Dataset Information

Cardiovascular and renal outcomes by baseline albuminuria status and renal function: Results from the LEADER randomized trial.

ABSTRACT: 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.

SUBMITTER: Mosenzon O

PROVIDER: S-EPMC7689857 | biostudies-literature | 2020 Jul

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Cardiovascular and renal outcomes by baseline albuminuria status and renal function: Results from the LEADER randomized trial.

Mosenzon Ofri O Bain Stephen C SC Heerspink Hiddo J L HJL Idorn Thomas T Mann Johannes F E JFE Persson Frederik F Pratley Richard E RE Rasmussen Søren S Rossing Peter P von Scholten Bernt Johan BJ Raz Itamar I

Diabetes, obesity & metabolism 20200807 11

<h4>Aim</h4>To assess cardiorenal outcomes by baseline urinary albumin-to-creatinine ratio (UACR) and estimated glomerular filtration rate (eGFR) in the contemporary LEADER cohort.<h4>Materials and methods</h4>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. Primar ...[more]

PMID: 32618386

Similar Datasets

Project description:BACKGROUND:Canagliflozin is approved for glucose lowering in type 2 diabetes and confers cardiovascular and renal benefits. We sought to assess whether it had benefits in people with chronic kidney disease, including those with an estimated glomerular filtration rate (eGFR) between 30 and 45 mL/min/1.73 m2 in whom the drug is not currently approved for use. METHODS:The CANVAS Program randomized 10 142 participants with type 2 diabetes and eGFR >30 mL/min/1.73 m2 to canagliflozin or placebo. The primary outcome was a composite of cardiovascular death, nonfatal myocardial infarction, or nonfatal stroke, with other cardiovascular, renal, and safety outcomes. This secondary analysis describes outcomes in participants with and without chronic kidney disease, defined as eGFR <60 and ?60 mL/min/1.73 m2, and according to baseline kidney function (eGFR <45, 45 to <60, 60 to <90, and ?90 mL/min/1.73 m2). RESULTS:At baseline, 2039 (20.1%) participants had an eGFR <60 mL/min/1.73 m2, 71.6% of whom had a history of cardiovascular disease. The effect of canagliflozin on the primary outcome was similar in people with chronic kidney disease (hazard ratio, 0.70; 95% CI, 0.55-0.90) and those with preserved kidney function (hazard ratio, 0.92; 95% CI, 0.79-1.07; P heterogeneity = 0.08). Relative effects on most cardiovascular and renal outcomes were similar across eGFR subgroups, with possible heterogeneity suggested only for the outcome of fatal/nonfatal stroke ( P heterogeneity = 0.01), as were results for almost all safety outcomes. CONCLUSIONS:The effects of canagliflozin on cardiovascular and renal outcomes were not modified by baseline level of kidney function in people with type 2 diabetes and a history or high risk of cardiovascular disease down to eGFR levels of 30 mL/min/1.73 m2. Reassessing current limitations on the use of canagliflozin in chronic kidney disease may allow additional individuals to benefit from this therapy. CLINICAL TRIAL REGISTRATION:URL: https://www.clinicaltrials.gov . Unique identifiers: NCT01032629, NCT01989754.

