Abstract
Introduction
The centennial year of insulin discovery offered ample opportunity to review the past success and the future wishes regarding novel insulin preparations, more universal insulin availability, and worldwide implication of diabetes technology to reduce the daily burden (1). Distinguishing basal and prandial insulin has been a cornerstone of treatment, whether it was delivered by injections or insulin pumps. With the increased availability of various systems for automated insulin delivery (AID), this distinction disappears. The traditional concepts of “basal” and “bolus” insulin become less useful with AID, as both types of insulin delivery are used to mitigate hypoglycemia and respond to hyperglycemia. A single type of insulin is modulated with lower or higher microboluses delivered in frequent intervals, and the distinction between what is an automated correction bolus or merely an elevation of the basal rate is becoming less meaningful. Nevertheless, it is likely that this type of therapy will neither be generally available nor desired by every insulin‐requiring individual.
The pursuit of creating ultra‐long‐acting basal insulin analogs allowing once‐weekly subcutaneous administration may soon become a clinical reality as promising data from the first phase 2 clinical trials with one of these analogs—insulin icodec developed by Novo Nordisk—having been published over the last year. The molecular engineering behind this analog includes three amino acid substitutions (A14Glu, B16His, B25His), which results in reduced insulin receptor affinity and clearance, and a 20‐carbon fatty diacid moiety attached via a hydrophilic linker leading to durable binding to circulating albumin and very protracted release (2). With these modifications, the half‐life of icodec has been extended to about 8 days with a flat and stable pharmacokinetic profile, low peak‐to‐trough variations, and evenly distributed glucose‐lowering efficacy within a weekly dosing interval (3).
From a global perspective, biosimilar insulins (BioIns) are starting to have an impact on the insulin market as more companies come to the market. However, up to now the market has not been flooded with a number of different BioIns due to a number of barriers (4 –7). In 2015, the first available BioIns were launched in the EU and the United States under the names Abasaglar (EU) and Basaglar (U.S.). Technically, Basaglar is not a biosimilar in the United States but rather a follow‐on biologic, as it was regulated and approved by the Food and Drug Administration (FDA) under the Food, Drug, and Cosmetic Act (FD&C Act), Section 505(b)(2), new drug application pathway. Since March 2020, insulin products are approved as biosimilars in the United States under the 351(k) Biologics License Application (BLA) process under the Public Health Service Act (8 –11). It is possible that the FDA would have approved more BioIns in the last year, but the focus on COVID has delayed many developments. In addition, many clinical studies were halted or delayed due to the pandemic. Today, the FDA appears to be in an intensive communication process with a number of other insulin manufacturers of BioIns based on the number of respective guidance documents that the FDA has recently released.
Thus, the future of insulin treatment continues to be driven by innovation in insulin molecular science, diabetes technology, and efforts of all stakeholders to make the treatments that were initiated by the discovery of insulin in Toronto 100 years ago available worldwide to all individuals in need.
Key Articles Reviewed for the Article
Rosenstock J, Bajaj HS, Janež A, Silver R, Begtrup K, Hansen MV, Jia T, Goldenberg R for the NN1436‐4383 Investigators
Bajaj HS, Bergenstal RM, Christoffersen A, Davies MJ, Gowda A, Isendahl J, Lingvay I, Senior PA, Silver RJ, Trevisan R, and Rosenstock J
Lingvay I, Buse JB, Franek E, Hansen MV, Koefoed MM, Mathieu C, Pettus J, Stachlewska K, and Rosenstock J
Lucidi P, Candeloro P, Cioli P, Marinelli Andreoli A, Pascucci C, Gambelunghe A, Bolli GB, Fanelli CG, Porcellati F
Laviola L, Porcellati F, Bruttomesso D, Larosa M, Chiara Rossi A, Nicolucci A
Mauricio D, Westerbacka J, Nicholls C, Wu J, Gupta R, Eliasson B
Kosinski C, Herzig D, Laesser CI, Nakas CT, Melmer A, Vogt A, Vogt B, Laimer M, Bally L, Stettler C
Kapitza C, Nosek L, Schmider W, Teichert L, Mukherjee B, Nowotny I
Shah VN, Franek E, Wernicke‐Panten K, Pierre S, Mukherjee B, Sadeharju K
Liu H, Yu H, Sun L, Qiao J, Wai S, Li S, Li J, Tan H, Yu Y
Sun B, Sengupta N, Rao A, Donnelly C, Waichale V, Roy AS, Ramaswamy S, Pathak D, Bowsher RR, Raiter Y, Aubonnet P, Barve A
Avgerinos I, Papanastasiou G, Karagiannis T, Michailidis T, Liakos A, Mainou M, Matthews DR, Tsapas A, Bekiari E
Warren M, Bode B, Cho JI, Liu R, Tobian J, Hardy T, Chigutsa F, Phillip M, Horowitz B, Ignaut D
Billion 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 C
Danne T, Schweitzer MA, Keuthage W, Kipper S, Kretzschmar Y, Simon J, Wiedenmann T, Ziegler R
Faggionato E, Schiavon M, Dalla Man C
Grosman B, Wu D, Parikh N, Roy A, Voskanyan G, Kurtz N, Sturis J, Cohen O, Ekelund M, Vigersky R
Hsu L, Buckingham B, Basina M, Ekhlaspour L, von Eyben R, Wang J, Lal RA
Ozer K, Cooper AM, Ahn LP, Waggonner CR, Blevins TC
Bode BW, Carlson A, Liu R, Hardy T, Bergenstal RB, Boyd J, Morrett S, Ignaut DA
Russell SJ, Balliro C, Ekelund M, El‐Khatib F, Graungaard T, Greaux E, Hillard M, Jafri RZ, Rathor N, Selagamsetty R, Sherwood J, Damiano ER
Lee MH, Paldus B, Vogrin S, Morrison D, Zaharieva DP, Lu J, Jones HM, Netzer E, Robinson L, Grosman B, Roy A, Kurtz N, Ward GW, MacIsaac RJ, Jenkins AJ, O'Neal DN
Colmegna P, Cengiz E, Garcia‐Tirado J, Kraemer K, Breton MD
Svehlikova E, Mursic I, Augustin T, Magnes C, Gerring D, Jezek J, Schwarzenbacher D, Ratzer M, Wolf M, Howell S, Zakrzewski L, Urschitz M, Tschapeller B, Gatschelhofer C, Feichtner F, Lawrence F, Pieber TR
Andersen G, Meiffren G, Famulla S, Heise T, Ranson A, Seroussi C, Eloy R, Gaudier M, Charvet R, Chan YP, Soula O, Hans DeVries J
Majdpour D, Tsoukas MA, Yale JF, El Fathi A, Rutkowski J, Rene J, Garfield N, Legault L, Haidar A
THIRD‐GENERATION ULTRA‐LONG‐ACTING BASAL INSULIN ANALOGS INTENDED FOR ONCE‐WEEKLY ADMINISTRATION
Once‐Weekly Insulin for Type 2 Diabetes Without Previous Insulin Treatment
Rosenstock J1, Bajaj HS2,3, Janež A5, Silver R6, Begtrup K7, Hansen MV7, Jia T7, Goldenberg R4 for the NN1436‐4383 Investigators
1Dallas Diabetes Research Center at Medical City, Dallas; 2LMC Diabetes and Endocrinology, Brampton, Ontario, Canada; 3Leadership Sinai Centre for Diabetes, Mount Sinai Hospital, Toronto, Ontario, Canada; 4LMC Diabetes and Endocrinology, Vaughan, Ontario, Canada; 5Department of Endocrinology, Diabetes and Metabolic Diseases, University Medical Center Ljubljana, Ljubljana, Slovenia; 6Southern New Hampshire Diabetes and Endocrinology, Nashua, NH; 7Novo Nordisk, Søborg, Denmark
Background
Insulin icodec is a novel basal insulin analog intended for once‐weekly administration. The aim of this phase 2 trial was to investigate the efficacy and safety of icodec in insulin‐naïve persons with type 2 diabetes, with insulin glargine U100 as a comparator.
Methods
A 26‐week, randomized, double‐blind, double‐dummy trial in 247 persons with type 2 diabetes with inadequate glycemic control (HbA1c 7.0–9.5%) while being on treatment with metformin ± a dipeptidyl peptidase 4 (DPP4) inhibitor. The participants were randomly assigned 7.0%–9.5%) while being on treatment with metformin ± a dipeptidyl peptidase 4 (DPP4) inhibitor. The participants were randomly assigned (1:1) and received icodec once weekly or glargine U100 once daily. The primary outcome was change in HbA1c from baseline to week 26. The authors also evaluated safety end points, including hypoglycemic episodes and other insulin‐related adverse events.
Results
Baseline characteristics were comparable in the two groups with mean baseline HbA1c being 8.09% in the icodec group and 7.96% in the glargine group. The estimated mean change in HbA1c at week 26 was −1.33% in the icodec users and −1.15% in the glargine users, to estimated HbA1c means of 6.69% and 6.87%, respectively; the estimated between‐group difference being −0.18% (95% CI; −0.38 to 0.02, P=0.08). Rates of hypoglycemic events with blood glucose <54 mg/dL (level 2) or with severe cognitive impairment (level 3) were low (0.53 events per patient‐year in the icodec group and 0.46 events per patient‐year in the glargine group) the estimated rate ratio being 1.09 (95% CI: 0.45 to 2.65). Insulin‐related adverse events were similar in the two groups, and rates of hypersensitivity and local injection‐site reactions were low. Most adverse events were rated mild, and no serious events were related to the study medications.
Conclusions
Once‐weekly administration of the basal insulin analog icodec provided glucose‐lowering efficacy and a safety profile similar to once‐daily insulin glargine treatment.
Switching to Once‐Weekly Insulin Icodec Versus Once‐Daily Insulin Glargine U100 in Type 2 Diabetes Inadequately Controlled on Daily Basal Insulin: A Phase 2 Randomized Controlled Trial
Bajaj HS1,2, Bergenstal RM3, Christoffersen A4, Davies MJ5,6, Gowda A4, Isendahl J4, Lingvay I7, Senior PA8, Silver RJ9, Trevisan R10, and Rosenstock J11
1LMC Diabetes and Endocrinology, Brampton, Ontario, Canada; 2Leadership Sinai Centre for Diabetes, Mount Sinai Hospital, Toronto, Ontario, Canada; 3International Diabetes Center at HealthPartners, Minneapolis, MN; 4Novo Nordisk A/S, Søborg, Denmark; 5Diabetes Research Centre, University of Leicester, Leicester, UK; 6NIHR Leicester Biomedical Research Centre, Leicester, UK; 7University of Texas Southwestern Medical Center, Dallas, TX; 8University of Alberta, Edmonton, Alberta, Canada; 9Southern New Hampshire Diabetes and Endocrinology, Nashua, NH; 10Azienda Socio Sanitaria Territoreale Papa Giovanni XXIII, Bergamo, Italy; 11Dallas Diabetes Research Center, Dallas, TX
Background
This phase 2 trial aimed to investigate two ways of switching to once‐weekly administration of icodec versus once‐daily glargine U100 (IGlar) in persons with type 2 diabetes using basal insulin plus one or more oral glucose‐lowering drugs.
Methods
A multicenter, open‐label, treat‐to‐target trial where adults with inadequately controlled type 2 diabetes [HbA1c 7.0%–10.0% (53.0–85.8 mmol/mol)] while on basal insulin treatment (total daily dose 10–50 units) were randomized (1:1:1) to either receive icodec with an initial doubling of the first dose (icodec LD), icodec with no loading dose (icodec NLD), or IGlar U100 for 16 weeks. The primary end point was percent time in range [TIR; 3.9–10.0 mmol/L (70–180 mg/dL)] during the two last weeks of the study period, as assessed with continuous glucose monitoring. Key secondary end points included HbA1c, adverse events and hypoglycemia.
