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BackgroundSodium-glucose co-transporter-2 inhibitors (SGLT2i) reduce glucose levels, body weight, and blood pressure, possibly resulting in cardiovascular protection. In phase III trials, SGLT2i were shown to increase HDL cholesterol. We aimed to evaluate whether the SGLT2i dapagliflozin affects HDL function in a randomized placebo-controlled trial.MethodsThirty-three type 2 diabetic patients were randomized to receive dapagliflozin 10 mg or placebo for 12 weeks on top of their glucose lowering medications. The primary end-point was the change in cholesterol efflux capacity (CEC) from macrophages at study end versus baseline. Secondary endpoints were changes in: distribution of HDL subfractions, lipid profile, activity of enzymes that mediate HDL antioxidant properties (PON1 and ARE) and cholesterol metabolism (CETP), HbA1c, body weight and composition.ResultsThirty-one patients completed the study, n = 16 in the placebo group and n = 15 in the dapagliflozin group. Patients randomized to dapagliflozin were older and had lower adiposity indexes, although these differences disappeared after correction for multiple testing. Therapy with dapagliflozin reduced HbA1c by 0.9% and body weight by 3.1 kg, mainly attributable to reduction of body water and lean mass. As compared to placebo, dapagliflozin reduced CEC (−6.7 ± 2.4 versus 0.3 ± 1.8%; p = 0.043), but this effect was no longer significant after adjusting for age and BMI. No change was detected in HDL cholesterol, HDL subfractions, activity of PON1, ARE, and CETP.ConclusionsDespite improvements in glucose control and reduction in body weight, therapy with dapagliflozin exerted no significant effect on HDL cholesterol levels and HDL functionality. Trial registration EudraCT 2014-004270-42; NCT02327039Electronic supplementary materialThe online version of this article (doi:10.1186/s12933-017-0529-3) contains supplementary material, which is available to authorized users.

Snake presynaptic phospholipase A2 neurotoxins (SPANs) bind to the presynaptic membrane and hydrolyze phosphatidylcholine with generation of lysophosphatidylcholine (LysoPC) and fatty acid (FA). The LysoPC ؉ FA mixture promotes membrane fusion, inducing the exocytosis of the ready-to-release synaptic vesicles. However, also the reserve pool of synaptic vesicles disappears from nerve terminals intoxicated with SPAN or LysoPC ؉ FA. Here, we show that LysoPC ؉ FA and SPANs cause a large influx of extracellular calcium into swollen nerve terminals, which accounts for the extensive synaptic vesicle release. This is paralleled by the change of morphology and the collapse of membrane potential of mitochondria within nerve bulges. These results complete the picture of events occurring at nerve terminals intoxicated by SPANs and define the LysoPC ؉ FA lipid mixture as a novel and effective agonist of synaptic vesicle release.

Objectives Institutionalized older adults have a high prevalence of frailty and disability, which may make them more vulnerable to the negative consequences of COVID-19. We investigated the impact of COVID-19 on the level of frailty, physical and cognitive performance in nursing home residents. Design Nested case-control study. Setting and participants. The study included nursing home residents who were infected with COVID-19 ( case group , n=76), matched by age to a control group (n=76). Methods Participants’ sociodemographic and medical data were collected, and they were also assessed for physical function (handgrip and walking speed), cognitive performance (Mini-Mental State Examination [MMSE]) and frailty (Frail-NH scale) before the first wave of the COVID-19 pandemic (October to December 2019, "pre-COVID-19") and after (June to July 2020, "post-COVID-19"). COVID-19 symptoms and clinical course were recorded for the cases . Results Between the pre- and post-COVID-19 assessments, we found a 19% greater deterioration in handgrip, a 22% greater increase in walking speed, and a 21% greater increase in Frail-NH scores in cases compared with controls. In both cases and controls, on the other hand, there was a significant 10% decrease in MMSE scores over the study period. Multivariable logistic regression showed that COVID-19 survivors had a four-fold increased chance of developing frailty compared with controls (OR = 4.95, 95% CI: 1.13-21.6, p =0.03), but not cognitive decline. Conclusions and implications COVID-19 can accelerate the aging process of institutionalized older adults in terms of physical performance and frailty by around 20%. However, we found similar levels of decline in cognitive performance in both cases and controls, likely due to the burden of social isolation and containment measures on neuropsychological health.

In randomized controlled trials (RCTs), sodium‐glucose co‐transporter‐2 (SGLT2) inhibitors have been shown to confer glycaemic and extra‐glycaemic benefits. The DARWIN‐T2D (DApagliflozin Real World evIdeNce in Type 2 Diabetes) study was a multicentre retrospective study designed to evaluate the baseline characteristics of patients receiving dapagliflozin vs those receiving selected comparators (dipeptidyl peptidase‐4 inhibitors, gliclazide, or glucagon‐like peptide‐1 receptor agonists), and drug effectiveness in routine clinical practice. From a population of 281 217, the analysis included 17 285 patients initiating dapagliflozin or comparator glucose‐lowering medications (GLMs), 6751 of whom had a follow‐up examination. At baseline, participants starting dapagliflozin were younger, had a longer disease duration, higher glycated haemoglobin (HbA1c) concentration, and a more complex history of previous GLM use, but the clinical profile of patients receiving dapagliflozin changed during the study period. Dapagliflozin reduced HbA1c by 0.7%, body weight by 2.7 kg, and systolic blood pressure by 3.0 mm Hg. Effects of comparator GLMs were also within the expected range, based on RCTs. This real‐world study shows an initial channelling of dapagliflozin to difficult‐to‐treat patients. Nonetheless, dapagliflozin provided significant benefits with regard to glucose control, body weight and blood pressure that were in line with findings from RCTs.

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