Comparative Effectiveness of DPP-4 Inhibitors Versus Sulfonylurea for the Treatment of Type 2 Diabetes in Routine Clinical Practice: A Retrospective Multicenter Real-World Study

Introduction: DPP-4 inhibitors (DPP4i) and sulfonylureas are popular second-line therapies for type 2 diabetes (T2D), but there is a paucity of real-world studies comparing their effectiveness in routine clinical practice. Methods: This was a multicenter retrospective study on diabetes outpatient clinics comparing the effectiveness of DPP4i versus gliclazide extended release. The primary endpoint was change from baseline in HbA1c. Secondary endpoints were changes in fasting plasma glucose, body weight, and systolic blood pressure. Automated software extracted data from the same clinical electronic chart system at all centers. Propensity score matching (PSM) was used to generate comparable cohorts to perform outcome analysis. Results: We included data on 2410 patients starting DPP4i and 1590 patients starting gliclazide (mainly 30–60 mg/day). At baseline, the two groups differed in disease duration, body weight, blood pressure, HbA1c, fasting glucose, HDL cholesterol, triglycerides, liver enzymes, eGFR, prevalence of microangiopathy, and use of metformin. Among DPP4i molecules, no difference in glycemic effectiveness was detected. In matched cohorts (n = 1316/group), patients starting DPP4i, as compared with patients starting gliclazide, experienced greater reductions in HbA1c (− 0.6% versus − 0.4%; p < 0.001), fasting glucose (− 14.1 mg/dl versus − 8.8 mg/dl; p = 0.007), and body weight (− 0.4 kg versus − 0.1 kg; p = 0.006) after an average 6 months follow-up. DPP4i improved glucose control more than gliclazide, especially in patients who had failed with other glucose-lowering medications or were on basal insulin. Conclusions: This large retrospective real-world study shows that, in routine clinical practice, starting a DPP4i allows better glycemic control than starting low-dose gliclazide. Funding: The Italian Diabetes Society, with external support from AstraZeneca

Outcomes of integrated management versus specialized care for patients with type 2 diabetes: An observational study

AIMS: To compare type 2 diabetes (T2D) patients included in a Diabetes Integrated Management (DIM) program with those followed in Diabetes Specialized Care (DSC), investigating differences in general characteristics, changes in clinical outcomes, and factors related with the inclusion in the DIM program. METHODS: T2D patients living in the ASLTO3 district and included into the DIM program, a shared disease management between general practitioners and diabetes specialists, from 2008 to 2014 were compared with T2D patients living in the same district and in charge of the local DSC. Demographic, anthropometric and clinical data for both groups of patients were obtained from the electronic records of DSC. RESULTS: 1326 DIM patients were compared with 3494 DSC patients. A higher proportion of females was observed among DIM patients than among DSC patients. DIM patients were older, more frequently in therapy with diet only or with oral hypoglycemic, and had HbA1c and creatinine lower than DSC patients. The analyses of changes in clinical parameters during the study period showed a good and statistically significant improvement of most parameters, independently of the inclusion in DIM or DSC, with the exception of creatinine level. CONCLUSIONS: Integrated Management is an efficient and effective way to achieve good long-term clinical outcomes for patients with diabetes

Glucagon-like peptide 1-related peptides increase nitric oxide effects to reduce platelet activation

