The effect of insulin degludec on risk of symptomatic nocturnal hypoglycaemia in adults with type 1 diabetes and high risk of nocturnal severe hypoglycaemia (the HypoDeg trial): study rationale and design.

BACKGROUND: Hypoglycaemia, especially nocturnal, remains the main limiting factor of achieving good glycaemic control in type 1 diabetes. The effect of first generation long-acting insulin analogues in reducing nocturnal hypoglycaemia is well documented in patient with type 1 diabetes. The effect of the newer long-acting insulin degludec on risk of nocturnal hypoglycaemia remains undocumented in patients with type 1 diabetes and recurrent severe nocturnal hypoglycaemia. The HypoDeg trial is designed to investigate whether insulin degludec in comparison with insulin glargine U100 is superior in limiting the occurrence of nocturnal hypoglycaemia in patients with recurrent nocturnal severe hypoglycaemia. This paper reports the study design of the HypoDeg trial. METHODS/DESIGN: A Danish investigator-initiated, prospective, randomised, open, blinded endpoint (PROBE), multicentre, two-year cross-over study investigating the effect of insulin degludec versus insulin glargine U100 on frequency of nocturnal hypoglycaemia in patients with type 1 diabetes and one or more episodes of nocturnal severe hypoglycaemia during the preceding two years as the major inclusion criteria. Patients are randomised (1:1) to basal therapy with insulin degludec or insulin glargine. Insulin aspart is used as bolus therapy in both treatment arms. DISCUSSION: In contrast to most other insulin studies the HypoDeg trial includes only patients at high risk of hypoglycaemia. The HypoDeg trial will compare treatment with insulin degludec to insulin glargine U100 in terms of risk of nocturnal hypoglycaemic episodes in patients with type 1 diabetes with the greatest potential to benefit from near-physiological insulin replacement therapy. www.clinicaltrials.gov : NCT02192450.

Suboptimal behaviour and knowledge regarding overnight glycaemia in adults with type 1 diabetes is common.

BACKGROUND: In people with type 1 diabetes (T1D), nocturnal hypoglycaemia (NH) can be slept through and can cause seizures, arrhythmias and death. Hypoglycaemia avoidance can induce hyperglycaemia and ketosis. Patient behaviour impacts clinical outcomes and may be changed by education. AIM: To develop and utilise a survey to evaluate patient self-management of overnight glycaemia in adults with T1D. METHODS: Adults with T1D attending two Australian tertiary referral diabetes clinics completed a survey about their diabetes self-management and glycaemic control, including responses to hypothetical pre-bed blood glucose (BG) levels (4-20 mmol/L). Statistical analyses included t-tests, Chi square tests and ANOVA with significance considered at P < 0.05. RESULTS: There were 205 participants (103 females), with a mean (SD) age of 41 (17) years, T1D duration of 20 (16) years, HbA1c of 7.8(1.4)%, (61.3(8.2) mmol/mol), 38% on insulin pump therapy (CSII) and 36% with impaired hypoglycaemia awareness (IHA). Mean (SD) number of BG tests/day was 5.4 (2.7). Patients set higher BG target levels at bedtime and overnight: 7.5(1.4) and 7.1(1.3) mmol/L, respectively, compared to daytime (6.9(1.0); P < 0.0001 and P = 0.002 respectively). Only 36% of participants reported treating nocturnal hypoglycaemia (NH) with the recommended refined, then complex, carbohydrate. Only 28% of patients made safe choices in all bedtime BG scenarios, with higher rates for CSII users, P = 0.0005. Further education was desired by 32% of respondents, with higher rates in those with (44%) versus without IHA (25%), P = 0.006. CONCLUSIONS: Many adults with T1D have suboptimal knowledge and behaviour regarding overnight BG self-management. A survey, piloted herein, may facilitate the identification of patients who could benefit from further education.

Intensive insulin therapy combined with metformin is associated with reduction in both glucose variability and nocturnal hypoglycaemia in patients with type 2 diabetes.

