Severe Hypoglycemia In Patients Research Articles

Practicality of non-invasive glucagon-loaded dissolving microneedle for life-saving treatment of severe hypoglycemia in a diabetic rat model

The development of dissolving microneedles (DMNs) has brought light to the transdermal delivery of biomolecules that are released into the skin through the rapid dissolution of the matrix material to enter the systemic circulation and exert therapeutic effects. Herein, we aimed to prepare, characterize, and analyze the effectiveness of a glucagon-loaded DMN system that rapidly increases blood sugar levels in rats with diabetic hypoglycemia. The stability and content of biological drugs following DMNs preparation was assessed using circular dichroism and bicinchoninic acid kit for protein determination kits(BCA kits). The maximum drug loading capacity of DMNs was approximately 140 μg in each patch, and the microneedles could be stored for up to 14 days under dry storage conditions. In vitro skin permeation studies were conducted using a Franz diffusion cell apparatus for glucagon-loaded DMNs. To investigate the efficacy of transdermal drug delivery, drug-laden DMNs were administered to rats with hypoglycemic diabetes. Compared to subcutaneous injections, microneedle drug release demonstrated comparable efficacy in raising blood glucose levels in vivo. Therefore, this study demonstrated that glucagon-loaded DMNs may be a promising approach for efficient transdermal drug delivery as an alternative to subcutaneous injection for the treatment of severe hypoglycemia in patients with diabetes.

Blood glucose trends in glycogen storage disease type Ia: A cross-sectional study.

Glycogen storage disease type Ia (GSDIa) is caused by biallelic pathogenic variants in the glucose-6-phosphatase gene (G6PC) and mainly characterized by hypoglycemia, hepatomegaly, and renal insufficiency. Although its symptoms are reportedly mild in patients carrying the G6PC c.648G>T variant, the predominant variant in Japanese patients, details remain unclear. Therefore, we examined continuous glucose monitoring (CGM) data and daily nutritional intake to clarify their associations in Japanese patients with GSDIa with G6PC c.648G>T. This cross-sectional study enrolled 32 patients across 10 hospitals. CGM was performed for 14 days, and nutritional intake was recorded using electronic diaries. Patients were divided according to genotype (homozygous/compound heterozygous) and age. The durations of biochemical hypoglycemia and corresponding nutritional intake were analyzed. Multiple regression analysis was performed to identify factors associated with the duration of biochemical hypoglycemia. Data were analyzed for 30 patients. The mean daily duration of hypoglycemia (<4.0 mmol/L) in the homozygous group increased with age (2-11 years [N = 8]: 79.8 min; 12-18 years [5]: 84.8 min; ≥19 years [10]: 131.5 min). No severe hypoglycemic symptoms were recorded in the patients' diaries. The mean frequency of snack intake was approximately three times greater in patients aged 2-11 years (7.1 times/day) than in those aged 12-18 years (1.9 times/day) or ≥19 years (2.2 times/day). Total cholesterol and lactate were independently associated with the duration of biochemical hypoglycemia. Although nutritional therapy prevents severe hypoglycemia in patients with GSDIa with G6PC c.648G>T, patients often experience asymptomatic hypoglycemia.

Differential Associations of GAD Antibodies (GADA) and C-Peptide With Insulin Initiation, Glycemic Responses, and Severe Hypoglycemia in Patients Diagnosed With Type 2 Diabetes.

We examined the associations of GAD antibodies (GADA) and C-peptide (CP) with insulin initiation, glycemic responses, and severe hypoglycemia in type 2 diabetes (T2D). In 5,230 Chinese patients (47.6% men) with T2D (mean ± SD age: 56.5 ± 13.9 years; median diabetes duration: 6 [interquartile range 1, 12] years), enrolled consecutively in 1996-2012 and prospectively observed until 2019, we retrospectively measured fasting CP and GADA in stored serum and examined their associations with aforementioned outcomes. At baseline, 28.6% (n = 1,494) had low CP (<200 pmol/L) and 4.9% (n = 257) had positive GADA (GADA+). In the low-CP group, 8.0% had GADA+, and, in the GADA+ group, 46.3% had low CP. The GADA+ group had an adjusted hazard ratio (aHR) of 1.46 (95% CI 1.15-1.84, P = 0.002) for insulin initiation versus the GADA- group, while the low-CP group had an aHR of 0.88 (0.77-1.00, P = 0.051) versus the high-CP group. Following insulin initiation, the GADA+ plus low-CP group had the largest decrements in HbA1c (-1.9% at month 6; -1.5% at month 12 vs. -1% in the other three groups). The aHR of severe hypoglycemia was 1.29 (95% CI 1.10-1.52, P = 0.002) in the low-CP group and 1.38 (95% CI 1.04-1.83, P = 0.024) in the GADA+ group. There is considerable heterogeneity in autoimmunity and β-cell dysfunction in T2D with GADA+ and high CP associated with early insulin initiation, while GADA+ and low CP, increased the risk of severe hypoglycemia. Extended phenotyping is warranted to increase the precision of classification and treatment in T2D.

Epidemiological, Social and Economic Burden of Severe Hypoglycaemia in Patients with Diabetes Mellitus in Portugal: A Structured Literature Review.

The aim of this review was to identify and review studies reporting on the epidemiological, social and economic impact associated with severe hypoglycaemia (SH) in people with diabetes mellitus (DM) in Portugal. A structured literature search was carried out in PubMed and Embase using a predefined selection criterion. Studies published in either Portuguese or English, between January 2010 and February 2021 were deemed eligible for inclusion. Twelve studies including adults (aged ≥ 18years) with type 1 and/or type 2 diabetes mellitus (T1DM/T2DM) were eligible for inclusion. Epidemiological estimates varied according to the setting and type of data source used. The proportion of patients who experienced ≥ 1 SH episode (SHE) in the previous 6-12months varied from 3.1% in adults with T2DM to 36.8% in adults with T1DM. In adults with T2DM the prevalence in a community-based study was highest in the insulin and secretagogue combination treated group (9.1%), while in an emergency department setting prevalence was highest in the insulin-based therapy group and the oral hypoglycaemic agent without secretagogues group (32.0% and 20.0%, respectively). The prevalence of SH in other studies in patients with DM ranged from 0.1% (emergency department) to 18.1% (hospital ward). Patients treated with secretagogues had the highest rates of hospitalisations. In patients with T1DM, the annual rate of SHE was higher in those with impaired hypoglycaemia awareness than in those with intact awareness. Mean total cost (direct and indirect) per SHE ranged from €1493.00 in patients with T2DM treated in an emergency setting to €2608.51 in patients with T1DM who were hospitalised. Hypoglycaemic events, especially SHE, have a significant effect on the life of persons living with DM and their caregivers. Studies show that the prevalence of this acute complication of diabetes is not negligible. In addition to the negative impact on the quality of life, the burden of SHE in Portugal translates into a significant impact on the global health expenditure.

Severe hypoglycemia in patients with liver cirrhosis and type 2 diabetes.

Advanced liver disease with massive liver damage may affect the metabolism of hypoglycemic agents and increase the risk of hypoglycemia. We conduct this research to compare the risk of severe hypoglycemia between patients with type 2 diabetes, with and without compensated liver cirrhosis. From Taiwan's National Health Insurance Research Database, we identified persons with type 2 diabetes with cirrhosis (n = 18,209) and without cirrhosis (n = 538,510) from January 1, 2000, to December 31, 2010. Cox proportional hazards models were adopted to assess risks of all-cause mortality and severe hypoglycemia. The mean follow-up period of this study was 3.7 years. The incidence rates of death during follow-up were 26.54 and 2.75 per 1,000 patient-years [aHR 7.63 (6.70-8.70)] for patients with cirrhosis and without cirrhosis, respectively. The incidence rates of severe hypoglycemia during follow-up were 0.53 and 0.14 per 1,000 patient-years [aHR 2.74 (1.52-4.92)] for patients with and without cirrhosis, respectively. The subgroup analysis of hypoglycemia risks in patients with and without cirrhosis disclosed no significant interaction for variables such as age, sex, chronic kidney disease, sulfonylurea use, number of oral antidiabetic drugs, insulin, b-blocker, and fibrate. This cohort study demonstrated that patients with type 2 diabetes and compensated cirrhosis showed a higher risk of mortality and severe hypoglycemia than those without liver cirrhosis.

Managing Severe Hypoglycaemia in Patients with Diabetes: Current Challenges and Emerging Therapies.

