U-500 Insulin Research Articles

100 years of insulin-enormous gratitude for my extra 65 years!

My name is Peter Davies, and with this year being the one hundredth anniversary of insulin, it is a tremendous honour to be invited to write this account of my life with Diabetes.

141-LB: MOVE! Enhanced: A Virtual Diabetes and Weight Management Pilot

Obese Veterans with diabetes and other comorbidities are at increased risk for complications and mortality. In this pilot, we examined the effectiveness of a multidisciplinary virtual intervention aimed to achieve weight loss and improve glycemic control in 10 high-risk obese Veterans with diabetes. Inclusion criteria were: age 18-75, BMI ≥ 30, A1c ≥ 8% or on high insulin doses (≥ 1 unit/kg or any dose of U-500 insulin), and at least one of the following: cardiovascular, kidney, nonalcoholic fatty liver, degenerative joint disease, or sleep apnea. All patients were recruited by the MOVE! Coordinator and enrolled in the Home Telehealth Program for diabetes and weight management. Participants worked with the dietitian to restrict carbohydrate intake (goal of 30-45 grams/meal) and with the occupational therapist to increase their physical activity through virtual sessions. A clinical pharmacist reviewed medications and made therapeutic recommendations in collaboration with the diabetes physician. Weekly huddles were held where information including glucose trends were discussed for each patient. With a mean duration of 5.5 months, participants have shown on average significant weight loss (-21.5 lbs or - 8.3%), improvement in glycemic control (-1.1% A1c), and decreased total daily insulin doses (-52.6%). At the end of the 12 months pilot duration, changes in other cardiometabolic markers, impact on quality of life, and cost will be assessed.View largeDownload slideView largeDownload slide DisclosureC. E. Mendez: None. J. M. Hansen: None. A. Feest: None. J. Taxman: None. K. Bertram: None. A. V. Hanley: None.

High Insulin Resistance in Pancreatic Adenocarcinoma

Abstract Introduction: Diabetes mellitus and obesity is associated with increased risk of pancreatic cancer which has been postulated to be due to pancreatic beta cell dysfunction and increased insulin resistance. Pancreatic cancer also exerts its effect on pancreatic beta cells, reducing insulin secretion, affecting glucose uptake and increasing insulin resistance. We present a case of pancreatic adenocarcinoma with severe insulin resistance and uncontrolled diabetes which reversed after tumor removal. Clinical Description: 79 year old male patient with no prior diagnosis of diabetes, history of hypertension, atrial fibrillation, cerebrovascular accident got admitted to the hospital with painless jaundice, dark colored urine and pruritus for a month. He also endorsed polyuria, polydipsia and weight loss for 2 months. He underwent Magnetic Resonance Cholangiopancreatography and was diagnosed with a 2.8 cm pancreatic head mass, consistent with adenocarcinoma along with intraductal papillary mucinous neoplasm. He was diagnosed with new onset of diabetes, A1c 12.6% during that hospitalization. He weighed about 75 kg and height 170cm (BMI 26.6). Labs showed normal renal function, deranged liver enzymes with direct hyperbilirubinemia, elevated transaminases and alkaline phosphatase. C-peptide level was 1.2 ng/ml for a blood glucose of 197 mg/dl. He was discharged on once daily insulin Glargine 25 units and mealtime insulin Lispro 10 units three times a day (TID) requiring 0.7 units/kg. During follow-up, his insulin requirement started to increase despite proper insulin injection technique and medication compliance. He required glargine 150 units/day and U500 insulin 50 units TID requiring about 4 units/kg. He underwent Whipple’s procedure, partial pancreas resection after a month of his diagnosis. Patient was started on clear liquid diet and his blood glucose started to get better on post-op day 1 with just correctional insulin. He was discharged on Repaglinide 0.5mg TID with each meal and all his insulin was discontinued. His blood glucose was in range of 80 to 160 mg/dl with Repaglinide during clinical follow-up with regular diabetic diet. His severe insulin resistance got reversed after the resection of pancreatic neoplasm. Conclusion: The pathogenesis of pancreatic cancer associated diabetes has not been studied well. Basic science research found that adrenomedullin, an amionopeptide, is up-regulated in patients with pancreatic cancer and causes insulin resistance in β Cells. Cancer theories also found about metabolic reprogramming and metabolic cross talk happens between pancreatic cancer and peripheral tissue, inhibiting cellular glucose intake and inducing insulin resistance. More research is required to understand these paraneoplastic phenomenon caused by diabetogenic tumor-secreted product in pancreatic cancer associated diabetes.

Clinical Impact of Initiation of U-500 Insulin vs Continuation of U-100 Insulin in Subjects With Diabetes.

