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

Can we IMPROVE cardiovascular outcomes through phosphate lowering in CKD? Rationale and protocol for the IMpact of Phosphate Reduction on Vascular End-points in Chronic Kidney Disease (IMPROVE-CKD) study

Introduction: Patients with chronic kidney disease (CKD) are at heightened cardiovascular risk, which has been associated with abnormalities of bone and mineral metabolism. A deeper understanding of these abnormalities should facilitate improved treatment strategies and patient-level outcomes, but at present there are few large, randomised controlled clinical trials to guide management. Positive associations between serum phosphate and fibroblast growth factor 23 (FGF-23) and cardiovascular morbidity and mortality in both the general and CKD populations have resulted in clinical guidelines suggesting that serum phosphate be targeted towards the normal range, although few randomised and placebo-controlled studies have addressed clinical outcomes using interventions to improve phosphate control. Early preventive measures to reduce the development and progression of vascular calcification, left ventricular hypertrophy and arterial stiffness are crucial in patients with CKD. Methods and analysis: We outline the rationale and protocol for an international, multicentre, randomised parallel-group trial assessing the impact of the non-calcium-based phosphate binder, lanthanum carbonate, compared with placebo on surrogate markers of cardiovascular disease in a predialysis CKD population—the IM pact of P hosphate R eduction O n V ascular E nd-points (IMPROVE)-CKD study. The primary objective of the IMPROVE-CKD study is to determine if the use of lanthanum carbonate reduces the burden of cardiovascular disease in patients with CKD stages 3b and 4 when compared with placebo. The primary end-point of the study is change in arterial compliance measured by pulse wave velocity over a 96-week period. Secondary outcomes include change in aortic calcification and biochemical parameters of serum phosphate, parathyroid hormone and FGF-23 levels. Ethics and dissemination: Ethical approval for the IMPROVE-CKD trial was obtained by each local Institutional Ethics Committee for all 17 participating sites in Australia, New Zealand and Malaysia prior to study commencement. Results of this clinical trial will be published in peer-reviewed journals and presented at conferences.Nicole Lioufas, Nigel D Toussaint, Eugenia Pedagogos, Grahame Elder, Sunil V Badve, Elaine Pascoe, Andrea Valks, Carmel Hawley, Geoffrey A Block, Neil C Boudville, Katrina Campbell, James D Cameron, Sylvia S M Chen, Randall J Faull, Stephen G Holt, Lai S Hooi, Dana Jackson, Meg J Jardine, David W Johnson, Peter G Kerr, Kenneth K Lau, Alicia Morrish, Vlado Perkovic, Kevan R Polkinghorne, Carol A Pollock, Donna Reidlinger, Laura Robison, Edward R Smith, Robert J Walker, Angela Yee Moon Wang

Establishing a clinical trials network in nephrology: Experience of the Australasian Kidney Trials Network

Chronic kidney disease is a major public health problem globally. Despite this, there are fewer high-quality, high-impact clinical trials in nephrology than other internal medicine specialties, which has led to large gaps in evidence. To address this deficiency, the Australasian Kidney Trials Network, a Collaborative Research Group, was formed in 2005. Since then, the Network has provided infrastructure and expertise to conduct patient-focused high-quality, investigator-initiated clinical trials in nephrology. The Network has not only been successful in engaging the nephrology community in Australia and New Zealand but also in forming collaborations with leading researchers from other countries. This article describes the establishment, development, and functions of the Network. The article also discusses the current and future funding strategies to ensure uninterrupted conduct of much needed clinical trials in nephrology to improve the outcomes of patients affected by kidney diseases with cost-effective intervention

Differences in peritoneal dialysis technique survival between patients treated with peritoneal dialysis systems from different companies

BACKGROUND:A number of peritoneal dialysis (PD) systems are available but there have been few studies comparing them. The aim of this study was to examine technique failure and patient survival between different PD company systems. METHODS:The study included all patients who commenced PD between 1995 and 2014 in Australia and New Zealand. Groups were compared according to the initial PD company system that they received. The primary outcome was a composite of PD technique failure and death. RESULTS:A total of 16 575 patients commenced PD using systems manufactured by Baxter [n = 13 438 (81%)], Fresenius Medical Care [n = 2848 (17%)] or Gambro [n = 289 (2%)]. Of these, 11 870 (72%) developed technique failure, including 5421 (33%) who died. The median time to technique failure or death for all patients was 625 [interquartile range (IQR) 318-1114] days: 629.5 (IQR 321-1121) days with Baxter, 620.5 (IQR 311-1069) days with Fresenius Medical Care and 538 (IQR 272-1001) days with Gambro systems (P = 0.023). There was a statistically significant increase in technique failure or mortality rates in patients on Gambro {adjusted incidence rate ratio [IRR] 1.46 [95% confidence interval (CI) 1.33-1.62]} and Fresenius [adjusted IRR 1.10 (95% CI 1.01-1.19)] systems compared with Baxter systems. No difference in patient survival was observed between the three PD systems. CONCLUSIONS:PD systems manufactured by different companies may be associated with important differences in PD technique survival. This needs to be confirmed with adequately powered, prospective randomized controlled clinical trials.Neil Boudville, Shahid Ullah, Phil Clayton, Kamal Sud, Monique Borlace, Sunil V Badve ... et al

The association between body mass index and mortality in incident dialysis patients

Objectives: To study the body mass index (BMI) trajectory in patients with incident end-stage kidney disease and its association with all-cause mortality

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

Representativeness of the PDOPPS cohort compared to the Australian PD population

Published online 10 Nov 2021BACKGROUND: The Peritoneal Dialysis Outcomes and Practice Patterns Study (PDOPPS) is an international, prospective study following persons treated by peritoneal dialysis (PD) to identify modifiable practices associated with improvements in PD technique and person survival. The aim of this study was to assess the representativeness of the Australian cohort included in PDOPPS compared to the complete Australian PD population, as reported to the Australia and New Zealand Dialysis and Transplant (ANZDATA) Registry. METHODS: Adults with at least one PD treatment reported to ANZDATA Registry during the census period of PDOPPS Phase I (November 2014 to April 2018) were compared to the Australian PDOPPS cohort. The primary outcomes were the representativeness of centres and persons. Secondary outcomes explored the association of person characteristics with consent to study participation. RESULTS: After data linkage, 511 PDOPPS participants were compared to 5616 Australians treated with PD. Within centres eligible for PDOPPS, selected centres were similar to other Australian centres. The PDOPPS participants' cohort tended to include older persons, more males, a higher proportion of Caucasians and more persons with higher socioeconomic advantage compared to the Australian PD population. Differences in distribution across sex and ethnicities between the PDOPPS cohort and the overall PD population were in part due to the selection and consent processes, during which females and non-Caucasians were more likely to not consent to PDOPPS participation. CONCLUSION: Sampling methods used in PDOPPS allowed for good national representativeness of the included centres. However, representativeness of the unweighted PDOPPS sample was suboptimal in regard to some participant characteristics.Isabelle Ethier, Neil Boudville, Stephen McDonald, Fiona Brown, Peter G Kerr, Rowan Walker, Stephen Geoffroy Holt, Sunil V Badve, Yeoungjee Cho, Carmel Hawley, Laura Robison, Donna Reidlinger, Elasma Milanzi, Brian Bieber, Keith McCullough, David W Johnso