OBJECTIVECystic fibrosis (CF)-related diabetes (CFRD) diagnosis and management have considerably changed since diabetes was first shown to be associated with a poor prognosis in subjects with CF. Current trends in CFRD prevalence, incidence, and mortality were determined from a comprehensive clinical database.RESEARCH DESIGN AND METHODSData were reviewed from 872 CF patients followed at the University of Minnesota during three consecutive intervals: 1992–1997, 1998–2002, and 2003–2008.RESULTSCFRD is currently present in 2% of children, 19% of adolescents, and 40–50% of adults. Incidence and prevalence are higher in female subjects aged 30–39 years; otherwise, there are no sex differences. In younger individuals, CFRD without fasting hyperglycemia predominates, but fasting hyperglycemia prevalence rises with age. CFRD mortality has significantly decreased over time. From 1992–1997 to 2003–2008, mortality rate in female subjects dropped by >50% from 6.9 to 3.2 deaths per 100 patient-years and in male subjects from 6.5 to 3.8 deaths per 100 patient-years. There is no longer a sex difference in mortality. Diabetes was previously diagnosed as a perimorbid event in nearly 20% of patients, but of 61 patients diagnosed with diabetes during 2003–2008, only 2 died. Lung function but not nutritional status is still worse in CF patients with diabetes compared with those without diabetes. Nutritional status and pulmonary status are similar between patients without fasting hyperglycemia and those with fasting hyperglycemia.CONCLUSIONSPreviously noted sex differences in mortality have disappeared, and the gap in mortality between CF patients with and without diabetes has considerably narrowed. We believe that early diagnosis and aggressive treatment have played a major role in improving survival in these patients.

OBJECTIVETreatment of severe hypoglycemia with loss of consciousness or seizure outside of the hospital setting is presently limited to intramuscular glucagon requiring reconstitution immediately prior to injection, a process prone to error or omission. A needle-free intranasal glucagon preparation was compared with intramuscular glucagon for treatment of insulin-induced hypoglycemia.RESEARCH DESIGN AND METHODSAt eight clinical centers, a randomized crossover noninferiority trial was conducted involving 75 adults with type 1 diabetes (mean age, 33 ± 12 years; median diabetes duration, 18 years) to compare intranasal (3 mg) versus intramuscular (1 mg) glucagon for treatment of hypoglycemia induced by intravenous insulin. Success was defined as an increase in plasma glucose to ≥70 mg/dL or ≥20 mg/dL from the glucose nadir within 30 min after receiving glucagon.RESULTSMean plasma glucose at time of glucagon administration was 48 ± 8 and 49 ± 8 mg/dL at the intranasal and intramuscular visits, respectively. Success criteria were met at all but one intranasal visit and at all intramuscular visits (98.7% vs. 100%; difference 1.3%, upper end of 1-sided 97.5% CI 4.0%). Mean time to success was 16 min for intranasal and 13 min for intramuscular (P < 0.001). Head/facial discomfort was reported during 25% of intranasal and 9% of intramuscular dosing visits; nausea (with or without vomiting) occurred with 35% and 38% of visits, respectively.CONCLUSIONSIntranasal glucagon was highly effective in treating insulin-induced hypoglycemia in adults with type 1 diabetes. Although the trial was conducted in a controlled setting, the results are applicable to real-world management of severe hypoglycemia, which occurs owing to excessive therapeutic insulin relative to the impaired or absent endogenous glucagon response.

