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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., 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.

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).

Background: Hypoglycaemia, especially nocturnal, remains a main limiting factor of achieving good glycemic control in type 1 diabetes. The long-acting insulin analog degludec reduces the risk of nocturnal hypoglycemia in patients with type 1 diabetes but is not studied in patients specifically prone to severe nocturnal hypoglycemia. The study aims to investigate whether insulin degludec in comparison with insulin glargine U100 reduces the risk of nocturnal hypoglycaemia in patients with previous severe nocturnal hypoglycaemia. Methods: Investigator-initiated, prospective, randomized, open, blinded endpoint (PROBE), multicenter, cross-over study. A one-year plus one-year treatment period was specified. Each one-year treatment period consisted of a three-month run-in/cross-over period followed by a nine-month maintenance period. A total of 149 adult patients with type 1 diabetes and at least one episode of nocturnal severe hypoglycemia during the preceding two years were included. Participants were randomized 1:1 to basal- bolus therapy with insulin degludec and insulin aspart or insulin glargine U100 and insulin aspart. The primary endpoint was number of nocturnal symptomatic hypoglycemic episodes during the maintenance period, analysed by intention-to-treat. Findings: Treatment with insulin degludec resulted in a 28% (95%CI: 9-43; p=0·02) and 37% (95%CI: 16-53; p=0·002) relative rate reduction (RRR) of level 1 (≤3·9 mmol/L) and level 2 (≤3·0 mmol/L) nocturnal (00:00 to 05:59) symptomatic hypoglycaemia, respectively, compared to insulin glargine U100. Similar results were demonstrated when defining night-time from 23:00 to 06:59 with a 28% (95%CI: 4-45; p=0·01) and 34% (95%CI:17-48; p<0·001) RRR for level 1 and 2 hypoglycaemia, respectively. Interpretation: Patients with type 1 diabetes prone to nocturnal severe hypoglycaemia have lower rates of nocturnal symptomatic hypoglycaemia with insulin degludec as compared with insulin glargine U100.

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.

Background: Type 1 diabetes is associated with increased risk of cardiovascular disease and the diabetic complication cardiovascular autonomic neuropathy in itself entails increased cardiovascular risk by mechanisms not yet fully understood. Arterial calcification is an important predictor of cardiovascular events; the aim of this study was to investigate the level of generalised arterial calcification in patients with long-term, normoalbuminuric type 1 diabetes and the association with cardiovascular autonomic neuropathy, as these factors have not been investigated in type 1 diabetes. Methods: Participants were examined for calcification of coronary and carotid arteries through non-contrast multi-detector computed tomography scans. Generalised arterial calcification was defined as the presence of calcium in both the coronary and carotid arteries. Results: A total of 53 patients with type 1 diabetes were included. Coronary and carotid artery calcium scores were correlated (r = 0.720, p < 0.0001). Cardiovascular autonomic neuropathy was associated with increased coronary (p = 0.002) and carotid (p = 0.001) artery calcium scores. Seventeen of 20 patients with cardiovascular autonomic neuropathy (85%) demonstrated generalised arterial calcification compared to 11 (33%) patients without cardiovascular autonomic neuropathy; patients with cardiovascular autonomic neuropathy had an odds ratio of 11.3 (95% confidence interval = 2.7–47.1, p < 0.001) for generalised arterial calcification. Conclusion: Cardiovascular autonomic neuropathy is associated with increased level of generalised arterial calcification in patients with normoalbuminuric, long-term type 1 diabetes.

AIMS: Type 1 diabetes is associated with increased cardiovascular (CV) morbidity and mortality, and cardiovascular autonomic neuropathy (CAN) is an important CV risk factor. The study aimed to explore associations between CAN and altered cardiac chamber sizes in persons with type 1 diabetes.METHODS: This was a cross-sectional study of 71 asymptomatic, normoalbuminuric participants with long-term type 1 diabetes (39 with CAN, determined by >1 abnormal autonomic function test) examined with cardiac multi detector computed tomography scans, which allowed measurements of left ventricular mass and all four cardiac chamber volumes. Cardiac chambers were indexed according to body surface area (ml/m2 or g/m2).RESULTS: Persons with and without CAN had mean ± SD age of 57 ± 7 and 50 ± 8 years (p < 0.001) and diabetes duration of 36 ± 11 and 32 ± 9 years (p < 0.05), respectively. Increasing autonomic dysfunction, evaluated by decrease in heart rate variability during deep breathing (in beats per minute), was associated with larger right (-0.5, 95% CI -1.0 to -0.0, p < 0.05) and trend towards larger left (-0.4, 95% CI -0.8-0.0, p < 0.1) ventricular volumes in multivariable linear regression.CONCLUSIONS: Our results suggest that impaired autonomic function may be associated with modest enlargement of ventricular volumes; this might be an early sign of progression towards heart failure.

Aims: Type 1 diabetes entails increased cardiovascular morbidity and cardiac chamber sizes are associated with cardiovascular disease. The aim of this study was to compare cardiac chamber sizes in normoalbuminuric persons with type 1 diabetes to a background population without diabetes. Methods: In a cross-sectional study, we examined 71 normoalbuminuric persons with long-term type 1 diabetes without known cardiovascular disease using cardiac multi-detector computed tomography. Cardiac chamber sizes and left ventricular remodelling were compared to persons without diabetes from the Copenhagen General Population Study. Results: Participants were median (interquartile range) 54 (48–60) (type 1 diabetes) and 57 (50–64) (without diabetes) years old and 59% were men (both groups). Participants with type 1 diabetes had smaller left ventricular mass (−3.5 g/m2, 95% confidence interval −5.8 to −1.3) and left (−4.0 mL/m2, 95% confidence interval −6.9 to −1.0) and right (−11.7 mL/m2, 95% confidence interval −15.4 to −7.9) ventricular volumes in multivariable analyses (adjusted for age, sex, body composition, blood pressure and antihypertensive medication), but no differences in atrial volumes. Conclusion: Persons with long-term type 1 diabetes had smaller left ventricular mass and biventricular volumes, yet similar atrial sizes, compared to a background population without diabetes. These findings may reflect subclinical development of diabetic cardiomyopathy.

Introduction: In the struggle for tight glycemic control many type 1 diabetes patients daily experience large blood glucose fluctuations. It has been demonstrated that increased glucose variability is a predictor of hypoglycemia, which is the main limiting factor for achieving the recommended HbA1c target. The relationship between glucose variability and hypoglycemia might seem intuitive, but the exact nature of the relationship is difficult to elucidate. In this study we wanted to clarify the relationship between occurrence of non-severe hypoglycemia and glycemic variability in type 1 diabetic patients at high risk of severe hypoglycemia. Material and Methods: 72 patients participated for 4 x 3 days of blinded CGM recordings during a 2-year randomized balanced cross-over study with human insulins (regular/NPH) and insulin analogs (aspart/detemir). CGM recordings were used to calculate the coefficient of variation (CV) in glucose. Results: Treatment with insulin analogs resulted in a significant lower nocturnal CV (mean 29.2%, SD 9.1) than treatment with human insulin (mean 36.9%, SD 9.1) (p<0.0001). CV was a significant risk marker of nocturnal asymptomatic hypoglycemia ?3.9 mmol/l in a multivariate analysis. A 1% increase in CV corresponds to a 5% (p<0.0001) increase in asymptomatic hypoglycemia. CV did not predict hypoglycemia during daytime at this threshold. Conclusion: Treatment with insulin analogs provides less glycemic variability during night-time. The coefficient of variation in patients suffering from recurrent severe hypoglycemia predicts the occurrence of especially nocturnal hypoglycemia.