Novel antidiabetic drugs and cardiovascular risk: Primum non nocere

Aims Diabetes treatments aim at preventing undesirable metabolic effects of hyperglycemia and at preventing/reducing tissue damage, including cardiovascular (CV) events. For approval, novel diabetes drugs undergo early systematic investigation to assess CV safety. This review provides an updated analysis of the results of recent studies examining novel diabetes medications and CV outcomes. Data synthesis The new regulatory guidelines enforce adjudication of all CV events when testing novel diabetes drugs. Endpoints of CV mortality, myocardial infarction (MI), stroke and hospitalization for heart failure (HF) were included in the most recent clinical studies on novel antihyperglycemics. These are: the incretin mimetics glucagon-like peptide 1 (GLP-1) receptor agonists (GLP1-RA), the incretin enhancers dipeptidylpeptidase-4 (DPP-4) inhibitors (DPP4-I or gliptins), and the sodium-glucose cotransporter (SGLT2) inhibitors (SGLT2-I or gliflozins). The studies ELIXA and EXAMINE, testing lixisenatide and alogliptin, respectively, revealed non-inferiority versus placebo in terms of CV safety. The SAVOR-TIMI 53 results confirmed overall CV safety of saxagliptin, but raised a warning related to the increase in the risk of hospitalization for HF in the saxagliptin group. Recently, TECOS revealed a particularly favorable CV profile for sitagliptin while EMPA-REG showed a significant CV risk reduction in empagliflozin treated subjects. Ongoing studies will provide additional data on CV safety for other GLP1-RAs, DPP4-I and SGLT2-I. Conclusions Results of safety outcome studies focused on CV events, including HF and mortality for CV causes, are not homogeneous. A critical analysis of these studies may help cardiologists and diabetes specialists to adapt their therapeutic choices to individual patients

Glycaemic Control with Insulin Glargine 300 U/mL in Individuals with Type 2 Diabetes and Chronic Kidney Disease : A REALI European Pooled Data Analysis

Altres ajuts: Sanofi (Paris, France)Introduction: Management of type 2 diabetes mellitus (T2DM) in patients with chronic kidney disease is complex. Using the REALI European pooled database, we determined the impact of baseline renal function on the effectiveness and safety of insulin glargine 300 U/mL (Gla-300) initiated in adults with inadequately controlled T2DM. Methods: Data from 1712 patients with available estimated glomerular filtration rate (eGFR) at baseline were pooled from six 24-week prospective studies. Patients who received once-daily subcutaneous injections of Gla-300 were classified into four renal function subgroups, according to baseline eGFR: ≥ 90 (N = 599), 60-89 (N = 786), 45-59 (N = 219), and 15-44 mL/min/1.73 m (N = 108). Results: Compared to those with baseline eGFR ≥ 60 mL/min/1.73 m, patients with lower eGFR values tended to be older, had a longer T2DM duration, and were more likely to present diabetic complications. After 24 weeks of Gla-300 therapy, the least-squares mean (95% confidence interval) decrease in haemoglobin A1c (HbA1c) from baseline (− 1.14% [− 1.28 to − 1.00], − 1.21% [− 1.34 to − 1.08], − 1.19% [− 1.36 to − 1.01], and − 0.99% [− 1.22 to − 0.76]) and the proportion of patients achieving HbA1c < 7.5% (53.3%, 51.3%, 49.5%, and 51.5%) were comparable in the ≥ 90, 60-89, 45-59, and 15-44 mL/min/1.73 m subgroups, respectively. Although the incidence of hypoglycaemia was overall low, more patients in the eGFR 15-44 mL/min/1.73 m subgroup experienced hypoglycaemia at night or at any time of the day compared with higher eGFR subgroups. There were no notable differences between the renal function subgroups in the changes in Gla-300 daily dose and body weight from baseline to week 24. Conclusion: Although an eGFR of 15-44 mL/min/1.73 m was associated with a slightly increased risk of hypoglycaemia among patients with inadequately controlled T2DM, Gla-300 provided glycaemic improvement with an overall favourable safety profile regardless of baseline eGFR

Rationale and methodology for a European pooled analysis of postmarketing interventional and observational studies of insulin glargine 300 U/mL in diabetes: protocol of REALI project

INTRODUCTION: Type 2 diabetes mellitus (T2DM) is a common and heterogeneous disease. Using advanced analytic approaches to explore real-world data may identify different disease characteristics, responses to treatment and progression patterns. Insulin glargine 300 units/mL (Gla-300) is a second-generation basal insulin analogue with preserved glucose-lowering efficacy but reduced risk of hypoglycaemia. The purpose of the REALI pooled analysis described in this paper is to advance the understanding of the effectiveness and real-world safety of Gla-300 based on a large European patient database of postmarketing interventional and observational studies. METHODS AND ANALYSIS: In the current round of pooling, REALI will include data from up to 10 000 subjects with diabetes mellitus (mostly T2DM) from 20 European countries. Outcomes of interest include change from baseline to week 24 in haemoglobin A1c, fasting plasma glucose, self-measured plasma glucose, body weight, insulin dose, incidence and rate of any-time-of-the-day and nocturnal hypoglycaemia. The data pool is being investigated using two complementary methodologies: a conventional descriptive, univariate and multivariable prognostic analysis; and a data-mining approach using subgroup discovery to identify phenotypic clusters of patients who are highly associated with the outcome of interest. By mid-2019, deidentified data of 7584 patients were included in the REALI database, with a further expected increase in patient number in 2020 as a result of pooling additional studies. ETHICS AND DISSEMINATION: The proposed study does not involve collection of primary data. Moreover, all individual study protocols were approved by independent local ethics committees, and all study participants provided written informed consent. Furthermore, patient data is deidentified before inclusion in the REALI database. Hence, there is no requirement for ethical approval. Results will be disseminated via peer-reviewed publications and presentations at international congresses as data are analysed

Uric acid is a biomarker of beta cell function in patients with newly diagnosed type 2 diabetes

Background and aims: The relationship between uric acid and insulin resistance has been widely studied, whereas little is known about a potential interaction between uric acid and beta-cell function. Goal of this study was to investigate the relationship, if any, between uricaemia and beta-cell function in patients with newly diagnosed type 2 diabetes. Materials and methods: In 569 GAD negative, drug naive patients (median [interquartile range]: age 60 [52-66] years, BMI 29.3 [26.6-32.9] kg/m2, HbA1c 6.6 [6.1-7.4]%, uric acid 0.32 [0.27-0.37] mmol/L) with newly diagnosed type 2 diabetes we assessed insulin sensitivity by the euglycemic insulin clamp (M clamp: 605 [381-845] \u3bcmol\ub7min-1\ub7m-2 BSA) and beta-cell function by state-of-art modelling of glucose/C-peptide curves during an oral glucose tolerance test (OGTT). There are two main outputs of the model: derivative control (DC: amount of insulin secreted in response to the rate of plasma glucose increase; median [interquartile range]: 444 [66-929] [pmol\ub7m-2 BSA]/ [mM\ub7min-1]) and proportional control of beta-cell function (PC: stimulusresponse curve linking glucose concentration to insulin secretion rate; mean \ub1 SD at the preselected glucose concentrations of 5.5, 8.0, 11.0, 15.0 and 20.0 mM: 158\ub167, 228\ub1124, 376\ub1229, 602\ub1397, 889\ub1623 pmol\ub7min-1\ub7m-2 BSA). Results: In univariate analysis, serum uric acid concentration was positively related to both DC (p<0.01) and PC (p<0.01) of beta-cell function. In multiple regression analysis, after adjusting for age, gender, BMI, insulin sensitivity and glomerular filtration rate, this positive relationship stayed statistically significant (p<0.01 e p<0.01 for DC and PC respectively). Consistently with this result, uricaemia was inversely correlated to HbA1c (p<0.01), fasting glucose (p<0.01), 1-hour and 2-hour OGTT glucose (p<0.01 and p<0.01 respectively). Patients in the 3rd tertile of uric acid had a 37% increase in DC (p<0.01) and a 21-30% increase in PC (p<0.01) of beta-cell function, when compared to those in the 1st tertile. Conclusions: In patients with newly diagnosed type 2 diabetes there exists a strong positive correlation between serum uric acid concentration and betacell function. This finding might reflect antioxidant activity of uric acid. However, to determine whether uric acid improves beta-cell function per se or through other factors, mechanistic studies will be required

Role of tissue specific blood flow and tissue recruitment in insulin-mediated glucose uptake of human skeletal muscle

