Liraglutide enhances insulin secretion and prolongs the remission period in adults with newly diagnosed type 1 diabetes (the NewLira study): A randomized, double-blind, placebo-controlled trial.

AIM: To test the effect of the glucagon-like peptide-1 receptor agonist, liraglutide, on residual beta-cell function in adults with newly diagnosed type 1 diabetes. MATERIALS AND METHODS: In a multicentre, double-blind, parallel-group trial, adults with newly diagnosed type 1 diabetes and stimulated C-peptide of more than 0.2 nmol/L were randomized (1:1) to 1.8-mg liraglutide (Victoza) or placebo once daily for 52 weeks with 6 weeks of follow-up with only insulin treatment. The primary endpoint was the between-group difference in C-peptide area under the curve (AUC) following a liquid mixed-meal test after 52 weeks of treatment. RESULTS: Sixty-eight individuals were randomized. After 52 weeks, the 4-hour AUC C-peptide response was maintained with liraglutide, but decreased with placebo (P = .002). Six weeks after end-of-treatment, C-peptide AUCs were similar for liraglutide and placebo. The average required total daily insulin dose decreased from 0.30 to 0.23 units/kg/day with liraglutide, but increased from 0.29 to 0.43 units/kg/day in the placebo group at week 52 (P < .001). Time without the need for insulin treatment was observed in 13 versus two patients and lasted for 22 weeks (from 3 to 52 weeks) versus 6 weeks (from 4 to 8 weeks) on average for liraglutide and placebo, respectively. Patients treated with liraglutide had fewer episodes of hypoglycaemia compared with placebo-treated patients. The adverse events with liraglutide were predominantly gastrointestinal and transient. CONCLUSIONS: Treatment with liraglutide improves residual beta-cell function and reduces the dose of insulin during the first year after diagnosis. Beta-cell function was similar at 6 weeks postliraglutide treatment.

Liraglutide changes body composition and lowers added sugar intake in overweight persons with insulin pump-treated type 1 diabetes.

AIMS: To present secondary outcome analyses of liraglutide treatment in overweight adults with insulin pump-treated type 1 diabetes (T1D), focusing on changes in body composition and dimensions, and to evaluate changes in food intake to identify potential dietary drivers of liraglutide-associated weight loss. MATERIALS AND METHODS: A 26-week randomized placebo-controlled study was conducted to investigate the efficacy and safety of liraglutide 1.8 mg daily in 44 overweight adults with insulin pump-treated T1D and glucose levels above target, and demonstrated significant glycated haemoglobin (HbA1c)- and body weight-reducing effects. For secondary outcome analysis, dual X-ray absorptiometry scans were completed at Weeks 0 and 26, and questionnaire-based food frequency recordings were obtained at Weeks 0, 13 and 26 to characterize liraglutide-induced changes in body composition and food intake. RESULTS: Total fat and lean body mass decreased in liraglutide-treated participants (fat mass -4.6 kg [95% confidence interval {CI} -5.7; -3.5], P < 0.001; lean mass -2.5 kg [95% CI -3.2;-1.7], P < 0.001), but remained stable in placebo-treated participants (fat mass -0.3 kg [95% CI -1.3;0.8], P = 0.604; lean mass 0.0 kg [95% CI -0.7;0.7]; P = 0.965 [between-group P values <0.001]). Participants reduced their energy intake numerically more in the liraglutide arm (-1.1 MJ [95% CI -2.0;-0.02], P = 0.02) than in the placebo arm (-0.9 MJ [95% CI -2.0;0.1], P = 0.22), but the between-group difference was statistically insignificant (P = 0.42). However, energy derived from added sugars decreased by 27% in the liraglutide arm compared with an increase of 14% in the placebo arm (P = 0.004). CONCLUSIONS: Liraglutide lowered fat and lean body mass compared with placebo. Further, liraglutide reduced intake of added sugars. However, no significant difference in total daily energy intake was detected between liraglutide- and placebo-treated participants.

Liraglutide reduces hyperglycaemia and body weight in overweight, dysregulated insulin-pump-treated patients with type 1 diabetes: The Lira Pump trial-a randomized, double-blinded, placebo-controlled trial.

AIM: To investigate the efficacy of adding the glucagon-like peptide-1 receptor agonist liraglutide to continuous subcutaneous insulin infusion (CSII) in overweight or obese persons with type 1 diabetes and non-optimal glycaemic control. MATERIALS AND METHODS: A 26-week, randomized, double-blind, placebo-controlled trial including 44 overweight or obese adults with type 1 diabetes randomized 1:1 to liraglutide 1.8 mg once daily (QD) or placebo added to CSII treatment. The primary endpoint was change in haemoglobin A1c (HbA1c). Secondary endpoints included change in insulin dose, CSII settings, glycaemic variability, body weight and patient-reported outcome measures. Finally, adverse effects including hypoglycaemic events were registered. RESULTS: HbA1c was reduced by 5 mmol/mol (0.5%) from a baseline of 66 mmol/mol (8.2%) in patients treated with liraglutide compared with a non-significant change of +2.3 mmol/mol (0.2%) from a baseline of 66 mmol/mol (8.1%) in patients treated with placebo (between-group difference 7 mmol/mol [0.7%], P < 0.001). Liraglutide reduced total insulin dose by 8 units/day or 16% of total insulin dose (P = 0.008). Mean body weight was reduced by 6.3 kg (P < 0.001) compared with placebo. Concomitantly, time spent in glycaemic target range 4-10 mmol/L (71-180 mg/dL) increased while the risk of hypoglycaemia did not differ between groups at the end of treatment. CONCLUSION: Liraglutide treatment reduced HbA1c, total daily insulin dose and body weight without increasing the risk of hypoglycaemia in CSII-treated patients with type 1 diabetes and insufficient glycaemic control. Liraglutide may be considered a potential add-on therapy to insulin in this subgroup of patients.

Detection of Hypoglycemia Using Measures of EEG Complexity in Type 1 Diabetes Patients.

Previous literature has demonstrated that hypoglycemic events in patients with type 1 diabetes (T1D) are associated with measurable scalp electroencephalography (EEG) changes in power spectral density. In the present study, we used a dataset of 19-channel scalp EEG recordings in 34 patients with T1D who underwent a hyperinsulinemic-hypoglycemic clamp study. We found that hypoglycemic events are also characterized by EEG complexity changes that are quantifiable at the single-channel level through empirical conditional and permutation entropy and fractal dimension indices, i.e., the Higuchi index, residuals, and tortuosity. Moreover, we demonstrated that the EEG complexity indices computed in parallel in more than one channel can be used as the input for a neural network aimed at identifying hypoglycemia and euglycemia. The accuracy was about 90%, suggesting that nonlinear indices applied to EEG signals might be useful in revealing hypoglycemic events from EEG recordings in patients with T1D.

Liraglutide as adjunct to insulin treatment in type 1 diabetes does not interfere with glycaemic recovery or gastric emptying rate during hypoglycaemia: A randomized, placebo-controlled, double-blind, parallel-group study.

AIM: Glucagon-like peptide-1 receptor agonist (GLP-1RA) therapy is a potential treatment as adjunct to insulin in type 1 diabetes (T1D). However, GLP-1RAs inhibit glucagon secretion and delay the gastric emptying (GE) rate and may impair recovery from hypoglycaemia. We evaluated the effect of the GLP-1RA liraglutide on counterregulatory responses and GE rate during hypoglycaemia in persons with T1D. MATERIALS AND METHODS: In a 12-week, randomized, double-blind, placebo-controlled study, 20 patients aged >18 years with T1D and HbA1c ≥8% (64 mmol/mol) were randomly assigned (1:1) to liraglutide 1.2 mg once daily or placebo as add-on to insulin treatment. Before and at end of treatment a hypoglycaemic clamp (plasma glucose target 2.5 mmol/L) was carried out, followed by a liquid meal. Primary endpoint was change in GE rate (evaluated by area under the paracetamol curve and time to peak). Secondary endpoints included changes in glycaemic recovery, counter-regulatory hormones, pancreatic polypeptide (PP), GLP-1, blood pressure and heart rate. RESULTS: During the period June 2013 to October 2014, 20 patients were enrolled. After 12 weeks of treatment, changes in GE rates did not differ significantly between groups ( P = .96), with no significant changes from baseline, whether evaluated from AUCs or time to peak. The secondary endpoints, glycaemic recovery, counter-regulatory hormone responses, systolic blood pressure and GLP-1 and PP responses, were also similar. Heart rate increased with liraglutide from 69 ± 4 to 80 ± 5 beats/min ( P = .02). CONCLUSIONS: Liraglutide does not compromise glycaemic recovery, GE rate or counter-regulatory hormone responses in T1D patients during hypoglycaemia. No treatment-related safety issues were identified.

