New Therapies for Diabetes Management

Abstract

Diabetes Technology & TherapeuticsVol. 15, No. S1 Original ArticlesFree AccessNew Therapies for Diabetes ManagementSatish K. GargSatish K. GargSearch for more papers by this authorPublished Online:26 Feb 2013https://doi.org/10.1089/dia.2013.1514AboutSectionsPDF/EPUB ToolsPermissionsDownload CitationsTrack CitationsAdd to favorites Back To Publication ShareShare onFacebookTwitterLinked InRedditEmail IntroductionDespite all of the advances in the availability of new drugs and devices in the past two decades, the diabetes treatment outcome continues to be suboptimal. Part of the reason for not achieving target A1c in subjects with diabetes may be due to improper timing and implementation of these drugs and devices in day-to-day management. In this chapter, we review current therapies (insulin and oral medications) for management of type 1 and type 2 diabetes. We are not going to address any of the devices, and some of the insulin treatments, in this chapter as they have been previously discussed in other chapters on the use of CGM, insulin pump, and insulin treatment options.SGLT2 inhibitors: a new emerging therapeutic class in the treatment of type 2 diabetes mellitusGhosh RK 1, Ghosh SM2, Chawla S3, Jasdanwala SA11Maulana Azad Medical College, New Delhi, India; 2Lady Hardinge Medical College, New Delhi, India; and 3University of Delhi, New Delhi, IndiaClin Pharmacol 2012;52: 457–63The global incidence of type 2 diabetes mellitus continues to increase. Existing therapeutic classes of antidiabetic drugs are not adequate for maintaining long-term glycemic control in most patients, even when used in combination. Sodium glucose cotransporter 2 (SGLT2) inhibitors represent a promising new therapeutic class of antidiabetic drugs. SGLT2 accounts for 90% of glucose reabsorption in the kidney. SGLT2 inhibitors increase urinary excretion of glucose, resulting in lower plasma glucose concentrations independent of insulin levels. Dapagliflozin is the lead molecule in development in this class. It is currently in a phase III clinical trial. Other members of this class (e.g., sergliflozin and remogliflozin) are in various stages of clinical testing. This class of novel agents can effectively control blood sugar level without producing weight gain or hypoglycemia. Results of ongoing phase III clinical trials will be critical for determining whether the risk–benefit ratio will support the approval of this new class of drugs for the management of type 2 diabetes mellitus.A novel series of glucagon receptor antagonists with reduced molecular weight and lipophilicityFilipski KJ, Bian J, Ebner DC, Lee EC, Li JC, Sammons MF, Wright SW, Stevens BD, Didiuk MT, Tu M, Perreault C, Brown J, Atkinson K, Tan B, Salatto CT, Litchfield J, Pfefferkorn JA, Guzman-Perez APfizer Worldwide Research & Development, Groton, CTBioorg Med Chem Lett 2012;22: 415–20A novel series of glucagon receptor antagonists with better druglike properties than existing molecules has been discovered. These pyrazole ethers and aminopyrazoles have lower molecular weight and increased polarity. The work presented here describes two new glucagon receptor antagonists, compounds 44 and 50, which were shown to have good pharmacokinetic properties in dogs, compared to rats, in which clearance was high. This study also evaluated compound 49, which demonstrated a dose-dependent reduction in glucose excursion in a rat glucagon challenge experiment.Linagliptin: the newest dipeptidyl peptidase-4 inhibitor for type 2 diabetes mellitusAletti R, Cheng-Lai ADepartment of Pharmacy, Montefiore Medical Center/Jack D. Weiler Hospital of the Albert Einstein College of Medicine, Bronx, NYCardiol Rev 2012;20: 45–51Dipeptidyl peptidase-4 (DPP-4) inhibitors are some of the newest medications used in the management of patients with type 2 diabetes mellitus. By inhibiting DPP-4 enzyme, these compounds increase the amount of circulating incretin hormones, leading to greater insulin release and suppression of glucagon secretion. Linagliptin is the third DPP-4 inhibitor approved by the U.S. Food and Drug Administration. It has the potential for use as monotherapy or as an adjunctive therapy in dual or triple combination regimens with other oral