Fotagliptin monotherapy with alogliptin as an active comparator in patients with uncontrolled type 2 diabetes mellitus: a randomized, multicenter, double-blind, placebo-controlled, phase 3 trial.

BACKGROUND: Dipeptidyl peptidase-4 inhibitors (DPP-4i) have become firmly established in treatment algorithms and national guidelines for improving glycemic control in type 2 diabetes mellitus (T2DM).To report the findings from a multicenter, randomized, double-blind, placebo-controlled phase 3 clinical trial, which was designed to assess the efficacy and safety of a novel DPP-4 inhibitor fotagliptin in treatment-naive patients with T2DM. METHODS: Patients with T2DM were randomized to receive fotagliptin (n = 230), alogliptin (n = 113) or placebo (n = 115) at a 2:1:1 ratio for 24 weeks of double-blind treatment period, followed by an open-label treatment period, making up a total of 52 weeks. The primary efficacy endpoint was to determine the superiority of fotagliptin over placebo in the change of HbA1c from baseline to Week 24. All serious or significant adverse events were recorded. RESULTS: After 24 weeks, mean decreases in HbA1c from baseline were -0.70% for fotagliptin, -0.72% for alogliptin and -0.26% for placebo. Estimated mean treatment differences in HbA1c were -0.44% (95% confidence interval [CI]: -0.62% to -0.27%) for fotagliptin versus placebo, and -0.46% (95% CI: -0.67% to -0.26%) for alogliptin versus placebo, and 0.02% (95%CI: -0.16% to 0.19%; upper limit of 95%CI < margin of 0.4%) for fotagliptin versus alogliptin. So fotagliptin was non-inferior to alogliptin. Compared with subjects with placebo (15.5%), significantly more patients with fotagliptin (37.0%) and alogliptin (35.5%) achieved HbA1c < 7.0% after 24 weeks of treatment. During the whole 52 weeks of treatment, the overall incidence of hypoglycemia was low for both of the fotagliptin and alogliptin groups (1.0% each). No drug-related serious adverse events were observed in any treatment group. CONCLUSIONS: In summary, the study demonstrated improvement in glycemic control and a favorable safety profile for fotagliptin in treatment-naive patients with T2DM. TRIAL REGISTRATION: ClinicalTrail.gov NCT05782192.

Diabetes mellitus in patients with type 1 autoimmune pancreatitis at diagnosis and after corticosteroid therapy.

BACKGROUND: A high prevalence of diabetes mellitus (DM) coexisting with autoimmune pancreatitis (AIP) is observed. However, evidence on the circumstances under which corticosteroid therapy (CST) for AIP improves or worsens DM is scarce. This study aimed to demonstrate and identify predictors of DM control under the influence of CST. METHODS: Patients diagnosed with type 1 AIP were enrolled from a prospectively maintained cohort and were classified into three groups according to the chronology in which AIP and DM were diagnosed: pre-existing DM (pDM), concurrent DM (cDM), and non-DM (nDM). The responses of DM to CST were assessed when corticosteroid was ceased or tapered to a maintenance dose and classified as 'improvement' and 'non-improvement' (including 'no change' and 'exacerbation'). RESULTS: Among 101 patients with type 1 AIP, 52 (51.5%) patients were complicated with DM at the time of AIP diagnosis, with 36 patients in the cDM group and 16 patients in the pDM group. The incidences of diffuse pancreatic swelling (72.2%) and pancreatic body/tail involvement (91.7%) were significantly higher in the cDM group than in both the pDM and nDM groups. Of the 52 patients with DM, CST was administered in 48 cases. Multivariate logistic analysis identified that elevated serum gamma-glutamyl transferase (GGT) level at AIP diagnosis [odds ratio (OR) = 0.032, 95% confidence interval (CI): 0.003-0.412, P = 0.008] and pancreatic atrophy after CST (OR = 0.027, 95% CI: 0.003-0.295, P = 0.003) were negatively associated with DM control improvement. CONCLUSIONS: Patients with diffuse pancreatic swelling and pancreatic body/tail involvement in pancreatitis tended to be complicated with cDM at AIP diagnosis. CST exerted a beneficial effect on the clinical course of DM in nearly half of the AIP patients complicated with DM at diagnosis, particularly in those without elevated serum GGT levels at diagnosis and who did not experience pancreatic atrophy after CST.

Peripancreatic vascular involvement in patients with type 1 autoimmune pancreatitis.

Background: Type 1 autoimmune pancreatitis (AIP) is the pancreatic manifestation of IgG4-related disease. However, this benign disease can result in the peripancreatic vascular involvement (PVI) on occasion, which increases the difficulty of diagnosis and treatment of this clinical entity as well as for differentiating it from pancreatic malignancies. Methods: We retrospectively reviewed the information on demographics, clinical presentation, laboratory, imaging and endoscopic findings of 101 hospitalized patients with type 1 AIP treated in our department. All the patients were divided into non-PVI and PVI groups according to the first hospitalized medical data. Univariate and multivariate analyses were performed to analyse the potential predictive parameter(s) of PVI in AIP patients. Results: Among the 101 type 1 AIP patients, 52 (51.5%) exhibited PVI, with a male/female ratio 5.5:1. Their average age was 58.37±8.68 years old. Univariate analysis revealed that the location of pancreatitis lesions, including the pancreatic tail (P=0.010), the presence of splenomegaly (P=0.001) and the white blood cell (WBC) number in peripheral blood (P=0.020), were significantly associated with PVI. The location of pancreatitis lesions, including the pancreatic tail (P=0.023), and the presence of splenomegaly (P=0.010) were found to be independent predictors of the development of PVI by a multivariable regression analysis. A total of 18 out of 25 patients in PVI group who underwent corticosteroid treatment and no less than 6 months radiological follow-up showed improvement in vascular lesions, and no case exhibited exacerbation of PVI lesions during follow-up. Of 36 patients in non-PVI group who were followed up for no less than 6 months, only one case exhibited PVI. Conclusions: This retrospective study demonstrated that type 1 AIP was associated with a high proportion of PVI. Pancreatic tail involvement and splenomegaly may predict the PVI in type 1 AIP. PVI lesions are reversible in a subset of patients.

