Changes in Albuminuria Predict Cardiovascular and Renal Outcomes in Type 2 Diabetes: A Post Hoc Analysis of the LEADER Trial

OBJECTIVE A post hoc analysis to investigate the association between 1-year changes in albuminuria and subsequent risk of cardiovascular and renal events. RESEARCH DESIGN AND METHODS LEADER was a randomized trial of liraglutide up to 1.8 mg/day versus placebo added to standard care for 3.5-5 years in 9,340 participants with type 2 diabetes and high cardiovascular risk. We calculated change in urinary albumin-to-creatinine ratio (UACR) from baseline to 1 year in participants with >30% reduction (n = 2,928), 30-0% reduction (n = 1,218), or any increase in UACR (n = 4,124), irrespective of treatment. Using Cox regression, risks of major adverse cardiovascular events (MACE) and a composite nephropathy outcome (from 1 year to end of trial in subgroups by baseline UACR [= 300 mg/g]) were assessed. The analysis was adjusted for treatment allocation alone as a fixed factor and for baseline variables associated with cardiovascular and renal outcomes. RESULTS For MACE, hazard ratios (HRs) for those with >30% and 30-0% UACR reduction were 0.82 (95% CI 0.71, 0.94; P = 0.006) and 0.99 (0.82, 1.19; P = 0.912), respectively, compared with any increase in UACR (reference). For the composite nephropathy outcome, respective HRs were 0.67 (0.49, 0.93; P = 0.02) and 0.97 (0.66, 1.43; P = 0.881). Results were independent of baseline UACR and consistent in both treatment groups. After adjustment, HRs were significant and consistent in >30% reduction subgroups with baseline micro- or macroalbuminuria. CONCLUSIONS A reduction in albuminuria during the 1st year was associated with fewer cardiovascular and renal outcomes, independent of treatment. Albuminuria monitoring remains an important part of diabetes care, with great unused potential

Cardiovascular and renal outcomes by baseline albuminuria status and renal function — results from the LEADER randomized trial

Aim: To assess cardiorenal outcomes by baseline urinary albumin-to-creatinine ratio (UACR) and estimated glomerular filtration rate (eGFR) in the contemporary LEADER cohort. Materials and methods: LEADER was a multinational, double-blind trial. Patients with type 2 diabetes and high cardiovascular (CV) risk were randomized 1:1 to the glucagon-like peptide-1 analogue liraglutide (≤1.8 mg daily; n = 4668) or placebo (n = 4672) plus standard care and followed for 3.5 to 5 years. Primary composite outcomes were time to first non-fatal myocardial infarction, non-fatal stroke or CV death. Post hoc Cox regression analyses of outcomes by baseline UACR and eGFR subgroups were conducted with adjustment for baseline variables. Results: In the LEADER population, 1598 (17.5%), 2917 (31.9%), 1200 (13.1%), 1611 (17.6%), 845 (9.2%) and 966 (10.6%) had UACR = 0, >0 to <15, 15 to <30, 30 to <100, 100 to <300 and ≥300 mg/g, respectively. Increasing UACR and decreasing eGFR were linked with higher risks of the primary outcome, heart failure hospitalization, a composite renal outcome and death (P-values for the Cochran-Armitage test for trends were all <.0001). Across UACR and eGFR subgroups, risks of cardiorenal events and death were generally lower or similar with liraglutide versus placebo. Conclusions: In a contemporary type 2 diabetes population, increasing baseline UACR and declining eGFR were linked with higher risks of cardiorenal events and death

Circulating Glucagon 1-61 Regulates Blood Glucose by Increasing Insulin Secretion and Hepatic Glucose Production

Glucagon is secreted from pancreatic a cells, and hypersecretion (hyperglucagonemia) contributes to diabetic hyperglycemia. Molecular heterogeneity in hyperglucagonemia is poorly investigated. By screening human plasma using high-resolution-proteomics, we identified several glucagon variants, among which proglucagon 1-61 (PG 1-61) appears to be the most abundant form. PG 1-61 is secreted in subjects with obesity, both before and after gastric bypass surgery, with protein and fat as the main drivers for secretion before surgery, but glucose after. Studies in hepatocytes and in b cells demonstrated that PG 1-61 dose-dependently increases levels of cAMP, through the glucagon receptor, and increases insulin secretion and protein levels of enzymes regulating glycogenolysis and gluconeogenesis. In rats, PG 1-61 increases blood glucose and plasma insulin and decreases plasma levels of amino acids in vivo. We conclude that glucagon variants, such as PG 1-61, may contribute to glucose regulation by stimulating hepatic glucose production and insulin secretion

