Incorporating incretin-based therapies into clinical practice: Differences between glucagon-like peptide 1 receptor agonists and dipeptidyl peptidase 4 inhibitors

Mayo Clinic Proceedings

Volumn 85, Issue 12 SUPPL., 2010, Pages

  Davidson, Jaime A ^a  

^a UNIVERSITY OF TEXAS AT DALLAS   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

2,4 THIAZOLIDINEDIONE DERIVATIVE; ALBIGLUTIDE; ALOGLIPTIN; AMYLIN; DIPEPTIDYL PEPTIDASE IV INHIBITOR; EXENDIN 4; GLUCAGON LIKE PEPTIDE 1 RECEPTOR; INCRETIN; INSULIN; LINAGLIPTIN; LIRAGLUTIDE; LIXISENATIDE; METFORMIN; PLACEBO; SAXAGLIPTIN; SITAGLIPTIN; SULFONYLUREA; TASPOGLUTIDE; UNCLASSIFIED DRUG; VILDAGLIPTIN;

APPETITE; BODY WEIGHT; CARDIOVASCULAR RISK; CLINICAL PRACTICE; CLINICAL TRIAL; DIABETES MELLITUS; DRUG HALF LIFE; GLUCAGON RELEASE; GLUCONEOGENESIS; GLUCOSE BLOOD LEVEL; GLYCEMIC CONTROL; HUMAN; HYPOGLYCEMIA; INCIDENCE; INSULIN RELEASE; INSULIN RESISTANCE; MONOTHERAPY; NAUSEA; NON INSULIN DEPENDENT DIABETES MELLITUS; NONHUMAN; OBESITY; PANCREAS ISLET BETA CELL; PATHOPHYSIOLOGY; REVIEW; RISK FACTOR; VOMITING; WEIGHT REDUCTION;

EID: 78650106131     PISSN: 00256196     EISSN: None     Source Type: Journal    
DOI: 10.4065/mcp.2010.0469     Document Type: Review

References (93)

1. Wild S, Roglic G, Green A, Sicree R, King H. Global prevalence of diabetes: estimates for the year 2000 and projections for 2030. Diabetes Care. 2004;27(5):1047-1053.
2. US Department of Health and Human Services, National Diabetes Information Clearinghouse. National Diabetes Statistics, 2007. NIH Publication No. 08-3892. http://diabetes.niddk.nih.gov/dm/pubs/statistics/DM-Statistics.pdf. Last updated: June 2008. Accessed October 19, 2010.
3. International Diabetes Federation. Diabetes and impaired glucose tolerance: global burden: prevalence and projections, 2010 and 2030. International Diabetes Federation Website. http://www.diabetesatlas.org/content/ diabetes-and- impaired-glucose-tolerance. Accessed October 19, 2010.
4. Cheung BM, Ong KL, Cherny SS, et al. Diabetes prevalence and therapeutic target achievement in the United States, 1999 to 2006. Am J Med. 2009;122(5):443-453.
5. Huang ES, Basu A, O'Grady M, Capretta JC. Projecting the future diabetes population size and related costs for the US. Diabetes Care. 2009;32(12):2225-2229.
6. Narayan KM, Boyle JP, Thompson TJ, Sorensen SW, Williamson DF. Lifetime risk for diabetes mellitus in the United States. JAMA. 2003; 290(14):1884-1890.
7. Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults. Executive summary of the Third Report of the National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III). JAMA. 2001;285(19):2486-2497.
8. American Diabetes Association. Standards of medical care in diabetes - 2010. Diabetes Care. 2010;33(suppl 1):S11-S61.
9. Rodbard HW, Jellinger PS, Davidson JA, et al. AACE/ACE consensus statement: statement by an American Association of Clinical Endocrinologists/ American College of Endocrinology Consensus Panel on type 2 diabetes mellitus: an algorithm for glycemic control. Endocr Pract. 2009;15(6):540-559.
10. Gallwitz B. Implications of postprandial glucose and weight control in people with type 2 diabetes: understanding and implementing the International Diabetes Federation guidelines. Diabetes Care. 2009;32(suppl 2):S322-S325.
