Lispro Research Articles

Impact of a Weekly Glucagon-Like Peptide 1 Receptor Agonist, Albiglutide, on Glycemic Control and on Reducing Prandial Insulin Use in Type 2 Diabetes Inadequately Controlled on Multiple Insulin Therapy: A Randomized Trial.

OBJECTIVEThe principle of replacing prandial insulin lispro with a once-weekly glucagon-like peptide 1 receptor agonist (GLP-1RA) for type 2 diabetes inadequately controlled on a multiple daily insulin injections regimen was tested with albiglutide.RESEARCH DESIGN AND METHODSIn this treat-to-target study, basal plus prandial insulin was optimized over 4 weeks before participants were randomized (1:1) to albiglutide plus optimized basal insulin glargine and lispro (dose reduced by 50% at randomization; subsequently, lispro injections were fully discontinued 4 weeks later) (n = 402) or to continued optimized lispro plus optimized glargine (n = 412).RESULTSMean ± SD HbA1c at baseline, 7.8 ± 0.6% (61 ± 7 mmol/mol) in the albiglutide + glargine group and 7.7 ± 0.6% (60 ± 7 mmol/mol) in the lispro + glargine group, was reduced at week 26 to 6.7 ± 0.8% (49 ± 8 mmol/mol) and 6.6 ± 0.8% (48 ± 8 mmol/mol), respectively (least squares [LS] difference 0.06% [95% CI −0.05 to 0.17]; noninferiority P < 0.0001). In the albiglutide + glargine group, 218 participants (54%) replaced all prandial insulin without reintroducing lispro up to week 26. Total daily prandial insulin dose was similar at baseline but was lower by 62 units/day (95% CI −65.9 to −57.8; P < 0.0001) at week 26 in the albiglutide + glargine group, and the total number of weekly injections was also reduced from 29 to 13 per week. Less severe/documented symptomatic hypoglycemia (57.2% vs. 75.0%) occurred in the albiglutide + glargine group with meaningful weight differences (LS mean ± SE −2.0 ± 0.2 vs. +2.4 ± 0.2 kg; P < 0.0001) vs. lispro + glargine. Gastrointestinal adverse events were higher with albiglutide + glargine (26% vs. 13%).CONCLUSIONSA once-weekly GLP-1RA was able to substitute for prandial insulin in 54% of people, substantially reducing the number of prandial insulin injections; glycemic control improved, with the added benefits of weight loss and less hypoglycemia in the GLP-1RA arm. Replacing prandial insulin with a weekly GLP-1RA can simplify basal plus prandial insulin treatments and achieve better outcomes in type 2 diabetes.

Update on Biosimilar Insulins: A US Perspective.

The development of biosimilar insulin products has slowly evolved with only two follow-on biologics currently available to patients in the US. Both Basaglar® (insulin glargine) and Admelog® (insulin lispro) have undergone extensive testing, and have gained significant use by patients in the US. Despite the availability of these follow-on products, the price of insulin has remained stubbornly high. New regulatory guidance under the Biologics Price Competition and Innovations Act that came into effect in March 2020 introduced an abbreviated pathway for the approval of biosimilar insulins and introduced the option to apply for interchangeability of the biosimilar insulin with the reference product. This abbreviated clinical testing may open the doors for numerous follow-on insulin products, with unknown supply-chain and fiscal ramifications. This review will highlight the development process of biosimilar insulin in the US and the recent regulatory changes that can aid this process. We will also discuss challenges for prescribers and patients who are navigating this ever-changing landscape. These new regulations for biosimilar insulins will have ramifications for patients, healthcare providers, and third-party payers, though the direction and scope of these changes is unclear.

Identification of recombinant insulin analogues by peptide mapping method

Insulin human, containing 51 amino acids, is a small polypeptide hormone that regulates blood glucose homeostasis. Patients with insulin-dependent diabetes mellitus require insulin therapy through the administration of exogenous insulin to avoid ketoacidosis. Utilizing various genetic engineering techniques, pharmaceutical companies have developed a variety of rapid- or long-acting insulin analogues. Analytical methods for various types of insulin and insulin analogues are gradually being included in the United States Pharmacopeia (USP) and the European Pharmacopeia (Ph. Eur.), but not yet in the Chinese Pharmacopeia. Usually these insulin analogues only differ by 1 to 3 amino acids, which is too subtle to distinguish by most of analytical methods currently available. In this study a peptide mapping technique was employed to screen insulin analogues for quality assessment. Peptide mapping is capable of identifying single amino acid changes resulted from events such as errors in the reading of complementary DNA sequences or point mutations. Here we analyzed 6 insulin preparations including insulin human, insulin lispro, insulin aspart, insulin detemir, insulin glargine and insulin glulisine using peptide mapping analysis. The peptide fingerprints of the insulin products we tested all corresponded well to those of the standard materials. Our peptide mapping method is more accurate in identifying the subtle differences between the insulin analogues than chromatography is. We concluded that peptide mapping is a valuable initial screening tool for quality assessment of insulin analogues. In the future, we intend to continue to develop this technology for post-marketing surveillance of other biopharmaceuticals and biosimilars, such as somatropin, erythropoietin and G-CSF.

An ultrafast insulin formulation enabled by high-throughput screening of engineered polymeric excipients.

Insulin has been used to treat diabetes for almost 100 years; yet, current rapid-acting insulin formulations do not have sufficiently fast pharmacokinetics to maintain tight glycemic control at mealtimes. Dissociation of the insulin hexamer, the primary association state of insulin in rapid-acting formulations, is the rate-limiting step that leads to delayed onset and extended duration of action. A formulation of insulin monomers would more closely mimic endogenous postprandial insulin secretion, but monomeric insulin is unstable in solution using present formulation strategies and rapidly aggregates into amyloid fibrils. Here, we implement high-throughput-controlled radical polymerization techniques to generate a large library of acrylamide carrier/dopant copolymer (AC/DC) excipients designed to reduce insulin aggregation. Our top-performing AC/DC excipient candidate enabled the development of an ultrafast-absorbing insulin lispro (UFAL) formulation, which remains stable under stressed aging conditions for 25 ± 1 hours compared to 5 ± 2 hours for commercial fast-acting insulin lispro formulations (Humalog). In a porcine model of insulin-deficient diabetes, UFAL exhibited peak action at 9 ± 4 min, whereas commercial Humalog exhibited peak action at 25 ± 10 min. These ultrafast kinetics make UFAL a promising candidate for improving glucose control and reducing burden for patients with diabetes.