The prevalence of obesity and diabetes mellitus (DM) has each increased drastically according to the Centers for Disease Control and Prevention. Growth of severe insulinresistant DM is predicted. U-500 insulin is highly concentrated and can replace less concentrated formulations in patients that need high insulin dosages. The aim of this study was to compare clinical outcomes of U-500 and U-100 insulin regimens in veterans with obesity and insulin resistance. A single-site retrospective chart analysis of adult subjects was conducted from July 2002 to June 2011. Data for repeated measures spanned a period from 3 months before the intervention (baseline) through 12 months afterward. The main outcome was the variation in hemoglobin A1c (HbA1c). Other outcomes included incidence of severe hypoglycemia, weight changes, cardiovascular events, and number of injections. A total of 142 subjects (68 taking U-500 and 74 taking U-100) were included. Baseline characteristics were similar between the groups, except for weight, which was higher among U-500 subjects. Mean HbA1c was reduced by 0.84% and 0.56% in U-500 and U-100, respectively (P = .003). Severe hypoglycemia occurred in 5 subjects in the U-500 group and 1 in the U-100 group (P = .08). No significant difference was noted in the number of cardiovascular events. The mean number of daily injections was 2 in the U-500 group, and 4 in the U-100 group (P < .001). U-500 insulin, when compared with U-100 insulin regimens, led to a statistically significant reduction in HbA1c and number of insulin injections. Additional research is necessary to assess the risk of severe hypoglycemia in U-500 users. Neither regimen was associated with increased cardiovascular risk.

Numerical Simulation of Insulin Depot Formation in Subcutaneous Tissue Modeled as a Homogeneous Anisotropic Porous Media.

In this study, a numerical model of insulin depot formation in the subcutaneous adipose tissue of humans has been developed using the commercial computational fluid dynamics software. A better understanding of the underlying mechanisms can be helpful in the development of novel insulin administration devices and cannula geometries. Developing a model of insulin depot formation can provide faster results compared to extensive experimental studies which are typically done on porcine tissues. The injection method considered in this simulation involves an insulin pump that uses a rapid acting U100 insulin analogue. The depot formation has been studied by simulating Bolus injections ranging from 5 to 15 units of insulin, which corresponds to volumes of 50-150 μL. The insulin is injected into modeled subcutaneous tissues typically present in human abdominal regions. The subcutaneous tissue has been modeled as a fluid-saturated porous media. An anisotropic approach has been used to define the tissue permeability. The value of the porosity in parallel and perpendicular directions has been varied to modify the viscous resistance to the flow in these directions. The developed model has been validated by comparing with published experimental results, which show qualitative similarities in disk-shaped insulin depot formation. The validated model is then used to study formation of insulin depot inside the subcutaneous tissue at varying insulin flow rates involving different cannula geometries and arrays. The numerical model has been found to be an effective option to evaluate new cannula designs prior to the manufacturing and testing of prototypes, which can be rather time consuming and expensive.

Effect of basal insulin therapy with glargine U300 versus basal bolus insulin therapy in hospitalized patients with type 2 diabetes. Real-world study from India

Background. Basal-bolus insulin therapy is the most widely accepted method of glycemic control in non-critically ill patients with T2DM. In this regimen glargine U100 is the most commonly used basal insulin. American Diabetes Association recommends either basal or basal bolus therapy for patients with type 2 diabetes mellitus admitted in general medical and surgical ward with ideal glycemic target ranging between 140–180 mg/dL by estimating four or 6 hourly capillary blood glucose per day. Insulin glargine U300 is a second generation long acting insulin analogue, which has a prolonged pharmacokinetic /pharmacodynamic profile compared to insulin glargine U100 resulting in glucose lowering activity exceeding 24 hours. Aim. To assess the efficacy and safety of basal insulin regimen (glargine U300) compared to a basal-bolus insulin regimen in patients with type 2 diabetes. Methods. A prospective single centred parallel group study comparing the efficacy and safety of basal insulin regimen with basal-bolus insulin regimen. A total of 60 patients with type 2 diabetes mellitus admitted in general medical and surgical ward for elective surgery and medical emergency were randomized to either of the two regimens. The baseline glycaemic parameters were assessed by capillary blood glucose testing thrice before meal and at bedtime with a target capillary blood glucose (CBG) between 140–180 mg/dL. All pa-tients were followed up for seven days. Results. The number of CBG readings within the target range were higher in basal insulin monotherapy (glargine U300) compared to basal-bolus regimen using (glargine U100 and regular human insulin) which was statistically significant. The incidence of hypoglycaemia was lower in the basal insulin regimen. Fewer units of insulin were required in the basal insulin regimen with lower glycaemic variability as compared to basal-bolus regimen. Conclusion. Glargine U 300 monotherapy as a basal insulin is non-inferior to basal- bolus therapy in non-critically ill hospitalised patients in glycaemic control, with fewer incidences of hypoglycaemia, less amount of insulin requirement to achieve target capillary blood glucose level and lower glycaemic variability.

