Portal de Periódicos da CAPES

New Insulins, Biosimilars, and Insulin Therapy

2021; Mary Ann Liebert, Inc.; Volume: 23; Issue: S2 Linguagem: Inglês

10.1089/dia.2021.2504

1557-8593

Thomas Danne, Lutz Heinemann, Jan Bolinder,

Pancreatic function and diabetes

Diabetes Technology & TherapeuticsVol. 23, No. S2 Original ArticlesFree AccessNew Insulins, Biosimilars, and Insulin TherapyThomas Danne, Lutz Heinemann, and Jan BolinderThomas DanneDiabetes-Zentrum für Kinder and Jugendliche, Kinder- und Jugendkrankenhaus AUF DER BULT, Hannover, GermanySearch for more papers by this author, Lutz HeinemannScience Consulting in Diabetes GmbH, Neuss, GermanySearch for more papers by this author, and Jan BolinderDepartment of Medicine, Karolinska University Hospital Huddinge, Karolinska Institutet, Stockholm, SwedenSearch for more papers by this authorPublished Online:31 May 2021https://doi.org/10.1089/dia.2021.2504AboutSectionsPDF/EPUB Permissions & CitationsPermissionsDownload CitationsTrack CitationsAdd to favorites Back To Publication ShareShare onFacebookTwitterLinked InRedditEmail IntroductionIt has been one hundred years since Frederick Banting and Charles Best extracted insulin with the help of chemist James Collip in John Macleod's Toronto lab in 1921. This centenary marks one hundred years of efforts to improve insulin formulations that are still ongoing despite all the other diabetes treatment options that have been developed in the meantime. This article summarizes last year's progress in creating better insulins for treating people with type 1 diabetes and creating other options for people with type 2 diabetes. Nevertheless, even today a crisis like the current COVID-19 pandemic leads to situations in which pharmacies have told patients they are out of insulin due to “manufacturer backorder.” This underlines the fact that access and affordability of this life-saving and essential medicine remain an issue that needs our attention.One avenue to improving the situation is the clinical development of biosimilar insulins (BioIns), which aim to demonstrate similarity to existing insulins. In contrast to generics, which are believed to be chemically identical to their reference product, biologics such as insulin will always show slight differences in their available counterparts due to different starting materials (host cells, tissues, etc.) and differences in the manufacturing processes. Market approval of BioIns means that these insulins have similar pharmacokinetic (PK) and pharmacodynamic (PD) properties in comparison to the reference insulin product (also no immunological differences in a phase 3 study should be seen; see below). During the approval process, the preclinical data are also evaluated carefully. Regulatory guidelines were developed and updated several times in the last decades, in particular from the European and U.S. agencies, to lead applicants through the various requirements for demonstrating biosimilarity.A limited number of BioIns have become available on the market by now; however, further developments are under way as the patent protection of several available insulins are nearing expiration. Currently, more than 20 companies have BioIns in clinical development, and some have progressed considerably in the clinical development process.Regarding new insulin formulations, this year's focus was on both ultra-rapid and ultra-long insulins. With the publication of the final regulatory trials of the ONSET program for Novo Nordisk's ultra-rapid insulin faster aspart (FiAsp) and the EDITION junior for Sanofi's U-300 glargine (Toujeo), approval was achieved also for the pediatric population. With recent publication of the results of the PRONTO-study program for E. Lilly's new ultra-rapid mealtime insulin