Bioequivalence of Ultra Rapid Lispro (URLi) U100 and U200 Formulations in Healthy Subjects.

IntroductionUltra rapid lispro (URLi) is a novel insulin lispro formulation that was developed to more closely match physiological insulin secretion. The aims of this study were to demonstrate the bioequivalence (BE) of a concentrated formulation (U200) of URLi to the U100 formulation of URLi after subcutaneous (SC) administration and to evaluate the glucodynamics (GD) of these formulations.MethodsThis phase 1, randomized, two‐sequence, four‐period, double-blind, replicate crossover study was conducted in 68 healthy subjects. At each dosing visit, subjects received a 15-U SC dose of either U100 URLi or U200 URLi followed by a 10-h euglycemic clamp procedure. Serum insulin lispro and blood glucose concentrations were measured, and the glucose infusion rate was continuously adjusted during the clamp to maintain the target blood glucose.ResultsBioequivalence of U200 URLi relative to U100 URLi was demonstrated. The 90% confidence intervals (CIs) of the ratios of geometric least squares (LS) means for the maximum insulin concentration and total exposure were within the BE limits of 0.80–1.25. Additionally, the 90% CIs for the ratios of geometric LS means for maximum glucose infusion rate and total glucose infused were within the BE limits.The early 50% tmax occurred at approximately the same time for the U100 and U200 URLi formulations, and the insulin exposure within the first 15 min was similar for both formulations. The tolerability of the two URLi formulations was comparable.ConclusionsThis study demonstrated that the U100 and U200 URLi formulations are bioequivalent. The accelerated insulin absorption observed for the U100 formulation was maintained with the U200 URLi formulation. Further, the GD were similar for both formulations, supporting the ability of individuals to transfer from U100 to U200 URLi in a 1:1 unit conversion.Trial RegistrationNCT03616977.

1019-P: Variability of 501 Inhaled Insulin Absorption and Action

501 inhaled insulin (INH) is a novel liquid formulation of human insulin for inhalation with faster onset of action than s.c. insulin lispro (LIS). This randomized, replicated cross-over trial investigated the variability of INH vs. LIS during 10-hour glucose clamps in non-smoking subjects with T1D. Fourteen subjects (age [mean±SD] 32.5±7.9 years, BMI 26.5±2.1 kg/m2, HbA1c 7.5±0.8 %) received 2 single doses of 92.2 IU INH via the Afina inhaler (n=13 completing subjects) and 2 injections of an equivalent 12 U LIS dose (n=12). The inhalations were performed by the subjects after a brief training on the correct inhalation technique; injections were given by trained staff. Repeated dosing of INH by the same subject resulted in reproducible insulin absorption and insulin action, with lower or similar variability vs. LIS (Table 1). The response to INH between subjects was more variable than for LIS. The 13.8±8.1% mean relative biopotency of INH was consistent with previous findings. INH was well tolerated, adverse events (8 with INH, 13 with LIS) were mild to moderate in severity. No cough and no acute changes in spirometry were observed with any inhalation. In conclusion, the intra-individual response to self-administration of 501 inhaled insulin is as reproducible as that of s.c. insulin lispro injected by experienced staff. This is a clinically meaningful outcome and enables individual dose titration of 501 insulin in future treatment. Disclosure E. Zijlstra: Employee; Self; Profil. Speaker’s Bureau; Self; Aerami Therapeutics, Eli Lilly and Company, Novo Nordisk A/S. G. Andersen: Employee; Self; Profil Institute for Clinical Research. L. Plum-Moerschel: Other Relationship; Self; Eli Lilly and Company, Novo Nordisk A/S. M. Rhodes: None. R. Patton: None. B. Bueche: None. M. Kuo: None. T.H. Le: None. B.J. Stedman: None. J.S. Patton: Board Member; Self; Dance Biopharm Holdings, Inc.

63-OR: Towards Point-of-Care Devices: First Evaluation of an Insulin Immunosensor for Type 1 Diabetes

