U-500 Insulin Research Articles

8475 Automated Insulin Delivery System with Concentrated Regular U500 Insulin in Cushing Syndrome

Abstract Disclosure: F. Erenler: None. J. Aurora: None. Background: Concentrated regular U-500 (U-500R) insulin is commonly used in patients with T2DM, who are highly insulin-resistant, requiring more than 200 units of insulin per day. Utilizing U-500R reduces the number of daily injections, decreases injection volume, and improves cost effectiveness. There has been a case report with U-500R in an automated insulin delivery (AID) system with successful results (1). To our knowledge there is no data on AID system use in Cushing patients with T2DM using U-500R. We present a case of a patient with Cushing Syndrome (CS) with poor BG control using >250 units/day of SC U-500R with improved BG control after switching to Omnipod 5 AID system. Clinical Case: A 57 y.o. male initially presented with hypogonadotropic hypogonadism and subsequently diagnosed with ACTH-dependent CS, which is complicated by obesity, uncontrolled T2DM, lower extremity wounds, and DVTs. He was diagnosed with CS with multiple abnormal 1 mg dexamethasone suppression tests (DST) (max AM cortisol 5.9 mcg/dL; RR <1.8 mcg/dL, dexamethasone level 300), elevated urine free cortisol (UFC) (max UFC/Cr 77.6 mcg/mg/L; RR: 5-64 mcg/24-hr) and elevated salivary cortisol (max cortisol 0.2 mcg/dL; RR: <0.09 mcg/dL). He had suppressed cortisol with 8 mg DST. An MRI sella showed left-sided hypoechoic 0.9 cm mass. Desmopressin (DDAVP) stimulation test and Ga-68 DOTATATE-PET scan were negative. As a result of his abnormal MRI sella and elevated cortisol, he underwent transsphenoidal surgery of the left pituitary. Pathology was non-diagnostic for a pituitary adenoma. Post-op 24-hr UFC and 1 mg DST levels remained high. DDAVP stimulation test and Ga-68 DOTATATE-PET were repeated post-op and were negative. Due to complications of CS, he was initially treated with cabergoline, but switched to osilodrostat due to intolerances. He is currently on 2 mg BID dose and 24-hr UFC has been normal since then (UFC 20 mcg/L, Cr 0.67 mg, UFC/Cr 12 mcg/mg/L). He continued to have uncontrolled hyperglycemia despite normalization of UFC. On his CGM data, he was in target range (70-180 mg/dL) 5% of the time despite using U-500R 95 units SC TID. Given his severe hyperglycemia and insulin resistance, he was switched to an AID system with U-500R and his time in target range improved over 60% after a month of use and his total daily dose of insulin decreased to less than 200 units. Conclusion: U-500R proved to be safe and effective with Omnipod 5 AID. To our knowledge, this is the first reported patient with CS using U-500R with Omnipod 5 AID. In patients without CS, the AID algorithm continuously kept BG well below the set target, especially overnight. Notably, our patient did not have this overnight hypoglycemia trend, which should be expected with his disease. We are hoping to increase the awareness of U-500R with AID systems, especially for patients with incurable CS. Reference:1.Aurora J Jr, Saraswat A. J Endocr Soc. 2023;7(Suppl 1):bvad114.873. Presentation: 6/3/2024

956-P: Successful Use of U-500 Insulin with the Tandem X2 Pump with Control IQ (CIQ)

956-P: Successful Use of U-500 Insulin with the Tandem X2 Pump with Control IQ (CIQ)

Low Rates of Screening for Hypercortisolism Among Patients With Severe Insulin Resistance Requiring U-500 Insulin

Low Rates of Screening for Hypercortisolism Among Patients With Severe Insulin Resistance Requiring U-500 Insulin

Using insulin pump for glycemic control in patients with severe insulin resistance

BackgroundPatients with type 2 diabetes using a continuous subcutaneous insulin infusion (CSII) often require large doses of insulin and need to change their insulin administration sets frequently. A proposed solution to this problem is to use concentrated insulin in their insulin pump; however, insulin pumps are programmed to administer U-100 insulin. Therefore, these patients are at greater risk of hypoglycemia and are responsible for adjusting daily doses. Case summaryThe solution for our patient encountering this problem was to administer half of his daily basal insulin via subcutaneous injection and allow the CSII to administer the remainder through automated insulin delivery (AID). When this strategy was initiated, the patient’s A1C was > 14%. After 5 months of follow-up, the patient’s A1C was 8.3% and he reported improved quality of life. Practice implicationsThis technique allows patients with high insulin requirements to benefit from AID without the safety risks associated with using concentrated insulin.

