Empagliflozin and linagliptin combination therapy for treatment of patients with type 2 diabetes mellitus

Expert Opinion on Pharmacotherapy

Volumn 16, Issue 18, 2015, Pages 2819-2833

  Triplitt, C ^a   Solis Herrera, C ^a   Cersosimo, E ^a   Abdul Ghani, M ^a   Defronzo, Ralph A ^a  

^a University of Texas Health Science Center at San Antonio   (United States)

Author keywords

combination therapy; DPP 4 inhibitors; SGLT2 inhibitors; type 2 diabetes mellitus

Indexed keywords

EMPAGLIFLOZIN PLUS LINAGLIPTIN; GLUCAGON; HEMOGLOBIN A1C; INCRETIN; INSULIN; METFORMIN; SODIUM GLUCOSE COTRANSPORTER 2; ANTIDIABETIC AGENT; BENZHYDRYL DERIVATIVE; DIPEPTIDYL PEPTIDASE IV INHIBITOR; EMPAGLIFLOZIN; GLUCAGON LIKE PEPTIDE 1; GLUCOSE; GLUCOSIDE; LINAGLIPTIN; SLC5A2 PROTEIN, HUMAN;

BLOOD PRESSURE; BODY WEIGHT; CARDIOVASCULAR RISK; CLINICAL EFFECTIVENESS; DIABETIC PATIENT; DRUG MARKETING; DRUG SAFETY; DRUG TOLERABILITY; GLUCAGON BLOOD LEVEL; GLUCAGON RELEASE; GLUCOSE HOMEOSTASIS; GLUCOSURIA; GLUCOTOXICITY; HEMOGLOBIN BLOOD LEVEL; HUMAN; HYPOGLYCEMIA; INSULIN RELEASE; KIDNEY PROXIMAL TUBULE; META ANALYSIS (TOPIC); NON INSULIN DEPENDENT DIABETES MELLITUS; PANCREAS ISLET; PATHOPHYSIOLOGY; PHASE 3 CLINICAL TRIAL (TOPIC); PHASE 4 CLINICAL TRIAL (TOPIC); PROTEIN EXPRESSION; RANDOMIZED CONTROLLED TRIAL (TOPIC); REVIEW; ANTAGONISTS AND INHIBITORS; COMBINATION DRUG THERAPY; DIABETES MELLITUS, TYPE 2; METABOLISM;

BENZHYDRYL COMPOUNDS; DIABETES MELLITUS, TYPE 2; DIPEPTIDYL-PEPTIDASE IV INHIBITORS; DRUG THERAPY, COMBINATION; GLUCAGON-LIKE PEPTIDE 1; GLUCOSE; GLUCOSIDES; HUMANS; HYPOGLYCEMIC AGENTS; LINAGLIPTIN; SODIUM-GLUCOSE TRANSPORTER 2;

EID: 84952717693     PISSN: 14656566     EISSN: 17447666     Source Type: Journal    
DOI: 10.1517/14656566.2015.1114098     Document Type: Review

References (105)