Insulin monitoring is clinically relevant for diabetes management. We present a first evaluation of an insulin immunosensor as a step towards point-of-care devices to enhance automated insulin delivery for T1D. The sensor is a novel, wearable, minimally invasive microneedle/microfluidic device for real-time insulin monitoring. To validate the sensor, a mid-study analysis was performed on 4 adults with T1D (43±12 years, 75% male) using insulin pumps. Insulin lispro or aspart was injected via syringe just prior to breakfast. Insulin levels were collected prior to injection and over the next 4h. Insulin quantification was performed using the participants’ serum samples extracted from venous blood. The change in real-time immunosensor-measured insulin levels was compared with values obtained by ELISA in a central lab. At each time point, a median insulin level was derived from replicate immunosensor samples. Concordance of immunosensor and ELISA insulin levels was assessed as a comparison of their changes from baseline (Figure). The mean absolute relative difference between immunosensor and venous insulin levels was 16%, 8%, and 18% at 1, 2, and 4h after the baseline measurement, respectively. The results of the 1st phase real-time insulin immunosensor evaluation are promising and may provide data to improve current insulin decay curve assumptions used in insulin-on-board approximations. Disclosure K.L. Wolkowicz: None. E. Vargas: None. H. Teymourian: None. F. Tehrani: None. J.E. Pinsker: Advisory Panel; Self; Medtronic. Consultant; Self; Eli Lilly and Company, Tandem Diabetes Care. Research Support; Self; Dexcom, Inc., Eli Lilly and Company, Insulet Corporation, Medtronic, Tandem Diabetes Care. Speaker’s Bureau; Self; Tandem Diabetes Care. M. Church: None. M. Piper: None. F.J. Doyle: Research Support; Self; DreaMed Diabetes, Tandem Diabetes Care, Xeris Pharmaceuticals, Inc. Stock/Shareholder; Self; Mode AGC. Other Relationship; Self; Dexcom, Inc., Insulet Corporation, Roche Diabetes Care. M. Patti: Consultant; Self; Fractyl Laboratories, Inc. Research Support; Self; Dexcom, Inc., Xeris Pharmaceuticals, Inc. Other Relationship; Self; Academy of Nutrition and Dietetics, American Diabetes Association, American Society of Metabolic and Bariatric Surgery, Endocrine Society, Insulet Corporation, King Abdullah International Medical Research Center, SUNY Downstate. L.M. Laffel: Advisory Panel; Self; Roche Diabetes Care. Consultant; Self; Boehringer Ingelheim Pharmaceuticals, Inc., ConvaTec Inc., Dexcom, Inc., Insulet Corporation, Insulogic LLC, Janssen Pharmaceuticals, Inc., Lilly Diabetes, Novo Nordisk Inc., Sanofi US. J. Wang: None. E. Dassau: Consultant; Self; Eli Lilly and Company. Research Support; Self; Dexcom, Inc., DreaMed Diabetes, Tandem Diabetes Care, Xeris Pharmaceuticals, Inc. Speaker’s Bureau; Self; Roche Diabetes Care. Other Relationship; Self; Dexcom, Inc., Insulet Corporation, Roche Diabetes Care. Funding The Leona M. and Harry B. Helmsley Charitable Trust (2018PG-TID061); Dexcom, Inc. (IIS-2019-052)

1018-P: Ultra-Rapid Lispro (URLi) Showed Greater Reduction in Postprandial Glucose (PPG) vs. Humalog in Children, Adolescents, and Adult Patients with Type 1 Diabetes (T1D)

URLi is a novel insulin lispro formulation that was developed to more closely match physiological insulin secretion. This 2-site, randomized, 2-period crossover, double-blind study evaluated the pharmacokinetics and glucodynamics during a liquid test meal, after a single 0.2 U/kg SC dose of URLi or Humalog in 13 children, 14 adolescents, 15 adults with T1D. Onset of insulin appearance was faster with URLi vs. Humalog in children (1.1 vs. 6.5 min; p=0.0002), adolescents (1.9 vs. 6.4 min; p=0.001), and adults (0.9 vs. 4.8 min; p=0.004). Early exposure (AUC0-15min) was greater with URLi vs. Humalog: 7-fold (p&amp;lt;0.0001) in children, 4 fold (p=0.0003) in adolescents, 5-fold (p&amp;lt;0.0001) in adults; late exposure (AUC3-7h) was reduced by 58% (p&amp;lt;0.0001) in children, 40% (p=0.013) in adolescents, 37% (p=0.021) in adults. Total exposure was similar in URLi and Humalog. At 1h, URLi reduced PPG by 42 mg/dL (p=0.008) in children, 19 mg/dL (p=0.195) in adolescents, 34 mg/dL (p=0.018) in adults, vs. Humalog. At 2h, URLi reduced the PPG by 32 mg/dL (p=0.11) in children, 39 mg/dL (p=0.051) in adolescents and was not statistically different in adults, vs. Humalog. URLi was well tolerated in all age groups. In summary, URLi accelerated insulin lispro absorption, reduced late exposure and early PPG following a test meal vs. Humalog in children, adolescents, and adults with T1D. Disclosure R. Aronson: None. H. Linnebjerg: Employee; Self; Eli Lilly and Company. Stock/Shareholder; Self; Eli Lilly and Company. J. Leohr: None. E.S. LaBell: Employee; Self; Eli Lilly and Company. Stock/Shareholder; Self; Eli Lilly and Company, Johnson &amp; Johnson, Novartis AG. D.E. Coutant: Employee; Self; Eli Lilly and Company. Employee; Spouse/Partner; Eli Lilly and Company. Q. Zhang: Employee; Self; Eli Lilly and Company. Stock/Shareholder; Self; Eli Lilly and Company. T. Danne: Advisory Panel; Self; AstraZeneca, Boehringer Ingelheim International GmbH, Eli Lilly and Company, Medtronic, Novo Nordisk A/S, Sanofi. R.K. Pollom: Employee; Self; Eli Lilly and Company. Stock/Shareholder; Self; Eli Lilly and Company. Funding Eli Lilly and Company

26-LB: Exenatide and Renal Outcomes in Patients with Type 2 Diabetes and Diabetic Kidney Disease: A Multicenter, Randomized, Parallel Study