Results
Estimated mean TIR during weeks 15–16 was 72.9% with icodec LD (n=54), 66.0% with icodec NLD (n=50) and 65.0% with IGlar U100, respectively, with a statistically significant difference favoring icodec LD versus IGlar U100 [7.9%‐points (95% CI: 1.8–13.9%)]. Mean HbA1c was reduced from a baseline value of 7.9% (62.8 mmol/mol) to 7.1% (54.4 mmol/mol) in the icodec LD group and to 7.4% (57.6 mmol/mol) in both the icodec NDL and IGlar U100 groups. Events and rates of adverse events and hypoglycemia were similar in all study groups.
Conclusions
Switching from once‐daily basal insulin to once‐weekly icodec administration provided effective glycemic control and was well tolerated. Using an initial loading dose when changing to once‐weekly icodec significantly improved time in range (TIR) at weeks 15 and 16 compared with IGlar U100 and did not increase the risk of hypoglycemia.
A Randomized, Open‐Label Comparison of Once‐Weekly Insulin Icodec Titration Strategies Versus Once‐Daily Insulin Glargine U100
Lingvay I1,2, Buse JB3, Franek E4, Hansen MV5, Koefoed MM5, Mathieu C6, Pettus J7, Stachlewska K5, and Rosenstock J8
1Endocrinology Division, Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX; 2Department of Population and Data Sciences, University of Texas Southwestern Medical Center, Dallas, TX; 3School of Medicine, University of North Carolina at Chapel Hill, NC; 4Mossakowski Medical Research Centre, Warsaw, Poland; 5Novo Nordisk A/S, Søborg, Denmark; 6Clinical and Experimental Endocrinology, University of Leuven, Leuven, Belgium; 7School of Medicine, University of California, San Diego, San Diego, CA; 8Dallas Diabetes Research Center at Medical City, Dallas, TX
Background
This phase 2 trial assessed the efficacy and safety of initiating once‐weekly icodec treatment in insulin‐naïve adults with type 2 diabetes, using different once‐weekly titration algorithms.
Methods
This study was an open‐label, 16‐week, treat‐to‐target trial in 205 insulin‐naïve adults with type 2 diabetes, who showed HbA1c 7%–10% while on treatment with oral antidiabetic drugs. The participants were randomized to four different groups: in group A (n=51), the prebreakfast self‐measured blood glucose target was 80–130 mg/dL and the adjustment of the icodec dose was ±21 units/week; in group B (n=51), the prebreakfast blood glucose target was the same as in group A but the icodec adjustment was ±28 units/week; in group C (n=52), the prebreakfast blood glucose target was lower (70–108 mg/dL) with icodec adjustment ±28 units/week. Group D (n=51) received once‐daily insulin glargine U100 with a prebreakfast blood glucose target of 80–130 mg/dL and with adjustment ±4 units/day, titrated on a weekly basis. Primary outcome was the percentage of time in range (TIR; 70–180 mg/dL) during weeks 15–16, as measured with continuous glucose monitoring.
Results
Time in range improved from baseline to weeks 15–16 in all four groups: from 57.0% to 76.6% in group A, from 55.2% to 83.0% in B, from 51.0% to 80.9% in C, and from 55.3% to 75.9% in the insulin glargine U100 group. TIR was greater for titration B than for insulin glargine U100 with an estimated treatment difference of 7.08%‐points (95% CI: 2.12–12.04; P=0.005). Level 2 self‐reported hypoglycemic episodes (<54 mg/dL) were low in all four study groups; 0.05, 0.15, 0.38, and 0.00 events per patient‐year in groups A, B, C, and D, respectively, with no events of severe hypoglycemia. No unexpected safety signals were registered.
Conclusions
Once‐weekly icodec was effective and well tolerated in all the three titration algorithms assessed. The least aggressive treatment algorithm (titration A with prebreakfast blood glucose target 80–130 mg/dL, and icodec adjustments ±21 units/week) represented the best balance between glycemic control and risk of hypoglycemia.
Comment
The findings of the phase 2 trials indeed indicate that once‐weekly administration of icodec is feasible, with no major safety concerns. However, they also highlight that special considerations regarding starting doses and titration strategies apply when initiating treatment with this analog. In the study by Rosenstock et al. including insulin‐naïve adults with type 2 diabetes, the starting dose of icodec was 70 units and the dose was adjusted ±28 units weekly to attain a prebreakfast self‐monitored blood glucose target of 70–108 mg/dL (3.9–6.0 mmol/L). With this rather aggressive target protocol, the incidence of level 1 hypoglycemia (<70 mg/dL; <3.9 mmol/L) was higher with icodec (53.6%) than with glargine U100 (37.7%), whereas the incidence of level 2 (<54 mg/dL; 3.0 mmol/L) and level 3 hypoglycemia (severe cognitive impairment necessitating external assistance) was low and comparable in both groups. Likewise, in the study by Lingvay and coworkers, the group of prior insulin‐naïve participants who were allocated to icodec treatment with the same blood glucose target and icodec adjustments as in the former trial experienced the highest rates of hypoglycemia, whereas a less aggressive blood glucose target (80–130 mg/dL; 4.4–7.2 mmol/L) and smaller dose adjustments seemingly displayed the best balance between risk of hypoglycemia and improvement in glycemic control.
An additional challenge exists when persons already on basal insulin therapy are switched to once‐weekly icodec, as was investigated by Bajaj et al. In their study, the initial dose of icodec was based on the pre‐trial daily insulin dose multiplied by seven for those who had been on once‐daily basal insulin, whereas the first dose was reduced by 20% for those who had been on twice‐daily basal insulin (or glargine U300 once daily). Since the long half‐life of icodec will increase the time to reach steady‐state conditions, they also examined whether it might be advantageous to use an initial doubled loading dose. The titration algorithm then aimed at a fasting blood glucose of 80–130 mg/dL (4.4–7.2 mmol/L), with icodec adjustments ±28 units/week. Perhaps not surprisingly, the unit‐to‐unit switch to icodec resulted in an initial transitory increase in fasting blood glucose. This phenomenon, however, was prevented in those receiving a loading dose. Moreover, in the latter group, glycemic control (estimated mean TIR) at the end of the trial was significantly better than in the glargine U100 group, whereas rates of hypoglycemic events were comparable.
Coupling of the insulin molecule to the Fc‐domain of immunoglobulin G to form a Fc‐fusion protein is another way to enhance the pharmacokinetic and pharmacodynamic profiles. This novel concept is presently being explored by several pharmaceutical companies, and preliminary clinical data have recently been presented for Basal Insulin Fc (BIF), developed by Lilly. BIF is comprised of a human single‐chain insulin fused to a human IgG2 Fc domain via a peptide linker, and show reduced insulin receptor potency with complete agonism, selectivity against the human insulin‐like growth factor‐1 receptor, and functional characteristics comparable to native human insulin (12). Its half‐life was estimated to be about 17 days in adults with type 2 diabetes, and after an initial loading dose followed by weekly maintenance doses, a nearly peak‐less pharmacokinetic profile with very low peak‐to‐trough fluctuations was observed; at the same time, the glycemic control remained stable over time and was similar to that with insulin glargine (13). In a 32‐week phase 2 trial investigating the efficacy and safety of once‐weekly BIF at one of two dosing algorithms (fasting serum glucose ≤140 mg/dL or ≤120 mg/dL) in adults with type 2 diabetes previously treated with basal insulin, HbA1c noninferiority vs degludec (target serum glucose ≤100 mg/dL) was shown together with lower rates of documented and nocturnal hypoglycemic events ≤70 mg/dL and less weight gain. Moreover, no safety concerns with BIF were observed (14).
In conclusion, the prospect of having once‐weekly basal insulins in the arsenal of insulin therapies in the near future seems realistic. However, while this might be more convenient than daily insulin injections, the inability to adjust for daily variations in insulin requirement, for example, in connection with physical exercise or acute illnesses, might limit widespread use. Moreover, newer treatment options, like GLP‐1 RAs (Receptor‐Agonists), dual GIP/GLP‐1 RAs, and SGLT2‐inhibitors will probably lessen the need of basal insulin therapy in patients with type 2 diabetes, who otherwise would appear to be the most suitable users of once‐weekly insulin dosing. Evidently, further studies are needed to delineate in more detail how these novel supra‐long‐acting insulins should be initiated and titrated, and to which patient groups they should primarily be used. This will most certainly be followed in future Yearbooks.
NEW DATA ON THE SECOND‐GENERATION ULTRALONG‐ACTING INSULIN ANALOGS
Pharmacokinetic and Pharmacodynamic Head‐to‐Head Comparison of Clinical, Equivalent Doses of Insulin Glargine 300 Units Ml−1 and Insulin Degludec 100 Units Ml−1 in Type 1 Diabetes
Lucidi P1, Candeloro P1, Cioli P1, Marinelli Andreoli A1, Pascucci C1, Gambelunghe A2, Bolli GB1, Fanelli CG1, Porcellati F1
1Section of Endocrinology and Metabolism, Department of Medicine, University of Perugia Medical School, Perugia, Italy; 2Section of Occupational Medicine, Respiratory Diseases and Toxicology, Department of Medicine, University of Perugia School of Medicine, Perugia, Italy
Background
This study was conducted to compare the pharmacokinetic and pharmacodynamic characteristics of insulin glargine U300 and insulin degludec U100 under steady‐state conditions in people with type 1 diabetes, when administered in individual, clinically titrated doses.
Methods
Single‐blind, randomized, crossover trial, which included 22 adults with type 1 diabetes (mean age 44.3±12.4 years, diabetes duration 25.5±11.7 years, HbA1c 7.07±0.63% [53.7±6.9 mmol/mol], BMI 22.5±2.7 kg m−2) previously naïve to glargine U300 and degludec U100. After 3 months of optimal titration of basal (and bolus) insulin, 24 h, euglycemic clamps with individual, clinical doses of glargine 300 (0.34±0.08 units·kg−1) and degludec (0.26±0.06 units·kg−1) were performed, with dosing in the evening at 2000 h.
Results
At the end of the 3 months' titration phases, HbA1c was slightly lowered in a comparable way with both glargine U300 and degludec U100. Average plasma glucose was euglycemic during the clamp procedure (0–24 h) with both insulins, and the area under the curve of glucose infused (AUC ‐GIR[0–24 h]) was comparable (ratio 1.04; 90% CI: 0.91–1.18). Suppression of endogenous glucose production and reduction of circulating levels of free fatty acids, glycerol, and β‐hydroxybutyrate were 9%, 14%, 14%, and 18% greater, respectively, with glargine U300 than with degludec U100 during the first 12 h period of the clamp, whereas glucagon suppression showed no difference. Relative within‐day variability of glucose pharmacodynamics was 23% lower with glargine U300 than with degludec U100 (ratio 0.77; 90% CI: 0.63–0.92).
Conclusions
In subjects with type 1 diabetes, individualized, clinically titrated doses of glargine U100 and degludec U100 at steady‐state resulted in comparable glycemic control and similar pharmacodynamics during euglycemic clamps. Clinical doses of glargine U300 were higher than those with degludec U100, but with quite similar and even 24‐h distribution of pharmacodynamic effects on glucose utilization, endogenous glucose production, and anti‐lipolysis.
Comparative Effectiveness of Switching from First‐Generation Basal Insulin to Glargine 300 U/Ml or Degludec 100 U/Ml in Type 1 Diabetes: The RESTORE‐1 Study
Laviola L1, Porcellati F2, Bruttomesso D3, Larosa M4, Chiara Rossi A5, Nicolucci A5
1Endocrinology, Andrology, and Metabolic Diseases, University of Bari Aldo Moro, Bari, Italy; 2Section of Internal Medicine, Endocrinology and Metabolism, Department of Medicine, Perugia University School of Medicine, Perugia, Italy; 3Department of Medicine, University of Padova, Padua, Italy; 4Medical Affairs, Sanofi S.r.l., Milan, Italy; 5CORESEARCH, Center for Outcome Research and Clinical Epidemiology, Pescara, Italy
Background
The RESTORE‐1 study aimed to compare the efficacy and safety of insulin glargine U300 and degludec U100 in people with type 1 diabetes, who had switched from other basal insulins.
Methods
This was an observational, retrospective, noninferiority study, based on electronical medical records from 19 centers in Italy. All persons switching to glargine U300 or degludec U100 from first‐generation basal insulins were 1:1 propensity score matched (PSM). Changes in HbA1c (primary outcome), fasting plasma glucose (FPG), body weight, and insulin doses after 6 months were assessed, using linear mixed models for repeated measures. Incidence rates of hypoglycemic events were also investigated.
Results
Data were identified for 585 subjects in each propensity score matched cohort. For both groups, there were statistically significant reductions of HbA1c from baseline to 6 months; −0.20% (95% CI: −0.32 to −0.08) in the glargine U300 group, and −0.14% (95% CI: −0.24 to −0.04) in the degludec U100 group. Noninferiority of glargine U100 and degludec U100 was confirmed (noninferiority margin 0.30%; upper 95% CI 0.09%). Likewise, there were no statistically significant differences between the groups regarding FPG or bodyweight. Dose changes of basal and short‐acting insulin after switching to glargine U100 or degludec U100 were small, but significantly higher with glargine U100 than with degludec U100 (p<0.006). Hypoglycemic events (<54 mg/dL) were significantly reduced at 6 months in both groups. During the full follow‐up period, incidence rates (IR) of hypoglycemia (≤70 mg/dL and <54 mg/dL) were numerically lower with glargine U300 than with degludec U100 [IR ratios 0.82 (95%CI: 0.55–1.22), and 0.83 (95% CI: 0.38–1.83), respectively]. Seven severe hypoglycemic events were registered for degludec U100, whereas none were documented for glargine U300 (P=0.02).
Conclusions
Switching to the second‐generation basal insulins glargine U300 and degludec U100 in adults with type 1 diabetes resulted in comparable improvements in glycemic control and significant reductions of hypoglycemia, with no severe hypoglycemic events with glargine U300. The efficacy of both insulins was probably limited by under‐titration.
How Many People with Type 2 Diabetes Fulfill the Eligibility Criteria for Randomized, Controlled Trials of Insulin Glargine 300 U/Ml in a Real‐World Setting?
Mauricio D1, Westerbacka J2, Nicholls C3, Wu J4, Gupta R5, Eliasson B6
1Hospital de la Santa Creu i Sant Pau, CIBERDEM, Barcelona, Spain; 2Sanofi, Paris, France; 3Sanofi, Reading, UK; 4Sanofi, Bridgewater, New Jersey, NJ; 5Accenture, Florham Park, New Jersey, NJ; 6Department of Medicine, University of Gothenburg, Sahlgrenska University Hospital, Gothenburg, Sweden
Background
This study aimed to evaluate how representative selected people in randomized controlled trials (RCTs) assessing the efficacy of second‐generation basal insulin analogs are of “real‐world” type 2 diabetes populations.
Methods
This was a retrospective, observational study where characteristics of adults with type 2 diabetes using basal insulin analogs were obtained from electronic medical records from the Explorys database, which contain data from 39 integrated healthcare systems in the United States. Comparison was made with data from RCTs investigating insulin glargine U300 and degludec.
Results
Using eligibility criteria from the EDITION 1, 2, and 3 (RCTs comparing glargine U300 vs glargine U100) and BRIGHT (RCT comparing glargine U300 and degludec U100), only 17% (33,345/191,218) of subjects found in the Explorys database would have been eligible for inclusion in these trials. Those who did not qualify tended to be older, and had more prevalent comorbidities and higher rates of baseline hypoglycemia than those who were eligible. Using EMR data from another large U.S. database (Optum Humedica), only 15% (36,285/235,697) would have qualified for the EDITION/BRIGHT RCTs, and 7% for the CONCLUDE trial (RCT comparing degludec U200 vs glargine U300).
Conclusions
A large proportion of people with type 2 diabetes receiving treatment with basal insulin analogs would have been excluded from participating in RCTs as they do not meet the inclusion/exclusion criteria. Therefore, observational, real‐world studies are important by complementing findings from RCTs and giving additional knowledge about those groups who are not eligible for inclusion in RCTs.
A Single Load of Fructose Attenuates the Risk of Exercise‐Induced Hypoglycemia in Adults with Type 1 Diabetes on Ultra‐Long‐Acting Basal Insulin: A Randomized, Open‐Label, Crossover Proof‐Of‐Principle Study
Kosinski C1, Herzig D1, Laesser CI1, Nakas CT2,3, Melmer A1, Vogt A4, Vogt B5, Laimer M1, Bally L1, Stettler C1
1Department of Diabetes, Endocrinology, Nutritional Medicine and Metabolism, Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland; 2Laboratory of Biometry, School of Agriculture, University of Thessaly, Nea Ionia Magnesia, Greece; 3University Institute of Clinical Chemistry, Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland; 4Department of Anaesthesiology and Pain Medicine, Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland; 5Department of Nephrology and Hypertension, Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland
Background
Adjustment of insulin is not easily made to reduce exercise‐induced hypoglycemia in individuals with type 1 diabetes using ultra‐long‐acting basal insulin analogs. This proof‐of‐concept study tested whether pre‐exercise intake of fructose may be an alternative way to lessen the risk of exercise‐induced hypoglycemia.
Methods
The study included 14 adult males with type 1 diabetes treated with insulin degludec, who completed two 60‐min aerobic cycling sessions with or without prior (30 min) intake of 20 g of fructose, in a randomized, two‐period, crossover design. The exercise bout was performed in the morning in the fasted state without prior reduction of the basal insulin dose and after 48 h of standardized diet. The primary outcome was time to hypoglycemia (≤3.9 mmol/L) during exercise.
Results
One hypoglycemic event, occurring at 60 min, was observed after intake of fructose, as opposed to six hypoglycemic events occurring within 27.5±9.4 min during exercise without prior fructose, demonstrating a risk reduction of 87.8% (hazard ratio 0.12 [95% CI: 0.02−0.66]; P=0.015). Plasma glucose at the start of exercise averaged 7.3±1.4 mmol/L with fructose and 5.5±1.1 mmol/L without (p<0.001). Plasma lactate was higher in the initial 30 min after fructose intake (p<0.001), but not significantly different from the control experiments during exercise (P=0.32). Substrate oxidation during exercise did not differ significantly with or without fructose intake (P=0.73 for carbohydrate oxidation, and P=0.48 for fat oxidation). The ingestion of fructose was well tolerated.
Conclusions
Pre‐exercise intake of fructose is a feasible, effective, and well‐tolerated way to reduce the risk of exercise‐induced hypoglycemia without rebound hyperglycemia in subjects with type 1 diabetes using the ultra‐long‐acting basal insulin analog degludec.
Comment
In earlier ATTD Yearbooks, we have commented on the seemingly contradicting results regarding pharmacokinetic (PK) and pharmacodynamic (PD) characteristics of the second‐generation ultra‐long‐acting basal insulin analogs degludec and glargine U300 in persons with type 1 diabetes (15,16). In these studies, fixed insulin doses (0.4 U/kg) of both analogs were used in prolonged clamp experiments during steady‐state conditions. However, as somewhat higher doses of glargine U300 compared with degludec have been needed to attain similar glycemic control in clinical trials (17,18), it might be more appropriate to study PK/PD profiles in individualized, clinically titrated doses of the two insulin analogs, as was done by Lucidi and coworkers. In their randomized, crossover study, clamps were performed when individualized doses of each analog had been ascertained by tight surveillance and titration over a 3‐month period aiming at fasting plasma glucose of 90–110 mg/dL, with a 2‐month wash‐out period in‐between. As anticipated, higher doses of glargine U300 than degludec were recorded at the end of the titration periods. In this clinically relevant situation, the glucose‐lowering PD profiles were essentially the same with both analogs, although the within‐day variability was marginally lower with glargine U300. Likewise, the suppression of glucagon and lipolysis were comparable.
While the findings from the study by Lucidi et al. clearly indicate that there are no clinically meaningful differences in glucose‐lowering efficacy between degludec and glargine U300, we still lack randomized, controlled, head‐to‐head comparisons between the two analogs in persons with type 1 diabetes. The observational study by Laviola and coworkers, however, corroborates findings from an even larger, nationwide survey from the Swedish National Diabetes Registry (19) and suggests similar clinical effectiveness and safety in terms of glycemic control and hypoglycemia incidence when using the two analogs in adults with type 1 diabetes. In this context, the somewhat provocative data presented by Mauricio et al., showing that only a minor proportion of people with type 2 diabetes commonly seen in clinical practice were eligible for inclusion in randomized controlled trials (RCTs) of glargine U300 or degludec, should remind us about the peril of extrapolating and generalizing results from RCTs and the added value of “real‐world data” assessed with more intricate statistical methods.
Along with the use of longer‐acting basal insulins, the possibility to prevent exercise‐induced hypoglycemia by adjusting insulin doses becomes increasingly difficult. Ingestion of additional carbohydrates is probably the most frequently used method for this purpose (20) but may lead to rebound hyperglycemia and glycemic variability. The study by Kosinski et al., investigating the use of pre‐exercise intake of fructose to avoid these untoward effects, is an appealing alternative. Fructose is taken up from the intestinal tract via its specific receptor (GLUT5) and is extracted by splanchnic tissues where it is metabolized to glucose, lactate, and fatty acids, and therefore mediates a more sustained release of glucose. While their results indeed support the potential of fructose to prevent exercise‐induced hypoglycemia, more data are needed to delineate the best timing and amount of fructose ingestion in connection to different types and durations of exercise and ascertain that frequent intake of fructose does not result in any adverse metabolic consequences.
BIOSIMILAR INSULINS ON THE RISE
Introduction
As of April 2021, the EMA has approved five BioIns in the EU for sale and the FDA has approved three in the United States (Table 1). It is of interest to note that two of the three BioIns approved in the United States are manufactured by two of the established insulin manufacturers and not by competitors. However, there is a long list of other companies that have declared to work on BioIns (Table 2). Nevertheless, this list is probably not exhaustive as some companies have not made their interest to do so public. It is also not known if some of the listed (or non‐listed) companies have filed for approval in the EU or the United States but the approval has been rejected. Such a failure can happen if the pharmacokinetic (PK) and pharmacodynamic (PD) properties of the given insulin differ too much from that of the reference product.
The Indian company Biocon recently provided updates on its BioIns business, which they do in partnership with Viatris. The latter is a new company, which combined generics specialist Mylan and Pfizer's established medicines unit Upjohn. Viatris' BioIns product, Semglee, has acquired approvals in > 40 countries, including Europe, Australia, Japan, and South Korea, and is on the market in a number of these. It was approved by the FDA in 2020 and launched in August 2020. Semglee is indicated to improve glycemic control in children and adults with type 1 diabetes, and adults with type 2 diabetes.
