Lispro Research Articles

ODP244 SGLT2 Inhibitor-Induced Euglycemic DKA and its Challenges

Abstract Introduction Sodium-glucose cotransporter type 2 inhibitors (SGLT2-i) have proven to be a gamechanger for patients with diabetes, cardiovascular, and renal disease. However, this class of medications confers an increased risk for adverse side effects such as genitourinary infections and, rarely, euglycemic diabetic ketoacidosis (EDKA). Studies have shown that the risk of euglycemic DKA from SGLT2 inhibitors increase sevenfold in patients with type 2 diabetes mellitus (T2DM) with an overall incidence of approximately 0.1%. These side effects need to be taken into consideration when prescribing this type of therapy. Case Description Case of a 61-year-old male, with hypertension, type 2 diabetes mellitus on glargine, insulin lispro and empagliflozin, adherent to his regimen. Also, patient had a history of CAD s/p PCI (2015), and urethral stricture with self-catheterization who presented to the ED complaining of genital pain of 4 days evolution. Patient had been treated at home with clindamycin without improvement of symptoms. Upon evaluation at ED, laboratories were remarkable for WBC: 25.90, glucose: 144mg/dL, sodium: 134mmol/L, potassium: 5.3mmol/L, CO2: 10mmol/L, ketones: large. Arterial blood gases with metabolic acidosis and anion gap: 26.3. [LAG1] Glycated hemoglobin was 6.8%. Urinalysis was significant for glucosuria 1000 mg/dL, SG 1. 036, 30 mg/dL of protein, negative for nitrites and leukocyte esterase, and few bacteria. Blood glucose levels remained between 145-194 the first 24 hours after admission. Urology service performed a penile exploration with the finding of bilateral corpus cavernosum abscesses that were drained and cultured. Patient was diagnosed with EDKA and started therapy with IV insulin infusion as per DKA protocol, however 10% dextrose infusion was required to continue insulin IV infusion until ketoacidosis resolution. Broad spectrum IV antibiotics were initiated. However, his clinical condition deteriorated and developed respiratory failure requiring mechanical ventilation. After 36 hours of insulin infusion, IV antibiotics and fluids, his anion gap normalized. Abscess and blood cultures reported Candida Glabrata. Antifungal therapy was started and after seven days, the patient's clinical condition improved with resolution of his sepsis and DKA, and was successfully extubated. Patient was discharged to a rehabilitation facility. Conclusion EDKA presents a diagnostic and treatment challenge. It should be suspected in patients with metabolic acidosis, ketonemia and under treatment with a SGLT2-i, even in the absence of hyperglycemia. Prompt treatment initiation with IV insulin infusion along with IV dextrose is important for resolution of DKA. Five-percent dextrose solution should be started and titrated as needed, but if ketoacidosis does not resolve, 10% dextrose can be considered to maintain the insulin infusion. Prescribing this class of hypoglycemic medication should be avoided in those who are clearly at high risk of this well-known complications. Patient education regarding early recognition and to seek early medical evaluation are essential. [LAG1]Anadir unidades Presentation: No date and time listed

LBSUN293 Diabetic Hand Infection: A Case Report

Abstract Background Diabetes Mellitus is related to musculoskeletal and soft tissues complications in a very diverse way, and with no doubt, hands are also affected. Almost 40% of people living with Diabetes have significant problems in the hands that require medical attention. (1) Clinical Case: A 59-year-old women with history of Diabetes Mellitus diagnosed 20 years ago without control, treated with NPH and Lispro insulin (basal bolus regimen). She was admitted to the emergency room due to a third-degree boiling water burn in her right index finger. Before she came to the hospital, she was previously evaluated by a physician who prescribed antibiotics (clindamycin) for 5 days without response. At physical examination, erythema, edema, purulent secretion was found in the finger. In addition, fever and high glucose levels were also noted. During hospitalization, intravenous antibiotics such as tigecycline and oxacillin were used with no improvement. Blood samples demonstrated leukocytosis and C-reactive protein (CPR) elevated levels. Secretion culture was positive to Methicillin-sensible Staphylococcus Aureus. Electromyography revealed severe lesions at sensory-motor peripheral nerves with chronic denervation in upper limbs. Due to the poor evolution of the injury, traumatologists indicated surgical cleaning. After 2 days, leukocytosis and CPR elevated levels persisted and despite all the efforts done to save the finger, traumatologists decided to perform an amputation. After 2 weeks of antibiotic treatment, the patient was discharged with normalized hemogram and CPR levels. Conclusion Diabetic hand infection is less recognized in the literature that the diabetic foot, main reason why it is easily ignored and underestimated; resulting in increased morbidity among diabetic patients. The combination of neuropathy, peripheral artery disease and impaired glucose levels made this patient had a poor outcome, resulting in the loss of a finger. It is very important to evaluate the hands during routine controls to avoid these sad events.

PSUN181 Diabetes-related outcomes following use of basal-bolus insulin vs. premixed insulin in a VA population with Type 2 diabetes: A retrospective chart review.

