Effects of the sodium–glucose co-transporter 2 inhibitor dapagliflozin in patients with type 2 diabetes and Stages 3b–4 chronic kidney disease

BACKGROUND: The sodium–glucose co-transporter 2 inhibitor dapagliflozin decreases haemoglobin A1c (HbA1c), body weight, blood pressure (BP) and urinary albumin:creatinine ratio (UACR) in patients with type 2 diabetes. The efficacy and safety of this drug have not been properly defined in patients with type 2 diabetes and Stages 3b–4 chronic kidney disease (CKD). METHODS: In a pooled analysis of 11 phase 3 randomized controlled clinical trials, we determined least square mean changes in HbA1c, body weight, BP, estimated glomerular filtration rate (eGFR) and UACR over 102 weeks in patients with type 2 diabetes and an eGFR between 12 to less than 45 mL/min/1.73 m2 receiving placebo (n = 69) or dapagliflozin 5 or 10 mg (n = 151). Effects on UACR were determined in a subgroup of patients with baseline UACR ≥30 mg/g (n = 136). RESULTS: Placebo-corrected changes in HbA1c with dapagliflozin 5 and 10 mg were 0.03% [95% confidence interval (CI) −0.3–0.3] and 0.03% (95% CI −0.2–0.3) during the overall 102-week period. Dapagliflozin 5 and 10 mg compared with placebo reduced UACR by − 47.1% (95% CI −64.8 to − 20.6) and −38.4% (95% CI −57.6 to − 10.3), respectively. Additionally, dapagliflozin 5 and 10 mg compared with placebo reduced BP and body weight. eGFR increased with placebo during the first 4 weeks but did not change with dapagliflozin. There were no between-group differences in eGFR at the end of follow-up. Adverse events associated with renal function occurred more frequently in the dapagliflozin 10-mg group. These events were mainly asymptomatic increases in serum creatinine. CONCLUSIONS: Dapagliflozin did not decrease HbA1c in patients with type 2 diabetes and Stages 3b–4 CKD, but decreased UACR, BP and body weight to a clinically meaningful extent. These results support a large outcome trial in this population to confirm long-term safety and efficacy in reducing adverse clinical endpoints

Effects of dapagliflozin on major adverse kidney and cardiovascular events in patients with diabetic and non-diabetic chronic kidney disease: a prespecified analysis from the DAPA-CKD trial

Background: Dapagliflozin reduces the risk of kidney failure and heart failure in patients with chronic kidney disease. We aimed to investigate the effects of dapagliflozin on kidney, cardiovascular, and mortality outcomes according to presence or absence of type 2 diabetes and according to underlying cause of chronic kidney disease, reported as diabetic nephropathy, chronic glomerulonephritides, ischaemic or hypertensive chronic kidney disease, or chronic kidney disease of other or unknown cause. Methods: DAPA-CKD was a multicentre, double-blind, placebo-controlled, randomised trial done at 386 study sites in 21 countries, in which participants with a urinary albumin-to-creatinine ratio of 200–5000 mg/g and an estimated glomerular filtration rate (eGFR) of 25–75 mL/min per 1·73m2 were randomly assigned (1:1) to dapagliflozin 10 mg once daily or matching placebo, as an adjunct to standard care. The primary outcome was a composite of sustained decline in eGFR of at least 50%, end-stage kidney disease, or kidney-related or cardiovascular death. Secondary efficacy outcomes were a kidney-specific composite (the same as the primary outcome but excluding cardiovascular death), a composite of cardiovascular death or hospital admission for heart failure, and all-cause mortality. In this study, we conducted a prespecified subgroup analysis of the DAPA-CKD primary and secondary endpoints by presence or absence of type 2 diabetes and by aetiology of chronic kidney disease. DAPA-CKD is registered with ClinicalTrials.gov, NCT03036150. Findings: The study took place between Feb 2, 2017, and June 12, 2020. 4304 participants were randomly assigned (2152 to dapagliflozin and 2152 to placebo) and were followed up for a median of 2·4 years (IQR 2·0–2·7). Overall, 2906 (68%) participants had a diagnosis of type 2 diabetes, of whom 396 (14%) had chronic kidney disease ascribed to causes other than diabetic nephropathy. The relative risk reduction for the primary composite outcome with dapagliflozin was consistent in participants with type 2 diabetes (hazard ratio [HR] 0·64, 95% CI 0·52–0·79) and those without diabetes (0·50, 0·35–0·72; pinteraction=0·24). Similar findings were seen for the secondary outcomes: kidney-specific composite outcome (0·57 [0·45–0·73] vs 0·51 [0·34–0·75]; Pinteraction=0·57), cardiovascular death or hospital admission for heart failure (0·70 [0·53–0·92] vs 0·79 [0·40–1·55]; Pinteraction=0·78), and all-cause mortality (0·74 [0·56–0·98] vs 0·52 [0·29–0·93]; Pinteraction=0·25). The effect of dapagliflozin on the primary outcome was also consistent among patients with diabetic nephropathy (n=2510; HR 0·63, 95% CI 0·51–0·78), glomerulonephritides (n=695; 0·43, 0·26–0·71), ischaemic or hypertensive chronic kidney disease (n=687; 0·75, 0·44–1·26), and chronic kidney disease of other or unknown cause (n=412; 0·58, 0·29–1·19; Pinteraction=0·53), with similar consistency seen across the secondary outcomes. The proportions of participants in the dapagliflozin and placebo groups who had serious adverse events or discontinued study drug due to adverse events did not vary between those with and those without type 2 diabetes. Interpretation: Dapagliflozin reduces the risks of major adverse kidney and cardiovascular events and all-cause mortality in patients with diabetic and non-diabetic chronic kidney disease

Dietary Re-education, Exercise Program, Performance and Body Indexes Associated with Risk Factors in Overweight/Obese Women

This study observed the effect of a dietary re-education plus regular physical activity on body composition, risk factors and physical test performance of sedentary overweight/obese women and to correlate these variables one with each other. Fifty women (36 ± 10 yrs; 31 ± 6 body mass index (BMI, kg/m2)) volunteered for the study. Body compositions were obtained by anthropometry and bioimpedance and some body indexes were established. One-repetition maximum (1-RM) and treadmill VO2max tests were carried out and blood samples were obtained for lipid, glucose and uric acid analyses before (T1) and after two months of intervention (T2). Diet was established by indirect calorimetry. Body fat, glucose, uric acid, total cholesterol, HDL-cholesterol and systolic blood pressure were significantly reduced. The 1-RM and VO2max tests were significantly increased. Neck circumference (NC) was correlated with body composition, back muscle 1-MR, HDL and LDL cholesterol, total cholesterol/HDL ratio, uric acid, and resting energy expenditure. BMI was found to be significantly correlated with waist/hip ratio, circumference sum, and body fat percentage by anthropometry and bioimpedance. Body fat percentage determined by bioimpedance and anthropometry was significantly correlated with arm fat area and arm fat area corrected respectively, and both with BMI at T1 and T2. This study suggests that a dietary reeducation plus physical activity around 200 min/week improved body composition and the health of these women. Many anthropometry measurements have correspondence to risk factors and NC could be a simple approach to reflect these results, without other more complex techniques

Maturation of GABAergic Inhibition Promotes Strengthening of Temporally Coherent Inputs among Convergent Pathways

Spike-timing-dependent plasticity (STDP), a form of Hebbian plasticity, is inherently stabilizing. Whether and how GABAergic inhibition influences STDP is not well understood. Using a model neuron driven by converging inputs modifiable by STDP, we determined that a sufficient level of inhibition was critical to ensure that temporal coherence (correlation among presynaptic spike times) of synaptic inputs, rather than initial strength or number of inputs within a pathway, controlled postsynaptic spike timing. Inhibition exerted this effect by preferentially reducing synaptic efficacy, the ability of inputs to evoke postsynaptic action potentials, of the less coherent inputs. In visual cortical slices, inhibition potently reduced synaptic efficacy at ages during but not before the critical period of ocular dominance (OD) plasticity. Whole-cell recordings revealed that the amplitude of unitary IPSCs from parvalbumin positive (Pv+) interneurons to pyramidal neurons increased during the critical period, while the synaptic decay time-constant decreased. In addition, intrinsic properties of Pv+ interneurons matured, resulting in an increase in instantaneous firing rate. Our results suggest that maturation of inhibition in visual cortex ensures that the temporally coherent inputs (e.g. those from the open eye during monocular deprivation) control postsynaptic spike times of binocular neurons, a prerequisite for Hebbian mechanisms to induce OD plasticity

High secondary failure rate of rebanding after failed gastric banding

BACKGROUND: Over the last decade, more than 130,000 laparoscopic adjustable gastric bandings (LAGB) have been performed for the treatment of morbid obesity. Nowadays, longer follow-up data are available in the literature and increasing numbers of late complications and treatment failures of gastric banding have been reported. The aim of the present study was the long-term evaluation of two different rescue operations after failed LAGB: conversion to laparoscopic Roux-en-Y bypass (LRYGB) versus laparoscopic gastric rebanding. METHODS: Between January 1997 and November 2002, 74 consecutive patients underwent either laparoscopic gastric rebanding (n = 44) or LRYGB (n = 30) after failed LAGB. There were 14 men and 60 women, with a median age of 42 (23-60) years. The indication for reoperation was an increasing body mass index (BMI) and band-related complications such as pouch dilatation, band slippage, and penetration after LAGB. Rebandings were done by preference during the initial period of the study and LRYGB was the treatment of choice during the latter period. The success of the rescue operation was assessed by postoperative changes in the BMI, improvements of co-morbidities, and the need for further reoperations (secondary failure). The median follow-up was 36 months (range, 24-60 months). RESULTS: Patients who underwent LRYGB had a significantly better weight loss than patients with a rebanding operation (mean -6.1 versus +1.5 BMI points). In addition, the LRYGB patients showed a significantly better control of serum cholesterol during the long term follow-up (-0.6 versus +0.1 mmol/l). Almost half of the patients (45%) in the rebanding group needed a further operative revision, whereas only 20% underwent reoperation after rescue LRYGB. Thus, the secondary failure rate in the rebanding group was significantly higher compared to the bypass group (p = 0.028). CONCLUSIONS: The present long-term study confirms our previous finding that LRYGB is a better treatment than rebanding after failed laparoscopic gastric banding regarding weight loss and treatment of co-morbidities. During the long-term follow-up the reoperation rate due to secondary failure became significantly higher in the rebanding group. We therefore recommend that LRYGB should be preferred as rescue procedure after failed laparoscopic adjustable gastric banding