11. Preis SR, Pencina MJ, Hwang SJ, et al. Trends in cardiovascular disease risk factors in individuals with and without diabetes mellitus in the Framingham Heart Study. Circulation. 2009;120(3):212-220.
12. Koopman RJ, Mainous AG III, Diaz VA, Geesey ME. Changes in age at diagnosis of type 2 diabetes mellitus in the United States, 1988 to 2000. Ann Fam Med. 2005;3(1):60-63.
13. Karam JG, McFarlane SI. Prevention of type 2 DM: implications for adolescents and young adults. Pediatr Endocrinol Rev. 2008;5(suppl 4):980-988.
14. Fagot-Campagna A, Pettitt DJ, Engelgau MM, et al. Type 2 diabetes among North American children and adolescents: an epidemiologic review and a public health perspective. J Pediatr. 2000;136(5):664-672.
15. Khan LK, Sobush K, Keener D, et al; Centers for Disease Control and Prevention. Recommended community strategies and measurements to prevent obesity in the United States. MMWR Recomm Rep. 2009;58(RR-7):1-26.
16. Geiss LS, Pan L, Cadwell B, Gregg EW, Benjamin SM, Engelgau MM. Changes in incidence of diabetes in U.S. adults, 1997-2003. Am J Prev Med. 2006;30(5):371-377.
17. Flegal KM, Carroll MD, Ogden CL, Curtin LR. Prevalence and trends in obesity among US adults, 1999-2008. JAMA. 2010;303(3):235-241.
18. Alberti KG, Eckel RH, Grundy SM, et al. Harmonizing the metabolic syndrome: a joint interim statement of the International Diabetes Federation Task Force on Epidemiology and Prevention; National Heart, Lung, and Blood Institute; American Heart Association; World Heart Federation; International Atherosclerosis Society; and International Association for the Study of Obesity. Circulation. 2009;120(16):1640-1645.
19. Eeg-Olofsson K, Cederholm J, Nilsson PM, et al. Risk of cardiovascular disease and mortality in overweight and obese patients with type 2 diabetes: an observational study in 13,087 patients. Diabetologia. 2009;52(1):65-73.
20. Centers for Disease Control and Prevention (CDC). National diabetes fact sheet, 2007. Department of Health and Human Services. http://www.cdc.gov/ diabetes/pubs/pdf/ndfs-2007.pdf. Accessed October 19, 2010.
21. Cherry DK, Hing E, Woodwell DA, Rechtsteiner EA. National Ambulatory Medical Care Survey: 2006 summary. Natl Health Stat Report. 2008;6(3):1-39.
22. Nathan DM, Buse JB, Davidson MB, et al; American Diabetes Association; European Association for Study of Diabetes. Medical management of hyperglycemia in type 2 diabetes: a consensus algorithm for the initiation and adjustment of therapy: a consensus statement of the American Diabetes Association and the European Association for the Study of Diabetes. Diabetes Care. 2009;32(1):193-203.
23. DeFronzo RA. Banting Lecture: from the triumvirate to the ominous octet: a new paradigm for the treatment of type 2 diabetes mellitus. Diabetes. 2009;58(4):773-795.
24. Reichard P, Nilsson BY, Rosenqvist U. The effect of long-term intensi- fied insulin treatment on the development of microvascular complications of diabetes mellitus. N Engl J Med. 1993;329(5):304-309. (Pubitemid 23210681)
25. Diabetes Control and Complications Trial (DCCT) Research Group. The effect of intensive treatment of diabetes on the development and progression of long-term complications in insulin-dependent diabetes mellitus. N Engl J Med. 1993;329(14):977-986.
26. Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications Research Group. Retinopathy and nephropathy in patients with type 1 diabetes 4 years after a trial of intensive therapy. N Engl J Med. 2000;342(6):381-389.
27. UK Prospective Diabetes Study (UKPDS) Group 33. Intensive blood-glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes. Lancet. 1998;352(9131):837-853.