Effectiveness and safety of Glargine U-100 and detemir insulin in hyperglycemic pregnancy: a record-based observational study

Effectiveness and safety of Glargine U-100 and detemir insulin in hyperglycemic pregnancy: a record-based observational study

SAT167 Risk Of Life Threatening Hypoglycemia When Using U-100 Insulin Syringes To Administer R U-500 Insulin

Abstract Disclosure: T. Rizwan: None. M. Alchalabi: None. G. Arora: None. U.N. Qureshi: None. F. Qureshi: None. Background: Humulin R U-500 is a concentrated human insulin indicated to improve glycemic control in adults and children with diabetes mellitus requiring more than 200 units of insulin per day. R U-500 insulin is five times more concentrated than U-100 insulin. Clinical Case: A 42-Year-old woman with medical history of depression, hidradenitis, morbid obesity, hypertension, hyperlipidemia, chronic headache, and type 2 diabetes mellitus was on R U-500 insulin, Jardiance, and Victoza. Patient presented with low blood glucose levels. Patient reported that her home insulin regimen is 20 units of R U-500 insulin with meals. Her home glucose diary showed blood glucose levels as low as 30-50 mg/dL. Recent hemoglobin A1c was 6.5%. Of note, the patient was unaware of hypoglycemic symptoms. Upon taking detailed history, and discussing insulin injection technique, it was apparent that the patient was administering insulin correctly. Upon further inquiry, the patient reported not being aware of the specialized R U-500 syringe. Patient expressed unfamiliarity after being shown images of the correct R U-500 syringe. It became apparent that the patient was using a U-100 insulin syringe to draw from R U-500 insulin vial which means she was receiving an incorrect dosage. Filling the U-100 syringe to the 20-unit mark with R U-500 insulin will deliver 100 units of R U-500 insulin which puts the patient at risk of severe hypoglycemia. During hospital stay, U-500 R insulin, Victoza, and Jardiance were stopped, the patient was started on basal and bolus insulin regimen, and blood glucose levels were monitored with meals and at bedtime. Blood glucose levels improved to 140-180 mg/dL. Upon hospital discharge, the patient was encouraged to switch to R U-500 KwikPen as this will be more accurate and safe. Conclusion: The U.S. Food and Drug Administration approved a dedicated syringe for the administration of Humulin R U-500 insulin, which is now the only device approved for use with U-500 insulin vial. Do not switch between types of syringes because it may increase the risk of dosing errors. Presentation: Saturday, June 17, 2023

THU350 Rapid Decrease Of Glycemic Levels In Three Patients With Severe Insulin Resistance Associated With Bell’s Palsy.

Abstract Disclosure: E. Chuki: None. M. Lightbourne: None. B. Abel: None. R.J. Brown: None. Bell’s palsy (BP) is associated with diabetic angiopathy and facial nerve ischemia and may be the first sign of diabetic mononeuropathy. Specific risk factors for diabetic mononeuropathy have not been well established. Rapid tightening of glycemic control has been associated with worsening diabetic retinopathy. However, this association has not been reported previously in the development of diabetic mononeuropathy or BP. We describe three patients with extreme insulin resistance, in whom rapid correction of hyperglycemia was temporally associated with development of BP. Case 1: A 63 year-old African American male with history of type 2 diabetes (T2D) and peripheral neuropathy was admitted with sudden onset severe insulin resistance and DKA, leading to a diagnosis of type B insulin resistance. Serum glucose was >600 mg/dl and A1c was 13.4%. He was treated with an insulin drip, then transitioned to subcutaneous insulin U-500 at a total daily dose of ∼3000 units, resulting in blood glucose between 140 and 180 mg/dl. On Day 5 after initiating U-500 and achieving tight control of glycemia, the patient developed bilateral Bell’s Palsy, which resolved after 4 years. Case 2: A 25 year-old African American female with history of T2D was admitted with sudden onset severe insulin resistance and DKA requiring an insulin drip of ∼3,000 units per day, leading to a diagnosis of type B insulin resistance. A1c on admission was 14%. After ∼5 days, she transitioned to U-500 that was titrated over 2 weeks to a total daily dose of 3,000 units with blood glucose between 98 and 177 mg/dL. She developed bilateral BP approximately 43 days from onset of DKA and 36 days after starting U-500 insulin with improved glycemic control. At last follow up 5 years later she still had residual facial weakness. Case 3: A 25 year-old Caucasian male with history of diabetes due to type A insulin resistance (Rabson-Mendenhall Syndrome) and recurrent ketosis on U500 insulin >1,000 units daily had poor adherence to insulin and diet with A1c of 14.3%. 3 weeks after A1c measurement he was started on a Continuous Glucose Monitor (CGM), leading to dramatic change in diet and medication adherence, with reduction in the estimated A1c based on glucose management indictor (GMI) to 7.7% within 3 weeks. 3 weeks after starting CGM use with improved compliance and glycemic control, he developed unilateral BP, which fully recovered after 1 month.We report 3 cases in which onset of BP was observed in rapid temporal correlation with massive increases in insulin dose and/or improvement in glycemia. Severe insulin resistance and rapid decrease of glycemic levels may lower intravascular volume and narrow vessels, leading to microvascular disruption of the vasa nervorum, ultimately causing mononeuropathy. A more gradual approach to glycemia management in patients with severe insulin resistance may be warranted to mitigate this risk. Presentation: Thursday, June 15, 2023

FRI654 Concentrated Regular U-500 Insulin In An Automated Insulin Delivery System: A Case Report

Abstract Disclosure: J. Aurora: None. A. Saraswat: None. Background: Concentrated regular U-500 (U-500R) insulin is commonly used in patients with T2DM who are highly insulin-resistant, requiring more than 200 units of insulin per day. Utilizing U-500R reduces the number of daily injections, decreases injection volume, and improves cost effectiveness. There have been clinical trials using U-500R for continuous subcutaneous insulin infusion (CSII), particularly in Omnipod which has been shown to improve glycemic control and patient satisfaction without an increase in hypoglycemia (1). In addition, U-500R administration via multiple daily injections (MDI) and an investigational U-500R CSII, have been compared and demonstrated improved glycemic control with both modalities, but an increase in nocturnal hypoglycemia with CSII (2). Automated insulin delivery (AID) systems, or hybrid closed loop systems, have not formally been studied in patients with T2DM using U-500R. We present a case of a patient with T2DM with high insulin resistance using U-500R with Omnipod 5 AID system. Clinical Case: A 54-year-old female with T2DM with high insulin resistance was initially on Omnipod Dash with U-100 insulin lispro with baseline A1c 12.1%. She was transitioned to Omnipod 5 in 2022, and over 4 months A1c improved to 8.8%, GMI 8.8%, TIR 38%, TAR 62%, TBR 0%, CV 35.9%, and automated mode 97%. However, her total daily dose was 134 units leading to pod changes every 1.5 days. She expressed interest in switching to U-500R to reduce pod changes while utilizing her current CSII technology. We switched to U-500R, continued automated mode, increased her 24-hour BG target from 120 mg/dL to 130 mg/dL to reduce hypoglycemia risk, and increased her active insulin time from 3 to 6 hours to reflect U-500R kinetics. After 4 weeks, her GMI improved to 8.0%, TIR 47%, TAR 52%, TBR 1%, CV 45.9%, and automated mode 94%. Although nocturnal BG readings were normal, ranging from 70-130 mg/dL, she was having nightly symptoms of relative hypoglycemia. We then adjusted her BG target overnight to 150 mg/dL, which kept BG between 80-130 mg/dL with resolution of her symptoms. Conclusion: U-500R proved to be safe and effective with Omnipod 5 AID. Despite setting a higher BG target, the algorithm continuously kept BG well below this, particularly overnight. However, the safety mechanisms incorporated with the CSII suspended insulin delivery for predicted hypoglycemia. Further research will be required to adapt the automated dosing algorithm to U-500R to reduce the risk of nocturnal hypoglycemia.

THU026 Severe Insulin Resistance In Type 1 Diabetes Due To Growth Hormone Producing Pituitary Macroadenoma

Abstract Disclosure: R. Pansare: None. D. Khurram: None. L. Folsom: None. Background: Acromegaly is a rare disorder with an incidence ranging from 28 to 137 per million. Elevated IGF-1 in acromegaly is associated with severe insulin resistance and diabetes mellitus in the absence of visceral adiposity. We present a case of acromegaly identified in a lean individual with type 1 diabetes with progressive, severe insulin resistance requiring U-500 insulin via insulin pump. Clinical Case: A 28-year-old individual with type 1 diabetes mellitus diagnosed at age 17 years, hyperlipidemia, PCOS, rheumatoid arthritis, depression, and fibromyalgia presented with symptoms of brain fog, fatigue, functional decline, and nocturnal hyperhidrosis. Vital signs obtained in endocrinology clinic revealed blood pressure 100/70 mmHg and BMI 27 kg/m2. Glycemic control was suboptimal with HbA1c ranging from 7.5-9.5% over the past 2 years. The patient had developed progressive insulin resistance with subsequently increased insulin needs, ultimately requiring U-500 insulin administered via insulin pump. Brain MRI ordered due to additional symptoms revealed a sellar mass. Dedicated pituitary MRI confirmed a 2.1 cm anterior pituitary macroadenoma with compression of the optic chiasm, without cavernous sinus invasion. Biochemical evaluation at 9:57am revealed elevated IGF-1 801 ng/ml (93 - 297), Z-score +5.1. Additional testing revealed ACTH 17.9 pg/ml (7.2 - 63.3), cortisol 9.6 mcg/dl (3.7 - 19.4), TSH 0.741 mIU/L (0.27 - 4.2), free T4 1.32 ng/dl (0.93 - 1.7), prolactin 8.4 ng/ml (5.2 - 26.5), leptin 14.4 ng/ml (0.5 - 15.2), LDL 151 mg/dl (0 - 100), triglycerides 203 mg/dl (0 - 149). The patient subsequently underwent transsphenoidal resection of the pituitary macroadenoma. Discussion: Diabetes mellitus in acromegaly is associated with increased mortality. When elevated, IGF-1 level has been shown to be an independent predictor for risk of development of diabetes mellitus in acromegaly and correlates with insulin resistance. A unique challenge arises when the diagnosis of acromegaly is suspected in existing uncontrolled diabetes, as IGF-1 levels may be elevated, normal, or low. Post-surgical reduction in serum IGF-1 level is associated with early postoperative improvement in glucose tolerance. As such, once the diagnosis is confirmed, prompt surgical intervention is imperative to decrease this risk, as well as to improve hyperglycemia and decrease insulin requirements. Although de novo type 2 diabetes in acromegaly is common, our case is novel as it highlights the need to expand the differential diagnosis to include exogenous causes for progressively worsening insulin resistance in individuals with type 1 diabetes. Presentation: Thursday, June 15, 2023

SAT364 A Rare Cause of Hyperandrogenism in a Premenopausal Woman

Abstract Disclosure: L. El Musa Penna: None. W. Medina-Torres: None. L.R. Sepulveda-Garcia: None. L.N. Madera Marin: None. A. Rosado-Burgos: None. M.A. Ortiz-Rivera: None. B. Torres Rivera: None. M. Alvarado: None. M. Ramirez: None. L.A. Gonzalez-Rodriguez: None. M. Marcos Martínez: None. M. Correa Rivas: None. N. Bracero, MD: None. Hyperandrogenism in premenopausal women is most commonly associated to polycystic ovarian syndrome (PCOS). Approximately 10% of females in reproductive age present with clinical and/or biochemical findings of androgen excess, such as hirsutism, acne, alopecia, oligo-amenorrhea or if hyperandrogenism is severe it can lead to extreme virilization. Androgen excess can also contribute to insulin resistance. In this case we discuss a patient with severe hyperandrogenism, extreme insulin resistance and a rare cause of androgen excess in a woman of childbearing age. 34-year-old female patient G0P0 with type 2 diabetes mellitus (T2DM) on continuous insulin infusion system (CIIS), familial partial lipodystrophy, PCOS and severe hyperandrogenism, who was referred to our clinics for management of uncontrolled T2DM. Patient was on CIIS with regular insulin U-500 using a total daily dose of 95 units. She referred amenorrhea for the past 12 years and significant progression of hirsutism, alopecia and acanthosis nigricans in the past two years. Patient had clinical findings of hyperandrogenism such as hirsutism evaluated with modified Ferriman-Gallwey scale with a score of 32, alopecia Ludwig class 3 and marked acanthosis nigricans in neck and abdomen.Pre-operative laboratories: hemoglobin (Hgb) level 15.13 g/dL, hematocrit (Ht) 44.59 %, total testosterone level 525 ng/dL (13-53 ng/dL) and DHEAS 113 ug/dL (95.8-511.7 ug/dL), suggesting an ovarian source of androgen excess. Transvaginal ovarian ultrasound showed at the posteromedial edge of right ovary a hyperechoic structure measuring 1.5 cm long x 1.0 cm AP representing a lesion of unknown etiology. After discussion with patient a decision for oophorectomy was made. Pathology report described the ovary negative for neoplasia with findings consistent with hyperthecosis. Laboratories two weeks post-operative showed significant decrease in total testosterone to 81 ng/dL and in Hgb/ Ht (12.50 g/dL and 37.8% respectively). Insulin requirement decreased and she was able to be transitioned to U-100 insulin lispro with a total daily dose of 100. Four weeks after surgery patient had her menstrual period. Ovarian hyperthecosis is a disorder where there is an increased tissue with luteinized theca cells in the ovarian stroma; these cells are ovarian interstitial cells that differentiate into steroidogenically active cells. It is most commonly observed in post-menopausal women, but it has been described in women of childbearing age presenting with worsening hirsutism, virilization and insulin resistance. Monitoring patterns and progression of androgen excess is important in premenopausal women with a diagnosis of PCOS. Severe biochemical or clinical presentation, as well as progression of hyperandrogenism should increase suspicion of additional pathological entities as it will improve patient’s quality of life with the appropriate management. Presentation Date: Saturday, June 17, 2023

1851-PUB: Intractable Diabetic Ketoacidosis with Enfortumab Vedotin

Enfortumab Vedotin (EV) is an antibody-drug conjugate for metastatic urothelial carcinoma. Hyperglycemia and diabetic ketoacidosis (DKA) have been reported in patients using EV. The incidence increases with higher BMI. The one case report available on the association between EV and DKA resulted in development of multiorgan failure and death. This case, however, describes a positive outcome with recovery from DKA. We present a case of a 59 year-old Caucasian woman with morbid obesity, prediabetes and recurrent metastatic urothelial cell carcinoma who presented with hyperglycemia after 2 doses of EV. Labs were indicative of DKA without an infectious etiology. She was admitted to the ICU for intravenous insulin drip treatment. Hyperglycemia and ketosis persisted despite using a maximum insulin drip rate of 60 units/hour. Starvation ketosis was a factor, so a diet was started. On day 2, NPH insulin and prandial lispro were added along with the insulin drip, resulting in a total daily insulin dose of 1660 units. Nevertheless, hyperglycemia persisted. U-500 regular insulin was initiated and by day 4, the patient received a total of 2940 units of insulin in one day with normalized serum ketones. Insulin drip requirements decreased with blood glucose controlled solely on subcutaneous insulin. She remained euglycemic, so U-500 insulin was switched to daily glargine. Eventually, she was off all insulin and maintained blood glucose below 130 mg/dL. Work up for insulin resistance included a C-peptide of 42.6 ng/mL (normal 1.1-4.4) with glucose of 230 mg/dL, negative glutamic acid decarboxylase 65 and insulin antibodies, and a glucagon level of 213 pg/mL (normal ≤80) with glucose of 220 mg/dL. Although the mechanism by which EV causes hyperglycemia is not known, this case illustrates that hyperglycemia was due to severe insulin resistance associated with EV. Understanding this, along with glycemic effects of targeted therapies with Vedotin are necessary to investigate the causal mechanism and treatment for EV related hyperglycemia/DKA. Disclosure A.Elahi: None. J.Duron: None. T.Porter: None.

Pharmacokinetics and Pharmacodynamics of a Novel U500 Insulin Aspart Formulation: A Randomized, Double-Blind, Crossover Study in People With Type 1 Diabetes.

To evaluate the pharmacokinetics, pharmacodynamics, and safety of a novel U500 insulin aspart formulation (AT278 U500) compared with insulin aspart (IAsp U100). This single-center, randomized, double-blind study was conducted in 38 men with type 1 diabetes (body weight ≤100 kg and total insulin dose <1.2 units/kg/day). Participants received a single dose of either AT278 U500 or IAsp U100 (0.3 units/kg s.c.) in a crossover design, followed by an 8-h euglycemic clamp in the absence of basal insulin. With AT278 U500, onset of appearance in serum was 6 min earlier (P < 0.0001) and reached 50% of maximum concentration 23 min faster (P < 0.0001). Insulin exposure with AT278 U500 was 4.0-fold higher within the first 30 min (95% CI 3.29, 4.90), 1.5-fold higher within the first 60 min (95% CI 1.35, 1.76), and statistically superior up to 90 min postdose (P < 0.05). With AT278 U500, onset of action was 10 min earlier (P < 0.0001) and reached 50% of maximum glucose infusion rate 20 min faster (P < 0.0001). The glucose-lowering effect with AT278 U500 was 8.9-fold higher within the first 30 min (95% CI 5.96, 17.46), 2.4-fold higher within the first 60 min (95% CI 1.92, 3.22), and statistically superior up to 2 h postdose (P < 0.0001). Overall insulin exposure and glucose-lowering effect were comparable. No significant safety findings were observed. AT278 U500 offers rapid-acting characteristics in a reduced dose volume, with accelerated absorption and onset of action compared with IAsp U100 in the studied population.

U500 insulin for the management of severe insulin resistance in pregnancy

U500 insulin for the management of severe insulin resistance in pregnancy

Glycemic Outcomes of Hospitalized Patients on Ambulatory Humulin-R U-500 Insulin

ObjectiveManaging hospitalized patients on ambulatory U-500 insulin is challenging because of limited guidance on how to safely adjust insulin doses during admission. We sought to evaluate glycemic outcomes in relation to inpatient insulin doses in patients receiving U-500 prior to hospitalization. MethodsRetrospective study of hospitalized patients on ambulatory U-500 seen consecutively from January 2015 to December 2019. Primary outcomes were inpatient hypoglycemia, hyperglycemia, and normoglycemia at different insulin dosages expressed as weight-based (unit/kg/d) inpatient total daily dose (TDD) and ratio of inpatient to outpatient TDD. ResultsWe identified 66 admissions of 46 unique patients. The median (interquartile range) body mass index was 41.0 kg/m2 (35.1, 46.8), home TDD 212 units (120, 300), and home insulin dose 1.6 units/kg/d (1.1, 2.2). The median (interquartile range) inpatient insulin dose was 0.7 unit/kg/d (0.3, 1.0) and the ratio of inpatient to outpatient TDD was 0.4 (0.2, 0.8). Hyperglycemia persisted throughout the hospitalization. For the outcomes of hyperglycemia and normoglycemia, we found no association between increased levels of insulin dosages. For the outcome of hypoglycemia, significantly higher odds were observed when non-fasting patients received an inpatient TDD that was either > 40% of their home TDD or > 0.6 unit/kg/d of insulin. ConclusionPatients on ambulatory U-500 have significant hyperglycemia during admission. Inpatient insulin doses of 40% of home TDD or ≤ 0.6 unit/kg were not associated with increased hypoglycemia risk. Further prospective studies are needed to determine effective doses in these high-risk patients.

Combination Use of U-500 Regular Insulin via Insulin Pump and Rapid-Acting U-100 Prandial Injections for Treatment of Pre-Existing Type 2 Diabetes in Pregnancy.

The high-dose large-volume insulin injections that may become necessary during pregnancy due to marked pregnancy-induced insulin resistance may result in suboptimal therapeutic effectiveness. Use of U-500 insulin, a concentrated insulin formulation, has been suggested during pregnancy. However, the pharmacokinetic properties of U-500 insulin monotherapy can impede achievement of strict pregnancy glycemic targets. We propose a novel regimen for treatment of severe pregnancy-induced insulin resistance that enables precise delivery of U-500 basal insulin therapy through continuous subcutaneous insulin infusion (CSII) while maintaining the desired kinetics of prandial rapid-acting U-100 insulin therapy. This combination approach, guided by continuous glucose monitoring data, enabled achievement of pregnancy glycemic targets while reducing basal insulin requirements by approximately one-third. We report our method for (1) conversion to U-500 insulin delivery through CSII during pregnancy and (2) conversion from U-500 basal insulin delivery through CSII to U-100 intravenous insulin infusion therapy at delivery, to offer clinicians who encounter similar challenging scenarios a novel approach to diabetes management during pregnancy in the setting of marked insulin resistance.

Treatment Patterns and Outcomes Before and After HumulinR U-500 Initiation Among US Patients with Type2 Diabetes Previously Prescribed ≤ 200Units/day of U-100 Insulin.

IntroductionHumulin R U-500 (U-500R) utilization has increased in the past few years, raising concerns as U-500R is indicated only for patients requiring > 200 units of insulin. Thus, evidence of dispensed total daily dose (dTDD) > 200 units of prior U-100 insulin based on pharmacy claims is increasingly used as a criterion to determine appropriate switching to U-500R by payers. The study compared the treatment patterns and outcomes before and after U-500R initiation among patients who were identified with ≤ 200 units/day U-100 insulin fill in order to understand the appropriateness of switching.MethodsPatients with type 2 diabetes who initiated U-500R (index date = first fill) with ≤ 200 units/day pre-index dTDD and > 200 units/day post-index dTDD were identified in a Veterans Health Administration dataset between 1 January 2014 and 30 June 2017. Descriptive analysis was conducted on treatment patterns (dTDD, insulin dosage [units/kg], adherence, number of prescription fills) and clinical outcomes (HbA1c, symptomatic hypoglycemic events). Associations between U-500R exposure and outcomes were evaluated using mixed-effects models. Subgroups of U-500R syringe and KwikPen users were analyzed separately.ResultsAmong 1191 U-500R initiators identified in the study the mean dTDD increased from the pre- to post-index periods (147.2 vs 346.3; p < 0.0001). The mean HbA1c decreased from pre- to post-initiation (9.6% vs 8.6%; p < 0.0001), and symptomatic hypoglycemia events per patient per year increased (2.0 vs 3.3, p < 0.0001). Mixed-effects models confirmed the significance of the changes (p < 0.0001). Device subgroups followed similar trends.ConclusionsU-500R initiation was associated with large dTDD increases, improved glycemic control, and modest increases in hypoglycemia events, suggesting U-500R initiation may have corrected previous treatment compliance issues. Imposing dTDDs > 200 units before switching to U-500R criterion could hurt the opportunities for patients who need a simplified regimen for better outcomes.Supplementary InformationThe online version contains supplementary material available at 10.1007/s13300-022-01209-z.

A multifaceted approach in leveraging electronic health record tools for safe inpatient use of concentrated U-500 insulin.

The Institute for Safe Medication Practices classifies subcutaneous insulin as a high-risk medication. Concentrated U-500 insulin carries additional risks in comparison to conventional U-100 insulin, as the 5-fold more concentrated nature of this product, limitations to insulin pen dosing, and various devices for dose measurement may lead to miscommunication of patient-reported doses, resulting in downstream errors in ordering, verification, or administration. We describe a multifaceted approach to leveraging technical tools within the electronic health record (EHR) for U-500 insulin use. At Cleveland Clinic, the U-500 insulin use process evolved in a number of phases using EHR tools. Phase 1 included new clinical decision support and documentation tools during order entry, including a customized alert that fired during order entry recommending that the prescriber order a consult with endocrinology and requiring the prescriber to provide the patient's home insulin measuring device and the source of the patient's reported home dose. In order verification, a customized alert fired directing the pharmacist to contact the patient or patient's nurse and validate the information provided by the prescriber. Phase 2 involved transitioning dispensing of patient-specific doses from tuberculin syringes to U-500 insulin syringes. Phase 3 transitioned to use of U-500 insulin pens and included automatic dose rounding of ordered doses down to the nearest 5 units, and an additional customized pharmacist alert intended for cost conservation was added to fire if the patient had a recent administration of U-500 insulin documented, directing the pharmacist to determine whether the nurse needed a new pen dispensed. Cleveland Clinic successfully implemented customized tools and processes within the EHR pertaining to the prescribing, verification, dispensing, and administration of U-500 insulin.

The switch from rapid-acting to concentrated regular insulin improves glucose control in type 2 diabetes patients on pump therapy: A cohort survey

BackgroundTo evaluate the impact of switching from U-100 to U-500 insulin in patients with type 2 diabetes mellitus (T2DM) uncontrolled with continuous subcutaneous insulin infusion (CSII) by pump. MethodsWe retrospectively collected data from patients with T2DM, treated by U-100 CSII, who were switched to U-500 regular insulin where haemoglobin A1c (HbA1c) was >8% and/or insulin total daily dose (TDD) was >100 UI/d. Data collection from patient medical records included HbA1c, lipid levels, liver biomarkers, weight, TDD, declared hypoglycaemic episodes and measured by continuous glucose monitoring (CGM). ResultsSixty-five patients were included, aged 63.9 ± 8.6 years, insulin pump since 3.7 ± 3 years, TDD 186 ± 52 U/day, body mass index 39.4 ± 5.3 kg/m², HbA1c 9.03 ± 1.6%. After switching to U-500 insulin, HbA1c dropped by -0.96% (P < 0.0001) at one year with the effect maintained at three years (- 0.95%, P < 0.01). A subgroup analysis (n=42/65) using a severity score which covered the three previous years on U-100 and the next three years on U-500 insulin confirmed the latter's efficacy. Body weight increased by + 4.8 kg and TDD by 16% at three years. Declared non-severe hypoglycaemia increased significantly three- to four-fold during follow up, but % time-below-range at six months did not differ between the two treatments. Baseline HbA1c correlated with improved glucose control with U-500. ConclusionsU-100 to U-500 insulin switch improves glucose control in CSII T2DM patients, especially with high baseline HbA1c. Use of concentrated insulin in pumps may represent an advance in the strategy for treating T2DM insulin resistant states with uncontrolled hyperglycaemia after a switch from multiple daily injections to pump therapy.

Efficacy and safety of different basal and prandial insulin analogues for the treatment of type 2 diabetes: a network meta-analysis of randomized controlled trials.

The aim of the present network meta-analysis is to assess the efficacy and safety across different long and short-acting analogs for the treatment of type 2 diabetes. A PubMed, EMBASE, and Cochrane Central Register of Controlled Trials databases search (20th May, 2020) for all trials with a duration ≥24 weeks comparing an analogue with another or human insulin was performed. Indirect comparisons were performed by NMA choosing glargine U100 and human regular insulin, as the reference for long- and short-acting analogues, respectively. Primary endpoints were HbA1c at 24, 52, and 104 weeks. The weighted difference in means (WDM) and Mantel-Haenzel Odds Ratio [MH-OR] with 95% Confidence Intervals (CI) were calculated for categorical and continuous variables, respectively. Fifty trials (n = 43) and 7 for basal and prandial analogues, respectively, enrolling 25,554 and 3184 patients with type 2 and 1 diabetes, respectively, were included. At NMA, detemir was less effective than glargine U-100 at 52 weeks. A significant reduction of 24-week HbA1c (WMD [IC]: -0.10 [-0.17, -0.03]%); and risk of total (MH-OR [IC]: 0.80 [0.70, 0.91]), and nocturnal hypoglycemia (MH-OR [IC]: 0.57 [0.45, 0.73]) was observed for basal analogues versus NPH insulin. At NMA, glargine U300 and degludec were associated with a significant reduction in the risk of nocturnal hypoglycemia. No significant differences across different short-acting insulin were observed. This paper supports the use of long-acting analogues, rather than NPH insulin, as basal insulin for the treatment of type 2 diabetes, without any preferences for any individual long-acting analogue over the others. The evidence on short acting analogues is limited.

Treatment patterns and outcomes before and after human regular U-500 insulin initiation via KwikPen® among US veterans with type 2 diabetes mellitus.

A dedicated Humulin R U-500 (U-500R) prefilled disposable insulin pen (KwikPen) became available in 2016, yet limited evidence exists on treatment patterns and outcomes of U-500R via KwikPen (U500-KP). This is a retrospective observational study among adults with ≥2 claims for type 2 diabetes initiating U500-KP (index date: first claim) identified in Veterans Health Administration database. Treatment patterns and outcomes were evaluated in 9-month pre- and post-index periods, including dispensed total daily insulin dosage derived from claims expressed in units (dTDD) and units/kg, HbA1c, symptomatic hypoglycemia, and body weight. Multivariable modeling was used to confirm the associations between U500-KP initiation and outcomes. A total of 647 U500-KP initiators were identified. The mean age was 64years, and mean Quan-Charlson Comorbidity-index score was 3.8. Before U500-KP initiation, 62% of patients had dTDD≤200units with mean A1c 9.5%. Mean dTDD increased from 188.2 to 269.9units after U500-KP initiation with mean A1c decreased by 0.83% (SD=1.67) and mean weight gain of 1.5kg (SD=6.74). Hypoglycemia events increased from 4.3 to 5.3 (p<0.05) per person per year. Initiation of U500-KP brought significant improvement in dispensed insulin dose and glycemic control accompanied by moderate increases in hypoglycemia and weight.