Objective To evaluate the effects of exenatide on body mass index (BMI) and cardiometabolic risk factors in adolescents with severe obesity. Design Three-month, randomized, double-blind, placebo-controlled, multicenter clinical trial followed by a three-month open label extension. Setting An academic medical center and an outpatient pediatric endocrinology clinic. Patients Twenty-six adolescents (age 12–19 years) with severe obesity (BMI ≥ 1.2 times the 95th percentile or ≥ 35 kg/m2). Intervention All patients received lifestyle modification counseling and were equally randomized to exenatide or placebo injection, twice per day. Main Outcome Measures The primary endpoint was the mean percent change in BMI measured at baseline and three-months. Secondary endpoints included absolute change in BMI, body weight, body fat, blood pressure, hemoglobin A1c, fasting glucose, fasting insulin, and lipids at three-months. Results Twenty-two patients completed the trial. Exenatide elicited a greater reduction in percent change in BMI compared to placebo (−2.70%, 95% CI (−5.02, −0.37), P = 0.025). Similar findings were observed for absolute change in BMI (−1.13 kg/m2, 95% CI (−2.03, −0.24), P = 0.015) and body weight (−3.26 kg, 95% CI (−5.87, −0.66), P = 0.017). Although not reaching the level of statistical significance, reduction in systolic blood pressure was observed with exenatide. During the open label extension, BMI was further reduced in those initially randomized to exenatide (cumulative BMI reduction of 4%). Conclusions These results provide preliminary evidence supporting the feasibility, safety, and efficacy of glucagon-like peptide-1 receptor agonist therapy for the treatment of severe obesity in adolescents. Trial Registration This study is registered on the www.clinicaltrials.gov website (ClinicalTrials.gov identifier: NCT01237197).

OBJECTIVETreatment of severe hypoglycemia outside of the hospital setting is limited to intramuscular glucagon requiring reconstitution prior to injection. The current study examined the safety and dose-response relationships of a needle-free intranasal glucagon preparation in youth aged 4 to <17 years.RESEARCH DESIGN AND METHODSA total of 48 youth with type 1 diabetes completed the study at seven clinical centers. Participants in the two youngest cohorts (4 to <8 and 8 to <12 years old) were randomly assigned to receive either 2 or 3 mg intranasal glucagon in two separate sessions or to receive a single, weight-based dose of intramuscular glucagon. Participants aged 12 to <17 years received 1 mg intramuscular glucagon in one session and 3 mg intranasal glucagon in the other session. Glucagon was given after glucose was lowered to <80 mg/dL (mean nadir ranged between 67 and 75 mg/dL).RESULTSAll 24 intramuscular and 58 of the 59 intranasal doses produced a ≥25 mg/dL rise in glucose from nadir within 20 min of dosing. Times to peak plasma glucose and glucagon levels were similar under both intramuscular and intranasal conditions. Transient nausea occurred in 67% of intramuscular sessions versus 42% of intranasal sessions (P = 0.05); the efficacy and safety of the 2- and 3-mg intranasal doses were similar in the youngest cohorts.CONCLUSIONSResults of this phase 1, pharmacokinetic, and pharmacodynamic study support the potential efficacy of a needle-free glucagon nasal powder delivery system for treatment of hypoglycemia in youth with type 1 diabetes. Given the similar frequency and transient nature of adverse effects of the 2- and 3-mg intranasal doses in the two youngest cohorts, a single 3-mg intranasal dose appears to be appropriate for use across the entire 4- to <17-year age range.

The objective of this pilot study was to evaluate the effects of exenatide on body mass index (BMI) (primary endpoint) and cardiometabolic risk factors in non-diabetic youth with extreme obesity. Twelve children and adolescents (age 9–16 years old) with extreme obesity (BMI ≥1.2 times the 95th percentile or BMI ≥35 kg/m2) were enrolled in a 6-month, randomized, open-label, crossover, clinical trial consisting of two, 3-month phases: 1) a control phase of lifestyle modification and 2) a drug phase of lifestyle modification plus exenatide. Participants were equally randomized to phase-order (i.e., starting with control or drug therapy) then crossed-over to the other treatment. BMI, body fat percentage, blood pressure, lipids, oral glucose tolerance (OGTT), adipokines, plasma biomarkers of endothelial activation, and endothelial function were assessed at baseline, 3-, and 6-months. The mean change over each 3-month phase was compared between treatments. Compared to control, exenatide significantly reduced BMI (−1.7 kg/m2, 95% CI (−3.0, −0.4), P = 0.01), body weight (−3.9 kg, 95% CI (−7.11, −0.69), P = 0.02), and fasting insulin (−7.5 mU/L, 95% CI (−13.71, −1.37), P = 0.02). Significant improvements were observed for OGTT-derived insulin sensitivity (P = 0.02) and beta cell function (P = 0.03). Compliance with the injection regimen was excellent (≥94%) and exenatide was generally well-tolerated (the most common adverse event was mild nausea in 36%). These preliminary data suggest that exenatide should be evaluated in larger, well-controlled trials for its ability to reduce BMI and improve cardiometabolic risk factors in youth with extreme obesity.