Saxagliptin: A new DPP-4 inhibitor for the treatment of type 2 diabetes mellitus

Advances in Therapy

Volumn 26, Issue 3, 2009, Pages 249-262

  Tahrani, Abd A ^a   Piya, Milan K ^b,c   Barnett, Anthony H ^b,c  

^a BIRMINGHAM HEARTLANDS HOSPITAL   (United Kingdom)

^b UNIVERSITY OF BIRMINGHAM   (United Kingdom)

^c UNIVERSITY HOSPITALS BIRMINGHAM NHS FOUNDATION TRUST   (United Kingdom)

Author keywords

DPP 4; GLP 1; Hypoglycemia; Incretin; Saxagliptin; Sitagliptin; Type 2 diabetes mellitus; Vildagliptin

Indexed keywords

ALPHA GLUCOSIDASE INHIBITOR; ALUMINUM MAGNESIUM HYDROXIDE; DIGOXIN; DILTIAZEM; DIPEPTIDYL PEPTIDASE IV; DIPEPTIDYL PEPTIDASE IV INHIBITOR; EXENDIN 4; FAMOTIDINE; GASTRIC INHIBITORY POLYPEPTIDE; GLIBENCLAMIDE; GLITAZONE DERIVATIVE; GLUCAGON LIKE PEPTIDE 1; HEMOGLOBIN A1C; INCRETIN; INSULIN; KETOCONAZOLE; LIRAGLUTIDE; MAALOX MAX; MEGLITINIDE; METFORMIN; OMEPRAZOLE; PIOGLITAZONE; PLACEBO; ROSIGLITAZONE; SAXAGLIPTIN; SIMVASTATIN; SITAGLIPTIN; SULFONYLUREA; UNCLASSIFIED DRUG; VILDAGLIPTIN;

ADD ON THERAPY; APOPTOSIS; AREA UNDER THE CURVE; BACKACHE; CLINICAL TRIAL; DIARRHEA; DRUG BLOOD LEVEL; DRUG DOSE TITRATION; DRUG EFFICACY; DRUG HALF LIFE; DRUG INDUCED HEADACHE; DRUG SAFETY; DRUG STRUCTURE; DRUG TOLERABILITY; ENZYME ACTIVITY; ENZYME DEGRADATION; ENZYME INHIBITION; GASTROINTESTINAL SYMPTOM; GLYCEMIC CONTROL; HUMAN; HYPERCHOLESTEROLEMIA; HYPERTENSION; HYPOGLYCEMIA; IC 50; INFLUENZA; INSULIN RESISTANCE; LEG PAIN; LOW DRUG DOSE; MAXIMUM PLASMA CONCENTRATION; NON INSULIN DEPENDENT DIABETES MELLITUS; NONHUMAN; OBESITY; ORAL GLUCOSE TOLERANCE TEST; PERIPHERAL EDEMA; PROTEIN EXPRESSION; REVIEW; RHINOPHARYNGITIS; SIDE EFFECT; STRUCTURE ANALYSIS; UPPER RESPIRATORY TRACT INFECTION; URINARY TRACT INFECTION; WEIGHT GAIN;

ADAMANTANE; AGE FACTORS; DIABETES MELLITUS, TYPE 2; DIPEPTIDES; DIPEPTIDYL-PEPTIDASE IV INHIBITORS; DRUG INTERACTIONS; DRUG THERAPY, COMBINATION; GLUCAGON-LIKE PEPTIDE 1; HUMANS; HYPOGLYCEMIC AGENTS; INCRETINS; RANDOMIZED CONTROLLED TRIALS AS TOPIC; SEX FACTORS; TIME FACTORS;

EID: 73449117555     PISSN: 0741238X     EISSN: None     Source Type: Journal    
DOI: 10.1007/s12325-009-0014-9     Document Type: Review

References (65)

