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Decline in Estimated Glomerular Filtration Rate After Dapagliflozin in Heart Failure With Mildly Reduced or Preserved Ejection Fraction: A Prespecified Secondary Analysis of the DELIVER Randomized Clinical Trial.
Mc Causland, FR, Claggett, BL, Vaduganathan, M, Desai, A, Jhund, P, Vardeny, O, Fang, JC, de Boer, RA, Docherty, KF, Hernandez, AF, et al
JAMA cardiology. 2024;(2):144-152
Abstract
IMPORTANCE An initial decline in estimated glomerular filtration rate (eGFR) is expected after initiating a sodium-glucose cotransporter-2 inhibitor (SGLT2i) and has been observed across patients with diabetes, chronic kidney disease, and heart failure. OBJECTIVE To examine the implications of initial changes in eGFR among patients with heart failure with mildly reduced ejection fraction (HFmrEF) or preserved ejection fraction (HFpEF) enrolled in the Dapagliflozin Evaluation to Improve the Lives of Patients With Preserved Ejection Fraction Heart Failure (DELIVER) trial. DESIGN, SETTING, AND PARTICIPANTS This was a prespecified analysis of the results of the DELIVER randomized clinical trial, which was an international multicenter study of patients with EF greater than 40% and eGFR greater than or equal to 25. The DELIVER trial took place from August 2018 to March 2022. Data for the current prespecified study were analyzed from February to October 2023. INTERVENTION Dapagliflozin, 10 mg per day, or placebo. MAIN OUTCOMES AND MEASURES In this prespecified analysis, the frequency of an initial eGFR decline (baseline to month 1) was compared between dapagliflozin and placebo. Cox models adjusted for baseline eGFR and established prognostic factors were fit to estimate the association of an initial eGFR decline with cardiovascular (cardiovascular death or heart failure event) and kidney (≥50% eGFR decline, eGFR<15 or dialysis, death from kidney causes) outcomes, landmarked at month 1, stratified by diabetes. RESULTS Study data from 5788 participants (mean [SD] age, 72 [10] years; 3253 male [56%]) were analyzed. The median (IQR) change in eGFR level from baseline to month 1 was -1 (-6 to 5) with placebo and -4 (-9 to 1) with dapagliflozin (difference, -3; P < .001). A higher proportion of patients assigned to dapagliflozin developed an initial eGFR decline greater than 10% vs placebo (1144 of 2892 [40%] vs 737 of 2896 [25%]; odds ratio, 1.9; 95% CI, 1.7-2.1; P difference <.001). An initial eGFR decline of greater than 10% (vs ≤10%) was associated with a higher risk of the primary cardiovascular outcome among those randomized to placebo (adjusted hazard ratio [aHR], 1.33; 95% CI, 1.10-1.62) but not among those randomized to dapagliflozin (aHR, 0.90; 95% CI, 0.74-1.09; P for interaction = .01). Similar associations were observed when alternative thresholds of initial eGFR decline were considered and when analyzed as a continuous measure. An initial eGFR decline of greater than 10% was not associated with adverse subsequent kidney composite outcomes in dapagliflozin-treated patients (aHR, 0.94; 95% CI, 0.49-1.82). CONCLUSIONS AND RELEVANCE Among patients with HFmrEF or HFpEF treated with dapagliflozin, an initial eGFR decline was frequent but not associated with subsequent risk of cardiovascular or kidney events. These data reinforce clinical guidance that SGLT2is should not be interrupted or discontinued in response to an initial eGFR decline. TRIAL REGISTRATION ClinicalTrials.gov Identifier: NCT03619213.
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Impact of vasodilators on diuretic response in patients with congestive heart failure: A mechanistic trial of cimlanod (BMS-986231).
Pellicori, P, Cleland, JGF, Borentain, M, Taubel, J, Graham, FJ, Khan, J, Bruzzese, D, Kessler, P, McMurray, JJV, Voors, AA, et al
European journal of heart failure. 2024;(1):142-151
Abstract
AIM: To investigate the effects of Cimlanod, a nitroxyl donor with vasodilator properties, on water and salt excretion after an administration of an intravenos bolus of furosemide. METHODS AND RESULTS In this randomized, double-blind, mechanistic, crossover trial, 21 patients with left ventricular ejection fraction <45%, increased plasma concentrations of N-terminal pro-B-type natriuretic peptide (NT-proBNP) and receiving loop diuretics were given, on separate study days, either an 8 h intravenous (IV) infusion of cimlanod (12 μg/kg/min) or placebo. Furosemide was given as a 40 mg IV bolus four hours after the start of infusion. The primary endpoint was urine volume in the 4 h after the bolus of furosemide during infusion of cimlanod compared with placebo. Median NT-proBNP at baseline was 1487 (interquartile range: 847-2665) ng/L. Infusion of cimlanod increased cardiac output and reduced blood pressure without affecting cardiac power index consistent with its vasodilator effects. Urine volume in the 4 h post-furosemide was lower with cimlanod (1032 ± 393 ml) versus placebo (1481 ± 560 ml) (p = 0.002), as were total sodium excretion (p = 0.004), fractional sodium excretion (p = 0.016), systolic blood pressure (p < 0.001), estimated glomerular filtration rate (p = 0.012), and haemoglobin (p = 0.010), an index of plasma volume expansion. CONCLUSIONS For patients with heart failure and congestion, vasodilatation with agents such as cimlanod reduces the response to diuretic agents, which may offset any benefit from acute reductions in cardiac preload and afterload.
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Effect of Dapagliflozin Versus Placebo on Symptoms and 6-Minute Walk Distance in Patients With Heart Failure: The DETERMINE Randomized Clinical Trials.
McMurray, JJV, Docherty, KF, de Boer, RA, Hammarstedt, A, Kitzman, DW, Kosiborod, MN, Maria Langkilde, A, Reicher, B, Senni, M, Shah, SJ, et al
Circulation. 2024;(11):825-838
Abstract
BACKGROUND Sodium-glucose cotransporter 2 inhibitors reduce the risk of worsening heart failure (HF) and cardiovascular death in patients with HF irrespective of left ventricular ejection fraction. It is important to determine whether therapies for HF improve symptoms and functional capacity. METHODS The DETERMINE (Dapagliflozin Effect on Exercise Capacity Using a 6-Minute Walk Test in Patients With Heart Failure) double-blind, placebo-controlled, multicenter trials assessed the efficacy of the sodium-glucose cotransporter 2 inhibitor dapagliflozin on the Total Symptom Score (TSS) and Physical Limitation Scale (PLS) of the Kansas City Cardiomyopathy Questionnaire (KCCQ) and 6-minute walk distance (6MWD) in 313 patients with HF with reduced ejection fraction (DETERMINE-Reduced) and in 504 patients with HF with preserved ejection fraction (DETERMINE-Preserved) with New York Heart Association class II or III symptoms and elevated natriuretic peptide levels. The primary outcomes were changes in the KCCQ-TSS, KCCQ-PLS, and 6MWD after 16 weeks of treatment. RESULTS Among the 313 randomized patients with HF with reduced ejection fraction, the median placebo-corrected difference in KCCQ-TSS from baseline at 16 weeks was 4.2 (95% CI, 1.0, 8.2; P=0.022) in favor of dapagliflozin. The median placebo-corrected difference in KCCQ-PLS was 4.2 (95% CI, 0.0, 8.3; P=0.058). The median placebo-corrected difference in 6MWD from baseline at 16 weeks was 3.2 meters (95% CI, -6.5, 13.0; P=0.69). In the 504 patients with HF with preserved ejection fraction, the median placebo-corrected 16-week difference in KCCQ-TSS and KCCQ-PLS was 3.2 (95% CI, 0.4, 6.0; P=0.079) and 3.1 (-0.1, 5.4; P=0.23), respectively. The median 16-week difference in 6MWD was 1.6 meters (95% CI, -5.9, 9.0; P=0.67). In an exploratory post hoc analysis of both trials combined (DETERMINE-Pooled), the median placebo-corrected difference from baseline at 16 weeks was 3.7 (1.5, 5.9; P=0.005) for KCCQ-TSS, 4.0 (0.3, 4.9; P=0.036) for KCCQ-PLS, and 2.5 meters (-3.5, 8.4; P=0.50) for 6MWD. CONCLUSIONS Dapagliflozin improved the KCCQ-TSS in patients with HF with reduced ejection fraction but did not improve KCCQ-PLS or 6MWD. Dapagliflozin did not improve these outcomes in patients with HF with preserved ejection fraction. In a post hoc analysis including all patients across the full spectrum of ejection fraction, there was a beneficial effect of dapagliflozin on KCCQ-TSS and KCCQ-PLS but not 6MWD. REGISTRATION URL: https://www.clinicaltrials.gov; Unique identifiers: NCT03877237 and NCT03877224.