Hypoglycaemia is common in patients with diabetes mellitus and is a limiting factor for achieving adequate glycaemic control. In the vast majority of cases, hypoglycaemia develops due to the imbalance between food intake and insulin injections. As recurrent hypoglycaemia leads to significant morbidity and mortality, the recognition and immediate treatment of hypoglycaemia in diabetic patients is thus important. In the last 20 years, the introduction of improved insulin analogues, insulin pump therapy, continuous glucose monitoring (CGM), and sensor-augmented pump therapy have all made significant improvements in helping to reduce and prevent hypoglycaemia. In terms of treatment, the American Diabetes Association recommends oral glucose as the first-line treatment option for all conscious patients with hypoglycaemia. The second line of treatment (or first line in unconscious patients) is the use of glucagon. Novel formulations of glucagon include the nasal form, the Gvoke HypoPen which is a ready-to-deliver auto-injector packaged formulation and finally a glucagon analogue, Dasiglucagon. The Dasiglucagon formulation has recently been approved for the treatment of severe hypoglycaemia. It is a ready-to-use, similar to endogenous glucagon and its potency is also the same as native glucagon. It does not require reconstitution before injection and therefore ensures better compliance. Thus, significant improvements including development of newer insulin analogues, insulin pump therapy, continuous glucose monitoring (CGM), sensor-augmented pump therapy and novel formulations of glucagon have all contributed to reducing and preventing hypoglycaemia in diabetic individuals. However, considerable challenges remain as not all patients have access to diabetes technologies and to the newer glucagon formulations to help reduce and prevent hypoglycaemia.

Classification and prediction of hypoglycemia in diabetic patients using machine learning techniques

Type 1 diabetics can lower their risk of microvascular and macrovascular problems by carefully regulating their blood glucose levels. The downside is that these measures are incredibly challenging because of the wide diversity across individuals, as well as other factors that affect glycemic management. Keeping glucose levels under control is difficult due to the possibility of severe hypoglycemia in patients receiving intensive insulin therapy. In people with diabetes, hypoglycemia is a common complication, which has a negative impact on overall health and well-being. Improving patient safety by anticipating unfavourable glycemic events has become a practical approach to enhanced patient safety using machine learning decision assistance. This paper suggests the use of three machine learning techniques to solve the problem of diabetic safety: (1) Random Forest for continuous glucose predictions, (2) support vector machines for postprandial period predictions, and (3)artificial neural networks for overnight hypoglycemic predictions. It has the two different categorization and prediction capabilities already established. A major system feature is the overall reduction in bouts of hypoglycemia, which results in an increase in patient safety and provides better confidence in treatment decisions.

Dasiglucagon for treating severe hypoglycemia in patients with diabetes

Introduction Diabetic patients are prone to hypoglycemia when treated with insulin. Dasiglucagon is a water-soluble and ready-to-use glucagon analog developed for treating hypoglycemia in patients with diabetes. Areas covered A comprehensive literature search was conducted in PubMed. Key search terms included dasiglucagon and hypoglycemia. The pharmacological characteristics, clinical evidence, and place in therapy of dasiglucagon were reviewed. Expert opinion Dasiglucagon is a glucagon analogue that is stable in water-soluble formulation. It can increase plasma glucose in a dose-dependent manner. Clinical studies have shown that dasiglucagon rapidly and effectively increased insulin-induced hypoglycemia in patients with diabetes. Dasiglucagon was well tolerated and the common adverse events included nausea and vomiting.

383-P: Clinical Practice Gap Analysis of Severe Hypoglycemia Assessment and Treatment in Patients with Diabetes

