Saxagliptin clinical trials: evaluation of CV risk

Diabetes is Australia's fastest growing chronic disease with approximately 890,000 patients currently diagnosed with diabetes. 1 By 2031 it is predicted that 3.3 million Australians will have type 2 diabetes mellitus, 2 thus increasing the demand for treatment. However, several diabetes, obesity, and lipid drug trials have had unexpected and unfavourable cardiovascular (CV) results. The saxagliptin (SAXA) phase 2b/3 program enrolled a range of patients with diabetes and included a controlled, long-term safety extension phase. SAXA is a potent, selective dipeptidyl peptidase-4 (DPP-4) inhibitor. In the SAXA clinical data, the primary endpoint, major adverse cardiovascular events (MACE; stroke, myocardial infarction or CV death, analysed post hoc) and acute cardiovascular events (ACE; acute, clinically significant events, including cardiac revascularisation procedures) were identified using selected MedDRA Preferred Terms. CV events were analysed in a comprehensive dataset: 8 randomised, double-blind, phase 2b/3 trials, which included 4607 patients (3206 randomised to SAXA 2.5, 5, or 10 mg; 150 randomised to SAXA 20, 40, or 100 mg; and 1251 randomised to placebo, metformin, or up-titrated glyburide). Overall exposure was 3758 patient-years on SAXA and 1293 patient-years on comparators. Within the SAXA population, 81% had at least 1 CV risk factor in addition to diabetes, with hypertension (52%), dyslipidaemia (44%), or history of smoking (39%) the most common; 12% had known prior CV disease. Comparator group had similar proportions. Numbers of patients with events are shown in Table. The Cox proportional hazard ratio for MACE was 0.44 (95% CI: 0.24–0.82) and for ACE was 0.59 (95% CI: 0.35–1.00). A series of sensitivity analyses using related endpoints and alternative analytic methods produced consistent results. Based on a >5000 patient-year clinical trial experience, there was no evidence of increased CV risk with SAXA treatment ― as monotherapy or in combination with other oral antidiabetic agents. These data raise the hypothesis of a cardioprotective effect of SAXA, which will be studied in the SAVOR trial

β-cell stimulation by saxagliptin in patients with type 2 diabetes

Diabetes is Australia’s fastest growing chronic disease with approximately 890,000 patients currently diagnosed with diabetes.1By 2031 it is predicted that 3.3 million Australians will have type 2 diabetes2thus increasing the demand for prevention strategies and an emphasis on early diagnosis and treatment. Saxagliptin (SAXA) is a potent, selective DPP-4 inhibitor, specifically designed for extended inhibition of the DPP-4 enzyme. DPP-4 inactivates incretins that stimulate glucose-dependent insulin secretion and inhibit glucagon secretion. A proposed MOA of SAXA involves protecting incretins from DPP-4 degradation, thus improving β-cell response. This randomised, parallel-group, double-blind, PBO-controlled study (CV181-041) assessed SAXA’s effect on β-cell function by intravenous hyperglycaemic clamp (IV HC) in T2DM patients. Patients were assessed at baseline (BL) and wk 12 in the fasting state (0-180min, IV HC) and after stimulating incretin secretion by orally ingesting 75g glucose (180-480min, IV-oral HC). HC infusions were adjusted to maintain plasma glucose at 280mg/dL. Insulin secretion was calculated by C-peptide deconvolution. Primary endpoint was %Δfrom BL in total insulin secretion (%Δinsulin) during IV-oral HC (180-480min). Secondary endpoint was %Δinsulin during IV HC (120-180min). Patients were drug-naïve with T2DM aged 43-69yrs with BL A1C range 5.9%-8.1%. Twenty patients received SAXA 5mg od; 16 received PBO. After 12 wks, SAXA significantly increased %Δinsulin from BL during IV-oral HC (adj% difference of 18.5% vs PBO, p=.035). In the fasting state during IV HC SAXA significantly increased %Δinsulin from BL (adj% difference of 27.9% vs PBO, p=.020). At wk 12 insulin secretion increased from BL with SAXA but not with PBO (Fig). Glucagon AUC during IV-oral HC also improved from BL with SAXA, (adj% difference of –21.8% vs PBO, p=.031). SAXA was generally safe and well-tolerated. In conclusion, SAXA improved pancreatic β-cell function in the postprandial and fasting states and decreased postprandial glucagon concentration

Absence of vertical transmission of Helicobacter pylori in an experimental murine model