trepostinil lispro or URLi (ultra-rapid lispro, brand name Liumjev), it can be expected that this treatment option will be on the market soon.Another hot topic in the pipeline includes the once-weekly basal insulins. Preliminary findings with a novel supra-long-acting insulin, Icodec from Novo Nordisk, with a terminal half-life of almost 200 hours (1) indicate similar glucose-lowering effectiveness and comparable rates of hypoglycemia versus glargine U100 in insulin-naive adults with type 2 diabetes (2). Once injected, insulin icodec binds strongly but reversibly to albumin (a similar behavior occurs in both Detemir and Degludec, but not to the same extent). The injection volume of once-weekly insulin icodec is equivalent to daily insulin glargine U100 due to the concentrated formulation that it uses. Lilly also presented first data at the 2020 virtual ADA Scientific sessions on their weekly basal insulin Fc (BIF), a fusion protein that combines a novel-signal chain variant of insulin with a human IgG Fc domain (3). It is claimed that BIF is a selective insulin receptor agonist with >100-fold selectivity versus the IGF1 receptor and leads to a prolonged glucose-lowering effect for up to 10 days. Both companies announced a large clinical study program, and we expect first publications to be part of next year's yearbook.Key Articles Reviewed for the ArticleRisk of hypoglycaemia with insulin degludec versus insulin glargine U300 in insulin-treated patients with type 2 diabetes: the randomised, head-to-head CONCLUDE trialPhilis-Tsimikas A, Klonoff DC, Khunti K, Bajaj HS, Leiter LA, Hansen MV, Troelsen LN, Ladelund S, Heller S, Pieber TR, on behalf of the CONCLUDE Study GroupDiabetologia 2020;63: 698–710Similar glycaemic control and less hypoglycaemia during active titration after insulin initiation with glargine 300 Units/mL and degludec 100 Units/mL: a subanalysis of the BRIGHT studyCheng A, Harris S, Giorgino F, Seufert J, Ritzel R, Khunti K, Lauand F, Melas-Melt L, Westerbacka J, Bosnyak Z, Rosenstock JDiabetes Obes Metab 2020;22: 346–354Differential glycaemic control with basal insulin glargine 300 U/mL versus degludec 100 U/mL according to kidney function in type 2 diabetes: a subanalysis from the BRIGHT trialHaluzik M, Cheng A, Müller-Wieland D, Westerbacka J, Bosnyak Z, Lauand F, Melas-Melt L, Karalliedde J, Rosenstock J, Bolli GBDiabetes Obes Metab 2020;22: 1369–1377Efficacy and safety of insulin glargine 300 units/mL (Gla-300) versus insulin glargine 100 units/mL (Gla-100) in children and adolescents (6–17 years) with type 1 diabetes: results of the EDITION JUNIOR randomized controlled trialDanne T, Tamborlane WV, Malievsky OA, Franco DR, Kawamura T, Demissie M, Niemoeller E, Goyeau H, Wardecki M, Battelino TDiabetes Care 2020;43: 1512–1519Efficacy and safety of treatment with new basal insulin analogues in type 1 diabetes: nation-wide surveySvensson A-M, Ekelund J, Miftaraj M, Eliasson BDiabetes Ther 2020;11: 725–734In silico head-to-head comparison of insulin glargine 300 U/mL and insulin degludec 100 U/mL in type 1 diabetesSchiavon M, Visentin R, Giegerich C, Sieber J, Dalla Man C, Cobelli C, Klabunde TDiabetes Technol Ther 2020;22: 553–561A forskolin-conjugated insulin analog targeting endogenous glucose-transporter for glucose-responsive insulin deliveryWang J, Wang Z, Yu J, Zhang Y, Zeng Y, Gu ZBiomater Sci 2019;7: 4508–4513Smart microneedles with porous polymer layer for glucose-responsive insulin deliveryUllah A, Choi HJ, Jang M, An S, Kim GMPharmaceutics 2020;12: 606A randomized trial evaluating the efficacy and safety of fast-acting insulin aspart compared with insulin aspart, both in combination with insulin degludec with or without Metformin, in adults with type 2 diabetes (ONSET 9)Lane