BACKGROUND: The effect on glucose variability in patients with intensive insulin therapy has not been fully understood. This observational study investigated the different glucose variability and hypoglycaemia patterns in type 2 diabetes patients treated with continuous subcutaneous insulin infusion (CSII) or multiple daily injections (MDI) with or without metformin administration. METHODS: During hospitalization, a total of 501 patients with poor glycaemic control and in initial treatment with either CSII alone (n = 187), CSII + Metformin (n = 81), MDI alone (n = 146), or MDI + Metformin (n = 87) were involved in the final analysis. Data obtained from continuous glucose monitoring were used to assess blood glucose fluctuation and nocturnal hypoglycaemia. RESULTS: Among the 4 groups, no difference was found in mean blood glucose levels. Results in parameters reflecting glucose fluctuation: continuous overlapping net glycaemic action in CSII + Metformin and mean amplitude of glycaemic excursions in MDI + Metformin were significantly lower than those in either CSII alone or MDI alone, respectively, even after adjustment (P = .031 and .006). Frequency of nocturnal hypoglycaemia was significantly decreased in CSII + Metformin as compared with CSII alone (0.6% vs 1.8%) and in MDI + Metformin as compared with MDI alone (1.6% vs 2.3%), with the highest frequency observed in MDI alone and the lowest in CSII + Metformin (all between group P < .001). Consistent results were obtained in between-group comparisons for hypoglycaemia duration. Subgroup analysis matched with baseline body mass index, and glycated haemoglobin and fasting blood glucose further confirmed these findings. CONCLUSION: Metformin added to initial CSII or MDI therapy is associated with a reduction in both glucose fluctuation and nocturnal hypoglycaemic risk in patients with type 2 diabetes.

MD-Logic overnight type 1 diabetes control in home settings: A multicentre, multinational, single blind randomized trial.

AIMS: To evaluate the safety, efficacy and need for remote monitoring of the MD-Logic closed-loop system during short-term overnight use at home. METHODS: Seventy-five patients (38 male; aged 10-54 years; average A1c, 7.8% ± 0.7%, 61.8 ± 7.2 mmol/mol) were enrolled from 3 clinical sites. Patients were randomly assigned to participate in 2 overnight crossover periods, each including 4 consecutive nights, 1 under closed-loop control and 1 under sensor-augmented pump (SAP) therapy in the patient's home. Both study arms were supervised using a remote-monitoring system in a blinded manner. Primary endpoints were time spent with glucose levels below 70 mg/dL and percentage of nights in which mean overnight glucose levels were within 90 to 140 mg/dL. RESULTS: The median [interquartile range] percentage of time spent in hypoglycaemia was significantly lower on nights when MD-Logic was used, compared to SAP therapy (2.07 [0, 4.78] and 2.6 [0, 10.34], respectively; P = .004) and the percentage of individual nights with a mean overnight glucose level in target was significantly greater (75 [42, 75] and 50 [25,75], respectively; P = .008). The time spent in target range was increased by a median of 28% (P = .001), with the same amount of insulin (10.69 [7.28, 13.94] and 10.41[6.9, 14.07], respectively; P = .087). The remote monitoring triggered calls for hypoglycaemia at twice the rate during SAP therapy compared to closed-loop control (62 and 29, respectively; P = .002). CONCLUSIONS: The MD-Logic system demonstrated a safe and efficient profile during overnight use by children, adolescents and adults with type 1 diabetes and, therefore, provides an effective means of mitigating the risk of nocturnal hypoglycaemia.

Reduced nocturnal hypoglycaemia with basal insulin peglispro compared with insulin glargine: pooled analyses of five randomized controlled trials.

Basal insulin peglispro (BIL) is a novel basal insulin with hepato-preferential action, resulting from reduced peripheral effects. This report summarizes hypoglycaemia data from five BIL phase III studies with insulin glargine as the comparator, including three double-blind trials. Prespecified pooled analyses (n = 4927) included: patients with type 2 diabetes (T2D) receiving basal insulin only, those with T2D on basal-bolus therapy, and those with type 1 diabetes (T1D). BIL treatment resulted in a 36-45% lower nocturnal hypoglycaemia rate compared with glargine, despite greater reduction in glycated haemoglobin (HbA1c) and higher basal insulin dosing. The total hypoglycaemia rate was similar in patients with T2D on basal treatment only, trended towards being higher (10%) in patients with T2D on basal-bolus treatment (p = .053), and was 15% higher (p < .001) with BIL versus glargine in patients with T1D, with more daytime hypoglycaemia in the T1D and T2D groups who were receiving basal-bolus therapy. In T1D, during the maintenance treatment period (26-52 weeks), the total hypoglycaemia rate was not significantly different. There were no differences in severe hypoglycaemia in the T1D or T2D pooled analyses. BIL versus glargine treatment resulted in greater HbA1c reduction with less nocturnal hypoglycaemia in all patient populations, higher daytime hypoglycaemia with basal-bolus therapy in the T1D and T2D groups, and an associated increase in total hypoglycaemia in the patients with T1D.

