Clinical Care/Education/Nutrition/Psychosocial Research ORIGINAL ARTICLE Insulin Degludec Versus Insulin Glargine in Insulin-Naive Patients With Type 2 Diabetes A 1-year, randomized, treat-to-target trial (BEGIN Once Long) 1 6 BERNARD ZINMAN, MD LARS ENDAHL, PHD as a result of b-cell failure. Approximately 2 7 ATHENA PHILIS-TSIMIKAS, MD CHANTAL MATHIEU, MD 3 50% of patients with type 2 diabetes may BERTRAND CARIOU, MD, PHD ON BEHALF OF THE NN1250-3579 4 require insulin therapy in addition to oral YEHUDA HANDELSMAN, MD (BEGIN ONCE LONG)TRIAL 5 antidiabetic drugs (OADs) within 6 years HELENA W. RODBARD, MD INVESTIGATORS* 6 of diabetes diagnosis (2,3). Clinical guide- THUE JOHANSEN, MD lines by the American Diabetes Associa- tion and European Association for the OBJECTIVEdTo compare ultra–long acting insulin degludec with glargine for efficacy and Study of Diabetes currently recommend safety in insulin-naive patients with type 2 diabetes inadequately controlled with oral antidiabetic initiating basal insulin in patients with drugs (OADs). type 2 diabetes either directly after met- formin or after maximizing a combination RESEARCH DESIGN AND METHODSdIn this 1-year, parallel-group, randomized, of OADs with or without glucagonlike 2 open-label, treat-to-target trial, adults with type 2 diabetes with A1C of 7 10% taking OADs peptide-1 receptor agonists and then ti- were randomized 3:1 to receive once daily degludec or glargine, both with metformin. Insulin trating insulin to meet a glycosylated he- was titrated to achieve prebreakfast plasma glucose (PG) of 3.924.9 mmol/L. The primary end fi moglobin (A1C) target of 7% without point was con rmation of noninferiority of degludec to glargine in A1C reduction after 52 weeks fi in an intent-to-treat analysis. signi cant hypoglycemia (4,5). Several barriers to introducing insulin RESULTSdIn all, 1,030 participants (mean age 59 years; baseline A1C 8.2%) were random- have been identified that may result in ized (degludec 773, glargine 257). Reduction in A1C with degludec was similar (noninferior) to delayed achievement of glycemic control that with glargine (1.06 vs. 1.19%), with an estimated treatment difference of degludec to and progression of diabetes complica- glargine of 0.09% (95% CI 20.04 to 0.22). Overall rates of confirmed hypoglycemia (PG ’ , tions (6,7). These barriers include patients 3.1 mmol/L or severe episodes requiring assistance) were similar, with degludec and glargine fear of injections and misconceptions at 1.52 versus 1.85 episodes/patient-year of exposure (PYE). There were few episodes of noc- ’ turnal confirmed hypoglycemia in the overall population, and these occurred at a lower rate with about insulin therapy, clinicians fear of degludec versus glargine (0.25 vs. 0.39 episodes/PYE; P = 0.038). Similar percentages of patients perceived complexity of insulin regimens, in both groups achieved A1C levels ,7% without hypoglycemia. End-of-trial mean daily insulin andbothparties’ fear that introducing doses were 0.59 and 0.60 units/kg for degludec and glargine, respectively. Adverse event rates insulin will negatively affect patient life- were similar. style and weight gain (8). Additionally, d the risk, consequences, and fear of hy- CONCLUSION Insulins degludec and glargine administered once daily in combination poglycemia remain a significant limiting with OADs provided similar long-term glycemic control in insulin-naive patients with type 2 diabetes, with lower rates of nocturnal hypoglycemia with degludec. factor in intensifying insulin therapy and optimizing glycemic control (9). Long-acting insulin analogs have beendevelopedtoproduceamorephys- iological basal insulin action than seen he increasing prevalence of type 2 The landmark U.K. Prospective Diabetes fi with such human insulin preparations as Tdiabetes and its associated com- Study demonstrated the bene ts of im- neutral protamine Hagedorn (NPH) in- fi plications pose a signi cant global proved glucose control and highlighted sulin, and they are associated with lower health care and economic burden (1). the progressive nature of type 2 diabetes hypoglycemia rates (particularly noctur- ccccccccccccccccccccccccccccccccccccccccccccccccc nal) while achieving similar glycemic 1 control (10–12). These analogs have low- From the Samuel Lunenfeld Research Institute, Mount Sinai Hospital, University of Toronto, Toronto, Ontario, Canada; the 2Scripps Whittier Diabetes Institute, La Jolla, California; the 3Clinique d’Endocrinologie, ered the barrier for insulin introduction in l’Institut du Thorax, CHU Nantes, Nantes, France; the 4Metabolic Institute of America, Tarzana, California; patients with type 2 diabetes and are rec- 5Endocrine and Metabolic Consultants, Rockville, Maryland; 6Novo Nordisk A/S, Søborg, Denmark; and 