WS, Favaro E, Rathor N, Jang HC, Kjærsgaard MIS, Oviedo A, Rose L, Senior P, Sesti G, Gonzalez AS, Franek EDiabetes Care 2020;43: 1710–1716The association between anti-insulin aspart antibodies and the pharmacokinetic and pharmacodynamic characteristics of fast-acting insulin aspart in children and adolescents with type 1 diabetesBiester T, von dem Berge T, Bendtsen LQ, Bendtsen MD, Rathor N, Danne T, Haahr HPediatr Diabetes 2020;21: 781–790Ultrarapid lispro lowers postprandial glucose and more closely matches normal physiological glucose response compared to other rapid insulin analogues: a phase 1 randomized, crossover studyHeise T, Linnebjerg H, Coutant D, LaBell E, Zijlstra E, Kapitza C, Bue-Valleskey J, Zhang Q, Dellva MA, Leohr JDiabetes Obes Metab 2020;22: 1789–1798Ultra rapid lispro improves postprandial glucose control compared with lispro in patients with type 1 diabetes: results from the 26-week PRONTO-T1D studyKlaff L, Cao D, Dellva MA, Tobian J, Miura J, Dahl D, Lucas J, Bue-Valleskey JDiabetes Obes Metab 2020;22: 1799–1807Compatibility and safety of ultra rapid lispro with continuous subcutaneous insulin infusion in patients with type 1 diabetes: PRONTO-Pump studyBode B, Garg S, Norwood P, Morales C, Hardy T, Liu R, Ignaut DDiabetes Technol Ther 2021;23: 41–50Ultra-rapid lispro improves postprandial glucose control and time in range in type 1 diabetes compared to lispro: PRONTO-T1D continuous glucose monitoring substudyMalecki MT, Cao D, Liu R, Hardy T, Bode B, Bergenstal RM, Bue-Valleskey JDiabetes Technol Ther 2020;22: 853–860Randomized double-blind clinical trial comparing ultra rapid lispro with lispro in a basal-bolus regimen in patients with type 2 diabetes: PRONTO-T2DBlevins T, Zhang Q, Frias JP, Jinnouchi H, Chang AM for the PRONTO-T2D InvestigatorsDiabetes Care 2020;43: 2991–2998Faster compared with standard insulin aspart during day-and-night fully closed-loop insulin therapy in type 1 diabetes: a double-blind randomized crossover trialDovc K, Piona C, Yeşiltepe Mutlu G, Bratina N, Jenko Bizjan B, Lepej D, Nimri R, Atlas E, Muller I, Kordonouri O, Biester T, Danne T, Phillip M, Battelino TDiabetes Care 2020; 43: 29–36Effect of Afrezza on glucose dynamics during HCL treatmentGalderisi A, Cohen N, Calhoun P, Kraemer K, Breton M, Weinzimer S, Cengiz EDiabetes Care 2020;43: 2146–2152Hypoglycaemia is reduced with use of inhaled Technosphere® insulin relative to insulin aspart in type 1 diabetes mellitusSeaquist ER, Blonde L, McGill JB, Heller SR, Kendall DM, Bumpass JB, Pompilio FM, Grant MLDiabetic Med 2020;37: 752–759Divergent hypoglycemic effects of hepatic-directed prandial insulin: a 6-month phase 2b study in type 1 diabetesKlonoff D, Bode B, Cohen N, Penn M, Geho WB, Muchmore DBDiabetes Care 2019;42: 2154–2157An ultrafast insulin formulation enabled by high-throughput screening of engineered polymeric excipientsMann JL, Maikawa CL, Smith AAA, Grosskopf AK, Baker SW, Roth GA, Meis CM, Gale EC, Liong CS, Correa S, Chan D, Stapleton LM, Yu AC, Muir B, Howard S, Postma A, Appel EAASci Transl Med 2020;12: eaba6676Single-dose euglycemic clamp study demonstrating pharmacokinetic and pharmacodynamic similarity between sar341402 insulin aspart and US- and EU-approved versions of insulin aspart in subjects with type 1 diabetesKapitza C, Nosek L, Schmider W, Teichert L, Nowotny IDiabetes Technol Ther 2020;22: 278–284Efficacy and safety of insulin aspart biosimilar SAR341402 versus originator insulin aspart in people with diabetes treated for 26 weeks with multiple daily injections in combination with insulin glargine: a randomized open-label trial (GEMELLI 1)Garg SK, Wernicke-Panten K, Wardecki M, Kramer D, Delalande F, Franek E, Sadeharju K, Monchamp T, Mukherjee B, Shah VNDiabetes Technol Ther 2020;22: 