661 U500 insulin for the management of severe insulin resistance in pregnancy

Pregnancy exacerbates insulin resistance in diabetic women. In pregnant women with severe insulin resistance (SIR), administration of large amounts of insulin is often difficult and impractical. U500 insulin is five times more concentrated than regular insulin (U100) thus, it can be a valuable tool in the treatment of women with SIR. The objective of our study was to evaluate glycemic control and hypoglycemia in pregnant women treated with U500 insulin. A retrospective cohort study of pregnant women with SIR with a need for greater than 200 units of U100 insulin per day in a tertiary care center between the years of 2016 to 2020. Outcomes of interest were: 1) glycemic control, assessing mean fasting and postprandial blood sugars 2) hypoglycemia, defined as blood sugars less than 60. Outcomes were analyzed in two groups: 1) glycemic control and hypoglycemia prior to and following initiation of U500 2) glycemic control and hypoglycemia prior to admission for delivery in women on U100 compared to women on U500 insulin. Glucose values were collected by patients using a wireless blood glucometer which sends glucose values directly to the healthcare team. Twenty-nine women with SIR were treated with U500, 28 were treated with U100. Following initiation of U500, improvements in mean fasting sugars were noted (97.15 vs 123.72, p<.001). Compared to patients who received solely U100, women who received U500 had improvements in fasting (97.15 vs 112.98, p=0.07) and post-breakfast blood sugars (127.70 vs 140.50, p=0.04). There was no significant difference in maternal hypoglycemia in pre vs post U500 (12 vs 17, p=0.286) and in U100 vs U500 insulin (13 vs 17, p=0.399). The initiation of U500 as compared to U100 insulin improves glycemic control in fasting and post-breakfast blood sugars. Although women using U500 should be monitored closely for hypoglycemia, there was not an increased prevalence of hypoglycemia in patients on U500 as compared to U100 insulin. Due to improved glycemic control with U500, clinicians should consider offering this to their pregnant patients with SIR.View Large Image Figure ViewerDownload Hi-res image Download (PPT)

The Effect of Prestudy Insulin Therapy on Safety and Efficacy of Human Regular U-500 Insulin by Pump or Injection: A Posthoc Analysis

ObjectiveWe conducted a posthoc analysis of the VIVID study (Safety and Efficacy of Human Regular U-500 Insulin Administered by Continuous Subcutaneous Insulin Infusion Versus Multiple Daily Injections in Subjects With Type 2 Diabetes Mellitus: A Randomized, Open-Label, Parallel Clinical Trial), comparing 2 delivery methods of human regular U-500 insulin (U-500R), continuous subcutaneous insulin infusion (CSII) versus multiple daily injection (MDI), in type 2 diabetes requiring high insulin, to determine influence of prestudy insulin on glycemic outcomes. MethodsWe compared A1C, total daily insulin dose (TDD), weight, and hypoglycemia by subgroups of prestudy insulin (prestudy U-500R vs non-U-500R) and treatment (CSII vs MDI). ResultsAt baseline, prestudy U-500R had higher TDD, higher body mass index, lower A1C and fasting plasma glucose, and higher rate of hypoglycemia compared to non-U-500R. Active titration of U-500R reduced A1C in both subgroups, with maximum benefit at 8 weeks. At 26 weeks, CSII provided the greatest reduction in A1C in both subgroups, with a greater reduction in non-U-500R. MDI provided an A1C reduction in both subgroups, with the greater reduction in non-U-500R. At 8 weeks, prestudy U-500R reached its lowest A1C; thereafter, A1C rebounded with MDI and remained stable with CSII. In non-U-500R, A1C continued to decrease to study end. In non-U-500R, hypoglycemia increased during active titration, but then decreased in the posttitration maintenance period. In both subgroups, TDD increased from baseline with MDI but not with CSII. Body weight increased in both subgroups but was greater in prestudy U-500R with CSII compared to MDI. ConclusionRegardless of previous insulin, people on high-dose insulin could lower A1C with U-500R, with additional benefit from CSII. These results may provide guidance for use of U-500R in clinical practice.

Pharmacokinetics and Pharmacodynamics of Human Regular U-500 Insulin Administered via Continuous Subcutaneous Insulin Infusion Versus Subcutaneous Injection in Adults With Type 2 Diabetes and High-Dose Insulin Requirements.

Human regular U-500 insulin (U-500R) is approved for subcutaneous (SC) injection in patients with diabetes requiring >200 units/day of insulin. Here, pharmacokinetic and pharmacodynamic (PK/PD) profiles following U-500R administered by continuous subcutaneous insulin infusion (CSII) and SC injection in adults with type 2 diabetes (T2D) on high-dose insulin were studied. In this randomized, crossover, euglycemic clamp study, patients received a 100-unit bolus of U-500R via SC injection or CSII with basal infusion using a U-500R specific pump. PK parameters were estimated using non-compartmental methods. PD estimates were derived from the glucose infusion rate during the euglycemic clamp procedure. When corrected for the basal infusion, the PK profiles for the 100-unit bolus of U-500R were similar for CSII and SC injection. Without correction for basal infusion, PK and PD profiles showed a greater insulin concentration and effect when U-500R was administered via CSII compared to SC injection, primarily due to basal insulin infusion for CSII. The ratio of geometric least squares AUC0-tlast means SC:CSII (90% CI) is 0.857 (0.729, 1.01) with correction (mean AUC0-tlast: 5230 pmol*L/h [SC injection] and 6070 pmol*L/h [CSII, with correction]) and 0.424 (0.361, 0.499) without correction (mean AUC0-tlast: 12300 pmol*L/h [CSII, without correction]). Median time-to-peak insulin concentration was six hours (range 0.5-8 hours) via SC injection and five hours (0.5-12 hours) via CSII. In adults with T2D on high-dose insulin, U-500R PK/PD parameters were similar for a 100-unit bolus when given by SC injection or CSII via a U-500R pump.

Treatment Patterns and Characteristics of Individuals Initiating High-Dose Insulin for Type 2 Diabetes Mellitus.

