Butler PC. Pancreatitis, pancreatic, and thyroid cancer with glucagon-like peptide-1-based therapies. Gastroenterology. 2011;141:150–6.
61. Singh S, Chang HY, Richards TM, Weiner JP, Clark JM, Segal JB. Glucagonlike peptide 1-based therapies and risk of hospitalization for acute pancreatitis in type 2 diabetes mellitus: a population-based matched case-control study. JAMA Intern Med. 2013;173:534–9.
62. Engel SS, Round E, Golm GT, Kaufman KD, Goldstein BJ. Safety and tolerability of sitagliptin in type 2 diabetes: pooled analysis of 25 clinical studies. Diabetes Ther. 2013;4:119–45.
63. Li L, Shen J, Bala MM, et al. Incretin treatment and risk of pancreatitis in patients with type 2 diabetes mellitus: systematic review and meta-analysis of randomised and non-randomised studies. BMJ. 2014;348:g2366.
64. Raz I, Bhatt DL, 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. Diabetes Care. 2014;37:2435–41.