Influence of Erythropoietin on Cognitive Performance during Experimental Hypoglycemia in Patients with Type 1 Diabetes Mellitus: A Randomized Cross-Over Trial

<div><p>Introduction</p><p>The incidence of severe hypoglycemia in type 1 diabetes has not decreased over the past decades. New treatment modalities minimizing the risk of hypoglycemic episodes and attenuating hypoglycemic cognitive dysfunction are needed. We studied if treatment with the neuroprotective hormone erythropoietin (EPO) enhances cognitive function during hypoglycemia.</p> <p>Materials and Methods</p><p>Eleven patients with type 1 diabetes, hypoglycemia unawareness and recurrent severe hypoglycemia completed the study. In a double-blind, randomized, balanced, cross-over study using clamped hypoglycemia they were treated with 40,000 IU of EPO or placebo administered intravenously six days before the two experiments. Cognitive function (primary endpoint), hypoglycemic symptoms, and counter-regulatory hormonal response were recorded.</p> <p>Results</p><p>Compared with placebo, EPO treatment was associated with a significant reduction in errors in the most complex reaction time task (−4.7 (−8.1 to −1.3), p = 0.01) and a less reaction time prolongation (−66 (−117 to −16) msec, p = 0.02). EPO treatment did not change performance in other measures of cognition. Hypoglycemic symptoms, EEG-changes, and counter-regulatory hormone concentrations did not differ between EPO and placebo treatment.</p> <p>Conclusion</p><p>In patients with type 1 diabetes and hypoglycemia unawareness, treatment with EPO is associated with a beneficial effect on cognitive function in a complex reaction time task assessing sustained attention/working memory. Hypoglycemic symptoms and hormonal responses were not changed by EPO treatment.</p> <p>Trial Registration</p><p>ClinicalTrials.gov <a href="http://clinicaltrials.gov/ct2/show/NCT00615368" target="_blank">NCT00615368</a></p> </div

Baseline characteristics.

<p>Baseline demographic and diabetes-related characteristics of 11 patients with type 1 diabetes. Numbers are means (range) unless otherwise stated.</p>a<p>C-peptide at baseline visit. Detection limit 0.2 nmol/l.</p

Counter-regulatory hormones.

<p>Hematological and cardiovascular parameters and counter-regulatory hormones at baseline and during hypoglycemia six days after an intravenous injection of 40,000 IU of EPO or placebo in 11 patients with type 1 diabetes. P-values refer to comparisons between baseline and hypoglycemic values in a paired t-test. The adjusted effect of EPO compared to placebo is presented in the two columns at the right (ANCOVA). The hypoglycemic values are all peak-values, except for potassium and diastolic blood pressure, which are nadir values. Abbreviations: EPO = erythropoietin. ANCOVA = analysis of co-variance.</p>*<p> = calculated on logarithmic values (log10) and in the ANCOVA back-transformed to percent.</p

Additional file 1 of The impact of prior exposure to hypoglycaemia on the inflammatory response to a subsequent hypoglycaemic episode

Additional file 1. Supplement 1: in-and exclusions criteria

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.</p

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.</p

Hypo-METRICS: Hypoglycaemia-MEasurement, ThResholds and ImpaCtS-A multi-country clinical study to define the optimal threshold and duration of sensor-detected hypoglycaemia that impact the experience of hypoglycaemia, quality of life and health economic outcomes: The study protocol

Introduction: Hypoglycaemia is a significant burden to people living with diabetes and an impediment to achieving optimal glycaemic outcomes. The use of continuous glucose monitoring (CGM) has improved the capacity to assess duration and level of hypoglycaemia. The personal impact of sensor-detected hypoglycaemia (SDH) is unclear. Hypo-METRICS is an observational study designed to define the threshold and duration of sensor glucose that provides the optimal sensitivity and specificity for events that people living with diabetes experience as hypoglycaemia. Methods: We will recruit 600 participants: 350 with insulin-treated type 2 diabetes, 200 with type 1 diabetes and awareness of hypoglycaemia and 50 with type 1 diabetes and impaired awareness of hypoglycaemia who have recent experience of hypoglycaemia. Participants will wear a blinded CGM device and an actigraphy monitor to differentiate awake and sleep times for 10 weeks. Participants will be asked to complete three short surveys each day using a bespoke mobile phone app, a technique known as ecological momentary assessment. Participants will also record all episodes of self-detected hypoglycaemia on the mobile app. We will use particle Markov chain Monte Carlo optimization to identify the optimal threshold and duration of SDH that have optimum sensitivity and specificity for detecting patient-reported hypoglycaemia. Key secondary objectives include measuring the impact of symptomatic and asymptomatic SDH on daily functioning and health economic outcomes. Ethics and dissemination: The protocol was approved by local ethical boards in all participating centres. Study results will be shared with participants, in peer-reviewed journal publications and conference presentations

