Associations of clinical, psychological, and sociodemographic characteristics and ecological momentary assessment completion in the 10-week Hypo-METRICS study: Hypoglycaemia MEasurements ThResholds and ImpaCtS.

INTRODUCTION: Reporting of hypoglycaemia and its impact in clinical studies is often retrospective and subject to recall bias. We developed the Hypo-METRICS app to measure the daily physical, psychological, and social impact of hypoglycaemia in adults with type 1 and insulin-treated type 2 diabetes in real-time using ecological momentary assessment (EMA). To help assess its utility, we aimed to determine Hypo-METRICS app completion rates and factors associated with completion. METHODS: Adults with diabetes recruited into the Hypo-METRICS study were given validated patient-reported outcome measures (PROMs) at baseline. Over 10 weeks, they wore a blinded continuous glucose monitor (CGM), and were asked to complete three daily EMAs about hypoglycaemia and aspects of daily functioning, and two weekly sleep and productivity PROMs on the bespoke Hypo-METRICS app. We conducted linear regression to determine factors associated with app engagement, assessed by EMA and PROM completion rates and CGM metrics. RESULTS: In 602 participants (55% men; 54% type 2 diabetes; median(IQR) age 56 (45-66) years; diabetes duration 19 (11-27) years; HbA1c 57 (51-65) mmol/mol), median(IQR) overall app completion rate was 91 (84-96)%, ranging from 90 (81-96)%, 89 (80-94)% and 94(87-97)% for morning, afternoon and evening check-ins, respectively. Older age, routine CGM use, greater time below 3.0 mmol/L, and active sensor time were positively associated with app completion. DISCUSSION: High app completion across all app domains and participant characteristics indicates the Hypo-METRICS app is an acceptable research tool for collecting detailed data on hypoglycaemia frequency and impact in real-time.

Effect of insulin degludec versus insulin glargine U100 on nocturnal glycaemia assessed by plasma glucose profiles in people with type 1 diabetes prone to nocturnal severe hypoglycaemia.

AIM: To compare nocturnal glucose profiles according to hourly plasma glucose measurements during treatment with insulin degludec and insulin glargine U100 in a cohort of people with type 1 diabetes prone to nocturnal severe hypoglycaemia. MATERIALS AND METHODS: The HypoDeg trial is a 2-year investigator-initiated, randomized, controlled crossover trial in 149 participants randomized to treatment with insulin degludec and insulin glargine U100 for 12 months each. The 51 participants in this predefined substudy stayed at least one night in hospital during each treatment arm for plasma glucose samples to be taken. Endpoints were glucose profiles, including mean plasma glucose, glycaemic variability and risk of hypoglycaemia. RESULTS: There were no differences between treatments regarding mean plasma glucose. We saw a flatter glucose profile during insulin degludec compared with insulin glargine U100 treatment, which had a nadir at 4:00 AM, with a subsequent rise. During treatment with insulin degludec, the participants had lower glycaemic variability, with an estimated treatment difference of -4.3% (95% confidence interval [CI] -8.1 to -0.5; P < 0.05). Participants treated with insulin degludec were less likely to experience nocturnal hypoglycaemia below 3.0 mmol/L (hazard ratio 0.36 [95% CI 0.17-0.73; P < 0.05]). CONCLUSION: Based on nocturnal plasma glucose measurements, treatment with insulin degludec compared with insulin glargine U100 administered in the evening results in lower glycaemic variability and lower risk of nocturnal hypoglycaemia without differences in mean plasma glucose.

Comparison of treatment with insulin degludec and glargine U100 in patients with type 1 diabetes prone to nocturnal severe hypoglycaemia: The HypoDeg randomized, controlled, open-label, crossover trial.