1. Centers for disease control and prevention: National diabetes report: estimates of diabetes and its burden in the United States, 2014. Atlanta (GA): US department of health and human services; 2014 [cited 2015 Jul 3]. Available from: www.cdc.gov/ diabetes/data/statistics/2014statisticsreport. html
2. UK Prospective Diabetes Study (UKPDS) Group. Intensive blood-glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33). Lancet. 1998;352:837-853.
3. Stratton IM, Adler AI, Neil HAW, et al. Association of glycaemia with macrovascular and microvascular complications of type 2 diabetes (UKPDS 35): prospective observational study. BMJ. 2000;321: 405-412.
4. UK Prospective Diabetes Study (UKPDS) Group. Effect of intensive blood-glucose control with metformin on complications in overweight patients with type 2 diabetes (UKPDS 34). Lancet. 1998;352:854-865.
5. Kahn SE, Haffner SM, Heise MA, et al. Glycemic durability of rosiglitazone, metformin, or glyburide monotherapy. N Eng J Med. 2006;355:2427-2443.
6. DeFronzo RA. From the triumvirate to the ominous octet: a new paradigm for the treatment of type 2 diabetes mellitus. Diabetes. 2009;58:773-795.
7. Nathan DM, Buse JB, Kahn SE, et al. Rationale and design of the glycemia reduction approaches in diabetes: a comparative effectiveness study (GRADE). Diabetes Care. 2013;36:2254-2261.
8. Abdul-Ghani MA, Puckett C, Triplitt C, et al. Initial combination therapy with metformin, pioglitazone and exenatide is more effective than sequential add-on therapy in subjects with new-onset diabetes. Results from the efficacy and durability of initial combination therapy for type 2 diabetes (EDICT): a randomized trial. Diabetes Obes Metab. 2015;17:268-275.
9. Harrison LB, Adams-Huet B, Li X, et al. Intensive therapy in newly diagnosed type 2 diabetes: results of a 6-year randomized trial. J Investig Med. 2014;62:676-686.
10. Poulsen MK, Henriksen JE, Hother-Nielsen O, et al. The combined effect of triple therapy with rosiglitazone, metformin, and insulin aspart in type 2 diabetic patients. Diabetes Care. 2003;26:3273-3279.
11. Ali MK, Bullard KM, Saaddine JB, et al. Achievement of goals in U.S. diabetes care, 1999-2010. N Engl J Med. 2013;368:1613-1624.
12. Casagrande SS, Fradkin JE, Sayday SH, et al. The prevalence of meeting A1C, blood pressure, and LDL goals among people with diabetes, 1988-2010. Diabetes Care. 2013;36:2271-2279.
13. Laiteerapong N, John PM, Nathan AG, et al. Public health implications of recommendations to individualize glycemic targets in adults with diabetes. Diabetes Care. 2013;36:84-89.
14. Garber AJ, Abrahamson MJ, Barzilay JI, et al. AACE/ACE comprehensive diabetes management algorithm 2015. Endocr Pract. 2015;21:438-447.
15. Inzucchi SE, Bergenstal RM, Buse JB, et al. Management of hyperglycemia in type 2 diabetes, 2015: a patient-centered approach: update to a position statement of the American diabetes association and the European association for the study of diabetes. Diabetes Care. 2015;38:140-149.
16. Solis-Herrera C, Triplitt C, Garduno-Garcia Jde J, et al. Mechanisms of glucose lowering of dipeptidyl peptidase-4 inhibitor sitagliptin when used alone or with metformin in type 2 diabetes: a doubletracer study. Diabetes Care. 2013;36:2756-2762.
17. Merovci A, Solis-Herrera C, Daniele G, et al. Dapagliflozin improves muscle insulin sensitivity but enhances endogenous glucose production. J Clin Invest. 2014;124:509-514.
18. Ferrannini E, Muscelli E, Frascerra S, et al. Metabolic response to sodium-glucose cotransporter 2 inhibition in type 2 diabetic patients. J Clin Invest. 2014;124:499-508.
19. Balas B, Baig MR, Watson C, et al. The dipeptidyl peptidase IV inhibitor vildagliptin suppresses endogenous glucose production and enhances islet function after single-dose administration in type 2 diabetic patients. J Clin Endocrinol Metab. 2007;92:1249-1255.