Introduction: Understanding clinical practice gaps in the assessment and treatment of severe hypoglycemia in patients with diabetes can inform development of tools to improve physician practices. Methods: A survey instrument of 25 multiple choice, knowledge- and case-based questions allowed participants to assess their knowledge, attitudes, and confidence with regard to severe hypoglycemia. The survey was available online to physicians across the globe without monetary compensation or charge. Respondent confidentiality was maintained and responses were de-identified and aggregated prior to analyses. Initial data collection occurred from May 4, 2021, to July 12, 2021. Results: In total, 64 diabetologists/endocrinologists (D/Es) and 187 primary care physicians (PCPs) completed the full assessment within the data collection period. When asked how many of their patients with diabetes have a prescription for glucagon, 88% of D/Es estimated &amp;lt;50% (and 69% estimated &amp;lt;20%) , 93% of PCPs estimated &amp;lt;50% (and 87% estimated &amp;lt;20%) . Conclusion: This educational research on assessment of physicians’ clinical practices yielded important insights into clinical gaps related to assessment and treatment of severe hypoglycemia in patients with diabetes. Further studies are planned to assess the effect of medical education on decreasing these clinical practice gaps. Disclosure A.Larkin: None. A.Le: None. J.Schrand: None. Funding Developed through independent educational grant from Xeris Pharmaceuticals

Trends of severe hypoglycemia in patients with type 2 diabetes in Korea: A longitudinal nationwide cohort study.

To estimate the trends in the prevalence of severe hypoglycemia (SH) in patients with type 2 diabetes in Korea, we investigated the total number of SH episodes among type 2 diabetes patients aged ≥30 years who visited the emergency department between 2002 and 2019, using the Korean National Health Insurance Service database. The prevalence of SH events increased from 2002 to 2012; however, it has decreased gradually since 2012. In 2019, the prevalence of SH was 0.6%, with an incidence rate of 4.43 per 1,000 person‐years. Approximately 23,000 SH events occur every year in Korea. Although the incidence is steadily decreasing, there are a considerable number of SH events in type 2 diabetes patients. The decline in the incidence of SH seems to most likely be due to the increased prescription rate of hypoglycemic agents without hypoglycemia risk, less‐strict treatment goals and the individualization of therapy.

Analysis of Severe Hypoglycemia Among Adults With Type 2 Diabetes and Nonalcoholic Fatty Liver Disease

Previous studies have indicated that liver cirrhosis is associated with hypoglycemia, but there have been no studies investigating the association between nonalcoholic fatty liver disease (NAFLD) and hypoglycemia in noncirrhotic populations with type 2 diabetes. To explore the association of NAFLD with severe hypoglycemia among patients with type 2 diabetes. This nationwide population-based retrospective cohort study using the National Health Insurance System of South Korea included individuals aged 20 years or older who had undergone a medical health examination between January 1, 2009, and December 31, 2012, and were diagnosed with type 2 diabetes. Participants were followed up until December 31, 2015. Data analyses were performed between January 1, 2019, and February 2, 2021. The baseline fatty liver index (FLI) was used as a surrogate marker for NAFLD. The outcome of interest, severe hypoglycemia, was measured using hospital admission and emergency department visit records with a primary diagnosis of hypoglycemia. Among 1 946 581 individuals with type 2 diabetes, 1 125 187 (57.8%) were male. During a median (IQR) follow-up of 5.2 (4.1-6.1) years, 45 135 (2.3%) experienced 1 or more severe hypoglycemia events. Participants with severe hypoglycemia, vs those without severe hypoglycemia, were older (mean [SD] age, 67.9 [9.9] years vs 57.2 [12.3] years; P < .001) and had lower mean (SD) body mass index (24.2 [3.43] vs 25.1 [3.4]; P < .001). Patients with NAFLD tended to have less severe hypoglycemia without consideration of obesity status. However, after adjustment of multiple clinical covariates, including body mass index, there was a J-shaped association between FLI and severe hypoglycemia (5th decile: adjusted hazard ratio [aHR], 0.86; 95% CI, 0.83-0.90; 9th decile: aHR, 1.02; 95% CI, 0.96-1.08; 10th decile: aHR, 1.29; 95% CI, 1.22-1.37), and the estimated risk of hypoglycemia was higher in participants with NAFLD (aHR, 1.26; 95% CI, 1.22-1.30). The association was more prominent in female participants (aHR, 1.29; 95% CI, 1.23-1.36) and those with underweight (aHR, 1.71; 95% CI, 1.02-2.88). In this study, NAFLD was associated with a higher risk of severe hypoglycemia in patients with type 2 diabetes independent of obesity status. Presence of NAFLD should be considered when evaluating vulnerability to hypoglycemia in patients with type 2 diabetes.

Peptide receptor radionuclide therapy as a tool for the treatment of severe hypoglycemia in patients with primary inoperable insulinoma

Abstract Objectives Severe hypoglycemia in a course of inoperable insulinoma may be life-threating and often it is not well controlled, even by high doses of diazoxide requiring second line treatment. Among available methods PRRT is characterized by relatively low toxicity and is connected with favorable antitumor effect. The aim of the study was an evaluation of the PRRT effectiveness in control of hypoglycemia in patients with primary inoperable insulinoma. Methods Three patients (female with metastatic insulinoma, male with primary inoperable pancreatic tumor, female with MEN1 syndrome and hepatic metastases) were treated with PRRT due to severe hypoglycemia poorly controlled by diazoxide in course of primary inoperable insulinoma. Results Patient 1 baseline fasting glucose concentration increased from 2.4 mmol/L [3.30–5.60] to 5.9 mmol/L after PRRT. In patient 2 fasting glucose level 2.30 mmol/L increased after PRRT to 7.0 mmol/L, while baseline insulin level initially 31.15 uU/mL [2.6–24.9] decreased to 15.4 uU/mL. In patients 3, baseline fasting glucose level 2.5 mmol/L increased after PRRT to 7.9 mmol/L, and insulin decreased from 57.9 uU/mL to 6.3 uU/mL. In imaging there was partial response (PR) in patient 1 and 2 and stabilization of the tumor size in patient 3. In patient 2 reduction of tumor infiltration let for curative surgery performed 4 months after PPRT. Conclusions PRRT may be effective as a first or second line treatment in management of hypoglycemia for patients with hormonally active inoperable insulinoma.

Dasiglucagon: an effective medicine for severe hypoglycemia.

Patients with type 1 diabetes mellitus (T1DM) receiving insulin therapy commonly suffer from insulin-mediated hypoglycemia and require glucagon for glycemic control to achieve normal plasma glucose (PG) levels. Severe hypoglycemia will endanger the life of patients and require intervention. Stable glucagon analog dasiglucagon was approved for the treatment of patients with severe hypoglycemia and is administered via Zegalogue autoinjector/Zegalogue prefilled syringe.The main purpose of this review article is to review the basic properties and clinical effects of dasiglucagon. We search related literature on CNKI, Web of Science and PubMed by keywords dasiglucagon, hypoglycemia, type 1 diabetes, glucagon. Carry out a careful review of the included literature. Dasiglucagon information on clinicaltrials.gov and https://www.fda.gov/ has been adopted. Dasiglucagon is a novel peptide analog of human glucagon, which can effectively rescue insulin-induced severe hypoglycemia in patients with T1DM and rapidly increase glycemic levels in a small dose under normal and hypoglycemic conditions. It has been proven that dasiglucagon has definite stability and solubility in aqueous formulations. Dasiglucagon has a higher absorption rate and longer plasma elimination half-life than traditional reconstituted glucagon. In three randomized, double-blind, placebo-controlled trials in children aged 6 to 17years and adults with T1DM the median time to glycemic recovery in 10min after dasiglucagon administration was significantly faster than placebo and 99% of patients recovered within 15min after subcutaneous injection of dasiglucagon in the key phase 3 clinical trial. The most common adverse reactions in these phase 3 trials were vomiting, nausea, diarrhea, headache, and injection site pain.

352-P: Assessment of a Deep Learning Model Based on Three-Year Longitudinal Electronic Health Record Data for Predicting Severe Hypoglycemia in Patients with Type 2 Diabetes

Background: This study aimed to investigate the ability of a deep learning model to predict the outcome of severe hypoglycemia (SH) using longitudinal electronic medical records data. Methods: Structured data were extracted from the clinical data warehouse, including demographics, laboratory, medications, and diagnostic information. Between January 2010 and December 2012, 17,670 adult patients were enrolled; participants had type 2 diabetes, were aged over 30 years, and visited the diabetes centers of two hospitals. The primary outcome was SH, defined as diagnostic codes for hypoglycemia (E16.x, E11.63, E13.63, E14.63) in hospitalization or emergency room records. The performance of the longitudinal deep learning model (gated recurrent units) in predicting SH was quantified using the area under the receiver operating characteristic curve (AUROC) and evaluated in terms of net reclassification improvement (NRI) versus a traditional logistic regression model. Based on predicted risk of SH, we stratified patients into four risk groups: low (&amp;lt;1.0%), intermediate (1.0% to &amp;lt;2.0%), high (2.0% to &amp;lt;5.0%), and very high (≥5.0%). Results: Of 17,670 patients, 528 patients developed SH events during the follow-up period (mean of 6.4 years). The performance of the longitudinal deep learning model was superior to the logistic model for predicting SH (AUROC of logistic model, 0.788 [95% CI 0.781-0.793] vs. longitudinal deep learning model, 0.858 [0.853-0.863]). The very high-risk group of SH categorized using the deep learning model had 73 times higher risk of SH than the low-risk group. The deep learning model improved case reclassification (NRI, 13.4%). Conclusion: We found that the longitudinal deep learning model showed better performance and classification ability for predicting than the conventional logistic model. Disclosure G. Lee: None. S. Ko: None. Y. Ahn: None. E. Lee: None. S. Cha: None. D. Kim: None. J. Yun: None. Funding Korean Diabetes Association (2018-F to J-S.Y.)

Abstract #995396: Inpatient Sulfonylurea-induced Hypoglycemia and the Transition to Outpatient: Addressing Chronic Overtreatment in High-risk Patients

The risk of severe hypoglycemia in patients with diabetes treated aggressively with glucose-lowering therapies is well recognized and may result in serious cardiovascular and cognitive complications and even death. Sulfonylureas (SU) remain a common cause of severe hypoglycemia but are still used in high-risk individuals due to affordability and the convenience of routine. We present the case of an elderly patient with multiple comorbidities and hypoglycemia unawareness in whom inpatient evaluation led to the recognition of inappropriate SU therapy use and, importantly, resulted in a change in his aggressive long-term diabetes management.

Losartan Induced Hypoglycemia in the Absence of Diabetes Mellitus - a Concealed Diagnosis

Background: Losartan has been shown to attenuate symptomatic and hormonal responses to hypoglycemia in prior studies. This results predominantly from blocking AT-II receptors blunting the hypoglycemia-induced rise in plasma epinephrine predisposing them to hypoglycemia unawareness. To our knowledge, however there are no case reports describing losartan induced hypoglycemia in a nondiabetic patient. This abstract is the first description of a patient without diabetes mellitus experiencing severe hypoglycemia induced by the ARB, Losartan. Clinical Case: A 51- year old nondiabetic female was found to be somnolent and in acute respiratory failure. Blood sugar was 34 mg/dL. She received D10 by EMS while coming to the hospital. She was intubated and treated for atypical pneumonia based on bilateral interstitial infiltrates. She remained persistently hypoglycemic around 62 mg/dL. Her most recent A1c was 4.4%. Thyroid function was within normal limits. AM cortisol was 16.8 mcg/dL so there was no concern of adrenal insufficiency. She had no history of gastric bypass surgery. She underwent a 72-hour fast and developed symptomatic hypoglycemia. Her venous blood glucose at this time was 49 mg/dL. Her hypoglycemia panel obtained at this time showed C-peptide 0.7 ng/mL, total insulin 2.9 microU/mL, proinsulin 3.1 pmol/L, IGF 45 ng/mL and BHOB 13.5 mmol/L. Her oral hypoglycemic agent screen was negative. Based on levels that were obtained during the hypoglycemic episode, this correlated to a non-diagnostic study for conventionally described causes of hypoglycemia including exogenous insulin, insulinoma, NIPHS, PGBH, oral hypoglycemic agent, insulin autoimmune or IGF-mediated. Her medication list was analyzed again. We learnt that she had recently been started on losartan about a month prior to this admission for her heart failure management. On further review, the patient mentioned that she was noticing these hypoglycemic events in the last month and that seemed to coincide with when she was started on losartan. We subsequently held losartan which resulted in profound improvement in her glycemic control and her blood sugars improved to a range of 110–140 mg/dL consistently. She was discharged from hospital off losartan. Blood sugar was stable on repeat testing outpatient after discharge.Conclusion: This is the first case that demonstrates the role of losartan in causing severe hypoglycemia in patients without a history of diabetes mellitus. Discontinuation of losartan resulted in prompt improvement of hypoglycemia. Reference: (1) Deininger E, Oltmanns KM, Wellhoener P, Fruehwald-Schultes B, Kern W, Heuer B, Dominiak P, Born J, Fehm HL, Peters A. Losartan attenuates symptomatic and hormonal responses to hypoglycemia in humans. Clin Pharmacol Ther. 2001 Oct;70(4):362–9. PMID: 11673752.