Relationship Between Sensor-Detected Hypoglycemia and Patient-Reported Hypoglycemia in People With Type 1 and Insulin-Treated Type 2 Diabetes: The Hypo-METRICS Study

OBJECTIVE Use of continuous glucose monitoring (CGM) has led to greater detection of hypoglycemia; the clinical significance of this is not fully understood. The Hypoglycaemia–Measurement, Thresholds and Impacts (Hypo-METRICS) study was designed to investigate the rates and duration of sensor-detected hypoglycemia (SDH) and their relationship with person-reported hypoglycemia (PRH) in people living with type 1 diabetes (T1D) and insulin-treated type 2 diabetes (T2D) with prior experience of hypoglycemia. RESEARCH DESIGN AND METHODS We recruited 276 participants with T1D and 321 with T2D who wore a blinded CGM and recorded PRH in the Hypo-METRICS app over 10 weeks. Rates of SDH <70 mg/dL, SDH <54 mg/dL, and PRH were expressed as median episodes per week. Episodes of SDH were matched to episodes of PRH that occurred within 1 h. RESULTS Median [interquartile range] rates of hypoglycemia were significantly higher in T1D versus T2D; for SDH <70 mg/dL (6.5 [3.8–10.4] vs. 2.1 [0.8–4.0]), SDH <54 mg/dL (1.2 [0.4–2.5] vs. 0.2 [0.0–0.5]), and PRH (3.9 [2.4–5.9] vs. 1.1 [0.5–2.0]). Overall, 65% of SDH <70 mg/dL was not associated with PRH, and 43% of PRH had no associated SDH. The median proportion of SDH associated with PRH in T1D was higher for SDH <70 mg/dL (40% vs. 22%) and SDH <54 mg/dL (47% vs. 25%) than in T2D. CONCLUSIONS The novel findings are that at least half of CGM hypoglycemia is asymptomatic, even below 54 mg/dL, and many reported symptomatic hypoglycemia episodes happen above 70 mg/dL. In the clinical and research setting, these episodes cannot be used interchangeably, and both need to be recorded and addressed.</p

The impact of hypoglycaemia on daily functioning among adults with diabetes: a prospective observational study using the Hypo-METRICS Application

Aims/hypothesis: To examine the impact of hypoglycaemia on daily functioning among adults with type 1 diabetes or insulin-treated type 2 diabetes, using the novel Hypo-METRICS application. RESEARCH DESIGN AND METHODS For 70 consecutive days, 594 adults (type 1 diabetes: n=274; type 2diabetes: n=320) completed brief morning and evening Hypo-METRICS ‘check-ins’ about their experiencedhypoglycaemia and daily functioning. Participants wore a blinded glucose sensor for the study duration.Days   and   nights   with   or   without   person-reported   hypoglycaemia   (PRH)   and/or   sensor-detectedhypoglycaemia (SDH) were compared using multilevel regression models.  RESULTS  Participants submitted a mean of 86.3±12.5% morning and 90.8±10.7% evening check-ins.  Forboth types of diabetes, SDH alone had no significant associations to the changes in daily functioning scores.However, daytime and night-time PRH (with or without SDH) were significantly associated with worseningof   energy   levels,   mood,   cognitive   functioning,   negative   affect   and   fear   of   hypoglycaemia   later   thatday/while asleep. In addition, night-time PRH (with or without SDH) was significantly associated withworsening of sleep quality (type 1 and 2 diabetes), and memory (type 2 diabetes). Further, daytime PRH(with or without SDH), was associated with worsening of fear of hyperglycemia while asleep (type 1diabetes), memory (type 1 and 2 diabetes) and social functioning (type 2 diabetes). CONCLUSIONS This prospective, real-world study reveals impact on several domains of daily functioningfollowing PRH, but not following SDH alone.These data suggest that the observed negative impact is mainlydriven   by   subjective   awareness   of   hypoglycaemia   (i.e.,   PRH),   through   either   symptoms   or   sensoralerts/readings and/or the need to take action to prevent or treat them.</p

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 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