| 1. |
- McMurray, J. J. V., et al.
(författare)
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Dapagliflozin in Patients with Heart Failure and Reduced Ejection Fraction
- 2019
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Ingår i: New England Journal of Medicine. - 0028-4793 .- 1533-4406. ; 381:21, s. 1995-2008
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND In patients with type 2 diabetes, inhibitors of sodium-glucose cotransporter 2 (SGLT2) reduce the risk of a first hospitalization for heart failure, possibly through glucose-independent mechanisms. More data are needed regarding the effects of SGLT2 inhibitors in patients with established heart failure and a reduced ejection fraction, regardless of the presence or absence of type 2 diabetes.METHODS In this phase 3, placebo-controlled trial, we randomly assigned 4744 patients with New York Heart Association class II, III, or IV heart failure and an ejection fraction of 40% or less to receive either dapagliflozin (at a dose of 10 mg once daily) or placebo, in addition to recommended therapy. The primary outcome was a composite of worsening heart failure (hospitalization or an urgent visit resulting in intravenous therapy for heart failure) or cardiovascular death.RESULTS Over a median of 18.2 months, the primary outcome occurred in 386 of 2373 patients (16.3%) in the dapagliflozin group and in 502 of 2371 patients (21.2%) in the placebo group (hazard ratio, 0.74; 95% confidence interval [CI], 0.65 to 0.85; P<0.001). A first worsening heart failure event occurred in 237 patients (10.0%) in the dapagliflozin group and in 326 patients (13.7%) in the placebo group (hazard ratio, 0.70; 95% CI, 0.59 to 0.83). Death from cardiovascular causes occurred in 227 patients (9.6%) in the dapagliflozin group and in 273 patients (11.5%) in the placebo group (hazard ratio, 0.82; 95% CI, 0.69 to 0.98); 276 patients (11.6%) and 329 patients (13.9%), respectively, died from any cause (hazard ratio, 0.83; 95% CI, 0.71 to 0.97). Findings in patients with diabetes were similar to those in patients without diabetes. The frequency of adverse events related to volume depletion, renal dysfunction, and hypoglycemia did not differ between treatment groups.CONCLUSIONS Among patients with heart failure and a reduced ejection fraction, the risk of worsening heart failure or death from cardiovascular causes was lower among those who received dapagliflozin than among those who received placebo, regardless of the presence or absence of diabetes.
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| 2. |
- Inzucchi, S. E., et al.
(författare)
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Dapagliflozin and the incidence of type 2 diabetes in patients with heart failure and reduced ejection fraction: An exploratory analysis from DAPA-HF
- 2021
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Ingår i: Diabetes Care. - : American Diabetes Association. - 0149-5992 .- 1935-5548. ; 44:2, s. 586-594
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Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVE The sodium–glucose cotransporter 2 inhibitor dapagliflozin reduced the risk of cardiovascular mortality and worsening heart failure in the Dapagliflozin and Prevention of Adverse Outcomes in Heart Failure (DAPA-HF) trial. This report explores the effect of dapagliflozin on incident type 2 diabetes (T2D) in the cohort without diabetes enrolled in the trial. RESEARCH DESIGN AND METHODS The subgroup of 2,605 patients with heart failure and reduced ejection fraction (HFrEF), no prior history of diabetes, and an HbA1c of <6.5% at baseline was randomized to dapagliflozin 10 mg daily or placebo. In this exploratory analysis, surveillance for new-onset diabetes was accomplished through periodic HbA1c testing as part of the study protocol and comparison between the treatment groups assessed through a Cox proportional hazards model. RESULTS At baseline, the mean HbA1c was 5.8%. At 8 months, there were minimal changes, withaplacebo-adjusted change inthedapagliflozin groupof20.04%. Over a median follow-up of 18 months, diabetes developed in 93 of 1,307 patients (7.1%) in the placebogroup and 64 of 1,298 (4.9%) in the dapagliflozingroup. Dapagliflozin led to a 32% reduction in diabetes incidence (hazard ratio 0.68, 95% CI 0.50–0.94; P 5 0.019). More than 95% of the participants who developed T2D had prediabetes at baseline (HbA1c 5.7–6.4%). Participants who developed diabetes in DAPA-HF had a higher subsequent mortality than those who did not. CONCLUSIONS In this exploratory analysis among patients with HFrEF, treatment with dapagliflozin reduced the incidence of new diabetes. This potential benefit needs confirmation in trials of longer duration and in people without heart failure. © 2020 by the American Diabetes Association.
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| 3. |
- Furtado, R. H. M., et al.
(författare)
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Efficacy and Safety of Dapagliflozin in Type 2 Diabetes According to Baseline Blood Pressure: Observations From DECLARE-TIMI 58 Trial
- 2022
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Ingår i: Circulation. - : Ovid Technologies (Wolters Kluwer Health). - 0009-7322 .- 1524-4539. ; 145:21, s. 1581-1591
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Dapagliflozin improved heart failure and kidney outcomes in patients with type 2 diabetes (T2DM) with or at high risk for atherosclerotic cardiovascular disease in the DECLARE-TIMI 58 trial (Dapagliflozin Effect on Cardiovascular Events - Thrombolysis in Myocardial Infarction 58). Here, the aim was to analyze the efficacy and safety of dapagliflozin stratified according to baseline systolic blood pressure (SBP). METHODS: The DECLARE-TIMI 58 trial randomly assigned patients with T2DM and either previous atherosclerotic cardiovascular disease or atherosclerotic cardiovascular disease risk factors to dapagliflozin or placebo. Patients were categorized by baseline SBP levels: <120, 120 to 129, 130 to 139, 140 to 159, and >= 160 mm Hg (normal, elevated, stage 1, stage 2, and severe hypertension, respectively). Efficacy outcomes of interest were hospitalization for heart failure and a renal-specific composite outcome (sustained decrease in estimated glomerular filtration rate by 40%, progression to end-stage renal disease, or renal death). Safety outcomes included symptoms of volume depletion, lower extremity amputations, and acute kidney injury. RESULTS: The trial comprised 17160 patients; mean age, 64.0 +/- 6.8 years; 37.4% women; median duration of T2DM, 11 years; 40.6% with prevalent cardiovascular disease. Overall, dapagliflozin reduced SBP by 2.4 mm Hg (95% CI, 1.9-2.9; F<0.0001) compared with placebo at 48 months. The beneficial effects of dapagliflozin on hospitalization for heart failure and renal outcomes were consistent across all baseline SBP categories, with no evidence of modification of treatment effect (P-interactions = 5 0.28 and 0.52, respectively). Among normotensive patients, the hazard ratios were 0.66 (95% CI, 0.42-1.05) and 0.39 95% CI, 0.19-0.78), respectively, for hospitalization for heart failure and the renal-specific outcome. Events of volume depletion, amputation, and acute kidney injury did not differ with dapagliflozin overall or within any baseline SBP group. CONCLUSIONS: In patients with T2DM with or at high atherosclerotic cardiovascular disease risk, dapagliflozin reduced risk for hospitalization for heart failure and renal outcomes regardless of baseline SBP, with no difference in adverse events of interest at any level of baseline SBP. These results indicate that dapagliflozin provides cardiorenal benefits in patients with T2DM at high atherosclerotic cardiovascular disease risk independent of baseline blood pressure.
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| 4. |
- Wiviott, Stephen D, et al.
(författare)
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Dapagliflozin and Cardiovascular Outcomes in Type 2 Diabetes.
