Dataset Information

Dapagliflozin and Prevention of Kidney Disease Among Patients With Type 2 Diabetes: Post Hoc Analyses From the DECLARE-TIMI 58 Trial.

ABSTRACT:

Objective

In patients with moderate to severe albuminuric kidney disease, sodium-glucose cotransporter 2 inhibitors reduce the risk of kidney disease progression. These post hoc analyses assess the effects of dapagliflozin on kidney function decline in patients with type 2 diabetes (T2D), focusing on populations with low kidney risk.

Research design and methods

In the Dapagliflozin Effect on Cardiovascular Events-Thrombolysis in Myocardial Infarction 58 (DECLARE-TIMI 58) trial, patients with T2D at high cardiovascular risk were randomly assigned to dapagliflozin versus placebo. Outcomes were analyzed by treatment arms, overall, and by Kidney Disease: Improving Global Outcomes (KDIGO) risk categories. The prespecified kidney-specific composite outcome was a sustained decline ≥40% in the estimated glomerular filtration rate (eGFR) to <60 mL/min/1.73 m2, end-stage kidney disease, and kidney-related death. Other outcomes included incidence of categorical eGFR decline of different thresholds and chronic (6 month to 4 year) or total (baseline to 4 year) eGFR slopes.

Results

Most participants were in the low-moderate KDIGO risk categories (n = 15,201 [90.3%]). The hazard for the kidney-specific composite outcome was lower with dapagliflozin across all KDIGO risk categories (P-interaction = 0.97), including those at low risk (hazard ratio [HR] 0.54, 95% CI 0.38-0.77). Risks for categorical eGFR reductions (≥57% [in those with baseline eGFR ≥60 mL/min/1.73 m2], ≥50%, ≥40%, and ≥30%) were lower with dapagliflozin (HRs 0.52, 0.57, 0.55, and 0.70, respectively; P < 0.05). Slopes of eGFR decline favored dapagliflozin across KDIGO risk categories, including the low KDIGO risk (between-arm differences of 0.87 [chronic] and 0.55 [total] mL/min/1.73 m2/year; P < 0.0001).

Conclusions

Dapagliflozin mitigated kidney function decline in patients with T2D at high cardiovascular risk, including those with low KDIGO risk, suggesting a role of dapagliflozin in the early prevention of diabetic kidney disease.

SUBMITTER: Mosenzon O

PROVIDER: S-EPMC9862307 | biostudies-literature | 2022 Oct

REPOSITORIES: biostudies-literature

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Publications

Dapagliflozin and Prevention of Kidney Disease Among Patients With Type 2 Diabetes: Post Hoc Analyses From the DECLARE-TIMI 58 Trial.

Mosenzon Ofri O Raz Itamar I Wiviott Stephen D SD Schechter Meir M Goodrich Erica L EL Yanuv Ilan I Rozenberg Aliza A Murphy Sabina A SA Zelniker Thomas A TA Langkilde Anna Maria AM Gause-Nilsson Ingrid A M IAM Fredriksson Martin M Johansson Peter A PA Wilding John P H JPH McGuire Darren K DK Bhatt Deepak L DL Leiter Lawrence A LA Cahn Avivit A Dwyer Jamie P JP Heerspink Hiddo J L HJL Sabatine Marc S MS

Diabetes care 20221001 10

<h4>Objective</h4>In patients with moderate to severe albuminuric kidney disease, sodium-glucose cotransporter 2 inhibitors reduce the risk of kidney disease progression. These post hoc analyses assess the effects of dapagliflozin on kidney function decline in patients with type 2 diabetes (T2D), focusing on populations with low kidney risk.<h4>Research design and methods</h4>In the Dapagliflozin Effect on Cardiovascular Events-Thrombolysis in Myocardial Infarction 58 (DECLARE-TIMI 58) trial, pa ...[more]