20. Bullock BP, Heller RS, Habener JF. Tissue distribution of messenger ribonucleic acid encoding the rat glucagon-like peptide-1 receptor. Endocrinology. 1996;137:2968-2978.
21. Brubaker PL, Drucker DJ. Structurefunction of the glucagon receptor family of G protein-coupled receptors: the glucagon, GIP, GLP-1, and GLP-2 receptors. Receptors Channels. 2002;8:179-188.
22. Svegliati-Baroni G, Saccomanno S, Rychlicki C, et al. Glucagon-like peptide-1 receptor activation stimulates hepatic lipid oxidation and restores hepatic signaling alteration induced by a high-fat diet in nonalcoholic steatohepatitis. Liver Int. 2011;31:1285-1297.
23. Seghieri M, Rebelos E, Gastaldelli A, et al. Direct effect of GLP-1 infusion on endogenous glucose production in humans. Diabetologia. 2013;56:156-161.
24. Gedulin B, Lawler R, Jodka C, et al. Amylin inhibits pentagastrin-stimulated gastric acid secretion: comparison with glucagon-like peptide-1 and exendin-4 (abstract). Diabetes. 1997;46:188A.
25. DeFronzo RA, Okerson T, Viswanathan P, et al. 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;24:2943-2952.
26. Schernthaner G, Barnett AH, Emser A, et al. Safety and tolerability of linagliptin: a pooled analysis of data from randomized controlled trials in 3572 patients with type 2 diabetes mellitus. Diabetes Obes Metab. 2012;14:470-478.
27. Abdul-Ghani M, DeFronzo RA. Inhibition of renal glucose reabsorption: a novel strategy for achieving glucose control in type 2 diabetes mellitus. Endocr Pract. 2008;14:782-790.
28. Wright EM, Loo DDF, Hirayama B. Biology of human sodium glucose transporters. Physiol Rev. 2011;91: 733-794.
29. Abdul-Ghani MA, DeFronzo RA, Norton L. Novel hypothesis to explain why SGLT2 inhibitors inhibit only 30-50% of filtered glucose load in humans. Diabetes. 2013;62:3324-3328.
30. Vallon V, Rose M, Gerasimova M, et al. Knockout of Na-glucose transporter SGLT2 attenuated hyperglycemia and glomerular hyperfiltration but not kidney growth or injury in diabetes mellitus. Am J Physiol Renal Physiol. 2013;304:F156-F167.
31. Powell DR, DaCosta CM, Gay J, et al. Improved glycemic control in mice lacking sglt1 and sglt2. Am J Physiol Endocrinol Metab. 2013;304:E117-E130.
32. DeFronzo RA, Davidson JA, Del Prato S. The role of the kidneys in glucose homeostasis: a new path toward normalizing glycaemia. Diabetes Obes Metab. 2012;14:5-14.
33. Rahmoune J, Thompson PW, Ward JM, et al. Glucose transporters in human renal proximal tubular cells isolated from the urine of patients with non-insulin-dependent diabetes. Diabetes. 2005;54: 3427-3434.
34. Vasilakou D, Karagiannis T, Athanasiadou E, et al. Sodium-glucose cotransporter 2 inhibitors for type 2 diabetes: a systematic review and meta-analysis. Ann Intern Med. 2013;159:262-274.
35. DeFronzo RA. Pathogenesis of type 2 diabetes: metabolic and molecular implications for identifying diabetes genes. Diabetes Reviews. 1997;5:177-269.
36. DeFronzo RA. Lilly lecture. The triumvirate: beta-cell, muscle, liver. A collusion responsible for NIDDM. Diabetes. 1988;37:667-687.
37. DeFronzo RA. Pathogenesis of type 2 diabetes mellitus. Med Clin N Am. 2004;88:787-835.
38. Kahn SE. Clinical Review 135. The importance of B-cell failure in the development and progression of type 2 diabetes. J Clin Endocrinol Metab. 2001;86: 4047-4058.
39. Bergman RN, Finegood DT, Kahn SE. The evolution of B-cell dysfunction and insulin resistance in type 2 diabetes. Eur J Clin Invest. 2002;32:35-45.
40. Rossetti L, Giaccari A, DeFronzo RA. Glucose toxicity. Diabetes Care. 1990;13:610-630.
41. Bays H, Mandarino L, DeFronzo RA. Role of the adipocyte, free fatty acids, and ectopic fat in pathogenesis of type 2 diabetes mellitus: peroxisomal proliferators-activated receptor agonists provide a rational therapeutic approach. J Clin Endo Metab. 2004;89:463-478.
42. Rossetti L, Shulman GI, Zawalich W, et al. Effect of chronic hyperglycemia on in vivo insulin secretion in partially pancreatectomized rats. J Clin Invest. 1987;80:1037-1044.