Project description:Sodium-glucose co-transporter 2 inhibitors (SGLT2is) reduce albuminuria and hard renal outcomes (decline of renal function, renal replacement therapy and renal death) in patients with/without type 2 diabetes at high cardiovascular or renal risk. The question arises whether baseline albuminuria also influences renal outcomes with SGLT2is as reported with renin-angiotensin-aldosterone system inhibitors. Post hoc analyses focusing on albuminuria and renal outcomes of four cardiovascular outcome trials [EMPA-REG OUTCOME (Empagliflozin Cardiovascular Outcome Event Trial in Type 2 Diabetes Mellitus Patients), CANVAS (Canagliflozin Cardiovascular Assessment Study), DECLARE-TIMI 58 (Multicenter Trial to Evaluate the Effect of Dapagliflozin on the Incidence of Cardiovascular Events-Thrombolysis in Myocardial Infarction 58) and VERTIS CV (Evaluation of Ertugliflozin Efficacy and Safety Cardiovascular Outcomes Trial)] and some renal data from two heart failure trials [Dapagliflozin and Prevention of Adverse Outcomes in Heart Failure (DAPA-HF) and EMPEROR-Reduced (Empagliflozin Outcome Trial in Patients With Chronic Heart Failure With Reduced Ejection Fraction)] showed renal protection with SGLT2is without significant interaction (P > 0.10) when comparing renal outcomes according to baseline levels (A1, A2 and A3) of urinary albumin:creatinine ratio (UACR), a finding confirmed in a dedicated meta-analysis. Two trials [CREDENCE (Evaluation of the Effects of Canagliflozin on Renal and Cardiovascular Outcomes in Participants With Diabetic Nephropathy) and DAPA-CKD (Dapagliflozin and Prevention of Adverse Outcomes in Chronic Kidney Disease)] specifically recruited patients with CKD and UACRs of 200-5000 mg/g. A post hoc analysis of CREDENCE that distinguished three subgroups according to UACR (300-1000, 1000-3000 and >3000 mg/g) showed a greater relative reduction in UACR in patients with lower baseline albuminuria levels (P for interaction = 0.03). Patients with a UACR >1000 mg/g showed a significantly greater reduction in absolute (P for interaction < 0.001) and a trend in relative (P for interaction = 0.25) risk of renal events versus those with lower UACR levels. In conclusion, baseline UACR levels do not significantly influence the nephroprotection by SGLT2is, yet the greater protection in patients with very high UACRs in CREDENCE deserves confirmation. The underlying mechanisms of renal protection with SGLT2is might be different in patients with or without (high) UACR.

Project description:BackgroundCanagliflozin reduced renal and cardiovascular events in people with type 2 diabetes in the CREDENCE trial. We assessed efficacy and safety of canagliflozin by initial estimated glomerular filtration rate (eGFR).MethodsCREDENCE randomly assigned 4401 participants with an eGFR of 30 to <90 ml/min per 1.73 m2 and substantial albuminuria to canagliflozin 100 mg or placebo. We used Cox proportional hazards regression to analyze effects on renal and cardiovascular efficacy and safety outcomes within screening eGFR subgroups (30 to <45, 45 to <60, and 60 to <90 ml/min per 1.73 m2) and linear mixed effects models to analyze the effects on eGFR slope.ResultsAt screening, 1313 (30%), 1279 (29%), and 1809 (41%) participants had an eGFR of 30 to <45, 45 to <60, and 60 to <90 ml/min per 1.73 m2, respectively. The relative benefits of canagliflozin for renal and cardiovascular outcomes appeared consistent among eGFR subgroups (all P interaction >0.11). Subgroups with lower eGFRs, who were at greater risk, exhibited larger absolute benefits for renal outcomes. Canagliflozin's lack of effect on serious adverse events, amputations, and fractures appeared consistent among eGFR subgroups. In all subgroups, canagliflozin use led to an acute eGFR drop followed by relative stabilization of eGFR loss. Among those with an eGFR of 30 to <45 ml/min per 1.73 m2, canagliflozin led to an initial drop of 2.03 ml/min per 1.73 m2. Thereafter, decline in eGFR was slower in the canagliflozin versus placebo group (-1.72 versus -4.33 ml/min per 1.73 m2; between-group difference 2.61 ml/min per 1.73 m2).ConclusionsCanagliflozin safely reduced the risk of renal and cardiovascular events, with consistent results across eGFR subgroups, including the subgroup initiating treatment with an eGFR of 30 to <45 ml/min per 1.73 m2. Absolute benefits for renal outcomes were greatest in subgroups with lower eGFR.Clinical trial registry name and registration numberEvaluation of the Effects of Canagliflozin on Renal and Cardiovascular Outcomes in Participants With Diabetic Nephropathy (CREDENCE), NCT02065791.