SummaryGlucagon-like peptide 1 (GLP-1) is object of intensive investigation for not only its metabolic effects but also the protective vascular actions. Since platelets exert a primary role in the pathogenesis of atherosclerosis, inflammation and vascular complications, we investigated whether GLP-1 directly influences platelet reactivity. For this purpose, in platelets from 72 healthy volunteers we evaluated GLP-1 receptor (GLP-1R) expression and the effects of a 15-minute incubation with the native form GLP-1(7–36), the N-terminally truncated form GLP-1(9–36) and the GLP-1 analogue Liraglutide (100 nmol/l) on: i) aggregation induced by collagen or arachidonic acid (AA); ii) platelet function under shear stress; iii) cGMP and cAMP synthesis and cGMP-dependent protein kinase (PKG)-induced Vasodilator-Stimulated-Phosphoprotein (VASP) phosphorylation; iv) activation of the signalling molecules Phosphatidylinositol 3-Kinase (PI3-K)/Akt and Mitogen Activated Protein Kinase (MAPK)/ERK-1/2; and v) oxidative stress. Experiments were repeated in the presence of the nitric oxide donor Na–nitroprusside. We found that platelets constitutively express GLP-1R and that, independently of GLP-1R, GLP-1(7–36), GLP-1(9–36) and Liraglutide exert platelet inhibitory effects as shown by: a) increased NO-antiaggregating effects, b) increased the activation of the cGMP/PKG/VASP pathway, c) reduced the activation of PI3-K/Akt and MAPK/ERK-2 pathways, d) reduced the AA-induced oxidative stress. When the experiments were repeated in the presence of the antagonist of GLP-1R Exendin(9–39), the platelet inhibitory effects were maintained, thus indicating a mechanism independent of GLP-1R. In conclusion, GLP-1(7–36), its degradation product GLP-1(9–36) and Liraglutide exert similar inhibitory effects on platelet activation, suggesting a potential protective effect on the cardiovascular system.</jats:p

Cardioprotective Properties of Human Platelets Are Lost in Uncontrolled Diabetes Mellitus: A Study in Isolated Rat Hearts

Platelets affect myocardial damage from ischemia/reperfusion. Redox-dependent sphingosine-1-phosphate production and release are altered in diabetic platelets. Sphingosine-1-phosphate is a double-edged sword for ischemia/reperfusion injury. Therefore, we aimed to verify whether: (1) human healthy- or diabetic-platelets are cardioprotective, (2) sphingosine-1-phosphate receptors and downstream kinases play a role in platelet-induced cardioprotection, and (3) a correlation between platelet redox status and myocardial ischemia/reperfusion injury exists. Isolated rat hearts were subjected to 30-min ischemia and 1-h reperfusion. Infarct size was studied in hearts pretreated with healthy- or diabetic-platelets. Healthy-platelets were co-infused with sphingosine-1-phosphate receptor blocker, ERK-1/2 inhibitor, PI3K antagonist or PKC inhibitor to ascertain the cardioprotective mechanisms. In platelets we assessed (i) aggregation response to ADP, collagen, and arachidonic-acid, (ii) cyclooxygenase-1 levels, and (iii) AKT and ERK-phosphorylation. Platelet sphingosine-1-phosphate production and platelet levels of reactive oxygen species (ROS) were quantified and correlated to infarct size. Infarct size was reduced by about 22% in healthy-platelets pretreated hearts only. This cardioprotective effect was abrogated by either sphingosine-1-phosphate receptors or ERK/PI3K/PKC pathway blockade. Cyclooxygenase-1 levels and aggregation indices were higher in diabetic-platelets than healthy-platelets. Diabetic-platelets released less sphingosine-1-phosphate than healthy-platelets when mechanical or chemically stimulated in vitro. Yet, ROS levels were higher in diabetic-platelets and correlated with infarct size. Cardioprotective effects of healthy-platelet depend on the platelet’s capacity to activate cardiac sphingosine-1-phosphate receptors and ERK/PI3K/PKC pathways. However, diabetic-platelets release less S1P and lose cardioprotective effects. Platelet ROS levels correlate with infarct size. Whether these redox alterations are responsible for sphingosine-1-phosphate dysfunction in diabetic-platelets remains to be ascertained

Insulin resistance, diabetic kidney disease, and all-cause mortality in individuals with type 2 diabetes. a prospective cohort study