Few studies have examined patient characteristics and treatment patterns of high-dose insulin therapy (> 200 units/day) among patients with type 2 diabetes mellitus (T2DM). To understand patient characteristics, dosing, adherence, and persistence related to high-dose insulin therapy. This was a retrospective observational study that used administrative claims from a large national health plan. Patients were identified who had been diagnosed with T2DM and who were aged 18-89 years, enrolled in a commercial or Medicare Advantage Prescription Drug plan, newly initiated on a total daily dose (TDD) > 200 units of insulin between January 2011 and August 2015. Patients were required to be enrolled 6 months before and 12 months after the index date. Patients were categorized to Regimen-100 if treated with U-100 insulin only or Regimen-500 if treated with U-500R with or without U-100. Baseline demographic and clinical characteristics were evaluated. An adjustment factor for the days supply was calculated as the ratio of median time between insulin claims, and median pharmacy reported days supply for each insulin prescription. Adjusted days supply, quantity, and concentration were used to calculate TDD for each quarter after the index date. Adherence was measured as the proportion of days covered (PDC) for each regimen. Persistence was measured in 2 ways: the percentage of patients remaining on index medications in each quarter and the proportion of patients who maintained TDD > 200 units during all 4 quarters of the 12-month post-index period. We identified 2,339 patients newly titrated up to TDD > 200 units on either Regimen-100 (2,062, 88.2%) or Regimen-500 (277, 11.8%). Patients on Regimen-500 were slightly younger with higher prevalence of comorbidities. The mean TDD (SD) for Regimen-100 decreased from 228.6 (36.0) units during the first quarter to 194.2 (181.4) units during the last quarter. The mean TDD (SD) for Regimen-500 increased from 294.2 (102.2) units in the first quarter to 304.8 (281.6) units in last quarter. The average adherence to the high-dose insulin regimen was 68.2% (30.7; median 72.6%) for the Regimen-100 cohort and 75.5% (27.0; median 85.2%) for the Regimen-500 cohort. In the Regimen-100 and Regimen-500 cohorts, 45.3% and 55.2% had a PDC ≥ 80%, respectively. Only 23.0% and 51.6% of patients maintained TDD > 200 units for the Regimen-100 and Regimen-500 cohorts, respectively, throughout the 4 quarters after the index date. We observed that many patients did not maintain high-dose insulin use over time, especially those on standard U-100 insulin only. This dosing pattern appears to reflect the differences in patient characteristics, insulin needs, and adherence/persistence behavior between those on Regimen-100 and those on Regimen-500. This study was supported by funding from Eli Lilly and Company to Humana as a collaborative research project involving employees of both companies. Chen, Brown, Fan, Taylor, and He are employees of Eli Lilly and Company. Nair and Meah are employees of Humana, which received funding to complete this research. Siadaty was an employee of Humana at the time of this study.

1235-P: Identifying Trends in the Management of Inpatient Diabetes at a University Teaching Hospital, 2008-2018

Introduction: A substantial proportion of inpatients experience hyperglycemia during hospitalization. Use of basal insulin has been recommended by ADA guidelines since 2007, however the uptake of this recommendation has been slow. Here, we characterize the adoption of basal insulin in inpatients at one adult academic hospital. Methods: De-identified data from the hospital’s electronic health record repository was used to identify a cohort of patients who received subcutaneous insulin during their hospitalization between 03/26/2008 and 12/30/2018. To capture patients for whom a generalist could be expected to manage their hyperglycemia, we excluded patients receiving insulin via pump, U-500 insulin, single doses &amp;gt;100U, or insulins ordered &amp;lt; 10 times, as well as those with a creatinine &amp;gt; 2mg/dL at any time during admission. Results: In the cohort of 61,947 inpatient encounters in which insulin was given, no basal insulin was ordered in 61%, decreasing from a 78% in 2008 to 53% in 2018. The annual number of encounters in which insulin was given increased &amp;gt;20% over the decade. The proportions of blood glucoses (BGs) &amp;gt; 200 mg/dL (28% vs. 14%) or &amp;lt;70 mg/dL (1.2% vs. 0.6%) were higher for patients ordered for basal insulin. Although hypoglycemia decreased over time (1.2% to 0.9% of BGs), hyperglycemia increased (16% to 26% of BGs). Conclusions: Despite improvements since basal insulin became a guidelines recommendation, the rate of inpatient basal insulin orders remained &amp;lt; 50% as of 2018 at one academic center. The number of patients receiving insulin and the proportion of hyperglycemia has increased, whereas the incidence of hypoglycemia in this population decreased over time. Disclosure I. Jankovic: None. J. Chen: None. Funding Diabetes, Endocrinology, and Metabolism Training Grant (5T32DK007217-44)

1031-P: Comparison of Two Approaches to Basal Insulin Management for Adults with Type 1 Diabetes Flying across Multiple Time Zones

