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. Systematic review registration PROSPERO CRD42019153180

Mortality Trends After Transfer From Peritoneal Dialysis to Hemodialysis

Introduction Transition to hemodialysis (HD) is a common outcome in peritoneal dialysis (PD), but the associated mortality risk is poorly understood. This study sought to identify rates of and risk factors for mortality after transitioning from PD to HD. Methods Patients with incident PD (between 2000 and 2014) who transferred to HD for ≥1 day were identified, using data from Australia and New Zealand Dialysis and Transplantation registry (ANZDATA), Canadian Organ Replacement Register (CORR), Europe Renal Association (ERA) Registry, and the United States Renal Dialysis System (USRDS). Crude mortality rates were calculated for the first 180 days after transfer. Separate multivariable Cox models were built for early (180 days) periods after transfer. Results Overall, 6683, 5847, 21,574, and 80,459 patients were included from ANZDATA, CORR, ERA Registry, and USRDS, respectively. In all registries, crude mortality rate was highest during the first 30 days after a transfer to HD declining thereafter to nadir at 4 to 6 months. Crude mortality rates were lower for patients transferring in the most recent years (than earlier). Older age, PD initiation in earlier cohorts, and longer PD vintage were associated with increased risk of death, with the strongest associations during the first 90 days after transfer and attenuating thereafter. Mortality risk was lower for men than women <90 days after transfer, but higher after 180 days. Conclusion In this multinational study, mortality was highest in the first month after a transfer from PD to HD and risk factors varied by time period after transfer. This study highlights the vulnerability of patients at the time of modality transfer and the need to improve transitions

Transition Between Different Renal Replacement Modalities: Gaps in Knowledge and Care-The Integrated Research Initiative

Patients with end-stage kidney disease (ESKD) have different options to replace the function of their failing kidneys. The "integrated care" model considers treatment pathways rather than individual renal replacement therapy (RRT) techniques. In such a paradigm, the optimal strategy to plan and enact transitions between the different modalities is very relevant, but so far, only limited data on transitions have been published. Perspectives of patients, caregivers, and health professionals on the process of transitioning are even less well documented. Available literature suggests that poor coordination causes significant morbidity and mortality.This review briefly provides the background, development, and scope of the INTErnational Group Research Assessing Transition Effects in Dialysis (INTEGRATED) initiative. We summarize the literature on the transition between different RRT modalities. Further, we present an international research plan to quantify the epidemiology and to assess the qualitative aspects of transition between different modalities

Establishing a core outcome set for peritoneal dialysis : report of the SONG-PD (standardized outcomes in nephrology-peritoneal dialysis) consensus workshop

Outcomes reported in randomized controlled trials in peritoneal dialysis (PD) are diverse, are measured inconsistently, and may not be important to patients, families, and clinicians. The Standardized Outcomes in Nephrology-Peritoneal Dialysis (SONG-PD) initiative aims to establish a core outcome set for trials in PD based on the shared priorities of all stakeholders. We convened an international SONG-PD stakeholder consensus workshop in May 2018 in Vancouver, Canada. Nineteen patients/caregivers and 51 health professionals attended. Participants discussed core outcome domains and implementation in trials in PD. Four themes relating to the formation of core outcome domains were identified: life participation as a main goal of PD, impact of fatigue, empowerment for preparation and planning, and separation of contributing factors from core factors. Considerations for implementation were identified: standardizing patient-reported outcomes, requiring a validated and feasible measure, simplicity of binary outcomes, responsiveness to interventions, and using positive terminology. All stakeholders supported inclusion of PD-related infection, cardiovascular disease, mortality, technique survival, and life participation as the core outcome domains for PD

Core outcome domains for trials in autosomal dominant polycystic kidney disease: An international Delphi survey

Rationale & Objective Outcomes reported in trials involving patients with autosomal dominant polycystic kidney disease (ADPKD) are heterogeneous and rarely include patient-reported outcomes. We aimed to identify critically important consensus-based core outcome domains to be reported in trials in ADPKD. Study Design An international 2-round online Delphi survey was conducted in English, French, and Korean languages. Setting & Participants Patients/caregivers and health professionals completed a 9-point Likert scale (7-9 indicating critical importance) and a Best-Worst Scale. Analytical Approach The absolute and relative importance of outcomes were assessed. Comments were analyzed thematically. Results 1,014 participants (603 [60%] patients/caregivers, 411 [40%] health professionals) from 56 countries completed round 1, and 713 (70%) completed round 2. The prioritized outcomes were kidney function (importance score, 8.6), end-stage kidney disease (8.6), death (7.9), blood pressure (7.9), kidney cyst size/growth (7.8), and cerebral aneurysm (7.7). Kidney cyst–related pain was the highest rated patient-reported outcome by both stakeholder groups. Seven themes explained the prioritization of outcomes: protecting life and health, directly encountering life-threatening and debilitating consequences, specificity to ADPKD, optimizing and extending quality of life, hidden suffering, destroying self-confidence, and lost opportunities. Limitations Study design precluded involvement from those without access to internet or limited computer literacy. Conclusions Kidney function, end-stage kidney disease, and death were the most important outcomes to patients, caregivers, and health professionals. Kidney cyst–related pain was the highest rated patient-reported outcome. Consistent reporting of these top prioritized outcomes may strengthen the value of trials in ADPKD for decision making