Project description:BackgroundSodium-glucose cotransporter 2 inhibitors improve outcomes in patients with heart failure with reduced ejection fraction, but additional information is needed about whether glycemic status influences the magnitude of their benefits on heart failure and renal events.MethodsPatients with Class II-IV heart failure and a left ventricular ejection fraction ≤40% were randomized to receive empagliflozin (10 mg daily) or placebo in addition to recommended therapy. We prespecified a comparison of the effect of empagliflozin in patients with and without diabetes.ResultsOf the 3730 patients enrolled, 1856 (50%) had diabetes, 1268 (34%) had prediabetes (hemoglobin A1c [HbA1c] 5.7-6.4%), and 606 (16%) had normoglycemia (HbA1c <5.7%). The risks of the primary outcome (cardiovascular death or hospitalization for heart failure), total hospitalizations for heart failure, and adverse renal outcomes were higher in patients with diabetes, but were similar between patients with prediabetes and normoglycemia. Empagliflozin reduced the risk of the primary outcome in patients with and without diabetes (hazard ratio, 0.72 [95% CI, 0.60-0.87] and 0.78 [95% CI, 0.64-0.97], respectively, P-interaction=0.57). Patients with and without diabetes also did not differ with respect to the effect of empagliflozin on total hospitalizations for heart failure, on the decline in estimated glomerular filtration rate over time, and on the risk of serious adverse renal outcomes. Among these end points, the effects of the drug did not differ in patients with prediabetes or normoglycemia. When analyzed as a continuous variable, baseline HbA1c did not significantly modify the benefits of empagliflozin on the primary outcome (P-interaction=0.40). Empagliflozin did not lower HbA1c in patients with prediabetes or normoglycemia and was not associated with increased risk of hypoglycemia.ConclusionsIn EMPEROR-Reduced (Empagliflozin Outcome Trial in Patients With Chronic Heart Failure With Reduced Ejection Fraction), empagliflozin significantly improved cardiovascular and renal outcomes in patients with heart failure and a reduced ejection fraction, independent of baseline diabetes status and across the continuum of HbA1c. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT03057977.

Project description:Background and objectivesThe kidney protective effects of renin-angiotensin system inhibitors are greater in people with higher levels of albuminuria at treatment initiation. Whether this applies to sodium-glucose cotransporter 2 (SGLT2) inhibitors is uncertain, particularly in patients with a very high urine albumin-to-creatinine ratio (UACR; ≥3000 mg/g). We examined the association between baseline UACR and the effects of the SGLT2 inhibitor, canagliflozin, on efficacy and safety outcomes in the Canagliflozin and Renal Endpoints in Diabetes with Established Nephropathy Clinical Evaluation (CREDENCE) randomized controlled trial.Design, setting, participants, & measurementsThe study enrolled 4401 participants with type 2 diabetes, an eGFR of 30 to <90 ml/min per 1.73 m2, and UACR of >300 to 5000 mg/g. Using Cox proportional hazards regression, we examined the relative and absolute effects of canagliflozin on kidney, cardiovascular, and safety outcomes according to a baseline UACR of ≤1000 mg/g (n=2348), >1000 to <3000 mg/g (n=1547), and ≥3000 mg/g (n=506). In addition, we examined the effects of canagliflozin on UACR itself, eGFR slope, and the intermediate outcomes of glycated hemoglobin, body weight, and systolic BP.ResultsOverall, higher UACR was associated with higher rates of kidney and cardiovascular events. Canagliflozin reduced efficacy outcomes for all UACR levels, with no evidence that relative benefits varied between levels. For example, canagliflozin reduced the primary composite outcome by 24% (hazard ratio [HR], 0.76; 95% confidence interval [95% CI], 0.56 to 1.04) in the lowest UACR subgroup, 28% (HR, 0.72; 95% CI, 0.56 to 0.93) in the UACR subgroup >1000 to <3000 mg/g, and 37% (HR, 0.63; 95% CI, 0.47 to 0.84) in the highest subgroup (Pheterogeneity=0.55). Absolute risk reductions for kidney outcomes were greater in participants with higher baseline albuminuria; the number of primary composite events prevented across ascending UACR categories were 17 (95% CI, 3 to 38), 45 (95% CI, 9 to 81), and 119 (95% CI, 35 to 202) per 1000 treated participants over 2.6 years (Pheterogeneity=0.02). Rates of kidney-related adverse events were lower with canagliflozin, with a greater relative reduction in higher UACR categories.ConclusionsCanagliflozin safely reduces kidney and cardiovascular events in people with type 2 diabetes and severely increased albuminuria. In this population, the relative kidney benefits were consistent over a range of albuminuria levels, with greatest absolute kidney benefit in those with an UACR ≥3000 mg/g.Clinical trial registry name and registration numberClinicalTrials.gov: CREDENCE, NCT02065791.PodcastThis article contains a podcast at https://www.asn-online.org/media/podcast/CJASN/2021_02_22_CJN15260920_final.mp3.

Dataset Information

Cardiovascular and renal outcomes by baseline albuminuria status and renal function: Results from the LEADER randomized trial.

Publications

Cardiovascular and renal outcomes by baseline albuminuria status and renal function: Results from the LEADER randomized trial.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets