OBJECTIVE To compare efficacy and safety of dulaglutide at doses of 3.0 and 4.5 mg versus 1.5 mg in patients with type 2 diabetes inadequately controlled with metformin. RESEARCH DESIGN AND METHODS Patients were randomly assigned to once-weekly dulaglutide 1.5 mg, 3.0 mg, or 4.5 mg for 52 weeks. The primary objective was determining superiority of dulaglutide 3.0 mg and/or 4.5 mg over 1.5 mg in HbA 1c reduction at 36 weeks. Secondary superiority objectives included change in body weight. Two estimands addressed efficacy objectives: treatment regimen (regardless of treatment discontinuation or rescue medication) and efficacy (on treatment without rescue medication) in all randomly assigned patients. RESULTS Mean baseline HbA 1c and BMI in randomly assigned patients ( N = 1,842) was 8.6% (70 mmol/mol) and 34.2 kg/m 2 , respectively. At 36 weeks, dulaglutide 4.5 mg provided superior HbA 1c reductions compared with 1.5 mg (treatment-regimen estimand: −1.77 vs. −1.54% [−19.4 vs. −16.8 mmol/mol], estimated treatment difference [ETD] −0.24% (−2.6 mmol/mol), P < 0.001; efficacy estimand: −1.87 vs. −1.53% [−20.4 vs. −16.7 mmol/mol], ETD −0.34% (−3.7 mmol/mol), P < 0.001). Dulaglutide 3.0 mg was superior to 1.5 mg for reducing HbA 1c , using the efficacy estimand (ETD −0.17% [−1.9 mmol/mol]; P = 0.003) but not the treatment-regimen estimand (ETD −0.10% [−1.1 mmol/mol]; P = 0.096). Dulaglutide 4.5 mg was superior to 1.5 mg for weight loss at 36 weeks for both estimands (treatment regimen: −4.6 vs. −3.0 kg, ETD −1.6 kg, P < 0.001; efficacy: −4.7 vs. −3.1 kg, ETD −1.6 kg, P < 0.001). Common adverse events through 36 weeks included nausea (1.5 mg, 13.4%; 3 mg, 15.6%; 4.5 mg, 16.4%) and vomiting (1.5 mg, 5.6%; 3 mg, 8.3%; 4.5 mg, 9.3%). CONCLUSIONS In patients with type 2 diabetes inadequately controlled by metformin, escalation from dulaglutide 1.5 mg to 3.0 mg or 4.5 mg provided clinically relevant, dose-related reductions in HbA 1c and body weight with a similar safety profile.

Page KC, Malik RE, Ripple JA, Anday EK. Maternal and postweaning diet interaction alters hypothalamic gene expression and modulates response to a high-fat diet in male offspring. Am J Physiol Regul Integr Comp Physiol 297: R1049 -R1057, 2009. First published August 5, 2009 doi:10.1152/ajpregu.90585.2008.-Epidemiological data and results from animal studies indicate that imbalances in maternal nutrition impact the expression of metabolic disorders in the offspring. We tested the hypothesis that consumption of excess saturated fats during pregnancy and lactation contributes to adult metabolic dysfunction and that these disturbances can be further influenced by the postweaning diet. Adult male offspring from chowfed dams were compared with males from dams fed a diet high in saturated fat (45 kcal/100 kcal) before mating, pregnancy, and lactation. Offspring were weaned to a standard chow diet or high fat diet. Animals were killed at 120 days after a 24-h fast. Body weight, energy intake, fat deposition, serum leptin, and insulin were significantly higher in offspring from control or high-fat dams if fed a high-fat diet from weaning to adulthood. Only fat-fed offspring from fat-fed dams were hyperglycemic. Leptin receptor, proopiomelanocortin, and neuropeptide Y (NPY) were also significantly increased in offspring exposed to excess saturated fat during gestation and into adulthood, whereas NPY 1 receptor was downregulated. Signal transducer and activator of transcription 3 mRNA level was significantly higher in offspring from high-fat-fed dams compared with controls; however, no change was detected in cocaine and amphetamine-regulated transcript or suppressor of cytokine signaling 3. An increase in agoutirelated protein expression did not reach significance. A significant reduction in phosphatidylinositol 3-kinase regulatory subunit (p85␣) coupled to an upregulation of protein kinase B was observed in offspring from high-fat-fed dams transitioned to chow food, whereas p85␣ expression was significantly increased in high-fat offspring weaned to the high-fat diet. These data support the hypothesis that early life exposure to excess fat is associated with changes in hypothalamic regulation of body weight and energy homeostasis and that postweaning diet influences development of metabolic dysfunction and obesity. development; hypothalamus; obesity OBESITY HAS BECOME one of the most prevalent and costly health issues to plague the developed world. The nutritional environment during early development has been shown to alter the expression of genes critical to regulation of energy intake and expenditure (20), and poor nutrition during intrauterine and early postnatal life is particularly disruptive. Recent evidence supports this hypothesis and underscores the importance of this critical time in the development of neuroendocrine feedback loops regulating energy homeostasis in the hypothalamus (2, 16). For example, offspring of undernourished mice have reduced birth weights. When these offspring are cross-fostered onto norma...