At the end of July 2021 Viatris and Biocon announced that the FDA‐approved Semglee as the first interchangeable BioIns under the 351(k) regulatory pathway. Semglee was submitted for interchangeability through this pathway, following its original filing as a non‐interchangeable biologic under the 505(b)(2) pathway. This approval allows substitution of Semglee for Lantus at the pharmacy level (i.e., without any action on part of the healthcare provider who prescribed Lantus). The process for achieving this biosimilar interchangeable designation is a rigorous one. This BioIns had to show no clinically meaningful differences in efficacy or safety from Lantus, the reference biological product already approved by the FDA. Over the last few years, the FDA has released new guidelines to help healthcare professionals (HCPs) better understand biosimilar and interchangeable biosimilar products.
Semglee is eligible for 12 months of market exclusivity before the FDA can approve another interchangeable BioIns to Lantus. It remains to be seen to what extent pharmacies are doing this on their own or if this is primarily driven by incentives from payers to try to move patients from the originator insulin to BioIns.
Viatris will encourage HCPs to prescribe “glargine U100” instead of Lantus, but will this happen in practice? Some patients may react negatively if they receive a long‐acting insulin they are not expecting at the pharmacy because a prescriber inadvertently or purposefully changes the insulin without discussion. Appropriate communication and education will be needed for pharmacists, HCPs, and patients. Until now the market uptake of Semglee has remained relatively limited (∼2%), despite considerable price differences to the originator insulin. This is not what was expected when the BLA pathway was opened for the introduction of BioIns in the United States; however, the interchangeable designation is anticipated to accelerate uptake going forward. This, in turn, is assumed to have an impact on the level of prices for insulin in the United States as the other (established) manufacturer will have to react (15). According to the FDA, biosimilars have typically launched with initial list prices 15% to 35% lower than comparative list prices of the reference products. The question is, how much price reduction will we truly see in the future with more BioIns on the market? It is possible that the benefit for patients and healthcare systems might not be as dramatic as with other biosimilars. However, one major insulin manufacturer has started to sell their insulin at a lower price in the United States. The retail giant Walmart announced in June 2021 that they will revolutionize insulin access and affordability for patients with diabetes with the launch of the first and only private brand analog insulin (insulin aspart by Novo Nordisk) (29). Sanofi is also releasing authorized generic lispro at a reduced price.
It will remain to be seen if all manufacturers of BioIns are able to meet the regulatory expectations for quality. Manufacturing a single batch with a sufficient quality is different than having to do so over and over again; keeping the batch‐to‐batch quality high requires technical mastery over the process. Process validation is a key aspect, which refers to efforts to confirm that drug product of a standard quality can reliably be produced consistently over time. Some reports from inspections by regulatory agencies in recent years, during which they reviewed the quality of the manufacturing process, have raised some concerns and might have at least delayed some BioIns applications. Nevertheless, it appears as if a number of pharmaceutical companies around the world are able and willing to produce BioIns consistently in massive quantities at high levels of purity, which is necessary for distribution. It remains to be seen if all such companies can make their BioIns a profitable business—the stakes are high. In the end, the number of players that are coming to the market—at least in the EU/United States—might be lower than expected. Biologics manufacturing not only requires a large capital investment; the process also has to be combined with the complex science of insulin manufacturing. Combining the scarcity of players that truly come to the market and the unwillingness to discount products heavily, the problems of low competition and high prices might persist.
Approved BioIns in Europe, the United States, and China
Companies Known to Develop BioIns but Without a Product on the Market in the EU/United States
It could be that some of these companies may encounter a barrage of legal opposition from entrenched insulin producers (14). The heavy patenting that originator companies do to protect themselves against competition represents a structural problem in this sense. So, a given company might face legal trouble even before they finish the clinical development/ have a product on the market. This requires that a company will need significant resources to endure these battles and finally get its product to market. Another hurdle in the United States is that the decision‐making right now is in the hands of pharmacy benefit managers (PBM) (30). Taking all structural conditions into account, this explains why currently only a “limited” number of companies have BioIns on the United States market.
When more BioIns come to the market, there will be a need for unbiased education material to inform patients and HCPs adequately, especially about products that have an interchangeability approval. Also, naming conventions can disturb patients. Such barriers might hamper the switch from brand products to BioIns.
By definition, BioIns cannot be 100% identical to the reference insulin; therefore, they might also differ in their immunogenic properties. Some studies presenting data from immunological studies were published in the last year, for example, for Semglee (see below), GP40071, and Basalin by Gan and Lee (31 –33). These studies—like data previously published—suggest that there are no clinically relevant differences in the immunological properties of BioIns in comparison to the originator insulin.
For their approval, BioIns do not require performance of clinical trials (phase II and III) because efficacy and safety of the originator insulin (the active pharmaceutical substance) have already been proven. The regulatory guidance documents put much focus on PK and PD bioequivalence phase 1 studies and immunological studies. The bioequivalence studies usually use the euglycemic hyperinsulinemic glucose clamp technique to show that the given insulin does not differ from the reference insulin in PK/PD properties. In principle, such a less expensive development program makes it possible to sell BioIns at a lower price. Despite these requirements, several clinical studies regarding BioIns were published in the last year, and they uniformly show no difference in efficacy and safety in comparison to the reference insulin (32,34,35). An evaluation of treatment satisfaction, safety, and effectiveness of a BioIns of insulin glargine in Japanese patients with type 2 diabetes mellitus after switching from insulin glargine or insulin degludec in real‐world clinical practice over 12 months did not indicate significant changes (36).
Most studies deal with BioIns of insulin glargine; however, other BioIns have also been studied. No differences were observed in an open‐label clinical study in which the safety and efficacy of a rapid‐acting insulin analog (insulin aspart; GP40071) developed in Russia was evaluated (31). In a very similar setting, the efficacy and safety of BioIns of Humalog Mix 25 was studied, again showing no differences (37). The use of a biphasic BioIns (developed and provided by Biocon) was also studied in daily clinical practice (38). In this open‐label, single‐arm, observational, marketing study, the patients used a biphasic isophane insulin over a period of 24 weeks. No differences in safety (adverse events including hypoglycemia) and effectiveness (HbA1c; fasting blood sugar, and patient's condition by patient and physician) were observed.
Sanofi—Insulin aspart SAR341402
Sanofi has now the second BioIns of a rapid‐acting insulin analog (=insulin aspart; SAR341402) approved in Europe. However, the other BioIns of a rapid‐acting insulin analog (insulin lispro) by Sanofi (Admelog®) has failed to gain meaningful traction in the United States to date. It appears that an insulin mixture by Sanofi will also become available as BioIns. This is relevant because—with considerable differences between countries—many patients with diabetes, especially those with type 2 diabetes, are using insulin mixtures for their insulin therapy.
A Single‐Dose Euglycaemic Clamp Study in Two Cohorts to Compare the Exposure of SAR341402 (Insulin Aspart) Mix 70/30 with US‐ and European‐Approved Versions of Insulin Aspart Mix 70/30 and SAR341402 Rapid‐Acting Solution in Subjects with Type 1 Diabetes
Kapitza C1, Nosek L1, Schmider W2, Teichert L2, Mukherjee B3, Nowotny I2
1Profil, Neuss, Germany; 2Sanofi‐Aventis Deutschland GmbH, Frankfurt, Germany; 3Sanofi, Paris, France
Background
To compare the pharmacokinetic exposure of SAR341402 Mix 70/30 (SARAsp ‐Mix) with U.S.‐ and European (EU)‐approved versions of insulin aspart Mix 70/30 (NovoLog Mix 70/30 [NN‐Mix‐US]/Novo Mix 30 [NN‐Mix‐EU]) and SAR341402 insulin aspart solution (SAR‐Asp) in subjects with type 1 diabetes.
Methods
This study was a randomized, double‐blind, crossover trial in two cohorts. In total, 52 subjects received a single subcutaneous 0.3 U/kg dose of each treatment and underwent a euglycemic clamp procedure lasting for a maximum of 24 hours after dosing. In cohort 1, subjects (N=36) were exposed once each to SARAsp ‐Mix, NN‐Mix‐US and NN‐Mix‐EU. In cohort 2, subjects (N=16) were exposed once each to SARAsp ‐Mix and SAR‐Asp.
Results
Of the 52 subjects randomized, 48 completed all treatment periods. In cohort 1, the extent of exposure (total and maximum concentration) was similar among the three treatments. The 90% confidence intervals for pairwise treatment ratios met the predefined acceptance range (0.80 to 1.25). In cohort 2, statistically significant differences (P < .001) in early (0–4 h) and intermediate (4–12 h) exposure to SARAsp ‐Mix compared with SAR‐Asp were observed, all exceeding a 20% difference. Pharmacodynamic results supported the pharmacokinetic findings for both cohorts. There were no relevant differences in safety variables among treatments, and all treatments were well tolerated by trial participants.
Conclusions
SARAsp ‐Mix showed similar pharmacokinetic exposure to commercially available insulin aspart Mix 70/30 formulations, and a distinct exposure profile compared with SAR‐Asp.
Comment
Studies such as this one with a sufficient sample size and appropriate subject group are essential for regulatory approval of such insulin analogs. Also, the automated clamp performance helps to avoid investigator related bias as it enables a double‐blind study design.
Efficacy, Safety, and Immunogenicity of Insulin Aspart Biosimilar SAR341402 Compared with Originator Insulin Aspart in Adults with Diabetes (GEMELLI 1): A Subgroup Analysis by Prior Type of Mealtime Insulin
Shah VN1, Franek E2,3, Wernicke‐Panten K4, Pierre S5, Mukherjee B5, Sadeharju K6
1Barbara Davis Center for Diabetes, University of Colorado Anschutz Medical Campus, Aurora, CO, USA; 2Mossakowski Clinical Research Centre, Polish Academy of Sciences, Warsaw, Poland; 3Central Clinical Hospital of the Ministry of Interior and Administration (CSK MSWiA), Warsaw, Poland; 4Sanofi‐Aventis Deutschland GmbH, Frankfurt, Germany; 5Sanofi, Paris, France; 6Terveystalo Seinäjoki, Seinäjoki, Finland
Background
The biosimilar SAR341402 insulin aspart (SAR‐Asp) was compared to its originator NovoLog®/NovoRapid® insulin aspart (NN‐Asp). Aspects of efficacy, safety, and immunogenicity were examined in adults with type 1 or type 2 diabetes switching from different rapid‐acting insulin analogs.
Methods
This phase 3, randomized, open‐label, multinational, 52‐week study (GEMELLI 1) enrolled participants with type 1 or type 2 diabetes (n=597). At randomization, participants transitioned from NovoLog/NovoRapid (n=380) or Humalog/Liprolog (n=217) to equivalent (1:1) doses (or a dose at the discretion of the investigator) of either SAR‐Asp or NN‐Asp (1:1 randomization). Participants were treated with multiple daily injections in combination with insulin glargine 100 U/mL (Lantus). In this subgroup analysis, efficacy measures (change in hemoglobin A1c [HbA1c], insulin dose [total, basal and mealtime]), and safety outcomes (hypoglycemia incidence, adverse events, anti‐insulin aspart antibodies) of SAR‐Asp were compared with those of NN‐Asp separately according to the participants' pre‐study mealtime insulin.
Results
At week 26 (the primary efficacy end point), the change in HbA1c was similar between SAR‐Asp and NN‐Asp in those participants pre‐treated with NovoLog/NovoRapid (least squares [LS] mean difference −0.04%, 95% confidence interval [CI] −0.182 to 0.106%) or Humalog/Liprolog (LS mean difference −0.15%, 95% CI −0.336 to 0.043%) (P value for treatment by subgroup interaction=0.36). This HbA1c response persisted over the 52 weeks of the study in a similar fashion for both treatments within each subgroup. In both subgroups, changes in insulin doses were similar between treatments over 26 weeks and 52 weeks, as were the incidences of severe—or any—hypoglycemia, adverse events (including hypersensitivity and injection site reactions), and anti‐insulin aspart antibodies.