Aim: This trial aimed to assess the effects of exenatide, a GLP-1RA, on renal outcomes in patients with T2DM and DKD. Methods: We performed a randomized, parallel study conducted in 4 general hospitals. T2DM patients with an eGFR≥30mL/min/1.73m2 and macroalbuminuria, defined as 24h-urinary albumin-creatinine ratio (UAER) &amp;gt;0.3g/24h, were randomized 1:1 to receive exenatide twice daily plus glargine or lispro insulin plus glargine for 24 weeks. The primary outcome was percentage change in 24h-UAER after 24 weeks of intervention comparing to baseline measurement. The secondary outcomes included the percentage change in urinary ACR, change in 24h-UAER, ACR, HbA1c, FPG, body weight and blood pressure. The safety outcomes include rates of hypoglycemia, adverse events and change in eGFR during the follow up. Results: Between March 2016 and April 2019, 92 patients were randomized and took at least one dose of study drug. The mean age of the participants was 56 years. At baseline, the median 24h-UAER was 1512.0 mg/24h (IQR 782.5-2818.0), and mean eGFR was 70.4 mL/min/1.73 m2 (SD 23.4). After 24 weeks, exenatide reduced the percentage change of the 24h-UAER (difference between groups was 29.7%, p=0.0255), the percentage change of ACR (difference between groups was 28.4%, p=0.0395) and the absolute change of ACR (difference between groups was 607.8 mg/g, p=0.0209) but had no significant difference on the absolute change of 24h-UAER than the control group. Meanwhile, the body weight declined by 1.3kg with exenatide (difference between groups was 2.7kg, p=0.0001). There was no difference between two groups on the change in HbA1c, FPG, blood pressure or eGFR. Comparing to the control group, lower frequency of hypoglycemia as well as more gastrointestinal adverse events were in intervention group. Conclusions: Exenatide twice daily plus glargine for 24 weeks resulted in significant reduction of albuminuria in T2DM patients with DKD. Disclosure X. Wang: None. Q. Zhang: None. M. Guan: None. S. Sheng: None. W. Mo: None. M. Zou: None. J. Li: None. J. Bi: None. X. Tang: None. J. He: None. G. Xu: None. P. Li: None. H. Zhang: None. Y. Xue: None.

1012-P: Study of Insulin Stability Impact on Pump Therapy: Test Model Development

Objective: Develop a test methodology for evaluating the reason for infusion set (IS) failure in persons with diabetes using insulin pump therapy (Continuous Sub-cutaneous Insulin Infusion, CSII). Insulin stability (physical, chemical, and microbiological) and/or the loss of preservatives in the infusate are thought to play significant roles in shortening IS wear time. In-vitro and in-vivo methods were used to assess the cause(s) site inflammation and the loss of preservatives. Method: Fast-acting insulin (insulin aspart and lispro) were pumped through different infusion sets (&amp;gt;4) under simulated-use conditions. The pumped insulin and non-pumped insulin controls were characterized for physical, chemical, and microbiological properties. The pumped insulin, combined with fibrinogen (an initiator for material foreign body responses), were tested in murine macrophage cell culture for inflammatory responses. The corresponding infusion sets were tested in vivo in a diabetic porcine model to determine IS wear-time. Result: Pumped insulins in ≥8 insulin/IS combinations met corresponding criteria in USP insulin monographs, indicating no significant chemical changes. Lower preservative content was found to increase insulin aggregates in-vitro/in-vivo. Pro-inflammatory cytokines (MIP-1α, and MCP-1) increased significantly in the inflammatory in-vitro model. The IS wear-time was shortened from 4.9±0.3 days (control) to 1.7±0.3 days (p&amp;lt;0.0001) with lower preservative content (&amp;lt;50% per label claim). Conclusion: Preliminary findings from in-vitro and in-vivo test model development indicate that macrophage number, the inflammatory response, and device wear time were significantly impacted by loss of preservative and trace aggregates/particles. The new test methodology can further our understanding as to how to improve IS wear time. Disclosure S. Chattaraj: Employee; Self; Medtronic. G. Zhang: None. E. Anselmo: Employee; Self; Medtronic. J.C. Fusselman: None.

107-LB: Single Ascending Dose Study to Assess the Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of MK-1092 in Healthy Subjects (HS)

Background: MK-1092, a first-in-class insulin receptor partial agonist, is being developed as a novel basal insulin for patients with T1DM and T2DM. The primary objective of this first-in-human study was to assess safety and tolerability of single subcutaneous (SC) doses of MK-1092 in HS. Secondary objectives were to estimate PK profiles, to determine the maximal glucose infusion rate (GIRmax) required to maintain target glucose levels during euglycemic clamp conditions and to explore the glycemic effect of insulin lispro when added to a single dose of MK-1092 in HS. Methods: In part 1 of this single-site study, 5 cohorts of HS (n=8/cohort) were blinded and randomized (3:1) to receive MK-1092 (4, 8, 16, 32 or 64 nmol/kg) or glargine (3 nmol/kg [0.5 units/kg]). Subjects received single SC doses of MK-1092 or glargine and placebo matched to the alternative active treatment under euglycemic clamp conditions. Part 2 of the study was started once a safe and tolerated MK-1092 dose that achieved GIRmax ~1-2 mg/kg/min was identified in Part 1. In the open-label part 2 of the study, 4 HS received lispro (1.2 nmol/kg [0.2 units/kg], IV) approximately 12 hr after a single SC dose of MK-1092 (8 nmol/kg) to confirm high dose lispro could reduce hyperglycemia (defined as GIRmax &amp;gt; 4mg/kg/min) after MK-1092 dosing. Results: All doses tested were safe and well tolerated. There were no SAEs and no discontinuations due to AEs. AEs were mild or moderate and resolved spontaneously. The geometric mean of apparent terminal t1/2 ranged from 5.4 to 9.3 hr, Tmax ranged from 12 to 18 hr, AUC0-∞ ranged from 10.6 to 161 nM*hr and Cmax ranged from 0.38 to 6.82 nM at 4 to 64 nmol/kg MK-1092. Mean GIRmax for glargine was 2.72 mg/kg/min and 0.92, 1.69, 3.10, 3.32 and 4.39 mg/kg/min for 4, 8, 16, 32 and 64 nmol/l MK-1092, respectively. Adding lispro to 8.0 nmol/kg MK-1092 resulted in a mean GIRmax of 11.34 mg/kg/min. Conclusion: Single doses of MK-1092 are well-tolerated and lower glucose in healthy subjects. Disclosure L. Morrow: Employee; Spouse/Partner; Lilly Diabetes. Employee; Self; ProSciento. M. Grimm: None. C. Beysen: Employee; Self; ProSciento. G. Walford: Employee; Self; Merck &amp; Co., Inc. K. Duncan: Employee; Self; Merck &amp; Co., Inc. Stock/Shareholder; Self; Merck &amp; Co., Inc. P.K. Mitra: Employee; Self; Merck Sharp &amp; Dohme Corp. Stock/Shareholder; Self; Bristol-Myers Squibb. P. Vaddady: Employee; Self; Merck &amp; Co., Inc. Stock/Shareholder; Self; Merck &amp; Co., Inc. M. Hompesch: Board Member; Self; ProSciento. Employee; Self; ProSciento. Stock/Shareholder; Self; ProSciento.