43. Kashyap S, Belfort R, Gastaldelli A, et al. A sustained increase in plasma free fatty acids impairs insulin secretion in nondiabetic subjects genetically predisposed to develop type 2 diabetes. Diabetes. 2003;52:2461-2474.
44. Muller WA, Faloona GR, Aguilar-Parada E, et al. Abnormal alpha-cell function in diabetes. response to carbohydrate and protein ingestion. N Engl J Med. 1970;283:109-115.
45. Unger RH, Aguilar-Parada E, Muller WA, et al. Studies of pancreatic alpha cell function in normal and diabetic subjects. J Clin Invest. 1970;49:837-848.
46. Aguilar-Parada E, Eisentraut AM, Unger RH. Pancreatic glucagon secretion in normal and diabetic subjects. Am J Med Sci. 1969;257:415-419.
47. Matsuda M, DeFronzo RA, Consoli A, et al. Dose response curve relation plasma glucagon to hepatic glucose production and glucose disposal in type 2 diabetes mellitus. Metabolism. 2002;51: 1111-1119.
48. Wilding JP. The role of the kidneys in glucose homeostasis in type 2 diabetes. Clinical implications and therapeutic significance through sodium glucose cotransporter 2 inhibitors. Metabolism. 2014;63:1228-1237.
49. Daniele G, Iozzo P, Molia-Carrion M, et al. Exenatide regulates cerebral glucose metabolism in brain areas associated with glucose homeostasis and reward system. Diabetes. 2015 [cited 2015 Jun 17]. DOI:10.2337/dc14-2989.
50. Nauck M, Stockmann F, Ebert R, et al. Reduced incretin effect in type 2 (noninsulin-dependent) diabetes. Diabetologia. 1986;29:46-52.
51. Vilsboll T, Holst JJ. Incretins, insulin secretion and Type 2 diabetes mellitus. Diabetologia. 2004;47(3):357-366.
52. Drucker DJ. Glucagon-like peptides. Diabetes. 1998;47:159-169.
53. Jones IR, Owens DR, Luzio S, et al. The glucose dependent insulinotropic polypeptide response to oral glucose and mixed meals is increased in patients with type 2 (non-insulin-dependent) diabetes mellitus. Diabetologia. 1989;32:668-677.
54. 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;86:3717-3723.
55. Nauck MA, Heimesaat MM, Orskov C, et al. Preserved incretin activity of glucagon-like peptide-1 [7-36 amide] but not of synthetic human gastric inhibitory polypeptide in patients with type-2 diabetes mellitus. J Clin Invest. 1993;91:301-307.
56. 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.
57. Deacon CF. Incretin-based treatment of type 2 diabetes: glucagon-like peptide-1 receptor agonists and dipeptidyl peptidase-4 inhibitors. Diabetes Obes Metab. 2007;9 (suppl 1):23-31.
58. Ferrannini E, Bjorkman O, Reichard GA, et al. The disposal of an oral glucose load in healthy subjects. a quantitative study. Diabetes. 1985;34:580-588.
59. Ahren B. Gut peptides and type 2 diabetes mellitus treatment. Curr Diab Rep. 2003;3:365-372, 1534-4827.
60. Larsson H, Berglund G, Ahren B. Glucose modulation of insulin and glucagon secretion is altered in impaired glucose tolerance. J Clin Endocrinol Metab. 1995;80:1778-1782.
61. Ahren B, Larsson H. Impaired glucose tolerance (IGT) is associated with reduced insulin-induced suppression of glucagon concentrations. Diabetologia. 2001;44:1998-2003.
62. Larsson H, Ahren B. Glucose intolerance is predicted by low insulin secretion and high glucagon secretion: outcome of a prospective study in postmenopausal Caucasian women. Diabetologia. 2000;43:194-202.
63. Unger RH. Glucagon physiology and pathophysiology. N Engl J Med. 1971;285:443-449.
64. Heller RS, Kieffer TJ, Habener JF. Insulinotropic glucagon-like peptide I receptor expression in glucagon-producing alpha-cells of the rat endocrine pancreas. Diabetes. 1997;46:785-791.
65. Kolterman OG, Buse JB, Fineman MS, et al. Synthetic exendin-4 (exenatide) significantly reduces postprandial and fasting plasma glucose in subjects with type 2 diabetes. J Clin Endocrinol Metab. 2003;88:3082-3089.
66. Kawamori R, Inagaki N, Araki E, et al. Linagliptin monotherapy provides superior glycaemic control versus placebo or voglibose with comparable safety in Japanese patients with type 2 diabetes: a randomized, placebo and active comparatorcontrolled, double-blind study. Diabetes Obes Metab. 2012;14:348-357.
