Effects of semaglutide, empagliflozin and their combination on renal diffusion-weighted MRI and total kidney volume in patients with type 2 diabetes: a post hoc analysis from a 32 week randomised trial.

The apparent diffusion coefficient (ADC) derived from diffusion-weighted MRI (DWI-MRI) has been proposed as a measure of changes in kidney microstructure, including kidney fibrosis. In advanced kidney disease, the kidneys often become atrophic; however, in the initial phase of type 2 diabetes, there is an increase in renal size. Glucagon-like peptide-1 receptor agonists and sodium-glucose cotransporter 2 inhibitors both provide protection against progression of kidney disease in diabetes. However, the mechanisms are incompletely understood. To explore this, we examined the effects of semaglutide, empagliflozin and their combination on renal ADC and total kidney volume (TKV). This was a substudy of a randomised clinical trial on the effects of semaglutide and empagliflozin alone or in combination. Eighty patients with type 2 diabetes and high risk of CVD were randomised into four groups (n=20 in each) receiving either tablet placebo, empagliflozin, a combination of semaglutide and tablet placebo (herein referred to as the 'semaglutide' group), or the combination of semaglutide and empagliflozin (referred to as the 'combination-therapy' group). The semaglutide and the combination-therapy group had semaglutide treatment for 16 weeks and then had either tablet placebo or empagliflozin added to the treatment, respectively, for a further 16 weeks; the placebo and empagliflozin groups were treated with the respective monotherapy for 32 weeks. We analysed the effects of treatment on changes in ADC (cortical, medullary and the cortico-medullary difference [ΔADC; medullary ADC subtracted from cortical ADC]), as well as TKV measured by MRI. Both semaglutide and empagliflozin decreased cortical ADC significantly compared with placebo (semaglutide: -0.20×10-3 mm2/s [95% CI -0.30, -0.10], p<0.001; empagliflozin: -0.15×10-3 mm2/s [95% CI -0.26, -0.04], p=0.01). No significant change was observed in the combination-therapy group (-0.05×10-3 mm2/s [95%CI -0.15, 0.05]; p=0.29 vs placebo). The changes in cortical ADC were not associated with changes in GFR, albuminuria, TKV or markers of inflammation. Further, there were no changes in medullary ADC in any of the groups compared with placebo. Only treatment with semaglutide changed ΔADC significantly from placebo, showing a decrease of -0.13×10-3 mm2/s (95% CI -0.22, -0.04; p=0.01). Compared with placebo, TKV decreased by -3% (95% CI -5%, -0.3%; p=0.04), -3% (95% CI -5%, -0.4%; p=0.02) and -5% (95% CI -8%, -2%; p<0.001) in the semaglutide, empagliflozin and combination-therapy group, respectively. The changes in TKV were associated with changes in GFR, albuminuria and HbA1c. In a population with type 2 diabetes and high risk of CVD, semaglutide and empagliflozin significantly reduced cortical ADC compared with placebo, indicating microstructural changes in the kidneys. These changes were not associated with changes in GFR, albuminuria or inflammation. Further, we found a decrease in TKV in all active treatment groups, which was possibly mediated by a reduction in hyperfiltration. Our findings suggest that DWI-MRI may serve as a promising tool for investigating the underlying mechanisms of medical interventions in individuals with type 2 diabetes but may reflect effects not related to fibrosis. European Union Drug Regulating Authorities Clinical Trials Database (EudraCT) 2019-000781-38.

Vernstrøm L ，Gullaksen S ，Sørensen SS ，Ringgaard S ，Laustsen C ，Birn H ，Funck KL ，Laugesen E ，Poulsen PL ... -  《-》

Erratum: Eyestalk Ablation to Increase Ovarian Maturation in Mud Crabs.

《Jove-Journal of Visualized Experiments》

Falls prevention interventions for community-dwelling older adults: systematic review and meta-analysis of benefits, harms, and patient values and preferences.

About 20-30% of older adults (≥ 65 years old) experience one or more falls each year, and falls are associated with substantial burden to the health care system, individuals, and families from resulting injuries, fractures, and reduced functioning and quality of life. Many interventions for preventing falls have been studied, and their effectiveness, factors relevant to their implementation, and patient preferences may determine which interventions to use in primary care. The aim of this set of reviews was to inform recommendations by the Canadian Task Force on Preventive Health Care (task force) on fall prevention interventions. We undertook three systematic reviews to address questions about the following: (i) the benefits and harms of interventions, (ii) how patients weigh the potential outcomes (outcome valuation), and (iii) patient preferences for different types of interventions, and their attributes, shown to offer benefit (intervention preferences). We searched four databases for benefits and harms (MEDLINE, Embase, AgeLine, CENTRAL, to August 25, 2023) and three for outcome valuation and intervention preferences (MEDLINE, PsycINFO, CINAHL, to June 9, 2023). For benefits and harms, we relied heavily on a previous review for studies published until 2016. We also searched trial registries, references of included studies, and recent reviews. Two reviewers independently screened studies. The population of interest was community-dwelling adults ≥ 65 years old. We did not limit eligibility by participant fall history. The task force rated several outcomes, decided on their eligibility, and provided input on the effect thresholds to apply for each outcome (fallers, falls, injurious fallers, fractures, hip fractures, functional status, health-related quality of life, long-term care admissions, adverse effects, serious adverse effects). For benefits and harms, we included a broad range of non-pharmacological interventions relevant to primary care. Although usual care was the main comparator of interest, we included studies comparing interventions head-to-head and conducted a network meta-analysis (NMAs) for each outcome, enabling analysis of interventions lacking direct comparisons to usual care. For benefits and harms, we included randomized controlled trials with a minimum 3-month follow-up and reporting on one of our fall outcomes (fallers, falls, injurious fallers); for the other questions, we preferred quantitative data but considered qualitative findings to fill gaps in evidence. No date limits were applied for benefits and harms, whereas for outcome valuation and intervention preferences we included studies published in 2000 or later. All data were extracted by one trained reviewer and verified for accuracy and completeness. For benefits and harms, we relied on the previous review team's risk-of-bias assessments for benefit outcomes, but otherwise, two reviewers independently assessed the risk of bias (within and across study). For the other questions, one reviewer verified another's assessments. Consensus was used, with adjudication by a lead author when necessary. A coding framework, modified from the ProFANE taxonomy, classified interventions and their attributes (e.g., supervision, delivery format, duration/intensity). For benefit outcomes, we employed random-effects NMA using a frequentist approach and a consistency model. Transitivity and coherence were assessed using meta-regressions and global and local coherence tests, as well as through graphical display and descriptive data on the composition of the nodes with respect to major pre-planned effect modifiers. We assessed heterogeneity using prediction intervals. For intervention-related adverse effects, we pooled proportions except for vitamin D for which we considered data in the control groups and undertook random-effects pairwise meta-analysis using a relative risk (any adverse effects) or risk difference (serious adverse effects). For outcome valuation, we pooled disutilities (representing the impact of a negative event, e.g. fall, on one's usual quality of life, with 0 = no impact and 1 = death and ~ 0.05 indicating important disutility) from the EQ-5D utility measurement using the inverse variance method and a random-effects model and explored heterogeneity. When studies only reported other data, we compared the findings with our main analysis. For intervention preferences, we used a coding schema identifying whether there were strong, clear, no, or variable preferences within, and then across, studies. We assessed the certainty of evidence for each outcome using CINeMA for benefit outcomes and GRADE for all other outcomes. A total of 290 studies were included across the reviews, with two studies included in multiple questions. For benefits and harms, we included 219 trials reporting on 167,864 participants and created 59 interventions (nodes). Transitivity and coherence were assessed as adequate. Across eight NMAs, the number of contributing trials ranged between 19 and 173, and the number of interventions ranged from 19 to 57. Approximately, half of the interventions in each network had at least low certainty for benefit. The fallers outcome had the highest number of interventions with moderate certainty for benefit (18/57). For the non-fall outcomes (fractures, hip fracture, long-term care [LTC] admission, functional status, health-related quality of life), many interventions had very low certainty evidence, often from lack of data. We prioritized findings from 21 interventions where there was moderate certainty for at least some benefit. Fourteen of these had a focus on exercise, the majority being supervised (for > 2 sessions) and of long duration (> 3 months), and with balance/resistance and group Tai Chi interventions generally having the most outcomes with at least low certainty for benefit. None of the interventions having moderate certainty evidence focused on walking. Whole-body vibration or home-hazard assessment (HHA) plus exercise provided to everyone showed moderate certainty for some benefit. No multifactorial intervention alone showed moderate certainty for any benefit. Six interventions only had very-low certainty evidence for the benefit outcomes. Two interventions had moderate certainty of harmful effects for at least one benefit outcome, though the populations across studies were at high risk for falls. Vitamin D and most single-component exercise interventions are probably associated with minimal adverse effects. Some uncertainty exists about possible adverse effects from other interventions. For outcome valuation, we included 44 studies of which 34 reported EQ-5D disutilities. Admission to long-term care had the highest disutility (1.0), but the evidence was rated as low certainty. Both fall-related hip (moderate certainty) and non-hip (low certainty) fracture may result in substantial disutility (0.53 and 0.57) in the first 3 months after injury. Disutility for both hip and non-hip fractures is probably lower 12 months after injury (0.16 and 0.19, with high and moderate certainty, respectively) compared to within the first 3 months. No study measured the disutility of an injurious fall. Fractures are probably more important than either falls (0.09 over 12 months) or functional status (0.12). Functional status may be somewhat more important than falls. For intervention preferences, 29 studies (9 qualitative) reported on 17 comparisons among single-component interventions showing benefit. Exercise interventions focusing on balance and/or resistance training appear to be clearly preferred over Tai Chi and other forms of exercise (e.g., yoga, aerobic). For exercise programs in general, there is probably variability among people in whether they prefer group or individual delivery, though there was high certainty that individual was preferred over group delivery of balance/resistance programs. Balance/resistance exercise may be preferred over education, though the evidence was low certainty. There was low certainty for a slight preference for education over cognitive-behavioral therapy, and group education may be preferred over individual education. To prevent falls among community-dwelling older adults, evidence is most certain for benefit, at least over 1-2 years, from supervised, long-duration balance/resistance and group Tai Chi interventions, whole-body vibration, high-intensity/dose education or cognitive-behavioral therapy, and interventions of comprehensive multifactorial assessment with targeted treatment plus HHA, HHA plus exercise, or education provided to everyone. Adding other interventions to exercise does not appear to substantially increase benefits. Overall, effects appear most applicable to those with elevated fall risk. Choice among effective interventions that are available may best depend on individual patient preferences, though when implementing new balance/resistance programs delivering individual over group sessions when feasible may be most acceptable. Data on more patient-important outcomes including fall-related fractures and adverse effects would be beneficial, as would studies focusing on equity-deserving populations and on programs delivered virtually. Not registered.