Scientific and Regulatory Considerations for the Approval of the First Generic Glucagon

Glucagon for Injection (NDA 020928) is a polypeptide hormone identical to human glucagon approved 20 years ago for severe hypoglycemia in patients with diabetes mellitus. On Dec 28, 2020, the U.S. FDA approved the first generic version of glucagon for injection USP, 1 mg/vial packaged in an emergency kit. The generic and the reference listed drug (RLD) version, i.e., the innovator version, of glucagon were each produced through different manufacturing processes. The RLD version of glucagon is produced via recombinant DNA in yeast while the generic version of glucagon is produced by peptide synthesis. The FDA published its current thinking on how to ensure sameness between the generic and innovator peptide products prepared with different manufacturing processes in a Draft Guidance for Industry: Submission of Abbreviated New Drug Applications for Certain Highly Purified Synthetic Peptide Drug Products, which applies to five peptide drug products, including glucagon. In this presentation, we aim to provide an overview of the regulatory recommendations for submitting generic glucagon drug products for approval, as outlined in the aforementioned draft guidance. Although glucagon may be produced using different manufacturing processes, the sameness in glucagon can be adequately demonstrated using analytical methods, which involve demonstrating physicochemical properties, as well as primary and secondary structures, oligomers and aggregation states. Biological assays may also be used as part of the demonstration of active pharmaceutical ingredient sameness. Synthetic glucagon may have different impurity profiles when compared to the RLD recombinant product. As part of the ANDA review, impurities in the synthetic drugs are analyzed and controlled, in addition, the potential immunogenicity of new impurities, which are not in the RLD products, are assessed and compared using non-clinical assays. In this work, we will discuss non-clinical assays for assessing the immunogenicity risk of these impurities, for both adaptive and innate immune responses. In conclusion, the sameness of an approved generic synthetic glucagon to an RLD can be adequately established through various analytical methods and biological assays.

Unfortunate Case of Hypoglycemia Induced Seizures Resulting in Anoxic Encephalopathy

Background: Severe hypoglycemia in patient with diabetes mellitus can manifest as seizures and coma, most commonly occurring after excessive insulin administration. Clinical Case: A 35-year-old woman with uncontrolled type 1 diabetes mellitus on basal-bolus insulin, complicated by gastroparesis, hypoglycemia unawareness, and frequent hypoglycemic episodes due to a tendency to give more than the recommended amount of insulin, who presented with seizures and diffuse brain edema as severe manifestations of profound hypoglycemia. Hemoglobin A1c was 7.3% but patient had wide variation in blood glucose (40- 300 mmol/L) on her glucometer. Patient had initially self-treated overnight hypoglycemic symptoms by drinking soda and then fell asleep without re-checking her blood sugar. She was then unresponsive in the morning. Patient’s husband reported that there was no glucagon at home since he used the last one and did not refill. On EMS arrival, patient had a blood glucose of 25, for which she received dextrose and glucagon with improvement of blood glucose but no change in mentation. En route to the hospital, patient developed tonic-clonic seizures and decerebrate posturing. She received Ativan and was intubated for airway protection. On exam, she had bilateral dilated sluggishly reactive pupils, eyes opened spontaneously but did not track, and limbs moved spontaneously but there was no purposeful movement. Initial CT head without contrast showed significant diffuse brain edema. Repeat MRI brain with and without contrast showed bilateral basal ganglia diffusion restriction with associated T2 and FLAIR hyperintense signal, suggestive of toxic-metabolic etiology including hypoglycemia. Video EEG showed findings consistent with anoxic encephalopathy. Patient received IV mannitol and IV dexamethasone for cerebral edema and Keppra for seizure prophylaxis, but was unable to be weaned from the ventilator and had to undergo tracheostomy and PEG tube placement, and was eventually discharged to inpatient rehabilitation. Conclusion: This case highlights the dangers of accidental overcorrection of high blood sugar with short-acting insulin and not appropriately treating hypoglycemia, which can lead to irreversible brain injury due to prolonged hypoglycemia. This unfortunate case highlights the importance of educating patients with diabetes mellitus on insulin how to appropriately manage low sugars to avoid such outcomes.