BACKGROUND: Conflicting evidence exists concerning whether insulin-induced vasodilation plays a mechanistic role in the regulation of limb glucose uptake. It can be predicted that if insulin augments blood flow by causing tissue recruitment, this mechanism would enhance limb glucose uptake. METHODS AND RESULTS: Twenty healthy subjects were studied with the forearm perfusion technique in combination with the euglycemic insulin clamp technique. Ten subjects were studied at physiological insulin concentrations (approximately 400 pmol/L) and the other 10 at supraphysiological insulin concentrations (approximately 5600 pmol/L). Four additional subjects underwent a saline control study. Pulse injections of a nonmetabolizable extracellular marker (1-[3H]-L-glucose) were administered into the brachial artery, and its washout curves were measured in one ipsilateral deep forearm vein and used to estimate the extracellular volume of distribution and hence the amount of muscle tissue drained by the deep forearm vein. Both during saline infusion and at physiological levels of hyperinsulinemia we observed no changes in blood flow and/or muscle tissue drained by the deep forearm vein. However, supraphysiological hyperinsulinemia accelerated total forearm blood flow (45.0+/-1.8 versus 36.5+/-1.3 mL x min(-1) x kg(-1), P<0.01) and increased the amount of muscle tissue drained by the deep forearm vein (305+/-46 versus 229+/-32 g, P<0.05). The amount of tissue newly recruited by insulin was strongly correlated to the concomitant increase in tissue glucose uptake (r=0.789, P<0.01). CONCLUSIONS: Acceleration of forearm blood flow mediated by supraphysiological hyperinsulinemia is accompanied by tissue recruitment, which may be a relevant determinant of forearm (muscle) glucose uptake

Empagliflozin does not reverse lipotoxicity-induced impairment in human myeloid angiogenic cell bioenergetics.

info:eu-repo/semantics/publishe

High-normal HbA1c is a strong predictor of type 2 diabetes in the general population.

OBJECTIVE\u2014Glycosylated hemoglobin (HbA1c) recently has been recommended for the diagnosis of diabetes by the American Diabetes Association, but its value in the prediction of type 2 diabetes is poorly understood. In this study we evaluated how high-normal HbA1c levels predict type 2 diabetes.RESEARCH DESIGN AND METHODS\u2014We measured HbA1c in 919 Caucasian subjects, aged 40\u201379 years, and recorded new cases of type 2 diabetes in the following 15 years. Diabetes was diagnosed with HbA1c.RESULTS\u2014Subjects were stratified according to baselineHbA1c (,5.0, 5.00\u20135.49 [reference], 5.50\u20135.99, and 6.00\u20136.49%). Sex- and age-adjusted hazard ratios (95% CI) for type 2 diabetes were 1.11 (0.30\u20134.41), 1.00, 3.79 (1.79\u20138.06), and 12.50 (5.51\u201328.34), respectively. Results did not change after adjusting for several putative confounding factors and were confirmed when models with updated variables were used.CONCLUSIONS\u2014HbA1c is an independent risk factor for type 2 diabetes. Subjects with high-normal levels of HbA1c deserve particular attention because they have a strong risk of developing diabetes

"Presence and titer of GAD antibodies are determinants of beta cell function in patients with newly diagnosed type 2 diabetes mellitus: further insights in the metabolic phenotype of LADA patients"

Latent Autoimmune Diabetes in Adults (LADA) is a metabolic disorder at the crossroad between type 1 (T1DM) and type 2 diabetes (T2DM). Aim of our study was to carefully assess beta cell function and insulin sensitivity in patients with LADA, in comparison to patients with either type 2 diabetes clinically undistinguishable from LADA or typical type 2 diabetes. In 35 (M/F=19/16) patients (mean\ub1SEM: age 57.4\ub11.6 years, BMI 27.5\ub10.9 kg/m2) with newly diagnosed LADA were compared to 35 patients with newly diagnosed T2DM matched for age, gender, BMI and HbA1c (LADA-like). The latter group was extracted from the database of the Verona Newly Diagnosed Type 2 diabetes (VNDS; N=589 GADA-negative patients) The rest of VNDS patients herein represent typical T2DM. LADA patients were further divided in two groups according to GADA levels (median 4 kU/L): low GAD-LADA (GADA 4 kU/L). In all patients we performed on separate days: 1. prolonged (5-hours) frequently sampled OGTT to assess derivative control (DC) and proportional control (PC) of beta cell function by state of art mathematical modeling of glucose and C-peptide curves; 2. standard euglycemic insulin clamp to assess insulin sensitivity (SI). SI was not statistically different (p<0.12) in LADA-like and in LADA patients, but in the latter was higher (+28%) than in VNDS (812\ub1SEM vs 635\ub1SEM \ub5mol.min-1.m-2 BSA, respectively; p=0.01). The DC of beta cell function was impaired in LADA compared to LADA-like (p<0.01) and to VNDS (p<0.05). The PC in LADA was similar to LADA-like (p=0.42), but it was reduced when compared to VNDS (p<0.03). High GAD- and low GAD-LADA had similar SI, but the former had worse PC of beta cell function than the latter (p<0.01). In conclusion, patients with newly diagnosed LADA display more severe defects in beta cell function even when compared to LADA-like patients with newly diagnosed T2DM; furthermore, the higher the GADA titer, the worse is beta cell dysfunction. These data may be of help in optimizing metabolic therapy and in refining metabolic prognosis of these patients