Pillay J ，Gaudet LA ，Saba S ，Vandermeer B ，Ashiq AR ，Wingert A ，Hartling L ... -  《Systematic Reviews》

Semaglutide combined with empagliflozin vs. monotherapy for non-alcoholic fatty liver disease in type 2 diabetes: Study protocol for a randomized clinical trial.

Nonalcoholic fatty liver disease (NAFLD) is strongly associated with type 2 diabetes mellitus (T2DM). Lifestyle intervention remains a preferred treatment modality for NAFLD. The glucagon-like peptide (GLP-1) receptor agonists and sodium-glucose cotransporter-2 (SGLT-2) inhibitors have been developed as new glucose-lowering drugs, which can improve fatty liver via an insulin-independent glucose-lowering effect. However, studies exploring the efficacy of GLP-1 receptor agonists combined with SGLT-2 inhibitors in patients with NAFLD and T2DM are scanty. Thus, the present randomised controlled trial aims at comparing the efficacy and safety of semaglutide plus empagliflozin with each treatment alone in patients with NAFLD and T2DM. This 52-week double-blinded, randomised, parallel-group, active-controlled trial evaluates the effects of semaglutide, empagliflozin and semaglutide + empagliflozin in 105 eligible overweight/obese subjects with NAFLD and T2DM. The primary outcome will be a change from baseline to week 52 in the controlled attenuation parameter, free fatty acid and glucagon. Secondary endpoints include changes in liver stiffness measurement, liver enzymes, blood glucose, lipid levels, renal function, electrolyte balances, minerals and bone metabolism, cytokines, high-sensitivity C-reactive protein, ferritin, anthropometric indicators, nonalcoholic fatty liver fibrosis score, fibrosis 4 score and homeostatic model assessment for insulin resistance. In addition, intention-to-treat, interim analysis and safety analysis will be performed. This double-blinded, randomised, clinical trial involves a multi-disciplinary approach and aims to explore the synergistic effects of the combination of semaglutide and empagliflozin. The results can provide important insights into mechanisms of GLP-1 receptor agonists and/or SGLT-2 inhibitors in patients with NAFLD and T2DM. This study has been registered with Chinese Clinical Trial Registry (ChiCTR2300070674).

Lin YH ，Zhang ZJ ，Zhong JQ ，Wang ZY ，Peng YT ，Lin YM ，Zhang HP ，Tian JQ ... -  《PLoS One》

Conservative, physical and surgical interventions for managing faecal incontinence and constipation in adults with central neurological diseases.

People with central neurological disease or injury have a much higher risk of both faecal incontinence (FI) and constipation than the general population. There is often a fine line between the two symptoms, with management intended to ameliorate one risking precipitating the other. Bowel problems are observed to be the cause of much anxiety and may reduce quality of life in these people. Current bowel management is largely empirical, with a limited research base. The review is relevant to individuals with any disease directly and chronically affecting the central nervous system (post-traumatic, degenerative, ischaemic or neoplastic), such as multiple sclerosis, spinal cord injury, cerebrovascular disease, Parkinson's disease and Alzheimer's disease. This is an update of a Cochrane Review first published in 2001 and subsequently updated in 2003, 2006 and 2014. To assess the effects of conservative, physical and surgical interventions for managing FI and constipation in people with a neurological disease or injury affecting the central nervous system. We searched the Cochrane Incontinence Specialised Register (searched 27 March 2023), which includes searches of the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, MEDLINE In-Process, MEDLINE Epub Ahead of Print, ClinicalTrials.gov, WHO ICTRP as well as handsearching of journals and conference proceedings; and all reference lists of relevant articles. We included randomised, quasi-randomised (where allocation is not strictly random), cross-over and cluster-randomised trials evaluating any type of conservative, physical or surgical intervention against placebo, usual care or no intervention for the management of FI and constipation in people with central neurological disease or injury. At least two review authors independently assessed the risk of bias in eligible trials using Cochrane's 'Risk of bias' tool and independently extracted data from the included trials using a range of prespecified outcome measures. We produced summary of findings tables for our main outcome measures and assessed the certainty of the evidence using GRADE. We included 25 studies with 1598 participants. The studies were generally at high risk of bias due to lack of blinding of participants and personnel to the intervention. Half of the included studies were also at high risk of bias in terms of selective reporting. Outcomes were often reported heterogeneously across studies, making it difficult to pool data. We did not find enough evidence to be able to analyse the effects of interventions on individual central neurological diseases. Additionally, very few studies reported on the primary outcomes of self-reported improvement in FI or constipation, or Neurogenic Bowel Dysfunction Score. Conservative interventions compared with usual care, no active treatment or placebo Thirteen studies assessed this comparison. The interventions included assessment-based nursing, holistic nursing, probiotics, psyllium, faecal microbiota transplantation, and a stepwise protocol of increasingly invasive evacuation methods. Conservative interventions may result in a large improvement in faecal incontinence (standardised mean difference (SMD) -1.85, 95% confidence interval (CI) -3.47 to -0.23; 3 studies; n = 410; low-certainty evidence). We interpreted SMD ≥ 0.80 as a large effect. It was not possible to pool all data from studies that assessed improvement in constipation, but the evidence suggested that conservative interventions may improve constipation symptoms (data not pooled; 8 studies; n = 612; low-certainty evidence). Conservative interventions may lead to a reduction in mean time taken on bowel care (data not pooled; 5 studies; n = 526; low-certainty evidence). The evidence is uncertain about the effects of conservative interventions on condition-specific quality of life and adverse events. Neurogenic Bowel Dysfunction Score was not reported. Physical therapy compared with usual care, no active treatment or placebo Twelve studies assessed this comparison. The interventions included massage therapy, standing, osteopathic manipulative treatment, electrical stimulation, transanal irrigation, and conventional physical therapy with visceral mobilisation. Physical therapies may make little to no difference to self-reported faecal continence assessed using the St Mark's Faecal Incontinence Score, where the minimally important difference is five, or the Cleveland Constipation Score (MD -2.60, 95% CI -4.91 to -0.29; 3 studies; n = 155; low-certainty evidence). Physical therapies may result in a moderate improvement in constipation symptoms (SMD -0.62, 95% CI -1.10 to -0.14; 9 studies; n = 431; low-certainty evidence). We interpreted SMD ≥ 0.5 as a moderate effect. However, physical therapies may make little to no difference in Neurogenic Bowel Dysfunction Score as the minimally important difference for this tool is 3 (MD -1.94, 95% CI -3.36 to -0.51; 7 studies; n = 358; low-certainty evidence). We are very uncertain about the effects of physical therapies on the time spent on bowel care, condition-specific quality of life and adverse effects (all very low-certainty evidence). Surgical interventions compared with usual care, no active treatment or placebo No studies were found for surgical interventions that met the inclusion criteria for this review. There remains little research on this common and, for patients, very significant issue of bowel management. The available evidence is almost uniformly of low methodological quality. The clinical significance of some of the research findings presented here is difficult to interpret, not least because each intervention has only been addressed in individual trials, against control rather than compared against each other, and the interventions are very different from each other. Understanding whether there is a clinically-meaningful difference from the results of available trials is largely hampered by the lack of uniform outcome measures. This is due to an absence of core outcome sets, and development of these needs to be a research priority to allow studies to be compared directly. Some studies used validated constipation, incontinence or condition-specific measures; however, others used unvalidated analogue scales to report effectiveness. Some studies did not use any patient-reported outcomes and focused on physiological outcome measures, which is of relatively limited significance in terms of clinical implementation. There was evidence in favour of some conservative interventions, but these findings need to be confirmed by larger, well-designed controlled trials, which should include evaluation of the acceptability of the intervention to patients and the effect on their quality of life.

Todd CL ，Johnson EE ，Stewart F ，Wallace SA ，Bryant A ，Woodward S ，Norton C ... -  《Cochrane Database of Systematic Reviews》