233-OR: Ultra-Rapid Lispro (URLi) Demonstrates Similar Time-in-Target Range to Humalog with the Medtronic MiniMed 670G Hybrid Closed-Loop System

URLi is a novel ultra rapid formulation of insulin lispro that shows improved postprandial glucose control and similar compatibility with continuous subcutaneous insulin infusion (CSII) vs. Humalog. In this study URLi was evaluated for the first time in a hybrid closed-loop system using the Medtronic MiniMed 670G. Primary objective was to compare URLi to Humalog with respect to the percentage of time with glucose values within target range 70-180 mg/dL (%TIR). This double-blind, crossover study included two 4-week treatment periods with URLi or Humalog. After a 2-week lead-in on Humalog, 42 adults with type 1 diabetes using personal MiniMed 670G pumps were randomized to 1 of the 2 treatment sequences with boluses initiated 0-2 minutes before meals. Both treatments achieved good glycemic control with mean TIR &amp;gt;75% (Fig 1). Mean time above and below range met consensus recommendations for both treatments. The percentage of time in Auto Mode was similar between treatments: URLi 92.0%; Humalog 91.4%. Insulin doses and pump settings were generally similar between treatments. There were no serious adverse events or early discontinuations. Overall incidence of treatment-emergent adverse events was similar between treatments. URLi demonstrated comparable glycemic control and a similar safety profile to Humalog with the MiniMed 670G system in patients with type 1 diabetes. Disclosure B.W. Bode: Advisory Panel; Self; InPen, Medtronic. Consultant; Self; ADOCIA, Eli Lilly and Company, Lexicon Pharmaceuticals, Inc., Novo Nordisk A/S, Pfizer Inc. Research Support; Self; Dexcom, Inc., Diasome Pharmaceuticals, Inc., Eli Lilly and Company, Gan &amp; Lee Pharmaceuticals, Medtronic, Novo Nordisk A/S, Provention Bio, Inc., Senseonics, Xeris Pharmaceuticals, Inc. Speaker’s Bureau; Self; AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Inc., InPen, Janssen Pharmaceuticals, Inc., MannKind Corporation, Medtronic, Novo Nordisk A/S, Sanofi, Sanofi, Senseonics, Xeris Pharmaceuticals, Inc. Stock/Shareholder; Self; Glytec. A.L. Carlson: Consultant; Self; Medtronic. Research Support; Self; Abbott, Dexcom, Inc., Eli Lilly and Company, Insulet Corporation, Medtronic, Novo Nordisk A/S, Sanofi, UnitedHealth Group. R. Liu: Employee; Self; Eli Lilly and Company. Employee; Spouse/Partner; Eli Lilly and Company. T. Hardy: Other Relationship; Self; Eli Lilly and Company. J. Boyd: None. R.M. Bergenstal: Consultant; Self; Ascensia Diabetes Care, Johnson &amp; Johnson. Other Relationship; Self; Abbott, Dexcom, Inc., Hygieia, Lilly Diabetes, Medtronic, Novo Nordisk A/S, Onduo, Roche Diabetes Care, Sanofi, UnitedHealth Group. S. Morrett: Other Relationship; Self; Eli Lilly and Company. D.A. Ignaut: Employee; Self; Eli Lilly and Company. Stock/Shareholder; Self; Eli Lilly and Company. Funding Eli Lilly and Company

1036-P: Bioequivalence of Ultra-Rapid Lispro (URLi) U100 and U200 Formulations in Healthy Subjects

URLi is a novel insulin lispro formulation developed to more closely match physiological insulin secretion. URLi U200 is a concentrated formulation. This randomized, double-blind, 4-period, replicated crossover, euglycemic clamp study (NCT03616977) assessed pharmacokinetics (PK) and glucodynamics (GD) after 15 U subcutaneous doses of U100 and U200 URLi in 68 healthy subjects (mean ± SD age 39.6 ± 9.6 y). Similar mean PK and GD profiles were observed after dosing U100 and U200 URLi. The formulations were bioequivalent (BE): the 90% CI of ratios of geometric least-square means for the maximum insulin concentration (Cmax) and total exposure (AUC0-∞) were within BE limits of 0.80-1.25. Additionally, the 90% CI for the ratios of geometric means for maximum (Gtot) and total glucose infused (Rmax) were within the BE limits. The time to early half Cmax (early 50% tmax) occurred at approximately the same time for both formulations. Additionally, insulin exposure within the first 15 and 30 minutes was similar for U100 and U200 URLi. The tolerability of the U200 and U100 URLi formulations were comparable. This study demonstrated that U100 and U200 URLi formulations were BE and the faster insulin absorption was maintained in the U200 formulation. The GD were similar and support the ability of patients to transfer from U100 to U200 URLi in a 1:1 unit conversion. Disclosure H. Linnebjerg: Employee; Self; Eli Lilly and Company. Stock/Shareholder; Self; Eli Lilly and Company. E.S. LaBell: Employee; Self; Eli Lilly and Company. Stock/Shareholder; Self; Eli Lilly and Company, Johnson &amp; Johnson, Novartis AG. M.A. Dellva: Employee; Self; Eli Lilly and Company. S. Lim: Employee; Self; Eli Lilly and Company. D.E. Coutant: Employee; Self; Eli Lilly and Company. Employee; Spouse/Partner; Eli Lilly and Company. J. Leohr: None. Funding Eli Lilly and Company

1044-P: The Impact of Basal Insulin Type, Prandial Dosing Plan, and Baseline Postprandial Glucose (PPG) on Glycemic Control after Treatment with Ultra-Rapid Lispro (URLi) or Humalog in Type 1 Diabetes: Planned Subgroup Analyses from PRONTO-T1D

URLi is a novel prandial insulin lispro formulation developed to more closely match physiological insulin secretion and improve PPG control. In PRONTO-T1D, a phase 3, 26-week, treat-to-target study comparing URLi to Humalog in patients with T1D on a multiple daily injection regimen with insulin glargine or degludec, mealtime URLi was non-inferior to mealtime Humalog for change from baseline HbA1c and superior for PPG control, with a similar safety profile to Humalog. Randomization to treatment was stratified by basal insulin type, baseline HbA1c and prandial insulin dosing plan (carb counting, yes/no). The impact of these subgroups and baseline 2-hour PPG on the efficacy and safety of URLi was assessed from the double-blind treatment groups: mealtime URLi (n=451) and mealtime Humalog (n=442). No significant treatment-subgroup interactions were noted (all p&amp;gt;0.1) but occasional treatment differences were seen within each subgroup (p&amp;lt;0.05) (Table 1.). Numerically, results suggest that basal insulin type, starting PPG, and starting HbA1c, but not prandial dosing plan, may influence the magnitude of the HbA1c improvement and/or hypoglycemia risk reduction among patients treated with URLi. Disclosure J.M. Bue-Valleskey: Employee; Self; Eli Lilly and Company. J. Cho: None. T. Hardy: Other Relationship; Self; Eli Lilly and Company. Funding Eli Lilly and Company

1040-P: Ultra-Rapid Lispro (URLi) Accelerates Insulin Lispro Absorption and Insulin Action vs. Humalog (Lispro) Consistently across Study Populations: A Meta-analysis of Pharmacokinetic and Glucodynamic Data

URLi is a novel insulin lispro formulation developed to more closely match physiological insulin secretion and improve postprandial glucose control. This meta-analysis compared and assessed the consistency of the pharmacokinetics and glucodynamics between URLi and Humalog® in healthy subjects and patients with T1D or T2D. The analysis included 4 randomized, double-blind, crossover, single dose studies [healthy subjects (n=74), patients with T1D (n=80), and T2D (n=38)], evaluating subcutaneous doses of 7, 15, or 30 U of URLi and Humalog®. An 8 to10-h euglycemic clamp was conducted to assess pharmacodynamics. Meta-analysis showed a ∼5 min faster (95% CI:-5.38, -4.12 min) onset of appearance with URLi vs. Humalog. The early insulin exposure was ∼8 times greater (95% CI:6.63, 8.51) in first 15 min and 3 times greater (95% CI:2.74, 3.22) in the first 30 min after URLi vs. Humalog. URLi reduced the late insulin exposure after 3 hours by 43% (ratio 0.57; 95% CI:0.53, 0.60) and the duration of exposure by 68 min (95% CI:-76.86, -59.53 min) vs. Humalog. URLi had a faster onset of action occurring 10 min earlier (95% CI:-12.01, -8.64 min), and early action was increased 3-fold in the first 30 min (95% CI:2.72, 3.50 min) with URLi vs. Humalog. Late insulin action (glucose infused 4 h to end of the clamp) was reduced by 35% (ratio 0.65; 95% CI:0.61, 0.70) and duration of action was 44 min shorter with URLi (95% CI:-58.60, -29.02 min). Total exposure and glucose infused during the clamp was similar between URLi vs. Humalog across the dose range and in each study population. Across the studied dose range and study populations, URLi consistently had faster absorption, reduced late exposure, and an overall shorter exposure duration compared to Humalog. URLi demonstrated an earlier insulin action while reducing the late insulin action compared to Humalog across the studied dose range and study populations. Disclosure J. Leohr: None. M.A. Dellva: Employee; Self; Eli Lilly and Company. K. Carter: None. E.S. LaBell: Employee; Self; Eli Lilly and Company. Stock/Shareholder; Self; Eli Lilly and Company, Johnson &amp; Johnson, Novartis AG. H. Linnebjerg: Employee; Self; Eli Lilly and Company. Stock/Shareholder; Self; Eli Lilly and Company. Funding Eli Lilly and Company

1046-P: Effect of Age on HbA1c, Postprandial Glucose (PPG) Control, and Hypoglycemia in Patients with T2D Treated with Ultra-Rapid Lispro (URLi) or Humalog: PRONTO-T2D

URLi is a novel prandial insulin lispro formulation developed to more closely match physiological insulin secretion. PRONTO-T2D, a Phase 3, double-blind, treat-to-target study in pts with T2D, showed URLi, in a basal-bolus regimen with glargine or degludec, was non-inferior for HbA1c with superior PPG control vs. Humalog. Subgroup analyses were performed in pts &amp;lt;65 vs. ≥65 years. Baseline characteristics were similar except age and duration of T2D (Table 1). With 26 weeks of study treatment, HbA1c improved in both treatment/age groups with endpoint mean HbA1c 6.8-6.9%. URLi significantly reduced 1- and 2-hour PPG excursions with standardized meal tests vs. Humalog in both age groups. Insulin dosing was not significantly different. Severe hypoglycemia incidence was low. While there was no treatment difference in documented hypoglycemia (glucose &amp;lt;54 mg/dL), relative rate (URLi/Humalog) was lower in pts ≥65 vs. &amp;lt; 65 years, with a significant treatment-by-age interaction. Nocturnal hypoglycemia was not significantly different between groups. Incidence of overall treatment-emergent adverse events was similar between treatment/age groups. URLi in a basal-bolus regimen resulted in endpoint HbA1c &amp;lt;7% and significantly lower PPG excursions vs. Humalog in both age groups, with reduced documented hypoglycemia in older vs. younger pts. Disclosure A.M. Chang: Employee; Self; Eli Lilly and Company. Stock/Shareholder; Self; Eli Lilly and Company. T. Hardy: Other Relationship; Self; Eli Lilly and Company. Q. Zhang: Employee; Self; Eli Lilly and Company. Stock/Shareholder; Self; Eli Lilly and Company. Funding Eli Lilly and Company

