Risk of hospitalization for heart failure in patients with type 2 diabetes newly treated with DPP-4 inhibitors or other oral glucose-lowering medications: A retrospective registry study on 127,555 patients from the Nationwide OsMed Health-DB Database

Aims Oral glucose-lowering medications are associated with excess risk of heart failure (HF). Given the absence of comparative data among drug classes, we performed a retrospective study in 32 Health Services of 16 Italian regions accounting for a population of 18 million individuals, to assess the association between HF risk and use of sulphonylureas, DPP-4i, and glitazones. Methods and results We extracted data on patients with type 2 diabetes who initiated treatment with DPP-4i, thiazolidinediones, or sulphonylureas alone or in combination with metformin during an accrual time of 2 years. The endpoint was hospitalization for HF (HHF) occurring after the first 6 months of therapy, and the observation was extended for up to 4 years. A total of 127 555 patients were included, of whom 14.3% were on DPP-4i, 72.5% on sulphonylurea, 13.2% on thiazolidinediones, with average 70.7% being on metformin as combination therapy. Patients in the three groups differed significantly for baseline characteristics: age, sex, Charlson index, concurrent medications, and previous cardiovascular events. During an average 2.6-year follow-up, after adjusting for measured confounders, use of DPP-4i was associated with a reduced risk of HHF compared with sulphonylureas [hazard ratio (HR) 0.78; 95% confidence interval (CI) 0.62-0.97; P = 0.026]. After propensity matching, the analysis was restricted to 39 465 patients, and the use of DPP-4i was still associated with a lower risk of HHF (HR 0.70; 95% CI 0.52-0.94; P = 0.018). Conclusion In a very large observational study, the use of DPP-4i was associated with a reduced risk of HHF when compared with sulphonylureas

Immunogenicity of advanced glycation end products (AGEs) in diabetic patients and in nephropathic non diabetic patients on hemodialysis or after kidney transplantation

Advanced glycation end products (AGE) increase as a consequence of diabetic hyperglycemia and, in nephropathic patients, following renal function loss. Protein-bound AGE behave as immunogens, inducing formation of specific antibodies (Ab-AGE). In this work AGE immunogenicity was studied in 42 diabetic patients, 26 nephropathic patients on hemodialysis and 26 patients with end-stage renal disease who underwent kidney transplantation and in 20 normal subjects. Non-oxidation-derived AGE (nox-AGE), oxidation-derived AGE (ox-AGE) and Ab-AGE were measured by competitive or direct enzyme-linked immunosorbent assay (ELISA) and circulating immune complexes (CIC) by C1q ELISA. Nox- AGE increased significantly in all patient groups (p≤0.05 to ≤0.0001) except in patients on hemodialysis for less than 6 yr. Ox-AGE were only significantly increased in patients transplanted more than 3 yr previously (p<0.05). Ab-AGE were significantly lower than controls in both diabetic groups and in patients on hemodialysis for more than 6 yr (p<0.005 to <0.0001) and not unlike controls in the other groups. These results demonstrate that hemodialysis or renal tranplantation can, initially, reduce either nox- or ox-AGE levels, which however go back to being high in time. Renal transplantation fails to normalize nox-AGE. More importantly, plasma Ab-AGE levels are reduced or unchanged in all patient groups in comparison with controls, despite higher circulating AGE levels. This suggests the importance of tissue-bound AGE as Ab-AGE targets. Additional interventions are needed to control AGE levels in treated nephropathic patients. The search and quantification of specific Ab-AGE would give more meaningful results if performed over specific tissue specimens

Nucleus basalis magnocellularis lesions rease histochemically reactive zinc stores in the rat brain: effect of choline alphoscerate treatment.