Conclusions
Efficacy and safety profiles, including immunogenicity, of SAR‐Asp are similar to those of NN‐Asp over 52 weeks in adults with diabetes, irrespective of prior type of mealtime insulin.
This BioIns rounds out Sanofi's insulin portfolio, which already includes two rapid‐acting insulin analogs approved by European regulators. Sanofi has now all three rapid‐acting insulin analogs in their portfolio—that is, insulin glulisine, lispro, and aspart.
HEC Pharm—Insulin aspart (= RD10046)
Not many of the new companies that are developing insulin for approval as a BioIns have published data from phase I trials yet. One is from a Chinese company that, according to their homepage, has three different insulin analogs commercially available (39).
Similar Pharmacokinetics and Pharmacodynamics of a New Biosimilar and Reference Insulin Aspart in Healthy Chinese Males
Liu H1, Yu H1, Sun L1, Qiao J1, Wai S2, Li S2, Li J1, Tan H1, Yu Y1
1Department of Endocrinology and Metabolism, West China Hospital, Sichuan University, Chengdu City, Sichuan Province, People's Republic of China; 2Yichang HEC Changjiang Pharmaceutical Co., Ltd., Yidu, Yichang City, Hubei Province, People's Republic of China
Background
Insulin aspart (IAsp) is one of the main therapies used to control blood glucose after a meal. This study aimed to compare the pharmacokinetics (PK) and pharmacodynamics (PD) of two rapid‐acting IAsp products: a new IAsp biosimilar (RD10046) and NovoRapid.
Methods
This study (registry number: CTR20180517, registration date: 2018‐05‐30) was a single‐center, randomized, single‐dose, two‐period, crossover, euglycemic clamp study, in which healthy Chinese males were randomized to receive 0.2 U/kg of the IAsp biosimilar RD10046 and NovoRapid under fasted conditions on two separate occasions. PK and PD were assessed for up to 10 h.
Results
All randomized subjects—30 participants—completed both treatment periods. The PK (area under the curve [AUC] of total IAsp; maximum observed IAsp concentration [Cmax]) and PD (maximum glucose infusion rate [GIRmax]; total glucose infusion during the clamp [AUC GIR,0–10h]) were similar between the new IAsp biosimilar RD10046 and NovoRapid. In all cases, the 90% CIs for the ratios of the geometric means were completely contained in the pre‐specified acceptance limits of 0.80–1.25. No hypoglycemic events, allergic reactions, or local injection adverse reactions occurred in this trial.
Conclusions
We concluded that the studied IAsp biosimilar (RD10046) was bioequivalent to NovoRapid.
Comment
In this study, healthy male subjects were studied, not patients with type 1 diabetes, as it is recommended for example by the EMA for such studies. Details of the euglycemic clamp procedure are not presented, which hamper statements about the quality of the study. It appears as though this was a manual clamp procedure, which is difficult to perform in case rapid changes in glucose infusion rates are needed to keep blood glucose levels close to the target level, especially with a rapid‐acting insulin analog. However, the data presented indicate that the PK/PD properties of this insulin aspart are comparable to that of the reference insulin.
Viatris/Biocon—Insulin glargine (Semglee [= Mylan MYL‐1501])
Besides Semglee®, Viatris and Biocon have now an approval for their BioIns of insulin aspart in the EU. Most probably they will also get an approval in the United States, although it remains to be seen if it will get approved as an interchangeable insulin. Biocon expects to submit all future insulins as interchangeable insulins, which would mainly address insulin lispro. In the last year, no data from a new clinical study was published. However, data about the immunological response induced in patients with type 1 or type 2 diabetes and an interesting and detailed description of the physicochemical and functional characterization of this BioIns was published in June 2021(40).
Similar Immunogenicity Profiles Between the Proposed Biosimilar MYL‐1501D and Reference Insulin Glargine in Patients with Diabetes Mellitus: The Phase 3 INSTRIDE 1 and INSTRIDE 2 Studies
Sun B1, Sengupta N2, Rao A2, Donnelly C1, Waichale V2,3, Roy AS2,4, Ramaswamy S2, Pathak D2,5, Bowsher RR6, Raiter Y1, Aubonnet P7, Barve A1
1Viatris Inc, Canonsburg, PA; 2Biocon Research Limited, Electronic City, Bangalore, India; 3Agilex Biolabs, SA, Thebarton, Australia; 4Cliantha Research Limited, Ahmedabad, India; 5Altasciences, QC, Laval, Canada; 6B2S Life Sciences, Franklin, IN; 7Viatris Inc, Steinhausen, Switzerland
BMC Endocr Disord 2021;
Background
MYL‐1501D is a proposed biosimilar to insulin glargine. The noninferiority of MYL‐1501D was demonstrated in patients with type 1 diabetes and type 2 diabetes in two phase 3 trials. Both studies also examined the immunogenicity of MYL‐1501D and reference insulin glargine.
Methods
INSTRIDE 1 and INSTRIDE 2 were multicenter, open‐label, randomized, parallel‐group studies. In INSTRIDE 1, patients with type 1 diabetes received MYL‐1501D or insulin glargine over a 52‐week period. In INSTRIDE 2, patients with type 2 diabetes treated with oral antidiabetic drugs, insulin‐naïve or not, received MYL‐1501D or reference insulin glargine over a 24‐week period. To determine incidence rates and change from baseline in relative levels of antidrug antibodies (ADA) and anti‐host cell protein (anti‐HCP) antibodies in both treatment groups, a radioimmunoprecipitation assay and a bridging immunoassay, was used, respectively. A mixed‐effects model (INSTRIDE 1) or a nonparametric Wilcoxon rank sum test (INSTRIDE 2) was used to analyze the results.
Methods
The total enrollment in INSTRIDE 1 was 558 patients, while INSTRIDE 2 had 560 patients. The incidence of total and cross‐reactive ADA was comparable between treatment groups in INSTRIDE 1 and INSTRIDE 2 (P>0.05 for both). A similar proportion of patients had anti‐HCP antibodies in both treatment groups in INSTRIDE 1 at week 52 (MYL‐1501D, 93.9%; reference insulin glargine, 89.6%; P=0.213) and in INSTRIDE 2 at week 24 (MYL‐1501D, 87.3%; reference insulin glargine, 86.9%; P>0.999).
Conclusions
In INSTRIDE 1 and INSTRIDE 2, similar immunogenicity profiles were observed for MYL‐1501D and reference insulin glargine in patients with type 1 diabetes and type 2 diabetes, respectively.
Comment
This follow‐up analysis of clinical studies that were published last year about a relevant topic showed that the immunogenicity profiles for this BioIns and the reference insulin glargine were quite similar in patients with type 1 diabetes or those with type 2 diabetes. However, a direct comparison of the immunogenicity profiles is hampered by several factors (e.g., the studies were not powered for this comparison). The clinical impact of immunogenicity observed is difficult to assess, as some patients with type 2 diabetes had previously been exposed to insulin therapy. This might have resulted in the presence of reactive antibodies before study initiation in these patients.
ULTRA‐RAPID INSULINS: IDENTIFYING CLINICALLY RELEVANT BENEFITS IN TYPE 1 AND TYPE 2 DIABETES
Ultra‐Rapid‐Acting Insulins for Adults with Diabetes: A Systematic Review and Meta‐Analysis
Avgerinos I1,2, Papanastasiou G1, Karagiannis T1,2, Michailidis T1,2, Liakos A1,2, Mainou M1, Matthews DR3,4, Tsapas A1,2,4, Bekiari E1,2
1Clinical Research and Evidence‐Based Medicine Unit, Second Medical Department, Aristotle University of Thessaloniki, Thessaloniki, Greece; 2Diabetes Centre, Second Medical Department, Aristotle University of Thessaloniki, Thessaloniki, Greece; 3Oxford Centre for Diabetes, Endocrinology and Metabolism, Churchill Hospital, Oxford, UK; 4Harris Manchester College, University of Oxford, Oxford, UK
Background
The authors performed a systematic review and meta‐analysis of randomized controlled trials to assess the efficacy and safety of the novel, ultra‐rapid‐acting insulins aspart and lispro in adults with type 1 or type 2 diabetes.
Methods
Our primary outcome was change in HbA1c from baseline. In addition, the authors assessed eight efficacy and six safety end point. They calculated weighted mean differences (WMD) for continuous outcomes and odds ratios (ORs) for dichotomous outcomes, alongside 95% confidence intervals (CIs). They also assessed statistical heterogeneity among studies with the I2 statistic, considering values greater than 60% as indicative of substantial heterogeneity.
Results
A total of 5,931 patients in nine studies were included in the systematic review. Of these, eight active‐controlled studies could be synthesized in terms of a meta‐analysis. Treatment with ultra‐rapid‐acting insulins had a similar effect on change in HbA1c compared with rapid‐acting insulins (WMD −0.02%, 95% CI −0.08 to 0.05, I2=61% for patients with type 1 diabetes and −0.02%, 95% CI −0.09 to 0.04, I2=19% for patients with type 2 diabetes). Similarly, no difference was evident in terms of change in fasting plasma glucose, self‐measured plasma glucose, body weight, basal or bolus insulin dose, incidence of serious adverse events, and hypoglycemia. Compared with rapid‐acting insulins, ultra‐rapid‐acting insulins reduced 1‐ and 2‐h postprandial glucose (PPG) increment based on a liquid meal test, both in patients with type 1 and type 2 diabetes (WMD −0.94 mmol/L, 95% CI −1.17 to −0.72, I2=0% and −0.56 mmol/L, 95% CI −0.79 to −0.32, I2=0%, respectively, for change in 1‐h PPG increment).
Conclusion
The authors concluded that ultra‐rapid‐acting insulins were as efficacious and safe as rapid‐acting insulins, showing a favorable effect solely on PPG control.
Improved Postprandial Glucose Control with Ultra Rapid Lispro Versus Lispro with Continuous Subcutaneous Insulin Infusion in Type 1 Diabetes: PRONTO‐Pump‐2
Warren M1, Bode B2, Cho JI3, Liu R3, Tobian J3, Hardy T3, Chigutsa F3, Phillip M4, Horowitz B5, Ignaut D3
1Physicians East, PA, Greenville, NC; 2Atlanta Diabetes Associates, Atlanta, GA; 3Eli Lilly and Company, Lilly Corporate Center, Indianapolis, IN; 4Schneider Children's Medical Center of Israel, Petah Tikva and Sackler Faculty of Medicine, Tel‐Aviv University, Tel‐Aviv, Israel; 5Metabolic Research Institute Inc., West Palm Beach, FL
Background
The authors aimed to evaluate the efficacy and safety of ultra‐rapid lispro (URLi) versus lispro (Humalog) in people with type 1 diabetes on continuous subcutaneous insulin infusion (CSII).
Materials and methods
This was a phase 3, 16‐week, treat‐to‐target study in patients randomized to double‐blind URLi (N=215) or lispro (N=217). The primary end point was change from baseline HbA1c (noninferiority margin 4.4 mmol/mol [0.4%]), with multiplicity‐adjusted objectives for postprandial glucose (PPG) levels during a meal test, and time spent in the target range of 70–180 mg/dL (TIR).