AIM: To investigate whether the long-acting insulin analogue insulin degludec compared with insulin glargine U100 reduces the risk of nocturnal symptomatic hypoglycaemia in patients with type 1 diabetes (T1D). METHODS: Adults with T1D and at least one episode of nocturnal severe hypoglycaemia during the last 2 years were included in a 2-year prospective, randomized, open, multicentre, crossover trial. A total of 149 patients were randomized 1:1 to basal-bolus therapy with insulin degludec and insulin aspart or insulin glargine U100 and insulin aspart. Each treatment period lasted 1 year and consisted of 3 months of run-in or crossover followed by 9 months of maintenance. The primary endpoint was the number of blindly adjudicated nocturnal symptomatic hypoglycaemic episodes. Secondary endpoints included the occurrence of severe hypoglycaemia. We analysed all endpoints by intention-to-treat. RESULTS: Treatment with insulin degludec resulted in a 28% (95% CI: 9%-43%; P = .02) relative rate reduction (RRR) of nocturnal symptomatic hypoglycaemia at level 1 (≤3.9 mmol/L), a 37% (95% CI: 16%-53%; P = .002) RRR at level 2 (≤3.0 mmol/L), and a 35% (95% CI: 1%-58%; P = .04) RRR in all-day severe hypoglycaemia compared with insulin glargine U100. CONCLUSIONS: Patients with T1D prone to nocturnal severe hypoglycaemia have lower rates of nocturnal symptomatic hypoglycaemia and all-day severe hypoglycaemia with insulin degludec compared with insulin glargine U100.

Hyperglycaemia in people with diabetes and chronic kidney disease.

Assessment and treatment of hyperglycaemia in people with diabetes and chronic kidney disease (CKD) are challenging. In advanced CKD HbA1c can be unreliable, and treatment adjustments should be supported by other glucose measurements (e.g., continuous glucose monitoring (CGM) or blood glucose measurements). Glucose-lowering treatments should be evaluated based on CKD and an individualised assessment of risk factors especially hypoglycaemia. This review aims at providing an overview of the options for glycaemic monitoring and glucose-lowering treatments in people with diabetes and CKD.

Associations Between Hypoglycemia Awareness Status and Symptoms of Hypoglycemia Among Adults with Type 1 or Insulin-Treated Type 2 Diabetes Using the Hypo-METRICS Smartphone Application.

Introduction: This study examined associations between hypoglycemia awareness status and hypoglycemia symptoms reported in real-time using the novel Hypoglycaemia-MEasurement, ThResholds and ImpaCtS (Hypo-METRICS) smartphone application (app) among adults with insulin-treated type 1 (T1D) or type 2 diabetes (T2D). Methods: Adults who experienced at least one hypoglycemic episode in the previous 3 months were recruited to the Hypo-METRICS study. They prospectively reported hypoglycemia episodes using the app for 10 weeks. Any of eight hypoglycemia symptoms were considered present if intensity was rated between "A little bit" to "Very much" and absent if rated "Not at all." Associations between hypoglycemia awareness (as defined by Gold score) and hypoglycemia symptoms were modeled using mixed-effects binary logistic regression, adjusting for glucose monitoring method and diabetes duration. Results: Of 531 participants (48% T1D, 52% T2D), 45% were women, 91% white, and 59% used Flash or continuous glucose monitoring. Impaired awareness of hypoglycemia (IAH) was associated with lower odds of reporting autonomic symptoms than normal awareness of hypoglycemia (NAH) (T1D odds ratio [OR] 0.43 [95% confidence interval {CI} 0.25-0.73], P = 0.002); T2D OR 0.51 [95% CI 0.26-0.99], P = 0.048), with no differences in neuroglycopenic symptoms. In T1D, relative to NAH, IAH was associated with higher odds of reporting autonomic symptoms at a glucose concentration <54 than >70 mg/dL (OR 2.18 [95% CI 1.21-3.94], P = 0.010). Conclusion: The Hypo-METRICS app is sensitive to differences in hypoglycemia symptoms according to hypoglycemia awareness in both diabetes types. Given its high ecological validity and low recall bias, the app may be a useful tool in research and clinical settings. The clinical trial registration number is NCT04304963.

A Comparison of the Rates of Clock-Based Nocturnal Hypoglycemia and Hypoglycemia While Asleep Among People Living with Diabetes: Findings from the Hypo-METRICS Study.