- 2019
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Ingår i: The New England journal of medicine. - 1533-4406. ; 380:4, s. 347-357
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Tidskriftsartikel (refereegranskat)abstract
- The cardiovascular safety profile of dapagliflozin, a selective inhibitor of sodium-glucose cotransporter 2 that promotes glucosuria in patients with type 2 diabetes, is undefined.We randomly assigned patients with type 2 diabetes who had or were at risk for atherosclerotic cardiovascular disease to receive either dapagliflozin or placebo. The primary safety outcome was a composite of major adverse cardiovascular events (MACE), defined as cardiovascular death, myocardial infarction, or ischemic stroke. The primary efficacy outcomes were MACE and a composite of cardiovascular death or hospitalization for heart failure. Secondary efficacy outcomes were a renal composite (≥40% decrease in estimated glomerular filtration rate to <60 ml per minute per 1.73 m2 of body-surface area, new end-stage renal disease, or death from renal or cardiovascular causes) and death from any cause.We evaluated 17,160 patients, including 10,186 without atherosclerotic cardiovascular disease, who were followed for a median of 4.2 years. In the primary safety outcome analysis, dapagliflozin met the prespecified criterion for noninferiority to placebo with respect to MACE (upper boundary of the 95% confidence interval [CI], <1.3; P<0.001 for noninferiority). In the two primary efficacy analyses, dapagliflozin did not result in a lower rate of MACE (8.8% in the dapagliflozin group and 9.4% in the placebo group; hazard ratio, 0.93; 95% CI, 0.84 to 1.03; P=0.17) but did result in a lower rate of cardiovascular death or hospitalization for heart failure (4.9% vs. 5.8%; hazard ratio, 0.83; 95% CI, 0.73 to 0.95; P=0.005), which reflected a lower rate of hospitalization for heart failure (hazard ratio, 0.73; 95% CI, 0.61 to 0.88); there was no between-group difference in cardiovascular death (hazard ratio, 0.98; 95% CI, 0.82 to 1.17). A renal event occurred in 4.3% in the dapagliflozin group and in 5.6% in the placebo group (hazard ratio, 0.76; 95% CI, 0.67 to 0.87), and death from any cause occurred in 6.2% and 6.6%, respectively (hazard ratio, 0.93; 95% CI, 0.82 to 1.04). Diabetic ketoacidosis was more common with dapagliflozin than with placebo (0.3% vs. 0.1%, P=0.02), as was the rate of genital infections that led to discontinuation of the regimen or that were considered to be serious adverse events (0.9% vs. 0.1%, P<0.001).In patients with type 2 diabetes who had or were at risk for atherosclerotic cardiovascular disease, treatment with dapagliflozin did not result in a higher or lower rate of MACE than placebo but did result in a lower rate of cardiovascular death or hospitalization for heart failure, a finding that reflects a lower rate of hospitalization for heart failure. (Funded by AstraZeneca; DECLARE-TIMI 58 ClinicalTrials.gov number, NCT01730534 .).
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| 5. |
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| 6. |
- Adamson, Carly, et al.
(författare)
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Liver Tests and Outcomes in Heart Failure with Reduced Ejection Fraction : Findings from DAPA-HF.
- 2022
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Ingår i: European journal of heart failure. - : Wiley. - 1388-9842 .- 1879-0844. ; 24:10, s. 1856-1868
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Tidskriftsartikel (refereegranskat)abstract
- AIMS: Reflecting both increased venous pressure and reduced cardiac output, abnormal liver tests are common in patients with severe heart failure and are associated with adverse clinical outcomes. We aimed to investigate the prognostic significance of abnormal liver tests in ambulatory patients with heart failure with reduced ejection fraction (HFrEF), explore any treatment interaction between bilirubin and sodium- glucose cotransporter 2 (SGLT2) inhibitors and examine change in liver tests with SGLT2 inhibitor treatment. METHODS AND RESULTS: We explored these objectives in the Dapagliflozin And Prevention of Adverse outcomes in Heart Failure (DAPA-HF) trial, with focus on bilirubin. We calculated the incidence of cardiovascular death or worsening heart failure by bilirubin tertile. Secondary cardiovascular outcomes were examined, along with the change in liver tests at the end-of-study visit. Baseline bilirubin was available in 4720 patients (99.5%). Participants in the highest bilirubin tertile (T3) have more severe HFrEF (lower left ventricular ejection fraction, higher N-terminal pro-B-type natriuretic peptide [NT-proBNP] and worse New York Heart Association class), had a greater burden of atrial fibrillation but less diabetes. Higher bilirubin (T3 vs. T1) was associated with worse outcomes even after adjustment for other predictive variables, including NT-proBNP and troponin T (adjusted hazard ratio for the primary outcome 1.73 [95% confidence interval 1.37-2.17], p $<$ 0.001; and 1.52 [1.12-2.07], p = 0.01 for cardiovascular death). Baseline bilirubin did not modify the benefits of dapagliflozin. During follow-up, dapagliflozin had no effect on liver tests. CONCLUSION: Bilirubin concentration was an independent predictor of worse outcomes but did not modify the benefits of dapagliflozin in HFrEF. Dapagliflozin was not associated with change in liver tests. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov NCT03036124.
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| 7. |
- Dewan, Pooja, et al.
(författare)
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Effects of Dapagliflozin in Heart Failure with Reduced Ejection Fraction and Chronic Obstructive Pulmonary Disease : An Analysis of DAPA-HF.
- 2021
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Ingår i: European journal of heart failure. - : Wiley. - 1388-9842 .- 1879-0844. ; 23:4, s. 632-643
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Tidskriftsartikel (refereegranskat)abstract
- AIMS: Chronic obstructive pulmonary disease (COPD) is an important comorbidity in heart failure (HF) with reduced ejection fraction (HFrEF), associated with worse outcomes and often suboptimal treatment because of under-prescription of beta-blockers. Consequently, additional effective therapies are especially relevant in patients with COPD. The aim of this study was to examine outcomes related to COPD in a post hoc analysis of the Dapagliflozin And Prevention of Adverse-outcomes in Heart Failure (DAPA-HF) trial. METHODS AND RESULTS: We examined whether the effects of dapagliflozin in DAPA-HF were modified by COPD status. The primary outcome was the composite of an episode of worsening HF or cardiovascular death. Overall, 585 (12.3%) of the 4744 patients randomized had a history of COPD. Patients with COPD were more likely to be older men with a history of smoking, worse renal function, and higher baseline N-terminal pro B-type natriuretic peptide, and less likely to be treated with a beta-blocker or mineralocorticoid receptor antagonist. The incidence of the primary outcome was higher in patients with COPD than in those without [18.9 (95% confidence interval 16.0-22.2) vs. 13.0 (12.1-14.0) per 100 person-years; hazard ratio (HR) for COPD vs. no COPD 1.44 (1.21-1.72); P $<$ 0.001]. The effect of dapagliflozin, compared with placebo, on the primary outcome, was consistent in patients with [HR 0.67 (95% confidence interval 0.48-0.93)] and without COPD [0.76 (0.65-0.87); interaction P-value 0.47]. CONCLUSIONS: In DAPA-HF, one in eight patients with HFrEF had concomitant COPD. Participants with COPD had a higher risk of the primary outcome. The benefit of dapagliflozin on all pre-specified outcomes was consistent in patients with and without COPD. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov ID NCT03036124.
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| 8. |
- Jackson, Alice M., et al.
(författare)
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Dapagliflozin and Diuretic Use in Patients With Heart Failure and Reduced Ejection Fraction in DAPA-HF.
- 2020
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Ingår i: Circulation. - 1524-4539. ; 142:11, s. 1040-1054
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: In the DAPA-HF trial (Dapagliflozin and Prevention of Adverse-Outcomes in Heart Failure), the sodium-glucose cotransporter 2 inhibitor dapagliflozin reduced the risk of worsening heart failure and death in patients with heart failure and reduced ejection fraction. We examined the efficacy and tolerability of dapagliflozin in relation to background diuretic treatment and change in diuretic therapy after randomization to dapagliflozin or placebo. METHODS: We examined the effects of study treatment in the following subgroups: no diuretic and diuretic dose equivalent to furosemide $<$40, 40, and $>$40 mg daily at baseline. We examined the primary composite end point of cardiovascular death or a worsening heart failure event and its components, all-cause death and symptoms. RESULTS: Of 4616 analyzable patients, 736 (15.9%) were on no diuretic, 1311 (28.4%) were on $<$40 mg, 1365 (29.6%) were on 40 mg, and 1204 (26.1%) were taking $>$40 mg. Compared with placebo, dapagliflozin reduced the risk of the primary end point across each of these subgroups: hazard ratios were 0.57 (95% CI, 0.36-0.92), 0.83 (95% CI, 0.63-1.10), 0.77 (95% CI, 0.60-0.99), and 0.78 (95% CI, 0.63-0.97), respectively (P for interaction=0.61). The hazard ratio in patients taking any diuretic was 0.78 (95% CI, 0.68-0.90). Improvements in symptoms and treatment toleration were consistent across the diuretic subgroups. Diuretic dose did not change in most patients during follow- up, and mean diuretic dose did not differ between the dapagliflozin and placebo groups after randomization. CONCLUSIONS: The efficacy and safety of dapagliflozin were consistent across the diuretic subgroups examined in DAPA-HF. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT03036124.
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| 9. |
- Lahtela, J., et al.
(författare)
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Effect of adding dapagliflozin as an adjunct to insulin on urinary albumin-to-creatinine ratio over 52 weeks in adults with type 1 diabetes
- 2019
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Konferensbidrag (övrigt vetenskapligt/konstnärligt)abstract
- Background and aims: Dapagliflozin (DAPA), as an adjunct to insulin, was reported to improve glycaemic control, reduce body weight, and was well tolerated (DEPICT-1 and 2 studies) in adults with inadequately controlled type 1 diabetes (T1D; HbA1c: 58-91 mmol/mol [7.5-10.5%]).Materials and methods: In this pooled post hoc analysis of the DEPICT-1 and -2 studies, the effect of DAPA on urinary albumin-to-creatinine ratio (UACR) was evaluated in individuals with T1D with baseline micro or macroalbuminuria.Results: UACR was recorded at baseline for 548, 565, and 532 individuals treated with DAPA 5 mg, DAPA 10 mg, and placebo, respectively; baseline albuminuria was found in 80, 84, and 87 of these individuals in the respective arms. Of these 251 individuals, baseline renal function measured as estimated glomerular filtration rate (eGFR) was normal (eGFR≥90 ml min-1[1.73 m]-2) in 93, mildly impaired in (eGFR≥60-<90 ml min-1[1.73 m]-2) 131, and moderately impaired in 27 individuals (eGFR <60 ml min-1[1.73 m]-2). Changes in eGFR were similar across the treatment arms (data not shown). Dose-dependent decrease in UACR was observed with DAPA treatment at Weeks 12, 18, 24, and 52 (Figure). At Week 52, the differences in UACR between DAPA 10 mg vs placebo and DAPA 5 mg vs placebo were−31.1% (95% CI:−49.9,−5.2) and−13.3 (95% CI:−37.2, 19.8), respectively.Conclusion: Treatment with DAPA, as an adjunct to insulin, provided a dose-dependent benefit in reducing UACR, suggesting renoprotective effects in individuals with T1D with baseline albuminuria.
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| 10. |
- Mathieu, C., et al.
(författare)
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Glucose Variables in Type 1 Diabetes Studies With Dapagliflozin: Pooled Analysis of Continuous Glucose Monitoring Data From DEPICT-1 and-2
- 2019
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Ingår i: Diabetes Care. - : American Diabetes Association. - 0149-5992 .- 1935-5548. ; 42:6, s. 1081-1087
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Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVEThis pooled analysis assessed continuous glucose monitoring (CGM) in patients with inadequately controlled type 1 diabetes (HbA(1c) >= 7.7 to <= 11.0% [>= 61 to <= 97 mmol/mol]) who received dapagliflozin as an adjunct to adjustable insulin.RESEARCH DESIGN AND METHODSCGM data were pooled from two 24-week, double-blind, randomized, phase 3 studies: Dapagliflozin Evaluation in Patients with Inadequately Controlled Type 1 Diabetes (DEPICT-1 and DEPICT-2). These studies comprised 1,591 patients receiving dapagliflozin 5 mg (n = 530), dapagliflozin 10 mg (n = 529), or placebo (n = 532).RESULTSBaseline characteristics were balanced between treatment groups. Patients receiving dapagliflozin 5 mg or 10 mg both spent more time with blood glucose in the range >3.9 to <= 10.0 mmol/L (>70 to <= 180 mg/dL) over 24 h than those receiving the placebo. The adjusted mean (SE) change from baseline at week 24 was 6.48% (0.60) with dapagliflozin 5 mg, 8.08% (0.60) with dapagliflozin 10 mg, and -2.59% (0.61) with placebo. At week 24, the mean amplitude of glucose excursion over 24 h, mean 24-h glucose values, and postprandial glucose values were also improved in patients receiving dapagliflozin over those receiving placebo. No marked differences were found at week 24 between dapagliflozin 5 or 10 mg and placebo in the percentage of glucose values <= 3.9 mmol/L (<= 70 mg/dL) or <= 3.0 mmol/L (<= 54 mg/dL) over 24 h, or in nocturnal (0000-0559 h) glucose values <= 3.9 mmol/L (<= 70 mg/dL).CONCLUSIONSIn patients with type 1 diabetes, treatment with dapagliflozin over 24 weeks improved time in range, mean glucose, and glycemic variability without increasing the time spent in the range indicating hypoglycemia.
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