Controversy about the relative efficacy of dipeptidyl peptidase IV inhibitors.

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Symbolic Software for the Painleve Test of Nonlinear Ordinary and Partial Differential Equations

The automation of the traditional Painleve test in Mathematica is discussed. The package PainleveTest.m allows for the testing of polynomial systems of ordinary and partial differential equations which may be parameterized by arbitrary functions (or constants). Except where limited by memory, there is no restriction on the number of independent or dependent variables. The package is quite robust in determining all the possible dominant behaviors of the Laurent series solutions of the differential equation. The omission of valid dominant behaviors is a common problem in many implementations of the Painleve test, and these omissions often lead to erroneous results. Finally, our package is compared with the other available implementations of the Painleve test.Comment: Published in the Journal of Nonlinear Mathematical Physics (http://www.sm.luth.se/math/JNMP/), vol. 13(1), pp. 90-110 (Feb. 2006). The software can be downloaded at either http://www.douglasbaldwin.com or http://www.mines.edu/fs_home/wherema

Canagliflozin inhibits interleukin-1β-stimulated cytokine and chemokine secretion in vascular endothelial cells by AMP-activated protein kinase-dependent and -independent mechanisms

YesRecent clinical trials of the hypoglycaemic sodium-glucose co-transporter-2 (SGLT2) inhibitors, which inhibit renal glucose reabsorption, have reported beneficial cardiovascular outcomes. Whether SGLT2 inhibitors directly affect cardiovascular tissues, however, remains unclear. We have previously reported that the SGLT2 inhibitor canagliflozin activates AMP-activated protein kinase (AMPK) in immortalised cell lines and murine hepatocytes. As AMPK has anti-inflammatory actions in vascular cells, we examined whether SGLT2 inhibitors attenuated inflammatory signalling in cultured human endothelial cells. Incubation with clinically-relevant concentrations of canagliflozin, but not empagliflozin or dapagliflozin activated AMPK and inhibited IL-1β-stimulated adhesion of pro-monocytic U937 cells and secretion of IL-6 and monocyte chemoattractant protein-1 (MCP-1). Inhibition of MCP-1 secretion was attenuated by expression of dominant-negative AMPK and was mimicked by the direct AMPK activator, A769662. Stimulation of cells with either canagliflozin or A769662 had no effect on IL-1β-stimulated cell surface levels of adhesion molecules or nuclear factor-κB signalling. Despite these identical effects of canagliflozin and A769662, IL-1β-stimulated IL-6/MCP-1 mRNA was inhibited by canagliflozin, but not A769662, whereas IL-1β-stimulated c-jun N-terminal kinase phosphorylation was inhibited by A769662, but not canagliflozin. These data indicate that clinically-relevant canagliflozin concentrations directly inhibit endothelial pro-inflammatory chemokine/cytokine secretion by AMPK-dependent and -independent mechanisms without affecting early IL-1β signalling.Project Grant (PG/13/82/30483 to IPS and TMP) and PhD studentships (FS/16/55/32731 and FS/14/61/31284 to DB and AS) from the British Heart Foundation and an equipment grant (BDA11/0004309 to IPS and TMP) from Diabetes UK. OJK was supported by a Scholarship from the Iraqi Ministry of Higher Education and Scientific Research. TAA was supported by a Libyan Ministry of Education PhD Studentship

Novel Assay of Metformin Levels in Patients With Type 2 Diabetes and Varying Levels of Renal Function: Clinical recommendations

AbstractObjective: To study trough levels of metformin in serum and its intra individual variation in patients using a newly developed assay. Research Design and Methods: Trough serum levels of metformin was measured once using Liquid Chromatography Tandem Mass Spectrometry (LcMSMS) in 137 type 2 diabetes patients with varying renal function (99 men) and followed repeatedly during two months in 20 patients (16 men) with estimated GFR (eGFR) below 60 ml/min/1.73 m(2) body surface. Results: Patients with eGFR >60, 30-60, and <30 ml/min/1.73 m(2) had a median trough metformin concentration of 4.5 mumol/l (range 0.1-20.7, n=107), 7.71 mumol/l (0.12-15.15, n=21), and 8.88 mumol/l (5.99-18.60, n=9), respectively. The median intraindividual overall coefficient of variation (CV) was 29.4 % (range 9,8-74,2). Conclusions: Determination of serum metformin with the LCMSMS technique is useful in patients on metformin treatment. Few patients had values over 20 mumol/L. Metformin measurement is less suitable for dose titration

Prevalence of diabetes, metabolic syndrome and metabolic abnormalities in schizophrenia over the course of the illness: a cross-sectional study