Abstract Background Treatment of diabetes mellitus (DM) with basal bolus insulin analogs (BB) requires up to five injections a day. The complexity of BB therapy may adversely influence patient compliance. A simpler and cheaper regimen with premixed insulin (PM) typically involves two injections a day but is perceived to be less effective in managing DM. The purpose of this research project was to compare DM-related outcomes between BB regimens (insulin detemir or glargine plus aspart, lispro or regular insulin) and PM insulin regimens (70/30 insulin NPH/regular) among our veteran population with type 2 DM. Research design and Methods This is a retrospective chart review that included 140 veterans (70 in BB group and 70 in PM group) with type2 DM. Subjects aged 18 years or above and those having A1C level ≥ 8% were included. Subjects with type 1 diabetes or who switched their insulin regimen during the follow-up period were excluded. The included subjects were followed for a year, after the start of respective insulin therapies to examine change in A1c (primary outcome) levels across groups. Data were analyzed using Chi-square/Fisher exact tests and logistic regression. All analyses were conducted using SPSS version 27 and SAS9.4. Results Out of 140 enrolled subjects, 94% were males with average age of 65.7 ± 10.1 years and DM duration of 12.9±9 years. There was no significant difference in age, gender, baseline A1c, BMI or duration of DM between the two groups. Following treatment initiation, there was no statistically significant difference between the BB and PM insulin groups for change in A1c (-1.9±1.8 vs -2.1±1.9%, p = 0.3) or for the rate of hypoglycemia (30% vs 21.4%, p = 0.3) respectively. Although the average BMI increased in both groups, the change was similar for both BB and PM groups (0.84±3.1 vs 0.4±2.2 kg/m2 respectively, p = 0.2). A logistic regression controlling for the confounders of hypoglycemia, found that the type of insulin used did not predict the development of hypoglycemia [OR 0.594, (0.251, 1.404)]. Conclusion There were no significant differences in A1c change, rate of hypoglycemia, and change in body mass index in patients treated with either BB or PM insulin among our study population. These results suggest that PM insulin is equally effective as the BB and its use can potentially improve patient compliance and reduce the cost of care. Presentation: Sunday, June 12, 2022 12:30 p.m. - 2:30 p.m.

ODP150 Hypertriglyceridemic Induced Acute Pancreatitis with Diabetic Ketoacidosis Treated with Insulin: A Case Report

Abstract Introduction Acute pancreatitis due to hypertriglyceridemia with DKA is a unique entity. The diagnosis of acute pancreatitis in DKA is challenging as most patients present with abdominal pain, and elevated amylase, and lipase are quite common in DKA. Hypertriglyceridemia-induced pancreatitis (HTGP) accounts for 1 to 35 percent of all cases of acute pancreatitis. Pancreatitis may occur in DKA with high anion gap metabolic acidosis. Lack of insulin results in lipolysis with release of free fatty acids. Increased free fatty acids presented to the liver, causes increased VLDL, which inhibits lipoprotein lipase in peripheral tissues and results in elevated triglycerides. Case presentation A 29-year-old morbidly obese male with Asperger's syndrome, prediabetes, and hyperlipidemia presented with a 3-day history of sharp, non-radiating, and progressively worsening right upper abdominal pain, associated with nausea, non-bilious vomiting, and shortness of breath. His past medical history was notable for a prior bout of gallstone pancreatitis, for which he underwent a laparoscopic cholecystectomy. On his arrival in the emergency department, he was afebrile, but tachycardic (HR 139), mildly hypertensive (BP 149/98) with a Kussmaul breathing saturating 98% on room air. His lung sounds were clear but diminished and his abdomen was soft but diffusely tender, without peritoneal signs. Initial laboratory tests showed a neutrophilic leukocytosis of 12K, glucose of 867 mg/dL, hyponatremia (corrected 131), ketonuria, with elevated lipase 1,164 U/L. Venous blood gas showed a pH of 7.18 and PCO2 24 mmHg. He also had severe hypertriglyceridemia with a total triglyceride level of > 9,000 mg/dL. His CT abdomen showed peripancreatic inflammation consistent with acute pancreatitis. He was admitted to the ICU, and initially managed with aggressive intravenous fluids and pain control, then was started on an insulin drip for diabetic ketoacidosis and hypertriglyceridemia. His hospital course was notable for the development of acute kidney injury requiring hemodialysis. His triglyceride level gradually decreased and was 396 U/L on hospital day #9. He was discharged on fenofibrate, Lantus 20 units daily and insulin lispro 10 units with meals. Conclusion Hypertriglyceridemia is an uncommon but a well-established cause of acute pancreatitis leading to significant morbidity and mortality. In this case, a prediabetic patient presented with DKA and further investigation revealed HTGP. There is currently a paucity of data to support an optimal treatment for this condition; however, both insulin and plasmapheresis have been successfully employed. Plasmapheresis helps remove plasma lipoproteins and reduces triglyceride more rapidly than insulin and has been recommended for severe cases. In our case, insulin infusion alone significantly reduced the triglyceride level. Presentation: No date and time listed

PSUN239 Severe Insulin Resistance and Hyperglycemia with Mild COVID-19 Infection

Abstract Introduction Covid-19 infection (CI) is known to cause hyperglycemia and insulin resistance in patients with and without diabetes. Prior reports have correlated the degree of hyperglycemia to the severity of the CI. However, not much data is available regarding severe insulin resistance in patients with mild CI who are otherwise asymptomatic and not on steroids. Case We report a 48-year old male with type-1 diabetes, asymptomatic CI and renal failure, on dialysis who was admitted with diabetic ketoacidosis (DKA). Patient had refused insulin and hemodialysis treatments for one week and was noted to be confused by staff in his long-term facility. Upon presentation, he was initiated on intravenous (IVIT) insulin infusion therapy and transitioned to subcutaneous (SQ) insulin the following morning. That evening, hyperglycemia worsened (>500 mg/dl), necessitating reinstatement of the IVIT. Hyperglycemia persisted (no excess carbohydrate intake reported by nursing) and IVIT was continued as attempts to change to SQ therapy were unsuccessful. He was dialyzed for two consecutive days after admission and then changed to alternate day schedule. On day 4, hyperglycemia worsened to >500 mg/dl persistently, IVIT rate was increased to 24 units/hr but blood sugars persisted in the >500 range. Work up for evaluating Covid-related inflammation and insulin resistance was sent. After 6 hours of IVIT at 24 U/hr, he was given a relatively higher dose of SQ-insulin (insulin glargine 20 units and insulin lispro 30 units SQ). IVIT rate was gradually tapered based on blood sugars and stopped 6 hours after SQ-insulin was given. Approximately eight hours after receiving SQ-insulin, he was noted to be hypoglycemic, and he received two amps of D-50. His blood sugar stabilized, and he continued to do well subsequently and was maintained on basal-bolus therapy. The on-call nurse confirmed good IV access for the IVIT access line. The IV insulin infusion fluid from bag was sent for analysis which showed that insulin was present in the infusion bag. Inflammatory markers showed high levels of cortisol, ferritin, growth hormone, C-reactive protein and sedimentation rate. Insulin antibodies were also present. D-dimer was normal, and fibrinogen was only mildly elevated. Conclusion This is a rare case of severe insulin resistance in a patient with mild Covid-19 infection and underlying type 1 diabetes, who developed severe insulin resistance with poor response to high doses IV insulin. He ultimately responded a combination of high dose subcutaneous insulin and high doses IV insulin infusion therapy with resolution of ketoacidosis and hyperglycemia. Presentation: Sunday, June 12, 2022 12:30 p.m. - 2:30 p.m.

A Multicenter Randomized Trial Evaluating the Insulin-Only Configuration of the Bionic Pancreas in Adults with Type 1 Diabetes.

Objective: To evaluate the insulin-only configuration of the iLet® bionic pancreas (BP) using insulin aspart or insulin lispro in adults with type 1 diabetes (T1D). Methods: In this multicenter, randomized, controlled trial, 161 adults with T1D (18-79 years old, baseline HbA1c 5.5%-13.1%, 32% using multiple daily injections, 27% using a pump without automation, 5% using a pump with predictive low glucose suspend, and 36% using a hybrid closed loop system before the study) were randomly assigned 2:1 to use the BP (N = 107) with insulin aspart or insulin lispro (BP group) or a standard-of-care (SC) control group (N = 54) using their usual insulin delivery plus continuous glucose monitoring (CGM). The primary outcome was HbA1c at 13 weeks. Results: Mean HbA1c decreased from 7.6% ± 1.2% at baseline to 7.1% ± 0.6% at 13 weeks with BP versus 7.6% ± 1.2% to 7.5% ± 0.9% with SC (adjusted difference = -0.5%, 95% confidence interval -0.6% to -0.3%, P < 0.001). Over 13 weeks, mean time in range 70-180 mg/dL (TIR) increased by 11% (2.6 h/d) and mean CGM glucose was reduced by 16 mg/dL with BP compared with SC (P < 0.001). Improvement in these metrics was seen during the first day of BP use and by the end of the first week reached levels that remained relatively stable through 13 weeks. Analyses of time >180 mg/dL, time >250 mg/dL, and standard deviation of CGM glucose all favored the BP group (P < 0.001). The CGM-measured hypoglycemia was low at baseline (median time <54 mg/dL of 0.21% [3 min/d] for the BP group and 0.11% [1.6 min/d] for the SC group) and not significantly different between groups over the 13 weeks (P = 0.51 for time <70 mg/dL and 0.33 for time <54 mg/dL). There were 7 (6.5% of 107 participants) severe hypoglycemic events in the BP group and 2 events in the SC group (1.9% of 54 participants, P = 0.40). Conclusions: In adults with T1D, use of the BP with insulin aspart or insulin lispro improved HbA1c, TIR, and hyperglycemic metrics without increasing CGM-measured hypoglycemia compared with standard of care. Clinical Trial Registry: clinicaltrials.gov; NCT04200313.

Positive Impact of the Bionic Pancreas on Diabetes Control in Youth 6-17 Years Old with Type 1 Diabetes: A Multicenter Randomized Trial.

Objective: To evaluate the insulin-only configuration of the iLet® bionic pancreas (BP) in youth 6-17 years old with type 1 diabetes (T1D). Research Design and Methods: In this multicenter, randomized, controlled trial, 165 youth with T1D (6-17 years old; baseline HbA1c 5.8%-12.2%; 35% using multiple daily injections, 36% using an insulin pump without automation, 4% using an insulin pump with low glucose suspend, and 25% using a hybrid closed-loop system before the study) were randomly assigned 2:1 to use BP (n = 112) with insulin aspart or insulin lispro (BP group) or to a control group (n = 53) using their personal standard care insulin delivery (SC group) plus real-time continuous glucose monitoring (CGM). The primary outcome was HbA1c at 13 weeks. Results: Mean HbA1c decreased from 8.1% ± 1.2% at baseline to 7.5% ± 0.7% at 13 weeks with BP versus 7.8% ± 1.1% at both baseline and 13 weeks with SC (adjusted difference = -0.5%, 95% CI -0.7% to -0.2%, P < 0.001). Participants with baseline HbA1c ≥9.0% (n = 34) decreased mean HbA1c from 9.7% ± 0.8% to 7.9% ± 0.6% after 13 weeks with BP compared with 9.7% ± 0.5% to 9.8% ± 0.8% with SC. Over 13 weeks, mean time in range (TIR) 70-180 mg/dL increased by 10% (2.4 h per day) and mean CGM glucose was reduced by 15 mg/dL with BP compared with SC (P < 0.001). Analyses of time >180 mg/dL, time >250 mg/dL, and standard deviation of CGM glucose favored BP (P < 0.001). Time <54 mg/dL was low at baseline (median 0.2%) and not significantly different between groups over 13 weeks (P = 0.24). A severe hypoglycemia event occurred in 3 (2.7%) participants in the BP group and in 1 (1.9%) in the SC group. Conclusions: In youth 6-17 years old with T1D, use of insulin-only configuration of BP improved HbA1c, TIR, and hyperglycemic metrics without increasing CGM-measured hypoglycemia compared with standard of care. Improvement in glycemic metrics was most pronounced in participants with high baseline HbA1c levels. Clinical Trial Registry: clinicaltrials.gov; NCT04200313.