Characteristics of Nocturnal Hypoglycaemic Events and Their Impact on Glycaemia.

BACKGROUND: Nocturnal hypoglycaemia is a burden for people with diabetes, particularly when treated with multiple daily injections (MDI) therapy. However, the characteristics of nocturnal hypoglycaemic events in this patient group are only poorly described in the literature. METHOD: Continuous glucose monitoring (CGM) data from 185 study participants with type 1 diabetes using MDI therapy were collected under everyday conditions for up to 13 weeks. Hypoglycaemic events were identified as episodes of consecutive CGM readings <70 mg/dl or <54 mg/dl for at least 15 minutes. Subsequently, the time <54 mg/dl (TB54), time below range (TBR), time in range (TIR), time above range (TAR), glucose coefficient of variation (CV), and incidence of hypoglycaemic events were calculated for diurnal and nocturnal periods. Furthermore, the effect of nocturnal hypoglycaemic events on glucose levels the following day was assessed. RESULTS: The incidence of hypoglycaemic events <70 mg/dl was significantly lower during the night compared to the day, with 0.8 and 3.8 events per week, respectively, while the TBR, TB54, and incidence of events with CGM readings <54 mg/dl was not significantly different. Nocturnal hypoglycaemic events <70 mg/dl were significantly longer (60 vs 35 minutes) and enveloped by less rapidly changing glucose levels. On days following nights containing hypoglycaemic events, there was a decrease in TAR, mean CGM glucose level and morning glucose levels and an increase in TB54, TBR, and CV. CONCLUSIONS: The results showed that nocturnal hypoglycaemic events are a common occurrence in persons with type 1 diabetes using MDI with significant differences between the characteristics of nocturnal and diurnal events.

Hypoglycaemia assessment tool (HAT) study: subanalysis of the Lebanese cohort.

BACKGROUND: Diabetic hypoglycaemia affects medication adherence, patients' productivity and quality of life. It is also associated with an increased risk of cardiovascular complications. AIMS: To examine the impact of hypoglycaemia in insulin-treated patients in the Lebanese cohort of the Hypoglycaemia Assessment Tool (HAT) study. METHODS: The HAT study was an observational study covering a 6-month retrospective and a 4-week prospective period in 24 countries including Lebanon. Data were collected using self-assessment questionnaires and patient diaries from 1158 invited lebanese patients, aged ≥ 18 years, with type 1 or type 2 diabetes mellitus (T1DM/T2DM) treated with insulin for > 12 months. The primary endpoint was the proportion of patients experiencing ≥ 1 hypoglycaemic event during the 4-week follow-up period. RESULTS: After 4 weeks of follow-up, 177/225 [78.7%; 95% confidence interval (CI): 72.7-83.8] of patients with T1DM and 291/630 (46.2%; 95% CI: 42.2-50.2) patients with T2D experienced at least 1 hypoglycaemic event. Rates of nocturnal and severe hypoglycaemia were 10.7 (95% CI: 9.1-12.3) and 13.2 (95% CI: 11.5-14.9) events/patient-year for T1DM, and 3.3 (95% CI: 2.8-3.8) and 4.2 events/patient-year (95% CI: 3.6-4.8) for T2DM, respectively. Fear of hypoglycaemia was significantly associated with nocturnal and severe hypoglycaemia in both diabetes types (P < 0.001). CONCLUSION: The results suggest that the less-advanced healthcare systems in Lebanon are implicated in lower levels of patient knowledge about hypoglycaemia and related preventive measures. Treatment strategies and glycaemia goals should be individualized according to patient preference, medical benefits, and risk of hypoglycaemia.

Hypoglycaemia Remains the Key Obstacle to Optimal Glycaemic Control - Continuous Glucose Monitoring is the Solution.