Patient-reported quality of life outcomes for children with serious congenital heart defects

Objective To compare patient-reported, health-related quality of life (QoL) for children with serious congenital heart defects (CHDs) and unaffected classmates and to investigate the demographic and clinical factors influencing QoL. Design Retrospective cohort study. Setting UK National Health Service. Patients UK-wide cohort of children with serious CHDs aged 10–14 years requiring cardiac intervention in the first year of life in one of 17 UK paediatric cardiac surgical centres operating during 1992–1995. A comparison group of classmates of similar age and sex was recruited. Main outcome measures Child self-report of healthrelated QoL scores (Pediatric Quality of Life Inventory, PedsQL) and parental report of schooling and social activities. Results Questionnaires were completed by 477 children with CHDs (56% boys; mean age 12.1 (SD 1.0) years) and 464 classmates (55%; 12.0 (SD 1.1) years). Children with CHDs rated QoL significantly lower than classmates (CHDs: median 78.3 (IQR 65.0–88.6); classmates: 88.0 (80.2–94.6)) and scored lower on physical (CHDs: 84.4; classmates: 93.8; difference 9.4 (7.8 to 10.9)) and psychosocial functioning subscales (CHDs: 76.7, classmates: 85.0; difference 8.3 (6.0 to 10.6)). Cardiac interventions, school absence, regular medications and non-cardiac comorbidities were independently associated with reduced QoL. Participation in sport positively influenced QoL and was associated with higher psychosocial functioning scores. Conclusions Children with serious CHDs experience lower QoL than unaffected classmates. This appears related to the burden of clinical intervention rather than underlying cardiac diagnosis. Participation in sports activities is positively associated with increased emotional well-being. Child self-report measures of QoL would be a valuable addition to clinical outcome audit in this age group.RLK was awarded an MRC Special Training Fellowship in Health of the Public and Health Services Research (reference G106/1083). TD was supported by an NIHR Academic Clinical Fellowship. This work was supported by a British Heart Foundation project grant (reference PG/02/065/13934). The Centre for Paediatric Epidemiology and Biostatistics benefits from funding support from the Medical Research Council in its capacity as the MRC Centre of Epidemiology for Child Health (reference G04005546). Great Ormond St Hospital for Children NHS Trust and the UCL Institute of Child Health receives a proportion of funding from the Department of Health’s NIHR Biomedical Research Centres schem

The potential of GLP-1 receptor agonists in type 2 diabetes and chronic kidney disease: from randomised trials to clinical practice

Chronic kidney disease (CKD) affects around 10% of the global population and is most often caused by diabetes. Diabetes with CKD (diabetic kidney disease, DKD) is a progressive condition that may cause kidney failure and which contributes significantly to the excess morbidity and mortality in these patients. DKD is treated with direct disease-targeting therapies like blockers of the renin–angiotensin system, sodium–glucose cotransporter-2 (SGLT-2) inhibitors and non-steroidal mineralocorticoid receptor antagonists as well as indirect therapies impacting hyperglycaemia, dyslipidaemia, obesity and hypertension, which all together reduce disease progression. While no glucagon-like peptide-1 (GLP-1) receptor agonists (RAs) are currently indicated to improve kidney outcomes, accumulating evidence from cardiovascular outcomes trials (CVOTs) corroborates a kidney-protective effect in people with T2D and CKD, and GLP-1 RAs are now mentioned in international treatment guidelines for type 2 diabetes (T2D) with CKD. GLP-1 RAs are indicated to improve glycaemia in people with T2D; certain GLP-1 RAs are also approved for weight management and to reduce cardiovascular risk in T2D. Ongoing pivotal trials are assessing additional indications, including T2D with CKD. In this article, we review and discuss kidney outcomes from a multitude of completed clinical trials as well as real-world evidence and ongoing clinical trials