Conversations and Reactions Around Severe Hypoglycaemia (CRASH): Results from the German Cohort of a Global Survey of People with Type 1 Diabetes or Insulin-Treated Type 2 Diabetes and Caregivers.

BACKGROUND: A global cross-sectional survey (CRASH) was designed to provide information about the experiences of people with diabetes (PWD) and their caregivers in relation to severe hypoglycaemic events. METHODS: Adults with type 1 diabetes or insulin-treated type 2 diabetes who had experienced one or more severe hypoglycaemic events within the past 3 years, and adult caregivers for such people, were recruited from medical research panels using purposive sampling. We present here results from Germany. RESULTS: Approximately 100 individuals in each of the four participant groups completed a 30-minute online survey. Survey results indicated that the most recent severe hypoglycaemic event made many participants feel scared (80.4%), unprepared (70.4%), and/or helpless (66.5%). Severe hypoglycaemia was discussed by healthcare professionals at every visit with only 20.2% of participants who had ever had this conversation, and 53.5% of participants indicated that their insulin regimen had not changed following their most recent event. 37.1% of PWD/people with diabetes cared for by caregivers owned a glucagon kit at the time of survey completion. CONCLUSIONS: The survey identified areas for improvement in the prevention and management of severe hypoglycaemic events. For healthcare professionals, these include enquiring more frequently about severe hypoglycaemia and adjusting blood glucose-lowering medication after a severe hypoglycaemic event. For individuals with diabetes and their caregivers, potential improvements include ensuring availability of glucagon at all times. Changes in these areas could lead not only to improved patient wellbeing but also to reduced use of emergency services/hospitalisation and, consequently, lower healthcare costs.

Out-of-Hospital Management of Diabetic Emergencies in Germany: Structural and Process Quality.

AIMS: To collect and analyse representative data of structural and process quality in the management of diabetic emergencies in Germany in 2020. METHODS: A standardised questionnaire comprising detailed items concerning clinically relevant parameters on the structural and process quality of out-of-hospital management of diabetic emergencies was sent nationwide to medical directors of emergency medical service districts (EMSDs). Results were compared with those from a similar study conducted in 2001. RESULTS: The return rate of the questionnaires represented 126 EMSDs, serving a total population of > 40.1 million. Only 4% of ambulances carried glucagon (6% in 2001). In 2020, blood glucose determination increased significantly to 71% of all emergency interventions and to 29% of suspected cardiac emergencies (24% and 15%, respectively, in 2001). In 100% of EMSDs severe hypoglycaemia (SH) was treated by paramedics by administering intravenous dextrose before the arrival of a doctor compared to 63% in 2001. The potential value of nasal glucagon was acknowledged by 43% of responders. In selected patients, treatment of SH was conducted without hospital admission in 78% of EMDs (60% in 2001). Fifty-three percent of medical directors acknowledged the need for further training in diabetic emergencies (47% in 2001). Cooperation for medical education between emergency teams and a diabetes centre was reported by 14% (41% in 2001). CONCLUSION: Structural and process quality of the management of diabetic emergencies in Germany has improved considerably since 2001. Persisting deficiencies could be improved by providing better medical equipment in ambulances and ongoing education to the entire emergency teams.

Postmortem Analysis of Vitreous Humor For Detection of Antemortem Disorders in Glucose Metabolism. An Old Method Revisited.

It has been estimated that 15% up to one third of cases of deaths due to diabetic ketoacidosis occur in individuals with so far unknown diabetes. Moreover, cardiac arrhythmias that occur during nocturnal hypoglycaemia include bradycardia and ectopics that may provoke lethal arrhythmias. As postmortem capillary glucose concentrations have no diagnostic value, the postmortem forensic proof of hyperglycaemia or hypoglycaemia remains a challenge. The established but rarely applied method of postmortem determination of glucose and lactate in vitreous humor with or without calculation of the sum formula of Traub could provide reliable exclusion or proof of severe antemortem disorders in glucose metabolism. To date, diagnostic puncture of vitreous humor is more established for the postmortem detection of diabetic ketoacidosis than for the exclusion or proof of lethal hypoglycaemia. Vitreous humor is protected from postmortem degradation and contamination due to its isolated localization. The autolytic process in vitreous humor is considerably delayed compared to blood or liquor. In vitreous humor also the triggering agent of hypoglycaemia (insulin, insulin analogues) is easier to be detected than in blood since insulins are very unstable in postmortem blood. Furthermore, parameters of long term glycaemic control such as 1,5-anhydroglucitol, HbA1c and fructosamine can be determined in vitreous humor. However, limitations and interference factors of this method should be carefully considered. So far, clinical diabetology has taken no broad notice of this useful forensic procedure.