Results
URLi was noninferior to lispro for change in HbA1c, with a least‐squares mean (LSM) difference of 0.3 mmol/mol (95% confidence interval [CI] −0.6, 1.2) or 0.02% (95% CI −0.06, 0.11). URLi was superior to lispro in controlling 1‐ and 2‐h PPG levels after the meal test: LSM difference −1.34 mmol/L (95% CI −2.00, −0.68) or −24.1 mg/dL (95% CI −36.0, −12.2) at 1 h and −1.54 mmol/L (95% CI −2.37, −0.72) or −27.8 mg/dL (95% CI −42.6, −13.0) at 2 h; both p<.001. TIR and time in hyperglycemia were similar between groups but URLi resulted in significantly less time in hypoglycemia (<3.0 mmol/L [54 mg/dL]) over the daytime, nighttime, and 24‐h period: The LSM difference was −0.41%, −0.97%, and −0.52%, respectively, all p<.05. With URLi, the incidence of treatment‐emergent adverse events was higher (60.5% vs 44.7%), driven by infusion‐site reaction and infusion‐site pain, which was mostly mild or moderate. Both groups had similar rates of severe hypoglycemia and diabetic ketoacidosis.
Conclusions
URLi was efficacious, providing superior PPG control and less time in hypoglycemia but with more frequent infusion‐site reactions compared with lispro when administered by CSII.
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 Monitoring
Billion L1, Charleer S2, Verbraeken L1, Sterckx M1, Vangelabbeek K1, De Block N1, Janssen C2, Van Dessel K1, Dirinck E1, Peiffer F1, Bolsens N1, Mathieu C2, Gillard P2, De Block C1
1Department of Endocrinology, Diabetology and Metabolism, Antwerp University Hospital, and Faculty of Medicine and Health Sciences, University of Antwerp, Antwerp, Belgium; 2Department of Endocrinology, University Hospitals Leuven‐KU Leuven, Leuven, Belgium
Background
This study aimed to evaluate the efficacy and safety of switching from traditional mealtime insulins to fast‐acting insulin aspart (Fiasp) in a “real‐world” clinical practice setting in adults with type 1 diabetes (PWD1) who were using intermittently scanned or real‐time continuous glucose monitoring (isCGM or rtCGM, respectively).
Materials and methods
Data from 438 adult PWD1 (60% men, age 44.6±16.2 years, diabetes duration 21.5±14.0 years, isCGM/rtCGM: 391/47, multiple daily injections/continuous subcutaneous insulin infusion: 409/29), who initiated Fiasp from January 2018 to May 2020, were analyzed. The primary objective was the evolution of time in range (TIR; 70–180 mg/dL) at 6 and 12 months. Secondary objectives included change in HbA1c, body mass index (BMI), insulin doses, time below range (<70 and <54 mg/dL), and time above range (>180 and >250 mg/dL).
Results
At 6 months, TIR improved from 50.3%±15.6% to 54.3%±15.1% (n=425) and at 12 months to 55.5%±15.2% (n=385) (P<.001), corresponding to 57 min/d at 6 months and 75 min/d at 12 months. Time spent below 54 mg/dL evolved from 3.1%±3.3% to 3.1%±3.7% and 2.5%±3.0% at 6 and 12 months, respectively (P=.011). Also, time spent above 180 mg/dL decreased from 42.3%±16.7% at start by 4.2% at 6 months and by 4.6% at 12 months (P<.001). The proportion of people reaching TIR increased more than 70% from 11.0% to 14.8% (P=.002), and those spending less than 4% at time less than 70 mg/dL increased from 36.1% to 42.1% (P=.002). After 12 months, HbA1c, insulin doses, and BMI did not change significantly.
Conclusions
In a Belgian real‐world setting, when studying adult PWD1, the authors found that switching to Fiasp was associated with a 5% increased TIR after 12 months, corresponding to 75 min/d, in combination with less time spent below and above range.
Impact of Fast‐Acting Insulin Aspart on Glycemic Control in Patients with Type 1 Diabetes Using Intermittent‐Scanning Continuous Glucose Monitoring Within a Real‐World Setting: The GoBolus Study
Danne T1, Schweitzer MA2, Keuthage W3, Kipper S2, Kretzschmar Y2, Simon J4, Wiedenmann T2, Ziegler R5
1Diabetes Center for Children and Adolescents, Children's Hospital on the Bult, Hanover Medical School, Hanover, Germany; 2Novo Nordisk Pharma GmbH, Mainz, Germany; 3Schwerpunktpraxis für Diabetes und Ernährungsmedizin, Muenster, Germany; 4Medizinisches Versorgungszentrum im Altstadt‐Carree Fulda GmbH, Fulda, Germany; 5Diabetes Clinic for Children and Adolescents, Muenster, Germany
Background
The GoBolus study investigated the real‐world effectiveness of faster aspart in patients with type 1 diabetes (T1D) using intermittent‐scanning continuous glucose monitoring (iscCGM) systems.
Methods
This 24‐week, multicenter, single‐arm, noninterventional study investigated adults with T1D (HbA1c, 7.5%–9.5%) receiving multiple daily injections (MDI) of insulin and using iscCGM within local healthcare settings for ≥ 6 months before switching to faster aspart at study start (week 0; baseline). Primary end point was HbA1c change from baseline to week 24. Exploratory end point was change in iscCGM metrics from baseline to week 24.
Results
Overall, 243 patients were included (55.6% male), with mean age/diabetes duration, 49.9/18.8 years; mean HbA1c, 8.1%. By week 24, HbA1c had decreased by 0.19% (−2.1 mmol/mol, P<0.0001) with no mean change in insulin doses or basal/bolus insulin ratios. For patients with sufficient available iscCGM data (n=92): “time in range” (TIR; 3.9–10.0 mmol/L) increased from 46.9% to 50.1% (P=0.01), corresponding to an increase of 46.1 min/day; time in hyperglycemia decreased from 49.1% to 46.1% (>10.0 mmol/L, P=0.026) and 20.4% to 17.9% (>13.9 mmol/L, P=0.013), corresponding to 43.5 (P=0.024) and 35.6 (P=0.015) fewer minutes per day on average spent in these ranges, respectively; no change for time in hypoglycemia (<3.9 and <3.0 mmol/L). Mean interstitial and postprandial glucose improved from 10.4 to 10.1 mmol/L (P=0.035) and 11.9 to 11.0 mmol/L (P=0.002), respectively.
Conclusion
Real‐world switching to faster aspart in adults with T1D on MDI improved HbA1c, increased TIR, and decreased time in hyperglycemia without affecting time in hypoglycemia.
THE SEARCH FOR THE IDEAL PUMP INSULIN FOR AUTOMATED INSULIN DELIVERY: ULTRA‐RAPID INSULIN OR MIXED WITH PRAMLINTIDE?
Modeling Between‐Subject Variability in Subcutaneous Absorption of a Fast‐Acting Insulin Analogue by a Nonlinear Mixed Effects Approach
Faggionato E, Schiavon M, Dalla Man C
Department of Information Engineering, University of Padova, Padova, Italy
Background
Despite the great progress made in insulin preparation and titration, many patients with diabetes are still experiencing dangerous fluctuations in their blood glucose levels. This is mainly due to the large between‐ and within‐subject variability, which considerably hampers insulin therapy, leading to defective dosing and timing of the administration process.
Methods
In this work, the authors presented a nonlinear mixed effects model that describes the between‐subject variability observed in the subcutaneous absorption of fast‐acting insulin.
Results
A set of 14 different models was identified on a large and frequently sampled database of lispro pharmacokinetic data. This data was collected from 116 subjects with type 1 diabetes. The authors compared the tested models and selected the best one on the basis of the ability to fit the data, the precision of the estimated parameters, and parsimony criteria. The selected model was able to accurately describe the typical trend of plasma insulin kinetics, as well as the between‐subject variability present in the absorption process, which was found to be related to the subject's body mass index.
Conclusions
The model provided a deeper understanding of the insulin absorption process. In future, it can be incorporated into simulation platforms to test and develop new open‐ and closed‐loop treatment strategies, which will allow a step forward toward personalized insulin therapy.
Fast‐Acting Insulin Aspart (Fiasp®) Improves Glycemic Outcomes When Used with Minimed TM 670G Hybrid Closed‐Loop System in Simulated Trials Compared to Novolog®
Grosman B1, Wu D1, Parikh N1, Roy A1, Voskanyan G1, Kurtz N1, Sturis J2, Cohen O1, Ekelund M2, Vigersky R1
1Medtronic Diabetes, CA; 2Novo Nordisk AS, Denmark
Introduction
A virtual patient simulator for modeling and predicting insulin therapy outcomes has been developed by Medtronic for people with type 1 diabetes (T1D). An enhanced simulator was created to use clinical data to estimate outcomes when using the MiniMed 670G system with standard NovoLog (EU: NovoRapid, U.S.: NovoLog) versus Fiasp.
Methods
Sixty‐seven participants' PK profiles were generated per type of insulin, for a total of 134 PK profiles. 7,485 virtual patients' PK measurements were matched with one of the 67 NovoLog PK Tmax values. These 7,485 virtual patients were then simulated using the Medtronic MiniMed 670G algorithm following an IN SILICO protocol of 90 days: 14 days in open loop (in manual mode) followed by 76 days in closed loop (in auto mode). The simulation study was repeated, with each NovoLog PK profile being replaced by its corresponding Fiasp PK profile in the same virtual patient. To validate our IN SILICO analysis, the authors compared the results of “actual” 19 “real‐life” patients from a clinical study.
Results
In all age groups, simulated overall and postprandial glycemic outcomes improved with Fiasp. The percentage of time in the euglycemic range increased by about ∼2.2% with Fiasp, in all age groups (p<0.01). The percentage of time spent at <70 mg/dL was reduced by about ∼0.6% with insulin Fiasp (p <0.01) and the mean glucose was reduced by about 1.3 mg/dL (p<0.01), excluding those age <7 years. The simulated mean postprandial SG was reduced by ∼5 mg/dL, a significant difference for all age groups. Similar improvements were shown with MiniMed 670G system when switching from NovoLog to Fiasp, in a clinical study.
Conclusions
The simulation studies indicate that using Fiasp in place of NovoLog with the MiniMed 670G system will significantly improve the time spent in the healthy, euglycemic range and reduce exposure to hyperglycemia and hypoglycemia in most patients.
Fast‐Acting Insulin Aspart Use with the MiniMedTM 670G System
Hsu L1,2, Buckingham B1,2, Basina M2,3, Ekhlaspour L1,2, von Eyben R4, Wang J2, Lal RA1,2,3
1Division of Endocrinology, Department of Pediatrics, Stanford University School of Medicine, Stanford, CA; 2Stanford Diabetes Research Center, Stanford, CA; 3Division of Endocrinology, Department of Medicine, Stanford University School of Medicine, Stanford, CA; 4Department of Radiation Oncology, Stanford University School of Medicine, Stanford, CA
Background
This study assessed the efficacy and safety of ultra‐rapid insulin Fiasp in the hybrid closed‐loop MiniMed 670G system.
Methods
This was a pilot randomized double‐blinded crossover study among established MiniMed 670G users comparing percentage time in range (TIR) and hypoglycemia for Novolog and Fiasp. After 2 weeks of optimization with their home insulin, participants were randomized to receive Novolog or Fiasp for 2 weeks, followed by the other insulin for the next 2 weeks. Data from the second week of blinded insulin use were analyzed to allow 1 week for 670G adaptation. During the second week, individuals were asked to eat the same breakfast for 3 days to assess differences in meal pharmacodynamics.
Results
Nineteen adults were recruited with mean age of 40±18 years, diabetes duration of 27±12 years, and median hemoglobin A1c of 7.1% (6.9, 7.5), using 0.72 (0.4, 1.2) units/(kg·day). For Novolog and Fiasp, respectively, the %TIR (70–180 mg/dL) was 75.3±9.5 and 78.4±9.3; %time <70 mg/dL was 3.1±2.1 and 2.3±2.0; %time >180 mg/dL was 21.6±9.0 and 19.3±8.9; mean glucose was 147±12 and 146±12 mg/dL; coefficient of variation was 28.6%±4.5% and 26.8%±4.4%; %time in auto mode 86.4±9.2 and 84.4±9.2. All comparisons were nonsignificant for insulin type. Total daily dose (NovoLog 48.8±28.4 vs Fiasp 52.4±31.7 units; P=0.01) and daily basal (NovoLog 17.6 [15.5, 33.8] vs Fiasp 19.1 [15.3, 38.5] units; P=0.07) correlated with TIR and %time >180 mg/dL. For insulin delivery in auto mode, there was no statistical difference in total daily dose or daily basal between arms. Paired analysis for matched breakfast meals revealed no significant differences in time to maximum glucose, peak glucose, or glucose excursion.
