Dataset Information

Dedicated kidney disease-focused outcome trials with sodium-glucose cotransporter-2 inhibitors: Lessons from CREDENCE and expectations from DAPA-HF, DAPA-CKD, and EMPA-KIDNEY.

ABSTRACT: In the past decade, many cardiovascular outcome trials (CVOT) on the efficacy and safety of glucose-lowering agents have been completed. Amongst newer agents available for treatment of type 2 diabetes mellitus (T2DM), sodium-glucose cotransporter-2 (SGLT2) inhibitors have garnered much attention in contemporary clinical practice due to observed benefits on cardiovascular and kidney outcomes among patients with T2DM, as reported in large randomized controlled trials (RCT). These findings are reflected in the updated clinical guidelines of several major professional societies. Herein, we briefly review the mechanism of action of SGLT2 inhibitors and their pleiotropic effects, summarize key findings and limitations of initial CVOTs, then discuss three major kidney disease-focused outcome trials, including the Canagliflozin and Renal Events in Diabetes and Established Nephropathy Clinical Evaluation (CREDENCE) trial as well as two ongoing RCTs: Dapagliflozin and Prevention of Adverse Outcomes in Heart Failure-chronic kidney disease and EMPA-KIDNEY.

SUBMITTER: Rhee JJ

PROVIDER: S-EPMC8018526 | biostudies-literature | 2020 Apr

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Dedicated kidney disease-focused outcome trials with sodium-glucose cotransporter-2 inhibitors: Lessons from CREDENCE and expectations from DAPA-HF, DAPA-CKD, and EMPA-KIDNEY.

Rhee Jinnie J JJ Jardine Meg J MJ Chertow Glenn M GM Mahaffey Kenneth W KW

Diabetes, obesity & metabolism 20200401

In the past decade, many cardiovascular outcome trials (CVOT) on the efficacy and safety of glucose-lowering agents have been completed. Amongst newer agents available for treatment of type 2 diabetes mellitus (T2DM), sodium-glucose cotransporter-2 (SGLT2) inhibitors have garnered much attention in contemporary clinical practice due to observed benefits on cardiovascular and kidney outcomes among patients with T2DM, as reported in large randomized controlled trials (RCT). These findings are refl ...[more]

PMID: 32267076

Similar Datasets

Project description:BackgroundThe Dapagliflozin and Prevention of Adverse Outcomes in CKD (DAPA-CKD) trial enrolled patients with estimated glomerular filtration rate 25-75 mL/min/1.73 m2 and urine albumin-to-creatinine ratio >200 mg/g. The Dapagliflozin Effect on CardiovascuLAR Events-Thrombolysis in Myocardial Infarction 58 (DECLARE-TIMI 58) trial enrolled patients with type 2 diabetes, a higher range of kidney function and no albuminuria criterion. The study objective was to estimate the cost-effectiveness of dapagliflozin in a broad chronic kidney disease population based on these two trials in the UK, Spain, Italy and Japan.MethodsWe adapted a published Markov model based on the DAPA-CKD trial but to a broader population, irrespective of urine albumin-to-creatinine ratio, using patient-level data from the DAPA-CKD and DECLARE-TIMI 58 trials. We sourced cost and utility inputs from literature and the DAPA-CKD trial. The analysis considered healthcare system perspectives over a lifetime horizon.ResultsTreatment with dapagliflozin was predicted to attenuate disease progression and extend projected life expectancy by 0.64 years (12.5 versus 11.9 years, undiscounted) in the UK, with similar estimates in other settings. Clinical benefits translated to mean quality-adjusted life year (QALY; discounted) gains between 0.45 and 0.68 years across countries. Incremental cost-effectiveness ratios in the UK, Spain, Italy and Japan ($10 676/QALY, $14 479/QALY, $7771/QALY and $13 723/QALY, respectively) were cost-effective at country-specific willingness-to-pay thresholds. Subgroup analyses suggest dapagliflozin is cost-effective irrespective of urinary albumin-to-creatine ratio and type 2 diabetes status.ConclusionTreatment with dapagliflozin may be cost-effective for patients across a wider spectrum of estimated glomerular filtration rates and albuminuria than previously demonstrated, with or without type 2 diabetes, in the UK, Spanish, Italian and Japanese healthcare systems.