Self-reported Hypoglycaemic Events in 2 430 Patients with Insulin-treated Diabetes in the German Sub-population of the HAT Study.

Data concerning true hypoglycaemic incidence in insulin-treated patients with diabetes in real-world clinical practice are lacking in Germany. The aim of this analysis was to determine the incidence of hypoglycaemia experienced by the German cohort of patients enrolled in the global Hypoglycaemia Assessment Tool (HAT) study. This was a non-interventional, 6-month retrospective and 4-week prospective study using self-assessment questionnaires and patient diaries assessing patients aged ≥18 years in Germany, with type 1 diabetes (T1D) (n=811) or type 2 diabetes (T2D) (n=1 619) treated with insulin for >12 months. The primary endpoint was the percentage of patients experiencing ≥1 hypoglycaemic event during the prospective observational period (4 weeks after baseline). Predictive and continuous factors (such as age, gender, duration of insulin use and HbA1c) contributing to hypoglycaemia risk were explored.During the prospective period, at least one hypoglycaemic event was reported by 81.3% of patients with T1D and 39.7% of patients with T2D, indicating that hypoglycaemia is a common acute complication among patients with insulin-treated diabetes. Severe hypoglycaemia was reported by 9.1% of patients with T1D and 5.4% of patients with T2D. Higher rates of any and severe hypoglycaemia were reported prospectively than retrospectively, regardless of diabetes type, indicating that patients retrospectively under-report hypoglycaemia. Prospective rates (events per patient-year) of any, nocturnal and severe hypoglycaemia were 80.3, 9.9 and 3.0 for T1D and 15.6, 2.4 and 1.1 for T2D, respectively. Given the potential for recall bias in retrospective reporting, this prospective assessment of hypoglycaemia appears more reliable than retrospective assessment. Trial number: NCT01696266.

Accumulation of severe hypoglycemia at weekends and in warm seasons in patients with type 1 diabetes but not with type 2 diabetes.

AIMS: To determine the influence of daytime, weekdays and seasons on the frequency of severe hypoglycemia (SH) in a German population. METHODS: Prospective population-based observational study capturing all episodes of SH between 2007 and 2014 in the Lippe-Detmold area. SH was defined as a symptomatic event requiring treatment with intravenous glucose or administration of glucagon and being confirmed by a blood glucose measurement of <2.8mmol/l. RESULTS: A total of 1080 episodes of SH in 747 patients were registered. 37.5% of cases (405/1080) were related to T1DM, 51.9% (561/1080) to T2DM, 3.2% (35/1080) to pancreatic diabetes and 7.3% (79/1080) to non-diabetic individuals. In cases with T1DM we observed a significantly higher event rate of SH at weekends versus the rest of the week: 2.87 events/weekend-hour versus 2.15 events/weekday-hour (p=0.004), especially on Saturdays. We found significantly increased incidences of SH in spring (31.2%) and summer (26.7%) versus autumn (20.3%) and winter (21.8%). There were no corresponding significant seasonal variations of HbA1c and insulin doses. The seasonal distribution of SH in subjects with T2DM was balanced with no peak incidence at weekends. CONCLUSIONS: For the risk of SH, time factors appear to contribute more substantially in individuals with T1DM than in patients with T2DM. The enhanced frequency of SH in patients with T1DM at weekends and in warm seasons was probably caused by short-term changes in behavior. Intensification of diabetes care and education with better adjustment of insulin doses in these susceptible periods could be an appropriate approach to prevent SH.

Insulinoma as rare cause of severe post-partum hypoglycemia.