Mendelian randomization in blood metabolites identifies triglycerides and fatty acids saturation level as associated traits linked to pancreatitis risk.

Background: There is very limited evidence on the causal effects of blood metabolites on pancreatitis risks. To reveal the causal associations between plasma metabolites and pancreatitis risks, we performed two-sample Mendelian randomization (MR) and Bayesian model averaging (MR-BMA) analyses in European ancestry. Methods: The summary-level statistics from two genome-wide association studies with 249 and 123 metabolic traits derived from two separate cohorts involving ~115,000 (UK Biobank) and ~25,000 individuals from European ancestry were used for the analyses. The summary statistics of four pancreatitis datasets from FinnGen R5 and two pancreatitis datasets from UK Biobank were exploited as the outcome. We first performed univariable MR analysis with different metabolic GWAS data on multiple pancreatitis datasets to demonstrate the association pattern among different metabolites categories. Next, we exploited the MR-BMA method to pinpoint the dominating factors on the increased risk of pancreatitis. Results: In the primary analysis with 249 traits, we found that plasma triglycerides were positively associated with pancreatitis risk. Intriguingly, a large number of traits associated with saturation or unsaturation of fatty acids also demonstrated causal associations. The replication study analyzing 123 metabolic traits suggested that bisallylic groups levels and omega-3 fatty acids were inversely correlated with pancreatitis risk. MR-BMA analyses indicated that the ratio of triglycerides to total lipid in various HDL particles played leading roles in pancreatitis susceptibility. In addition, the degree of unsaturation, the ratio of polyunsaturated fatty acids to monounsaturated fatty acids and the level of monounsaturated fatty acids showed causal associations with either decreased or increased pancreatitis susceptibility. Conclusions: Our MR study provided an atlas of causal associations of genetically predicted blood metabolites on pancreatitis, and offered genetic insights showing intervention in triglycerides and the supplementation of unsaturated fatty acids are potential strategies in the primary prevention of pancreatitis.

Selection of the optimal trading model for stock investment in different industries.

In general, the stock prices of the same industry have a similar trend, but those of different industries do not. When investing in stocks of different industries, one should select the optimal model from lots of trading models for each industry because any model may not be suitable for capturing the stock trends of all industries. However, the study has not been carried out at present. In this paper, firstly we select 424 S&P 500 index component stocks (SPICS) and 185 CSI 300 index component stocks (CSICS) as the research objects from 2010 to 2017, divide them into 9 industries such as finance and energy respectively. Secondly, we apply 12 widely used machine learning algorithms to generate stock trading signals in different industries and execute the back-testing based on the trading signals. Thirdly, we use a non-parametric statistical test to evaluate whether there are significant differences among the trading performance evaluation indicators (PEI) of different models in the same industry. Finally, we propose a series of rules to select the optimal models for stock investment of every industry. The analytical results on SPICS and CSICS show that we can find the optimal trading models for each industry based on the statistical tests and the rules. Most importantly, the PEI of the best algorithms can be significantly better than that of the benchmark index and "Buy and Hold" strategy. Therefore, the algorithms can be used for making profits from industry stock trading.

Intracerebroventricular injection of stresscopin-related peptide enhances cardiovascular function in conscious rats.

Stresscopin-related peptide (SRP), which is a member of the corticotropin-releasing factor (CRF) family, is a high-affinity ligand for the type 2 corticotropin-releasing factor receptor (CRF-R2) and is involved in stress-coping responses. Central treatment with SRP suppresses food intake, delays gastric emptying and decreases heat-induced edema, but the effects of central administration of SRP on the cardiovascular system are unclear. Here we examined the effects of intracerebroventricular (i.c.v.) administration of SRP on cardiovascular function, and compared the cardiovascular effects of SRP and stresscopin (SCP). Our results showed that i.c.v. administration of SRP (0.5nmol) increased mean arterial blood pressure (MABP) and heart rate (HR), but failed to increase plasma norepinephrine and epinephrine levels. Compared with an equivalent dose of SCP, the area under the curve (AUC) values for the changes in MABP and HR were significantly smaller with SRP, indicating that the cardiovascular effects of SRP were weaker than those mediated by SCP. Pre-treatment with a selective CRF-R2 antagonist, antisauvagine-30 (4nmol, i.c.v.) abolished the SRP and SCP induced changes in MABP and HR. These results indicate that central administration of SRP induces a weaker enhancement of cardiovascular function through CRF-R2 than that induced by SCP and that these effects are mediated without increasing plasma norepinephrine and epinephrine levels.