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Ambient heat exposure and kidney function in patients with chronic kidney disease: a post-hoc analysis of the DAPA-CKD trial.
Zhang, Z, Heerspink, HJL, Chertow, GM, Correa-Rotter, R, Gasparrini, A, Jongs, N, Langkilde, AM, McMurray, JJV, Mistry, MN, Rossing, P, et al
The Lancet. Planetary health. 2024;(4):e225-e233
Abstract
BACKGROUND Higher temperatures are associated with higher rates of hospital admissions for nephrolithiasis and acute kidney injury. Occupational heat stress is also a risk factor for kidney dysfunction in resource-poor settings. It is unclear whether ambient heat exposure is associated with loss of kidney function in patients with established chronic kidney disease. We assessed the association between heat index and change in estimated glomerular filtration rate (eGFR) in participants from the DAPA-CKD trial in a post-hoc analysis. METHODS DAPA-CKD was a randomised controlled trial of oral dapagliflozin 10 mg once daily or placebo that enrolled participants aged 18 years or older, with or without type 2 diabetes, with a urinary albumin-to-creatinine ratio of 200-5000 mg/g, and an eGFR of 25-75 mL/min per 1·73 m2. In this post-hoc analysis, we explored the association between time-varying daily centre-level heat index (ERA5 dataset) and individual-level change in eGFR in trial participants using linear mixed effect models and case-time series. The DAPA-CKD trial is registered with ClinicalTrials.gov, NCT03036150. FINDINGS Climate and eGFR data were available for 4017 (93·3%) of 4304 participants in 21 countries (mean age: 61·9 years; mean eGFR: 43·3 mL per 1·73 m2; median 28 months follow-up). Across centres, a heat index of more than 30°C occurred on a median of 0·6% of days. In adjusted linear mixed effect models, within each 120-day window, each 30 days' heat index of more than 30°C was associated with a -0·6% (95% CI -0·9% to -0·3%) change in eGFR. Similar estimates were obtained using case-time series. Additional analyses over longer time-windows showed associations consistent with haemodynamic or seasonal variability, or both, but overall estimates corresponded to an additional 3·7 mL per 1·73 m2 (95% CI 0·1 to 7·0) loss of eGFR per year in a patient with an eGFR of 45 mL per 1·73 m2 located in a very hot versus a temperate environment. INTERPRETATION Higher ambient heat exposure is associated with more rapid eGFR decline in those with established chronic kidney disease. Efforts to mitigate heat exposure should be tested as part of strategies to attenuate chronic kidney disease progression. FUNDING None.
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Efficacy and Safety of Dapagliflozin in Patients With Chronic Kidney Disease Across the Spectrum of Frailty.
Vart, P, Butt, JH, Jongs, N, Schechter, M, Chertow, GM, Wheeler, DC, Pecoits-Filho, R, Langkilde, AM, Correa-Rotter, R, Rossing, P, et al
The journals of gerontology. Series A, Biological sciences and medical sciences. 2024;(2)
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BACKGROUND A sizeable proportion of patients with chronic kidney disease (CKD) are reported to be frail. Here we examined the safety and efficacy of dapagliflozin in patients with CKD by frailty level. METHODS Adults with CKD, with/without type 2 diabetes, with an estimated glomerular filtration rate (eGFR) of 25-75 mL/min/1.73 m2, and urinary albumin-to-creatinine ratio 200-5 000 mg/g were randomized to dapagliflozin (10 mg/day) or placebo. The primary endpoint was a composite of sustained ≥50% eGFR decline, end-stage kidney disease (ESKD), or death from kidney or cardiovascular (CV) causes. RESULTS Frailty index (FI), assessed by Rockwood cumulative deficit approach, was calculable in 4 303/4 304 (99.9%) patients: 1 162 (27.0%) in not-to-mildly frail (FI ≤0.210), 1 642 (38.2%) in moderately frail (FI 0.211-0.310), and 1 499 (34.8%) in severely frail categories (FI >0.311). Dapagliflozin reduced the risk of the primary composite endpoint across all FI categories (hazard ratios [95% confidence interval {CI}]: 0.50 [0.33-0.76], 0.62 [0.45-0.85], and 0.64 [0.49--0.83], respectively; p-interaction = 0.67). Results were similar for secondary outcomes including kidney composite outcome (sustained ≥50% eGFR decline, ESKD or death from kidney cause; p-interaction = 0.44), CV endpoint (heart failure hospitalization or CV death; p-interaction = 0.63), and all-cause mortality (p-interaction p = .42). Results were consistent when using FI as a continuous variable. Occurrence of serious adverse events was numerically lower in patients receiving dapagliflozin versus placebo in all FI categories (16.9% vs 20.1%, 26.3% vs 30.7%, and 42.9% vs 47.8%, in not-to-mildly, moderately, and severely frail categories, respectively). CONCLUSIONS The relative benefit of dapagliflozin for all outcomes was consistent across all frailty categories, with no difference in associated safety.
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Sodium Glucose Co-transporter 2 Inhibitors and Major Adverse Cardiovascular Outcomes: A SMART-C Collaborative Meta-Analysis.
Patel, SM, Kang, YM, Im, K, Neuen, BL, Anker, SD, Bhatt, DL, Butler, J, Cherney, DZI, Claggett, BL, Fletcher, RA, et al
Circulation. 2024
Abstract
BACKGROUND Sodium glucose co-transporter 2 inhibitors (SGLT2i) consistently improve heart failure and kidney-related outcomes; however, effects on major adverse cardiovascular events (MACE) across different patient populations are less clear. METHODS This was a collaborative trial-level meta-analysis from the SGLT2i meta-analysis cardio-renal trialists consortium, which includes all phase 3, placebo-controlled, outcomes trials of SGLT2i across three patient populations (diabetes at high risk for atherosclerotic cardiovascular disease [ASCVD], heart failure [HF], or chronic kidney disease [CKD]). The outcomes of interest were MACE (composite of CV death, myocardial infarction [MI], or stroke), individual components of MACE (inclusive of fatal and non-fatal events), all-cause mortality, and death subtypes. Effect estimates for SGLT2i vs. placebo were meta-analyzed across trials and examined across key subgroups (established ASCVD, prior MI, diabetes, prior HF, albuminuria, CKD stages and risk groups). RESULTS A total of 78,607 patients across 11 trials were included: 42,568 (54.2%), 20,725 (26.4%), and 15,314 (19.5%) were included from trials of patients with diabetes at high risk for ASCVD, HF, or CKD, respectively. SGLT2i reduced the rate of MACE by 9% (HR 0.91 [95% CI 0.87-0.96], p<0.0001) with a consistent effect across all three patient populations (I2=0%) and across all key subgroups. This effect was primarily driven by a reduction in CV death (HR 0.86 [0.81-0.92], p<0.0001), with no significant effect for MI in the overall population (HR 0.95 [0.87-1.04], p=0.29), and no effect on stroke (HR 0.99 [0.91-1.07], p=0.77). The benefit for CV death was driven primarily by reductions in HF death and sudden cardiac death (HR 0.68 [0.46-1.02] and HR 0.86 [0.78-0.95], respectively) and was generally consistent across subgroups, with the possible exception of being more apparent in those with albuminuria (Pint=0.02). CONCLUSIONS SGLT2i reduce the risk of MACE across a broad range of patients irrespective of ASCVD, diabetes, kidney function or other major clinical characteristics at baseline. This effect is driven primarily by a reduction of CV death, particularly HF and sudden cardiac death, without a significant effect on MI in the overall population, and no effect on stroke. These data may help inform selection for SGLT2i therapies across the spectrum of cardiovascular-kidney-metabolic disease.
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Dapagliflozin and Mode of Death in Heart Failure With Improved Ejection Fraction: A Post Hoc Analysis of the DELIVER Trial.
Vardeny, O, Desai, AS, Jhund, PS, Fang, JC, Claggett, B, de Boer, RA, Hernandez, AF, Inzucchi, SE, Kosiborod, MN, Lam, CSP, et al
JAMA cardiology. 2024;(3):283-289
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IMPORTANCE Heart failure with improved ejection fraction (HFimpEF), defined as prior left ventricular ejection fraction (LVEF) 40% or lower that has increased to greater than 40%, is understudied. OBJECTIVE To examine mode of death and the association of dapagliflozin with reductions in cause-specific death in patients with HFimpEF. DESIGN, SETTING, AND PARTICIPANTS This was a post hoc analysis from the Dapagliflozin Evaluation to Improve the Lives of Patients With Preserved Ejection Fraction Heart Failure (DELIVER) randomized clinical trial, conducted from August 2018 to December 2020. The trial randomly assigned patients with HF with LVEF greater than 40%, New York Heart Association class II to IV symptoms, and elevated natriuretic peptides to treatment with dapagliflozin (10 mg, once daily) or placebo. The presence of HFimpEF was captured through study case report forms. The primary outcome was a composite of worsening HF events (hospitalization or urgent HF visits) or cardiovascular death. Clinical outcomes were adjudicated by a blinded clinical end points committee. Data were analyzed from May 2022 to August 2023. INTERVENTION Dapagliflozin vs placebo. MAIN OUTCOMES AND MEASURES The mode of death in relation to HFimpEF status was examined, as well as the association of randomized treatment with cause-specific death in Cox regression models. RESULTS Of 1151 patients with HFimpEF in DELIVER, 190 (16.5%) died, compared with 833 patients (16.3%) of 5112 with LVEF consistently greater than 40%. The overall distribution of mode of death was similar in those with HFimpEF compared with those with LVEF consistently greater than 40% (noncardiovascular death: 103 of 190 [54%] vs 428 of 833 [51%]; cardiovascular death: 87 of 190 [46%] vs 405 of 833 [49%], respectively). Most deaths in individuals with HFimpEF were noncardiovascular (103 of 180 [54%]). For cardiovascular deaths, sudden deaths were most common (36 of 190 events [19%]), followed by HF-related (29 of 190 events [15%]). Among patients with HFimpEF, treatment with dapagliflozin was associated with lower rates of cardiovascular death relative to placebo, a difference primarily due to lower rates of sudden death (hazard ratio, 0.38; 95% CI, 0.18-0.79; P for interaction = .01). CONCLUSIONS AND RELEVANCE The findings in this study support current guideline recommendations for use of sodium-glucose transport protein 2 inhibitor therapy, and further suggest that the addition of a sodium-glucose transport protein 2 inhibitor therapy to other guideline-directed medical therapies may help reduce cardiovascular mortality in patients with HFimpEF. TRIAL REGISTRATION ClinicalTrials.gov Identifier: NCT03619213.
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Impact of COVID-19 in patients with heart failure with mildly reduced or preserved ejection fraction enrolled in the DELIVER trial.
Bhatt, AS, Kosiborod, MN, Claggett, BL, Miao, ZM, Vaduganathan, M, Lam, CSP, Hernandez, AF, Martinez, FA, Inzucchi, SE, Shah, SJ, et al
European journal of heart failure. 2023;(12):2177-2188
Abstract
AIM: COVID-19 may affect clinical risk in patients with heart failure. DELIVER began before and was conducted during the COVID-19 pandemic. This study aimed to evaluate the association between COVID-19 and clinical outcomes among DELIVER participants. METHODS AND RESULTS Participants with chronic heart failure with mildly reduced or preserved ejection fraction (HFmrEF/HFpEF) were randomized to dapagliflozin or placebo across 350 sites in 20 countries. COVID-19 was investigator-reported and the contribution of COVID-19 to death was centrally adjudicated. We assessed (i) the incidence of COVID-19, (ii) event rates before/during the pandemic, and (iii) risks of death after COVID-19 diagnosis compared to risks of death in participants without COVID-19. Further, we performed a sensitivity analysis assessing treatment effects of dapagliflozin vs. placebo censored at pandemic onset. Of 6263 participants, 589 (9.4%) developed COVID-19, of whom 307 (52%) required/prolonged hospitalization. A total of 155 deaths (15% of all deaths) were adjudicated as definitely/possibly COVID-19-related. COVID-19 cases and deaths did not differ by randomized assignment. Death rate in the 12 months following diagnosis was 56.1 (95% confidence interval [CI] 48.0-65.6) versus 6.4 (95% CI 6.0-6.8)/100 participant-years among trial participants with versus without COVID-19 (adjusted hazard ratio [aHR] 8.60, 95% CI 7.18-10.30). Risk was highest 0-3 months following diagnosis (153.5, 95% CI 130.3-180.8) and remained elevated at 3-6 months (12.6, 95% CI 6.6-24.3/100 participant-years). After excluding investigator-reported fatal COVID-19 events, all-cause death rates in the 12 months following diagnosis among COVID-19 survivors (n = 458) remained higher (aHR 2.46, 95% CI 1.83-3.33) than rates for all trial participants from randomization, with censoring of participants who developed COVID-19 at the time of diagnosis. Dapagliflozin reduced cardiovascular death/worsening HF events when censoring participants at COVID-19 diagnosis (HR 0.81, 95% CI 0.72-0.91) and pandemic onset (HR 0.72, 95% CI 0.58-0.89). There were no diabetic ketoacidosis or major hypoglycaemic events within 30 days of COVID-19. CONCLUSION DELIVER is one of the most extensive experiences with COVID-19 of any cardiovascular trial, with >75% of follow-up time occurring during the pandemic. COVID-19 was common, with >50% of cases leading to hospitalization or death. Treatment benefits of dapagliflozin persisted when censoring at COVID-19 diagnosis and pandemic onset. Patients surviving COVID-19 had a high early residual risk. CLINICAL TRIAL REGISTRATION ClinicalTrials.gov Identifier NCT03619213.
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Heart failure, peripheral artery disease, and dapagliflozin: a patient-level meta-analysis of DAPA-HF and DELIVER.
Butt, JH, Kondo, T, Yang, M, Jhund, PS, Docherty, KF, Vaduganathan, M, Claggett, BL, Hernandez, AF, Lam, CSP, Inzucchi, SE, et al
European heart journal. 2023;(24):2170-2183
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AIMS: Because an increased risk of amputation with canagliflozin was reported in the CANVAS trials, there has been a concern about the safety of sodium-glucose cotransporter 2 inhibitors in patients with peripheral artery disease (PAD) who are at higher risk of amputation. METHODS AND RESULTS A patient-level pooled analysis of the DAPA-HF and DELIVER trials, which evaluated the efficacy and safety of dapagliflozin in patients with heart failure (HF) with reduced, mildly reduced/preserved ejection fraction, respectively, was conducted. In both trials, the primary outcome was the composite of worsening HF or cardiovascular death, and amputation was a prespecified safety outcome. Peripheral artery disease history was available for 11 005 of the total 11 007 patients. Peripheral artery disease was reported in 809 of the 11 005 patients (7.4%). Median follow-up was 22 months (interquartile range 17-30). The rate of the primary outcome (per 100 person-years) was higher in PAD patients than that in non-PAD patients: 15.1 [95% confidence interval (CI) 13.1-17.3) vs. 10.6 (10.2-11.1]; adjusted hazard ratio 1.23 (95% CI 1.06-1.43). The benefit of dapagliflozin on the primary outcome was consistent in patients with [hazard ratio 0.71 (95% CI 0.54-0.94)] and without PAD [0.80 (95% CI 0.73-0.88)] (Pinteraction = 0.39). Amputations, while more frequent in PAD patients, were not more common with dapagliflozin, compared with placebo, irrespective of PAD status (PAD, placebo 4.2% vs. dapagliflozin 3.7%; no PAD, placebo 0.4% vs. dapagliflozin 0.4%) (Pinteraction = 1.00). Infection rather than ischaemia was the main trigger for amputation, even in patients with PAD. CONCLUSION The risk of worsening HF or cardiovascular death was higher in patients with PAD, as was the risk of amputation. The benefits of dapagliflozin were consistent in patients with and without PAD, and dapagliflozin did not increase the risk of amputation.
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Estimated lifetime benefit of novel pharmacological therapies in patients with type 2 diabetes and chronic kidney disease: A joint analysis of randomized controlled clinical trials.
Heerspink, HJL, Vart, P, Jongs, N, Neuen, BL, Bakris, G, Claggett, B, Vaduganathan, M, McCausland, F, Docherty, KF, Jhund, PS, et al
Diabetes, obesity & metabolism. 2023;(11):3327-3336
Abstract
AIM: To estimate the lifetime benefit of a combination treatment of sodium-glucose co-transporter 2 (SGLT2) inhibitors and mineralocorticoid-receptor antagonists (MRA) in patients with type 2 diabetes and chronic kidney disease (CKD). MATERIALS AND METHODS The cumulative effect of combination treatment was derived from trial-level estimates of the effect of an SGLT2 inhibitor (canagliflozin) and MRA (finerenone) from the CREDENCE (N = 4401) and FIDELIO (N = 5734) trials, respectively. The cumulative effect was applied to the control group of patients with type 2 diabetes in the DAPA-CKD trial (N = 1451) to estimate long-term gains in event-free and overall survival. The analysis was repeated in an observational study. The primary outcome was a composite endpoint of doubling of serum creatinine, end-stage kidney disease or death because of kidney failure. RESULTS The hazard ratio of combination treatment for the primary outcome was 0.50 [95% confidence interval (CI): 0.44, 0.57]. At age 50 years, the estimated event-free survival from the primary outcome was 16.7 years (95% CI: 18.1, 21.0) with combination treatment versus 10.0 years (95% CI: 6.8, 12.3) with angiotensin-converting enzyme inhibitors/angiotensin receptor blockers resulting in an incremental gain of 6.7 years (95% CI: 5.5, 7.9). In an observational study, the estimated gain in event-free survival regarding primary outcome was 6.3 years (95% CI: 5.2, 7.3). In a conservative scenario, assuming low adherence (70% of the observed adherence) and less pronounced efficacy (70% of the observed efficacy with 2% yearly decline) of combination therapy, gain in event-free survival regarding primary outcome was 2.5 years (95% CI: 2.0, 2.9). CONCLUSIONS Combined disease-modifying treatment with an SGLT2 inhibitor and MRA in patients with type 2 diabetes and CKD may substantially increase the number of years free from kidney failure and mortality.