Conclusions
In this pilot study, the use of either Novolog or Fiasp in a commercially available MiniMed 670G system operating in auto mode resulted in clinically similar glycemic outcomes, with a slight increase in daily insulin requirements using Fiasp.
Fast Acting Insulin Aspart Compared with Insulin Aspart in the Medtronic 670G Hybrid Closed Loop System in Type 1 Diabetes: An Open Label Crossover Study
Ozer K, Cooper AM, Ahn LP, Waggonner CR, Blevins TC
Texas Diabetes and Endocrinology, Austin, TX
Background
This is a single‐center randomized open‐label active‐controlled crossover trial comparing efficacy and safety of fast acting insulin aspart (FA) (Fiasp) versus insulin aspart (IAsp) (NovoLog) when used in the Medtronic 670G system in auto mode in patients with type 1 diabetes.
Methods
Forty patients were randomized to either IAsp or FA. Each treatment period was 7 weeks and a standardized meal test was administered 6 weeks after the start of each treatment period. The primary end point was postprandial glucose (PPG) increment after the meal test at 1 h.
Results
Treatment with FA using the MiniMed 670G hybrid closed loop (HCL) led to a greater reduction in 1‐h postprandial glucose increase compared with treatment with IAsp during the standardized mixed meal test. Change in glucose: [estimated treatment difference (ETD ± standard deviation [SD]); 95% confidence interval]: 70.27 (±17.36) mg/dL (3.9±1.0 mmol/L) with FA versus 98.42 (±17.36) mg/dL (5.5±1.0 mmol/L) with IAsp (P=0.008). Patients spent 1.81% (P=0.016) more time (equivalent to 26 min per day) in the 70–180 mg/dL (3.89–9.99 mmol/L) range with FA than with IAsp. The entire sample spent only 0.5% of time <54 mg/dL (<3.0 mmol/L) range. The increment in the 1 h postmeal test glucose was significantly lower with FA versus IAsp.
Conclusions
FA in a HCL setting is safe and effective with patients spending more time in the 70–180 mg/dL (3.89–9.99 mmol/L) target range than with IAsp.
Ultrarapid Lispro Demonstrates Similar Time in Target Range to Lispro with a Hybrid Closed‐Loop System
Bode BW1, Carlson A2, Liu R3, Hardy T3, Bergenstal RB2, Boyd J1, Morrett S3, Ignaut DA3
1Atlanta Diabetes Associates, Atlanta, GA; 2International Diabetes Center, Minneapolis, MN; 3Eli Lilly and Company, Indianapolis, IN
Background
Automated insulin delivery systems are associated with improved glycemic outcomes for patients with diabetes. Ultra rapid lispro (URLi), which has an accelerated pharmacokinetic profile and shows superior postprandial glucose control compared to lispro (Humalog), is a potential candidate for use in these systems.
Methods
In this double‐blind, crossover trial over two 4‐week treatment periods, we evaluated URLi in a hybrid closed‐loop system using the Medtronic MiniMed 670G system (670G). After a 2‐week lead‐in on lispro, 42 adults with type 1 diabetes were randomized to one of two treatment sequences of URLi and lispro delivered via the 670G. Primary end point was the percentage of time with glucose values within target range 3.9–10.0 mmol/L (70–180 mg/dL; %TIR).
Results
Both treatments achieved %TIR over the 24‐hour period that was above the 70% minimum recommended by the International Consensus Guidance: URLi, 77.0%; lispro, 77.8%; P=0.339. %Time <3.0 mmol/L (54 mg/dL) was similar between treatments (URLi, 0.3%; lispro, 0.4%; P=0.548) and %time <3.9 mmol/L (70 mg/dL) was lower with URLi (1.5%) vs lispro (2.2%); P=0.009 while %time >10.0 mmol/L (180 mg/dL) was higher with URLi (21.5% [309.4 min] vs 19.9% [287.2 min]; P=0.088). Mean sensor glucose was significantly higher with URLi versus lispro with a least‐squares mean difference of 0.17 mmol/L or 3.0 mg/dL (P=0.011) between treatments. Insulin dose, %time in auto mode per week, and pump settings were similar between treatments. No serious adverse events (including severe hypoglycemia), or discontinuations occurred, and the incidence of treatment‐emergent adverse events was similar between treatments. Although the overall incidence and rate of unplanned infusion set changes was similar between treatments, a significantly higher rate of unplanned infusion set changes due to infusion site reactions was seen during URLi treatment compared with lispro: 0.12 versus 0.00 events/30 days (P=0.063).
Conclusions
URLi demonstrated good glycemic control that was comparable to lispro and showed a similar safety profile to lispro with the 670G hybrid closed‐loop system.
Improvements in Glycemic Control Achieved by Altering the t max Setting in the iLet® Bionic Pancreas When Using Fast‐Acting Insulin Aspart: A Randomized Trial
Russell SJ 1, Balliro C1, Ekelund M2, El‐Khatib F3,6, Graungaard T4, Greaux E1, Hillard M1, Jafri RZ3,7, Rathor N5, Selagamsetty R3,6, Sherwood J1, Damiano ER3
1Diabetes Research Center, Massachusetts General Hospital, Boston, MA; 2Type 1 Diabetes and Functional Insulins, Novo Nordisk A/S, Søborg, Denmark; 3Department of Biomedical Engineering, Boston University, Boston, MA; 4Biostatistics, Novo Nordisk A/S, Aalborg, Denmark; 5Novo Nordisk Service Centre India Private Ltd., Bangalore, India; 6Research and Innovation, Beta Bionics, Inc., Boston, MA; 7Division of Pediatric Endocrinology, University of Texas Health Science Center, San Antonio, TX
Introduction
In adults with type 1 diabetes, the authors investigated the safety of, and glucose control by, the insulin‐only configuration of the iLet bionic pancreas delivering fast‐acting insulin aspart (faster aspart), using the same insulin‐dosing algorithm but different time to maximal serum drug concentration (tmax) settings.
Methods
The authors performed a single‐center, single‐blinded, crossover (two 7‐day treatment periods) escalation trial over three sequential cohorts. Participants from each cohort were randomized to a default tmax setting (t65 [tmax=65 min]) followed by a non‐default tmax setting (t50 [tmax=50 min; cohort 1], t40 [tmax=40 min; cohort 2], t30 [tmax=30 min; cohort 3]), or vice versa, all with faster aspart. If escalation‐stopping criteria were not met in the previous cohort, each cohort randomized eight new participants.
Results
Overall, 24 participants were randomized into three cohorts. Two participants discontinued treatment, one due to reported “low blood glucose” during the first treatment period of cohort 3 (t30). Mean time in low sensor glucose (<54 mg/dL, primary end point) was <1.0% for all tmax settings. Mean sensor glucose in cohorts 1 and 2 was significantly lower at non‐default versus default tmax settings, with comparable insulin dosing. The mean time sensor glucose was in range (70–180 mg/dl) was >70% for all cohorts, except the default tmax setting in cohort 1. No severe hypoglycemic episodes were reported. No clinically significant differences in adverse events between the groups were found.
Conclusion
No safety concerns were found with faster aspart in the iLet at non‐default tmax settings. Mean sensor glucose without increases in low sensor glucose at non‐default tmax settings showed improvements.
Fast‐Acting Insulin Aspart Versus Insulin Aspart Using a Second‐Generation Hybrid Closed‐Loop System in Adults with Type 1 Diabetes: A Randomized, Open‐Label, Crossover Trial
Lee MH1,2, Paldus B1,2, Vogrin S1, Morrison D1, Zaharieva DP3, Lu J1, Jones HM1,2, Netzer E 1, Robinson L1, Grosman B4, Roy A4, Kurtz N4, Ward GW2,5, MacIsaac RJ1,2, Jenkins AJ1,2,6, O'Neal DN1,2
1Department of Medicine, University of Melbourne, Melbourne, Australia; 2Department of Endocrinology & Diabetes, St Vincent's Hospital Melbourne, Melbourne, Australia; 3Division of Endocrinology, Department of Pediatrics, School of Medicine, Stanford University, Stanford, CA; 4Medtronic, Northridge, CA; 5Department of Pathology, University of Melbourne, Melbourne, Australia;
6National Health and Medical Research Council Clinical Trials Centre, University of Sydney, Sydney, Australia
Objective
The authors had the objective of evaluating glucose control using fast‐acting insulin aspart (faster aspart) compared with insulin aspart (IAsp) delivered by the MiniMed Advanced Hybrid Closed‐Loop (AHCL) system in adults with type 1 diabetes.
Research design and methods
In this randomized, open‐label, crossover study, participants were assigned to receive faster aspart or IAsp in random order. For stages 1 and 2, participants spent 6 weeks in closed loop, preceded by 2 weeks in open loop. This was followed by stage 3, whereby participants changed directly back to the insulin formulation used in stage 1 for 1 week in closed loop. Except for two standardized meal tests, a missed meal bolus, and late meal bolus, participants chose their own meals. The primary outcome was the percentage of time sensor glucose values were from 70 to 180 mg/dL (time in range [TIR]).
Results
Twenty‐five adults (52% male) were recruited; the median (interquartile range) age was 48 (37, 57) years, and the median HbA1c was 7.0% (6.6, 7.2) (53 [49, 55] mmol/mol). Faster aspart demonstrated greater overall TIR compared with IAsp (82.3% [78.5, 83.7] vs 79.6% [77.0, 83.4], respectively; mean difference 1.9% [0.5, 3.3]; P=0.007). Four‐hour postprandial glucose TIR was higher using faster aspart compared with IAsp for all meals combined (73.6% [69.4, 80.2] vs 72.1% [64.5, 78.5], respectively; median difference 3.5% [1.0, 7.3]; P=0.003). There was no ketoacidosis or severe hypoglycemia.
Conclusions
Faster aspart safely improved glucose control compared with IAsp in a group of adults with well‐controlled type 1 diabetes using AHCL. The modest improvement was mainly related to mealtime glycemia. Given an overall difference in TIR of 1.9%, although the primary outcome demonstrated statistical significance, the clinical impact may be small.
Impact of Accelerating Insulin on an Artificial Pancreas System Without Meal Announcement: An In Silico Examination
Colmegna P1,2, Cengiz E3,4, Garcia‐Tirado J1, Kraemer K3, Breton MD1
1Center for Diabetes Technology, University of Virginia, Charlottesville, VA; 2National Scientific and Technical Research Council, Buenos Aires, Argentina; 3Division of Pediatric Endocrinology and Diabetes, Yale University School of Medicine, New Haven, CT; 4Bahcesehir University School of Medicine, Istanbul, Turkey
Background
Given the delays in absorption and action of subcutaneously injected insulin during conventional and artificial pancreas (AP) system diabetes treatment, controlling postprandial blood glucose without the benefit of an appropriately sized premeal insulin bolus has been challenging. The authors aimed to understand the impact of accelerating insulin and increasing aggressiveness of the AP controller as potential solutions to address the postprandial hyperglycemia challenge posed by unannounced meals through a simulation study.