BACKGROUND: Patients with schizophrenia are at high risk of developing metabolic abnormalities. METHOD: A prospective study focusing on metabolic disturbances in patients with schizophrenia, including an oral glucose tolerance test, is currently ongoing at our University Hospital and affiliate services. The prevalence of metabolic abnormalities at baseline was assessed in a cohort of 415 patients with schizophrenia. The sample was divided into 4 groups according to duration of illness: first-episode patients (<1.5 years), recent-onset patients (between 1.5 and 10 years), subchronic patients (between 10 and 20 years) and chronic patients (>20 years). RESULTS: Metabolic abnormalities were already present in first-episode patients, and considerably increased with increasing duration of illness. When compared to the general population matched for age and gender, much higher rates of the metabolic syndrome (MetS) and diabetes were observed for patients with schizophrenia. For MetS, the increase over time was similar to that of the general population. In contrast, the difference in the prevalence of diabetes in patients with schizophrenia and the general population dramatically and linearly increased from 1.6% in the 15–25 age-band to 19.2% in the 55–65 age-band. CONCLUSION: Thus, the current data suggest that on the one hand metabolic abnormalities are an inherent part of schizophrenic illness, as they are already present in first-episode patients. On the other hand, however, our results suggest a direct effect of the illness and/or antipsychotic medication on their occurence. The data underscore the need for screening for metabolic abnormalities in patients diagnosed with schizophrenia, already starting from the onset of the illness

3 years of liraglutide versus placebo for type 2 diabetes risk reduction and weight management in individuals with prediabetes: a randomised, double-blind trial

Background Liraglutide 3\ub70 mg was shown to reduce bodyweight and improve glucose metabolism after the 56-week period of this trial, one of four trials in the SCALE programme. In the 3-year assessment of the SCALE Obesity and Prediabetes trial we aimed to evaluate the proportion of individuals with prediabetes who were diagnosed with type 2 diabetes. Methods In this randomised, double-blind, placebo-controlled trial, adults with prediabetes and a body-mass index of at least 30 kg/m2, or at least 27 kg/m2 with comorbidities, were randomised 2:1, using a telephone or web-based system, to once-daily subcutaneous liraglutide 3\ub70 mg or matched placebo, as an adjunct to a reduced-calorie diet and increased physical activity. Time to diabetes onset by 160 weeks was the primary outcome, evaluated in all randomised treated individuals with at least one post-baseline assessment. The trial was conducted at 191 clinical research sites in 27 countries and is registered with ClinicalTrials.gov, number NCT01272219. Findings The study ran between June 1, 2011, and March 2, 2015. We randomly assigned 2254 patients to receive liraglutide (n=1505) or placebo (n=749). 1128 (50%) participants completed the study up to week 160, after withdrawal of 714 (47%) participants in the liraglutide group and 412 (55%) participants in the placebo group. By week 160, 26 (2%) of 1472 individuals in the liraglutide group versus 46 (6%) of 738 in the placebo group were diagnosed with diabetes while on treatment. The mean time from randomisation to diagnosis was 99 (SD 47) weeks for the 26 individuals in the liraglutide group versus 87 (47) weeks for the 46 individuals in the placebo group. Taking the different diagnosis frequencies between the treatment groups into account, the time to onset of diabetes over 160 weeks among all randomised individuals was 2\ub77 times longer with liraglutide than with placebo (95% CI 1\ub79 to 3\ub79, p<0\ub70001), corresponding with a hazard ratio of 0\ub721 (95% CI 0\ub713\u20130\ub734). Liraglutide induced greater weight loss than placebo at week 160 (\u20136\ub71 [SD 7\ub73] vs 121\ub79% [6\ub73]; estimated treatment difference 124\ub73%, 95% CI 124\ub79 to 123\ub77, p<0\ub70001). Serious adverse events were reported by 227 (15%) of 1501 randomised treated individuals in the liraglutide group versus 96 (13%) of 747 individuals in the placebo group. Interpretation In this trial, we provide results for 3 years of treatment, with the limitation that withdrawn individuals were not followed up after discontinuation. Liraglutide 3\ub70 mg might provide health benefits in terms of reduced risk of diabetes in individuals with obesity and prediabetes. Funding Novo Nordisk, Denmark

Inhibiteurs du SGLT2 dans les néphropathies diabétiques et non diabétiques [SGLT2 inhibitors in diabetic and non-diabetic nephropathies]

SGLT2 inhibitors (SGLT2i) will change the clinical practice of nephrology with their therapeutic cardiorenal and antidiabetic properties. By inhibiting proximal tubular sodium and glucose reabsorption, these new drugs decrease intraglomerular pressures. Over the last 5 years several breakthrough studies have demonstrated the SGLT2i protective effects on outcomes such as cardiovascular mortality, hospital admission for heart failure, sustained decreases in eGFR in patients with diabetic nephropathy and the development of ESKD. With the new DAPA-CKD study revealing protective effects of SGLT2i in CKD patients without diabetes, therapeutic recommendations will now have to evolve towards including these drugs in the chronic management of all most proteinuric CKD patients

SERENADE: The Study Evaluating Rimonabant Efficacy in Drug-Naive Diabetic Patients : Effects of monotherapy with rimonabant, the first selective CB1 receptor antagonist, on glycemic control, body weight, and lipid profile in drug-naive type 2 diabetes

OBJECTIVE—The purpose of this study was to assess the glucose-lowering efficacy and safety of rimonabant monotherapy in drug-naive type 2 diabetic patients