Multicenter, Randomized Trial of a Bionic Pancreas in Type 1 Diabetes

BackgroundCurrently available semiautomated insulin-delivery systems require individualized insulin regimens for the initialization of therapy and meal doses based on carbohydrate counting for routine operation. In contrast, the bionic pancreas is initialized only on the basis of body weight, makes all dose decisions and delivers insulin autonomously, and uses meal announcements without carbohydrate counting.MethodsIn this 13-week, multicenter, randomized trial, we randomly assigned in a 2:1 ratio persons at least 6 years of age with type 1 diabetes either to receive bionic pancreas treatment with insulin aspart or insulin lispro or to receive standard care (defined as any insulin-delivery method with unblinded, real-time continuous glucose monitoring). The primary outcome was the glycated hemoglobin level at 13 weeks. The key secondary outcome was the percentage of time that the glucose level as assessed by continuous glucose monitoring was below 54 mg per deciliter; the prespecified noninferiority limit for this outcome was 1 percentage point. Safety was also assessed.ResultsA total of 219 participants 6 to 79 years of age were assigned to the bionic-pancreas group, and 107 to the standard-care group. The glycated hemoglobin level decreased from 7.9% to 7.3% in the bionic-pancreas group and did not change (was at 7.7% at both time points) in the standard-care group (mean adjusted difference at 13 weeks, −0.5 percentage points; 95% confidence interval [CI], −0.6 to −0.3; P<0.001). The percentage of time that the glucose level as assessed by continuous glucose monitoring was below 54 mg per deciliter did not differ significantly between the two groups (13-week adjusted difference, 0.0 percentage points; 95% CI, −0.1 to 0.04; P<0.001 for noninferiority). The rate of severe hypoglycemia was 17.7 events per 100 participant-years in the bionic-pancreas group and 10.8 events per 100 participant-years in the standard-care group (P=0.39). No episodes of diabetic ketoacidosis occurred in either group.ConclusionsIn this 13-week, randomized trial involving adults and children with type 1 diabetes, use of a bionic pancreas was associated with a greater reduction than standard care in the glycated hemoglobin level. (Funded by the National Institute of Diabetes and Digestive and Kidney Diseases and others; ClinicalTrials.gov number, NCT04200313.)

Formulation Excipients and Their Role in Insulin Stability and Association State in Formulation.

While excipients are often overlooked as the "inactive" ingredients in pharmaceutical formulations, they often play a critical role in protein stability and absorption kinetics. Recent work has identified an ultrafast absorbing insulin formulation that is the result of excipient modifications. Specifically, the insulin monomer can be isolated by replacing zinc and the phenolic preservative metacresol with phenoxyethanol as an antimicrobial agent and an amphiphilic acrylamide copolymer excipient for stability. A greater understanding is needed of the interplay between excipients, insulin association state, and stability in order to optimize this formulation. Here, we formulated insulin with different preservatives and stabilizing excipient concentrations using both insulin lispro and regular human insulin and assessed the insulin association states using analytical ultracentrifugation as well as formulation stability. We determined that phenoxyethanol is required to eliminate hexamers and promote a high monomer content even in a zinc-free lispro formulation. There is also a concentration dependent relationship between the concentration of polyacrylamide-based copolymer excipient and insulin stability, where a concentration greater than 0.1g/mL copolymer is required for a mostly monomeric zinc-free lispro formulation to achieve stability exceeding that of Humalog in a stressed aging assay. Further, we determined that under the formulation conditions tested zinc-free regular human insulin remains primarily hexameric and is not at this time a promising candidate for rapid-acting formulations.

An autopsy case of fatal insulin preparation overdose

Insulin preparations, a group of drugs used to treat diabetes, are of great forensic interest because they are difficult to detect in blood while they are sometimes intentionally administered in large doses for suicide or murder. In this study, we validated a quantification method for insulin glargine and insulin lispro using liquid chromatography-tandem mass spectrometry (LC-MS/MS) in the blood sample from a case of suicidal overdose with insulin. Case: A woman in her 30s had a history of mental illness and diabetes. A day before her death, she informed her partner that she had self-administered large doses of insulin preparations and prescription drugs. Bovine insulin was used as the internal standard (IS). The blood sample (250 μL) was added to the diluent and IS solution, followed by 250 μL each of hexane and N,N-dimethylformamide, and the mixture was centrifuged (10000 g × 10 min). The supernatant was collected and 900 μL of 5% ammonium solution was added. The extract was analyzed using Nexera 30A, LCMS8060 (Shimadzu), L-column3 ODS C18 metal-free column (150 × 2.1 mm, 3 μm), ionization method: electrospray ionization+, multiple reaction monitoring conditions: insulin glargine [M + 6H]6+ 1011.5 > 1179.4, insulin lispro[M + 6H]6+ 968.9 > 217.0, bovine insulin (IS) [M + 6H]6+ 956.3 > 1120.9. The autopsy revealed no evidence of fatal injuries. Coronary artery stenosis was observed as a finding of endogenous disease, but there were no significant histopathological changes in the myocardium. Biochemical tests revealed the following: blood glucose level, 6 mg/dL; glucose in the vitreous region, 6 mg/dL; glycated hemoglobin (HbA1c), 11.2%; blood insulin level estimated using the chemiluminescent enzyme immunoassay method, 1.03 μU/mL (6.27 pmol/mL); and C-peptide concentration, 0.6 ng/mL (16.8 pmol/L). A drug screening test and simple quantification using LC-MS/MS detected many prescription drugs, but none of them were at intoxicating concentrations. The insulin analysis showed insulin glargine concentrations of 429 μU/mL in femoral blood and 1362 μU/mL in cardiac blood, and insulin lispro was detected in femoral and cardiac blood below the lower limit of quantification (<50 μU/mL). The cardiac/peripheral blood ratio, a measure of postmortem redistribution, was 3.2. Although the therapeutic ranges of insulin glargine and insulin lispro have not been defined, the femoral and cardiac blood concentrations of insulin lispro in this case was lower than the serum concentration (155 μU/mL) listed in the package insert. However, while the femoral and cardiac blood insulin glargine concentrations were considerably higher than the serum concentration (15 μU/mL) listed in the package insert. Considering that insulin is easily degraded in whole blood due to hemolysis, it is possible that insulin concentrations were even higher at the time of administration and death than those observed in autopsy specimens on the third postmortem day. However, since insulin lispro is a fast-acting analog of insulin (1–3 hours), it may have contributed to hypoglycemia but was not the direct cause of death, and hypoglycemia due to insulin glargine overdose was the most likely cause of death in this case. We quantified insulin lispro and insulin glargine in a case of suicide to determine insulin glargine's involvement in causing death. In future, it is necessary to examine postmortem degradation and redistribution of insulin and consider the appropriate concentration in postmortem samples of insulin poisoning.

Difficulties in interpreting a therapeutic blood concentration of insulin lispro in postmortem blood: A case report

Illustrate the complexity of interpreting a postmortem therapeutic blood concentration of insulin in a probable case of suicide using insulin lispro. The identification and quantification of insulin and its analogues continues to be a challenge in the field of forensic toxicology. Its use is not always limited to the treatment of diabetes but is often used illicitly. Numerous cases of suicides and suicide attempts have been described in the literature and nevertheless, this number still seems to be underestimated due to both the inability of laboratories to identify and discriminate between synthetic analogues of human insulin and due to the chemical instability of insulin especially in postmortem samples. Our case concerns a 63-year-old man who was found dead by his brother at home. Three empty Humalog® insulin pens and a letter mentioning his suicide intention were found next to his bed. At the request of the prosecutor, an external examination of the corpse was performed and revealed only an asphyxial syndrome not specific to a cause of death. The presence of a blood glucose monitoring device on the right arm was also observed, suggesting that the subject was diabetic. External examination was unable to determine the exact cause of death. For this reason, the pathologist was oriented on a toxic death. In order to proceed to further toxicological investigations, peripheral blood, urine and hair samples were collected. It is important to underline that, due to the long period elapsed between the external examination and the pathologist's conclusion (enabling the initiation of the toxicological analysis) and due to administrative delays, insulin testing was performed only 9 months after the samples collection. Blood and urine samples were stored at +4 °C until analysis. The identification and quantification of insulin lispro was performed in the postmortem blood after precipitation in the presence of bovine insulin (internal standard), by a mixture of acetonitrile/methanol (ratio 1:1) followed by a step of ultrafiltration using Amicon® centrifugal filters (3 kDa) and a step of immunopurification using Iso-Insulin ELISA coated wells. The analysis was performed with a UHPLC- Q-TOF (XEVO G2-XS). Detection of insulin lispro was performed using the precursor molecular ion m/z 1162.543 (charge state 5 +). Since human insulin and insulin lispro share the exact same molecular mass (5807 Da), discrimination cannot be made using the multi-charged molecular ion. The distinction is based on fragment m/z 217 which is present only in insulin lispro spectrum. Toxicological tests performed on the blood sample did not reveal any xenobiotic of toxic nature. Insulin lispro was detected in the femoral blood sample at 1,1 ng/mL, whereas human insulin was not detected. Following the administration of a therapeutic dose of 0.2 U/kg of insulin Humalog ®, a maximum concentration of 1.66 ± 0.42 ng/mL is achieved. Consequently, the concentration found in our case was therapeutic. Nevertheless, given the unstable nature of insulin, especially in postmortem blood, it is not possible to exclude that death was caused by an insulin overdose. The long period between collection and analysis (9 months), the hemolyzed state of the blood, the storage of the sample in unsuitable tubes and the fact that we were able to detect even small concentrations of insulin lispro suggest that the concentration at the time of death was much higher. The pathologist concluded that the cause of death was probably an overdose of insulin lispro. This case highlights that the interpretation of a postmortem insulin concentration requires a complex approach involving the assessment of many factors such as the subject's medical history and the time, mode and state of preservation of the sample.

A comparison of the rapid-acting insulin analogue glulisine with lispro and aspart for the pump treatment of patients with type 1 diabetes.

(1) To describe the population of patients with type 1 diabetes (T1DM) using the rapid-acting insulin analogue glulisine versus lispro and aspart during continuous subcutaneous insulin infusion (CSII); (2) to describe insulin relative effectiveness based on hemoglobin A1c (HbA1c), fasting blood glucose (FBG) and dose; (3) to determine rates of hyperglycemia, hypoglycemia, and diabetic ketoacidosis (DKA). The analysis used March 2021 data from the Diabetes-Patienten-Verlaufsdokumentation registry, which contains data of 618,903 patients with diabetes. Patients were propensity-matched by age, sex, and diabetes duration. Overall, 42,736 patients of any age were eligible for analysis based on insulin pump usage with either glulisine (N = 707) or lispro/aspart (N = 42,029) between 2004 and 2020. Patients receiving glulisine were older (median 20.0 vs. 16.2years), equally often male (47.2% vs. 47.8%) and had a longer diabetes duration (median 9.4 vs. 7.4years). After propensity score matching, 707 pairs remained (total N = 1414). Patient characteristics between groups were similar. Achieved HbA1c values were also comparable: 8.04%, 64mmol/mol versus 7.96%, 63mmol/mol for glulisine and lispro/aspart [LS mean difference 0.08 (95%CI -0.08, 0.25)]. FBG was 9.37mmol/L (168.9mg/dL) and 9.58mmol/L (172.6mg/dL) in the glulisine and lispro/aspart groups [LS mean diff. -0.21; (95%CI -1.13, 0.72)]. Total daily insulin doses and prandial to total insulin ratios were also similar. Glulisine group patients had higher rates of lipodystrophy (0.85% vs. 0.71%) (LS mean diff. 0.18 [95% CI -1.01, 1.38]) and non-severe DKA (3.11% vs. 0.57%; p = 0.002). Fewer patients in the glulisine group had severe hypoglycemic events (7.66 vs. 9.09; p = 0.333) and severe ketoacidosis events (0.57% vs. 1.56%; p = 0.082) but more had hypoglycemic coma events (p = 0.773), although the differences were not statistically significant. Insulin glulisine had comparable glucose control to lispro/aspart. The use of glulisine was less frequent in the present analysis compared to the previous trials.

Ultra rapid lispro improves postprandial glucose control versus lispro in combination with insulin glargine/degludec in adults with type 2 diabetes: a prospective, randomized, double-blind, phase 3 trial

Ultra rapid lispro (URLi) is a novel formulation of insulin lispro designed to more closely match the physiological insulin response to a meal, with the aim of improving postprandial glucose (PPG) control. We conducted a multinational, multicenter, randomized, double-blind, treat-to-target, 26-week, phase 3 trial to evaluate the efficacy and safety of URLi in adults with type 2 diabetes (T2D). After an 8-week lead-in period during which basal insulin glargine or degludec was optimized, adults with T2D were randomized (2:1) to prandial URLi (n = 395) or lispro (n = 200). The primary endpoint was non-inferiority of URLi versus lispro in glycated hemoglobin A1c (HbA1c) change from baseline to week 26. Multiplicity-adjusted analyses were performed to assess the superiority of URLi in 1- and 2-h PPG excursions during a mixed-meal tolerance test (MMTT) and HbA1c change at week 26. URLi showed non-inferiority for HbA1c change at week 26 versus lispro (least-squares mean [LSM] difference, 0.07%; 95% confidence interval: −0.07, 0.21). HbA1c was reduced by 0.56% and 0.63% with URLi and lispro, respectively, with no significant treatment difference (P = 0.321). URLi provided superior PPG excursion control versus lispro at 1 h (LSM difference: −14.6 mg/dL, P < 0.001) and 2 h (LSM difference: −21.8 mg/dL, P < 0.001) as well as other time points (30–240 min) during the MMTT. Incremental area under the glucose curve during the MMTT was also significantly lower with URLi versus lispro. The safety profiles were generally similar between treatment groups. In conclusion, URLi was superior to lispro for PPG control, with non-inferiority in HbA1c improvement, in adults with T2D.

Probing for peptidic drugs (2-10kDa) in doping control blood samples.

Bioactive peptides with a molecular mass between 2 and 10kDa represent an important class of substances banned in elite sports, which has been recognized with an increasing number and variety of substances by anti-doping organizations. Also, the annually renewed list of prohibited substances of the World Anti-Doping Agency (WADA) explicitly mentions more and more of these peptides, and efficient testing procedures are required. Even under simplified sample preparation conditions, liquid chromatography coupled to high-resolution mass spectrometry (with resolution properties>100,000 full width at half maximum) offers suitable conditions for this task and can therefore be used as an initial testing procedure. In contrast to urine, blood analysis essentially relies on the detection of intact peptide hormones, and the expected concentrations are commonly higher in blood samples than in urine. This facilitates the analysis, and a generic sample preparation by means of mixed-mode solid-phase extraction could be realized in this study. Co-extraction and analysis of several different peptides such as insulins (human, lispro, aspart, glulisine, tresiba, detemir, glargine, bovine insulin and porcine insulin), growth hormone releasing hormones (sermorelin, CJC-1295 and tesamorelin), insulin-like growth factors (long-R3-IGF-I, R3-IGF-I and Des1-3-IGF-I) and mechano growth factors (human MGF and MGF-Goldspink) with criteria that fulfil the requirements of the WADA documents (TD2022 MRPL) for doping controls. The proof of principle was shown by the analysis of post administration samples after treatment with synthetic insulin analogues.

Physicochemical and microbiological stability of insulin eye drops in an artificial tear vehicle used in the treatment of refractory neurotrophic keratopathy

Neurotrophic keratopathy (NK) is a degenerative corneal disease with a loss of corneal sensitivity and impairment of corneal healing. Low dose insulin eyedrops have been shown to be a simple and effective treatment for refractory NK when the response to the usual treatment is incomplete. At present, there are no commercially available forms, and there is no data regarding the stability of these products as prepared by compounding pharmacies. In this work, we studied the physicochemical and microbiological stability of an insulin ophthalmic formulation obtained by mixing insulin lispro in artificial tears with a polyethylene and propylene glycol base. The stability of this 1IU/mL insulin ophthalmic formulation was analysed for 12 months in low-density polyethylene (LDPE) multidose eye droppers at 4°C.The studied parameters of physicochemical stability were: visual inspection, turbidity, UV spectral absorption, osmolality and pH. In addition, insulin and m-cresol concentrations and quantification of impurities (insulin covalent aggregates and insulin fragments) were studied thanks to the development of a new Size Exclusion Chromatographic method. For unopened eye droppers, all tested physicochemical parameters remained stable for 12 months at 4°C, and excellent microbiological stability was obtained. In conditions of simulated use, these parameters also remained stable for one month at 4°C, and no impact of potential temperature rises on the insulin and m-cresol concentrations in the insulin eyedropper was observed.

Glucagon and Its Underutilization in Diabetes Self-Management: A Teachable Moment.

Commentaries| July 08 2023 Glucagon and Its Underutilization in Diabetes Self-Management: A Teachable Moment Katherine Wolfe; Katherine Wolfe 1Department of Pharmacy, Spartanburg Medical Center, Spartanburg, SC Search for other works by this author on: This Site PubMed Google Scholar Jennifer Nicole Clements 0000-0003-2431-6651 Jennifer Nicole Clements 2Department of Nursing Administration, Spartanburg Regional Healthcare System, Spartanburg, SC Corresponding author: Jennifer Nicole Clements, jclements1027@outlook.com Search for other works by this author on: This Site PubMed Google Scholar Corresponding author: Jennifer Nicole Clements, jclements1027@outlook.com Clin Diabetes 2023;41(2):286–288 https://doi.org/10.2337/cd22-0015 Views Icon Views Article contents Figures & tables Video Audio Supplementary Data Peer Review Share Icon Share Facebook Twitter LinkedIn MailTo Cite Icon Cite Get Permissions Citation Katherine Wolfe, Jennifer Nicole Clements; Glucagon and Its Underutilization in Diabetes Self-Management: A Teachable Moment. Clin Diabetes 1 April 2023; 41 (2): 286–288. https://doi.org/10.2337/cd22-0015 Download citation file: Ris (Zotero) Reference Manager EasyBib Bookends Mendeley Papers EndNote RefWorks BibTex toolbar search Search Dropdown Menu toolbar search search input Search input auto suggest filter your search All ContentAll JournalsClinical Diabetes Search Advanced Search A woman with type 1 diabetes of 14 years’ duration is admitted to a noncritical care unit after presenting to the emergency center with hypoglycemia. According to her family member and emergency medical services personnel, the person’s blood glucose was noted to be 28 mg/dL. Pharmacy records indicate that her treatment regimen before admission included insulin glargine 40 units subcutaneously in the morning and insulin lispro 5 units subcutaneously before each meal, with a correction factor of 24 (1 unit of insulin for every 24 mg/dL above target) and that she received enough blood glucose monitoring supplies to perform four checks per day. Normal organ function is noted, and her A1C is found to have decreased from 9 to 6.2% in the past 3 months. During her 4-day hospitalization, her insulin therapy included insulin glargine 20 units subcutaneously in the morning and insulin lispro with a correction scale of 0–8... You do not currently have access to this content.

Efficacy and Safety of Ultra-Rapid Lispro in Younger and Older Patients with Type 2 Diabetes: Randomized Double-Blind PRONTO-T2D Study.

IntroductionUltra-rapid lispro (URLi) is a new prandial insulin lispro formulation. In the PRONTO-T2D study, URLi, in a basal-bolus regimen with glargine or degludec, was non-inferior to lispro (Humalog®) for HbA1c reduction and superior for postprandial glucose (PPG) control. We evaluated the efficacy and safety of URLi compared to lispro in younger versus older patients in PRONTO-T2D.MethodsPRONTO-T2D was a phase 3, 26-week, double-blind, treat-to-target study in people with type 2 diabetes. In this sub-group analysis, we compared URLi to lispro on the change from baseline in HbA1c and rate of level 2 hypoglycemia (< 54 mg/dl) in patients aged < 65 (N = 406) and ≥ 65 years (N = 267).ResultsAt baseline, patients < 65 versus ≥ 65 years had mean age of 54.9 versus 69.2 years and duration of diabetes 14.6 versus 19.4 years. Mean HbA1c at screening and randomization was 8.35 and 7.34%, respectively, in patients < 65 years, and 8.21 and 7.23%, respectively, in patients ≥ 65 years. At endpoint, mean HbA1c with URLi versus lispro was 6.92 versus 6.90%, respectively, in patients < 65 years and 6.89 versus 6.79%, respectively, in patients ≥ 65 years. URLi significantly reduced 1- and 2-h PPG excursions with a standardized meal test in both age groups: between-treatment differences at 1-h postmeal for younger and older patients was – 9.8 and – 15.1 mg/dl, respectively; and at 2-h postmeal, – 18.7 and – 15.1 mg/dl, respectively, all p < 0.05. Severe and nocturnal hypoglycemia were similar between groups. The relative rate (URLi/Humalog) of level 2 hypoglycemia was lower in older versus younger patients, with a significant treatment-by-age interaction observed. No differential treatment effects were noted for insulin dose, weight, and fasting and maximum glucose after the meal test.ConclusionsURLi, in a basal-bolus regimen, resulted in endpoint HbA1c < 7% and significantly lower PPG excursions compared to lispro in both age groups, with reduced level 2 hypoglycemia in older versus younger patients.Trial registrationClinicalTrials.gov, NCT03214380.Supplementary InformationThe online version contains supplementary material available at 10.1007/s13300-022-01290-4.

The Price and Market Share Evolution of the Original Biologics and Their Biosimilars in Finland.

BackgroundBiological drugs are generally expensive and produce a continuously growing share of drug costs. Yet they are essential in the treatment of many chronic diseases. Biosimilars, clinically equivalent to biological originator products, are expected to restrain drug costs in the biological market.ObjectiveThis study aimed to examine the impact of the biosimilar market entry on the prices of the reference products in outpatient care in Finland, investigate the impact of biosimilar market entries on price competition among biological medicinal products, and examine how the prices and market shares of outpatient biosimilars have developed in Finland during 2009–2020.MethodsThis retrospective register study applied data from IQVIA covering national community pharmacy wholesale data between 1 January, 2009, and 31 August, 2020, for somatropin, epoetin, filgrastim, follitropin, insulin glargine, insulin lispro, etanercept, pegfilgrastim, adalimumab, teriparatide, and enoxaparin biosimilars and their reference products, in addition to two relevant insulin products. We determined the monthly wholesale amounts in defined daily doses and wholesale weighted average prices (excluding value-added tax) per defined daily dose for each product. We analyzed the evolution of the price and market shares. We performed a linear segmented regression analysis to examine the impact of the market entry of biosimilars on the prices of reference products.ResultsThe prices of the reference products mainly decreased after the biosimilar entered the market. If the reference product price was not reduced, it was no longer reimbursable after evaluation under the Health Insurance Act, leading to marginal market shares. The changes in the prices of biosimilars were not as remarkable as the changes in the prices of reference products after the biosimilar market entry. For most active substances, biosimilar prices were stable or decreased. The utilization of biosimilars varied widely between different active substances at the end of the observation period.ConclusionsChanges in pricing policy and the public reimbursement scheme related to the market entry of biosimilars were the main reasons for the decrease in the prices of reference products. Therefore, biosimilars did not generate genuine price competition between biological products. In many of the drug groups examined, the market shares of biosimilars have growth potential in the future.Supplementary InformationThe online version contains supplementary material available at 10.1007/s40259-022-00540-y.

What is the value of faster acting prandial insulin? Focus on ultra rapid lispro.

Rapid‐acting insulins (RAIs) have been instrumental in the management of diabetes because of their improved postprandial glucose (PPG) control compared with regular human insulin. However, their absorption rate and time action following subcutaneous administration still falls short of the normal physiological response to meal consumption, increasing the risk of early postmeal hyperglycaemia and late postmeal hypoglycaemia. Increased demand for faster acting insulins, which can quickly control PPG excursions without increasing the risk of late hypoglycaemia, led to the development of ultra‐rapid–acting insulins, including ultra‐rapid lispro (URLi). URLi is a novel formulation of insulin lispro with accelerated absorption driven by two excipients: treprostinil, which increases local vasodilation, and citrate, which increases local vascular permeability. Clinical pharmacology studies consistently showed an earlier onset and shorter duration of action with URLi compared with Lispro. In a head‐to‐head study with Faster aspart, Aspart and Lispro, URLi was absorbed faster, provided earlier insulin action, and more closely matched physiological glucose response than the other insulins tested. URLi's unique pharmacokinetic properties increase its potential for improved PPG control beyond that achieved with RAIs. Indeed, in pivotal phase 3 trials, URLi was superior to Lispro for PPG control both at 1 and 2 hours after a meal in type 1 and type 2 diabetes with multiple daily injections, and in type 1 diabetes with continuous subcutaneous insulin infusion. This was achieved without increasing the risk of hypoglycaemia. In this review, we focus on the clinical and pharmacological evidence for URLi in the treatment of diabetes and discuss the potential benefits and considerations with URLi compared with RAIs.

Photoacoustic imaging reveals mechanisms of rapid-acting insulin formulations dynamics at the injection site

ObjectiveUltra-rapid insulin formulations control postprandial hyperglycemia; however, inadequate understanding of injection site absorption mechanisms is limiting further advancement. We used photoacoustic imaging to investigate the injection site dynamics of dye-labeled insulin lispro in the Humalog® and Lyumjev® formulations using the murine ear cutaneous model and correlated it with results from unlabeled insulin lispro in pig subcutaneous injection model. MethodsWe employed dual-wavelength optical-resolution photoacoustic microscopy to study the absorption and diffusion of the near-infrared dye-labeled insulin lispro in the Humalog and Lyumjev formulations in mouse ears. We mathematically modeled the experimental data to calculate the absorption rate constants and diffusion coefficients. We studied the pharmacokinetics of the unlabeled insulin lispro in both the Humalog and Lyumjev formulations as well as a formulation lacking both the zinc and phenolic preservative in pigs. The association state of insulin lispro in each of the formulations was characterized using SV-AUC and NMR spectroscopy. ResultsThrough experiments using murine and swine models, we show that the hexamer dissociation rate of insulin lispro is not the absorption rate-limiting step. We demonstrated that the excipients in the Lyumjev formulation produce local tissue expansion and speed both insulin diffusion and microvascular absorption. We also show that the diffusion of insulin lispro at the injection site drives its initial absorption; however, the rate at which the insulin lispro crosses the blood vessels is its overall absorption rate-limiting step. ConclusionsThis study provides insights into injection site dynamics of insulin lispro and the impact of formulation excipients. It also demonstrates photoacoustic microscopy as a promising tool for studying protein therapeutics. The results from this study address critical questions around the subcutaneous behavior of insulin lispro and the formulation excipients, which could be useful to make faster and better controlled insulin formulations in the future.