1. International Diabetes Federation. The Diabetes Atlas. 3rd edition. Brussels: International Diabetes Federation; 2006.
2. M. De Groot R. Anderson K.E. Freedland R.E. Clouse P.J. Lustman 2001 Association of depression and diabetes complications: a meta-analysis Psychosom Med 63 619 630 11485116 (Pubitemid 32695143)
3. Wanless D. Securing our future health: taking a long-term view. HM Treasury. 2002. Available at: http://www.hm-treasury.gov.uk/d/letter-to-chex. pdf. Accessed February 2009.
4. A.M. Jacobson 2004 Impact of improved glycemic control on quality of life in patients with diabetes Endocr Pract 10 502 508 16033724
5. F.S. Facchini N. Hua F. Abbasi G.M. Reaven 2001 Insulin resistance as a predictor of age-related diseases J Clin Endocrinol Metab 86 3574 3578 11502781 10.1210/jc.86.8.3574 1:CAS:528:DC%2BD3MXlvFektrc%3D (Pubitemid 32755946)
6. M. Stumvoll B.J. Goldstein T.W. van Haeften 2005 Type 2 diabetes: principles of pathogenesis and therapy Lancet 365 1333 1346 15823385 10.1016/S0140-6736(05)61032-X 1:CAS:528:DC%2BD2MXjtF2iu7g%3D
7. G.M. Reaven 1988 Role of insulin resistance in human disease Diabetes 37 1595 1607 3056758 10.2337/diabetes.37.12.1595 1:STN:280:DyaL1M%2Flt12msQ%3D%3D
8. S.E. Kahn R.L. Hull K.M. Utzschneider 2006 Mechanisms linking obesity to insulin resistance and type 2 diabetes Nature 444 840 846 17167471 10.1038/nature05482 1:CAS:528:DC%2BD28XhtlShtrzP (Pubitemid 46024990)
9. S.E. Kahn 1993 Quantification of the relationship between insulin sensitivity and B-cell function in human subjects Evidence for a hyperbolic function. Diabetes 42 1663 1672 1:CAS:528:DyaK3sXms1ejsr4%3D
10. M. Perley D.M. Kipnis 1966 Plasma insulin responses to glucose and tolbutamide of normal weight and obese diabetic and nondiabetic subjects Diabetes 15 867 874 5957477 1:CAS:528:DyaF2sXjs1GgsQ%3D%3D
11. K.S. Polonsky B.D. Given E. Van Cauter 1988 Twentyfour-hour profiles and patterns of insulin secretion in normal and obese subjects J Clin Invest 81 442 448 3276730 10.1172/JCI113339 1:CAS:528:DyaL1cXhvVCltL4%3D (Pubitemid 18075238)
12. S.E. Kahn 2001 The importance of beta-cell failure in the development and progression of type 2 diabetes J Clin Endocrinol Metab 86 4047 4058 11549624 10.1210/jc.86.9.4047 1:CAS:528:DC%2BD3MXmvFCktrY%3D (Pubitemid 32848511)
13. R. Burcelin C. Knauf P.D. Cani 2008 Pancreatic alphacell dysfunction in diabetes Diabetes Metab 34 suppl.2 S49 S55 18640586 10.1016/S1262-3636(08)73395- 0 1:CAS:528:DC%2BD1cXnvVGgs7s%3D (Pubitemid 351978284)
14. P.S. Del C. Bianchi P. Marchetti 2007 Β-cell function and anti-diabetic pharmacotherapy Diabetes Metab Res Rev 23 518 527 10.1002/dmrr.770 1:CAS:528:DC%2BD2sXhtlCqs7nO (Pubitemid 350018025)
15. S.E. Kahn S.M. Haffner M.A. Heise 2006 Glycemic durability of rosiglitazone, metformin, or glyburide monotherapy N Engl J Med 355 2427 2443 17145742 10.1056/NEJMoa066224 1:CAS:528:DC%2BD28Xht12ntrzF (Pubitemid 44903747)
16. C. Black P. Donnelly L. McIntyre P.L. Royle J.P. Shepherd S. Thomas 2007 Meglitinide analogues for type 2 diabetes mellitus Cochrane Database Syst Rev 2 CD004654 17443551