agents. Linagliptin results in a decrease in glycosylated hemoglobin by about 0.4% when used as monotherapy and by about 0.5% to 1.1% when used in combination with other oral antihyperglycemic agents. (The body excretes about 80% of linagliptin via the enterohepatic system.) Since only a minimal amount is eliminated through renal excretion, dosage adjustment is not necessary in patients with renal impairment. Another advantage of linagliptin is its favorable safety profile, with nasopharyngitis being one of the more commonly observed side effects. The promising safety and efficacy profiles of linagliptin make it a good alternative to the other two agents in this class, especially for patients with renal impairment. This article reviews the pharmacologic and pharmacokinetic properties of linagliptin. Key differences among the three available DPP-4 inhibitors are also examined.Empagliflozin, a novel selective sodium glucose cotransporter-2 (SGLT-2) inhibitor: characterisation and comparison with other SGLT-2 inhibitorsGrempler R 1, Thomas L1, Eckhardt M2, Himmelsbach F2, Sauer A3, Sharp DE4, Bakker RA1, Mark M 1, Klein T 1, Eickelmann P 11CardioMetabolic Diseases Research, Boehringer Ingelheim Pharma GmbH & Co.KG, Biberach, Germany; 2Medicinal Chemistry, Boehringer Ingelheim Pharma GmbH & Co.KG, Biberach, Germany; 3Drug Discovery Support, Boehringer Ingelheim Pharma GmbH & Co.KG, Biberach, Germany; and 4Drug Metabolism and Pharmacokinetics, Boehringer Ingelheim Pharmaceuticals Inc., Ridgefield, CTDiabetes Obes Metab 2012;14: 83–90ObjectivesEmpagliflozin is a selective sodium glucose cotransporter-2 (SGLT-2) inhibitor in clinical testing for the treatment of patients with type 2 diabetes mellitus. The purpose of this study was to assess the pharmacological properties of empagliflozin in vitro as well as its pharmacokinetic properties in vivo and to compare the drug's potency and selectivity with other SGLT-2 inhibitors.Methods[(14)C]-alpha-methyl glucopyranoside (AMG) uptake experiments were performed in stable cell lines over-expressing human (h)SGLT-1, 2, and 4. Two new cell lines over-expressing hSGLT-5 and hSGLT-6 were established, and [(14)C]-mannose and [(14)C]-myo-inositol uptake assays were developed. To analyze binding kinetics, a radioligand binding assay with [(3)H]-labeled empagliflozin and HEK293-hSGLT-2 cell membranes was used. Tests to assess acute in vivo pharmacokinetics were performed in normoglycemic beagle dogs and Zucker diabetic fatty (ZDF) rats.ResultsEmpagliflozin has an IC(50) of 3.1 nM for hSGLT-2. Binding of empagliflozin to SGLT-2 is competitive with glucose (half-life approximately 1 h). Compared with other SGLT-2 inhibitors, empagliflozin has a high degree of selectivity over SGLT-1, 4, 5, and 6. Species differences in SGLT-1 selectivity were identified. Pharmacokinetic studies in ZDF rats demonstrated moderate total plasma clearance (CL) and bioavailability (BA), while in beagle dogs CL was low and BA was high.ConclusionsEmpagliflozin is a potent and competitive SGLT-2 inhibitor with an excellent selectivity profile and the highest selectivity window of the tested SGLT-2 inhibitors over hSGLT-1. Empagliflozin represents an innovative therapeutic option for the treatment of patients with diabetes.Novel heterocyclic DPP-4 inhibitors for the treatment of type 2 diabetesSutton JM 1, Clark DE 1, Dunsdon SJ 1, Fenton G1, Fillmore A1, Harris NV1, Higgs C1, Hurley CA1, Krintel SL1, MacKenzie RE1, Duttaroy A2, Gangl E2, Maniara W2, Sedrani R3, Namoto K3, Ostermann N3, Gerhartz B3, Sirockin F3, Trappe J3, Hassiepen U3, Baeschlin DK31Argenta Discovery 2009 Ltd, Harlow, United Kingdom; 2Novartis Institutes for BioMedical Research, Cambridge, MA; and 3Novartis Institutes for BioMedical Research, Novartis Campus, Basel, SwitzerlandBioorg Med Chem Lett 2012;22: 1464–8Erratum in Bioorg Med Chem Lett 2012;22: 2359Newly discovered deazaxanthine-based DPP-4 inhibitors are shown to be potent (IC(50) <10nM) and highly selective compared to other dipeptidyl peptidases. This report describes their synthesis, SAR, and initial efforts to improve their pharmacokinetic profile by modification of the deazaxanthine core. Optimization of compound 3a led to the identification of compound (S)-4i, which displayed