Project description:Background The DAPA-CKD (Dapagliflozin and Prevention of Adverse Outcomes in Chronic Kidney Disease) trial (NCT03036150) demonstrated that dapagliflozin reduced the risk of kidney and cardiovascular events in patients with chronic kidney disease and albuminuria with and without type 2 diabetes. We aimed to determine whether baseline cardiovascular medication use modified the dapagliflozin treatment effect. Methods and Results We randomized 4304 adults with baseline estimated glomerular filtration rate 25 to 75 mL/min per 1.73 m2 and urinary albumin:creatinine ratio 200 to 5000 mg/g to dapagliflozin 10 mg or placebo once daily. The primary end point was a composite of ≥50% estimated glomerular filtration rate decline, end-stage kidney disease, and kidney or cardiovascular death. Secondary end points included a kidney composite end point (primary composite end point without cardiovascular death), a cardiovascular composite end point (hospitalized heart failure or cardiovascular death), and all-cause mortality. We categorized patients according to baseline cardiovascular medication use/nonuse. Patients were required by protocol to receive a stable (and maximally tolerated) dose of a renin-angiotensin-aldosterone system inhibitor. We observed consistent benefits of dapagliflozin relative to placebo, irrespective of baseline use/nonuse of renin-angiotensin-aldosterone system inhibitors (98.1%), calcium channel blockers (50.7%), β-adrenergic antagonists (39.0%), diuretics (43.7%), and antithrombotic (47.4%), and lipid-lowering (15.0%) agents. Use of these drugs in combination with dapagliflozin did not increase the number of serious adverse events. Conclusions The safety profile and efficacy of dapagliflozin on kidney and cardiovascular end points in patients with chronic kidney disease were consistent among patients treated and not treated at baseline with a range of cardiovascular medications. Registration Information clinicaltrials.gov. Identifier: NCT03036150.

Project description:BackgroundThe Dapagliflozin and Prevention of Adverse outcomes in Chronic Kidney Disease (DAPA-CKD; NCT03036150) trial was designed to assess the effect of the sodium-glucose co-transporter 2 (SGLT2) inhibitor dapagliflozin on kidney and cardiovascular events in participants with CKD with and without type 2 diabetes (T2D). This analysis reports the baseline characteristics of those recruited, comparing them with those enrolled in other trials.MethodsIn DAPA-CKD, 4304 participants with a urinary albumin:creatinine ratio (UACR) ≥200 mg/g and estimated glomerular filtration rate (eGFR) between 25 and 75 mL/min/1.73 m2 were randomized to dapagliflozin 10 mg once daily or placebo. Mean eGFR was 43.1 mL/min/1.73 m2 and median UACR was 949 mg/g (108 mg/mmol).ResultsOverall, 2906 participants (68%) had a diagnosis of T2D and of these, 396 had CKD ascribed to a cause other than diabetes. The most common causes of CKD after diabetes (n = 2510) were ischaemic/hypertensive nephropathy (n = 687) and chronic glomerulonephritis (n = 695), of which immunoglobulin A nephropathy (n = 270) was the most common. A total of 4174 participants (97%) were receiving an angiotensin-converting enzyme inhibitor or angiotensin receptor blocker, 1882 (43.7%) diuretics, 229 (5.3%) mineralocorticoid receptor antagonists and 122 (2.8%) glucagon-like peptide 1 receptor agonists. In contrast to the Canagliflozin and Renal Events in Diabetes with Established Nephropathy Clinical Evaluation (CREDENCE), the DAPA-CKD trial enrolled participants with CKD due to diabetes and to causes other than diabetes. The mean eGFR of participants in the DAPA-CKD trial was 13.1 mL/min/1.73 m2 lower than in CREDENCE, similar to that in the Finerenone in Reducing Kidney Failure and Disease Progression in DKD (FIDELIO-DKD) trial and the Study Of diabetic Nephropathy with AtRasentan (SONAR).ConclusionsParticipants with a wide range of underlying kidney diseases receiving renin-angiotensin system blocking therapy have been enrolled in the DAPA-CKD trial. The trial will examine the efficacy and safety of dapagliflozin in participants with CKD Stages 2-4 and increased albuminuria, with and without T2D.