7 ommended when OADs alone cannot UZ Leuven, University of Leuven, Leuven, Belgium. maintain glucose control (10,12,13). Corresponding author: Chantal Mathieu, [email protected]. Received 21 June 2012 and accepted 28 August 2012. There is still a need, however, for the devel- DOI: 10.2337/dc12-1205. Clinical trial reg. no. NCT00765817, clinicaltrials.gov. opment of basal insulins with improved This article contains Supplementary Data online at http://care.diabetesjournals.org/lookup/suppl/doi:10 pharmacokinetics and pharmacodynamics, .2337/dc12-1205/-/DC1. with the goal of achieving glycemic targets *A complete listing of trial investigators are listed in the Supplementary Data online. © 2012 by the American Diabetes Association. Readers may use this article as long as the work is properly in more patients with even less hypogly- cited, the use is educational and not for profit, and the work is not altered. See http://creativecommons.org/ cemic risk (14). Insulin degludec is a licenses/by-nc-nd/3.0/ for details. novel, ultra–long acting basal insulin. On care.diabetesjournals.org DIABETES CARE 1 Diabetes Care Publish Ahead of Print, published online October 5, 2012 Initiating insulin degludec in type 2 diabetes subcutaneous injection, degludec forms a frequency of OADs (metformin mono- measured blood glucose with a glucose depot of soluble multihexamers that dis- therapy or metformin in any combination meter (Abbott Diabetes Care, Abbot Park, sociates slowly and consistently, resulting with insulin secretagogues [sulfonyl- IL), with test strips calibrated to plasma in a flat, stable profile and a duration of urea or glinide, DPP-4 inhibitor] or a- values to obtain PG readings. The frequent action longer than 42 h (15,16). A previ- glucosidase-inhibitor) for $3months visit schedule for first 26 weeks and treat- ous phase 2 clinical trial comparing once before screening. Participants were ex- to-target approach were chosen to ensure daily degludec with glargine in insulin- cluded if they received thiazolidinediones, optimal titration. naive patients with type 2 diabetes (17) and exenatide or liraglutide within 3 months The primary end point was change in two phase 3 studies comparing once daily of screening or if they had clinically signi- A1C from baseline after 52 weeks. Other degludec with glargine in basal-bolus ficant cardiovascular, hepatic, renal or efficacy assessments included change therapy in patients with type 1 (18) and oncologic disease; recurrent severe hypo- from baseline in central laboratory– type 2 diabetes (19) demonstrated that glycemia; hypoglycemia unawareness; or measured fasting PG (FPG), SMBG, A1C degludec provides similar glycemic con- proliferative retinopathy. ,7% responders, and functional health trol with less hypoglycemia than glargine. Eligible participants were random- status (assessed by the 36-item short- BEGIN Once Long is the largest phase ized 3:1 to receive once daily degludec form health survey version 2.0 [SF-36]). 3 study in the clinical development pro- (100 U/mL, 3 mL PDS290; Novo Nor- Safety assessments included adverse gram of insulin degludec and was de- disk, Bagsværd, Denmark) or glargine events (AEs), hypoglycemic episodes, in- signed as a 52-week, treat-to-target trial to (Lantus, 100 U/mL, 3 mL SoloStar; sanofi- sulin dose, body weight, injection site compare the efficacy and safety of insulin aventis, Paris, France) by means of a cen- reactions, abnormal findings related degludec with those of insulin glargine, tralized, computer–generated, interactive to physical examination, vital signs, both administered in a basal regimen in voice and web response system that gener- fundoscopy, electrocardiogram (ECG), combination with metformin, in insulin- ated randomization blocks. Randomization and laboratory tests (including insulin naive participants with type 2 diabetes (3:1) ensured adequate exposure to de- antibodies). Confirmed hypoglycemic ep- inadequately controlled with OADs. gludec in accordance with regulatory guide- isodes included either episodes con- lines (22). Investigators and participants firmed by SMBG corresponding to PG RESEARCH DESIGN AND were not blinded to treatment. Treatment value ,3.1mmol/Lorsevereepisodes METHODSdThis 52-week, random- group assignment was blinded for individ- requiring assistance (no SMBG confirma- ized, controlled, parallel-group, open- uals involved as titration surveillance mon- tion) (4). Hypoglycemic episodes occur- label, multinational, treat-to-target, itors, internal safety committee members, ring from 0001 to 0559 h (inclusive) were noninferiority trial compared the efficacy external committee members responsible classified as nocturnal. Treatment-emergent and safety of once daily insulin degludec for cardiovascular