28. Fox CS, Sullivan L, D'Agostino RB Sr, Wilson PW; Framingham Heart Study. The significant effect of diabetes duration on coronary heart disease mortality: the Framingham Heart Study. Diabetes Care. 2004;27(3):704-708. (Pubitemid 38280537)
29. Wei M, Gaskill SP, Haffner SM, Stern MP. Effects of diabetes and level of glycemia on all-cause and cardiovascular mortality: the San Antonio Heart Study. Diabetes Care. 1998;21(7):1167-1172. (Pubitemid 28368527)
30. Skyler JS, Bergenstal R, Bonow RO; American Diabetes Association; American College of Cardiology Foundation; American Heart Association. Intensive glycemic control and the prevention of cardiovascular events: implications of the ACCORD, ADVANCE, and VA Diabetes Trials: a position statement of the American Diabetes Association and a Scientific Statement of the American College of Cardiology Foundation and the American Heart Association. Diabetes Care. 2009;32(1):187-192.
31. Reaven PD, Moritz TE, Schwenke DC, et al; Veterans Affairs Diabetes Trial. Intensive glucose-lowering therapy reduces cardiovascular disease events in veterans affairs diabetes trial participants with lower calcified coronary atherosclerosis. Diabetes. 2009;58(11):2642-2648.
32. Nathan DM, Cleary PA, Backlund JY, et al; Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications (DCCT/EDIC) Study Research Group. Intensive diabetes treatment and cardiovascular disease in patients with type 1 diabetes. N Engl J Med. 2005;353(25):2643-2653.
33. Ray KK, Seshasai SR, Wijesuriya S, et al. Effect of intensive control of glucose on cardiovascular outcomes and death. Lancet. 2009;373(9677):1765-1772.
34. Kelly TN, Bazzano LA, Fonseca VA, Thethi TK, Reynolds K, He J. Systematic review: glucose control and cardiovascular disease in type 2 diabetes. Ann Intern Med. 2009;151(6):394-403.
35. American Diabetes Association. New ADA initiative move beyond 'metabolic syndrome.' DOC News. 2006;3(7):1-19. http://docnews.diabetesjournals.org/ content/3/7/1.1.full. Accessed October 19, 2010.
36. Elrick H, Stimmler L, Hlad CJ Jr, Arai Y. Plasma insulin response to oral and intravenous glucose administration. J Clin Endocrinol Metab. 1964; 24:1076-1082.
37. 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(9548):1696-1705.
38. Stonehouse A, Okerson T, Kendall D, Maggs D. Emerging incretin based therapies for type 2 diabetes: incretin mimetics and DPP-4 inhibitors. Curr Diabetes Rev. 2008;4(2):101-109.
39. Scrocchi LA, Brown TJ, MaClusky N, et al. Glucose intolerance but normal satiety in mice with a null mutation in the glucagon-like peptide 1 receptor gene. Nat Med. 1996;2(11):1254-1258.
40. Ruiz-Grande C, Alarcon C, Alcantara A, et al. Renal catabolism of truncated glucagon-like peptide 1. Horm Metab Res. 1993;25(12):612-616. (Pubitemid 24001825)
41. Deacon CF. What do we know about the secretion and degradation of incretin hormones? Regul Pept. 2005;128(2):117-124.
42. Lambeir AM, Durinx C, Scharpé S, De Meester I. Dipeptidyl-peptidase IV from bench to bedside: an update on structural properties, functions, and clinical aspects of the enzyme DPP IV. Crit Rev Clin Lab Sci. 2003;40(3):209-294. (Pubitemid 36775376)
43. Amori RE, Lau J, Pittas AG. Efficacy and safety of incretin therapy in type 2 diabetes: systematic review and meta-analysis. JAMA. 2007;298(2):194-206.
44. Toft-Nielsen MB, Damholt MB, Madsbad S, et al. Determinants of the impaired secretion of glucagon-like peptide-1 in type 2 diabetic patients. J Clin Endocrinol Metab. 2001;86(8):3717-3723. (Pubitemid 32755966)
45. Holst JJ, Vilsbøll T, Deacon CF. The incretin system and its role in type 2 diabetes mellitus. Mol Cell Endocrinol. 2009;297(1-2):127-136.
