PMID- 23911013 OWN - NLM STAT- MEDLINE DCOM- 20150512 LR - 20221207 IS - 1463-1326 (Electronic) IS - 1462-8902 (Linking) VI - 16 IP - 2 DP - 2014 Feb TI - Dapagliflozin in patients with type 2 diabetes receiving high doses of insulin: efficacy and safety over 2 years. PG - 124-36 LID - 10.1111/dom.12187 [doi] AB - AIMS: Dapagliflozin, a selective inhibitor of sodium-glucose cotransporter 2 (SGLT2), has been shown to improve glycaemic control, stabilize insulin dosing and mitigate insulin-associated weight gain over 48 weeks in patients whose type 2 diabetes mellitus (T2DM) was inadequately controlled despite high doses of insulin. Here the efficacy and safety of dapagliflozin therapy after a total of 104 weeks are evaluated in this population. METHODS: This was a 24-week, randomized, placebo-controlled, double-blinded, multicentre trial followed by two site- and patient-blinded extension periods of 24 and 56 weeks (NCT00673231), respectively. A total of 808 patients, whose T2DM was inadequately controlled on insulin >/=30 IU/day, with or without up to two oral antidiabetic drugs, were randomly assigned to receive placebo or 2.5, 5 or 10 mg/day of dapagliflozin for 104 weeks. At 48 weeks, patients on dapagliflozin 5 mg were switched to 10 mg. Outcomes over 104 weeks included change from baseline in HbA1c, insulin dose and body weight; analyses used observed cases and included data after insulin up-titration. Adverse events (AEs) were evaluated throughout 104 weeks. RESULTS: Five hundred and thirteen patients (63.6%) completed the study. Mean HbA1c changes from baseline at 104 weeks were -0.4% in the placebo group and -0.6 to -0.8% in the dapagliflozin groups. In the placebo group, mean insulin dose increased by 18.3 IU/day and weight increased by 1.8 kg at 104 weeks, whereas in the dapagliflozin groups, insulin dose was stable and weight decreased by 0.9-1.4 kg. AEs, including hypoglycaemia, were balanced across groups. Proportions of patients with events suggestive of genital infection and of urinary tract infection (UTI) were higher with dapagliflozin versus placebo (genital infection 7.4-14.3% vs. 3.0%; UTI 8.4-13.8% vs. 5.6%) but most occurred in the first 24 weeks and most were single episodes that responded to routine management. CONCLUSIONS: Dapagliflozin improved glycaemic control, stabilized insulin dosing and reduced weight without increasing major hypoglycaemic episodes over 104 weeks in patients whose T2DM was inadequately controlled on insulin. However, rates of genital infection and of UTI were elevated with dapagliflozin therapy. CI - (c) 2013 John Wiley & Sons Ltd. FAU - Wilding, J P H AU - Wilding JP AD - Diabetes and Endocrinology Research Group, Department of Obesity & Endocrinology, Clinical Sciences Centre, University Hospital Aintree, Liverpool, UK. FAU - Woo, V AU - Woo V FAU - Rohwedder, K AU - Rohwedder K FAU - Sugg, J AU - Sugg J FAU - Parikh, S AU - Parikh S CN - Dapagliflozin 006 Study Group LA - eng SI - ClinicalTrials.gov/NCT00673231 PT - Journal Article PT - Multicenter Study PT - Randomized Controlled Trial PT - Research Support, Non-U.S. Gov't DEP - 20130829 PL - England TA - Diabetes Obes Metab JT - Diabetes, obesity & metabolism JID - 100883645 RN - 0 (Benzhydryl Compounds) RN - 0 (Blood Glucose) RN - 0 (Glucosides) RN - 0 (Glycated Hemoglobin A) RN - 0 (Hypoglycemic Agents) RN - 0 (Insulin) RN - 0 (SLC5A2 protein, human) RN - 0 (Sodium-Glucose Transporter 2) RN - 0 (Sodium-Glucose Transporter 2 Inhibitors) RN - 0 (hemoglobin A1c protein, human) RN - 1ULL0QJ8UC (dapagliflozin) RN - 9100L32L2N (Metformin) SB - IM MH - Adolescent MH - Adult MH - Aged MH - Aged, 80 and over MH - Benzhydryl Compounds/administration & dosage/adverse effects/*therapeutic use MH - Blood Glucose/drug effects/metabolism MH - Diabetes Mellitus, Type 2/blood/*drug therapy MH - Double-Blind Method MH - Drug Therapy, Combination MH - Female MH - Genital Diseases, Female/chemically induced MH - Genital Diseases, Male/chemically induced MH - Glucosides/administration & dosage/adverse effects/*therapeutic use MH - Glycated Hemoglobin/drug effects MH - Humans MH - Hypoglycemia/chemically induced MH - Hypoglycemic Agents/*therapeutic use MH - Insulin/administration & dosage MH - Male MH - Metformin/adverse effects/*therapeutic use MH - Middle Aged MH - Sodium-Glucose Transporter 2 MH - *Sodium-Glucose Transporter 2 Inhibitors MH - Treatment Outcome MH - Urinary Tract Infections/chemically induced MH - Weight Loss/drug effects OTO - NOTNLM OT - SGLT2 inhibitor OT - glycaemic control OT - insulin OT - randomized trial OT - renal glucose handling OT - type 2 diabetes FIR - Hoppichler, F IR - Hoppichler F FIR - Luger, A IR - Luger A FIR - Prager, R IR - Prager R FIR - Roden, M IR - Roden M FIR - Kotter, T IR - Kotter T FIR - Schernthaner, G IR - Schernthaner G FIR - Borisova, A IR - Borisova A FIR - Daskalova, I IR - Daskalova I FIR - Hristozov, K IR - Hristozov K FIR - Lazarova, G IR - Lazarova G FIR - Orbetzova, M IR - Orbetzova M FIR - Petkova, M IR - Petkova M FIR - Slavcheva, A IR - Slavcheva A FIR - Stoykova, Y IR - Stoykova Y FIR - Tankova, C IR - Tankova C FIR - Veleva, N IR - Veleva N FIR - Zaharieva, S IR - Zaharieva S FIR - Ardilouze, J IR - Ardilouze J FIR - Aronson, R IR - Aronson R FIR - Boucher, P IR - Boucher P FIR - Carthy, J IR - Carthy J FIR - Dzongowski, P IR - Dzongowski P FIR - Gaudet, D IR - Gaudet D FIR - Godsell, S IR - Godsell S FIR - Goldenberg, R IR - Goldenberg R FIR - Hart, R IR - Hart R FIR - Houlden, R IR - Houlden R FIR - Kaiser, S IR - Kaiser S FIR - Khandwala, H IR - Khandwala H FIR - Landry, D IR - Landry D FIR - Lau, D IR - Lau D FIR - O'Keefe, D IR - O'Keefe D FIR - Sigalas, J IR - Sigalas J FIR - Tellier, G IR - Tellier G FIR - Twum-Barima, Y IR - Twum-Barima Y FIR - Woo, V IR - Woo V FIR - Alanko, J IR - Alanko J FIR - Kurl, S IR - Kurl S FIR - Makela, J IR - Makela J FIR - Niskanen, L IR - Niskanen L FIR - Paul, R IR - Paul R FIR - Perhonen, M IR - Perhonen M FIR - Pihlman, S IR - Pihlman S FIR - Rissanen, A IR - Rissanen A FIR - Strand, J IR - Strand J FIR - Valle, T IR - Valle T FIR - Bieler, T IR - Bieler T FIR - Fuchs, F IR - Fuchs F FIR - Gotze, D IR - Gotze D FIR - Hanefeld, M IR - Hanefeld M FIR - Molle, A IR - Molle A FIR - Paschen, B IR - Paschen B FIR - Rose, L IR - Rose L FIR - Schumacher, M IR - Schumacher M FIR - Semmler, S IR - Semmler S FIR - Sehnert, W IR - Sehnert W FIR - Tillenburg, B IR - Tillenburg B FIR - Wendisch, U IR - Wendisch U FIR - Winkelmann, B IR - Winkelmann B FIR - Bain, S IR - Bain S FIR - Farmer, I IR - Farmer I FIR - Jassel, G S IR - Jassel GS FIR - Owen, D IR - Owen D FIR - Reed, R IR - Reed R FIR - Simpson, H IR - Simpson H FIR - Strang, C IR - Strang C FIR - Wilding, J IR - Wilding J FIR - Deak, L IR - Deak L FIR - Gurzo, M IR - Gurzo M FIR - Hegyi, I IR - Hegyi I FIR - Kerenyi, Z IR - Kerenyi Z FIR - Laszloczky, A IR - Laszloczky A FIR - Pall, K IR - Pall K FIR - Penzes, J IR - Penzes J FIR - Reiber, I IR - Reiber I FIR - Revesz, K IR - Revesz K FIR - Somogyi, A IR - Somogyi A FIR - Tamas, G IR - Tamas G FIR - Vandorfi, G IR - Vandorfi G FIR - Castro Cabezas, M IR - Castro Cabezas M FIR - de Koning, E IR - de Koning E FIR - Timmerman, R IR - Timmerman R FIR - van de Wiel, A IR - van de Wiel A FIR - Crisan, C IR - Crisan C FIR - Ferariu, I IR - Ferariu I FIR - Vlaiculescu, M IR - Vlaiculescu M FIR - Arutyunov, G IR - Arutyunov G FIR - Dreval, A IR - Dreval A FIR - Grineva, E IR - Grineva E FIR - Karpova, I IR - Karpova I FIR - Kobalava, Z IR - Kobalava Z FIR - Krasilnikova, E IR - Krasilnikova E FIR - Kukharchuk, V IR - Kukharchuk V FIR - Lantseva, O IR - Lantseva O FIR - Pavlova, M IR - Pavlova M FIR - Privalov, D IR - Privalov D FIR - Strongin, L IR - Strongin L FIR - Tereschenko, S IR - Tereschenko S FIR - Vorokhobina, N IR - Vorokhobina N FIR - Zhelninova, T IR - Zhelninova T FIR - Belesova, K IR - Belesova K FIR - Fabry, J IR - Fabry J FIR - Kupcova, T IR - Kupcova T FIR - Macko, M IR - Macko M FIR - Paulovic, V IR - Paulovic V FIR - Tomasova, L IR - Tomasova L FIR - Truban, J IR - Truban J FIR - Vargova, A IR - Vargova A FIR - Calle Pascual, A IR - Calle Pascual A FIR - De Teresa Parreno, L IR - De Teresa Parreno L FIR - Duran Garcia, S IR - Duran Garcia S FIR - Freixenet, N IR - Freixenet N FIR - Gomis de Barbara, R IR - Gomis de Barbara R FIR - Gonzalez Albarran, O IR - Gonzalez Albarran O FIR - Gonzalez Clemente, J M IR - Gonzalez Clemente JM FIR - Bernstein, R IR - Bernstein R FIR - Brusco, O IR - Brusco O FIR - Graf, R IR - Graf R FIR - Freeman, J IR - Freeman J FIR - Hoekstra, J IR - Hoekstra J FIR - Khairi, R IR - Khairi R FIR - Lubin, B IR - Lubin B FIR - Norwood, P IR - Norwood P FIR - Reed, J IR - Reed J FIR - Rosenstock, J IR - Rosenstock J FIR - Soler, N IR - Soler N FIR - Sugimoto, D IR - Sugimoto D FIR - Wahl, T IR - Wahl T EDAT- 2013/08/06 06:00 MHDA- 2015/05/13 06:00 CRDT- 2013/08/06 06:00 PHST- 2013/05/16 00:00 [received] PHST- 2013/06/21 00:00 [revised] PHST- 2013/07/18 00:00 [accepted] PHST- 2013/08/06 06:00 [entrez] PHST- 2013/08/06 06:00 [pubmed] PHST- 2015/05/13 06:00 [medline] AID - 10.1111/dom.12187 [doi] PST - ppublish SO - Diabetes Obes Metab. 2014 Feb;16(2):124-36. doi: 10.1111/dom.12187. Epub 2013 Aug 29.