The effects of monolateral lesioning of the nucleus basalis magnocellularis (NBM) and of choline alphoscerate treatment on histochemically reactive vesicular zinc stores were assessed in the rat brain using the sulphide-silver histochemical technique. Histochemically reactive zinc stores are located primarily within association fibres of the neuropil of the cerebral cortex as well as in the mossy fibres of the hippocampus. The density of cortical and hippocampal sulphide-silver positive fibres, which might have a role in cognitive and mnemonic processes, parallels the density of zinc-containing presynaptic buttons. Unilateral lesions of NBM caused a remarkable decrease of sulphide-silver positive fibres from the 4th week after lesioning in the neuropil of the ipsilateral fronto-parietal cortex and from the 3rd week in the mossy fibres of the ipsilateral hippocampus. Treatment with choline alphoscerate, which is a precursor in the biosynthesis of brain phospholipids that increases the bioavailability of acetylcholine in the nervous tissue, restored, in part, the density and pattern of sulphide-silver positive fibres in the fronto-parietal cortex and in the hippocampus. The data suggest that, analogously to reports from Alzheimer's disease patients, lesions of the NBM cause a decrease of zinc stores in the rat brain. Choline alphoscerate treatment is able to counter the expression of this phenomenon which accompanies experimental lesions of the NBM

Immunogenicity of advanced glycation end products in diabetic patients and in nephropathic non-diabetic patients on hemodialysis or after renal transplantation

Advanced glycation end products (AGE) increase as a consequence of diabetic hyperglycemia and, in nephropathic patients, following renal function loss. Protein-bound AGE behave as immunogens, inducing formation of specific antibodies (Ab-AGE). In this work AGE immunogenicity was studied in 42 diabetic patients, 26 nephropathic patients on hemodialysis and 26 patients with end-stage renal disease who underwent kidney transplantation and in 20 normal subjects. Non-oxidation-derived AGE (nox-AGE), oxidation-derived AGE (ox-AGE) and Ab-AGE were measured by competitive or direct enzyme-linked immunosorbent assay (ELISA) and circulating immune complexes (CIC) by C1q ELISA. Nox- AGE increased significantly in all patient groups (p &lt; or = 0.05 to &lt; or = 0.0001) except in patients on hemodialysis for less than 6 yr. Ox-AGE were only significantly increased in patients transplanted more than 3 yr previously (p &lt; 0.05). Ab-AGE were significantly lower than controls in both diabetic groups and in patients on hemodialysis for more than 6 yr (p &lt; 0.005 to &lt; 0.0001) and not unlike controls in the other groups. These results demonstrate that hemodialysis or renal transplantation can, initially, reduce either nox- or ox-AGE levels, which however go back to being high in time. Renal transplantation fails to normalize nox-AGE. More importantly, plasma Ab-AGE levels are reduced or unchanged in all patient groups in comparison with controls, despite higher circulating AGE levels. This suggests the importance of tissue-bound AGE as Ab-AGE targets. Additional interventions are needed to control AGE levels in treated nephropathic patients. The search and quantification of specific Ab-AGE would give more meaningful results if performed over specific tissue specimens

Two polyclonal antisera detect different AGE epitopes in human plasma samples

Advanced glycation end products (AGEs), involved in the pathogenesis of diabetic complications, comprise a series of related chemical structures which might possess dissimilar immunogenic characteristics. In this study the levels of AGE in plasma samples from normal subjects (N/41) and diabetic patients (N/44) were measured by ELISA using two polyclonal antisera (named CF5 and CF199, respectively, and immunologically characterized) raised using two different immunogens and immunization techniques. Age levels were significantly higher in diabetic than in normal plasma samples (PB/0.0001) with both antisera. However, CF199 detected higher AGE levels than CF5 both in normal (PB/0.0001) and diabetic (PB/0.005) samples. Pre-incubation with AGE/ bovine serum albumin (BSA) caused the loss of most the reactivity of both antisera. Pre-incubation with carboxy-methyl-lysine/ BSA (an oxidation-derived AGE) induced the loss of nearly all CF5 reactivity while CF199 retained a significant amount of activity against AGE antigens. Moreover, CF5 lost over 90% of its reactivity against BSA incubated with high glucose under non-oxidative conditions, suggesting its recognition of mainly oxidation-derived AGE epitopes. The different AGE levels measured by the two antisera suggests, therefore, that one single antiserum is unable to recognize all the various AGE epitopes which might be present, at any time, in tissues and body fluids in health and disease