Safety and Efficacy of Incretin-Based Therapies in Patients With Type 2 Diabetes Mellitus and CKD: A Systematic Review and Meta-analysis.

BACKGROUND: The pharmacokinetics and pharmacodynamics of antidiabetic therapies for patients with type 2 diabetes are often altered in the context of chronic kidney disease (CKD). STUDY DESIGN: Systematic review and meta-analysis. SETTING & POPULATION: Patients with type 2 diabetes and CKD. SELECTION CRITERIA FOR STUDIES: 2 reviewers independently screened studies identified through bibliographic databases (Cochrane Library, PubMed, Embase, International Pharmaceutical Abstracts), clinical trial registries, and references from pertinent articles and clinical practice guidelines. Eligible studies included randomized controlled trials evaluating incretin-based therapy in adults with type 2 diabetes and estimated glomerular filtration rates < 60mL/min/1.73m2. INTERVENTIONS: Incretin-based therapies (dipeptidyl peptidase 4 inhibitors and glucagon-like peptide 1 receptor agonists) compared to placebo or active antidiabetic therapies. OUTCOMES: Changes in glycated hemoglobin (HbA1c), hypoglycemia, mortality, change in fasting plasma glucose, cardiovascular events, and end-stage renal disease. RESULTS: Of 1,619 nonduplicate records screened, 13 studies were included. Compared to placebo, incretin-based therapies significantly reduced HbA1c levels (n = 9; weighted mean difference, -0.64; 95% CI, -0.79 to -0.48; I2 = 43%); however, compared with active comparators, they did not (n = 4; weighted mean difference, -0.07; 95% CI, -0.25 to 0.12; I2 = 38%). Incretin-based therapies significantly increased the risk for hypoglycemia compared to placebo (n = 7; relative risk [RR], 1.38; 95% CI, 1.01-1.89; I2 = 0%) but no effect was observed versus active comparators (n = 4; RR, 0.24; 95% CI, 0.03-1.94; I2 = 52%). Limited evidence exists for all-cause mortality (placebo: n = 7 [RR, 1.21; 95% CI, 0.64-2.29; I2 = 0%]; active comparators: n = 3 [RR, 0.70; 95% CI, 0.32-1.54; I2 = 0%]). LIMITATIONS: Variation among interventions, small number of studies, heterogeneity between studies, and high risk for attrition bias in 7 of the selected studies. CONCLUSIONS: In patients with moderate or severe CKD, incretin-based therapies are effective in reducing HbA1c levels. Hypoglycemic events are rare, and wide CIs for the association preclude any definitive conclusions. Likewise, wide CIs were observed for mortality, cardiovascular events, and end-stage renal disease.

Chemical analysis and effect of blueberry and lingonberry fruits and leaves against glutamate-mediated excitotoxicity.

Phenolic compounds are a large class of phytochemicals that are widespread in the plant kingdom and known to have antioxidant capacities. This study aimed to determine the antioxidant capacities as well as the content of total soluble phenolics, anthocyanins, tannins, and flavonoids in the fruits and leaves of blueberries and lingonberries growing in Newfoundland. This study also determined the potential neuroprotective effect of extracts from fruits and leaves against glutamate-mediated excitotoxicity, which is believed to contribute to disorders such as stroke and neurodegenerative diseases. Lingonberry and blueberry plants were found to be rich sources of phenolic compounds. Total antioxidant capacities in terms of radical scavenging activity and reducing power were much higher in leaves of both plants as compared to their fruits. These results were in correlation with phenolic contents including total flavonoids, anthocyanins, and tannins. Brain-derived cell cultures from rats were prepared and grown for about 2 weeks. Cell cultures were treated with glutamate (100 µM) for 24 h, and the effect of extracts was determined on cells subjected to this excitotoxicity. Glutamate treatment caused approximately 23% cell loss when measured after 24 h of exposure. Whereas lingonberry fruit extract did not provide protection from glutamate toxicity, blueberry fruit extracts were extremely protective. Leaf extracts of both lingonberry and blueberry showed a significant neuroprotective effect. The greater protective effect of leaf extracts was in correlation with the levels of phenolics and antioxidant capacity. These findings suggest that berries or their components may contribute to protecting the brain from various pathologies.

Potential neuroprotective effects of oxyresveratrol against traumatic injury.

Oxyresveratrol is a potent antioxidant and free-radical scavenger found in mulberry wood (Morus alba L.) with demonstrated protective effects against cerebral ischemia. We analyzed the neuroprotective ability of oxyresveratrol using an in vitro model of stretch-induced trauma in co-cultures of neurons and glia, or by exposing cultures to high levels of glutamate. Cultures were treated with 25 µM, 50 µM or 100 µM oxyresveratrol at the time of injury. Trauma produced marked neuronal death when measured 24 h post-injury, and oxyresveratrol significantly inhibited this death. Microscopic examination of glia suggested signs of toxicity in cultures treated with 100 µM oxyresveratrol, as demonstrated by elevated S-100B protein release and a high proportion of cells with condensed nuclei. Cultures exposed to glutamate (100 µM) for 24 h exhibited ~ 37% neuronal loss, which was not inhibited by oxyresveratrol. These results show that the two pathologies of high glutamate exposure and trauma are differentially affected by oxyresveratrol treatment in vitro. Further studies using oxyresveratrol in trauma models are warranted, as toxicity to glia could be beneficial by inhibiting reactive gliosis, which often occurs after trauma.