<b>Objective:</b> To compare efficacy and safety of dulaglutide at doses of 3.0 and 4.5 mg versus 1.5 mg in patients with type 2 diabetes inadequately controlled with metformin. <p><b>Research Design and Methods:</b> Patients were randomized to once weekly dulaglutide 1.5 mg, 3.0 mg, or 4.5 mg for 52 weeks. Primary objective was superiority of dulaglutide 3.0 mg and/or 4.5 mg over 1.5 mg in HbA_1c reduction at 36 weeks. Secondary superiority objectives included change in body weight. Two estimands addressed efficacy objectives: treatment-regimen estimand (regardless of treatment discontinuation or rescue medication) and efficacy estimand (on treatment without rescue medication) in all randomized patients.</p> <p><b>Results:</b> Mean baseline HbA_1c and BMI in randomized patients (N=1842) was 8.6% (70 mmol/mol) and 34.2 kg/m², respectively. At 36 weeks, dulaglutide 4.5 mg provided superior HbA_1c reductions compared to 1.5 mg (treatment-regimen estimand: -1.77 vs ‑1.54% [-19.4 vs -16.8 mmol/mol], estimated treatment difference [ETD] -0.24% (-2.6 mmol/mol); P<0.001; efficacy estimand: -1.87 vs ‑1.53% [‑20.4 vs -16.7 mmol/mol], ETD -0.34% (-3.7 mmol/mol); P<0.001). Dulaglutide 3.0 mg was superior to 1.5 mg on HbA_1c reduction using the efficacy estimand (ETD -0.17% [-1.9 mmol/mol]; P=0.003) but not the treatment-regimen estimand (ETD -0.10% [-1.1 mmol/mol ]; P=0.096). Dulaglutide 4.5 mg was superior to 1.5 mg for weight loss at 36 weeks for both estimands (treatment-regimen estimand: -4.6 vs -3.0 kg, ETD -1.6 kg; P<0.001; efficacy estimand: -4.7 vs -3.1 kg; ETD -1.6 kg; P<0.001). Common adverse events through 36 weeks included nausea (1.5 mg, 13.4%; 3 mg, 15.6%; 4.5 mg, 16.4%) and vomiting (1.5 mg, 5.6%; 3 mg, 8.3%; 4.5 mg, 9.3%). </p> <p><b>Conclusion:</b> In patients with type 2 diabetes inadequately controlled on metformin, escalation from dulaglutide 1.5 mg to 3.0 mg or 4.5 mg provided clinically relevant, dose-related reductions in HbA_1c and body weight with a similar safety profile.</p>

Introduction: Randomized controlled trials (RCTs) have demonstrated the efficacy of dulaglutide in adults with type 2 diabetes mellitus (T2DM), but results may not be generalizable in routine practice. This pragmatic literature review aimed to summarize real-world evidence (RWE) for dulaglutide. Methods: The MEDLINE, EMBASE, NHS Economic Evaluation Database, and Health Technology Assessment databases were searched from January 2014 to July 2019 for studies providing RWE for dulaglutide in adults with T2DM regarding at least one outcome of interest (change in glycated hemoglobin [HbA1c]; weight; adherence; persistence; discontinuation; costs; healthcare resource utilization; health-related quality of life; patient satisfaction; and preference). Relevant congress abstracts were identified from EMBASE. Results: A total of 29 studies (11 articles; 18 abstracts) were included. RWE for dulaglutide was not identified for all outcomes of interest. Dulaglutide reduced HbA1c from baseline to 3-24 months by 0.5-2.2% across studies (n = 20), and 23.4-55.7% of patients achieved HbA1c \ 7.0%. Weight was reduced by 2.1-6.4 kg across studies of 3-12 months (n = 15). Based on outcomes from ten studies, 27.2-61.0% of dulaglutide patients were adherent. Mean persistence was 146-152 days and [ 250 days in 6-and 12-month studies, respectively. Most studies reported discontinuation rates of 26.2-37.0%. Adherence and persistence were consistently reported to be greater in dulaglutide-treated patients in RW settings compared with other glucagon-like peptide-1 receptor agonists. Dulaglutide was associated with lower costs per 1% reduction in HbA1c compared with exenatide, liraglutide, or basal insulin (n = 3 studies). Conclusion: Evidence from RWE studies suggests that dulaglutide may be associated with clinically relevant reductions in HbA1c, with a Digital Features To view digital features for this article go to

Although outcomes for children with cancer have significantly improved over the past 40 years, there has been little progress in the treatment of some pediatric cancers, particularly when advanced. Additionally, clinical trial options and availability are often insufficient. Improved genomic and immunologic understanding of pediatric cancers, combined with innovative clinical trial designs, may provide an enhanced opportunity to study childhood cancers. Master protocols, which incorporate the use of precision medicine approaches, coupled with the ability to quickly assess the safety and effectiveness of new therapies, have the potential to accelerate early-phase clinical testing of novel therapeutics and which may result in more rapid approval of new drugs for children with cancer. Designing and conducting master protocols for children requires addressing similar principles and requirements as traditional adult oncology trials, but there are also unique considerations for master protocols conducted in children with cancer. The purpose of this paper is to define the key challenges and opportunities associated with this approach in order to ensure that master protocols can be adapted to benefit children and adolescents and ensure that adequate data are captured to advance, in parallel, the clinical development of investigational agents for children with cancer.