Methods
Accelerated rapid‐acting insulin analogue is modeled within the UVA/Padova simulation platform by uniformly reducing its pharmacokinetic time constants (α multiplier) and used with a model‐predictive control, where the controller's aggressiveness depends on α. The authors performed two sets of single‐meal simulations: (1) where they only tune the controller's aggressiveness and (2) where they also accelerate insulin absorption and action to assess postprandial glycemic control during each intervention.
Results
Mean percent of time spent within the 70 to 180 mg/dL postprandial glycemic range is significantly higher in set (2) than in set (1): 79.9, 95% confidence interval [77.0, 82.7] vs 88.8 [86.8, 90.9] (P<.05) for α=2, and 81.4 [78.6, 84.3] vs 94.1 [92.6, 95.6] (P<.05) for α=3. A decrease in percent of time below 70 mg/dL is also detected: 0.9 [0.4, 2.2] vs 0.6 [0.2, 1.4] (P=.23) for α=2 and 1.4 [0.7, 2.8] vs 0.4 [0.1, 1.4] (P<.05) for α=3.
Conclusion
These proof‐of‐concept simulations suggest that an AP without prandial insulin boluses combined with significantly faster insulin analogues could match the glycemic performance obtained with an optimal hybrid AP.
Pharmacokinetics and Pharmacodynamics of Three Different Formulations of Insulin Aspart: A Randomized, Double‐Blind, Crossover Study in Men with Type 1 Diabetes
Svehlikova E1, Mursic I1, Augustin T2, Magnes C2, Gerring D3, Jezek J3, Schwarzenbacher D1, Ratzer M2, Wolf M1, Howell S3, Zakrzewski L3, Urschitz M1, Tschapeller B2, Gatschelhofer C1, Feichtner F2, Lawrence F3, Pieber TR1,2
1Division of Endocrinology and Diabetology, Department of Internal Medicine, Medical University of Graz, Graz, Austria; 2Joanneum Research Forschungsgesellschaft mbH, HEALTH ‐ Institute for Biomedicine and Health Sciences, Graz, Austria; 3Arecor Limited, Little Chesterford, UK
Objective
The authors aimed to investigate the pharmacokinetic and pharmacodynamic properties and safety of a novel formulation of insulin aspart (AT247), as compared with two currently marketed insulin aspart formulations (NovoRapid [IAsp] and Fiasp [faster IAsp]).
Research design and methods
This single‐center, randomized, double‐blind, three‐period, crossover study was conducted in 19 men with type 1 diabetes, receiving single dosing of trial products (0.3 units/kg) in a random order on three visits. During a euglycemic clamp lasting up to 8 h, pharmacokinetics and pharmacodynamics were assessed.
Results
The onset of insulin appearance was earlier for AT247 compared with IAsp (−12 min [95% CI −14; −8], P=0.0004) and faster IAsp (−2 min [−5; − 2], P=0.0003). The onset of action was accelerated compared with IAsp (−23 min [−37; −15], P=0.0004) and faster IAsp (−9 min [−11; −3], P=0.0006). A higher exposure was observed within the first 60 min for AT247 compared with IAsp by the area under the curve (AUC) glucose infusion rate (GIR) from 0 to 60 min (AUCAsp0–60min: treatment ratio vs IAsp 2.3 [1.9; 2.9] vs faster IAsp 1.5 [1.3; 1.8]). This was underpinned by a greater early glucose‐lowering effect (AUCGIR,0–60min: treatment ratio vs IAsp 2.8 [2.0; 5.5] vs faster IAsp 1.7 [1.3; 2.3]). Furthermore, an earlier offset of exposure was observed for AT247 compared with IAsp (−32 min [−58; −15], P=0.0015) and faster IAsp (−27 min [−85; −15], P=0.0017), while duration of the glucose‐lowering effect, measured by time to late half‐maximum effect, did not differ significantly.
Conclusions
AT247 exhibited an earlier insulin appearance, exposure, and offset, with corresponding enhanced early glucose‐lowering effect compared with IAsp and faster IAsp. Therefore, it represents a promising candidate in the pursuit for second‐generation prandial insulin analogs to improve postprandial glycemic control.
Trial registration: ClinicalTrials.gov NCT03959514.
ADO09, A Co‐Formulation of the Amylin Analogue Pramlintide and the Insulin Analogue A21G, Lowers Postprandial Blood Glucose Versus Insulin Lispro in Type 1 Diabetes
Andersen G1, Meiffren G2, Famulla S1, Heise T1, Ranson A2, Seroussi C2, Eloy R2, Gaudier M2, Charvet R2, Chan YP2, Soula O2, Hans DeVries J1
1Profil, Neuss, Germany; 2Adocia, Lyon, France
Aim
The authors aimed to compare the safety, pharmacokinetics, and pharmacodynamics of ADO09 with insulin lispro (Lispro) and separate subcutaneous injections of human insulin and pramlintide (Ins&Pram) in 24 subjects with type 1 diabetes.
Methods
At three dosing visits, participants received single doses of ADO09, Ins&Pram, or lispro. Immediately afterward, they ate a standardized mixed meal together with 1 g of acetaminophen, which was used as a surrogate marker to evaluate the kinetics of gastric emptying. Premeal blood glucose was adjusted to 126 mg/dL ±10% by means of insulin and glucose infusions. The insulin dose was 7.5 U and the pramlintide dose was 45 μg. Blood glucose, glucagon, and acetaminophen concentrations were assessed as pharmacodynamic end point; insulin and pramlintide concentrations were analyzed as pharmacokinetic end points, and safety and tolerability were assessed.
Results
ADO09 reduced postprandial blood glucose (ppBG) excursions by more than 95% in the first hour postmeal (mean ± SD ▵AUC BG 0–1 h: 1.4±9.9 mg*h/dL vs 43.5±15.3 mg*h/dL; p<.0001), as compared with lispro. The maximum ppBG was significantly improved with ADO09 (▵BGmax 87.0±35.5 mg/dL) versus both lispro (109.2±31.1 mg/dL; p=.0133) and Ins&Pram (109.4±44.3 mg/dL; p=.0357). Gastric emptying with ADO09 was similar to Ins&Pram and significantly slower than with lispro. All treatments were well tolerated and both adverse events and hypoglycemic events were rare during the meal test procedure.
Conclusion
Compared with lispro, ADO09 was well tolerated and markedly reduced ppBG. ADO09 formulation was generally similar to the separate administration of insulin and pramlintide, except for a better BG level in the 4–8 h interval postmeal. Further investigations with ADO09 are warranted based on these positive results.
Fully Automated Artificial Pancreas for Adults with Type 1 Diabetes Using Multiple Hormones: Exploratory Experiments
Majdpour D1,2, Tsoukas MA2,3, Yale JF2,3, El Fathi A1, Rutkowski J1, Rene J3, Garfield N3, Legault L2,4, Haidar A1
1Department of Biomedical Engineering, McGill University, Montréal, Québec, Canada; 2The Research Institute of McGill University Health Centre, Montréal, Québec, Canada; 3Royal Victoria Hospital, McGill University Health Centre, Montréal, Québec, Canada; 4Montreal Children's Hospital, McGill University Health Centre, Montréal, Québec, Canada
Objectives
Through pilot experiments on adults with type 1 diabetes, a fully automated insulin‐pramlintide‐glucagon artificial pancreas that alleviates the burden of carbohydrate counting without degrading glycemic control was iteratively enhanced until convergence.
Methods
Nine participants (age, 37±13 years; glycated hemoglobin, 7.7±0.7%) completed two 27‐hour interventions: a fully automated multihormone artificial pancreas and a comparator insulin‐alone artificial pancreas with carbohydrate counting. The baseline algorithm was a model‐predictive controller that administered insulin and pramlintide in a fixed ratio, with boluses triggered by a glucose threshold, and administered glucagon in response to low glucose levels.
Results
In two participants, the baseline multihormone dosing algorithm resulted in noninferior time in target range (3.9 to 10.0 mmol/L) (71%) compared with the insulin‐alone arm (70%), with minimal glucagon delivery. The algorithm was modified to deliver insulin and pramlintide more aggressively with the aim to increase time in range and maximize the benefits of glucagon. The modified algorithm displayed a similar time in range for the multihormone arm (79%) compared with the insulin‐alone arm (83%) in two participants. However, it also produced undesired glycemic fluctuations. Subsequently, the authors reduced the glucose threshold that triggers glucagon boluses, which resulted in inferior glycemic control for the multihormone arm (81% vs 91%) in two participants. Thereafter, a model‐based meal‐detection algorithm to deliver insulin and pramlintide boluses closer to mealtimes was added and glucagon was removed. In the last three participants, the final dual‐hormone system had comparable time in range (81% vs 83%).
Conclusion
The final version of the fully automated system that delivered insulin and pramlintide warrants a randomized controlled trial.
Comment
The clinical relevance of using ultra‐rapid insulins for optimal mealtime coverage and pump usage has been another focus in the past year. A recent meta‐analysis was unable to find differences regarding HbA1c, change in self‐measured plasma glucose, body weight, basal or bolus insulin dose, incidence of serious adverse events and hypoglycemia comparing rapid and ultra‐rapid analogs. However, as expected, ultra‐rapid‐acting insulins reduce 1‐ and 2‐hour postprandial glucose increments in meal tests (41). Two recent real‐world studies from Belgium (42) and Germany (43) using CGM in patients switching to faster insulin aspart confirmed that the better postprandial excursions seen in the research setting translate to improved time in range without increasing the time in hypoglycemia.
With more and more people with diabetes being treated with insulin pumps and widespread use of automated insulin delivery (AID) combining pumps and sensors, the quest for the ideal pump insulin has been a major focus this year and will likely continue for the years to come. Although IN SILICO modeling studies may deliver important data on potential benefits of new rapid and ultra‐rapid insulin preparations (44,45,46), these currently still need confirmation in proper clinical trials. For example, as already mentioned in last year's edition of the ATTD Yearbook, the second PRONTO‐pump study confirmed better postprandial glucose levels of the first study (47) but yet again raised concerns regarding premature infusion set failure with URLi (48). Several studies investigated the use of ultra‐rapid insulins in hybrid (49 –51) and advanced hybrid closed‐loop (52) systems. Although there is evidence for subtle improvements present when using the ultra‐rapid instead of the rapid‐acting analog for AID, it needs to be elucidated if tweaking the algorithm and/or altering AID settings are necessary to achieve the biggest advantage when using ultra‐rapid analogs in AID (53).
But the development of fast‐acting insulins is still ongoing. AT247 is a modified formulation of insulin aspart (IAsp) and exhibited an earlier insulin appearance, exposure, and offset compared with IAsp and faster IAsp (54). Another approach is the co‐formulation of the amylin analogue pramlintide and insulin analogs, which is investigated both for injection therapy (55) as well as for AID (56), which appears to be promising. Several groups are working on various approaches for glucose‐responsive insulin or “smart‐insulin” (57) as we have already mentioned now and then in previous articles of the ATTD Yearbooks and we hope to get some new clinical study data to discuss in the not‐so‐distant future. Clearly, in this centennial year of insulin discovery, the progress with diabetes technology in general and automated insulin delivery in particular has led to much greater improvements in clinical outcomes than the incremental steps recently achieved with new insulins.
Footnotes
Author Disclosure Agreement
JB has received honoraria for consulting and/or lecture fees from Abbott Diabetes Care, Novo Nordisk, and Sanofi.
LH is a consultant for a number of companies that are developing novel diagnostic and therapeutic options for diabetes treatment. He is a shareholder of the Profil Institut für Stoffwechselforschung GmbH, Neuss, Germany.
TD has received speaker's honoraria and research support from and has consulted for Abbott, AstraZeneca, Boehringer, DexCom, Lilly, Medtronic, Novo Nordisk, Roche, Sanofi, and Ypsomed and is a shareholder of DreaMed Ltd.