PMID: 35997319

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Project description:ObjectiveSodium-glucose cotransporter 2 inhibitors (SGLT2i) improve albuminuria in patients with high cardiorenal risk. We report albuminuria change in the Dapagliflozin Effect on Cardiovascular Events (DECLARE-TIMI 58) cardiovascular outcome trial, which included populations with lower cardiorenal risk.Research design and methodsDECLARE-TIMI 58 randomized 17,160 patients with type 2 diabetes, creatinine clearance >60 mL/min, and either atherosclerotic cardiovascular disease (CVD; 40.6%) or risk-factors for CVD (59.4%) to dapagliflozin or placebo. Urinary albumin-to-creatinine ratio (UACR) was tested at baseline, 6 months, 12 months, and yearly thereafter. The change in UACR over time was measured as a continuous and categorical variable (≤15, >15 to <30, ≥30 to ≤300, and >300 mg/g) by treatment arm. The composite cardiorenal outcome was a ≥40% sustained decline in the estimated glomerular filtration rate (eGFR) to <60 mL/min/1.73 m2, end-stage kidney disease, and cardiovascular or renal death; specific renal outcome included all except cardiovascular death.ResultsBaseline UACR was available for 16,843 (98.15%) participants: 9,067 (53.83%) with ≤15 mg/g, 2,577 (15.30%) with >15 to <30 mg/g, 4,030 (23.93%) with 30-300 mg/g, and 1,169 (6.94%) with >300 mg/g. Measured as a continuous variable, UACR improved from baseline to 4.0 years with dapagliflozin, compared with placebo, across all UACR and eGFR categories (all P < 0.0001). Sustained confirmed ≥1 category improvement in UACR was more common in dapagliflozin versus placebo (hazard ratio 1.45 [95% CI 1.35-1.56], P < 0.0001). Cardiorenal outcome was reduced with dapagliflozin for subgroups of UACR ≥30 mg/g (P < 0.0125, P interaction = 0.033), and the renal-specific outcome was reduced for all UACR subgroups (P < 0.05, P interaction = 0.480).ConclusionsIn DECLARE-TIMI 58, dapagliflozin demonstrated a favorable effect on UACR and renal-specific outcome across baseline UACR categories, including patients with normal albumin excretion. The results suggest a role for SGLT2i also in the primary prevention of diabetic kidney disease.

Project description:BackgroundThe objective of this study was to carry out a cost-effectiveness analysis of dapagliflozin, as an add-on therapy to standard of care (SoC), for the treatment of type 2 diabetes mellitus (T2DM) in Spain, based on the results of the DECLARE-TIMI 58 trial.MethodsA discrete event simulation model (Cardiff T2DM) based on the data observed in the DECLARE-TIMI 58 trial was adapted to the Spanish setting to estimate the costs and health outcomes of treatment with dapagliflozin in patients with T2DM who had or were at risk of atherosclerotic cardiovascular disease. Macrovascular events (hospitalization for heart failure, myocardial infarction, stroke, and unstable angina), end-stage renal disease and cardiovascular and non-cardiovascular mortality were modeled according to the survival equations of the DECLARE-TIMI 58 study. Microvascular events (blindness and ulcers) were estimated based on the risk equations of the UK Prospective Diabetes Study. The analysis was conducted from the Spanish National Health System perspective and the time horizon was 30 years. The results were evaluated in terms of cost per quality-adjusted life year (QALY) gained. Only direct health costs were included, and a 3% discount rate was applied to costs and health outcomes. Univariate and probabilistic sensitivity analyses (PSA) were made to assess the robustness of the results.ResultsIn the main analysis, dapagliflozin was a dominant therapeutic option compared with placebo, with greater effectiveness (0.08 QALYs) and lower associated total costs per patient (€ -2,921). The univariate sensitivity analysis and the PSA confirmed the robustness of the results. The PSA showed the probability that dapagliflozin was a dominant alternative compared with placebo was 84.2% and that it was cost-effective of 92.1%, under a willingness-to-pay of € 20,000/QALY gained.ConclusionsThe analysis of data from the DECLARE-TIMI 58 trial shows that dapagliflozin would be a cost-effective option in Spain for the treatment of adult patients with T2DM, as an add-on therapy to SoC, compared with placebo.

Project description:AimsTo investigate cardiovascular (CV) safety and event rates for dapagliflozin versus other glucose-lowering drugs (GLDs) in a real-world type 2 diabetes population after applying the main inclusion criteria and outcomes from the DECLARE-TIMI 58 study.MethodsPatients with new initiation of dapagliflozin and/or other GLDs were identified in Swedish nationwide healthcare registries for the period 2013 to 2016. Patients were included if they met the main DECLARE-TIMI 58 inclusion criteria: age ≥40 years and established CV disease or presence of multiple-risk factors, e.g. men aged ≥55 years and women aged ≥60 years with hypertension or dyslipidaemia. Propensity scores for the likelihood of dapagliflozin initiation were calculated, then 1:3 matching was carried out. DECLARE-TIMI 58 outcomes were hospitalization for heart failure (HHF) or CV-specific mortality, and major adverse CV events (MACE; CV-specific mortality, myocardial infarction, or stroke). Cox survival models were used to estimate hazard ratios (HRs).ResultsAfter matching, a total of 28 408 new-users of dapagliflozin and/or other GLDs were identified, forming the population for the present study (henceforth referred to as the DECLARE-like cohort. The mean age of this cohort was 66 years, and 34% had established CV disease. Dapagliflozin was associated with 21% lower risk of HHF or CV mortality versus other GLDs (HR 0.79, 95% confidence interval [CI] 0.69-0.92) and had no significant association with MACE (HR 0.90, 95% CI 0.79-1.03). HHF and CV mortality risks, separately, were lower at HR 0.79 (95% CI 0.67-0.93) and HR 0.75 (95% CI 0.57-0.97), respectively. Non-significant associations were seen for myocardial infarction and stroke: HR 0.91 (95% CI 0.74-1.11) and HR 1.06 (95% CI 0.87-1.30), respectively.ConclusionIn a real-world population similar to those included in the DECLARE-TIMI 58 study, dapagliflozin was safe with regard to CV outcomes and resulted in lower event rates of HHF and CV mortality versus other GLDs.