Effects of liraglutide on cardiovascular risk factors in patients with type 1 diabetes.

We investigated the short-term effect of adding liraglutide 1.8 mg once daily to insulin treatment on cardiovascular risk factors in patients with type 1 diabetes. In total, 100 overweight (BMI ≥25 kg/m2 ) adult patients (age ≥18 years) with type 1 diabetes and HbA1c ≥ 8% (64 mmol/mol) were randomized to liraglutide 1.8 mg or placebo added to insulin treatment in a 24-week double-blinded, placebo-controlled trial. At baseline and after 24 weeks of treatment, 24-hour blood pressure and heart rate, pulse pressure, pulse wave velocity and carotid intima-media thickness were evaluated. Compared with placebo, liraglutide increased 24-hour heart rate by 4.6 beats per minute (BPM); P = .0015, daytime heart rate by 3.7; P = .0240 and night-time heart rate by 7.5 BPM; P < .001 after 24 weeks. Diastolic nocturnal blood pressure increased by 4 mm Hg; P = .0362 in the liraglutide group compared with placebo. In conclusion, in patients with long-standing type 1 diabetes, liraglutide as add-on to insulin increased heart rate and did not improve other cardiovascular risk factors after 24 weeks of treatment.

Infrared thermographic assessment of changes in skin temperature during hypoglycaemia in patients with type 1 diabetes.

AIMS/HYPOTHESIS: Hypoglycaemia is associated with reduced skin temperature (Ts). We studied whether infrared thermography can detect Ts changes during hypoglycaemia in patients with type 1 diabetes and how the Ts response differs between patients with normal hypoglycaemia awareness and hypoglycaemia unawareness. METHODS: Twenty-four patients with type 1 diabetes (ten aware, 14 unaware) were studied during normoglycaemia (5.0-6.0 mmol/l), hypoglycaemia (2.0-2.5 mmol/l) and during recovery from hypoglycaemia (5.0-6.0 mmol/l) using hyperinsulinaemic glucose clamping. During each 1 h phase, Ts was measured twice by infrared thermography imaging in pre-defined areas (nose, glabella and the five left fingertips), symptoms of hypoglycaemia were scored and blood was sampled. RESULTS: Ts decreased during hypoglycaemia on the nose and glabella. The highest decrements were recorded on the nose (aware: -2.6 °C, unaware: -1.1 °C). In aware patients, the differences in temperature were statistically significant on both nose and glabella, whereas there was only a trend in the unaware group. There was a significant difference in hypoglycaemia-induced temperature changes between the groups. Patients in the aware group had higher hypoglycaemia symptom scores and higher adrenaline (epinephrine) levels during hypoglycaemia. CONCLUSIONS/INTERPRETATION: The hypoglycaemia-associated decrement in Ts can be assessed by infrared thermography and is larger in patients with normal hypoglycaemia awareness compared with unaware patients.

Efficacy and safety of meal-time administration of short-acting exenatide for glycaemic control in type 1 diabetes (MAG1C): a randomised, double-blind, placebo-controlled trial.

BACKGROUND: In type 2 diabetes, long-acting GLP-1 receptor agonists lower fasting plasma glucose and improve glycaemic control via their insulinotropic and glucagonostatic effects. In type 1 diabetes, their efficacy as an add-on treatment to insulin therapy is modest. Short-acting GLP-1 receptor agonists also lower postprandial glucose excursions in type 2 diabetes by decelerating gastric emptying rate. We aimed to test the efficacy of a short-acting GLP-1 receptor agonist in type 1 diabetes. METHODS: In the single-centre, parallel-group, randomised, double-blind, placebo-controlled MAG1C trial, patients with type 1 diabetes on multiple daily injection therapy aged 18 years and older with HbA1c 59-88 mmol/mol (7·5-10·0%) and a BMI of more than 22·0 kg/m2 were randomly assigned (1:1) through a computer-generated randomisation list to preprandial subcutaneous injection of 10 µg exenatide (Byetta) or placebo three times daily for 26 weeks as an add-on treatment to usual insulin therapy. Clinically assessed insulin titration was done by study staff. Participants and investigators were masked to treatment allocation. The primary endpoint was between-group difference in HbA1c after 26 weeks. Data were analysed with a baseline-adjusted linear mixed model in the intention-to-treat population. This study is registered with ClinicalTrials.gov, NCT03017352, and is completed. FINDINGS: Between Jan 4, 2017, and Jan 16, 2019, 108 participants were randomly assigned, 54 to exenatide and 54 to placebo; 23 participants discontinued treatment (17 in the exenatide group and six in the placebo group). From a baseline-adjusted mean of 66·4 mmol/mol (95% CI 64·9-67·8 [8·2%, 8·1-8·4]), HbA1c changed by -3·2 mmol/mol (-5·0 to -1·4 [-0·3%, -0·5 to -0·1]) with exenatide and -2·1 mmol/mol (-3·7 to -0·6 [-0·2%, -0·3 to -0·1]) with placebo after 26 weeks (estimated treatment difference of -1·1 mmol/mol (-3·4 to 1·2 [-0·1%, -0·3 to 0·1]; p=0·36). Exenatide increased the number of self-reported gastrointestinal adverse events (primarily nausea [48 events among 37 patients with exenatide, nine with placebo among 9 patients]). Two serious adverse events occurred in the exenatide group, and six occurred in the placebo group (none were considered to be related to the study drug). INTERPRETATION: Short-acting exenatide does not seem to have a future as a standard add-on treatment to insulin therapy in type 1 diabetes. FUNDING: AstraZeneca.

Hypoglycemia-Associated EEG Changes Following Antecedent Hypoglycemia in Type 1 Diabetes Mellitus.

BACKGROUND: Recurrent hypoglycemia has been shown to blunt hypoglycemia symptom scores and counterregulatory hormonal responses during subsequent hypoglycemia. We therefore studied whether hypoglycemia-associated electroencephalogram (EEG) changes are affected by an antecedent episode of hypoglycemia. METHODS: Twenty-four patients with type 1 diabetes mellitus (10 with normal hypoglycemia awareness, 14 with hypoglycemia unawareness) were studied on 2 consecutive days by hyperinsulinemic glucose clamp at hypoglycemia (2.0-2.5 mmol/L) during a 1-h period. EEG was recorded, cognitive function assessed, and hypoglycemia symptom scores and counterregulatory hormonal responses were obtained. RESULTS: Twenty-one patients completed the study. Hypoglycemia-associated EEG changes were identified on both days with no differences in power or frequency distribution in the theta, alpha, or the combined theta-alpha band during hypoglycemia on the 2 days. Similar degree of cognitive dysfunction was also present during hypoglycemia on both days. When comparing the aware and unaware group, there were no differences in the hypoglycemia-associated EEG changes. There were very subtle differences in cognitive function between the two groups on day 2. The symptom response was higher in the aware group on both days, while only subtle differences were seen in the counterregulatory hormonal response. CONCLUSION: Antecedent hypoglycemia does not affect hypoglycemia-associated EEG changes in patients with type 1 diabetes mellitus.

Treatment potential of the GLP-1 receptor agonists in type 2 diabetes mellitus: a review.