46. Byetta (exenatide BID) [package insert]. San Diego, CA: Amylin Pharmaceuticals, Inc; 2009. http://pi.lilly.com/us/byetta-pi.pdf. Accessed October 19, 2010.
47. Januvia (sitagliptin) [package insert]. Whitehouse Station, NJ: Merck & Co Inc; 2007. http://www.merck.com/product/usa/pi-circulars/j/januvia/ januvia-pi.pdf. Accessed October 19, 2010.
48. Onglyza (saxagliptin) [package insert]. Princeton, NJ: Bristol-Myers Squibb Co; 2009. http://packageinserts.bms.com/pi/pi-onglyza.pdf. Accessed October 2010.
49. Victoza (liraglutide) [package insert]. Princeton, NJ: Novo Nordisk Inc; 2010. http://www.novonordisk.co.uk/Images/2009/victoza-pil.pdf. Accessed October 19, 2010.
50. Drucker DJ. Development of glucagon-like peptide-1-based pharmaceuticals as therapeutic agents for the treatment of diabetes. Curr Pharm Des. 2001;7(14):1399-1412.
51. Drucker DJ. Glucagon-like peptides: regulators of cell proliferation, differentiation, and apoptosis. Mol Endocrinol. 2003;17(2):161-171.
52. Buse JB, Rosenstock J, Sesti G, et al. Liraglutide once a day versus exenatide twice a day for type 2 diabetes: a 26-week randomised, parallel-group, multinational, open-label trial (LEAD-6). Lancet. 2009;374(9683):39-47.
53. DeFronzo RA, Okerson T, Viswanathan P, Guan X, Holcombe JH, MacConell L. Effects of exenatide versus sitagliptin on postprandial glucose, insulin and glucagon secretion, gastric emptying, and caloric intake: a randomized, cross-over study. Curr Med Res Opin. 2008;24(10):2943-2952.
54. Drucker DJ, Buse JB, Taylor K, et al. DURATION-1 Study Group. Exenatide once weekly versus twice daily for the treatment of type 2 diabetes: a randomised, open-label, non-inferiority study. Lancet. 2008;372(9645):1240-1250.
55. Kendall DM, Cuddihy RM, Bergenstal RM. Clinical application of incretin-based therapy: therapeutic potential, patient selection and clinical use. Am J Med. 2009;122(6, suppl):S37-S50.
56. Madsbad S. Liraglutide effect and action in diabetes (LEAD™) trial. Expert Rev Endocrinol Metab. 2009;4(2):119-129.
57. Triplitt C, McGill JB, Porte D Jr, Conner CS. The changing landscape of type 2 diabetes: the role of incretin-based therapies in managed care outcomes. J Manag Care Pharm. 2007;13(9, suppl C):S2-S16.
58. Bergenstal R, Wysham C, Yan P, Macconell L, Malloy J, Porter L. DURATION-2: exenatide once weekly demonstrated superior glycemic control and weight reduction compared to sitagliptin or pioglitazone after 26 weeks of treatment [abstract 6-LB]. Johns Hopkins Studies in Medicine. Somerville, NJ: Galen Publishing; 2008. http://jhasim.com/endocrinehighlights/cs-set3.cfm. Accessed October 19, 2010.
59. Pratley RE, Nauck M, Bailey T, et al; 1860-LIRA-DPP-4 Study Group. Liraglutide versus sitagliptin for patients with type 2 diabetes who did not have adequate glycemic control with metformin: a 26-week, randomized, parallel-group, open-label trial. Lancet. 2010;375(9724):1447-1456.
60. Eng J, Kleinman WA, Singh L, Singh G, Raufman JP. Isolation and characterization of exendin-4, an exendin-3 analogue, from Heloderma suspectum venom: further evidence for an exendin receptor on dispersed acini from guinea pig pancreas. J Biol Chem. 1992;267(11):7402-7405.
61. Ahrén B. DPP-4 inhibitors. Best Pract Res Clin Endocrinol Metab. 2007;21(4):517-533.
62. Baggio LL, Drucker DJ, Maida A, Lamont BJ. ADA 2008: Incretin-based therapeutics. http://medscape.com/viewprogram/15786. Last updated: 2008. Accessed June 16, 2010.
63. Nauck MA, Vilsboll T, Gallwitz B, Garber A, Madsbad S. Incretin-based therapies: viewpoints on the way to consensus. Diabetes Care. 2009;32(suppl 2):S223-S231.
64. 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(11):2628-2635.
65. DeFronzo RA, Ratner RE, Han J, et al. Effects of exenatide (exendin-4) on glycemic control and weight over 30 weeks in metformin-treated patients with type 2 diabetes. Diabetes Care. 2005;28(5):1092-1100.
66. Kendall DM, Riddle MC, Rosenstock J, et al. Effects of exenatide (exendin-4) on glycemic control over 30 weeks in patients with type 2 diabetes treated with metformin and a sulfonylurea. Diabetes Care. 2005;28(5):1083-1091.
67. Kim T, Taylor K, Wilhelm K, Trautman M, Shuang D, Porter L. Exenatide once weekly treatment effects sustained glycemic control and weight loss over 2 years [abstract 159-OR]. Diabetes. 2009;58(suppl 1):A42.
68. Garber A, Henry R, Ratner R, Hale P, Chang CT, Bode B. Monotherapy with liraglutide, a once-daily human GLP-1 analog, provides sustained reductions in A1C, FPG, and weight compared with glimepiride in type 2 diabetes: LEAD-3 Mono 2 year results [abstract 162-OR]. Diabetes. 2009;58(suppl 1):A42.
69. Marre M, Shaw J, Brandle M, et al; LEAD-1 SU Study Group. Liraglutide, a once-daily human GLP-1 analogue, added to a sulphonylurea over 26 weeks produces greater improvements in glycaemic and weight control compared with adding rosiglitazone or placebo in subjects with type 2 diabetes (LEAD-1 SU). Diabet Med. 2009;26(3):268-278.
70. Zinman B, Gerich J, Buse JB, et al; LEAD-4 Study Investigators. Ef- ficacy and safety of the human glucagon-like peptide-1 analog liraglutide in combination with metformin and thiazolidinedione in patients with type 2 diabetes (LEAD-4 MET+TZD). Diabetes Care. 2009;32(7):1224-1230.
71. DeFronzo RA, Hissa MN, Garber AJ, et al; Saxagliptin 014 Study Group. 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(9):1649-1655.
72. Ahrén B, Gomis R, Standl E, Mills D, Schweizer A. Twelve- and 52-week efficacy of the dipeptidyl peptidase IV inhibitor LAF237 in metformin-treated patients with type 2 diabetes. Diabetes Care. 2004;27(12):2874-2880.
73. Rosenstock J, Brazg R, Andryuk PJ, Lu K, Stein P; Sitagliptin Study 019 Group. Efficacy and safety of the dipeptidyl peptidase-4 inhibitor, sitagliptin, added to ongoing pioglitazone therapy in patients with type 2 diabetes: a 24-week, multicenter, randomized, double-blind, placebo-controlled, parallelgroup study. Clin Ther. 2006;28(10):1556-1568. (Pubitemid 44841980)
74. Nauck MA, Meininger G, Sheng D, Terranella L, Stein PP; Sitagliptin Study 024 Group. Efficacy and safety of the dipeptidyl peptidase-4 inhibitor, sitagliptin, compared with the sulfonylurea, glipizide, in patients with type 2 diabetes inadequately controlled on metformin alone: a randomized, doubleblind, non-inferiority trial. Diabetes Obes Metab. 2007;9(2):194-205.
75. Klonoff DC, Buse JB, Nielsen LL, et al. Exenatide effects on diabetes, obesity, cardiovascular risk factors and hepatic biomarkers in patients with type 2 diabetes treated for at least 3 years. Curr Med Res Opin. 2008;24(1):275-286.
76. Vilsbøll T, Zdravkovic M, Le-Thi, et al. Liraglutide, a long-acting human glucagon-like peptide-1 analog, given as monotherapy significantly improves glycemic control and lowers body weight without risk of hypoglycemia in patients with type 2 diabetes. Diabetes Care. 2007;30(6):1608-1610. (Pubitemid 46871185)
77. Pannacciulli N, Le DS, Salbe AD, et al. Postprandial glucagon-like peptide-1 (GLP-1) response is positively associated with changes in neuronal activity of brain areas implicated in satiety and food intake regulation in humans. Neuroimage. 2007;35(2):511-517. (Pubitemid 46400565)
78. Williams-Herman D, Johnson J, Teng R, et al. Efficacy and safety of initial combination therapy with sitagliptin and metformin in patients with type 2 diabetes: a 54-week study. Curr Med Res Opin. 2009;25(3):569-583.
79. Neumiller JJ. Differential chemistry (structure), mechanism of action, and pharmacology of GLP-1 receptor agonists and DPP-4 inhibitors. J Am Pharm Assoc (2003). 2009;49(suppl 1):S16-S29.
80. Okerson T, Yan P, Stonehouse A, Brodows R. Effects of exenatide on systolic blood pressure in subjects with type 2 diabetes. Am J Hypertens. 2010;23(3):334-339.
81. Scott R, Loeys T, Davies MJ, Engel SS. Efficacy and safety of sitagliptin when added to ongoing metformin therapy in patients with type 2 diabetes. Diabetes Obes Metab. 2008;10(10):959-969.
82. Raz I, Chen Y, Wu M, et al. Efficacy and safety of sitagliptin added to ongoing metformin therapy in patients with type 2 diabetes. Curr Med Res Opin. 2008;24(2):537-550.
83. Mistry GC, Maes AL, Lasseter KC, et al. Effect of sitagliptin, a dipeptidyl peptidase-4 inhibitor, on blood pressure in nondiabetic patients with mild to moderate hypertension. J Clin Pharmacol. 2008;48(5):592-598.
84. Rosenstock J, Agulai-Salinas C, Klein E, et al. Effect of saxagliptin monotherapy in treatment-naïve patients with type 2 diabetes. Curr Med Res Opin. 2009;25(10):2401-2411.
85. Williams-Herman DE. Long-term efficacy with sitagliptin as monotherapy or add-on therapy to metformin: improvement in glycemic control over 2 years in patients with type 2 diabetes [abstract 540-P]. Diabetes. 2009;58(suppl 1):A144.
86. UK Prospective Diabetes Study Group. UK Prospective Diabetes Study 16: overview of 6 years' therapy of type II diabetes: a progressive disease. Diabetes. 1995;44(11):1249-1258.
87. Turner RC, Cull CA, Frighi V, Holman RR; UK Prospective Diabetes Study (UKPDS) Group. Glycemic control with diet, sulfonylurea, metformin, or insulin in patients with type 2 diabetes mellitus: progressive requirement for multiple therapies (UKPDS 49). JAMA. 1999;281(21):2005-2012. (Pubitemid 29254858)
88. Drucker DJ. The biology of incretins. Cell Metab. 2006;3(3):153-165.
89. Fehse F, Trautmann M, Holst JJ, et al. Exenatide augments first- and second-phase insulin secretion in response to intravenous glucose in subjects with type 2 diabetes. J Clin Endocrinol Metab. 2005;90(11):5991-5997.
90. Mari A, Nielsen LL, Nanayakkara N, DeFronzo RA, Ferrannini E, Halseth A. Mathematical modeling shows exenatide improved beta-cell function in patients with type 2 diabetes treated with metformin or metformin and a sulfonylurea. Horm Metab Res. 2006;38(12):838-844.
91. Bunck MC, Diamant M, Cornér A, et al. One-year treatment with exenatide improves beta-cell function, compared with insulin glargine, in metformin-treated type 2 diabetic patients: a randomized, controlled trial. Diabetes Care. 2009;32(5):762-768.
92. Riche DM, East HE, Riche KD. Impact of sitagliptin on markers of beta-cell function: a meta-analysis. Am J Med Sci. 2009;337(5):321-328.
93. Monami M, Marchionni N, Mannucci E. Glucagon-like peptide-1 receptor agonists in type 2 diabetes: a meta-analysis of randomized clinical trials. Eur J Endocrinol. 2009;160(6):909-917.