BACKGROUND: It is unclear whether insulin resistance (IR) contributes to excess mortality in patients with type 2 diabetes independent of diabetic kidney disease (DKD), which is strongly associated with IR and is a major risk factor for cardiovascular disease (CVD), the main cause of death in these individuals. We tested this hypothesis in patients with type 2 diabetes from the Renal Insufficiency And Cardiovascular Events Italian Multicentre Study.METHODS: This observational, prospective, cohort study enrolled 15,773 patients with type 2 diabetes attending 19 Italian Diabetes Clinics in 2006-2008. Insulin sensitivity was assessed as estimated glucose disposal rate (eGDR), which was validated against the euglycaemic-hyperinsulinemic clamp technique. Vital status on October 31, 2015, was retrieved for 15,656 patients (99.3%). Participants were stratified by eGDR tertiles from T1 (≥ 5.35mg/kg/min) to T3 (≤ 4.14mg/kg/min, highest IR).RESULTS: CVD risk profile was worse in T2 and T3 vs T1. eGDR tertiles were independently associated with micro- and macroalbuminuria and the albuminuric DKD phenotypes (albuminuria with preserved or reduced estimated glomerular filtration rate [eGFR]) as well as with eGFR categories or the nonalbuminuric DKD phenotype. Over a 7.4-year follow-up, unadjusted death rates and mortality risks increased progressively across eGDR tertiles, but remained significantly elevated after adjustment only in T3 vs T1 (age- and gender- adjusted death rate, 22.35 vs 16.74 per 1000 person-years, p&lt;0.0001, and hazard ratio [HR] adjusted for multiple confounders including DKD, 1.140 [95% confidence interval [CI], 1.049-1.238], p=0.002). However, eGDR was independently associated with mortality in participants with no DKD (adjusted HR, 1.214 [95% CI, 1.072-1.375], p=0.002) and in those with nonalbuminuric DKD (1.276 [1.034-1.575], p=0.023), but not in those with the albuminuric DKD phenotypes. Moreover, the association was stronger in males and in younger individuals and was observed in those without but not with prior CVD, though interaction was significant only for age.CONCLUSIONS: The proxy of insulin sensitivity eGDR predicts all-cause mortality in type 2 diabetes, independent of confounders including DKD. However, the impact of IR in individuals with albuminuric DKD may be mediated by its relationship with albuminuria.TRIAL REGISTRATION: ClinicalTrials.gov , NCT00715481, retrospectively registered 15 July 2008

Independent association of atherogenic dyslipidaemia with all-cause mortality in individuals with type 2 diabetes and modifying effect of gender. a prospective cohort study

Atherogenic dyslipidaemia has been implicated in the residual risk for cardiovascular morbidity and mortality, which remains despite attainment of LDL cholesterol goals especially in individuals with type 2 diabetes. However, its relationship with all-cause death has not been sufficiently explored. This analysis evaluated the independent association of increased triglycerides and triglyceride:HDL cholesterol ratio (TG:HDL) and decreased HDL cholesterol with total mortality and the possible modifying effect of gender in a large cohort of patients with type 2 diabetes

Distribution of cardiovascular disease and retinopathy in patients with type 2 diabetes according to different classification systems for chronic kidney disease: a cross-sectional analysis of the renal insufficiency and cardiovascular events (RIACE) Italian multicenter study

BACKGROUND: The National Kidney Foundation's Kidney Disease Outcomes Quality Initiative (NKF's KDOQI) staging system for chronic kidney disease (CKD) is based primarily on estimated GFR (eGFR). This study aimed at assessing whether reclassification of subjects with type 2 diabetes using two recent classifications based on both eGFR and albuminuria, the Alberta Kidney Disease Network (AKDN) and the Kidney Disease: Improving Global Outcomes (KDIGO), provides a better definition of burden from cardiovascular disease (CVD) and diabetic retinopathy (DR) than the NKF's KDOQI classification. METHODS: This is a cross-sectional analysis of patients with type 2 diabetes (n = 15,773) from the Renal Insufficiency And Cardiovascular Events Italian Multicenter Study, consecutively visiting 19 Diabetes Clinics throughout Italy in years 2007-2008. Exclusion criteria were dialysis or renal transplantation. CKD was defined based on eGFR, as calculated from serum creatinine by the simplified Modification of Diet in Renal Disease Study equation, and albuminuria, as measured by immunonephelometry or immunoturbidimetry. DR was assessed by dilated fundoscopy. Prevalent CVD, total and by vascular bed, was assessed from medical history by recording previous documented major acute events. RESULTS: Though prevalence of complications increased with increasing CKD severity with all three classifications, it differed significantly between NKF's KDOQI stages and AKDN or KDIGO risk categories. The AKDN and KDIGO systems resulted in appropriate reclassification of uncomplicated patients in the lowest risk categories and a more graded independent association with CVD and DR than the NKF's KDOQI classification. However, CVD, but not DR prevalence was higher in the lowest risk categories of the new classifications than in the lowest stages of the NKF's KDOQI, due to the inclusion of subjects with reduced eGFR without albuminuria. CVD prevalence differed also among eGFR and albuminuria categories grouped into AKDN and KDIGO risk category 1 and moderate, respectively, and to a lesser extent into higher risk categories. CONCLUSIONS: Though the new systems perform better than the NKF's KDOQI in grading complications and identifying diabetic subjects without complications, they might underestimate CVD burden in patients assigned to lower risk categories and should be tested in large prospective studies

Body mass index versus surrogate measures of central adiposity as independent predictors of mortality in type 2 diabetes

Background: An "obesity paradox" for mortality has been shown in chronic disorders such as diabetes, and attributed to methodological bias, including the use of body mass index (BMI) for obesity definition. This analysis investigated the independent association of BMI versus surrogate measures of central adiposity with all- cause mortality in individuals with type 2 diabetes.Methods: The Renal Insufficiency And Cardiovascular Events Italian Multicentre Study is a prospective cohort study that enrolled 15,773 patients in 19 Italian centres in 2006-2008. Exposures were BMI and the surrogate measures of central adiposity waist circumference (WC), waist-to-height ratio (WHtR), and A Body Shape Index (ABSI). Vital status was retrieved on 31 October 2015 for 15,656 patients (99.3%),Results: Age- and sex-adjusted hazard ratios and 95% confidence intervals were significantly higher in BMI-based underweight (1.729 [1.193-2.505), P = 0.004), moderately obese (1.214 [1.058-1.392), P = 0.006) and severely obese (1.703 [1.402-2.068), P &lt; 0.0001), lower in overweight (0.842 [0.775-0.915), P &lt; 0.0001) and similar in mildly obese (0.950 [0.864-1.045), P = 0.292), compared to normal-weight individuals. When further adjusting for smoking, physical activity (PA), and comorbidities, risk was lower also in mildly obese versus normal-weight patients. The BMI-mortality relationship did not change after sequentially excluding ever smokers, individuals with comorbidities, and those died within two years from enrollment and when analyzing separately participants below and above the median age. Conversely, a paradox relationship was observed among inactive/moderately inactive, but not moderately/highly active patients. Mortality risk adjusted for age, gender, smoking, PA and comorbidities was significantly higher in the highest tertile of WC (1.279 [1.089-1.501], P = 0.003), WHtR (1.372 [1.165-1.615], P &lt; 0.0001), and ABSI (1.263 [1.067-1.495], P = 0.007) versus the lowest tertile. However, risk was lower in the intermediate versus lowest tertile for WC (0.823 [0.693-0.979], P = 0.028), similar for WHtR, and higher, though not significantly, for ABSI.Conclusions: An "overweight paradox" remained after controlling for age, smoking, and comorbidities, arguing against a collider bias or reverse causation. However, it could be partly explained by confounding from PA level, possibly through its impact on lean mass and cardiorespiratory fitness. No obesity paradox was observed with WHtR and especially ABSI, which predicted mortality risk associated with central adiposity better than WC