an improved in vitro and ADME profile. Further enhancements to the PK profile were achieved by changing from the deazahypoxanthine to the deazaxanthine template, leading to the development of compound 12g, which displayed good ex vivo DPP-4 inhibition and a superior PK profile in rats, which suggests the potential for once-daily dosing in humans.Inhibition of apical sodium-dependent bile acid transporter as a novel treatment for diabetesChen L1, Yao X 1, Young A1, McNulty J 1, Anderson D 1, Liu Y 1, Nystrom C 1, Croom D 1, Ross S 1, Collins J2, Rajpal D3, Hamlet K 1, Smith C 1, Gedulin B 4Departments of 1Biology, 2Medicinal Chemistry, and 3Computational Biology, Quantitative Science, Metabolic Drug Discovery, GlaxoSmithKline, Inc., Research Triangle Park, NC; and 4Lumena Pharmaceuticals, Inc., San Diego, CAAm J Physiol Endocrinol Metab 2012;302: E68–76Bile acids modulate metabolic activity. This study evaluated the effects of a potent apical sodium-dependent bile acid transporter (Asbt) inhibitor (264W94), which blocks intestinal absorption of bile acids, on glucose homeostasis in Zucker diabetic fatty (ZDF) rats. Following two weeks of oral 264W94, fecal bile acid concentrations had increased and nonfasting plasma total Glp-1 was elevated. Treatment with 264W94 resulted in a significant decrease in HbA1c and glucose and prevented the drop in insulin levels typically seen in ZDF rats in a dose-dependent manner. An oral glucose tolerance test revealed up to a two-fold increase in plasma total Glp-1 and a three-fold increase in insulin in ZDF rats treated with 264W94 at doses sufficient to achieve glycemic control. Tissue mRNA analysis indicated a decrease in farnesoid X receptor (Fxr) activation in the small intestines and the liver; however, coadministration of an Fxr agonist (GW4064) did not attenuate the 264W94-induced glucose-lowering effects. These results demonstrate that inhibition of Asbt increases bile acid levels in the distal intestine and promotes Glp-1 release. This approach may represent an effective new strategy for treating patients with type 2 diabetes mellitus.CommentThe above six studies continue to explore new horizons in type 2 diabetes management, specifically SGLT-2 inhibitors, glucagon receptor antagonist, and DPP4 inhibitors. None of the SGLT-2 inhibitors have been approved by the FDA; however, one is pending FDA approval (canaglifozin). The long-term safety of these drugs is unknown, especially with Dapaglifozin. There was a disproportionate, though insignificant, increase in breast and bladder cancer. The future studies are ongoing to look at the effect of SGLT-2 inhibitions on other organs. There is also an attempt to study the effect of combined SGLT-2 and 1 inhibitors on glucose control. Some of the pharmaceutical companies are exploring the role of these drugs in type 1 diabetes. DPP4 inhibition has only shown modest response in glucose control in type 1 diabetes, especially in those individuals with positive C-peptide levels. There are studies that are ongoing in early stages of exploring the role of SGLT-2 inhibitors in type 1 diabetes.Interleukin-1 receptor antagonist: a new therapy for type 2 diabetes mellitusAkash MS, Shen Q, Rehman K, Chen SInstitute of Pharmacology, Toxicology and Biochemical Pharmaceutics, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, Zhejiang Province, ChinaJ Pharm Sci 2012;101: 1647–58A variety of complex mechanisms and pathways have a role in provoking low-grade local and systemic inflammation in β-cells of pancreatic islets and peripheral tissues, causing β-cell dysfunction and apoptosis, insulin resistance, and ultimately, overt type 2 diabetes mellitus (T2DM). Conventional antidiabetic agents have potential adverse effects, and there is a need for alternative treatments. Currently, Interleukin-1 receptor antagonist (IL-1Ra) is the only anti-inflammatory therapeutic modality that has been approved by U.S. Food and Drug Administration to treat patients with T2DM. We compared IL-1Ra with other anti-inflammatory agents and conventional antidiabetic agents. Although IL-1Ra has broad-spectrum, anti-inflammatory activity, it has disadvantages due to its short half-life. To overcome this problem, we fused IL-1Ra with recombinant human serum albumin and expressed it in Pichia pastoris. The bioactivity was confirmed in IL-1-induced A375.S2 apoptotic cells. We also formulated IL-1Ra with Pluronic F-127–based thermo sensitive gel and investigated its in vitro characteristics related to duration of its therapeutic effects. Further studies are required to evaluate IL-1Ra's therapeutic efficacy in diabetes and diabetes-associated complications.CommentInterleukin-1 has been evaluated for its role in type 2 diabetes. New modulation in type 2 diabetes may have an effect in protecting beta-cell destruction by reducing inflammation. It is unknown if this effect is autoimmune in nature.A novel technique for the transplantation of pancreatic islets within a vascularized device into the greater omentum to achieve insulin independenceKriz J 1, Vilk G2,3,4, Mazzuca DM2,3,4, Toleikis PM4, Foster PJ 1, White DJG1,2,3,41Robarts Research Institute, University of Western Ontario, London, Ontario, Canada; 2Departments of Surgery and Pathology, University of Western Ontario, London, Ontario, Canada; 3Islet Transplantation Program, London Health Sciences Center, London, Ontario, Canada; and 4Sernova Corp., London, Ontario, CanadaAm J Surg 2012;203: 793–7BackgroundThe greater omentum presents a promising location for islet transplantation due to its vascularization and blood flow. However, there is a need to provide a controlled and protected site for the islet cells within the omentum that would be suitable for use with donor islets and future stem cell technologies. This report describes a novel device with a subcutaneous delivery port that is implanted within the omentum and offers an environment for donor islets.MethodsA prototype cell-pouch device was wrapped in the greater omentum of diabetic Lewis rats. An islet implantation port was exposed subcutaneously. After tissue growth throughout the device, islet isografts were implanted and long-term glucose control was evaluated.ResultsThis technique resulted in long-term normal blood glucose levels in 7 of 10 diabetic rat recipients after minimal islet dose transplants. Histologic assessment confirmed collagen formation and vascularization within the device.ConclusionsThe implanted device provides a safe and efficacious environment to support the growth of transplanted pancreatic islet cells contained within a removable delivery device and administered as a cell therapy in a highly vascularized setting.CommentThere continues to be interest in improving implanted devices for pancreatic islets. This study was done in rats with the hope that it will be applicable in humans.Patients with type 2 diabetes initiating exenatide twice daily or insulin in clinical practice: CHOICE studyMatthaei S1, Reaney M2, Mathieu C3, Ostenson CG4, Krarup T5, Guerci B6, Kiljanski J7, Petto H8, Bruhn D9, Theodorakis M101Diabetes-Zentrum Quakenbr ck, Fachabteilung fur Diabetologie, Stoffwechsel und Endokrinologie am Christlichen Krankenhaus, Klinisches Diabeteszentrum der DDG, Akademisches Lehrkrankenhausder Medizinischen Hochschule Hannover, Quakenbruck, Germany; 2Eli Lilly, Windlesham, Surrey, United Kingdom; 3Department of Endocrinology, UZ Gasthuisberg, Leuven, Belgium; 4Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden; 5Department of Endocrinology I, Bispebjerg Hospital, Copenhagen, Denmark; 6Diabetologu, Nutrition, Metabolic Disroders, Brabois Hospital and Center of Clinical Investigation ILCV, CHU de Nancy, Vandoeuvre-Les-Nancy, France; 7Eli Lilly, Warsaw, Poland; 8Eli Lilly, Vienna, Austria; 9Eli Lilly, San Diego, CA; and 10Department of Clinical Therapeutics, University of Athens School of Medicine, Athens, GreeceDiabetes Ther 2012;3: 6IntroductionInitiating injectable therapy (CHOICE) is a European prospective, observational cohort study designed to assess time and factors associated with a significant change in therapy after patients with type 2 diabetes initiated their first injectable glucose-lowering therapy and to assess clinical outcomes over a 24-month period. Baseline data and factors associated with the injectable treatment regimen are reported.MethodsDemographic, clinical, and healthcare resource-use data were collected at initiation of injectable therapy and analyzed using univariate tests between cohorts and multivariate logistic regression analysis for treatment.ResultsOverall, 1,177 patients initiated therapy with exenatide twice daily (bid), and 1,315 began insulin therapy. Patient recruitment was mainly by secondary-care physicians. Univariate analyses revealed statistically significant differences between the characteristics of patients who initiated exenatide bid and patients who initiated insulin. On multivariate analysis, higher body mass index [BMI; 5 kg/m2 higher: odds ratio (OR) 2.10, 95% confidence intervals {CI; 1.84–2.40}, lower glycated hemoglobin (HbA1c; 1% higher: OR 0.77, 95% CI 0.69–0.86), and younger age (5 years older: OR 0.82, 95% CI 0.76–0.88) were the variables most strongly associated with increased probability of receiving exenatide bid (p<0.0001). Patients initiating exenatide bid had a mean BMI of 35.3±6.5 kg/m2, HbA(1c) of 8.4±1.4%, and age of 58±10 years; the comparative values for patients initiating insulin (p<0.0001) were 29.7±5.4 kg/m2, 9.2±1.9%, and 64±11 years, respectively. Other characteristics significantly associated with initiation of exenatide bid were “disinhibited eating” (Diabetes Health Profile-18), lower random blood glucose levels, less blood glucose self-monitoring, reduced low-density lipoprotein cholesterol levels, and receipt of diet/exercise advice.ConclusionsPatients who initiated exenatide bid were, on average, younger and more obese and had lower HbA(1c) concentrations than those initiating insulin.CommentThere are no guidelines for initiating injectable therapy (GLP analog or basal insulin) in subjects with type 2 diabetes who are failing oral treatment with metformin and/or sulfonylureas. It is entirely up to the physician when choosing the therapy for achieving target A1c in patients failing on orals. This study (CHOICE) further supports early treatment with incretins in lowering A1c values and an effective way to initiate treatment in younger obese subjects with diabetes. A much larger randomized control trial needs to be done that evaluates the effectiveness of the above two choices in initiating injectables in subjects with type 2 diabetes who are failing on oral treatment.New approaches for the treatment of diabetic macular oedema: recommendations by an expert panelBandello F 1, Cunha-Vaz J2, Chong NV3, Lang GE4, Massin P5, Mitchell P6, Porta M7, Prünte C8, Schlingemann R 9, 10, Schmidt-Erfurth U 111Department of Ophthalmology, University Vita-Salute, Scientific Institute San Raffaele, Milano, Italy; 2Association for Innovation and Biomedical Research on Light and Image, Coimbra, Portugal; 3Oxford Eye Hospital, University of Oxford, Oxford, United Kingdom; 4Department of Ophthalmology, University Eye Hospital, Ulm, Germany; 5Assistance Publique des Hôpitaux de Paris, Ophthalmology Department, Hôpital Lariboisière, Paris, France; 6Discipline of Ophthalmology, University of Sydney, Sydney, Australia; 7Department of Internal Medicine, University of Turin, Turin, Italy; 8Department of Ophthalmology and Optometry, Medical University of Vienna, Vienna, Austria and Vista Klinik, Binningen, Switzerland; 9Medical Retina Unit and Ocular Angiogenesis Group, Department of Ophthalmology, University of Amsterdam, Academic Medical Centre, Amsterdam, The Netherlands; 10Department of Clinical and Molecular Ophthalmogenetics, The Netherlands Institute for Neuroscience, Royal Netherlands Academy of Arts and Sciences (KNAW), Amsterdam, The Netherlands; and 11Department of Ophthalmology and Optometry, Medical University of Vienna, Vienna, AustriaEye (Lond) 2012;26: 485–93The current standard therapy for patients with diabetic macular edema (DME) is focal/grid laser photocoagulation; however, it does not usually improve impaired vision, and many patients lose their vision despite laser therapy. The European Medicines Agency's recent approval of ranibizumab to treat visual impairment due to DME fulfills the previously unmet medical need for a treatment that can improve visual acuity (VA) in these patients. We reviewed one- and two-year clinical trial findings for ranibizumab therapy in DME to formulate evidence-based treatment recommendations. Patients with DME with or without visual impairment should be considered for ranibizumab treatment when the condition fulfills the Early Treatment Diabetic Retinopathy Study (ETDRS) criteria for clinically significant edema. For DME with centre involvement and associated vision loss due to DME, monthly ranibizumab monotherapy with treatment interruption and re-initiation based on VA stability is recommended. Laser therapy based on ETDRS guidelines is recommended for other forms of clinically significant DME without centre involvement or when no vision loss has occurred despite centre involvement. These recommendations are based on randomized controlled trials of one to two years duration. Therefore, the guidance may need updating as long-term ranibizumab data become available and clinical trial results for additional therapeutic agents become available.CommentDiabetic retinopathy, especially in type 1 diabetes, has significantly decreased, but in type 2 diabetes continues to increase (new NIH data recently released). This study uses ranibizumab in treatment of diabetic macular edema. A similar study in the past using avastin has been shown to improve visual loss deterioration.Early basal insulin therapy decreases new-onset diabetes after renal transplantationHecking M 1, Haidinger M 1, Döller D 1, Werzowa J 1, Tura A2, Zhang J 3, Tekoglu H4, Pleiner J 5, Wrba T 4, Rasoul-Rockenschaub S6, Mühlbacher F 6, Schmaldienst S 1, Druml W 1, Hörl WH 1, Krebs M7, Wolzt M8, Pacini G2, Port FK3, Säemann MD1Departments of 1Nephrology, 4Informatics, 5Coordinating Center for Clinical Studies, 6Surgery, 7Endocrinology, and 8Clinical Pharmacology, Medical University of Vienna, Vienna, Austria; 2Metabolic Unit, Institute of Biomedical Engineering, National Research Council, Padova, Italy; and 3Arbor Research Collaborative for Health, Ann Arbor, MIJ Am Soc Nephrol 2012;23: 739–49New-onset diabetes after transplantation (NODAT) is an ongoing problem, and there are no effective interventions available to reduce this risk. The condition is associated with postoperative hyperglycemia and reduced patient and graft survival. In this one-year, proof-of-concept clinical trial, 50 renal transplant recipients were randomly assigned to receive immediate postoperative isophane insulin if they had evening blood glucose levels of 140 mg/dl (treatment group) or short-acting insulin and/or oral antidiabetic agents for blood glucose measurements of 180–250 mg/dl (standard-of-care/control group). The study only included patients without a history of diabetes who received tacrolimus. By the third postoperative evening, all patients in the treatment group had blood glucose 140 mg/dl and were subsequently treated with basal insulin. During the first three weeks after transplantation, the mean±SD daily insulin dosage was 17±11 IU/d. Among controls, 23 of 25 (92%) had blood glucose of 200 mg/dl, and 18 of 25 (72%) received standard-of-care anti-hyperglycemic treatment. Asymptomatic hypoglycemia occurred five times in the treatment group and once in the control group. Throughout follow-up, the treatment group had 73% lower odds of NODAT (odds ratio, 0.27) than the control group, and hemoglobin A1c was on average 0.38% lower in the treatment group than in the control group. Twelve months after transplantation, all patients in the treatment group were insulin-independent, whereas 7 of 25 (28%) patients in the control group required antidiabetic agents. The groups did not differ in terms of insulin sensitivity; however, the treatment group showed better beta-cell function throughout the one-year follow-up. In conclusion, this study suggests that regimens that include basal insulin significantly reduce the odds for NODAT after renal transplantation, presumably via insulin-mediated protection of beta cells.CommentThere continues to be an interest in initiating basal insulin therapy in early hyperglycemia for preventing diabetes. As we learned at the ADA, ORIGIN did not show any benefit on cardiovascular disease in basal insulin–treated group as compared to the standard therapy group. A larger sample size will be required to evaluate the true effect of early basal insulin treatment in post-renal transplant patients.Insulin degludec, an ultra-long-acting basal insulin, versus insulin glargine in basal-bolus treatment with mealtime insulin aspart in type 1 diabetes (BEGIN Basal-Bolus Type 1): a phase 3, randomised, open-label, treat-to-target non-inferiority trialHeller S1, Buse J2, Fisher M3, Garg S4, Marre M5, Merker L6, Renard E7, Russell-Jones D8,9, Philotheou A10, Francisco AM 11, Pei H 12, Bode B13, on behalf of the BEGIN Basal-Bolus Type 1 Trial Investigators1University of Sheffield, Sheffield, United Kingdom; 2University of North Carolina School of Medicine, Chapel Hill, NC; 3Glasgow Royal Infirmary, Glasgow, United Kingdom; 4Barbara Davis Center for Childhood Diabetes, Aurora, CO; 5Hôpital Bichat–Claude Bernard, Assistance Publique des Hôpitaux de Paris, France; 6Diabetes und Nierenzentrum, Dormagen, Germany; 7Montpellier University Hospital, Montpellier, France; 8Royal Surrey County Hospital, Surrey, United Kingdom; 9University of Surrey, Surrey, United Kingdom; 10University of Cape Town Private Academic Hospital, Cape Town, South Africa; 11Novo Nordisk, Søborg, Denmark; 12Novo Nordisk, Princeton, NJ; and 13Atlanta Diabetes Associates, Atlanta, GALancet 2012; 379: 1489–97BackgroundIn patients with type 1 diabetes mellitus, intensive basal-bolus insulin therapy has been shown to improve glycemic control and reduce the risk of long-term complications. Insulin degludec is a new, ultra-long-acting form of basal insulin. This study compared the efficacy and safety of insulin degludec and insulin glargine, both administered once daily with mealtime insulin aspart, in basal-bolus therapy for patients with type 1 diabetes.MethodsAn open-label, treat-to-target, non-inferiority trial was undertaken at 79 sites (hospitals and centers) in six countries. The study subjects were adults (aged ≥18 years) with type 1 diabetes (glycated hemoglobin [HbA1c] ≤10% [86 mmol/mol]) who had been treated with basal-bolus insulin for at least one year. They were randomly assigned in a 3:1 ratio, using a computer-generated blocked allocation sequence, to receive insulin degludec or insulin glargine without stratification by use of a central interactive response system. The primary outcome was non-inferiority of degludec to glargine, assessed as a reduction in HbA1c after 52 weeks, with the intention-to-treat analysis. This trial is registered with ClinicalTrials.gov, number NCT00982228.FindingsThe trial included 629 participants: 472 were randomly assigned to receive insulin degludec and 157 insulin glargine. All participants were analyzed in their respective treatment groups. At one year, HbA1c had fallen by 0.40% (SE 0.03) and 0.39% points (SE 0.07) with insulin degludec and insulin glargine, respectively (estimated treatment difference −0.01% [95% CI −0.14 to 0.11]; p<0.0001 for non-inferiority testing). Also at one year, 188 (40%) and 67 (43%) participants, respectively, achieved a target HbA1c of less than 7% (<53 mmol/mol). Rates of overall confirmed hypoglycemia (plasma glucose <3.1 mmol/L, characterized as severe) were similar in the insulin degludec and insulin glargine groups (42.54 vs. 40.18 episodes per patient-year of exposure; estimated rate ratio [degludec to glargine] 1.07 [0.89 to 1.28]; p=0·48). The rate of confirmed nocturnal hypoglycemia was 25% lower with degludec than with glargine (4.41 vs. 5.86 episodes per patient-year of exposure; 0.75 [0.59 to 0.96]; p=0·021). There were no substantial differences in serious adverse event rates (14 vs. 16 events per 100 patient-years of exposure) between the insulin degludec and insulin glargine groups.InterpretationInsulin degludec might be a useful form of basal insulin for patients with type 1 diabetes because it provides effective glycemic control while lowering the risk of nocturnal hypoglycemia, which is an important limiting factor in insulin therapy.Insulin degludec, an ultra-long-acting basal insulin, versus insulin glargine in basal-bolus treatment with mealtime insulin aspart in type 2 diabetes (BEGIN Basal-Bolus Type 2): a phase 3, randomised, open-label, treat-to-target non-inferiority trialGarber AJ 1, King AB2, Del Prato S3, Sreenan S4, Balci MK5, Muñoz-Torres M6, Rosenstock J7, Endahl LA8, Francisco AM8, Hollander P9, on behalf of the NN1250-3582 (BEGIN BB T2D) Trial Investigators1Baylor College of Medicine, Houston, TX; 2Diabetes Care Center, Salinas, CA; 3University of Pisa, Pisa, Italy; 4Connolly Hospital, Dublin, Ireland; 5Akdeni