67. Rauch T, Graefe-Mody U, Deacon CF. Linagliptin increases incretin levels, lowers glucagon, and improves glycemic control in type 2 diabetes mellitus. Diabetes Ther. 2012;3:10-23.
68. Graefe-Mody U, Rose P, Retlich S, et al. Pharmacokinetics of linagliptin in subjects with hepatic impairment. Br J Clin Pharmacol. 2012;74:75-85.
69. Tradjenta [package insert]. Ridgefield (CT), Boehringer Ingelheim Pharmaceuticals, 2014
70. Lewin A, DeFronzo RA, Patel S, et al. Initial combination of empagliflozin and linagliptin in subjects with type 2 diabetes. Diabetes Care. 2015;38:394-402.
71. DeFronzo RA, Lewin A, Patel S, et al. Combination of empagliflozin and linagliptin as second-line therapy in subjects with type 2 diabetes inadequately controlled on metformin. Diabetes Care. 2015;38:384-393.
72. Del Prato S, Barnett AH, Huisman J, et al. Effect of linagliptin monotherpay on glycaemic control and markers of B-cell function in patients with inadequately controlled type 2 diabetes: a randomized controlled trial. Diabetes Obes Metab. 2011;13:258-267.
73. Cersosimo E, Solis Herrera C, Trautmann ME, et al. Assessment of Pancreatic B-cell function: Review of Methods and Clinical Application. Curr Diabetes Rev. 2014;10:2-42.
74. 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.
75. Haak T, Meinicke T, Jones R, et al. Initial combination of linagliptin and metformin in patients with type 2 diabetes: efficacy and safety in a randomized, double-blind 1-year extension study. Int J Clin Prac. 2013;67:1283-1293.
76. McGill JB, Sloan L, Newman J, et al. Long-term efficacy and safety of linagliptin in patients with type 2 diabetes and severe renal impairment. a 1-year, randomized, double-blind placebo-controlled study. Diabetes Care. 2013;36:237-244.
77. Lehrke M, Marx N, Patel S, et al. Safety and tolerability of linagliptin in patients with type 2 diabetes: a comprehensive pooled analysis of 22 placebo-controlled studies. Clin Ther. 2014;36:1130-1146.
78. 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: 1317-1326.
79. Green JB, Bethel A, Armstrong PW, et al. Effect of sitagliptin on cardiovascular outcomes in type 2 diabetes. N Engl J Med. 2015 [cited 2015 Jun 8]. DOI:10.1056/ NEJMoa1501352.
80. Johansen OE, Neubacher D, Von Eynatten M, et al. Cardiovascular safety with linagliptin in patients with type 2 diabetes mellitus: a prespecified, prospective, and adjudicated meta-analysis of a phase 3 programme. Cardiovasc Diabetol. 2012;11:3-12.
81. Grempler R, Thomas L, Eckhardt M, et al. Empagliflozin, a novel selective sodium glucose cotransporter-2 (SGLT-2) inhibitor: characterization and comparison with other SGLT-2 inhibitors. Diabetes Obes Metab. 2012;14:83-90.
82. Nair S, Wilding JP. Sodium glucose cotransporter 2 inhibitors as a new treatment for diabetes mellitus. J Clin Endocrinol Metab. 2010;95:34-42.
83. Jardiance [package insert]. Ridgefield (CT), Boehringer Ingelheim Pharmaceuticals; 2015 Jun.
84. Heise T, Seewaldt-Becker E, Macha S, et al. Safety, tolerability, pharmacokinetics and pharmacodynamics following 4 weeks' treatment with empagliflozin once daily in patients with type 2 diabetes. Diabetes Obes Metab. 2013;15:613-621.
85. Roden M, Weng J, Eilbracht J, et al. Empagliflozin monotherapy with sitagliptin as an active comparator in patients with type 2 diabetes: a randomized, double-blind, placebo-controlled, phase 3 trial. Lancet Diabetes Endocrinol. 2013;1: 208-219.
86. Haring HU, Merker L, Seewaldt-Becker E, et al. Empagliflozin as add-on to metformin in patients with type 2 diabetes: a 24-week, randomized, double-blind, placebocontrolled trial. Diabetes Care. 2014;37:1650-1659.
87. Haring HU, Merker L, Seewaldt-Becker E, et al. Empagliflozin as add-on to metformin plus sulfonylurea in patients with type 2 diabetes: a 24-week, randomized, double-blind, placebo-controlled trial. Diabetes Care. 2013;36:3396-3404.
88. Kovacs CS, Seshiah V, Swallow R, et al. Empagliflozin improves glycaemic and weight control as add-on therapy to pioglitazone or pioglitazone plus metformin in patients with type 2 diabetes: a 24-week, randomized, placebo-controlled trial. Diabetes Obes Metab. 2014;16: 147-158.
89. Rosenstock J, Jelaska A, Frappin G, et al. Improved glucose control with weight loss, lower insulin doses, and no increased hypoglycemia with empagliflozin added to titrated multiple daily injections of insulin in obese inadequately controlled type 2 diabetes. Diabetes Care. 2014;37:1815-1823.
90. Liakos A, Karagiannis T, Athanasiadou E, et al. Efficacy and safety of empagliflozin for type 2 diabetes: a systematic review and meta-analysis. Diabetes Obes Metab. 2014;16:984-993.
91. Yokono M, Takasu T, Hayashizaki Y, et al. SGLT2 selective inhibitor ipragliflozin reduces body fat mass by increasing fatty acid oxidation in high-fat dietinduced obese rats. Eur J Pharmacol. 2014;727:66-74.
92. Zinman B, Wanner C, Lachin JM, et al. Empagliflozin, cardiovascular outcomes, and mortality in type 2 diabetes. N Engl J Med. 2015 [cited 2015 Sep 17]. DOI:10.1056/NEJMoa1504720.
93. Sha S, Polidori D, Heise T, et al. Effect of the sodium glucose co-transporter 2 inhibitor canagliflozin on plasma volume in patients with type 2 diabetes mellitus. Diabetes Obes Metab. 2014;16: 1087-1095.
94. Jardiance (empagliflozin). Food and Drug Administration, Center for Drug Evaluation and Research Application 2046orig1s000; [cited 2015 Jul 10]. Available from: www.accessdata.fda.gov/ drugsatfda-docs/nda/2014/ 204629Orig1s000RiskR.pdf
95. Barnett AH, Mithal A, Manassie J, et al. Efficacy and safety of empagliflozin added to existing antidiabetes treatment in patients with type 2 diabetes and chronic kidney disease: a randomised, doubleblind, placebo-controlled trial. Lancet Diabetes Endocrinol. 2014;2:369-384.
96. Peters AL, Bruschur EO, Buse JB, et al. Euglycemic diabetic ketoacidosis: a potential complication of treatment with sodium-glucose cotransporter 2 inhibition. Diabetes Care. 2015;38:1687-1693.
97. Rosenstock J, Ferrannini E. Euglycemic diabetic ketoacidosis: a predicable, detectable, and preventable safety concern with SGLT2 inhibitors. Diabetes Care. 2015;38:1638.
98. Jabbour SA, Hardy E, Sugg J, et al. Dapagliflozin is effective as add-on therapy to sitagliptin with or without metformin: a 24-week, multicenter, randomized, double-blind, placebo-controlled study. Diabetes Care. 2014;37:740-750.
99. Rosenstock J, Hansen L, Zee P, et al. Dual add-on therapy in poorly controlled type 2 diabetes on metformin: randomized, double-blind trial of saxagliptin + dapagliflozin vs saxagliptin and dapagliflozialone. Diabetes Care. 2015;38:376-383.
100. Sherifali D, Nerenberg K, Pullenayegum E, et al. The effect of oral antidiabetic agents on A1C levels: a systematic review and meta-analysis. Diabetes Care. 2010;33:1859-1864.
101. Bloomgarden ZT, Dodis R, Viscoli CM, et al. Lower baseline glycemia reduces apparent oral agent glucose-lowering efficacy: a meta-regression analysis. Diabetes Care. 2006;29:2137-2139.
102. DeFronzo RA, Stonehouse AH, Han J, et al. Relationship of baseline HbA1c and efficacy of current glucose-lowering therapies: a meta-analysis of randomized clinical trials. Diabet Med. 2010;27:309-317.
103. Jamison RA, Stark R, Dong J, et al. Hyperglucagonemia precedes a decline in insulin secretion and causes hyperglycemia in chronically glucose-infused rats. Am J Physiol Endocrinol Metab. 2100;301: E1174-E1183.
104. Rossetti L, Shulman GI, Zawalich W, et al. Effect of chronic hyperglycemia on in vivo insulin secretion in partially pancreatectomized rats. J Clin Invest. 1987;80:1037-1044.
105. Rossetti L, Smith D, Shulman GI, et al. Correction of hyperglycemia with phlorizin normalizes tissue sensitivity to insulin in diabetic rats. J Clin Invest. 1987;79:1510-1515.