Project description:Background and objectivesCKD imposes a significant burden on patients and health care providers, particularly upon reaching kidney failure when patients may require KRT. The Dapagliflozin and Prevention of Adverse Outcomes in CKD (DAPA-CKD) trial demonstrated that dapagliflozin, with standard therapy, reduced CKD progression and KRT requirement. The study objective was to estimate the cost-effectiveness of dapagliflozin for the treatment of CKD from payer perspectives in the United Kingdom, Germany, and Spain.Design, setting, participants, & measurementsWe constructed a lifetime Markov model to characterize outcomes in patients with CKD on the basis of the DAPA-CKD trial. Health states were defined by eGFR level and KRT type. Direct health care costs and utility values were sourced from published literature and the DAPA-CKD trial, respectively. Costs and benefits were discounted at 3.5% per annum in the United Kingdom and 3% in Germany and Spain.ResultsIn patients eligible for the DAPA-CKD trial, treatment with dapagliflozin was predicted to reduce rates of CKD progression, with patients predicted to spend 1.7 (95% credibility interval, 0.8 to 2.4) more years in the eGFR range 15-89 ml/min per 1.73 m2 versus standard therapy alone (12.1; 95% credibility interval, 8.9 to 14.1 versus 10.4; 95% credibility interval, 7.7 to 12.4 years). Life expectancy (undiscounted) was correspondingly predicted to increase by 1.7 (95% credibility interval, 0.7 to 2.5) years (15.5; 95% credibility interval, 11.1 to 18.2 versus 13.8; 95% credibility interval, 9.9 to 16.5 years). This in addition to reduced incidence of adverse clinical outcomes, including hospitalization for heart failure, resulted in modeled quality-adjusted life year (discounted) gains between 0.82 (95% credibility interval, 0.38 to 1.18) and 1.00 (95% credibility interval, 0.46 to 1.41). These gains translated to incremental cost-effectiveness ratios of $8280, $17,623, and $11,687 in the United Kingdom, Germany, and Spain, respectively, indicating cost-effectiveness at willingness-to-pay thresholds (United Kingdom: $27,510 per quality-adjusted life year; Germany and Spain: $35,503 per quality-adjusted life year).ConclusionsIn patients meeting the eligibility requirements for the DAPA-CKD trial, dapagliflozin is likely to be a cost-effective treatment within the UK, German, and Spanish health care systems.Clinical trial registry name and registration numberDapagliflozin and Prevention of Adverse Outcomes in CKD (DAPA-CKD), NCT03036150.

Project description:AimsThe VICTORIA trial demonstrated a significant reduction in the primary composite outcome of heart failure (HF) hospitalization or cardiovascular death with vericiguat relative to placebo in high-risk HF. This study aimed to contextualize treatment effects of vericiguat in populations with varying risk profiles simulated from the PARADIGM-HF and DAPA-HF trials.MethodsSubgroups of VICTORIA participants (n = 5050) were generated to simulate PARADIGM-HF and DAPA-HF trial populations. The PARADIGM-HF-eligible population excluded participants not meeting left ventricular ejection fraction (LVEF), estimated glomerular filtration rate (eGFR), and minimal dose criteria and those with high predicted probability of run-in failure. The DAPA-HF-eligible population excluded those not meeting LVEF and eGFR criteria or with recent (<30 days) HF hospitalization. The time-to-first-event analysis was performed using an unadjusted Cox proportional hazards model.ResultsA total of 1982 (39.2%) and 2543 (50.4%) VICTORIA participants were respectively deemed eligible for PARADIGM-HF and DAPA-HF. Vericiguat was associated with numerically larger reductions in the primary outcome of HF hospitalization or cardiovascular death in populations simulated from PARADIGM-HF [hazard ratio (HR) 0.85, 95% confidence interval (CI) 0.72-0.99] and DAPA-HF (HR 0.82, 95% CI 0.71-0.94) compared with the overall VICTORIA trial (HR 0.90). Significant reduction in HF hospitalization with vericiguat was also observed in the DAPA-HF-eligible population (HR 0.83, 95%CI 0.73-0.95) and with a nominal reduction in the PARADIGM-HF-eligible population (HR 0.86, 95% CI 0.74-1.01).ConclusionsA trend towards enhanced efficacy of vericiguat in populations simulated from PARADIGM-HF and DAPA-HF was observed. These findings support further exploration of vericiguat in lower-risk HF populations as is being investigated in the ongoing VICTOR (a study of vericiguat in participants with chronic heart failure with reduced ejection fraction) trial.

Dataset Information

Dedicated kidney disease-focused outcome trials with sodium-glucose cotransporter-2 inhibitors: Lessons from CREDENCE and expectations from DAPA-HF, DAPA-CKD, and EMPA-KIDNEY.

Publications

Dedicated kidney disease-focused outcome trials with sodium-glucose cotransporter-2 inhibitors: Lessons from CREDENCE and expectations from DAPA-HF, DAPA-CKD, and EMPA-KIDNEY.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets