Portal de Periódicos da CAPES

New Insulins, Biosimilars, and Insulin Therapy

2023; Mary Ann Liebert, Inc.; Volume: 25; Issue: S1 Linguagem: Inglês

10.1089/dia.2023.2504

1557-8593

Thomas Danne, Lutz Heinemann, Thomas R. Pieber,

Diabetes and associated disorders

Diabetes Technology & TherapeuticsVol. 25, No. S1 Original ArticlesFree AccessNew Insulins, Biosimilars, and Insulin TherapyThomas Danne, Lutz Heinemann, and Thomas R. PieberThomas DanneDiabetes-Zentrum für Kinder and Jugendliche, Kinder- und Jugendkrankenhaus "AUF DER BULT", Hannover, Germany.Search for more papers by this author, Lutz HeinemannScience Consulting in Diabetes GmbH, Kaarst, Germany.Search for more papers by this author, and Thomas R. PieberDepartment of Internal Medicine, Division of Endocrinology and Diabetology, Medical University of Graz, Graz, Austria.Search for more papers by this authorPublished Online:20 Feb 2023https://doi.org/10.1089/dia.2023.2504AboutSectionsPDF/EPUB Permissions & CitationsPermissionsDownload CitationsTrack CitationsAdd to favorites Back To Publication ShareShare onFacebookTwitterLinked InRedditEmail IntroductionDuring the past year, many articles showcased the breakthrough discovery of insulin as a life-saving drug 100 years ago. On this occasion, several reviews have focused on how this discovery of a molecule, which has only 51 amino acids, made its way from a purified animal extract to a spectrum of insulin analogues produced by genetically modified organisms; these reviews also chronicled the path to the game-changing systems of automated insulin delivery. Furthermore, the realization that insulin is an autoantigen and the primary autoimmune target in children with type 1 diabetes has led to novel approaches for immunotherapy using insulin for immune tolerance induction (1,2). Over the past century, better health outcomes for people living with diabetes have been achieved. However, despite the wishes of the discoverers of insulin, access to insulin and associated devices, and to diabetes care more broadly, remains limited in many countries today (3).The development of basal insulins has been achieved by employing different means of protraction to prolong the rate of insulin absorption from the subcutaneous injection site into the circulation. The first slow-release insulin (NPH insulin) was developed in 1946 by addition of protamine, which results in a protamine-insulin complex that precipitates in solution before injection. The first-generation basal insulin analogue, insulin glargine 100 units/mL, became available in the year 2000 and was soon followed by insulin detemir in 2005. With both basal insulin analogues the risk of hypoglycemia was lower than with NPH insulin, but further improvements regarding pharmacokinetics were considered helpful. The second-generation basal insulin analogues insulin glargine 300 units/mL and insulin degludec were introduced in 2015 (4). These two insulin preparations are now widely used, and new data have been presented in the last year.The development of basal insulins has gained new momentum due to the possibility of even longer duration of action. Currently, two once-weekly insulins are in clinical development: (i) basal insulin icodec, an insulin analogue acylated with a C20 fatty diacid (icosanedioic acid) side chain (Novo Nordisk) and (ii) basal insulin Fc (BIF), a fusion protein that combines a single-chain insulin variant with a human immunoglobulin G fragment crystallizable domain (Eli Lilly). Clinical trials are ongoing, and new data regarding molecular mode of action of both insulins have been made available in the last year.Nationally representative projections of insulin use have demonstrated that these new drugs and devices have quickly made their way into widespread clinical practice. Insulin use in the United States during the past 5 years remained dominated by the use of insulin analogues and insulin pen delivery devices, with increasing uptake of newer products. IQVIA's National Disease and Therapeutic Index (NDTI), a two-stage, all-payer, nationally representative audit of outpatient care from 4800 physicians each calendar quarter analyzed 27,860,691 insulin treatment visits; according to these data, insulin glargine was the most frequently used insulin. Insulin pen use increased from 36% in 2016 to 59% in 2020, while the use of insulin vials/syringes declined in parallel. Newer insulins were increasingly used, from 18% of total treatment visits in 2016 to 41% in 2020 (5). A German analysis based on the longitudinal prescription database (IQVIA) of 22,512 children and adolescents with type 1 diabetes children and adolescents in 2016 to 2019 described changes in insulin therapy patterns and insulin daily doses (6). Insulin aspart was the most common short-acting insulin. The total daily insulin dose of pump users was 10 units lower than those using multiple daily injections. While pump use increased over time in the pediatric age group, continuous subcutaneous insulin infusion (CSII) was used more than twice as much in the age group of younger than 6 years than in adolescents.The general decline in insulin sales in the last years might reflect that retail costs are falling because biosimilar insulins cost less than reference insulins; however, this can also be the result of the market success of other antidiabetic drugs. The insulin pricing and cost structures in various markets, especially in the United States, are highly complex; all insulin manufacturers provide a variety of savings programs for patients, and (confidential) rebates to insurance companies that influence the cost of drugs, including insulins. Nevertheless, this article provides evidence that innovation is continuing at the beginning of the second century of insulin and insulin therapy.Key Articles ReviewedComparison of Treatment with Insulin Degludec and Glargine U100 in Patients with Type 1 Diabetes Prone to Nocturnal Severe Hypoglycaemia: The Hypodeg Randomized, Controlled, Open-Label, Crossover TrialPedersen-Bjergaard U, Agesen RM, Brøsen JMB, Alibegovic AC, Andersen HU, Beck-Nielsen H, Gustenhoff P, Hansen TK, Hedetoft C, Jensen TJ, Juhl CB, Jensen AK, Lerche SS, Nørgaard K, Parving HH, Sørensen AL, Tarnow L, Thorsteinsson BDiabetes Obes Metab 2022;24: 257–267Continuous Glucose Monitoring-Recorded Hypoglycemia with Insulin Degludec or Insulin Glargine U100 in People with Type 1 Diabetes Prone to Nocturnal Severe HypoglycemiaBrøsen JMB, Agesen RM, Alibegovic AC, Andersen HU, Beck-Nielsen H, Gustenhoff P, Hansen TK, Hedetoft CGR, Jensen TJ, Stolberg CR, Juhl CB, Lerche SS, Nørgaard K, Parving HH, Tarnow L, Thorsteinsson T, Pedersen-Bjergaard UDiabetes Technol Ther 2022;24: 643–654Effect of Insulin Degludec Versus Insulin Glargine U100 on Time in Range: SWITCH PRO, a Crossover Study of Basal Insulin-Treated Adults with Type 2 Diabetes and Risk Factors for HypoglycaemiaGoldenberg RM, Aroda VA, Billings LK, Christiansen ASL, Donatsky AM, Rizi EP, Podgorski G, Raslova K, Klonoff DC, Bergenstal RMDiabetes Obes Metab. 