85–95Safety, immunogenicity, and glycemic control of insulin aspart biosimilar SAR341402 versus originator insulin aspart in people with diabetes also using insulin glargine: 12-month results from the GEMELLI 1 trialGarg SK, Wernicke-Panten K, Wardecki M, Kramer D, Delalande F, Franek E, Sadeharju K, Monchamp T, Miossec P, Mukherjee B, Shah VNDiabetes Technol Ther 2020;22: 516–526Safety and tolerability of insulin aspart biosimilar SAR341402 versus originator insulin aspart (NovoLog) when used in insulin pumps in adults with type 1 diabetes: a randomized, open-label clinical trialThrasher J, Polsky S, Hovsepian L, Nowotny I, Pierre S, Bois De Fer B, Bhargava A, Mukherjee B, Garg SKDiabetes Technol Ther 2020;22: 666–673Pharmacokinetic and pharmacodynamic bioequivalence of proposed biosimilar MYL-1501D with US and European insulin glargine formulations in patients with type 1 diabetes mellitusHeise T, Donnely C, Barve A, Aubonnet PDiabetes Obes Metab 2020;22: 521–529Efficacy and safety of MYL-1501D versus insulin glargine in patients with type 1 diabetes mellitus: results of the INSTRIDE 3 phase 3 switch studyBlevins TC, Barve A, Raiter Y, Aubonnet P, Athalye S, Sun B, Muniz RDiabetes Obes Metab 2020;22: 365–372UTLRA-LONG-ACTING INSULIN ANALOGS: HEAD-TO-HEAD AND REAL-WORLD OBSERVATIONAL COMPARISONS BETWEEN INSULIN GLARGINE U300 AND INSULIN DEGLUDECRisk of hypoglycaemia with insulin degludec versus insulin glargine U300 in insulin-treated patients with type 2 diabetes: the randomised, head-to-head CONCLUDE trialPhilis-Tsimikas A1, Klonoff DC2, Khunti K3, Bajaj HS4, Leiter LA5, Hansen MV6, Troelsen LN6, Ladelund S6, Heller S7, Pieber TR8, on behalf of the CONCLUDE Study Group1Scripps Whittier Diabetes Institute, San Diego, CA; 2Diabetes Research Institute, Mills-Peninsula Medical Center, San Mateo, CA; 3Diabetes Research Centre, University of Leicester, Leicester, UK; 4LMC Diabetes and Endocrinology, Brampton, ON, Canada; 5Li Ka Shing Knowledge Institute, Division of Endocrinology & Metabolism, St Michael's Hospital, University of Toronto, ON, Canada; 6Novo Nordisk A/S, Søborg, Denmark; 7Academic Unit of Diabetes, Endocrinology and Metabolism, University of Sheffield, Sheffield, UK; 8Division of Endocrinology and Diabetology, Department of Internal Medicine, Medical University of Graz, Graz, AustriaDiabetologia 2020;63: 698–710BackgroundHead-to-head comparison between the second-generation, ultra-long-acting insulin analogs degludec (U200) and glargine U300 regarding the risk of hypoglycemia in adults with type 2 diabetes.MethodsOpen-label, multicenter, treat-to-target trial in adults with type 2 diabetes previously treated with basal insulin±oral glucose-lowering drugs except insulin secretagogues, with HbA1c ≤80 mmol/mol (9.5%) and BMI ≤45 kg/m2, and with at least one predefined criterion for hypoglycemia risk. Participants were randomized to receive degludec U200 (n=733) or glargine U300 (n=734) once daily, and titrated to a fasting blood glucose target of 4.0–5.0 mmol/L. Endpoints were assessed during the last 36-week maintenance period of the trial and during the total treatment duration of up to 88 weeks. Primary endpoint was the rate of overall symptomatic hypoglycemic events (either severe hypoglycemia requiring third-party assistance or confirmed by blood glucose <3.1 mmol/L) in the maintenance period. Secondary hypoglycemia endpoints were number of nocturnal symptomatic events and number of severe hypoglycemic events during the same period.ResultsThe rates of overall symptomatic hypoglycemic events during the maintenance period were not significantly different between degludec U200 and glargine U300 users, the rate ratio (RR) being 0.88 (95% CI: 0.73–1.06). Consequently, further confirmatory testing for