We queried PubMed and other internet databases to identify studies, meta-analyses, review articles and other data sources regarding hypoglycaemia incidence/costs/impacts and continuous glucose monitoring (CGM) use. Our analysis of the evidence showed that hypoglycaemia remains a significant health concern and a primary obstacle to optimal adherence to prescribed diabetes treatment. In addition to its adverse clinical consequences, hypoglycaemia negatively impacts quality of life and places additional financial burdens on patients, patient families, employers and healthcare payers. Clinical trials have shown that the use of CGM can reduce the incidence and duration of hypoglycaemic episodes. This article reviews relevant CGM studies, discusses the prevalence and clinical/financial implications of hypoglycaemia, and explores the strengths and limitations of current CGM systems in minimising the burden of hypoglycaemia.

Sensor-based wearable system for the detection and automatic treatment of nocturnal hypoglycaemia.

Diabetic patients are prone to daily and severe health-related risks, namely hyper and hypoglycaemia. Hypoglycaemia phenomenon happens when the glucose level in patient's blood is lower than a well-determined sill. It may induce serious impacts, such as functional brain failure or even the death. Hypoglycaemia is especially dangerous when it occurs during the night while the patient is asleep because it becomes difficult to be detected by the patient itself or other persons around him. While all existing sensor-based solutions are detection-only driven, the proposed solution goes beyond and attempts to treat autonomously, and at low cost, the nocturnal hypoglycaemia. The presented system detects the nocturnal hypoglycaemia phenomenon based on accelerated heart-rate symptom and a progressive detection algorithm. The system treats then the detected nocturnal hypoglycaemia throughout safe and automatic injection of glucagon.

Auxiliendo, Primum Non Nocere: A Preliminary View of the DEVOTE Trial Comparing Cardiovascular Safety of Insulin Degludec Versus Insulin Glargine in Type 2 Diabetes.

A demonstration of cardiovascular safety is mandatory for all newly developed glucose-lowering agents, including insulin analogues. The vascular benefit of insulin is evident from the Diabetes Control and Complication Trial (DCCT) and United Kingdom Prospective Diabetes Study (UKPDS), and the cardiovascular safety of insulin glargine has been demonstrated in individuals with newly diagnosed diabetes or prediabetes in the ORIGIN trial (Outcome Reduction with an Initial Glargine Intervention). The top-line results of DEVOTE (Trial Comparing Cardiovascular Safety of Insulin Degludec vs. Insulin Glargine in Patients with Type 2 Diabetes at High Risk of Cardiovascular Events) have proven the cardiovascular safety of insulin degludec in persons with type 2 diabetes. In this commentary I discuss the interrelationship of insulin and cardiovascular health, while comparing the results of DEVOTE and ORIGIN.

Effect of insulin analogues on frequency of non-severe hypoglycaemia in patients with type 1 diabetes prone to severe hypoglycaemia: The HypoAna trial.

AIM: Insulin analogues reduce the risk of hypoglycaemia compared with human insulin in patients with type 1 diabetes (T1D) and minor hypoglycaemia problems. The HypoAna trial showed that, in patients with recurrent severe hypoglycaemia, treatment based on insulin analogues reduces the risk of severe hypoglycaemia. The present study aims to assess whether this also applies to non-severe hypoglycaemia events during the day and at night. METHODS: This 2-year investigator-initiated multicentre, prospective, randomized, open, blinded endpoint (PROBE) trial involved patients with T1D and at least two episodes of severe hypoglycaemia during the previous year. Using a balanced crossover design, patients were randomized to basal-bolus therapy based on analogue (detemir/aspart) or human (NPH/regular) insulins. A total of 114 participants were included. Endpoints were the number of severe hypoglycaemic events and non-severe events, including documented symptomatic and asymptomatic episodes occurring during the day and at night (ClinicalTrials.gov number: NCT00346996). RESULTS: Analogue-based treatment resulted in a 6% (2-10%; P=0.0025) overall relative risk reduction of non-severe hypoglycaemia. This was due to a 39% (32-46%; P<0.0001) reduction of non-severe nocturnal hypoglycaemia, seen for both symptomatic (48% [36-57%]; P<0.0001) and asymptomatic (28% [14-39%]; P=0.0004) nocturnal hypoglycaemia episodes. No clinically significant differences in hypoglycaemia occurrence were observed between the insulin regimens during the day. The time needed to treat one patient with insulin analogues to avoid one episode (TNT1) of non-severe nocturnal hypoglycaemia was approximately 3 months. CONCLUSION: In T1D patients prone to severe hypoglycaemia, treatment with analogue insulin reduced the risk of non-severe nocturnal hypoglycaemia compared with human insulin.