Introduction: Nocturnal hypoglycemia is generally calculated between 00:00 and 06:00. However, those hours may not accurately reflect sleeping patterns and it is unknown whether this leads to bias. We therefore compared hypoglycemia rates while asleep with those of clock-based nocturnal hypoglycemia in adults with type 1 diabetes (T1D) or insulin-treated type 2 diabetes (T2D). Methods: Participants from the Hypo-METRICS study wore a blinded continuous glucose monitor and a Fitbit Charge 4 activity monitor for 10 weeks. They recorded details of episodes of hypoglycemia using a smartphone app. Sensor-detected hypoglycemia (SDH) and person-reported hypoglycemia (PRH) were categorized as nocturnal (00:00-06:00 h) versus diurnal and while asleep versus awake defined by Fitbit sleeping intervals. Paired-sample Wilcoxon tests were used to examine the differences in hypoglycemia rates. Results: A total of 574 participants [47% T1D, 45% women, 89% white, median (interquartile range) age 56 (45-66) years, and hemoglobin A1c 7.3% (6.8-8.0)] were included. Median sleep duration was 6.1 h (5.2-6.8), bedtime and waking time ∼23:30 and 07:30, respectively. There were higher median weekly rates of SDH and PRH while asleep than clock-based nocturnal SDH and PRH among people with T1D, especially for SDH <70 mg/dL (1.7 vs. 1.4, P < 0.001). Higher weekly rates of SDH while asleep than nocturnal SDH were found among people with T2D, especially for SDH <70 mg/dL (0.8 vs. 0.7, P < 0.001). Conclusion: Using 00:00 to 06:00 as a proxy for sleeping hours may underestimate hypoglycemia while asleep. Future hypoglycemia research should consider the use of sleep trackers to record sleep and reflect hypoglycemia while asleep more accurately. The trial registration number is NCT04304963.

Protocol for a randomised controlled trial comparing warfarin with no oral anticoagulation in patients with atrial fibrillation on chronic dialysis: the Danish Warfarin-Dialysis (DANWARD) trial.

INTRODUCTION: Atrial fibrillation is highly prevalent in patients on chronic dialysis. It is unclear whether anticoagulant therapy for stroke prevention is beneficial in these patients. Vitamin K-antagonists (VKA) remain the predominant anticoagulant choice. Importantly, anticoagulation remains inconsistently used and a possible benefit remains untested in randomised clinical trials comparing oral anticoagulation with no treatment in patients on chronic dialysis. The Danish Warfarin-Dialysis (DANWARD) trial aims to investigate the safety and efficacy of VKAs in patients with atrial fibrillation on chronic dialysis. The hypothesis is that VKA treatment compared with no treatment is associated with stroke risk reduction and overall benefit. METHODS AND ANALYSIS: The DANWARD trial is an investigator-initiated trial at 13 Danish dialysis centres. In an open-label randomised clinical trial study design, a total of 718 patients with atrial fibrillation on chronic dialysis will be randomised in a 1:1 ratio to receive either standard dose VKA targeting an international normalised ratio of 2.0-3.0 or no oral anticoagulation. Principal analyses will compare the risk of a primary efficacy endpoint, stroke or transient ischaemic attack and a primary safety endpoint, major bleeding, in patients allocated to VKA treatment and no treatment, respectively. The first patient was randomised in October 2019. Patients will be followed until 1 year after the inclusion of the last patient. ETHICS AND DISSEMINATION: The study protocol was approved by the Regional Research Ethics Committee (journal number H-18050839) and the Danish Medicines Agency (case number 2018101877). The trial is conducted in accordance with the Helsinki declaration and standards of Good Clinical Practice. Study results will be disseminated to participating sites, at research conferences and in peer-reviewed journals. TRIAL REGISTRATION NUMBERS: NCT03862859, EUDRA-CT 2018-000484-86 and CTIS ID 2022-502500-75-00.

The effect of insulin analogs in people with type 1 diabetes at increased risk of severe hypoglycemia.

Type 1 diabetes is characterized by insulin deficiency, and treatment is to supply insulin mimicking the physiological endogenous insulin secretion. Since its discovery, insulin therapy has evolved, and since the 1990s, an increasing number of insulin analogs with various pharmacokinetic and pharmacodynamic profiles have become available. Despite the improvement of insulin therapy, hypoglycemia remains the main side effect and is a daily concern for many people with diabetes and their families. A proportion of people with type 1 diabetes are at increased risk of hypoglycemia and experience recurring episodes. When designing insulin trials, this group of people is most often excluded in order to reduce the risk of adverse study outcomes, even though it may be the group that may benefit the most from treatment with new insulins. The results of the phase III trials, therefore, underestimate the clinical impact and pharmacoeconomic effect of the implementation of new insulins in the broader type 1 diabetes population. This paper reviews the four insulin trials that include people at increased risk of hypoglycemia. In general, the studies confirm the results from phase III trials in terms of similar reduction and maintenance of HbA1c, as well as relative rate reductions of hypoglycemia. However, the absolute treatment differences in the reduction of hypoglycemia are even greater in the trials, including people at high risk of hypoglycemia. This emphasizes the importance of including people at high risk of hypoglycemia to assess the full clinical and pharmacoeconomic benefit of new insulins.

The Effect of Insulin Degludec Versus Insulin Glargine U100 on Glucose Metrics Recorded During Continuous Glucose Monitoring in People With Type 1 Diabetes and Recurrent Nocturnal Severe Hypoglycemia.

AIM: Comparing continuous glucose monitoring (CGM)-recorded metrics during treatment with insulin degludec (IDeg) versus insulin glargine U100 (IGlar-100) in people with type 1 diabetes (T1D) and recurrent nocturnal severe hypoglycemia. MATERIALS AND METHODS: This is a multicenter, two-year, randomized, crossover trial, including 149 adults with T1D and minimum one episode of nocturnal severe hypoglycemia within the last two years. Participants were randomized 1:1 to treatment with IDeg or IGlar-100 and given the option of six days of blinded CGM twice during each treatment. CGM traces were reviewed for the percentage of time-within-target glucose range (TIR), time-below-range (TBR), time-above-range (TAR), and coefficient of variation (CV). RESULTS: Seventy-four participants were included in the analysis. Differences between treatments were greatest during the night (23:00-06:59). Treatment with IGlar-100 resulted in 54.0% vs 49.0% with IDeg TIR (70-180 mg/dL) (estimated treatment difference [ETD]: -4.6%, 95% confidence interval [CI]: -9.1, -0.0, P = .049). TBR was lower with IDeg at level 1 (54-69 mg/dL) (ETD: -1.7% [95% CI: -2.9, -0.5], P < .05) and level 2 (<54 mg/dL) (ETD: -1.3% [95% CI: -2.1, -0.5], P = .001). TAR was higher with IDeg compared with IGlar-100 at level 1 (181-250 mg/dL) (ETD: 4.0% [95% CI: 0.8, 7.3], P < .05) and level 2 (> 250 mg/dL) (ETD: 4.0% [95% CI: 0.8, 7.2], P < .05). The mean CV was lower with IDeg than that with IGlar-100 (ETD: -3.4% [95% CI: -5.6, -1.2], P < .05). CONCLUSION: For people with T1D suffering from recurrent nocturnal severe hypoglycemia, treatment with IDeg, compared with IGlar-100, results in a lower TBR and CV during the night at the expense of more TAR.

[Christmas article: The search for the (glycaemic) optimal christmas dinner].

INTRODUCTION: The Danish Christmas meal is not the healthiest and might increase blood glucose fluctuations, which can affect health negatively. Studies have shown that these large blood sugar fluctuations can be reduced by eating a meal in a particular order rather than eating it all at once. We investigated if sequential eating of a Danish Christmas meal affected post-prandial glucose fluctuations. METHODS: In a prospective randomised trial, 11 healthy subjects ate a standardised Danish Christmas meal. The subjects ate the meal three times with a wash-out day in between. On the first day, the subjects consumed the meal as they preferred. The following meals were divided into a starter (fresh red cabbage or pork roast) and the rest of the meal, and the opposite starter on the last intervention day. The glucose levels of the participants were monitored by continuous glucose monitoring (Freestyle Libre 2). We used a linear mixed model to compare the effects of the different orders of meal intake on glucose fluctuations. RESULTS: Nine of 11 participants were women with a mean age of 41.2 (range 25.0-64.0) years and mean glucose levels of 5.2 mmol/L. No differences in the postprandial glucose levels between the meals were found (all p > 0,05). CONCLUSION: We found no differences in the postprandial glucose levels in relation to the order of intake of fibers (salad) or protein (roast pork) before carbohydrates. We conclude that it is safe in terms of glycaemic control for healthy people without diabetes to eat a traditional Danish Christmas meal in any order. FUNDING: none. TRIAL REGISTRATION: not relevant.

Continuous Glucose Monitoring-Recorded Hypoglycemia with Insulin Degludec or Insulin Glargine U100 in People with Type 1 Diabetes Prone to Nocturnal Severe Hypoglycemia.

Background and Aims: Nocturnal hypoglycemia is mainly a consequence of inappropriate basal insulin therapy in type 1 diabetes (T1D) and may compromise optimal glycemic control. Insulin degludec is associated with a lower risk of nocturnal hypoglycemia in T1D. As nocturnal hypoglycemia is often asymptomatic, we applied continuous glucose monitoring (CGM) to detect a more precise occurrence of nocturnal hypoglycemia in the HypoDeg trial, comparing insulin degludec with insulin glargine U100 in people with T1D and previous nocturnal severe hypoglycemia. Materials and Methods: In the HypoDeg trial, 149 people with T1D were included in an open-label randomized cross-over trial. Sixty-seven participants accepted optional participation in the predefined substudy of 4 × 6 days of blinded CGM requiring completion of at least one CGM period in each treatment arm. CGM data were reviewed for hypoglycemic events. Results: Treatment with insulin degludec resulted in a relative rate reduction (RRR) of 36% (95% confidence interval [CI]: 10%-54%; P < 0.05) in nocturnal CGM-recorded hypoglycemia (≤3.9 mmol/L), corresponding to an absolute rate reduction (ARR) of 0.85 events per person-week. In nocturnal CGM-recorded hypoglycemia (≤3.0 mmol/L), we found an RRR of 53% (95% CI: 36%-65%; P < 0.001), corresponding to an ARR of 0.75 events per person-week. At the lower detection limit of the CGM (≤2.2 mmol/L), treatment with insulin degludec resulted in a significant RRR of 58% (95% CI: 23%-77%; P = 0.005). The reductions were primarily due to significant RRRs in asymptomatic hypoglycemia. Conclusion: In people with T1D, prone to nocturnal severe hypoglycemia, insulin degludec compared with insulin glargine U100 significantly reduces nocturnal CGM-recorded hypoglycemia. www.clinicaltrials.gov (#NCT02192450).

[Christmas article: Influence of christmassy spices on blood glucose levels after intake of rice pudding meal].

Introduction The glucose-lowering effect of cinnamon is well known and has been used for this purpose since ancient times. Other christmassy spices, like ginger and cloves, have also been shown to affect blood glucose levels but are not as extensively examined. We aimed to explore the potential glucose-lowering effects of cinnamon, ginger and cloves by postprandial glucose excursions (PPGE) and maximum glucose level during rice pudding intake in healthy participants with use of continuous glucose monitoring during ingestion of the traditional Danish Christmas dish, rice pudding. Methods Participants wore an intermittently scanned continuous glucose monitor for five days in total. Day 0 was a 24h run-in stabilization period. Day 1 was used for baseline with ingestion of a standardized rice pudding meal without any spices. On days 2-4, participants had the same standardized rice pudding with one of the three Christmas spices on top. The participants ate rice pudding for breakfast (low-dose spice) and lunch (high-dose spice). A questionnaire was also developed to investigate the satisfaction level with the rice pudding and spice combinations. Results Data from 12 people were analyzed with mean age (range) of ~ 42 (25-63) years. Mean fasting glucose level (95% CI) was 4.7 (4.0-5.5) mmol/l. PPGE levels were higher for 6 g of ginger, compared to 3 g of ginger with mean difference of 1.02 mmol/l (0.12-1.92) (p = 0.030). No other differences between the different doses of spices or between spices and baseline were found regarding PPGE or the maximum glucose-level during intake of rice pudding. Most people preferred cinnamon on top of the rice pudding, however, eight out of 12 would rather risk complications from a higher blood glucose than eating Christmas spices on top of their rice pudding. Conclusion Putting christmassy spices on top of rice pudding did not have a glucose-lowering effect in this study. This was probably for the best, since we learned from the questionnaire, that the use of Christmas spices on top of rice pudding was rated worse than the risk of complications from having high blood glucose levels. Thus, implementation of Christmas spices as a preventative strategy is not recommended. Funding none. Trial registration none.

Rapidly progressing HELLP syndrome and massive liver destruction in a 22-year-old female pregnant with monochorionic diamniotic gemelli.

Haemolysis Elevated Liver parameters and Low Platelets (HELLP) syndrome can present with abdominal pain as the only symptom. It can be rapid with failure of multiple organs and is a cause of maternal death. A 22-year-old female pregnant with twins contacted her local hospital due to abdominal pain. Within 20 hours of the debut of the abdominal pain, a caesarean section was performed, the patient was re-operated due to the suspicion of abdominal bleeding. Bescause she was hypotensive and blood tests showed signs of liver destruction and acidosis, she was transferred to the intensive care unit (ICU). During an admission of 40 days, the patient received 5 plasmapheresis treatments and 10 courses of haemodialysis. CT scans showed massive liver haematomas intraparenchymal and subcapsular. The CT scan images are very interesting and included in the case report.This case presents a good prognosis after a rapid progression of HELLP in spite of a dramatic clinical presentation. This topic is of great interest to a wide spectre of clinicians, as an early multidisciplinary approach is necessary.