Project description:ImportanceDapagliflozin reduces the risk of hospitalizations for heart failure and the progression of chronic kidney disease in patients with and without type 2 diabetes (T2D), whereas the effects on reducing atherosclerotic events appear less clear.ObjectiveTo explore whether N-terminal pro-B-type natriuretic peptide (NT-proBNP) and high-sensitivity cardiac troponin T (hsTnT) levels can identify a subset of patients with T2D at higher risk and who might benefit more from dapagliflozin with regard to atherosclerotic events.Design, setting, and participantsThis was a secondary analysis of the DECLARE-TIMI 58 trial, a randomized clinical trial of dapagliflozin in patients with T2D and either multiple risk factors for atherosclerotic cardiovascular disease (ASCVD; approximately 60%) or established ASCVD (approximately 40%). All patients with available blood samples at randomization were included in these analyses. Data were collected from May 2013 to September 2018, and data were analyzed from May 2019 to June 2022.InterventionsDapagliflozin vs placebo.Main outcomes and measuresMajor adverse cardiovascular events (MACE), the composite of myocardial infarction, ischemic stroke, or cardiovascular death, which was one of dual primary outcomes of the main trial.ResultsOf 14 565 included patients, 9143 (62.8%) were male, and the mean (SD) age was 63.9 (6.8) years. When tested individually in a multivariable model for MACE risk, NT-proBNP and hsTnT were each significantly associated with the risk of MACE (adjusted hazard ratio [aHR] per 1 SD in log-transformed biomarker: NT-proBNP, 1.62; 95% CI, 1.49-1.76; hsTnT: 1.59; 95% CI, 1.46-1.74). The magnitude of the association was similar in patients with ASCVD (NT-proBNP: aHR, 1.60; 95% CI, 1.45-1.77; hsTnT: aHR, 1.62; 95% CI, 1.45-1.81) and multiple risk factors for ASCVD (NT-proBNP: aHR, 1.62; 95% CI, 1.40-1.88; hsTnT: aHR, 1.51; 95% CI, 1.29-1.77). Moreover, both biomarkers remained independently associated with MACE when both were included in the multivariable model (NT-proBNP: aHR, 1.46; 95% CI, 1.34-1.60; hsTnT: aHR, 1.39; 95% CI, 1.26-1.53). Modeled as a continuous variable, baseline biomarker levels did not modify the relative treatment effect of dapagliflozin vs placebo with MACE. However, the relative risk reduction numerically grew with higher biomarker levels, as did the baseline risk. Thus, MACE event rates were nominally lower in dapagliflozin-treated vs placebo-treated patients with biomarker concentrations in the top quartile (NT-proBNP: HR, 0.83; 95% CI, 0.71-0.97; absolute risk reduction [ARR], 2.4%; hsTnT: HR, 0.85; 95% CI, 0.72-0.99; ARR, 2.7%), whereas there was no significant treatment effect in patients with biomarkers levels in quartiles 1 to 3 (NT-proBNP: HR, 1.02; 95% CI, 0.88-1.18; ARR, 0%; hsTnT: HR, 0.97; 95% CI, 0.84-1.13; ARR, 0.2%).Conclusions and relevanceIn this study, NT-proBNP and hsTnT levels were associated with the risk for future cardiovascular events in both primary and secondary prevention patients with T2D. Both cardiac biomarkers were helpful to identify patients at very high risk for atherosclerotic events that may derive reduction in risk of MACE with dapagliflozin.Trial registrationClinicalTrials.gov Identifier: NCT01730534.

