Immunogenicity of the Novel Glucagon Analogue Dasiglucagon: Results of a Dedicated Immunogenicity Trial in Type 1 Diabetes.

Dasiglucagon is a next-generation glucagon analogue that is stable in aqueous formulation. This dedicated immunogenicity trial to support use as rescue treatment for severe hypoglycemia was conducted to evaluate the immunogenicity of repeated subcutaneous doses of dasiglucagon in subjects with type 1 diabetes. A total of 112 subjects were randomized 1:1 to receive three subcutaneous weekly doses of either 0.6 mg dasiglucagon or 1.0 mg recombinant glucagon (GlucaGen®) according to a double-blind parallel-group trial design. Subjects were followed for 15 weeks, with a multitiered testing approach planned for assessment of antidrug antibody (ADA) formation. For the primary immunogenicity endpoint, the overall ADA incidence was zero, as no subject demonstrated any treatment-induced or treatment-boosted ADA response at any time point in this trial involving three consecutive weekly doses of trial drug. No injection site reactions were reported for subjects receiving dasiglucagon. There were no unexpected safety findings for the trial.

Evaluating the Effectiveness of Switching to Insulin Degludec from Other Basal Insulins in a Real-World Canadian Population with Type 1 or Type 2 Diabetes: The CAN-TREAT Study.

INTRODUCTION: The aim of the study was to examine glycaemic control and safety of insulin degludec (degludec) in patients with either type 1 diabetes (T1D) or type 2 diabetes (T2D) under routine care settings in Canada. METHODS: Data were extracted from medical records of adults with T1D or T2D who switched to degludec (± prandial insulin) from another basal insulin (± prandial insulin) ≥ 6 months prior to data collection. The primary endpoint was change in glycated haemoglobin (HbA1c) at 6 ± 3 months after degludec initiation. Secondary endpoints included change in hypoglycaemia rate in the 6 months before versus the 6 months after switching, and change in mean total daily insulin dose. RESULTS: Of 667 patients assessed for eligibility, 626 were included. After 6 ± 3 months, HbA1c decreased from baseline in patients with T1D (- 0.3% [- 0.42, - 0.14]95% CI; p < 0.001) and in patients with T2D (- 0.4% [- 0.55, - 0.30]95% CI; p < 0.001). In patients with T1D, there were significant reductions in the rates of overall (rate ratio [RR] 0.70), non-severe (RR 0.69), non-severe nocturnal (RR 0.36), and severe nocturnal hypoglycaemia (RR 0.12; all p ≤ 0.004). In patients with T2D there was a significant reduction in non-severe nocturnal hypoglycaemia (RR 0.22; p < 0.001). Mean daily basal insulin dose decreased in patients with T1D (- 1.6 units [- 2.8, - 0.4]95% CI; p = 0.008); there was no significant change in patients with T2D (- 0.6 units [- 2.7, 1.4]95% CI; p = 0.543). CONCLUSION: In routine clinical practice, improved glycaemic control was observed in patients with T1D or T2D switching to insulin degludec from other basal insulins, with either improvement or no change in hypoglycaemia rates. TRIAL REGISTRATION: ClinicalTrials.gov NCT03674866.

Ethnic differences in antepartum glucose values that predict postpartum dysglycemia and neonatal macrosomia.

BACKGROUND AND OBJECTIVE: Gestational diabetes (GDM) occurs more often in women from certain ethnic groups and is also associated with fetal macrosomia. In this study, we investigated the ability of a gestational diabetes screening test (GDS), the 2 h 75 g-Oral Glucose Tolerance Test (OGTT), and glycated hemoglobin (HbA1c) in predicting postpartum dysglycemia and fetal macrosomia in women of Caucasian, Filipino, Chinese and South-Asian descent. METHODS: 848 women diagnosed with carbohydrate intolerance in pregnancy who completed a 2 h 75 g- OGTT within 6 months postpartum, were included in the study. Receiver Operating Characteristic curve analysis was used to test the ability of antepartum GDS, HbA1c and OGTT in predicting postpartum hyperglycemia, type 2 diabetes (T2D) and neonatal macrosomia (birth weight >4000 g). RESULTS: 20.2% had postpartum hyperglycemia while 3.8% had T2D. Those with postpartum dysglycemia were more likely to be non-Caucasian (South-Asian > Filipino > Chinese), have higher antepartum glucose values, require insulin during pregnancy and have cesarean births. Of HbA1c and the antepartum glucose values, a fasting glucose of ≥5.25 mmol/L was predictive of fetal macrosomia in Caucasians. 1 h glucose of ≥11.05 mmol/L was predictive of postpartum hyperglycemia, while 2 h glucose of ≥9.75 mmol/L was predictive of T2D; ethnicity influenced the predictive ability of these tests. CONCLUSIONS: Ethnicity influences the ability of antepartum glucose and HbA1c to predict the risk of macrosomia and postpartum dysglycemia. This information will help detect those most at risk of T2D.

Women with a history of gestational diabetes on long-term follow up have normal vascular function despite more dysglycemia, dyslipidemia and adiposity.

AIMS: Previous gestational diabetes (GDM) is a risk factor for type 2 diabetes and increased metabolic risk, but the link with vascular dysfunction is not clear. This study examined vascular function in women 4-10 years after a diagnosis of GDM who had a normal oral glucose tolerance test (OGTT) in the first postpartum year. METHODS: We studied 90 women with a history of GDM and 59 age-matched controls, examining differences in insulin resistance as measured by the Homeostatic Model Assessment (HOMA-IR) and glucose responses during an OGTT, adiposity, lipid profile and C-reactive protein (CRP). Using pulse wave analysis, we also measured cardiac function, vascular compliance, and systemic vascular resistance. RESULTS: Women with a history of GDM had higher measures of adiposity (body mass index 28.9 ± 6.5 vs. 26.6 ± 6.9 kg/m(2), P=0.04, waist-hip ratio 0.85 ± 0.06 vs. 0.79 ± 0.07, P<0.001), dyslipidemia (LDL cholesterol 2.78 ± 0.64 vs. 2.41 ± 0.56 mmol/L, P<0.001, total cholesterol: HDL cholesterol 3.93 ± 1.2 vs. 3.21 ± 0.82 mmol/L, P<0.001) and abnormal glucose metabolism (50% vs. 12%, P<0.001). However, there was no difference in CRP, HOMA-IR, or measures of cardiovascular function including pulse rate, pulse pressure, mean arterial pressure, cardiac output, systemic vascular resistance, small and large artery elasticity index. After controlling for adiposity, blood pressure, lipids and CRP, glycemic status did not contribute to vascular function. CONCLUSION: Despite a higher incidence of adiposity, dyslipidemia, and impaired glycemia, women with a history of GDM who had a normal postpartum OGTT did not have impaired vascular function 4-10 years postpartum, when compared to healthy controls.

Systematic review and meta-analysis of different dietary approaches to the management of type 2 diabetes.

BACKGROUND: There is evidence that reducing blood glucose concentrations, inducing weight loss, and improving the lipid profile reduces cardiovascular risk in people with type 2 diabetes. OBJECTIVE: We assessed the effect of various diets on glycemic control, lipids, and weight loss. DESIGN: We conducted searches of PubMed, Embase, and Google Scholar to August 2011. We included randomized controlled trials (RCTs) with interventions that lasted ≥6 mo that compared low-carbohydrate, vegetarian, vegan, low-glycemic index (GI), high-fiber, Mediterranean, and high-protein diets with control diets including low-fat, high-GI, American Diabetes Association, European Association for the Study of Diabetes, and low-protein diets. RESULTS: A total of 20 RCTs were included (n = 3073 included in final analyses across 3460 randomly assigned individuals). The low-carbohydrate, low-GI, Mediterranean, and high-protein diets all led to a greater improvement in glycemic control [glycated hemoglobin reductions of -0.12% (P = 0.04), -0.14% (P = 0.008), -0.47% (P < 0.00001), and -0.28% (P < 0.00001), respectively] compared with their respective control diets, with the largest effect size seen in the Mediterranean diet. Low-carbohydrate and Mediterranean diets led to greater weight loss [-0.69 kg (P = 0.21) and -1.84 kg (P < 0.00001), respectively], with an increase in HDL seen in all diets except the high-protein diet. CONCLUSION: Low-carbohydrate, low-GI, Mediterranean, and high-protein diets are effective in improving various markers of cardiovascular risk in people with diabetes and should be considered in the overall strategy of diabetes management.

The relationship of height and body fat to gender-assortative weight gain in children. A longitudinal cohort study (EarlyBird 44).

OBJECTIVE: Height, body fat and body mass index (BMI) are correlated in children, so we hypothesized that the gender-assortative associations in BMI recently reported in contemporary children might extend to their height and body fat. DESIGN: Prospective longitudinal cohort study. SUBJECTS: A total of 226 healthy trios (mother, father and child) from a 1995?1996 birth cohort randomly recruited in the city of Plymouth, UK. MEASUREMENTS: Height, weight, and BMI (kg/m(2)) were measured in each of the parents and, in addition, sum of five skin-folds (SF) in their children at 5, 6, 7 and 8 y. RESULTS: BMI and SF were strongly height-dependent in the children by 8 y (r = 0.41-0.56). SF was gender-assortative insofar as the mean SF was significantly greater in the daughters (but not the sons) of obese mothers (obese vs. normal weight: +2.5 cm p < 0.001) and in the sons (but not the daughters) of obese fathers (obese vs. normal: +1.3 cm p < 0.001). As expected, offspring height correlated with that of their parents, but overweight/obese children were systematically taller than normal weight children (boys: +1.02 SDS, girls: +1.14 SDS, p < 0.01), and this difference was independent of parental height or BMI. CONCLUSIONS: Height is transmitted by both parents, and the body fat of overweight/obese children largely by the same-sex parent, but the extra height associated with more fat in the child is unrelated to the height or weight of either parent. The secular trend in height among contemporary children may simply reflect their rising body fat. Excess fat is unhealthy, so the trend in height may not be healthy either.