Diabetologie und Stoffwechsel 2015; 10(05): 247-265
DOI: 10.1055/s-0041-107247
Übersicht
© Georg Thieme Verlag KG Stuttgart · New York

Empagliflozin – Insulinunabhängige Kontrolle der Glykämieparameter bei Diabetes mellitus Typ 2 durch Inhibition des Natrium-Glukose-Cotransporters SGLT2

Empagliflozin – Insulin Independent Control of Glycaemic Parameters in Diabetes Mellitus Type 2 by Inhibition of the Sodium Glucose Linked Transporter SGLT2
B. Gallwitz
1   Medizinische Klinik IV, Universitätsklinikum Tübingen, Germany
,
L. Merker
2   Diabetes- und Nierenzentrum Dormagen, Germany
,
C. Hohberg
3   Medical Affairs Deutschland, Boehringer Ingelheim Pharma GmbH & Co. KG, Ingelheim, Germany
,
V. Schmid
3   Medical Affairs Deutschland, Boehringer Ingelheim Pharma GmbH & Co. KG, Ingelheim, Germany
,
E. Mönnig
4   Medizinische Abteilung Diabetes, Lilly Deutschland GmbH, Bad Homburg, Germany
,
M. D. Brendel
4   Medizinische Abteilung Diabetes, Lilly Deutschland GmbH, Bad Homburg, Germany
› Author Affiliations
Further Information

Publication History

19 May 2015

11 September 2015

Publication Date:
03 November 2015 (online)

Zusammenfassung

Das neue orale Antidiabetikum Empagliflozin ist ein selektiver Inhibitor des aktiven natriumabhängigen Glukosecotransporters SGLT2 (sodium glucose linked transporter 2) zur insulinunabhängigen Kontrolle des Blutzuckers bei Typ-2-Diabetes mellitus, der seit Mai 2014 in den Ländern der Europäischen Union zugelassen ist. Die SGLT2-Inhibition ist ein neuer Therapieansatz zur Blutzuckersenkung durch Hemmung der Glukosereabsorption in der Niere mit erhöhter Glukoseausscheidung über den Harn. Die Senkung des Nüchtern- und des postprandialen Blutzuckers erfolgt unabhängig von Insulinwirkung und Insulinsekretion sowie unabhängig vom Ausmaß der Insulinresistenz und des Betazellfunktionsverlustes. Es besteht kein substanzeigenes Hypoglykämierisiko. Zusätzlich führt die SGLT2-Inhibition mit Empagliflozin zur Gewichtsabnahme und Blutdrucksenkung. Dieser Übersichtsartikel erläutert das Wirkprinzip der SGLT2-Inhibition und fasst klinische Daten zu Empagliflozin in der Monotherapie, den oralen Kombinationstherapien (einschließlich gepoolter Daten) und den Kombinationstherapien mit Insulin zusammen. Der primäre Studienendpunkt war die HbA1c-Änderung. In den sieben dargestellten Studien und in der gepoolten Analyse war die mittlere HbA1c-Senkung mit Empagliflozin (10 bzw. 25 mg/Tag) klinisch relevant und statistisch signifikant versus Placebo und dem Sulfonylharnstoff Glimepirid. Je nach Studie und Dosis lagen die mittleren placebokorrigierten HbA1c-Senkungen nach 24 Wochen Therapie mit Empagliflozin bei bis zu 0,9 %.

Abstract

The new oral antidiabetic drug empagliflozin is a selective inhibitor of the active sodium glucose linked transporter 2 (SGLT2) for an insulin independent control of blood sugar in diabetes mellitus type 2; it is approved in the EU since May 2014. Inhibition of SGLT2 is a new mode of action to lower blood glucose levels by inhibiting renal glucose reabsorption resulting in increased urinary glucose excretion. Lowering of fasting and postprandial blood glucose levels occurs independent of insulin action, insulin secretion, extent of insulin resistance, and loss of beta cell function. There is no intrinsic risk for hypoglycemia. In addition, SGLT2 inhibition through empagliflozin reduces body weight and lowers blood pressure. This review describes the mode of action of SGLT2 inhibition and summarizes the clinical data available on the use of empagliflozin as single agent, when combined with other oral antidiabetics (including pooled data), and when combined with insulins. Reduction of HbA1c was the primary outcome of these studies. In all seven studies, as well as in the pooled analysis, mean HbA1c reduction with empagliflozin (10 or 25 mg/day) was clinically relevant and statistically significant versus placebo and sulfonylurea glimepiride. Depending on study design and dosage used, empagliflozin showed placebo corrected HbA1c reductions of up to 0.9 % after 24 weeks of treatment.

 
  • Literatur

  • 1 Prentki M, Nolan CJ. Islet beta cell failure in type 2 diabetes. J Clin Invest 2006; 116 (07) 1802-1812
  • 2 American Diabetes Association. Standards of medical care in diabetes – 2014. Diabetes Care 2014; 37 (Suppl. 01) 14-80
  • 3 Matthaei S, Bierwirth R, Fritsche A et al. Medikamentöse antihyperglykämische Therapie des Diabetes mellitus Typ 2. Diabetologie 2009; 4: 32-64
  • 4 Inzucchi SE, Bergenstal RM, Buse JB et al. Management of hyperglycemia in type 2 diabetes: a patient-centered approach. Diabetes Care 2012; 35: 1364-1379
  • 5 Nationale Versorgungsleitlinie Therapie des Typ-2 Diabetes, Langfassung. 2014 Version 4 1. Auflage. http://www.versorgungsleitlinien.de/themen/diabetes2 / dm2_therapie/dpf/NVL-DM2-Ther-lang-2.pdf (abgerufen am 28 August 2015)
  • 6 European Medicines Agency (EMA). Forxiga (Dapagliflozin) – European Public Assessment Report. 2012 http://www.ema.europa.eu/ema/index.jsp?curl=pages/medicines/human/medicines/002322/human_med_001546.jsp&mid=WC0b01ac058001d124 (abgerufen am 28 August 2015)
  • 7 European Medicines Agency (EMA). Invokana (Canagliflozin) – European Public Assessment Report. 2013 http://www.ema.europa.eu/ema/index.jsp?curl=pages/medicines/human/medicines/002649/human_med_001707.jsp&mid=WC0b01ac058001d124 (abgerufen am 28 August 2015)
  • 8 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
  • 9 European Medicines Agency (EMA). Jardiance (Empagliflozin) – Jardiance (Empagliflozin) – European Public Assessment Report. 2014 http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Public_assessment_report/human/002677/WC500168594.pdf (abgerufen am 28 August 2015)
  • 10 Boehringer Ingelheim/Lilly. Fachinformation Jardiance® 10 mg oder 25 mg Filmtabletten. 2014 http://www.fachinfo.de (abgerufen am 28 August 2015)
  • 11 Heise T, Seman L, Macha S et al. Safety, tolerability, pharmacokinetics, and pharmacodynamics of multiple rising doses of empagliflozin in patients with type 2 diabetes mellitus. Diabetes Ther 2013; 4 (02) 331-345
  • 12 Ferrannini E, Seman L, Seewaldt-Becker E et al. A phase IIb, randomised, placebo-controlled study of the SGLT2 inhibitor empagliflozin in patients with type 2 diabetes. Diabetes Obes Metab 2013; 15 (08) 721-728
  • 13 Abdul-Ghani MA, DeFronzo RA. Inhibition of renal glucose reabsorption: a novel strategy for achieving glucose controlin type 2 diabetes mellitus. Endocrine Practice 2008; 14 (06) 782-790
  • 14 Hardman TC, Rutherford P, Dubrey SW et al. Sodium-glucose co-transporter 2 inhibitors: from apple tree to “sweet pee”. Curr Pharm Des 2010; 16: 3830-3838
  • 15 Wright EM, Loo DF, Hirayama BA et al. Surprising versatility of Na+-glucosecotransporters: SLC5. Physiology (Bethesda) 2004; 19 (02) 370-376