Project description:IntroductionSince 2008 United State (US) food drug administration mandate, several newer anti-diabetic drugs (ADD) have undergone a mandatory cardiovascular (CV) outcome trial (CVOT) in type diabetes (T2DM) patients with high CV risk. These includes CVOT done with dipeptidyl-peptidase-4 inhibitors, sodium-glucose co-transporter-2 inhibitors and glucagon-like peptide-1 receptor agonist (GLP-1RAs). Several double-blind, randomized, placebo-controlled CVOT have been presented and published in the last decade (2008-2018).Aims and objectivesWe systematically searched the database of PubMed and ClinicalTrials.gov from January 1, 2008 to December 31, 2018 using specific key words. Subsequently, we pooled the data of different cardiovascular endpoints and made a comparative forest plot using GraphPad software Inc. Prism Version 8, US.Results and conclusionSaxagliptin, alogliptin, sitagliptin and linagliptin are CV neutral drugs. Saxagliptin showed a significantly higher hospitalization due to heart failure (HHF). Empagliflozin and canagliflozin have shown a significant reduction in composite of 3-point major cardiac adverse events (3P-MACE). Additionally, empagliflozin, canagliflozin and dapagliflozin significantly reduced the HHF and the composite of CV death or HHF. Moreover, empagliflozin showed significant reduction in CV- and all-cause death in patients with T2DM with established CV disease. While both exendin-backbone-based GLP-1RAs such as lixisenatide and extended-release exenatide were CV neutral; GLP-1-backbone-based GLP-1RAs such as liraglutide, semaglutide and albiglutide shown a significant reduction in the composite of 3-P MACE. Additionally, liraglutide shown a significant reduction in CV- and all-cause death. Moreover, semaglutide reduced non-fatal stroke and albiglutide reduced myocardial infarction, while extended-release exenatide reduced all-cause death; however, P value of significance for these outcomes should be considered nominal.

Project description:Aims/hypothesisIn the Dapagliflozin and Prevention of Adverse Outcomes in Chronic Kidney Disease (DAPA-CKD) trial, dapagliflozin reduced the risks of progressive kidney disease, hospitalised heart failure or cardiovascular death, and death from all causes in patients with chronic kidney disease (CKD) with or without type 2 diabetes. Patients with more severe CKD are at higher risk of kidney failure, cardiovascular events and all-cause mortality. In this post hoc analysis, we assessed the efficacy and safety of dapagliflozin according to baseline Kidney Disease Improving Global Outcomes (KDIGO) risk categories.MethodsDAPA-CKD was a double-blind, placebo-controlled trial that randomised patients with an eGFR of 25-75 ml min-1 [1.73 m]-2 and urinary albumin/creatinine ratio (UACR) of ≥22.6 and <565.0 mg/mmol (200-5000 mg/g) to dapagliflozin 10 mg/day or placebo. The primary endpoint was a composite of ≥50% reduction in eGFR, end-stage kidney disease (ESKD), and death from a kidney or cardiovascular cause. Secondary endpoints included a kidney composite (≥50% reduction in eGFR, ESKD and death from a kidney cause), a cardiovascular composite (heart failure hospitalisation or cardiovascular death), and death from all causes. We used Cox proportional hazards regression analyses to assess relative and absolute effects of dapagliflozin across KDIGO risk categories.ResultsOf the 4304 participants in the DAPA-CKD study, 619 (14.4%) were moderately high risk, 1349 (31.3%) were high risk and 2336 (54.3%) were very high risk when categorised by KDIGO risk categories at baseline. Dapagliflozin reduced the hazard of the primary composite (HR 0.61; 95% CI 0.51, 0.72) and secondary endpoints consistently across KDIGO risk categories (all p for interaction >0.09). Absolute risk reductions for the primary outcome were also consistent irrespective of KDIGO risk category (p for interaction 0.26). Analysing patients with and without type 2 diabetes separately, the relative risk reduction with dapagliflozin in terms of the primary outcome was consistent across subgroups of KDIGO risk categories. The relative frequencies of adverse events and serious adverse events were also similar across KDIGO risk categories.Conclusion/interpretationsThe consistent benefits of dapagliflozin on kidney and cardiovascular outcomes across KDIGO risk categories indicate that dapagliflozin is efficacious and safe across a wide spectrum of kidney disease severity.Trial registrationClinicalTrials.gov NCT03036150.FundingThe study was funded by AstraZeneca.

Dataset Information

Dapagliflozin and Prevention of Kidney Disease Among Patients With Type 2 Diabetes: Post Hoc Analyses From the DECLARE-TIMI 58 Trial.

Objective

Research design and methods

Results

Conclusions

Publications

Dapagliflozin and Prevention of Kidney Disease Among Patients With Type 2 Diabetes: Post Hoc Analyses From the DECLARE-TIMI 58 Trial.

Similar Datasets

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