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

Supplementary Material for: Suboptimal Initiation of Home Hemodialysis: Determinants and Clinical Outcomes

<p><b><i>Background/Aims:</i></b> Suboptimal initiation of conventional hemodialysis is associated with poor clinical outcomes. In this study, we aimed to ascertain the determinants and adverse events associated with suboptimal starts in home hemodialysis (HHD). <b><i>Methods:</i></b> We conducted a retrospective cohort study including consecutive incident HHD patients from January 1996 to December 2011. All patients had HHD as their first renal replacement therapy or returned to HHD after kidney transplantation. A suboptimal start was defined by dialysis initiation as an inpatient or with a central venous catheter. The primary outcome was time to first hospitalization, technique failure or death. Secondary outcomes included hospitalization rate, hospital days and determinants of suboptimal starts. Suboptimal starts were further categorized as unavoidable as adjudicated by two independent observers with prespecified criteria. <b><i>Results:</i></b> Among 95 incident HHD patients, 44 (46%) and 51 (54%) had optimal and suboptimal starts, respectively. A suboptimal start was associated with a shorter time to the primary outcome (log-rank p < 0.001). In a multivariable Cox proportional hazards model, the hazard ratio for the composite outcome (comparing suboptimal to optimal starts) was 2.94 (95% confidence interval, CI, 1.49-5.78, p = 0.002). Transplantation clinic follow-up (OR 3.18, 95% CI 1.15-8.79) and the Charlson comorbidity index (OR 1.47, 95% CI 1.09-1.97) were associated with higher odds of suboptimal start. <b><i>Conclusion:</i></b> Suboptimal initiation of HHD is associated with adverse clinical events including early hospitalization. Given the high proportion of suboptimal starts in patients returning from transplantation, better incorporation of dialysis planning and renal replacement therapy education is warranted.</p

Center-specific factors associated with peritonitis risk-a multi-center registry analysis

Background: Previous studies have reported significant variation in peritonitis rates across dialysis centers. Limited evidence is available to explain this variability. The aim of this study was to assess center-level predictors of peritonitis and their relationship with peritonitis rate variations. Methods: All incident peritoneal dialysis (PD) patients treated in Australia between October 2003 and December 2013 were included. Data were accessed through the Australia and New Zealand Dialysis and Transplant Registry. The primary outcome was peritonitis rate, evaluated in a mixed effects negative binomial regression model. Peritonitis-free survival was assessed as a secondary outcome in a Cox proportional hazards model. Results: Overall, 8,711 incident PD patients from 51 dialysis centers were included in the study. Center-level predictors of lower peritonitis rates included smaller center size, high proportion of PD, low peritoneal equilibration test use at PD start, and low proportion of hospitalization for peritonitis. In contrast, a low proportion of automated PD exposure, high icodextrin exposure and low or high use of antifungal prophylaxis at the time of peritonitis were associated with a higher peritonitis rate. Similar results were obtained for peritonitis-free survival. Overall, accounting for center-level characteristics appreciably decreased peritonitis variability among dialysis centers (p = 0.02). Conclusion: This study identified specific center-level characteristics associated with the variation in peritonitis risk. Whether these factors are directly related to peritonitis risk or surrogate markers for other center characteristics is uncertain and should be validated in further studies.Annie-Claire Nadeau-Fredette, David W. Johnson, Carmel M. Hawley, Elaine M. Pascoe, Yeoungjee Cho, Philip A. Clayton, Monique Borlace, Sunil V. Badve, Kamal Sud, Neil Boudville and Stephen P. McDonal

Multicenter registry analysis of center characteristics associated with technique failure in patients on incident peritoneal dialysis