Helicobacter pylori (H. pylori) infection is acquired mainly in early childhood but the precise transmission routes are unclear. This study examined the maternal H. pylori infection status in order to determine the potential of perinatal transmission. These issues were investigated using an experimental murine model, the Mongolian gerbil, which has been reported to be the most suitable laboratory animal model for studying H. pylori. Pregnant Mongolian gerbils, infected experimentally with H. pylori, were divided into two groups. The stomachs of the mother and litters were isolated and assessed for the transmission of H. pylori at the prenatal period (2 weeks after pregnancy) and at the parturition day. The bacterial culture, polymerase chain reaction (PCR) and rapid urease test were used to examine the presence of the transmitted H. pylori. There was no H. pylori observed in any of the fetuses during pregnancy and in the litters at parturition. This suggests that vertical infection during the prenatal period or delivery procedure is unlikely to be route of mother-to-child transmission of a H. pylori infection

Relationship Between Intestinal Gas and the Development of Right Colonic Diverticula

BACKGROUNDS/AIMS: High intraluminal pressure has been reported to cause left colonic diverticula. However, the pathophysiology of right colonic diverticula is still unclear. Methane gas has been reported to delay small intestinal transit and to increase intraluminal pressure. The aim of this study was to evaluate the relationship between right colonic diverticula and intestinal gas produced by enteric bacteria. METHODS: Lactulose breath tests were performed in 30 patients who were diagnosed with right colonic diverticula via colonoscopy. The control group consisted of 30 healthy adults with no specific symptoms or medical histories. A hydrogen or methane producer was defined in 2 ways: either one that exhibited a breath hydrogen level > or = 20 ppm (methane > or = 10 ppm) baseline or one that exhibited an increase in breath hydrogen > or = 20 ppm (methane > or = 10 ppm) above baseline within the first 90 minutes of the test. RESULTS: The lactulose breath test (LBT) positivity in the diverticular group and the control group were 40.0% and 33.3%, respectively, without a statistically significant difference. The concentrations of methane and hydrogen gas measured by LBT increased over time, but there was no significant difference between the control and the diverticular groups. CONCLUSIONS: There was no significant relationship between right colonic diverticula and intestinal gases produced by enteric bacteria. However, time-dependent formation of diverticula should be taken into consideration, therefore long-term, large-scale follow-up studies may reveal further pathogenesis of right colonic diverticulosis.ope

Parallel Retention of Pdx2 Genes in Cartilaginous Fish and Coelacanths

The Pdx1 or Ipf1 gene encodes an important homeodomain-containing protein with key roles in pancreas development and function. Mutations in human PDX1 are implicated in developmental defects and disease of the pancreas. Extensive research, including genome sequencing, has indicated that Pdx1 is the only member of its gene family in mammals, birds, amphibians, and ray-finned fish, and with the exception of teleost fish, this gene forms part of the ParaHox gene cluster along with Gsx1 and Cdx2. The ParaHox cluster, however, is a remnant of a 4-fold genome duplication; the three other ParaHox paralogues lack a Pdx-like gene in all vertebrate genomes examined to date. We have used bacterial artificial chromosome cloning and synteny analysis to show that the ancestor of living jawed vertebrates in fact had more ParaHox genes, including two Pdx genes (Pdx1 and Pdx2). Surprisingly, the two Pdx genes have been retained in parallel in two quite distantly related lineages, the cartilaginous fish (sharks, skates, and chimeras) and the Indonesian coelacanth, Latimeria menadoensis. The Pdx2 gene has been lost independently in ray-finned fish and in tetrapods

Effects of Allergen Sensitization on Response to Therapy in Children with Eosinophilic Esophagitis