  • 16 Bakris GL, Fonseca VA, Sharma K et al. Renal sodium-glucose transport: role in diabetesmellitus and potential clinical implications. Kidney Int 2009; 75: 1272-1277
  • 17 Lee YJ, Lee YJ, Han HJ. Regulator mechanisms of Na+/glucose cotransporters in renal proximal tubule cells. Kidney International 2007; 72: S27-S35
  • 18 Wright EM, Hirayama BA, Loo DF. Active sugar transport in health and disease. J Intern Med 2007; 261: 32-43
  • 19 Tahrani AA, Barnett AH, Bailey CJ. SGLT inhibitors in management of diabetes. Lancet Diabetes Endocrinol 2013; 1: 140-151
  • 20 DeFronzo RA, Davidson JA, Del Patro S. The role of the kidneys in glucose homeostasis: a new path towards normalizing glycaemia. Diabetes Obesity Metab 2012; 14: 5-14
  • 21 Rahmoune H, 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 (05) 3427-3434
  • 22 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 (04) 773-795
  • 23 Del Prato S. Role of glucotoxicity and lipotoxicity in the pathophysiology of type 2 diabetes mellitus and emerging treatment strategies. Diabet Med 2009; 14: 5-14
  • 24 Ferrannini E, Muscelli E, Frascerra S et al. Metabolic response to sodium-glucose cotransporter 2 inhibition in type 2 diabetic patients. J of Clin Invest 2014; 142 (02) 499-508
  • 25 Stanton RC. Sodium glucose transport 2 (SGLT2) inhibition decreases glomerular hyperfiltration: is there a role for SGLT2 inhibitors in diabetic kidney disease?. Circulation 2014; 129: 542-544
  • 26 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
  • 27 Maruyama H, Hisatomi A, Orci L et al. Insulin within islets is a physiologic glucagon release inhibitor. J Clin Invest 1984; 74 (06) 2296-2299
  • 28 Bonner C, Kerr-Conte J, Gmyr V et al. Inhibition of the glucose transporter SGLT2 with dapagliflozin in pancreatic alpha cells trigers glucagon secretion. Nature Med 2015; 21 (05) 512-519
  • 29 Kern M, Klöting N, Mayoux E et al. The sodium glucose cotransporter-2 (SGLT-2) inhibitor Empagliflozin improves insulin sensitivity in db/db mice in a dose-dependent manner. [poster # 1024-P]. 72nd Scientific sessions of the American Diabetes Assocation, 8–12 June 2012 Philadelphia, PA, USA:
  • 30 Aires I, Calado J. BI-10773, a sodium-glucose cotransporter 2 inhibitor for the potential oral treatment of type 2 diabetes mellitus. Curr Opin Investig Drugs 2010; 11: 1182-1190
  • 31 Macha S, Jungnik A, Hohl K et al. Effect of food on the pharmacokinetics of empagliflozin, a sodium glucose cotrabsporter 2 (SGLT2) inhibitor, and assessment of dose proportionality in healthy volunteers. Int J Clin Phrmacol Ther 2013; 51 (11) 873-879
  • 32 Riggs MM, Staab A, Seman L et al. Population pharmacokinetics of empagliflozin, a sodium glucose cotransporter 2 inhibitor, in patients with type 2 diabetes. The Journal of Clinical Pharmacology 2013; 53 (10) 1028-1038
  • 33 Brand T, Macha S, Matteus M et al. Pharmacokinetics of empagliflozin, a sodium glucose cotransporter-2 (SGLT-2) inhibitor, coadministered with sitagliptin in healthy volunteers. Adv Ther 2012; 29 (10) 889-899
  • 34 Heise T, Macha S, Mattheus M et al. Lack of interaction between the sodium glucose cotransporter 2 inhibitor empagliflozin and hydrochlorothiazide or torasemide in patients with T2DM. [poster # 33-6]. Joint 9th International Diabetes Federation Western Pacific Region (IDF-WPR) Congress and 4th Scientific Meeting of the Asian Association for the Study of Diabetes (AASD), 24–27 November 2012 Kyoto, Japan:
  • 35 Friedrich C, Metzmann K, Rose P et al. A randomized, open-label, crossover study to evaluate the pharmacokinetics of empagliflozin and linagliptin after coadministration in healthy male volunteers. Clin Ther 2013; 35 (01) A33-A42
  • 36 Macha S, Mattheus M, Pinnetti S et al. Pharmacokinetics of empagliflozin, a sodium glucose cotransporter 2 inhibitor, and glimepiride following co-administration in healthy volunteers: a randomised, open-label, crossover study. Journal of Diabetes Research & Clinical Metabolism 2012; Published online DOI: http://dx.doi.org/10.7243/2050-0866-1-14.
  • 37 Macha S, Rose P, Mattheus M et al. Pharmacokinetics, safety and tolerability of empagliflozin, a sodium glucose cotransporter 2 inhibitor, in patients with hepatic impairment. Diabetes Obes Metab 2013; 16: 118-123
  • 38 Macha S, Sennewald R, Rose P et al. Lack of clinically relevant drug-drug interaction between empagliflozin, a sodium glucose cotransporter 2 inhibitor, and verapamil, Ramipril, or digoxin in healthy volunteers. Clin Ther 2013; 35 (03) 226-235
  • 39 Macha S, Dieterich S, Mattheus M et al. Pharmacokinetics of empagliflozin, a sodium glucose cotransporter 2 (SGLT2) inhibitor, and metformin following co administration in healthy volunteers. International Journal of Clinical Pharmacology and Therapeutics 2013; 51 (02) 132-140
  • 40 Macha S, Mattheus M, Pinnetti S et al. Effect of empagliflozin on the steady-state pharmacokinetics of ethinylestradiol and levonorgestrel in healthy female volunteers. Clin Drug Investig 2013; 33 (05) 351-357
  • 41 Ring A, Brand T, Macha S et al. The sodium glucose cotransporter 2 inhibitor empagliflozin does not prolong QT interval in a thorough QT (TQT) study. Cardiovasc Diabetol 2013; 12: 70
  • 42 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
  • 43 Roden M, Weng J, Eilbracht J. EMPA-REG MONO Trial Investigators et al. Empagliflozin monotherapy improves glucose control in drug-naive patients with type 2 diabetes (T2DM). [poster 69-LB]. 73rd Sci Sess of the American Diabetes Association (ADA), 21–25 June 2013 Chicago, IL, USA:
  • 44 Roden M, Weng J, Merker L et al. Empagliflozin Monotherapy in Drug-Naïve Patients with Type 2 Diabetes (EMPA-REG EXTEND™ MONO). (abstract # 264‑OR). 74th Sci Sess of the American Diabetes Association (ADA), 13–17 June 2014 San Francisco, CA, USA:
  • 45 Häring 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, placebo-controlled trial. Diabetes Care 2014; 37: 1650-1659
  • 46 Merker L, Häring HU, Christiansen AV et al. Empagliflozin as Add-on to Metformin in Patients with Type 2 Diabetes (EMPA-REG EXTEND™ MET). San Francisco, CA, USA. [poster # 1074‑P]. 74th Sci Sess of the American Diabetes Association (ADA), 13–17 June 2014
  • 47 Ridderstråle M, Andersen KR, Zeller C et al. Comparison of empagliflozin and glimepiride as add-on to metformin in patients with type 2 diabetes: a 104-week randomised, active-controlled, double-blind, phase 3 trial. Lancet Diabetes Endocrinol 2014; 2: 691-700
  • 48 Häring HU, Merker L, Seewaldt-Becker E et al. Empagliflozin as add-on to metformin plus sulfonylurea in patients with type 2 diabetes. Diabetes Care 2013; 36: 3396-3404
  • 49 Häring HU, Merker L, Christiansen AV et al. Empagliflozin as Add-on to Metformin Plus Sulphonylurea in Patients with Type 2 Diabetes. [poster # 1077‑P]. 10th National Conference of the Primary Care Diabetes Society (PCDS), 20–21 November 2014 Birmingham, UK:
  • 50 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, double-blind, placebo-controlled trial. Lancet Diabetes Endocrinol 2014; 2: 369-384
  • 51 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