111-LB: Hepatic Insulin Delivery to Minimize Hypoglycemic Events in Persons with Type 1 Diabetes: The OPTI-1 Study

Background: Subcutaneous (SC) insulin is non-physiologic, since normally insulin is secreted into the portal vein going directly to the liver. The OPTI-1 study was designed to determine whether delivery of Hepatic Directed Vesicles (HDV) admixed with Lispro (HDV-L) decreases hypoglycemia in well controlled adults with type 1 diabetes (T1D) using multiple daily insulin injections with an unblinded Dexcom G6 (CGM). Methods: OPTI-1 was a 6-month (mo) open label study of prandial insulin (lispro, 3 mo, then HDV-L, 3 mo) with basal insulin degludec and unblinded CGM in T1D with baseline A1C 6.5-8.5%. Target fasting blood glucose was 80-100 mg/dL. At 3 mo subjects were randomized to -10% or -40% basal dose to encourage titration with HDV-L. Physicians titrated basal insulin doses weekly. A hypoglycemic event was defined as ≥15 min of CGM ≤54 mg/dL. Results: In 61 participants, the mean baseline A1C was 7.3%. A1C was 6.9% after 3 mo lispro optimization, and 7.0% after 3 mo HDV-L optimization. At study end, the degludec dosage was similar, while HDV-L dose increased 0.03 u/kg/day (+13%, p=0.023) compared to optimal lispro. At baseline there were 1.11 hypoglycemic events per week (EPW) (1.04 Daytime “DT” and 1.39 Nighttime “NT” EPW), which decreased by 11% to 0.99 EPW (0.93 DT and 1.10 NT EPW) at 3 mo. The switch to HDV-L from lispro at 3 mo resulted in a further 20% decrease in events to 0.80 EPW (p=0.18; 0.86 DT, and 0.75 NT EPW p=0.08) by end of study. Discussion: The use of prandial HDV-L vs. lispro insulin reduced hypoglycemia, especially nocturnal hypoglycemia, without a rise in A1C. This reduction in hypoglycemia is consistent with the putative benefit of targeting insulin to the liver by inducing glycogen storage postprandially, which may lead to a decrease in hypoglycemia especially at night. We conclude that hepatic-directed insulin delivery in adults with T1D helps to restore hepatic physiology and reduce hypoglycemia. Disclosure B.W. Bode: Advisory Panel; Self; Medtronic, Novo Nordisk A/S. Consultant; Self; Eli Lilly and Company, Medtronic, Novo Nordisk A/S. Research Support; Self; Abbott, Advance, Boehringer Ingelheim Pharmaceuticals, Inc., Dexcom, Inc., Diasome Pharmaceuticals, Inc., Eli Lilly and Company, Insulet Corporation, Janssen Pharmaceuticals, Inc., MannKind Corporation, Medtronic, National Institutes of Health, Nova Biomedical, Novo Nordisk A/S, Provention Bio, Inc., Sanofi, Senseonics. Speaker’s Bureau; Self; AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Inc., Eli Lilly and Company, Janssen Pharmaceuticals, Inc., MannKind Corporation, Medtronic, Novo Nordisk A/S, Sanofi, Senseonics. Stock/Shareholder; Self; Aseko. R.S. Weinstock: Board Member; Self; JDRF. Consultant; Self; Insulogic LLC. Research Support; Self; Boehringer Ingelheim International GmbH, Diasome Pharmaceuticals, Inc., Eli Lilly and Company, Insulet Corporation, Jaeb Center for Health Research, Kowa Research Institute, Inc., Medtronic, Tolerion, Inc. S.K. Garg: Advisory Panel; Self; Boehringer Ingelheim Pharmaceuticals, Inc., Eli Lilly and Company, Medtronic, Novo Nordisk A/S, Roche Diagnostics France. Research Support; Self; Dexcom, Inc., Eli Lilly and Company, Medtronic. D.C. Klonoff: Consultant; Self; Abbott, Ascensia Diabetes Care, Dexcom, Inc., EOFlow, Fractyl Laboratories, Inc., Know Labs, LifeCare, Inc., Novo Nordisk Inc., Roche Diabetes Care. K.K. Singh: None. D.B. Muchmore: Consultant; Self; Capillary Biomedical, Inc., Diasome Pharmaceuticals, Inc., Zucara Therapeutics Inc. Stock/Shareholder; Self; Capillary Biomedical, Inc., Diasome Pharmaceuticals, Inc. M.S. Penn: Board Member; Self; Diasome Pharmaceuticals, Inc. Consultant; Self; Diasome Pharmaceuticals, Inc., Quest Diagnostics. W. Geho: Other Relationship; Self; Diasome Pharmaceuticals, Inc. C.E. El Sanadi: None.

Results of the Estimation of Biosimilarity of RinLiz® (LLC «GEROPHARM», Russia) and Humalog® (Lilly France, France) Using the Method of the Hyperinsulinemic Eulygemic Clamp on Healthy Voluntary