superiority was stopped. Still, secondary endpoints were analyzed according to prespecified statistical models but were instead considered exploratory, showing lower rates of nocturnal symptomatic hypoglycemia (RR 0.63 [95% CI: 0.48–0.84]) and severe hypoglycemia (RR 0.20 [95% CI: 0.07–0.57]) in favor of degludec U200.ConclusionsDuring the maintenance period, the rates of overall symptomatic hypoglycemia were comparable with insulin degludec U200 and glargine U300. Corresponding rates of nocturnal symptomatic hypoglycemia and severe hypoglycemia were nominally significantly lower with degludec U200 than with glargine U300.Similar glycaemic control and less hypoglycaemia during active titration after insulin initiation with glargine 300 Units/mL and degludec 100 Units/mL: a subanalysis of the BRIGHT studyCheng A1, Harris S2, Giorgino F3, Seufert J4, Ritzel R5, Khunti K6, Lauand F7, Melas-Melt L8, Westerbacka J7, Bosnyak Z7, Rosenstock J91Department of Medicine, University of Toronto, Toronto, Canada; 2Schulich School of Medicine and Dentistry, Western University, London, Ontario, Canada; 3Department of Emergency and Organ Transplantation, Section of Internal Medicine, Endocrinology, Andrology and Metabolic Diseases, University of Bari Aldo Moro, Bari, Italy; 4Division of Endocrinology and Diabetology, Department of Medicine II, Medical Center – University of Freiburg, Faculty of Medicine, University of Freiburg, Germany; 5Division of Endocrinology, Diabetes and Angiology, Klinikum Schwabing and Klinikum Bogenhausen, Munich, Germany; 6Diabetes Research Centre, University of Leicester, Leicester, UK; 7Sanofi, Paris, France; 8IVIDATA, Levallois-Perret, France; 9Dallas Diabetes Research Center at Medical City, Dallas, TXDiabetes Obes Metab 2020;22: 346–354BackgroundThis prespecified subanalysis of the BRIGHT trial, which was the first published clinical head-to-head comparison between insulin glargine U300 and insulin degludec, has focused on glycemic control and hypoglycemic events during the initial 12-week insulin titration period.MethodsThe BRIGHT trial was a multicenter, open-label, two-arm, parallel-group, 24-week, noninferiority study where insulin-naive adults with type 2 diabetes with inadequate glucose control were randomized to initiate once-daily basal insulin therapy with glargine U300 (n=466) or degludec U100 (n=463). In this report, predefined efficacy and safety outcomes were analyzed during the initial 12-week dose titration period. Moreover, clinical characteristics and outcomes were assessed in descriptive terms, stratified by confirmed (≤3.9 mmol/l) hypoglycemic events during the titration period.ResultsAt the end of the 12-week titration period, HbA1c was similar for glargine U300 (7.32%) and degludec U100 (7.23%) users, with comparable least squares (LS) mean reductions from baseline (−1.37% and −1.39%, respectively), the LS mean difference being 0.02 (95% CI: −0.08 to 0.12). Participants who had experienced hypoglycemic events during the titration period had numerically more pronounced HbA1c reductions at week 12 than those who did not (−1.46% vs. −1.28%) and had higher incidence of anytime (73.3% vs 35.7%) and nighttime (00:00–06.00 hours; 30.0% vs 11.9%) hypoglycemia during the remaining 13–24 weeks of the study period.ConclusionsThe use of glargine U300 or degludec U200 resulted in comparable improvements in glycemic control during the initial 12-week dose titration period of trial, when less anytime hypoglycemic events for glargine U300 than for degludec U100 were reported in the original BRIGHT trial publication. Having experienced hypoglycemic events shortly after starting basal insulin therapy with glargine U300 or degludec U100 may be associated with future risk of hypoglycemia.Differential