  • 52 Hach T, Gerich J, Salsali A et al. Empagliflozin improves glycemic parameters and cardiovascular risk factors in patients with type 2 diabetes (T2DM): pooled data from four pivotalphase III trials. [poster # P69-LB]. 73rd Scientific Sessions of the American Diabetes Association, 21–25 June 2013 Chicago, IL, USA:
  • 53 Kim G, Gerich J, Salsali A et al. Empagliflozin increases genital infections but not urinary tract infections (UTI) in pooled data from four pivotal phase III trials. [poster # 74-LB]. American Diabetes Association (ADA) 73rd Scientific Sessions, 21–25 June 2013 Chicago, IL, USA:
  • 54 Rosenstock J, Jelaska A, Wang F et al. Empagliflozin as add-on to basal insulin for 78 weeks improves glycemic control with weight loss in insulin-treated type 2 diabetes (T2DM). [poster # 1102-P]. 73rd Scientific Sessions of the American Diabetes Association, 21–25 June 2013, Chicago, IL, USA:
  • 55 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
  • 56 Ridderstrale M, Svaerd R, Zeller C et al. Rationale, design and baseline characteristics of a 4-year (208-week) phase III trial of empagliflozin, an SGLT2 inhibitor, versus glimepiride as add-on to metformin in patients with type 2 diabetes mellitus with insufficient glycemic control. Cardiovascular Diabetology 2013; 12 (01) 129
  • 57 Kohler S, Salsali A, Hantel S et al. Safety and tolerability of empagliflozin in patients with type 2 diabetes. [poster # 1173-P]. 75th Sci Sess of the American Diabetes Association (ADA), 5–9 June 2015 Boston, MA, USA:
  • 58 Hirji I, Guo Z, Andersson SW et al. Incidence of genital infection among patients with type 2 diabetes in the UK General Practice Research Database GPRD. J Diabetes Complications 2012; 26 (06) 501-505
  • 59 Hirji I, Guo Z, Andersson SW et al. Incidence of urinary tract infection among patients with type 2 diabetes in the UK General Practice Research Database GPRD). J Diabetes Complications 2012; 26 (06) 513-515
  • 60 Cherney D, von Eynatten M, Lund SS et al. Sodium Glucose Cotransporter 2 (SGLT2) Inhibition with Empagliflozin Reduces Microalbuminuria in Patients with Type-2 Diabetes. [poster # 1125-P]. 74th Sci Sess of the American Diabetes Association (ADA), 13–17 June 2014 San Francisco, CA, USA:
  • 61 Tikkanen I, Narko K, Zeller C et al. Empagliflozin Reduces Blood Pressure in Patients With Type 2 Diabetes and Hypertension (EMPA-REG BP). Diabetes Care 2015; 38 (03) 420-428
  • 62 Zinman B, Inzucchi SE, Lachin JM et al. Rationale, design, and baseline characteristics of a randomized, placebo-controlled cardiovascular outcome trial of empagliflozin (EMPA-REG OUTCOME™). Cardiovasc Diabetol 2014; 13: 102
  • 63 American Diabetes Association. Standards of medical care in diabetes – 2014. Diabetes Care 2014; 37 (Suppl. 01) 14-80
  • 64 Reaven GM. Banting lecture 1988: Role of insulin resistance in human disease. Diabetes 1988; 37: 1595-1607
  • 65 Prasad H, Ryan DA, Celzo MF et al. Metabolic syndrome: definition and therapeutic implications. Postgrad Med 2012; 124 (01) 21-30
  • 66 DeFronzo RA. Pathogenesis of type 2 diabetes mellitus. Med Clin North Am 2004; 88: 787-835
  • 67 Poitout V, Robertson RP. Minireview: Secondary β-Cell failure in type 2 diabetes – A Convergence of Glucotoxicity and Lipotoxicity. Endocrinology 2002; 143: 339-342
  • 68 Robertson RP, Harmon J, Tran PO et al. Glucose toxicity in β-Cells: type 2 diabetes, good radicals gone bad, and the glutathione connection. Diabetes 2003; 52: 581-587
  • 69 Rossetti L, Giaccari A, DeFronzo RA. Glucose toxicity. Diabetes Care 1990; 13: 610-630
  • 70 DeFronzo RA, Barzilai N, Simonson DC. Mechanism of metformin action in obese and lean non-insulin-dependent diabetic subjects. J Clin Endocrinol Metabol 1991; 73: 1294-1301
  • 71 Parving HH, Lewis JB, Ravid M et al. Prevalence and risk factors for microalbuminuria in a referred cohort of type II diabetic patients: a global perspective. Kidney Int 2006; 69: 2057-2063
  • 72 Merck. Fachinformation Glucophage® 500 mg/850 mg/1000 mg Filmtabletten. 2014 Abrufbar unter: www.fachinfo.de
  • 73 Holman RR, Cull CA, Turner RC. A randomized double blind trial of acarbose in type 2 diabetes shows improved glycemic control over 3 years (U.K. Prospective Diabetes Study 44). Diabetes Care 1999; 22 (06) 960-964
  • 74 Inzucchi SE. Oral antihyperglycemic therapy for type 2 diabetes: scientific review. JAMA 2002; 287 (03) 360-372
  • 75 Panten U, Burgfeld J, Goerke F et al. Control of insulin secretino by sulfonylureas, meglitinide and diazoxid in relation to their binding to their binding to the sulfonylurea receptor in pancreatic islets. Biochem Pharmacol 1989; 38 (08) 1217-1229
  • 76 Landgraf R, Kellerer M, Gallwitz B et al. Praxisempfehlungen DDG/DGIM: Therapie des Typ-2-Diabetes. Diabetologie und Stoffwechsel 2013; 2: 146-158
  • 77 United Kingdom Prosepctive 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
  • 78 Gallwitz B. The evolving place of incretin-based therapies in type 2 diabetes. Pediatr Nephrol 2010; 25: 1207-1217
  • 79 Karasik A, Aschner P, Katzeff H et al. Sitagliptin, a DPP-4 inhibitor for the treatment of patients with type 2 diabetes: a review of recent clinical trials. Curr Med Res Opin 2008; 24: 489-496
  • 80 Kung J, Henry RR. Thiazolidine safety. Expert Opin Drug Saf 2012; 11 (04) 565-579
  • 81 Takeda Pharma. Fachinformation Actos® 15 mg Tabletten. 2014 Abrufbar unter: www.fachinfo.de
  • 82 Drucker DJ, Nauck MA. The incretin system: glucagon-like peptide-1 receptor agonsits and dpetidyl peptidase-4 inhibitors in type 2 diabetes. Lancet 2006; 368: 1696-1705
  • 83 Meloni AR, DeYoung MB, Lowe C et al. GLP-1-receptor activated insulin secretion from pancreatic beta-cells: mechanism and glucose dependence. Diabetes Obes Metab 2013; 15 (01) 15-27
  • 84 Nauck MA, Vilsboll T, Gallwitz B et al. Incretin-based therapies. Viewpoints on the way to consensus. Diabetes Care 2009; 32 (Suppl. 02) 223-230
  • 85 AstraZeneca. Fachinformation BYETTA® 5 oder 10 µg Injektionslösung, Fertigpen. 2015 Abrufbar unter: www.fachinfo.de
  • 86 AstraZeneca. Fachinformation Bydureon® 2 mg Pulver und Lösungsmittel zur Herstellung einer Depot-Injektionssuspension in einem Fertigpen. 2015 Abrufbar unter: www.fachinfo.de
  • 87 Novo Nordisk. Fachinformation Victoza® 6 mg/ml Injektionslösung in einem Fertigpen. 2015 Abrufbar unter: www.fachinfo.de
  • 88 Brogden RN, Heel RC. Human insulin. A review of its biologica activity, pharmacokinetics and therapeutic use. Drugs 1987; 34 (03) 350-371
  • 89 Vajo Z, Duckworth WC. Genetically engineered insulin analogs: diabetes in the new millenium. Pharmacol Rev 2000; 52 (01) 1-9
  • 90 Lotz N, Bachmann W. Kombinationstherapie. In: Mehnert H, (Ed.) Diabetologie in Klinik und Praxis. Kap. 12. Stuttgart: Thieme; 2003: 270-280
  • 91 Bays HE, Chapman RH, Grandy S. SHIELD Investigators Group. The relationshop of body mass index to diabetes mellitus, hypertension and dyslipidaemia: comparison of data from two national surveys. In J Clin Pract 2007; 61 (05) 737-747
  • 92 Alexander CM, Landsman PB, Teutsch SM et al. NCEP-defined metabolic syndrome, diabetes, and prevalence of coronary heart disease among NHANES III participants age 50 years and older. Diabetes 2003; 52 (05) 1210-1214
  • 93 Wing RR, Marques B. Behavioral aspects of weight loss in type 2 diabetes. Curr Diabe Rep 2008; 8 (02) 126-131
  • 94 Hach T, Lambers Heerspink H et al. The sodium glucose cotransporter 2 (SGLT2) inhibitor empagliflozin lowers blood pressure independent of weight or HbA1c changes. [poster # 65]. Proceedings of the 4th World Congress on Controversies in Diabetes, Obesity, and Hypertension (CODHy), 8–11 November 2012 Barcelona, Spain:
  • 95 Scheen AJ. Evaluating SGLT2 inhibitors for type 2 diabetes: pharmacokinetic and toxicological considerations. Expert Opin Drug Metab Toxicol 2014; 10 (05) 647-663
  • 96 Cherney DZI, Perkins BA, Soleymanlou N et al. The effect of empagliflozin on arterial stiffness and heart rate variability in subjects with uncomplicated type 1 diabetes mellitus. Cardiovasc Diabet 2014; 13: 28
  • 97 Garber AJ, Abrahamson MJ, Barzilay JI. American Association of Clinical Endocrinologists. et al. AACE comprehensive diabetes management algorithm 2013. Endocr Pract 2013; 19 (02) 327-336
  • 98 Cherney DZ, Perkins BA, Soleymanlou N et al. The renal hemodynamic effect of SLGT2 inhibition in patients with type 1 diabetes. Circulation 2014; 129: 587-597
  • 99 Vallon V, Gerasimova M, Rose MA et al. SGLT2 inhibitor empagliflozin reduces renal growth and albuminuria in proportion to hyperglycemia and prevents glomerular hyperfiltration in diabetic Akita mice. Am J Physiol Renal Physiol 2014; 306 (02) 194-204
  • 100 Ruggenenti P, Remuzzi G. Dreaming of normoglycaemia with fewer diet restrictions. Lancet Diabetes Endocrinol 2014; 2 (05) 350-351
  • 101 Geerlings S, Fonseca V, Castro-Diaz D et al. Genital and urinary tract infections in diabetes: impact of pharmacologically-induced glucosuria. Diabetes Res Clin Pract 2014; 103 (03) 373-381
  • 102 Santer R, Kinner M, Lassen CL et al. Molecular analysis of the SGLT-2 gene in patients with renal glucosuria. J Am Soc Nephrol 2003; 14: 2873-2882
  • 103 Santer R, Calado J. Familial renal glucosuria and SGLT2: from a Mendelian trait to a therapeutic target. Clin J Am Soc Neph 2010; 5: 133-141
  • 104 Toto R, Wanner C, Gerich J et al. No Overall Increase in Volume Depletion Events with Empagliflozin (EMPA) in a Pooled Analysis of More Than 11000 Patients with Type 2 Diabetes (T2DM). [poster # SA‑PO373]. 46th Annual Meeting of the American Society of Nephrology, 5–11 November 2013, Atlanta, GA, USA