Introduction. Insulin is the most effective hypoglycemic agent currently used in the clinical practice. Compared with recombinant human insulin, insulin lispro have a blood glucose profile that is much closer to physiological. The clinical trials program of insulin bioassays includes pharmacology studies: pharmacokinetics (PK), pharmacodynamics (PD), and a clinical safety study.Aim. To compare PK and PD of RinLiz® U100, solution for intravenous and subcutaneous administration (LLC «GEROFARM», Russia) and Humalog® U100, solution for intravenous and subcutaneous administration (Lilly France, France) in hyperinsulinemic euglycemic clamp.Materials and methods. This was randomized double-blind, two-arm crossover study in 28 healthy volunteers (NCT03604575). The studied preparations were injected before the clamp with a dose of 0.3 U/kg once subcutaneously in the area of subcutaneous fat in the anterior abdominal wall. During the study, regular blood sampling was performed; the amount of insulin lispro was determined by ELISA in the samples. The results of the determination were used to calculate the PK parameters and construct the curves «concentration – time». Based on the measurement of glycemia, the glucose infusion rate was adjusted. These data were used to calculate the PD parameters. The comparability of the studied drugs was considered proven if 90 % confidence intervals (CI) for the ratio of geometric mean PK parameters Cins. max and AUCins. 0-8 and 95 % CI for the ratio of geometric mean PD parameters GIRmax and AUCGIR0-8,5 were in the range of 80–125 %. Statistical data processing and presentation of the results was carried out using software packages R 3.4.2.Results and discussion. In the course of CI comparative PK and PD of RinLiz® and Humalog®, it was revealed that they have comparable PK and PD profiles. The CI for the logarithmically converted ratios of the values of the PK parameters was Cins. max 85.99–96.85 % and AUCins. 0-8 90.58–97.28 %, the PD of the parameters were 95.64–118.94 for GIRmax and 96.5–121.36 for AUCGIR0-8.5, all the CIs correspond to the set the boundaries of 80–125 % to establish comparability between RinLiz® and the original drug.Conclusion. The results demonstrated the high degree of similarity of RinLiz® U100 and Humalog® U100 in terms of PK, PD profiles and safety.

SAT-689 Amantadine Induced Severe Hypoglycemia in a Patient With Type 1 Diabetes and Multiple Sclerosis

Introduction: Amantadine is one of the few options commonly used to treat fatigue associated with multiple sclerosis. However, in a previous trial investigating the effect of amantadine on oral glucose tolerance test results, amantadine caused a reduction in plasma glucose and glucagon levels while increasing insulin levels in healthy volunteers [1]. If amantadine can reduce glucagon levels, we hypothesized that it might also cause hypoglycemia in patients with type 1 diabetes. Case presentation: The patient is a 34-year-old African American male who has a past medical history of type 1 diabetes and multiple sclerosis. His baseline hemoglobin A1c values ranged from 6.9% to 7.6% and his weight was 88 Kg. His insulin glargine dose was 28 units daily while his insulin lispro was 10 units before meals. For almost one year he was followed in clinic and had no episodes of severe hypoglycemia (defined as hypoglycemia requiring assistance from another person).The patient complained about gait imbalance and fatigue from multiple sclerosis for which he was followed by a neurologist. To treat these symptoms, he was prescribed amantadine 100 mg twice daily. A couple of hours following his first dose of amantadine after eating his usual breakfast (with his sister), the patient was found unconscious by his sister. Emergency Medical Services (EMS) was called and he was found to have a blood glucose of 22 mg/dL. He was admitted to the hospital. During that admission, amantadine was discontinued, and he was discharged on insulin glargine 24 units daily and insulin lispro 10 units with meals. Discussion: We present a case of suspected amantadine induced severe hypoglycemia. In patients with type 1 diabetes, there is a loss of the pancreatic β-cells while the α-cells are preserved [2, 3]. We hypothesize that if amantadine reduces glucagon production from the α-cells, patients would be prone to severe hypoglycemia, presumably because of the unopposed insulin action. Although it is unlikely that the severe hypoglycemia was secondary to insulin since the patient was on stable doses, it cannot be completely excluded. We recommend caution when prescribing amantadine to patients on insulin therapy particularly within the first two hours after rapid acting insulin administration. More research is needed to explore this possibility.

MON-690 Euglycemic Diabetic Ketoacidosis Associated with SGLT-2 Inhibitors- an Under-recognized Diagnosis

BackgroundSodium glucose cotransporter-2 inhibitors (SGLT-2i) are a promising class of oral anti-hyperglycemic agents with mounting evidence of reduced cardiovascular risk and renal failure, in patients with type 2 diabetes mellitus. Recent increase in their use has led to identification of hitherto unknown side effects of these drugs. Euglycemic Diabetic Ketoacidosis (eDKA), found to be associated with SGLT-2i use, is a life-threatening condition and commonly goes unrecognized due to absence of the cardinal sign of hyperglycemia.Clinical CaseWe describe a 47 year old male with history of coronary artery disease and recently diagnosed type 2 diabetes mellitus who presented to our hospital with one week history of nausea, lethargy, progressive fatigue, and shortness of breath. He was diagnosed with type 2 diabetes three weeks prior, with HBA1c of 12%.His regimen included basal insulin and recent transition to empagliflozin due to severe GI intolerance with metformin use.On arrival he was noted to be tachycardic with a heart rate of 113/min, afebrile and normotensive. Physical exam was mostly unremarkable except for dry oral mucous membranes. Serum chemistry was consistent with high anion gap metabolic acidosis with bicarbonate of 6.9 mmol/L (21-32 mmol/L), anion gap of 29 mmol/L (10-20 mmol/L), mildly elevated blood glucose of 132 mg/dl (74-106 mg/dl), acute kidney injury with creatinine of 1.47 mg/dl (0.7- 1.3 mg/dl), and a beta hydroxybutyrate level of 82.7 mg/dl (0.20- 5.63 mg/dl). Urine analysis showed ketonuria. This was consistent with a clinical and biochemical diagnosis of eDKA. He was treated with IV D5%NS-20mEq/L KCL and an insulin drip. Upon resolution of his acidosis and normalization of the anion gap he was switched to subcutaneous Insulin Glargine and Lispro. Empagliflozin was held as it was thought to be contributing to the diagnosis of eDKA.ConclusionOur case yet again illustrates the importance of recognition of EDKA to aid prompt management, especially with the rising popularity of SGLT-2 inhibitors. It is also important to educate patients about this condition, mostly notable in the first two months of starting the medication, to recognize the concerning symptoms and precipitating factors like dehydration, improper insulin dosing, low calorie diet, alcohol, infection, surgery. An acceptable alternative to SGLT-2i can be glucagon like peptide receptor (GLP- 1) agonists, also associated with good cardiovascular outcomes.