Post-partum hypoglycemia in non-diabetic women is a rare condition. We report the exceptional case of a 38-year-old obese woman who experienced recurrent neuroglycopenia 3 weeks after delivery. Corresponding to severe hypoglycemia with blood glucose levels of <30 mg/dL, there was no suppression of insulin or C-peptide. Through endoscopic ultrasound we detected a hypoechoic lesion of 8 × 9 mm localized in the head of the pancreas. Thus, the diagnosis of insulinoma was most probable. Complete surgical enucleation of the insulinoma resulted in immediate and permanent resolution of hypoglycemia. The postoperative course was complicated by recurrent episodes of pancreatitis requiring endoscopic ultrasound-guided punctures of pseudocysts and temporary stenting of the pancreatic duct. In conclusion, insulinoma is a very rare, nonetheless important, differential diagnosis of post-partum hypoglycemia.

Severe hypoglycemia due to possible interaction between glibenclamide and sorafenib in a patient with hepatocellular carcinoma.

There is increasing evidence that tyrosine kinase inhibitors (TKIs) have significant blood glucose lowering effects. A 70-year old Caucasian male with liver cirrhosis Child-Pugh A, advanced hepatocellular carcinoma and diabetes had a stable glycemic control being treated with glibenclamide (3.5 mg twice daily). After the first daily dose of the TKI sorafenib (800 mg) the patient experienced acute nocturnal disorientation and somnolence with a corresponding blood glucose of 37 mg/dl. After administration of glucose intravenously the neurological disturbances were completely reversible. As there was no intercurrent deterioration neither of hepatic nor of renal function, the severe hypoglycemia can likely be attributed to a drug-drug interaction of sorafenib with the sulfonylurea. The complete inhibition of the CYP2C9 and CYP3A4 mediated metabolic pathway of glibenclamide through sorafenib might have resulted in a rapid accumulation of glibenclamide. Profound blood glucose lowering effects of sorafenib might have additionally contributed to the hypoglycemic episode.

CYP2C metabolism of oral antidiabetic drugs--impact on pharmacokinetics, drug interactions and pharmacogenetic aspects.

INTRODUCTION: The cytochrome P4502C enzymes account for the metabolism of approximately 20% of therapeutic drugs including certain oral antidiabetic drugs (OADs). AREAS COVERED: This review focuses on the effect of CYP2C enzymes on metabolism of sulphonylureas (SUs), meglitinides, and thiazolidinediones (TZDs) discussing their impact on pharmacokinetics, drug interactions and toxicological profiles. Pharmacogenetic aspects reflecting individual gene variants and variable drug effects are also considered. EXPERT OPINION: Genetic polymorphisms of CYP2C9 enzymes (*2/*2, *2/*3, *3/*3) influence the glycaemic response to SUs and impair their substrate metabolism. Restricted data from small-sized studies with heterogenous definitions of hypoglycaemia revealed no clear association between CYP2C9 genotypes and the risk of hypoglycaemia. Functional polymorphisms of CYP2C8- and CYP2C9 drug metabolizing genes affect markedly pharmacokinetics of meglitinides. Compared to wild-type carriers, patients treated with TZDs and carrying the common CYP2C8*3 and *4 variants showed a reduced glycaemic control. The strong CYP2C8 and OATP1B1 inhibitor gemfibrozil increases substantially the plasma concentrations of repaglinide and TZDs. Numerous metabolic drug interactions exist between SUs and commonly prescribed drugs, especially anti-infectives. The complex pharmacokinetic and pharmacogenetic properties and the unfavourable short and long term risk profile of glibenclamide and glimepiride raise the question whether their use can be justified any longer.

Substantial increase in incidence of severe hypoglycemia between 1997-2000 and 2007-2010: a German longitudinal population-based study.

OBJECTIVE: To compare the incidences of severe hypoglycemia and corresponding clinical circumstances in a German population between 2007-2010 and 1997-2000. RESEARCH DESIGN AND METHODS: A screening for severe hypoglycemia was performed in the Lippe-Detmold area in Germany to sensitively detect severe hypoglycemia. This was defined as a symptomatic event requiring treatment with intravenous glucose and being confirmed by a blood glucose measurement of <50 mg/dL. RESULTS: Severe hypoglycemia increased considerably from 264 events in 1997-2000 to 495 events in 2007-2010, which translated into an increase in frequency of severe hypoglycemia among all emergency admissions from 0.68 to 0.83% (P = 0.015). This was mostly related to intensification of antihyperglycemic therapy, particularly in the increasingly morbid group of hypoglycemic patients with type 2 diabetes indicated by lower HbA(1c), more comedication (3.3 vs. 7.7 drugs), and more concomitant diseases (3.6 vs. 4.4) (all P values <0.001). CONCLUSIONS: Within a 10-year period, there was an intensification of antihyperglycemic therapy in increasingly comorbid subjects, leading to a considerably higher incidence of severe hypoglycemia.

TCF7L2 and therapeutic response to sulfonylureas in patients with type 2 diabetes.

BACKGROUND: Variants in the TCF7L2 have been shown to be associated with an increased risk for type 2 diabetes (T2D). Since the association with diabetes could be explained by effects on insulin secretion, we investigated whether patients with diabetes risk alleles at rs7903146 might have an altered hypoglycaemic response to sulfonylureas (SUs). METHODS: We recruited 189 patients with T2D being treated with SUs and determined the rs7903146 diabetes risk genotype. We used a logistic regression with secondary SU failure defined as an A1C ≥7.0% after 6 months of SU treatment. RESULTS: In univariate regression analyses, TCF7L2 genotype was the only predictor of SU treatment failure. The rs7903146 T allele was significantly more frequent in the group of patients who failed to respond to SU (36%) than in the control group (26%) [P = 0.046; odds ratio (OR): 1.57 (1.01-2.45) in an additive mode of inheritance]. CONCLUSIONS: Our data suggest that patients with diabetes risk alleles in TCF7L2 have an altered hypoglycaemic response to SUs resulting in earlier secondary failure.

Impact of clinical factors and CYP2C9 variants for the risk of severe sulfonylurea-induced hypoglycemia.

AIMS: The established risk factors for severe sulfonylurea-induced hypoglycemia (SH) include low hemoglobin (Hb)A(1c), advanced age, long duration of diabetes, multimorbidity, and polypharmacy. As the genetically polymorphic cytochrome P450 (CYP), enzyme CYP2C9 is mainly responsible for the hepatic metabolism of sulfonylureas (SUs), we hypothesized that the slow-metabolizer genotypes *2/*2, *2/*3, and *3/*3 might be overrepresented in type 2 diabetic patients with SH. METHODS: In a prospective population-based case-control study, CYP2C9 allelic variants of 102 diabetic patients with SH were compared with a matched group of 101 SU-treated patients without a history of SH. The 203 Caucasian patients had been treated with the SUs glimepiride, glibenclamide, or gliquidone. SH was defined as a symptomatic event requiring treatment with intravenously administered glucose and was confirmed by a blood glucose measurement of <50 mg/dl (<2.8 mmol/l). As two control groups, we selected 337 Caucasian diabetic patients receiving antidiabetic drugs per os and 1,988 healthy Caucasian volunteers who had been genotyped earlier. RESULTS: In the univariate analysis, only a low HbA(1c) value (p = 0.0004) was shown as a risk factor for SH. There was no overrepresentation of the CYP2C9 *2/*2, *2/*3, and *3/*3 variants in the SH group (2%) compared with the control group (5%). However, in the control group, patients with CYP2C9 genotypes, predicting slower metabolism of SU drugs, were treated with significantly lower doses (p = 0.027) than were extensive metabolizers, whereas in the patient group with severe hypoglycemia, the dose was the same for all genotype groups. CONCLUSIONS: In the present cohort of 102 patients with SH, a low HbA(1c) value was related to the risk for SH. There was no overrepresentation observed of the CYP2C9 slow-metabolizer genotypes in the hypoglycemic patients group, but the drug exposure in the slow-metabolizer genotypes was estimated to be higher in hypoglycemic patients, which might partly have contributed to their risk for SH.