17. L.L. Baggio D.J. Drucker 2007 Biology of incretins: GLP-1 and GIP Gastroenterology 132 2131 2157 17498508 10.1053/j.gastro.2007.03.054 1:CAS:528:DC%2BD2sXmsVynsrY%3D (Pubitemid 46711096)
18. B. Moore 1906 On the treatment of diabetu mellitus by acid extract of duodenal mucous membrane Biochem J 1 28 38 16742013 1:CAS:528:DyaD28Xht1Git7Y%3D
19. H. Elrick L. Stimmler C.J. Hlad Jr. Y. Rai 1964 Plasma insulin response to oral and intravenous glucose administration J Clin Endocrinol Metab 24 1076 1082 14228531 1:CAS:528:DyaF2MXitlKgsw%3D%3D
20. B. Ahren 2003 Gut peptides and type 2 diabetes mellitus treatment Curr Diab Rep 3 365 372 12975025 10.1007/s11892-003-0079-9
21. B.D. Green P.R. Flatt 2007 Incretin hormone mimetics and analogues in diabetes therapeutics Best Pract Res Clin Endocrinol Metab 21 497 516 18054732 10.1016/j.beem.2007.09.003 1:CAS:528:DC%2BD2sXhsVSlsrzO (Pubitemid 350177567)
22. M.A. Nauck E. Homberger E.G. Siegel 1986 Incretin effects of increasing glucose loads in man calculated from venous insulin and C-peptide responses J Clin Endocrinol Metab 63 492 498 3522621 1:CAS:528:DyaL28XkvFWkt7g%3D
23. H.C. Fehmann R. Goke B. Goke 1995 Cell and molecular biology of the incretin hormones glucagon-like peptide-I and glucose-dependent insulin releasing polypeptide Endocr Rev 16 390 410 7671853 1:CAS:528:DyaK2MXmslCqtbY%3D
24. J.F. Gautier S.P. Choukem J. Girard 2008 Physiology of incretins (GIP and GLP-1) and abnormalities in type 2 diabetes Diabetes Metab 34suppl.2 S65 S72 10.1016/S1262-3636(08)73397-4 (Pubitemid 352014865)
25. J. Dupre S.A. Ross D. Watson J.C. Brown 1973 Stimulation of insulin secretion by gastric inhibitory polypeptide in man J Clin Endocrinol Metab 37 826 828 4749457 1:CAS:528:DyaE2cXms1yqsQ%3D%3D 10.1210/jcem-37-5-826
26. A. Trumper K. Trumper H. Trusheim R. Arnold B. Goke D. Horsch 2001 Glucose-dependent insulinotropic polypeptide is a growth factor for beta (INS-1) cells by pleiotropic signaling Mol Endocrinol 15 1559 1570 11518806 10.1210/me.15.9.1559 1:CAS:528:DC%2BD3MXms1Kiu74%3D (Pubitemid 32826409)
27. R.G. Yip M.M. Wolfe 2000 GIP biology and fat metabolism Life Sci 66 91 103 10666005 10.1016/S0024-3205(99)00314-8 1:CAS:528:DyaK1MXotFyis7c%3D
28. D.J. Drucker 2003 Glucagon-like peptides: regulators of cell proliferation, differentiation, and apoptosis Mol Endocrinol 17 161 171 12554744 10.1210/me.2002-0306 1:CAS:528:DC%2BD3sXhtFantLY%3D (Pubitemid 36183142)
29. D.J. Drucker J. Philippe S. Mojsov W.L. Chick J.F. Habener 1987 Glucagon-like peptide I stimulates insulin gene expression and increases cyclic AMP levels in a rat islet cell line Proc Natl Acad Sci U S A 84 3434 3438 3033647 10.1073/pnas.84.10.3434 1:CAS:528:DyaL2sXktlelsLk%3D (Pubitemid 17085418)
30. A.H. Barnett 2009 New treatments in type 2 diabetes - a focus on the incretin-based therapies Clin Endocrinol (Oxf) 70 343 353 10.1111/j.1365-2265. 2008.03396.x 1:CAS:528:DC%2BD1MXjvFOqsrg%3D
31. D.J. Drucker 2003 Glucagon-like peptide-1 and the islet beta-cell: augmentation of cell proliferation and inhibition of apoptosis Endocrinology 144 5145 5148 14645210 10.1210/en.2003-1147 1:CAS:528:DC%2BD3sXpsV2gt7s%3D (Pubitemid 37476039)
32. A. Barnett 2006 DPP-4 inhibitors and their potential role in the management of type 2 diabetes Int J Clin Pract 60 1454 1470 17073841 10.1111/j.1742-1241.2006.01178.x 1:CAS:528:DC%2BD28Xhtlajt7%2FK (Pubitemid 44560347)
33. L. Hansen C.F. Deacon C. Orskov J.J. Holst 1999 Glucagon-like peptide-1-(7-36)amide is transformed to glucagon-like peptide-1-(9-36)amide by dipeptidyl peptidase IV in the capillaries supplying the L cells of the porcine intestine Endocrinology 140 5356 5363 10537167 10.1210/en.140.11.5356 1:CAS:528:DyaK1MXmvFemtbs%3D (Pubitemid 30687147)
34. C.F. Deacon A.H. Johnsen J.J. Holst 1995 Degradation of glucagon-like peptide-1 by human plasma in vitro yields an N-terminally truncated peptide that is a major endogenous metabolite in vivo J Clin Endocrinol Metab 80 952 957 7883856 10.1210/jc.80.3.952 1:CAS:528:DyaK2MXktlOnurw%3D
35. R. Mentlein 1999 Dipeptidyl-peptidase IV (CD26) - role in the inactivation of regulatory peptides Regul Pept 85 9 24 10588446 10.1016/S0167-0115(99)00089-0 1:CAS:528:DyaK1MXntVCitLs%3D (Pubitemid 29505281)
36. D.J. Drucker M.A. Nauck 2006 The incretin system: glucagon-like peptide-1 receptor agonists and dipeptidyl peptidase-4 inhibitors in type 2 diabetes Lancet 368 1696 1705 17098089 10.1016/S0140-6736(06)69705-5 1:CAS:528: DC%2BD28XhtF2gurjM (Pubitemid 46048557)
37. B. Ahren 2007 DPP-4 inhibitors Best Pract Res Clin Endocrinol Metab 21 517 533 18054733 10.1016/j.beem.2007.07.005 1:CAS:528:DC%2BD2sXhsVSlsrzP (Pubitemid 350185859)
38. B.D. Green P.R. Flatt C.J. Bailey 2006 Dipeptidyl peptidase IV (DPP IV) inhibitors: a newly emerging drug class for the treatment of type 2 diabetes Diab Vasc Dis Res 3 159 165 17160910 10.3132/dvdr.2006.024 (Pubitemid 44902481)
39. B. Ahren J.J. Holst H. Martensson B. Balkan 2000 Improved glucose tolerance and insulin secretion by inhibition of dipeptidyl peptidase IV in mice Eur J Pharmacol 404 239 245 10980284 10.1016/S0014-2999(00)00600-2 1:CAS:528:DC%2BD3cXmt1aisL0%3D (Pubitemid 30682553)
40. B. Balkan L. Kwasnik R. Miserendino J.J. Holst X. Li 1999 Inhibition of dipeptidyl peptidase IV with NVPDPP728 increases plasma GLP-1 (7-36 amide) concentrations and improves oral glucose tolerance in obese Zucker rats Diabetologia 42 1324 1331 10550416 10.1007/s001250051445 1:CAS:528: DyaK1MXmvF2ms7k%3D (Pubitemid 29500969)
41. R.A. Pederson H.A. White D. Schlenzig R.P. Pauly C.H. McIntosh H.U. Demuth 1998 Improved glucose tolerance in Zucker fatty rats by oral administration of the dipeptidyl peptidase IV inhibitor isoleucine thiazolidide Diabetes 47 1253 1258 9703325 10.2337/diabetes.47.8.1253 1:CAS:528: DyaK1cXltFyrt78%3D (Pubitemid 28357002)
42. J.A. Pospisilik J. Martin T. Doty 2003 Dipeptidyl peptidase IV inhibitor treatment stimulates betacell survival and islet neogenesis in streptozotocininduced diabetic rats Diabetes 52 741 750 12606516 10.2337/diabetes.52.3.741 1:CAS:528:DC%2BD3sXitFajtrc%3D (Pubitemid 36323582)
43. J. Doupis A. Veves 2008 DPP4 inhibitors: a new approach in diabetes treatment Adv Ther 25 627 643 18641927 10.1007/s12325-008-0076-1 1:CAS:528:DC%2BD1cXhsVyqtL7K
44. B. Richter E. Bandeira-Echtler K. Bergerhoff C. Lerch 2008 Emerging role of dipeptidyl peptidase-4 inhibitors in the management of type 2 diabetes Vasc Health Risk Manag 4 753 768 19065993 1:CAS:528:DC%2BD1cXht1Shur%2FI
45. D.J. Augeri J.A. Robl D.A. Betebenner 2005 Discovery and preclinical profile of saxagliptin (BMS-477118): a highly potent, long-acting, orally active dipeptidyl peptidase IV inhibitor for the treatment of type 2 diabetes J Med Chem 48 5025 5037 16033281 10.1021/jm050261p 1:CAS:528:DC%2BD2MXlsVeltb0%3D (Pubitemid 41033142)
46. M.S. Kirby C. Dorso A. Wang 2008 In vitro enzymologic characteristics of saxagliptin, a highly potent and selective DPP4 inhibitor with "slow binding" characteristics Clin Chem Lab Med 46 A29
47. Wang A Dorso C Kopcho L Marcinkeviciene J Kirby MS. Implications of the prolonged dissociation rate of saxagliptin, a highly potent and selective DPP4 inhibitor, on plasma DPP measurements. Presented at: 68th Scientific Sessions of the American Diabetes Association; June 6-19, 2008; San Francisco, CA. Abstract 2088-PO.
48. Boulton DW Geraldes M. Safety, tolerability, pharmacokinetics and pharmacodynamics of oncedaily oral doses of saxagliptin for 2 weeks in type 2 diabetic and healthy subjects. Presented at: 67th Scientific Sessions of the American Diabetes Association; June 22-26, 2007; Chicago, IL. Abstract 0606-P.
49. Boulton DW Goyal A Li L Kornhauser DM Frevert U. The effects of age and gender on the singledose pharmacokinetics and safety of saxagliptin in healthy subjects. Presented at: 68th Scientific Sessions of the American Diabetes Association; June 6-19 2008; San Francisco, CA. Abstract 551-P.
50. R.N. Pugh I.M. Murray-Lyon J.L. Dawson M.C. Pietroni R. Williams 1973 Transection of the oesophagus for bleeding oesophageal varices Br J Surg 60 646 649 4541913 10.1002/bjs.1800600817 1:STN:280:DyaE3s3jsVWqsw%3D%3D
51. Patel C Castaneda L Frevert U Li L Kornhauser DM Boulton DW. Single-dose pharmacokinetics and safety of saxagliptin in subjects with hepatic impairment compared with healthy subjects. Presented at: 68th Scientific Sessions of the American Diabetes Association; June 6-19, 2008; San Francisco, CA. Abstract 537-P.
52. R.C. Turner C.A. Cull V. Frighi R.R. Holman 1999 Glycemic control with diet, sulfonylurea, metformin, or insulin in patients with type 2 diabetes mellitus: progressive requirement for multiple therapies (UKPDS 49). UK Prospective Diabetes Study (UKPDS) Group JAMA 281 2005 2012 10359389 10.1001/jama.281.21.2005 1:CAS:528:DyaK1MXjvFOls7g%3D (Pubitemid 29254858)
53. Patel CG Li L Komoroski B Boulton DW. No meaningful pharmacokinetic drug-drug interaction between saxagliptin and metformin in healthy subjects. Presented at: 36th Annual Meeting of the American College of Clinical Pharmacology; September 9-11, 2007; San Francisco, CA. Abstract.
54. Rosenstock J List J Sankoh S Chen R. Efficacy and tolerability of the dipeptidyl peptidase-4 inhibitor saxagliptin in drug-naïve subjects with type 2 diabetes: results from a phase 2 dose-ranging study. Presented at: 43rd annual meeting of the European Society for the Study of Diabetes; September 17-21, 2007; Amsterdam, Netherlands. Abstract.