glycaemic control with basal insulin glargine 300 U/mL versus degludec 100 U/mL according to kidney function in type 2 diabetes: a subanalysis from the BRIGHT trialHaluzik M1, Cheng A2, Müller-Wieland D3, Westerbacka J4, Bosnyak Z4, Lauand F4, Melas-Melt L5, Karalliedde J6, Rosenstock J7, Bolli GB81Diabetes Centre, Institute for Clinical and Experimental Medicine, Prague, Czech Republic; 2Department of Medicine, University of Toronto, Toronto, Canada; 3Department of Cardiology, University Hospital RWTH Aachen, Aachen, Germany; 4Sanofi, Paris, France; 5IVIDATA, Levallois-Perret, France; 6Department of Diabetes and Endocrinology, Guy's and St Thomas' NHS Trust, London, UK; 7Dallas Diabetes Research Center at Medical City, Dallas, TX; 8Section of Endocrinology and Metabolism, Department of Medicine, Perugia University Medical School, Perugia, ItalyDiabetes Obes Metab 2020;22: 1369–1377BackgroundIn this prespecified subgroup analysis from the BRIGHT trial, it was investigated whether clinical outcomes using glargine U300 and degludec U100 were influenced by kidney function.MethodsThe insulin-naive participants with type 2 diabetes who had been randomized to initiate basal insulin therapy with glargine U300 or degludec U100 were stratified according to baseline estimated glomerular filtration rate (eGFR) for the assessments.ResultsHeterogeneity of treatment effect across kidney function subgroups was demonstrated (P=0.02), showing a significantly greater mean reduction of HbA1c from baseline to end of trial (week 24) with glargine U300 vs degludec U100 in the eGFR <60 mL/min/1.73m2 subgroup, the least squares mean difference being 0.43% (95% CI: 0.74%−0.12%). No difference in incidence and rates of hypoglycemia were observed between the basal insulin analogs in this subgroup. In the other kidney function subgroups, HbA1c reductions were comparable between glargine U300 and degludec U100, but heterogeneity was noted for annualized rates of daily (24 h) and nocturnal (00:00–05.59 hours) confirmed hypoglycemia (≤3.9 mmol/L) over the 24-week study period, with less hypoglycemia in glargine U300 vs degludec U100 users in the ≥90 mL/min/1.73 m2 eGFR subgroup.ConclusionsKidney function appears to influence the glucose-lowering effects of glargine U300 vs degludec U100 in previously insulin-naive adults with type 2 diabetes. Greater HbA1c reductions without increase in risk of hypoglycemia using glargine U300 were observed in subjects with eGFR <60 mL/min/1.73 m2.Efficacy and safety of insulin glargine 300 units/mL (Gla-300) versus insulin glargine 100 units/mL (Gla-100) in children and adolescents (6–17 years) with type 1 diabetes: results of the EDITION JUNIOR randomized controlled trialDanne T1, Tamborlane WV2, Malievsky OA3, Franco DR4, Kawamura T5, Demissie M6, Niemoeller E6, Goyeau H7, Wardecki M8, Battelino T91Children's Hospital AUF DER BULT, Hannover Medical School, Hannover, Germany; 2Department of Pediatrics, Yale University School of Medicine, New Haven, CT; 3Department of Pediatrics, Bashkir State Medical University, Ufa, Russian Federation; 4CPCLIN Clinical Research Center, São Paulo, Brazil; 5Department of Pediatrics, Osaka City University Graduate School of Medicine, Osaka, Japan; 6Sanofi, Frankfurt, Germany; 7Sanofi, Chilly-Mazarin, France; 8Sanofi, Warsaw, Poland; 9UMC - University Children's Hospital and Faculty of Medicine, University of Ljubljana, Ljubljana, SloveniaDiabetes Care 2020;43: 1512–1519BackgroundTo compare efficacy and safety of insulin glargine 300 units/mL (Gla-300) and 100 units/mL (Gla-100) in children and adolescents (6–17 years old) with type 1 diabetes.MethodsEDITION JUNIOR was a noninferiority, international, open-label, two-arm, parallel-group, phase 3b trial. Participants were