Over the last decade, the discovery of glucagon-like peptide 1 receptor agonists (GLP-1 RAs) has increased the treatment options for patients with type 2 diabetes mellitus (T2DM). GLP-1 RAs mimic the effects of native GLP-1, which increases insulin secretion, inhibits glucagon secretion, increases satiety and slows gastric emptying. This review evaluates the phase III trials for all approved GLP-1 RAs and reports that all GLP-1 RAs decrease HbA1c, fasting plasma glucose, and lead to a reduction in body weight in the majority of trials. The most common adverse events are nausea and other gastrointestinal discomfort, while hypoglycaemia is rarely reported when GLP-1 RAs not are combined with sulfonylurea or insulin. Treatment options in the near future will include co-formulations of basal insulin and a GLP-1 RA.

Twelve-Week Treatment With Liraglutide as Add-on to Insulin in Normal-Weight Patients With Poorly Controlled Type 1 Diabetes: A Randomized, Placebo-Controlled, Double-Blind Parallel Study.

OBJECTIVE: This study investigated the efficacy and safety of once-daily liraglutide 1.2 mg versus placebo as add-on to insulin treatment in normal-weight patients with poorly controlled type 1 diabetes. RESEARCH DESIGN AND METHODS: In a randomized (1:1), double-blind, placebo-controlled design, 40 patients with type 1 diabetes (HbA1c ≥8% [64 mmol/mol]) received once-daily liraglutide 1.2 mg or placebo for 12 weeks. Continuous glucose monitoring was performed before and at the end of treatment. The primary end point was change in HbA1c. Secondary end points included change in insulin dose, weight, glycemic excursions, heart rate, and blood pressure. RESULTS: Baseline HbA1c was similar in the liraglutide and placebo group (8.8 ± 0.2 and 8.7 ± 0.1% [72.5 ± 2.2 and 71.8 ± 1.5 mmol/mol]). Change in HbA1c from baseline was -0.6 ± 0.2% (-6.22 ± 1.71 mmol/mol) with liraglutide and -0.5 ± 0.2% (-5.56 ± 1.67 mmol/mol) with placebo (P = 0.62). Variation in glycemic excursions did not change in either group. Change in body weight was -3.13 ± 0.58 and +1.12 ± 0.42 kg (P < 0.0001) with liraglutide and placebo, respectively. The bolus insulin dose decreased in liraglutide-treated patients and did not change with placebo treatment (4.0 ± 1.3 vs. 0.0 ± 1.0 IU, P = 0.02). Heart rate increased within the liraglutide group (P = 0.04) but not compared with placebo, whereas mean systolic blood pressure decreased compared with placebo (between-group difference 3.21 mmHg [95% CI -8.31 to 1.90], P = 0.04). Liraglutide was more frequently associated with gastrointestinal adverse effects. The incidence of hypoglycemia did not differ between groups. CONCLUSIONS: Liraglutide significantly reduces body weight and insulin requirements but has no additional effect on HbA1c in normal-weight patients with type 1 diabetes inadequately controlled on insulin alone.

Hypoglycemia-associated changes in the electroencephalogram in patients with type 1 diabetes and normal hypoglycemia awareness or unawareness.

Hypoglycemia is associated with increased activity in the low-frequency bands in the electroencephalogram (EEG). We investigated whether hypoglycemia awareness and unawareness are associated with different hypoglycemia-associated EEG changes in patients with type 1 diabetes. Twenty-four patients participated in the study: 10 with normal hypoglycemia awareness and 14 with hypoglycemia unawareness. The patients were studied at normoglycemia (5-6 mmol/L) and hypoglycemia (2.0-2.5 mmol/L), and during recovery (5-6 mmol/L) by hyperinsulinemic glucose clamp. During each 1-h period, EEG, cognitive function, and hypoglycemia symptom scores were recorded, and the counterregulatory hormonal response was measured. Quantitative EEG analysis showed that the absolute amplitude of the θ band and α-θ band up to doubled during hypoglycemia with no difference between the two groups. In the recovery period, the θ amplitude remained increased. Cognitive function declined equally during hypoglycemia in both groups and during recovery reaction time was still prolonged in a subset of tests. The aware group reported higher hypoglycemia symptom scores and had higher epinephrine and cortisol responses compared with the unaware group. In patients with type 1 diabetes, EEG changes and cognitive performance during hypoglycemia are not affected by awareness status during a single insulin-induced episode with hypoglycemia.