Sodium-glucose cotransporter protein-2 (SGLT-2) inhibitors and glucagon-like peptide-1 (GLP-1) receptor agonists for type 2 diabetes: systematic review and network meta-analysis of randomised controlled trials

Objective: To evaluate sodium-glucose cotransporter-2 (SGLT-2) inhibitors and glucagon-like peptide-1 (GLP-1) receptor agonists in patients with type 2 diabetes at varying cardiovascular and renal risk. Design: Network meta-analysis. Data sources: Medline, Embase, and Cochrane CENTRAL up to 11 August 2020. Eligibility criteria for selecting studies: Randomised controlled trials comparing SGLT-2 inhibitors or GLP-1 receptor agonists with placebo, standard care, or other glucose lowering treatment in adults with type 2 diabetes with follow up of 24 weeks or longer. Studies were screened independently by two reviewers for eligibility, extracted data, and assessed risk of bias. Main outcome measures: Frequentist random effects network meta-analysis was carried out and GRADE (grading of recommendations assessment, development, and evaluation) used to assess evidence certainty. Results included estimated absolute effects of treatment per 1000 patients treated for five years for patients at very low risk (no cardiovascular risk factors), low risk (three or more cardiovascular risk factors), moderate risk (cardiovascular disease), high risk (chronic kidney disease), and very high risk (cardiovascular disease and kidney disease). A guideline panel provided oversight of the systematic review. Results: 764 trials including 421 346 patients proved eligible. All results refer to the addition of SGLT-2 inhibitors and GLP-1 receptor agonists to existing diabetes treatment. Both classes of drugs lowered all-cause mortality, cardiovascular mortality, non-fatal myocardial infarction, and kidney failure (high certainty evidence). Notable differences were found between the two agents: SGLT-2 inhibitors reduced mortality and admission to hospital for heart failure more than GLP-1 receptor agonists, and GLP-1 receptor agonists reduced non-fatal stroke more than SGLT-2 inhibitors (which appeared to have no effect). SGLT-2 inhibitors caused genital infection (high certainty), whereas GLP-1 receptor agonists might cause severe gastrointestinal events (low certainty). Low certainty evidence suggested that SGLT-2 inhibitors and GLP-1 receptor agonists might lower body weight. Little or no evidence was found for the effect of SGLT-2 inhibitors or GLP-1 receptor agonists on limb amputation, blindness, eye disease, neuropathic pain, or health related quality of life. The absolute benefits of these drugs vary substantially across patients from low to very high risk of cardiovascular and renal outcomes (eg, SGLT-2 inhibitors resulted in 5 to 48 fewer deaths in 1000 patients over five years; see interactive decision support tool (https://magicevidence.org/match-it/200820dist/#!/) for all outcomes. Conclusions: In patients with type 2 diabetes, SGLT-2 inhibitors and GLP-1 receptor agonists reduced cardiovascular and renal outcomes, with notable differences in benefits and harms. Absolute benefits are determined by individual risk profiles of patients, with clear implications for clinical practice, as reflected in the BMJ Rapid Recommendations directly informed by this systematic review.Suetonia C Palmer ... Lucia Gagliardi ... et al

Home dialysis: conclusions from a Kidney Disease: Improving Global Outcomes (KDIGO) controversies conference

Home dialysis modalities (home hemodialysis [HD] and peritoneal dialysis [PD]) are associated with greater patient autonomy and treatment satisfaction compared with in-center modalities, yet the level of home-dialysis use worldwide is low. Reasons for limited utilization are context-dependent, informed by local resources, dialysis costs, access to healthcare, health system policies, provider bias or preferences, cultural beliefs, individual lifestyle concerns, potential care-partner time, and financial burdens. In May 2021, KDIGO (Kidney Disease: Improving Global Outcomes) convened a controversies conference on home dialysis, focusing on how modality choice and distribution are determined and strategies to expand home-dialysis use. Participants recognized that expanding use of home dialysis within a given health system requires alignment of policy, fiscal resources, organizational structure, provider incentives, and accountability. Clinical outcomes across all dialysis modalities are largely similar, but for specific clinical measures, one modality may have advantages over another. Therefore, choice among available modalities is preference-sensitive, with consideration of quality of life, life goals, clinical characteristics, family or care-partner support, and living environment. Ideally, individuals, their care-partners, and their healthcare teams will employ shared decision-making in assessing initial and subsequent kidney failure treatment options. To meet this goal, iterative, high-quality education and support for healthcare professionals, patients, and care-partners are priorities. Everyone who faces dialysis should have access to home therapy. Facilitating universal access to home dialysis and expanding utilization requires alignment of policy considerations and resources at the dialysis-center level, with clear leadership from informed and motivated clinical teams

Predictors of transfer to home hemodialysis after peritoneal dialysis completion

Background: The aim of the present study was to evaluate the predictors of transfer to home hemodialysis (HHD) after peritoneal dialysis (PD) completion. Methods: All Australian and New Zealand patients treated with PD on day 90 after initiation of renal replacement therapy between 2000 and 2012 were included. Completion of PD was defined by death, transplantation, or hemodialysis (HD) for 180 days or more. Patients were categorized as “transferred to HHD” if they initiated HHD fewer than 180 days after PD had ended. Multivariable logistic regression was used to evaluate predictors of transfer to HHD in a restricted cohort experiencing PD technique failure; a competing-risks analysis was used in the unrestricted cohort. Results: Of 10 710 incident PD patients, 3752 died, 1549 underwent transplantation, and 2915 transferred to HD, among whom 156 (5.4%) started HHD. The positive predictors of transfer to HHD in the restricted cohort were male sex [odds ratio (OR): 2.81], obesity (OR: 2.20), and PD therapy duration (OR: 1.10 per year). Negative predictors included age (OR: 0.95 per year), infectious cause of technique failure (OR: 0.48), underweight (OR: 0.50), kidney disease resulting from hypertension (OR: 0.38) or diabetes (OR: 0.32), race being Maori (OR: 0.65) or Aboriginal and Torres Strait Islander (OR: 0.30). Comparable results were obtained with a competing-risks model. Conclusions: Transfer to HHD after completion of PD is rare and predicted by patient characteristics at baseline and at the time of PD end. Transition to HHD should be considered more often in patients using PD, especially when they fulfill the identified characteristics.Annie-Claire Nadeau-Fredette, Carmel Hawley, Elaine Pascoe, Christopher T. Chan, Martine Leblanc, Philip A. Clayton, Kevan R. Polkinghorne, Neil Boudville and David W. Johnso

The relationship between body mass index and organism-specific peritonitis

Background: Obesity is increasingly prevalent worldwide, and a greater number of patients initiate renal replacement therapy with a high body mass index (BMI). This study aimed to evaluate the association between BMI and organism-specific peritonitis. Methods: All adult patients who initiated peritoneal dialysis (PD) in Australia between January 2004 and December 2013 were included. Data were accessed through the Australia and New Zealand Dialysis and Transplant (ANZDATA) Registry. The co-primary outcomes of this study were time to first organism-specific peritonitis episode, specifically gram-positive, gram-negative, culture-negative, and fungal. Secondary outcomes were individual rates of organism-specific peritonitis for the same 4 microbiological categories. Results: There were 7,381 peritonitis episodes among the 8,343 incident PD patients evaluated. After multivariable adjustment, obese patients (BMI 30 - 34.9 kg/m²) had an increased risk of fungal peritonitis (adjusted hazard ratio [HR] 1.69, 95% confidence interval [CI] 1.18 - 2.42), very obese patients (BMI ≥ 35 kg/m²) had a significantly higher risk of gram-positive peritonitis (HR 1.15, 95% CI 1.02 - 1.30), while both obese and very obese patients experienced significantly higher risks of gram-negative peritonitis (HR 1.29, 95% CI 1.11 - 1.50 and HR 1.30, 95% CI 1.08 - 1.57, respectively) compared with patients with normal BMI (20 - 24.9 kg/m²). Obesity and severe obesity were independently associated with increased incidence rate ratios of all forms of organism-specific peritonitis with a non-significant trend for severe obesity and gram-negative peritonitis association. Conclusion: Among Australian patients, obesity and severe obesity are associated with significantly increased rates of gram-positive, gram-negative, fungal, and culture-negative peritonitis.Dev Jegatheesan, David W. Johnson, Yeoungjee Cho, Elaine M. Pascoe, Darsy Darssan, Htay Htay, Carmel Hawley, Philip A. Clayton, Monique Borlace, Sunil V. Badve, Kamal Sud, Neil Boudville, Stephen P. McDonald and Annie-Claire Nadeau-Fredett

A third SARS-CoV-2 mRNA vaccine dose in people receiving hemodialysis overcomes B cell defects but elicits a skewed CD4⁺ T cell profile.

Cellular immune defects associated with suboptimal responses to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) mRNA vaccination in people receiving hemodialysis (HD) are poorly understood. We longitudinally analyze antibody, B cell, CD4 <sup>+</sup> , and CD8 <sup>+</sup> T cell vaccine responses in 27 HD patients and 26 low-risk control individuals (CIs). The first two doses elicit weaker B cell and CD8 <sup>+</sup> T cell responses in HD than in CI, while CD4 <sup>+</sup> T cell responses are quantitatively similar. In HD, a third dose robustly boosts B cell responses, leads to convergent CD8 <sup>+</sup> T cell responses, and enhances comparatively more T helper (T <sub>H</sub> ) immunity. Unsupervised clustering of single-cell features reveals phenotypic and functional shifts over time and between cohorts. The third dose attenuates some features of T <sub>H</sub> cells in HD (tumor necrosis factor alpha [TNFα]/interleukin [IL]-2 skewing), while others (CCR6, CXCR6, programmed cell death protein 1 [PD-1], and HLA-DR overexpression) persist. Therefore, a third vaccine dose is critical to achieving robust multifaceted immunity in hemodialysis patients, although some distinct T <sub>H</sub> characteristics endure