randomized 1:1 to Gla-300 or Gla-100, titrated to achieve fasting self-monitored plasma glucose levels of 90–130 mg/dL (5.0–7.2 mmol/L), with continuation of prior prandial insulin. The primary endpoint was change in HbA1c from baseline to week 26. Other assessments included change in fasting plasma glucose (FPG), hypoglycemia, hyperglycemia with ketosis, and adverse events.ResultsIn 463 randomized participants (Gla-300, n=233; Gla-100, n=230), comparable least squares (LS) mean (SE) reductions in HbA1c were observed from baseline to week 26 (−0.40% [0.06%] for both groups), with LS mean between-group difference of 0.004% (95% CI −0.17 to 0.18), confirming noninferiority at the prespecified 0.3% (3.3 mmol/mol) margin. Mean FPG change from baseline to week 26 was also similar between groups. During the 6-month treatment period, incidence and event rates of severe or documented (≤70 mg/dL [≤3.9 mmol/L]) hypoglycemia were similar between groups. Incidence of severe hypoglycemia was 6.0% with Gla-300 and 8.8% with Gla-100 (relative risk 0.68 [95% CI 0.35-1.30]). Incidence of any hyperglycemia with ketosis was 6.4% with Gla-300 and 11.8% with Gla-100.ConclusionsGla-300 provided similar glycemic control and safety profiles to Gla-100 in children and adolescents with type 1 diabetes, indicating that Gla-300 is a suitable therapeutic option in this population.Efficacy and safety of treatment with new basal insulin analogues in type 1 diabetes: nation-wide surveySvensson A-M1,2, Ekelund J2, Miftaraj M2, Eliasson B1,21Institute of Medicine, Sahlgrenska University Hospital, University of Gothenburg, Gothenburg, Sweden; 2National Diabetes Registry, Centre of Registers, Gothenburg, SwedenDiabetes Ther 2020;11: 725–734BackgroundIn this nationwide, observational study, the efficacy and safety of insulin glargine U300 and insulin degludec were investigated using data from the Swedish National Diabetes Registry together with other national health registries.MethodsThe analyses included adults (≥18 years) with type 1 diabetes using basal insulin supplementation with glargine U100, and who either continued this therapy (n=11340) or had switched to glargine U300 (n=2398) or degludec (n=1719). Differences in clinical characteristics at baseline (index date), and changes thereafter in glucose control (HbA1c), weight, hospitalization due to hypoglycemia, and cardiovascular disease or death, were assessed.ResultsAt baseline there were no apparent differences in clinical characteristics between the groups, although subjects remaining on glargine U100 were slightly older, and fewer in this group had previously been using insulin pumps and continuous glucose monitoring devices. Mean HbA1c levels were comparable between groups, and 4% of all subjects had evidence of cardiovascular disease. Mean follow-up time was 1.1 years for subjects who switched to glargine U300 or degludec and 1.6 years for those continuing with glargine U100. During this period, HbA1c was slightly reduced in all groups in a similar way, and body mass index remained unchanged. Rates of severe hyper- and hypoglycemia were small and comparable between groups. Percentages of overall cardiovascular mortality were 0.7%, 0.8%, and 1.95% with glargine U300, degludec, and glargine U100, respectively. All other severe adverse events were also numerically more evident in those using glargine U100, and with no apparent differences between glargine U300 and degludec.ConclusionsThe long-term efficacy and safety of using basal glargine U300 versus degludec seem to be comparable in adults with type 1 diabetes. The findings also suggest that these basal insulin analogs may provide additional advantages in comparison with glargine U100.In silico head-to-head comparison of insulin glargine 300 U/mL and insulin degludec 100 U/mL in type 1 diabetesSchiavon M1, Visentin R1, Giegerich C2, Sieber J3, Dalla Man C1, Cobelli C1, Klabunde T21Department of Information Engineering, University of Padua, Padova, Italy; 2Translational Disease Modeling, R&D Digital and Data Sciences, Sanofi-Aventis Deutschland GmbH, Frankfurt am Main, Germany; 3Medical Affairs Diabetes Care EMEA, Becton, Dickinson and CompanyDiabetes Technol Ther 2020;22: 553–561BackgroundThis study describes an in silico head-to-head comparison of glargine U300 and degludec U100 using the University of Virginia (UVA)/Padua type 1 diabetes (T1D) simulator, which describes the intra- and interday variability of glucose-insulin dynamics and can be used as a valid bench-test for assessing glucose control for different basal insulin therapies.MethodsA pharmacokinetic (PK) model, describing subcutaneous absorption of insulin degludec U100, was developed from T1D clinical data and, together with an already existing PK model for insulin glargine U300, fed into the simulator. One hundred in silico T1D subjects received once-daily (morning or evening dose) basal insulin with glargine U300 or degludec U100 for 12 weeks (8-week titration and 4-week stable maintenance dosing) in a basal/bolus regimen. Two different titration rules were used for up-titration to individual doses for all virtual subjects. Simulated continuous glucose monitoring data during the last 2-week period were used to assess various glycemic outcome metrics.ResultsThe simulations showed no statistically significant differences between glargine U300 and degludec U100 in the main endpoints, including the mean percentage of time in the target range within 70–140 mg/dL (primary outcome).ConclusionsThe simulations suggest similar glucose control using either glargine U300 or degludec U100 in T1D and have been used to guide the design of a clinical trial intended to compare the two ultra-long-acting basal insulin analogs.CommentLast year we commented on the BRIGHT trial (4), the first published head-to-head comparison between the two second-generation, long-acting, basal insulin analogs glargine U300 (Toujeo) and degludec (Tresiba). The trial, which was supported by Sanofi, was a noninferiority study and included insulin-naive adults with type 2 diabetes followed over 24 weeks after randomization. Change in HbA1c from baseline to study end (primary outcome) was comparable, demonstrating noninferiority of glargine U300 versus degludec. Likewise, measures of hypoglycemia incidence and event rates over the complete study period were similar with both insulin analogs, whereas during the initial 12-week dose titration period incidence and event rates of anytime (24 h) confirmed hypoglycemia (≤70 mg/dL and ≤54 mg/dL) were lower in favor of glargine U300. This year, the second direct head-to-head trial, the Novo Nordisk-supported CONCLUDE trial by Philis-Tsimikas et al., discussed previously, has been published, reporting comparable rates of overall symptomatic hypoglycemic events during the last 36-week maintenance period of the study (primary endpoint) but nominally lower rates of nocturnal symptomatic hypoglycemia and severe hypoglycemia in those using degludec.As commented by Del Prato (5), there are several differences between the two direct head-to-head trials that make a comparison difficult, and also whether the authors' proposed differences in secondary outcomes in favor of degludec are undisputable. In contrast to the BRIGHT trial, the CONCLUDE trial recruited adults with type 2 diabetes already using basal insulin therapy and fulfilling certain risk criterions for hypoglycemia, and the primary aim was to compare the efficacy of degludec versus glargine U300 to alleviate hypoglycemia exposu