For people with type 1 diabetes (T1D) using multiple daily insulin injections (MDI), we previously reported that maintaining optimal glucose control whilst travelling across multiple time zones is challenging. The aim of this pilot study was to compare flexibly-dosed U100 insulin degludec (DEG) with a structured pre-flight dose algorithm for U100 insulin glargine (GLA) in adults with T1D flying &amp;gt;6 hours. Beginning in Honolulu (HI, UTC -10), subjects flew eastward non-stop for 9.5 hours to New York (NY, UTC -5). After 72 hours in NY, subjects returned to HI (11 hour flight) staying up to 72 hours. After 2 weeks, they switched to the other insulin and repeated the travel. The primary endpoint was inflight Time in Range (TIR, 70-140 mg/dl) using blinded continuous glucose monitoring (CGM-Abbott Freestyle Libre Pro) during eastward and westward travel. Secondary end-points included time above and below range and glycemic variability (coefficient of variation [CV]). Between insulin comparisons were made using Pearson N1 chi-square tests for proportions, mean glucose via two-tailed independent t-tests and glycemic variability via two-sample F-tests. Twenty subjects, (60% female, age 34.9 ± 15.2 [mean ±SD] years, HbA1c 7.5 ± 1.2%) completed the study. Insulin doses during travel were similar (23.0 ± 11.4 for GLA and 21.8 ± 12.0 units for DEG). Overall, mean glucose on GLA was 148.0 ± 73.8 mg/dL (CV 50%) versus 158.5 ± 76.7 mg/dL (CV 48%) on DEG, p=0.01. While aggregate TIR was greater on GLA (44% versus 38% with DEG), there was less hypoglycemia &amp;lt;70 mg/dL on DEG (p&amp;lt;0.01). Significantly less time was also spent below &amp;lt;60 (p&amp;lt;0.01) and &amp;gt;250 mg/dL (p&amp;lt;0.01) during eastward travel and &amp;lt;70 (p&amp;lt;0.01) during westward travel on DEG. Inflight CV on DEG was also less during both eastward (43% vs. 49%, p&amp;lt;0.01) and westward (38% vs. 51%, p&amp;lt;0.0001) travel. In conclusion, for adults with T1D undertaking long-haul travel, DEG use was associated with less disruption to glucose control compared to GLA. Disclosure C. Axelrod: None. K.N. Castorino: Research Support; Self; Abbott, Dexcom, Inc., Medtronic, Mylan, Novo Nordisk Inc. W.C. Bevier: None. G. Haroush: None. C.C. Farfan: None. M.R. Mefford: None. K. Nelson: None. L.A. Spink: None. D. Kerr: Advisory Panel; Self; Novo Nordisk A/S, Sanofi-Aventis. Research Support; Self; Eli Lilly and Company. Stock/Shareholder; Self; Glooko, Inc. Funding Novo Nordisk

2195-PUB: Use of U500 Insulin in External Pump for Insulin-Resistant Diabetic Patients: A French Experience

Use of large insulin doses is more frequent in diabetes due to an increase in the prevalence of severe obesity worlwide. Insulin-associated treatments such as metformin or GLP-1 receptor agonists (GLP-1RA) can help and use of insulin concentrated at 500 IU/ml (U500) has been associated with an improve in glycemic control in previous studies including severe insulin resistant patients. We report our experience of U500 in subjects with high HbA1c despite insulin pump therapy (CSII) combined or not with metformin and/or GLP-1RA. Eighteen T2D and 3 T1D were studied (13M and 8F), age: 59.5 ± 9.6 years, diabetes duration : 18.8 ± 9.8 years. Eight subjects used metformin and 7 used GLP-1RA (5 used metformin and GLP-1RA). Treatment with U500 was carried out during a 5-day hospitalization. Metformin and/or GLP-1RA were continued or not during the follow-up according to the decision of the patient’s diabetologist. Mean duration of follow-up was 9 months. A decrease in HbA1c was found (initial vs. final) : 9.4 ± 1.2% vs. 8.5 ± 1.3% (p =0.05). No change was found for weight : 123.9 ± 26.4 kg vs. 121.0 ± 30.3 kg (NS), BMI : 41.5 ± 7.2 kg/m2 vs. 40.2 ± 7.3kg/m2 (NS), daily total insulin needs (U100 equivalent) : 198.4 ± 70.5 IU vs. 228 ± 121 IU (NS), basal needs : 81.8 ± 29.2 IU vs. 87 ± 36 IU (NS) and prandial needs : 116.5 ± 61.3 IU vs. 143 ± 110 IU (NS). No changes were found for lipidic parameters as total cholesterol (TC) : 1.85 ± 1.10 g/l vs. 1.80 ± 0.92 g/l (NS), HDL-C : 0.36 ± 0.08 g/l vs. 0.31 ± 0.06 g/l (NS), LDL-C : 0.83 ± 0.32 g/l vs. 0.71 ± 0.30 g/l (NS) and TG : 3.98 ± 7.56 g/l vs. 3.4 ± 5.3 g/l (NS). No change in use of metformine and/or GLP-1RA and no side effect were found during the follow-up. Conclusion: In our practice, use of U500 in insulin-resistant patients treated with CSII is well tolerated and is associated with a decrease in HbA1c despite no change in weight or daily insulin needs. Evolution of glycemic variability (including TIR and hypoglycemias) using continuous glucose monitoring is currently being analyzed. Disclosure Y. Oualit: None. D. Pâris: Board Member; Self; Novo Nordisk Inc. Consultant; Self; Eli Lilly and Company, Sanofi-Aventis. L. Kessler: Consultant; Self; Lilly Diabetes, Medtronic, Novartis Pharma K.K., Novo Nordisk A/S, Vertex Pharmaceuticals. T. Bahougne: None. N. Jeandidier: Consultant; Self; Sanofi-Aventis. Research Support; Self; Lilly Diabetes. L. Meyer: Board Member; Self; Abbott, Lilly Diabetes, Novo Nordisk A/S.

1039-P: Treatment Patterns and Outcomes before and after Human Regular U-500 Insulin Initiation in Patients with Type 2 Diabetes Previously on &amp;lt;200 Units/Day of Insulin

Introduction: U-500 regular insulin (U-500R) was developed to help severely insulin-resistant patients meet high insulin requirements (&amp;gt;200 units/day). Here, we described in real-world setting a patient cohort using ≤200 units/day of standard concentration insulin or non-U500R concentrated insulin per pharmacy claims, who were then transitioned to U-500R with an average total daily dose (TDD) of &amp;gt;200 units/day. Methods: Adults with ≥2 T2D claims who initiated U-500R (index) and had ≥1 HbA1c value in both 9-month pre- and 9-month post-index periods in the Veterans Health Administration database (01JAN2014-30JUN2017) were included. Treatment patterns and outcomes (observed TDDs for index claim, observed TDD, HbA1c, and hypoglycemia events per patient per year (PPPY) in pre and post-index periods) were assessed in both periods. Paired t-test or McNemar’s test was used for descriptives. Mixed linear model (MLM) and zero-inflated negative-binomial mixed model (ZINBM) were used to confirm the effect of U-500R exposure on HbA1c and hypoglycemia, respectively, adjusting for demographics, BMI, comorbidity index and TDD. Results: Of 1,191 U-500R initiators, mean age was 63 years with 82% white, 96% male, and a mean BMI of 40. TDD for index U-500R claim was 354 units. Mean TDDs (147 units vs. 346 units), HbA1c (9.6% vs. 8.6%), and hypoglycemia (2.0 vs. 3.3) differ significantly pre- and post-index (p≤0.05), respectively. MLM confirmed HbA1c significantly dropped by 0.8% (p&amp;lt;0.01). ZINBM showed a 0.5 PPPY increase in hypoglycemia post-index (p&amp;lt;0.01). Conclusions: Using insulin claims data, U-500R initiation resulted in a significant TDD increase of 199 units, which was accompanied by a significant drop in HbA1c and a slight increase in hypoglycemia. The low TDD and poor glucose control prior to U-500R initiation indicated poor patient compliance to the prescribers’ dosing intentions. Disclosure R.C. Hood: Advisory Panel; Self; Eli Lilly and Company, Insulet Corporation. Speaker’s Bureau; Self; Boehringer Ingelheim Pharmaceuticals, Inc., Eli Lilly and Company, Janssen Pharmaceuticals, Inc., Novo Nordisk Inc. L. Fan: Employee; Self; Eli Lilly and Company. Stock/Shareholder; Self; Eli Lilly and Company. R.D. Pollom: Employee; Self; Eli Lilly and Company. Employee; Spouse/Partner; Eli Lilly and Company. Stock/Shareholder; Self; Eli Lilly and Company. Stock/Shareholder; Spouse/Partner; Eli Lilly and Company. S. Borra: Employee; Self; STATinMED. Other Relationship; Self; Eli Lilly and Company. A. Huang: Employee; Self; STATinMED. Other Relationship; Self; Eli Lilly and Company. J. Chen: None.

Case Series of U-500 Insulin Use in Adults With Type 2 Diabetes and Severe Insulin Resistance

ObjectivesSevere insulin resistance results in large volumes of insulin to achieve glycemic control. These large volumes can result in patient discomfort and decreased satisfaction. Using the more concentrated U-500 insulin provides a solution to this problem. This case series demonstrates real-world use of U-500 insulin in a Canadian population. MethodsSeventeen patients were identified to have been started on U-500 insulin at an endocrinology clinic in Vancouver, British Columbia, Canada. The retrospective chart review looked at patients’ characteristics before starting U-500 insulin and at their 1-year follow-up appointment. ResultsAt follow up, patients demonstrated improved glycated hemoglobin with a mean improvement of 1.6% at 1 year (p<0.05). There was a statistically significant increase in hypoglycemia (p<0.05), and, on average, patients gained 5.6 kg over the course of the year (p<0.05). There was no statistically significant change in number of units of insulin, injections, lipids, renal function or blood pressure. ConclusionsThe initiation of U-500 insulin results in improved glycemic control at the cost of increased hypoglycemia and weight gain.

MON-685 Lipodystrophy, a Forgotten Syndrome

Background: Lipodystrophy comprises a group of heterogenous congenital and acquired disorders. These disorders may present as a complete or partial loss of adipose tissue. The magnitude of lipoatrophy correlates with the severity of the associated metabolic disturbances, which include severe insulin resistance, progressive liver disease, severe dyslipidemia, among others. The most prevalent form of lipodystrophy is related to antiviral use in patients with HIV. However, lipodystrophy occurring unrelated to medication side effect is often missed due to the heterogeneity and rarity of this disorder. Clinical Case: 31 year old female with medical history of type 2 diabetes mellitus, hypertension, mixed dyslipidemia and polycystic ovarian syndrome who was referred to our clinics due to difficult to control hyperglycemia. Family history was limited. She was diagnosed with diabetes mellitus at 12 years old after presenting with polyuria, polydipsia and polyphagia requiring oral antidiabetic therapy. Following poor response, she was started on insulin therapy. At 23 years old, the patient had an episode of pancreatitis associated with hypertriglyceridemia and eruptive xanthomas. Insulin pump therapy with regular U-100 insulin, total daily dose of 308 units, was initiated but failed to improve glycemic control. The patient was referred to our Endocrinology clinics due to high insulin resistance and a glycosylated hemoglobin (A1C) at 12% (n < 6.5%). Physical examination revealed a body mass index of 23 kg/m2, abnormal fat distribution predominantly over the neck and face, and acanthosis nigricans. Abdominal ultrasound revealed fatty liver infiltration consistent with intrabdominal fat deposition. Due to the constellation of the aforementioned findings, the diagnosis of partial lipodystrophy syndrome was presumed. She was started on antidiabetic therapy with metformin, pioglitazone and insulin pump therapy with U-500 insulin, and high-dose statin therapy plus fenofibrate for dyslipidemia. At follow up, the patient showed improvement in glycemic control and an improved lipid profile. She was referred to a geneticist for evaluation. Conclusion: Lipodystrophy syndromes are a group of heterogenous disorders, which may often be overlooked due to their rarity and lack of familiarity by physicians. The diagnosis of lipodystrophy is based on history, abnormal body fat distribution, and metabolic profile. The metabolic disturbances seen in these patients are mainly due to the lack of adipose tissue, which results in impaired energy storage. Early recognition of these syndromes is important because intensive treatment of hyperlipidemia and diabetes prevents development of severe complications. In this case we highlight this rare condition and the successful use of new therapeutic technology with insulin pumps and U-500 insulin in the glycemic control of a patient with lipodystrophy.

SAT-631 Increased Incidence of Diabetic Nephropathy in Veterans with Severe Insulin Resistance

Recently, cluster analysis has been used to classify adult onset diabetes based on pathophysiologic profile. Using autoimmunity status, BMI, insulin resistance, and beta cell function, this classification system can predict diabetes associated complications. Individuals with primarily insulin resistant phenotype have been associated with increased incidence of nephropathy while those with insulin deficient phenotype are associated with retinopathy. Clinically, patients with severe insulin resistance can be defined as those who require high doses of insulin to achieve glycemic control, such as patients on U-500 insulin requiring more than 200 units of insulin a day. To characterize the clinical and metabolic phenotype of insulin-resistant patients from a South Texas VA diabetes clinic, we evaluated presence of macro or microvascular complications and beta-cell autoimmunity and function in this population. A retrospective cohort study was completed at the South Texas VA Diabetes Clinic. Charts were reviewed for anthropometric measurements, presence of macro and microvascular complications, anti-diabetic medication, lipid profile and HbA1c over 3 visits, autoimmunity (anti-GADab), and beta-cell function (fasting C-peptide). Patients with insulin doses >200 U/day or on U-500 insulin were categorized as “severe insulin-resistant”. Those with insulin doses < 0.5 U/kg/day were categorized as “mild insulin resistance” as a control group. Out of 120 patients, 30 met criteria for severe insulin resistance (n=30, M/F=29/1 age 61±1.6 years (yr), BMI 41±0.9 kg/m2, duration of diabetes 18.3±0.3 yr, HbA1c -8.4±0.2%, total daily insulin dose (TDD) 301±31U). 30 patients with insulin use <0.5 U/kg/day met criteria for mild insulin resistance (N=30, M/F: 28/2, age 62±2 yr, BMI 30±1 kg/m2, duration of diabetes 12±1.2 yr, HbA1c 7.2±0.2%, TDD 17±2U). Prevalence of nephropathy was higher in the insulin resistant group vs the mild insulin resistant group (76% vs 43%, p<0.05). There was no difference in prevalence of retinopathy (p=0.095) or CAD (p=0.6) between the groups. There was no difference in use of ACE-i or SGLT-2i between the groups. Insulin resistant subjects had a higher plasma triglyceride (325±0.3 vs 202±0.3 mg/dl, p=0.04). Prevalence of GAD ab was not different between the groups (3% vs 0%). Fasting C-peptide concentrations were similar in both groups (5.6±0.3 vs 5.2±0.25 ng/ml, p=0.3). HbA1c in the insulin resistant group improved between visits 1 and 3 (p<0.01). Weight increased over three visits in the severe insulin resistant group as opposed to mild weight loss in the mild insulin resistant group.Our results support the high prevalence of diabetic nephropathy in patients with severe insulin resistance, although it is unclear that insulin resistance is the etiology. Long-term follow up of these patients may provide insight into the underlying mechanisms of these complications.

SUN-685 Approach to a Potential Liver Transplant Candidate with Insulin Antibody-Mediated Severe Insulin Resistance

Introduction: Insulin antibody (IA)-mediated insulin resistance is a rare autoimmune condition resulting in uncontrolled hyperglycemia. High titers of IA are associated with increased mortality secondary to severe insulin resistance and labile blood sugars. There is a paucity of standardized treatment for these patients. Although there have been reported cases of success with immunosuppressants, none of these cases involved patients with liver cirrhosis. We present a case of IA-mediated severe insulin resistance which resulted in uncontrolled hyperglycemia and ultimately delayed liver transplantation. Clinical Case: A 61-year-old male with IA-positive type 2 diabetes, decompensated hepatitis B and NASH cirrhosis presented with several episodes of diabetic ketoacidosis (DKA) and worsening insulin resistance. His liver transplant listing had been placed on hold until glycemic control is achieved. The patient was diagnosed with type 2 diabetes mellitus in 1998. He has no prior autoimmune history. His disease was controlled on Levemir 100 units daily until March 2019 when he presented with his first episode of DKA. He subsequently required 200 units of insulin degludec daily and U-500 insulin 200 units with meals. The patient was readmitted to our hospital in August 2019 for a variceal bleed. His hospital course was complicated by a second occurrence of DKA requiring 100-150 units/hour on an insulin drip for resolution. Labs were significant for HbA1c 8.7% and IA >625 uU/mL (negative if <5.0 uU/mL). He required increasing amounts of basal and prandial insulin after discharge. The patient was again admitted within two months for abdominal pain concerning for spontaneous bacterial peritonitis, which was complicated by his third episode of DKA. Glucoses remained uncontrolled in the range of 170 to 300 mg/dL despite high insulin doses upon discharge. Metformin was contraindicated due to episode of lactic acidosis in the setting of his cirrhosis and concern for repeated episodes of DKA prevented use of SGLT-2 inhibitors. Extensive multidisciplinary discussions led to the decision for an upcoming trial of mycophenolate mofetil followed by plasmapheresis. The goal is to improve glycemic control while also minimizing infection risk to ultimately list him for a liver transplant. Conclusion: This patient highlights a major therapeutic challenge related to uncontrolled hyperglycemia and insulin resistance from anti-insulin antibodies in a cirrhotic patient. This can place patients at high risk for infection, poor wound healing and most importantly prohibit liver transplantation. Immunosuppressant therapy and plasmapheresis may drastically lower insulin antibodies and improve glycemic control, however, it will increase the risk of infection.

Treatment Patterns, Adherence, and Persistence Associated With Human Regular U-500 Insulin: A Real-World Evidence Study.

OBJECTIVE | Human regular U-500 insulin (U-500R) is concentrated insulin with basal and prandial activity that can be used as insulin monotherapy. The goal of this study was to better understand treatment patterns (total daily dose [TDD] and concomitant medications), adherence, and persistence in real-world patients treated with U-500R. DESIGN AND METHODS | We selected patients from the Truven Health MarketScan database who initiated U-500R between 2010 and 2013. We collected data for three periods: pre-index (12 months before initiation), post-index (12 months after initiation or until a gap of ≥60 days in U-500R claims), and follow-up (12 months after post-index). Data were analyzed using descriptive statistics and a regression model as appropriate. RESULTS | We identified 1,582 patients who met the selection criteria. The median TDD of U-500R during the post-index period was 333 units/day, with 70.0% of patients using 300-400 units/day. During the post-index period, 74.1% of patients had U-500R claims that did not overlap with prescriptions for other insulins, interpreted as U-500R monotherapy. Among patients with ≥1 U-500R fill in the post-index period (n = 1,208), 54.4% had a medication possession ratio (MPR, a measure of adherence) ≥80%. Although 849 patients had a gap of ≥60 days in U-500R claims in the post-index period, 602 of those resumed U-500R in the follow-up period. Of the 733 patients who had no gap in U-500R claims in the post-index period, 286 had a gap of ≥60 days in claims in year 2, and 447 continued with U-500R treatment beyond 2 years. CONCLUSION | These results demonstrate that U-500R was commonly used as insulin monotherapy, with a median TDD >300 units/day. Compared with published, relevant studies of other insulins, U-500R showed similar or greater adherence and persistence rates. These new data may help guide clinical decision-making when choosing insulin therapy for patients requiring high doses of insulin.

Evaluation of a Conservative Pharmacist-led U-500R Insulin Management Protocol in the Primary Care Setting.

ObjectiveThe objective of this quality assurance study is to evaluate the impact of a conservative, pharmacist-led, U-500R insulin management protocol on diabetes control (A1c) and total daily dosage requirements between August 2016 and August 2018.MethodsThis was a retrospective chart review of adult patients, aged 18 to 79, with type 2 diabetes and managed with insulin, at 2 federally qualified healthcare clinics in Denver, Colorado. To determine if our conservative pharmacist-led U-500R insulin management protocol impacted efficacy and total daily dosage requirements when converting patients from U-100 to U-500R insulin, we compared the most effective dose of U-500R (defined as the total daily dose (TDD) of U-500R insulin at A1c goal or the lowest tolerated A1c) to the baseline A1c and TDD of U-100 insulin at time of conversion.ResultsFollowing conversion of U-100 to U-500R insulin, patients required an average of 21 fewer units of insulin with U-500R than U-100 and achieved an average A1c of 7.2% which reflected a reduction of 3.5 points from baseline. Five patients (62.5%) achieved A1c goal per ADA guidelines, and all patients achieved at least a 1.7 point reduction in A1c, with 1 patient achieving a 6.7 point reduction. Two patients (25%) were still in the process of U-500R titration at the time of data collection, and 1 patient (12.5%) did not achieve goal A1c while under pharmacy management at these clinics. Four of the five patients who achieved A1c goal did so with an overall reduction in total daily insulin dose (average of 57.5 units less than original U-100 dose) resulting in an average A1c decrease of 3.6 points.