Background and objectives: Technique failure is a major limitation of peritoneal dialysis. Our study aimed to identify center- and patient-level predictors of peritoneal dialysis technique failure. Design, setting, participants & measurements: All patients on incident peritoneal dialysis in Australia from 2004 to 2014 were included in the study using data from the Australia and New Zealand Dialysis and Transplant Registry. Center- and patient-level characteristics associated with technique failure were evaluated using Cox shared frailty models. Death-censored technique failure and cause-specific technique failure were analyzed as secondary outcomes. Results: The study included 9362 patients from 51 centers in Australia. The technique failure rate was 0.35 (95% confidence interval, 0.34 to 0.36) episodes per patient-year, with a sevenfold variation across centers that was mainly associated with center-level characteristics. Technique failure was significantly less likely in centers with larger proportions of patients treated with peritoneal dialysis (>29%; adjusted hazard ratio, 0.83; 95% confidence interval, 0.73 to 0.94) and more likely in smaller centers (<16 new patients per year; adjusted hazard ratio, 1.10; 95% confidence interval, 1.00 to 1.21) and centers with lower proportions of patients achieving target baseline serum phosphate levels (<40%; adjusted hazard ratio, 1.15; 95% confidence interval, 1.03 to 1.29). Similar results were observed for death-censored technique failure, except that center target phosphate achievement was not significantly associated. Technique failure due to infection, social reasons, mechanical causes, or death was variably associated with center size, proportion of patients on peritoneal dialysis, and/or target phosphate achievement, automated peritoneal dialysis exposure, icodextrin use, and antifungal use. The variation of hazards of technique failure across centers was reduced by 28% after adjusting for patient-specific factors and an additional 53% after adding center-specific factors. Conclusions: Technique failure varies widely across centers in Australia. A significant proportion of this variation is related to potentially modifiable center characteristics, including peritoneal dialysis center size, proportion of patients on peritoneal dialysis, and proportion of patients on peritoneal dialysis achieving target phosphate level.Htay Htay, Yeoungjee Cho, Elaine M. Pascoe, Darsy Darssan, Annie-Claire Nadeau-Fredett, Carmel Hawley, Philip A. Clayton, Monique Borlace, Sunil V. Badve, Kamal Sud, Neil Boudville, Stephen P. McDonald, David W. Johnso

Comparison of clinical outcomes and adverse events associated with glucose-lowering drugs in patients with type 2 diabetes a meta-analysis

IMPORTANCE Numerous glucose-lowering drugs are used to treat type 2 diabetes.OBJECTIVE To estimate the relative efficacy and safety associated with glucose-lowering drugs including insulin.DATA SOURCES Cochrane Library Central Register of Controlled Trials, MEDLINE, and EMBASE databases through March 21, 2016.STUDY SELECTION Randomized clinical trials of 24 weeks' or longer duration.DATA EXTRACTION AND SYNTHESIS Random-effects network meta-analysis.MAIN OUTCOMES AND MEASURES The primary outcome was cardiovascular mortality. Secondary outcomes included all-cause mortality, serious adverse events, myocardial infarction, stroke, hemoglobin A(1c) (HbA(1C)) level, treatment failure (rescue treatment or lack of efficacy), hypoglycemia, and body weight.RESULTS A total of 301 clinical trials (1 417 367 patient-months) were included; 177 trials (56 598 patients) of drugs given as monotherapy; 109 trials (53 030 patients) of drugs added to metformin (dual therapy); and 29 trials (10 598 patients) of drugs added to metformin and sulfonylurea (triple therapy). There were no significant differences in associations between any drug class as monotherapy, dual therapy, or triple therapy with odds of cardiovascular or all-cause mortality. Compared with metformin, sulfonylurea (standardized mean difference [SMD], 0.18 [95% CI, 0.01 to 0.34]), thiazolidinedione (SMD, 0.16 [95% CI, 0.00 to 0.31]), DPP-4 inhibitor (SMD, 0.33 [95% CI, 0.13 to 0.52]), and alpha-glucosidase inhibitor (SMD, 0.35 [95% CI, 0.12 to 0.58]) monotherapy were associated with higher HbA(1C) levels. Sulfonylurea (odds ratio [OR], 3.13 [95% CI, 2.39 to 4.12]; risk difference [RD], 10% [95% CI, 7% to 13%]) and basal insulin (OR, 17.9 [95% CI, 1.97 to 162]; RD, 10% [95% CI, 0.08% to 20%]) were associated with greatest odds of hypoglycemia. When added to metformin, drugs were associated with similar HbA(1C) levels, while SGLT-2 inhibitors offered the lowest odds of hypoglycemia (OR, 0.12 [95% CI, 0.08 to 0.18]; RD, -22% [-27% to -18%]). When added to metformin and sulfonylurea, GLP-1 receptor agonists were associated with the lowest odds of hypoglycemia (OR, 0.60 [95% CI, 0.39 to 0.94]; RD, -10% [95% CI, -18% to -2%]).CONCLUSIONS AND RELEVANCE Among adults with type 2 diabetes, there were no significant differences in the associations between any of 9 available classes of glucose-lowering drugs (alone or in combination) and the risk of cardiovascular or all-cause mortality. Metformin was associated with lower or no significant difference in HbA(1C) levels compared with any other drug classes. All drugs were estimated to be effective when added to metformin. These findings are consistent with American Diabetes Association recommendations for using metformin monotherapy as initial treatment for patients with type 2 diabetes and selection of additional therapies based on patient-specific considerations