Background: In children with eosinophilic esophagitis (EoE) foods are the most common disease triggers, but environmental allergens are also suspected culprits. Objective: To determine the effects of environmental allergen sensitization on response to treatment in children with EoE in the southeastern United States. Methods: Patients 2 to 18 years old who were referred to the Arkansas Children’s Hospital Eosinophilic Gastrointestinal Disorders Clinic from January 2012 to January 2016 were enrolled in a prospective, longitudinal cohort study with collection of demographics, clinical symptoms, medical history, allergy sensitization profiles, and response to treatment over time. Comparisons were made between complete responders (peak esophageal eosinophil count \u3c 15 per high-power field [HPF]) and nonresponders (\u3e 25 eosinophils per HPF) after treatment with diet elimination alone, swallowed corticosteroids alone, or diet elimination and swallowed corticosteroids. Sensitization patterns to environmental allergens found in the southeastern United States were analyzed for the effect on treatment response. Results: A total of 223 individuals were enrolled. Of these, 182 had environmental allergy profiling and at least one endoscopy while receiving proton pump inhibitor (PPI) therapy. Twenty-nine individuals had PPI-responsive EoE and were excluded from further analysis, leaving 123 individuals with none-PPI-responsive EoE who were further analyzed; 72 (58.5%) were complete responders and 33 (26.8%) were nonresponders. Seventeen individuals (13.8%) were partial responders (≥ 1 but ≤ 25 eosinophils per HPF) and excluded from further analysis. Nonresponders were more likely to be sensitized to perennial allergens (P = .02). There was no significant difference in response based on seasonal allergen sensitization. Individuals with mold or cockroach sensitization were more likely to fail combination diet and swallowed corticosteroid treatment (P = .02 and P = .002). Conclusion: Perennial allergen and mold sensitization may lead to nonresponse to EoE treatment in some patients. Additional studies are needed to further understand the effect of environmental allergens on EoE

Effects of esomeprazole treatment for gastroesophageal reflux disease on quality of life in 12- to 17-year-old adolescents: an international health outcomes study

<p>Abstract</p> <p>Background</p> <p>Although gastroesophageal reflux disease (GERD) is common in adolescents, the burden of GERD on health-related quality of life (HRQOL) in adolescents has not been previously evaluated. Therefore, the objective of the study was to examine the effect of GERD on HRQOL in adolescents.</p> <p>Methods</p> <p>This international, 31-site, 8-week safety study randomized adolescents, aged 12 to 17 years inclusive, with GERD to receive esomeprazole 20 or 40 mg once daily. The Quality of Life in Reflux and Dyspepsia questionnaire (QOLRAD), previously validated in adults, consists of 25 questions grouped into 5 domains: emotional distress, sleep disturbance, food/drink problems, physical/social functioning, and vitality. The QOLRAD was administered at the baseline and week-8 (final) visits.</p> <p>Results</p> <p>Of the 149 patients randomized, 134 completed the QOLRAD at baseline and final visits and were eligible for analysis of their HRQOL data. Baseline QOLRAD scores indicated GERD had a negative effect on the HRQOL of these adolescents, especially in the domains of vitality and emotional distress, and problems with food/drink. At the final visit, mean scores for all 5 QOLRAD domains improved significantly (<it>P </it>< .0001); change of scores (ie, delta) for all domains met or exceeded the adult QOLRAD minimal clinically significant difference standard of 0.5 units.</p> <p>Conclusion</p> <p>GERD had a negative effect on QOL in adolescents. After esomeprazole treatment, statistically and clinically significant improvements occurred in all domains of the QOLRAD for these adolescents.</p> <p>Trial Registration</p> <p>D9614C00098; ClinicalTrials.gov Identifier NCT00241501</p

Monitoring Bacterial Community of Human Gut Microbiota Reveals an Increase in Lactobacillus in Obese Patients and Methanogens in Anorexic Patients

Background: Studies of the bacterial communities of the gut microbiota have revealed a shift in the ratio of Firmicutes and Bacteroidetes in obese patients. Determining the variations of microbial communities in feces may be beneficial for the identification of specific profiles in patients with abnormal weights. The roles of the archaeon Methanobrevibacter smithii and Lactobacillus species have not been described in these studies. Methods and Findings: We developed an efficient and robust real-time PCR tool that includes a plasmid-based internal control and allows for quantification of the bacterial divisions Bacteroidetes, Firmicutes, and Lactobacillus as well as the methanogen M. smithii. We applied this technique to the feces of 20 obese subjects, 9 patients with anorexia nervosa, and 20 normal-weight healthy controls. Our results confirmed a reduction in the Bacteroidetes community in obese patients (p<0.01). We found a significantly higher Lactobacillus species concentration in obese patients than in lean controls (p = 0.0197) or anorexic patients (p = 0.0332). The M. smithii concentration was much higher in anorexic patients than in the lean population (p = 0.0171). Conclusions: Lactobacillus species are widely used as growth promoters in the farm industry and are now linked to obesity in humans. The study of the bacterial flora in anorexic patients revealed an increase in M. smithii. This increase might represent an adaptive use of nutrients in this population