2021;23: 2572–2581Pregnancy Outcomes in Women with Type 1 Diabetes Using Insulin DegludecRingholm L, Callesen Do N, Damm P, Mathiesen ERActa Diabetol 2022;59: 721–727Molecular and Pharmacological Characterization of Insulin Icodec: A New Basal Insulin Analog Designed for Once-Weekly DosingNishimura E, Pridal L, Glendorf T, Hansen BF, Hubálek F, Thomas Kjeldsen T, Kristensen NR, Lützen A, Lyby K, Madsen P, Pedersen TÅ, Ribel-Madsen R, Stidsen CE, Haahr HBMJ Open Diabetes Res Care 2021;9: e002301Preclinical Characterization of LY3209590, a Novel Weekly Basal Insulin Fc-Fusion ProteinMoyers JS, Hansen RJ, Day JW, Dickinson CD, Zhang C, Ruan X, Ding L, Brown RM, Baker HE, Beals JMJ Pharmacol Exp Ther 2022;382: 346–355Comparable Efficacy and Safety Between LY2963016 Insulin Glargine and Insulin Glargine (Lantus) in Chinese Patients with Type 1 Diabetes: A Phase III, Randomized, Controlled TrialYan X, Jiang S, Lou Y, Zhou ZDiabetes Obes Metab 2021;23: 2226–2233Biosimilar Insulin Aspart Premix SAR341402 Mix 70/30 Versus Originator Insulin Aspart Mix 70/30 (NovoMix 30) in People with Diabetes: A 26-Week, Randomized, Open-Label Trial (GEMELLI M)Aravind SR, Singh KP, Aquitania G, Mogylnytska L, Zalevskaya AG, Matyjaszek-Matuszek B, Wernicke-Panten K, Nguyên-Pascal ML, Pierre S, Rotthaeuser B, Kramer D, Mukherjee BDiabetes Ther 2022;13: 1053–1071Efficacy, Safety, and Immunogenicity of Biosimilar Insulin Aspart Premix SAR341402 Mix 70/30 Compared with Originator Insulin Aspart Mix 70/30 in Adults with Diabetes (GEMELLI M): A Subgroup Analysis by Prior Type of Premix InsulinAravind SR, Singh KP, Aquitania G, Mogylnytska L, Zalevskaya AG, Matyjaszek-Matuszek B, Wernicke-Panten K, Nguyên-Pascal ML, Pierre S, Rotthaeuser B, Kramer D, Mukherjee BDiabetes Ther 2022;13: 1299–1310Pharmacokinetic and Pharmacodynamic Similarity Between SAR341402 Insulin Aspart and Japan-Approved NovoRapid in Healthy Japanese SubjectsShiramoto M, Yoshihara T, Schmider W, Takagi H, Nowotny I, Kajiwara M, Muto HSci Rep 2021;11: 22931Pharmacokinetic and Pharmacodynamic Bioequivalence of Biosimilar MYL-1601D with US and European Insulin Aspart in Healthy Volunteers: A Randomized, Double-Blind, Crossover, Euglycaemic Glucose Clamp StudyHövelmann U, Raiter Y, Chullikana A, Liu M, Donnelly C, Lawrence T, Sengupta N, Gopu CL, Ranganna G, Barve ADiabetes Obes Metab 2021;23: 2670–2678Pharmacokinetic and Pharmacodynamic Equivalence of Biocon's Biosimilar Insulin-R with the US-Licensed Humulin R Formulation in Healthy Subjects: Results from the RHINE-1 (Recombinant Human Insulin Equivalence-1) StudyPlum-Mörschel L, Singh G, Murugesan SMN, Marwah A, Panda J, Loganathan S, Athalye SNDiabetes Obes Metab 2022;24: 713–721Pharmacokinetic and Pharmacodynamic Equivalence of Biocon's Biosimilar Insulin 70/30 with US-Licensed Humulin 70/30 Formulation in Healthy Subjects: Results from the RHINE-3 (Recombinant Human Insulin Equivalence-3) StudyPlum-Mörschel L, Klein O, Singh G, Murugesan SMN, Marwah A, Sharma N, Panda J, Loganathan S, Lakshmi GC, Athalye SNDiabetes Obes Metab 2022;24: 1819–1828Clinical Pharmacology of Insulin Aspart Biosimilar GP40071: Pharmacokinetic/Pharmacodynamic Comparability in Hyperinsulinemic Euglycemic Clamp ProcedureDrai RV, Karonova TL, Mayorov AY, Makarenko IE, Dorotenko AR, Kulesh VS, Kovalik VV, Andreeva ATClin Pharmacol Drug Dev 2022;11: 922–929A Randomized Pharmacokinetic and Pharmacodynamic Trial of Two Regular Human Insulins Demonstrates Bioequivalence in Type 1 Diabetes and Availability of Biosimilar Insulin May Improve Access to This MedicationVencio S, Caiado-Vencio R, Ferreira Caixeta L, Masierek M, Mlynarski W, Drzewoski J, Gregory JMDiabetes Obes Metab 2022;24: 1544–1552A Comparison of the Rapid-Acting Insulin Analogue Glulisine with Lispro and Aspart for the Pump Treatment of Patients with Type 1 DiabetesBramlage P, Tittel SR, Müther S, Reinhart-Steininger B, Haberland H, Khodaverdi S, Zimny S, Ohlenschläger U, Lanzinger S, Haak TActa Diabetol 2022 Aug 7. doi: 10.1007/s00592-022-01939-3. Online ahead of print.Glucose Control Using Fast-Acting Insulin Aspart in a Real-World Setting: A 1-Year, Two-Centre Study in People with Type 1 Diabetes Using Continuous Glucose MonitoringBillion L, Charleer S, Verbraeken L, Sterckx M, Vangelabbeek K, De Block N, Janssen C, Van Dessel K, Dirinck E, Peiffer F, Bolsens N, Mathieu C, Gillard P, De Block CDiabetes Obes Metab 2021;23: 2716–2727Glycaemic Control in People with Diabetes Starting Treatment with Fast-Acting Insulin Aspart: A US Database StudyLane W, Faurby M, Husemoen LLN, Markovich DL, Rathor N, De Block CDiabetes Ther 2021;12: 3067–3077Ultrarapid Lispro Demonstrates Similar Time in Target Range to Lispro with a Hybrid Closed-Loop SystemBode B, Carlson A, Liu R, Hardy T, Bergenstal R, Boyd J, Morrett S, Ignaut DDiabetes Technol Ther 2021;23: 828–836Comparable Glucose Control with Fast-Acting Insulin Aspart Versus Insulin Aspart Using a Second-Generation Hybrid Closed-Loop System During ExerciseMorrison D, Zaharieva DP, Lee MH, Paldus B, Vogrin S, Grosman B, Roy A, Kurtz N, O'Neal DNDiabetes Technol Ther 2022;24: 93–101The Switch from Rapid-Acting to Concentrated Regular Insulin Improves Glucose Control in Type 2 Diabetes Patients on Pump Therapy: A Cohort SurveyDeberles E, Morello R, Hardouin J, Amadou C, Benhamou PY, Prévost G, Schaepelynck P, Chaillous L, Joubert M, Reznik YDiabetes Metab 2022;48: 101300Continuous Glucose Monitoring Sensor Glucose Levels and Insulin Pump Infusion Set Wear-Time During Treatment with Fast-Acting Insulin Aspart: A Post Hoc Analysis of ONSET 5Gorst-Rasmussen A, Sturis J, Ekelund MDiabetes Technol Ther 2022;24: 10–17Photoacoustic Imaging Reveals Mechanisms of Rapid-Acting Insulin Formulations Dynamics at the Injection SiteKhadria A, Paavola CD, Maslov K, Valenzuela FA, Sperry AE, Cox AL, Cao R, Shi J, Brown-Augsburger PL, Lozano E, Blankenship RL, Majumdar R, Bradley SA, Beals JM, Oladipupo SS, Wang LVMol Metab 2022;62: 101522Comparison of Pharmacokinetics and Pharmacodynamics of Inhaled Technosphere Insulin and Subcutaneous Insulin Lispro in the Treatment of Type 1 Diabetes MellitusGrant M, Heise T, Baughman RClin Pharmacokinet 2022;61: 413–422Reduction in Postprandial Peak Glucose with Increased Technosphere Insulin DosageKaiserman KB, Christiansen M, Bhavsar S, Ulloa J, Santogatta B, Hanna J, Bailey TSJ Diabetes Sci Technol 2022;19322968221110622. doi: 10.1177/19322968221110622. Online ahead of print.Reduced Hypoglycaemia Using Liver-Targeted Insulin in Individuals with Type 1 DiabetesWeinstock RS, Bode BW, Garg SK, Klonoff DC, El Sanadi C, Geho WB, Muchmore DB, Penn MSDiabetes Obes Metab 2022;24: 1762–1769NEW DATA OF SECOND-GENERATION BASAL INSULIN ANALOGUESComparison of Treatment with Insulin Degludec and Glargine U100 in Patients with Type 1 Diabetes Prone to Nocturnal Severe Hypoglycaemia: The Hypodeg Randomized, Controlled, Open-Label, Crossover TrialPedersen-Bjergaard U1,2, Agesen RM1,2, Brøsen JMB1,2, Alibegovic AC3, Andersen HU3, Beck-Nielsen H4,5, Gustenhoff P6, Hansen TK7,8, Hedetoft C9, Jensen TJ10, Juhl CB11, Jensen AK12,13, Lerche SS14, Nørgaard K1,3,15, Parving HH2,10, Sørensen AL12, Tarnow L13,16, Thorsteinsson B1,21Department of Endocrinology and Nephrology, Nordsjællands Hospital, Hillerød, Denmark; 2Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark; 3Steno Diabetes Center Copenhagen, Gentofte, Denmark; 4Department of Endocrinology M, Odense University Hospital, Odense C, Denmark; 5Faculty of Health Sciences, University of Southern Denmark, Odense C, Denmark; 6Department of Endocrinology, Aalborg University Hospital, Aalborg, Denmark; 7Steno Diabetes Center Aarhus, Aarhus N, Denmark; 8Health, University of Aarhus, Aarhus C, Denmark; 9Department of Internal Medicine, Zealand University Hospital Koge, Køge, Denmark; 10Department of Medical Endocrinology, Copenhagen University Hospital (Rigshospitalet), Copenhagen, Denmark; 11Department of Medicine, Sydvestjysk Sygehus, Esbjerg, Denmark; 12Department of Public Health, Section of Biostatistics, University of Copenhagen, Copenhagen, Denmark; 13Department of Clinical Research, Nordsjællands Hospital, Hillerød, Denmark; 14Department of Diabetes and Hormonal Diseases, Lillebælt Hospital Kolding, Kolding, Denmark; 15Department of Endocrinology, Hvidovre University Hospital, Hvidovre, Denmark; 16Steno Diabetes Center Sjælland, Holbæk, DenmarkDiabetes Obes Metab 2022;24: 257–267BackgroundThe aim of this study is to determine whether insulin degludec, a long-acting insulin analogue, reduces the risk of nocturnal symptomatic hypoglycemia more than insulin glargine U100.MethodsAdults with T1D and a higher risk for hypoglycemia (at least one episode of severe nocturnal hypoglycemia during the last 2 years) were included in a 2-year prospective, randomized, open multicenter crossover trial. A total of 149 patients were randomized 1:1 to basal-bolus therapy with insulin degludec and insulin aspart or insulin glargine U100 and insulin aspart. Each treatment period lasted 1 year and consisted of 3 months of run-in or crossover followed by 9 months of maintenance. In an intention-to-treat analysis, the primary endpoint was the number of blindly adjudicated nocturnal symptomatic hypoglycemic episodes. Secondary endpoints included the occurrence of severe hypoglycemia.ResultsCompared to treatment with insulin glargine U100, treatment with insulin degludec resulted in a 28% (95% CI, 9%–43%; P=.02) relative rate reduction (RRR) of nocturnal symptomatic hypoglycemia at level 1 (≤3.9 mmol/L), a 37% (95% CI, 16%–53%; P=.002) RRR at level 2 (≤3.0 mmol/L), and a 35% (95% CI, 1%–58%; P=.04) RRR in all-day severe hypoglycemia.ConclusionsAmong patients with T1D, those who took insulin degludec had lower rates of nocturnal symptomatic hypoglycemia and all-day severe hypoglycemia than did those who took insulin glargine 100.Continuous Glucose Monitoring-Recorded Hypoglycemia with Insulin Degludec or Insulin Glargine U100 in People with Type 1 Diabetes Prone to Nocturnal Severe HypoglycemiaBrøsen JMB1,2, Agesen RM1,2,3, Alibegovic AC3,4, Andersen HU2,4, Beck-Nielsen H5,6, Gustenhoff P7, Hansen TK8,9, Hedetoft CGR10, Jensen TJ2,11, Stolberg CR5,12,13, Juhl CB12,13,14, Lerche SS15, Nørgaard K2,4,16, Parving HH2,11, Tarnow L17,18, Thorsteinsson T1,2, Pedersen-Bjergaard U1,21Department of Endocrinology and Nephrology, Copenhagen University Hospital - North Zealand, Hillerød, Denmark; 2Department of Clinical Medicine, Faculty of Health and Medical & Sciences, University of Copenhagen, Denmark; 3Department of Medical & Science, Novo Nordisk A/S, Søborg, Denmark; 4Steno Diabetes Center Copenhagen, Herlev, Denmark; 5Department of Endocrinology, Odense University Hospital, Odense, Denmark; 6Department of Regional Health Research, Faculty of Health and Sciences, University of Southern Denmark, Odense, Denmark; 7Steno Diabetes Center North, Aalborg, Denmark; 8Department of Clinical Medicine, Aarhus University, Aarhus, Denmark; 9Steno Diabetes Center Aarhus, Aarhus, Denmark; 10Department of Internal Medicine, Zealand University Hospital, Køge, Denmark; 11Department of Medical Endocrinology, Copenhagen University Hospital - Rigshospitalet, Copenhagen, Denmark; 12Department of Medicine, University Hospital South West Jutland, Esbjerg, Denmark; 13Department of Regional Health Research, University of Southern Denmark, Odense, Denmark; 14Steno Diabetes Center Odense, Odense, Denmark; 15Department of Diabetes and Hormonal Diseases, Lillebælt Hospital Kolding, Denmark; 16Department of Endocrinology, Copenhagen University Hospital - Amager and Hvidovre, Hvidovre, Denmark; 17Department of Clinical Research, Copenhagen University Hospital - North Zealand, Hillerød, Denmark; 18Steno Diabetes Center Zealand, Holbæk, DenmarkDiabetes Technol Ther 2022;24: 643–654BackgroundNocturnal hypoglycemia is mainly a consequence of inappropriate basal insulin therapy in type 1 diabetes (T1D) and may compromise optimal glycemic control. Nocturnal hypoglycemia is often asymptomatic; thus, continuous glucose monitoring (CGM) is a useful tool for quantification. Insulin degludec has been associated with a lower risk of nocturnal hypoglycemia in T1D. The HypoDeg trial compares insulin degludec with insulin glargine U100 in people with T1D and previous nocturnal severe hypoglycemia.MethodsIn the HypoDeg trial, 149 people with T1D were included in an open-label randomized crossover trial. Sixty-seven participants accepted optional participation in the predefined substudy of 4×6 days of blinded CGM requiring completion of at least one CGM period in each treatment arm. CGM data were reviewed for hypoglycemic events.ResultsTreatment with insulin degludec resulted in a relative rate reduction (RRR) of 36% (95% CI, 10%–54%; P>.05) in nocturnal CGM-recorded hypoglycemia (≤3.9 mmol/L), corresponding to an absolute rate reduction (ARR) of 0.85 events per person-week. In nocturnal CGM-recorded hypoglycemia (≤3.0 mmol/L), we found an RRR of 53% (95% CI, 36%–65%; P<.001), corresponding to an ARR of 0.75 events per person-week. At the lower detection limit of the CGM (≤2.2 mmol/L), treatment with insulin degludec resulted in a significant RRR of 58% (95% CI, 23%–77%; P=.005). The reductions were primarily due to significant RRRs in asymptomatic hypoglycemia.ConclusionIn people with T1D and a higher risk for hypoglycemia (at least one episode of nocturnal severe hypoglycemia during the last 2 years), insulin degludec reduces nocturnal CGM-recorded hypoglycemia at all levels significantly more than does insulin glargine U100.Effect of Insulin Degludec Versus Insulin Glargine U100 on Time in Range: SWITCH PRO, a Crossover Study of Basal Insulin-Treated Adults with Type 2 Diabetes and Risk Factors for HypoglycaemiaGoldenberg RM1, Aroda VA2, Billings LK3, Christiansen ASL4, Donatsky AM5, Rizi EP6, Podgorski G7, Raslova K8, Klonoff DC9, Bergenstal RM101LMC Diabetes and Endocrinology, Concord, Ontario, Canada; 2Diabetes Clinical Research, Division of Endocrinology, Diabetes & Hypertension, Brigham and Women's Hospital and Harvard Medical School, Boston, MA; 3Department of Medicine, NorthShore University Health System/University of Chicago Pritzker School of Medicine, Skokie, IL; 4Biostatistics, Insulin & Devices, Novo Nordisk, Søborg, Denmark; 5Medical & Science, New Generation Insulins, Novo Nordisk, Søborg, Denmark; 6Global Medical Affairs, Novo Nordisk, Søborg, Denmark; 7Internal Medicine, Greenacres Hospital, Port Elizabeth, South Africa; 8Metabolic Center Ltd, Bratislava, Slovakia; 9Diabetes Research Institute, Mills-Peninsula Medical Center, San Mateo, CA; 10International Diabetes Center and HealthPartners Institute, Minneapolis, MNDiabetes Obes Metab. 2021;23: 2572–2581BackgroundThe aim of this study is to compare insulin degludec U100 (degludec) with insulin glargine U100 (glargine U100) for treatment of type 2 diabetes by using time in range (TIR) values.MethodsWe conducted a randomized crossover multicenter trial comparing degludec and glargine U100 in basal insulin–treated adults with type 2 diabetes and ≥1 hypoglycemia risk factor. There were two treatment periods, each with 16-week titration and 2-week maintenance phases (with evaluation of glucose using blinded professional continuous glucose monitoring). The once-weekly titration (target: 3.9–5.0 mmol/L) was based on prebreakfast self-measured blood glucose. The primary endpoint was percentage of TIR (3.9–10.0 mmol/L). Secondary endpoints included overall and nocturnal percentage of time in tight glycemic range (3.9–7.8 mmol/L) and mean glycated hemoglobin (HbA1c) and glucose levels.ResultsAt baseline, participants (N=498) had a mean±SD age of 62.8±9.8 years, a diabetes duration of 15.1±7.7 years, and an HbA1c level of 59.6±11.0 mmol/mol (7.6% [1.0%]). Noninferiority and superiority were confirmed for degludec and glargine U100 for the primary endpoint, with a mean TIR of 72.1% for degludec and 70.7% for glargine U100 (estimated treatment difference [ETD] 1.43% [95% CI, 0.12–2.74; P=.03] or 20.6 min/d). Overall time in tight glycemic range was greater for degludec than for glargine U100 (ETD 1.5% [95% CI, 0.15–2.89] or 21.9 min/d). Degludec also reduced nocturnal time below range (TBR; <3.9 mmol/L) more than glargine U100 (ETD −0.88% [95% CI: −1.34, −0.42] or 12.7 min/night; post hoc). Significantly fewer nocturnal hypoglycemic episodes of <3.0 mmol/L were observed with degludec.ConclusionsCompared with patients who took glargine 100, those who took degludec spent longer time in range and longer time in tight glycemic range. In insulin-treated people with type 2 diabetes, nocturnal TBR was significantly lower in those treated with degludec than in those treated with glargine 100.Pregnancy Outcomes in Women with Type 1 Diabetes Using Insulin DegludecRingholm L1,2, Callesen Do N1,2,3, Damm P1,3,4, Mathiesen ER1,2,31Center for Pregnant Women with Diabetes, Rigshospitalet, Copenhagen, Denmark; 2Department of Endocrinology and Metabolism, Rigshospitalet, Copenhagen, Denmark; 3Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark; 4Department of Obstetrics, Rigshospitalet, Copenhagen, DenmarkActa Diabetol 2022;59: 721–727BackgroundThe aim of this study is to compare the effects of degludec, an ultra-long-lasting insulin analogue, with those of other long-acting insulin analogues in pregnant women with type 1 diabetes. The effects were examined in participants in a real-world setting throughout their pregnancies.MethodsThis was a secondary analysis of a prospective cohort study. The prospective cohort included consecutive, singleton pregnant women with type 1 diabetes receiving long-acting insulin analogues both before and during pregnancy: 67 women were using degludec, whereas 95 women were using other long-acting insulin analogues in a routine care setting.ResultsWomen using degludec had similar clinical characteristics as women using other long-acting insulin analogs including HbA1c at 9 gestational weeks (6.5% [6.2%–6.9%] or 48 [44–52] mmol/mol for degludec users vs 6.5% [6.0%–7.0%] or 47 [42–53] mmol/mol for other users; P=.52] and at 35 gestational weeks (6.0% [5.6%–6.5%] or 42 [38–47] mmol/mol for degludec users vs 6.1% [5.6%–6.5%] or 43 [38–48] mmol/mol for other users; P=.68). Pregnancy outcomes were similar regarding preeclampsia (10% [7/67] vs 8% [8/95], P=.66) and preterm delivery before 37 gestational weeks (16% [11/67] vs 23% [22/95], P=.29). There were no perinatal deaths, and neonatal outcomes for large for gestational age infants (37% [25/67] vs 39% [37/95], P=.83], small for gestational age infants (4% [3/67] vs 5% [5/95], P=1.0) and neonatal hypoglycemia (32% [21/65] vs 41% [34/83], P=.28] were similar between women using degludec and those using other long-acting insulin analogues.ConclusionsIn women with type 1 diabetes in a real-world setting, pregnancy outcomes were similar between those who used degludec and those who used other long-acting insulin analogues. These findings indicate that patients who start using degludec before they become pregnant can still use it during pregnancy.CommentsThe last year has seen some important studies comparing the efficacy of insulin degludec with insulin glargine U100. Based on the known efficacy profiles of degludec and glargine, Pedersen-Bjergaard in Hillerød, Denmark conducted the HypoDeg study (7). In this multicenter crossover study, patients with type 1 diabetes and increased risk of hypoglycemia were investigated. Increased risk of hypoglycemia was defined as "at least one episode of nocturnal severe hypoglycemia during the last 2 years." A total of 149 patients, many with hypoglycemia unawareness, were randomized 1:1 to insulin degludec or glargine U100, then therapy was optimized for the first 3 months, followed by 9 months of maintenance. The primary endpoint, nocturnal hypoglycemia, was statistically significantly reduced: level 1 symptomatic hypoglycemia by 28%, and level 2 symptomatic hypoglycemia by 37%. Severe adjudicated hypoglycemia was statistically significantly reduced by 35%. During this crossover study, HbA1c remained unchanged and the insulin dose for insulin degludec was overall 1.4 units lower.In a prospectively planned substudy, Brøsen and colleagues published the results of 67 participants in the HypoDeg study (8) who recorded blinded CGM for 4 x 6 days. The CGM data were analyzed according to hypoglycemia frequency. Insulin degludec achieved a significant RRR of 36% for level 1 hypoglycemia. Level 2 hypoglycemia was significantly reduced by 53%, and severe hypoglycemia (level 3) was reduced by 58%. It should be emphasized that most of the recorded instances of hypoglycemia were asymptomatic.The HypoDeg study is highly relevant for evaluation of the clinical value of the currently used basal insulins. The HypoDeg study examined patients with type 1 diabetes who had an increased risk of hypoglycemia. The 3-month optimization phase ensured that the insulin dose is individually optimized in the maintenance phase. The crossover design (and long observation period) allows direct comparison of outcomes as all patients act as their own controls. The primary endpoint, nocturnal hypoglycemia, is clinically of great importance. More than half of all hypoglycemia instances occur during sleep. Last but not least, the substudy with blinded CGM supported the positive results for insulin degludec. The differences between the two insulins observed during CGM are greater, probably also because quite a few instances of hypoglycemia that occur during the night are not noticed by those affected. Feeling unwell, headaches, and a drop in performance on the next day are typical consequences of nocturnal hypoglycemia, but they are not specific to low blood sugar. Here adds HypoDeg substantial data.The main limitation of the HypoDeg study is the open-label design, which is partly compensated by blinded adjudication of endpoints. Blinding of such a trial would require major efforts and resources, which are usually not available. Unfortunately, a similar study comparing insulin degludec with insulin glargine U300 is still missing. Nevertheless, the study design of HypoDeg could serve as a best practice for further investigations.Goldenberg and colleagues (9) investigated insulin degludec and insulin glargine U100 in patients with type 2 diabetes in the SWITCH PRO study. In this randomized, head-to-head study in basal insulin–treated adults with type 2 diabetes and at least one risk factor for hypoglycemia, the use of CGM showed that a treatment period with degludec was associated with significantly more TIR (3.9–10.0 mmol/L) compared with glargine U100, with an additional 20.6 minutes of TIR per day on average. This first study with CGM in type 2 diabetes was conducted in almost 500 patients in a crossover design. As seen with type 1 diabetes, CGM use with type 2 diabetes allows a more comprehensive capture of hypoglycemic events, especially during the night, than do conventional methods.