55. J. Rosenstock S. Sankoh J.F. List 2008 Glucose-lowering activity of the dipeptidyl peptidase-4 inhibitor saxagliptin in drug-naive patients with type 2 diabetes Diabetes Obes Metab 10 376 386 18355324 10.1111/j.1463-1326.2008.00876. x 1:CAS:528:DC%2BD1cXntVSrs7k%3D
56. Rosenstock J Aguilar-Salinas CA Klein E List J Blauwet MB Chen R. Once-daily saxagliptin monotherapy improves glycemic control in drug-naïve patients with type 2 diabetes. Presented at: 68th Scientific Sessions of the American Diabetes Association; June 6-19, 2008; San Francisco, CA. Abstract 517-P.
57. Defronzo RA Hissa M Blauwet MB Chen RS. Saxagliptin added to metformin improves glycemic control in patients with type 2 diabetes. Presented at: 67th Scientific Sessions of the American Diabetes Association; June 22-26, 2007; Chicago, IL. 2007. Abstract 0285-OR.
58. Ravichandran S Chacra AR Tan GH Apanovitch A Chen R. Saxagliptin added to a sulfonylurea is safe and more efficacious than up-titrating a sulfonylurea in patients with type 2 diabetes. Presented at: 44rd annual meeting of the European Society for the Study of Diabetes; September 7-11, 2008; Rome, Italy. Abstract.
59. Allen E Hollander P Li L Chen R. Saxagliptin added to a thiazolidinedione improves glycemic control in patients with inadequately controlled type 2 diabetes. Presented at: 44rd annual meeting of the European Society for the Study of Diabetes; September 7-11, 2008; Rome, Italy. Abstract.
60. Chen R Pfützner A Jadzinsky M Paz-Pacheco E Xu Z Allen E. Initial combination therapy with saxagliptin and metformin improves glycemic control compared with either monotherapy alone in drug-naïve patients with type 2 diabetes. Presented at: 44rd annual meeting of the European Society for the Study of Diabetes; September 7-11, 2008; Rome, Italy. Abstract.
61. Girgis S Patel CG Li L, et al. Effect of diltiazem on the pharmacokinetics of saxagliptin in healthy subjects. Presented at: 36th Annual Meeting of the American College of Clinical Pharmacology; September 9-11, 2007; San Francisco, CA. Abstract.
62. Girgis S You X Li L Maurer C Whigan D Boulton DW. Effect of simvastatin on the pharmacokinetics of saxagliptin in healthy subjects. Presented at: 36th Annual Meeting of the American College of Clinical Pharmacology; September 9-11, 2007; San Francisco, CA. Abstract.
63. Boulton DW Adams D Li L, et al. Maalox Maxr, famotidine or omeprazole do not meaningfully affect the pharmacokinetics of saxagliptin in healthy subjects. Presented at: 2008 American Society for Clinical Pharmacology and Therapeutics Annual Meeting; April 2-5, 2008; Orlando, FL. Abstract.
64. Boulton DW Li L Patel CG, et al. No pharmacokinetic interaction between saxagliptin and digoxin in healthy subjects. Presented at: 2008 American Society for Clinical Pharmacology and Therapeutics Annual Meeting; April 2-5, 2008; Orlando, FL. Abstract.
65. Patel CG Boulton DW Brenner E Royzman K Li L. Effect of ketoconazole on the pharmacokinetics of saxagliptin in healthy subjects. Presented at: 36th Annual Meeting of the American College of Clinical Pharmacology; September 9-11, 2007; San Francisco, CA. Abstract.