Monitoring the Impact of Aggressive Glycemic Intervention during Critical Care after Cardiac Surgery with a Glycemic Expert System for Nurse-Implemented Euglycemia: The MAGIC GENIE Project.

A novel, multi-dimensional protocol named GENIE has been in use for intensive insulin therapy (IIT, target glucose <140 mg/dL) in the surgical intensive care unit (SICU) after open heart surgery (OHS) at VA Pittsburgh since 2005. Despite concerns over increased mortality from IIT after the publication of the NICE-SUGAR Trial, it remains in use, with ongoing monitoring under the MAGIC GENIE Project showing that GENIE performance over 12 years (2005-2016) aligns with the current consensus that IIT with target blood glucose (BG) <140 mg/dL is advisable only if it does not provoke severe hypoglycemia (SH). Two studies have been conducted to monitor glucometrics and outcomes during GENIE use in the SICU. One compares GENIE (n = 382) with a traditional IIT protocol (FORMULA, n = 289) during four years of contemporaneous use (2005-2008). The other compares GENIE's impact overall (n = 1404) with a cohort of patients who maintained euglycemia after OHS (euglycemic no-insulin [ENo-I], n = 111) extending across 12 years (2005-2016). GENIE performed significantly better than FORMULA during contemporaneous use, maintaining lower time-averaged glucose, provoking less frequent, severe, prolonged, or repetitive hypoglycemia, and achieving 50% lower one-year mortality, with no deaths from mediastinitis (0 of 8 cases vs 4 of 9 on FORMULA). Those benefits were sustained over the subsequent eight years of exclusive use in OHS patients, with an overall one-year mortality rate (4.2%) equivalent to the ENo-I cohort (4.5%). The results of the MAGIC GENIE Project show that GENIE can maintain tight glycemic control without provoking SH in patients undergoing OHS, and may be associated with a durable survival benefit. The results, however, await confirmation in a randomized control trial.

Relationship between previous HbA1c value and subsequent severe hypoglycaemia in patients with coronary artery disease and type 2 diabetes. Data from the DMP in North Rhine, Germany

Abstract Background and purpose Based on the documentation data of DMP type 2 diabetes in North Rhine from 2018, it was examined to what extent the HbA1c value from 2012 influenced the emergence of severe hypoglycaemia from 2013 in patients with coronary artery disease (CAD). Methods The predictors were determined in separate logistic regression models. The database was the last follow-up documentation of 2018. For all patients it was determined which HbA1c value was available in 2012 and whether severe hypoglycaemia has been documented for the first time since 2013. Results Within a group of a total of 98,950 patients, 2,520 new cases of severe hypoglycaemia have been documented since 2013. Treatment with insulin (odds ratio OR 7.00; 95-%-CI 5.80–8.44), HbA1c over 8.5% in 2012 (OR 1.66; 1.43–1.93), and the presence of diabetic complications (OR 1.37; 1.23–1.52) were the greatest risk factors, adjusted for age, gender, duration of DMP care and blood pressure. When the up to 70-year-old patients were analyzed separately, the two main predictors turned out to be somewhat weaker (insulin OR 5.40; 3.76–7.76; HbA1c &amp;gt;8.5% OR 1.61; 1.23–2, 11), on the other hand, they were somewhat more pronounced for patients over 70 years of age (insulin OR 7.58; 6.09–9.44; HbA1c &amp;gt;8.5% OR 1.72; 1.42–2.07). The influence of comorbidity was comparably high in both subgroups (≤70 years, OR 1.45; 1.16–1.79; &amp;gt;70 years OR 1.34; 1.19–1.51). Conclusion In patients with CAD and type 2 diabetes, the insulin prescription, a previously high HbA1c value and comorbidity are significant predictors for the later recurrence of severe hypoglycaemia; these influences are somewhat weaker in younger patients and somewhat more pronounced in older patients. A association between low HbA1c values and an increased risk of new onset of severe hypoglycaemia could not be demonstrated even in older patients with CAD and T2D. Funding Acknowledgement Type of funding source: Public Institution(s). Main funding source(s): Joint Establishment Disease Management Programs North Rhine