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    [Cardiovascular and renal protection with SGLT2 inhibitors: from EMPA-REG OUTCOME to VERTIS CV]. Scheen André J Revue medicale suisse The landmark study EMPA-REG OUTCOME firstly demonstrated both a cardiovascular and renal protection with empagliflozin in patients with type 2 diabetes (T2DM) and established cardiovascular disease. Since 2015, two other trials showed a reduction in the hospitalisations for heart failure and the progression of the renal disease, also in patients with multiple risk factors, CANVAS with canagliflozin and DECLARE-TIMI 58 with dapagliflozin. CREDENCE (canagliflozin in T2DM patients with kidney disease) confirmed a renal protection and DAPA-HF (dapagliflozin in patients, with or without T2DM, but reduced ejection fraction) showed a less acute deterioration of heart failure. The positive effect of SGLT2 inhibitors on heart failure predominates, an effect recently confirmed in VERTIS CV with ertugliflozin.
    Sodium-glucose co-transporter-2 inhibitors and major adverse limb events: A trial-level meta-analysis including 51 713 individuals. Huang Chen-Yu,Lee Jen-Kuang Diabetes, obesity & metabolism AIM:To analyse large-scale cardiovascular outcome trials of sodium-glucose co-transporter-2 (SGLT-2) inhibitors to evaluate whether there are safety concerns with respect to major adverse limb events overall or among various high-risk subgroups of patients. METHODS:We performed a quantitative meta-analysis of randomized, placebo-controlled, cardiovascular outcome trials of SGLT-2 inhibitors in patients with type 2 diabetes. We searched the PubMed, Embase and Cochrane databases for trials published up until 30 June 2020. The efficacy outcomes analysed included amputations and were stratified by several subgroup variables, including age, duration of diabetes, glucose control, renal function, established peripheral artery disease and diabetes microvascular complications. This review was registered before completing the analysis. RESULTS:Among 383 records identified, six studies assessing the following three SGLT-2 inhibitors met our inclusion criteria: empagliflozin (EMPA-REG OUTCOME study), canagliflozin (CANVAS Program and CREDENCE study), dapagliflozin (DECLARE-TIMI 58 and DAPA-HF trials) and ertugliflozin (VERTIS CV study). Of a total of 51 713 participants, 858 required amputation operations. The event rates of amputation were 2.0% (535/26 778) and 1.3% (323/24 927) in the SGLT-2 inhibitor and control groups, respectively. The random effects model revealed that SGLT-2 inhibitors were not significantly associated with an increased risk of amputation with substantial heterogeneity (pooled risk ratio, 1.24; 95% confidence interval, 0.96 to 1.60; I = 67.5%). This neutral effect of SGLT-2 inhibitors was also consistent across different levels of subgroups, including subgroups with or without established peripheral artery disease (PAD). CONCLUSIONS:SGLT-2 inhibitors are not associated with increased risks of amputation operations even among various high-risk subgroups, including patients with PAD. The amputation events primarily arise from critical limb ischaemia and infection instead of acute limb ischaemia. A multi-centre study focused on major adverse limb events with a longer follow-up is needed to confirm these results and provide guidelines for clinical practice. 10.1111/dom.14159
    Renal Outcomes in Type 2 Diabetes: A Review of Cardiovascular and Renal Outcome Trials. Williams David M,Nawaz Asif,Evans Marc Diabetes therapy : research, treatment and education of diabetes and related disorders The development of chronic kidney disease (CKD) in people with diabetes is commonplace, and is frequently associated with a significant and unfavourable impact on patient outcomes along with a substantial economic burden. With the development of novel classes of drug therapies in diabetes, there has been a recent focus on cardiovascular safety measures, with dedicated cardiovascular outcome trials (CVOTs) carried out for all new diabetes medications. More recently, there has been a growing regulatory view that such trials should report more specific renal outcomes to ensure simpler comparability between drugs and drug classes. This article explores some of the possible mechanisms by which these drugs may improve renal function in people with diabetes, and it reviews important CVOTs that have reported renal outcomes to date. These include CVOTS of sodium-glucose cotransporter-2 inhibitors (EMPA-REG OUTCOME study, CANVAS study, CREDENCE trial, DECLARE-TIMI trial and DAPA-HF study), dipeptidyl peptidase-4 inhibitors (EXAMINE trial, SAVOR-TIMI 53, TECOS trial and CARMELINA trial) and glucagon-like peptide-1 analogues (ELIXA trial, LEADER trial, SUSTAIN-6 trial, PIONEER-6 trial, EXSCEL trial, HARMONY Outcomes study and the REWIND study). Ongoing cardiovascular and renal outcome studies such as Dapa-CKD, EMPA-KIDNEY, EMPEROR-Preserved and EMPEROR-Reduced are also discussed. The heterogeneity of patient characteristics and reported renal outcomes, which hinders comparisons between trials and drug classes, is highlighted. Novel classes of diabetes therapies present an important opportunity for nephroprotection beyond the blockade of the renin-angiotensin-aldosterone system in this high-risk group. Clinicians should be aware of such benefits when prescribing these medications for people with, and possibly those without, type 2 diabetes. 10.1007/s13300-019-00747-3
    SGLT2 inhibitors and cardiovascular outcomes: Do they differ or there is a class effect? New insights from the EMPA-REG OUTCOME trial and the CVD-REAL Study. Kyriakos Georgios,Quiles-Sanchez Lourdes Victoria,Garmpi Anna,Farmaki Paraskevi,Kyre Konstantina,Savvanis Spyridon,Antoniou Vasileios K,Memi Eleni Current cardiology reviews A new group of hypoglycemic drugs has been used to treat diabetes type 2. This group is active sodium glucose co-transporter (SGLT2) or SGLT2 inhibitors. It has been shown that besides the treatment of diabetes, this drug class is responsible for the mildness of the cardiovascular events shown in patients with diabetes type 2. However, there is an intriguing question regarding the range of SGLT2 inhibitors and if there is a difference between them or if there is a class effect among their results. EMPA-REG OUTCOME trial and the CVD-study are used to answer this question. Additional information from the DECLARE-TIMI 58 and Dapa-HF trials are studied. 10.2174/1573403X15666190730094215
    Dapagliflozin for Heart Failure with Preserved Ejection Fraction: Will the DELIVER Study Deliver? Williams David M,Evans Marc Diabetes therapy : research, treatment and education of diabetes and related disorders Drug therapies for people with heart failure and preserved ejection fraction (HFpEF) are often limited to diuretics to improve symptoms as no therapies demonstrate a mortality benefit in this cohort. People with diabetes have a high risk of developing HFpEF and vice versa, suggesting shared pathophysiological mechanisms exist, which in turn engenders the potential for shared treatments. Dapagliflozin is a sodium-glucose co-transporter 2 (SGLT2) inhibitor which has demonstrated significantly improved cardiovascular and hospitalisation for heart failure (HHF) outcomes in previous cardiovascular outcome trials (CVOTs). These CVOTs include the DECLARE-TIMI and DAPA-HF studies which observed significant benefits for people with heart failure and specifically those with heart failure and reduced ejection fraction (HFrEF), respectively. The ongoing DELIVER study is evaluating the use of dapagliflozin specifically in people with HFpEF, which may have enormous implications for treatment and considerable economic consequences. This will complement previous and other ongoing CVOTs evaluating dapagliflozin use. In this review we discuss the use of SGLT2 inhibitors in HFrEF and HFpEF with a focus on the DELIVER study and its potential health and economic implications. 10.1007/s13300-020-00911-0
    Sodium-Glucose Cotransporter-2 inhibitors are potential therapeutic agents for treatment of non-diabetic heart failure patients. Nakagawa Yasuaki,Kuwahara Koichiro Journal of cardiology Despite recent developments in various therapies, heart failure remains a leading cause of morbidity and mortality worldwide. New pharmacological approaches are therefore needed to improve the outcomes of patients with heart failure. Diabetes mellitus is an important risk factor for heart failure, but until recently there had been no evidence that hypoglycemic agents prevent heart failure. Sodium-glucose cotransporter-2 (SGLT2) inhibitors have now been shown to prevent cardiovascular events, especially hospitalization for heart failure, in three large randomized clinical trials: EMPA-REG OUTCOME, the CANVAS program, and the DECLARE-TIMI58 trial. It is expected, therefore, that SGLT2 inhibitors will be useful therapeutic agents for the treatment of heart failure. The DAPA-HF trial recently demonstrated that dapagliflozin significantly reduces cardiovascular death and hospitalization for heart failure in patients with heart failure with reduced ejection fraction (HFrEF). Importantly, these benefits of dapagliflozin were similarly observed in patients with or without diabetes, suggesting the drug's efficacy is independent of glycemic reduction. The results of that study highlight the significance of SGLT2 inhibition as a novel therapeutic approach to treating HFrEF, irrespective of the presence or absence of diabetes. Findings of the DAPA-HF trial may also challenge current assumptions about the mechanisms underlying the cardioprotective action of SGLT2 inhibitors. It is anticipated that ongoing clinical trials, mainly using dapagliflozin and empagliflozin, will provide further insight into the clinical importance of these drugs for the treatment of heart failure, including heart failure with preserved ejection fraction (HFpEF), and also the mechanisms underlying those clinical benefits. 10.1016/j.jjcc.2020.03.009
    Dapagliflozin in Patients with Heart Failure and Reduced Ejection Fraction. McMurray John J V,Solomon Scott D,Inzucchi Silvio E,Køber Lars,Kosiborod Mikhail N,Martinez Felipe A,Ponikowski Piotr,Sabatine Marc S,Anand Inder S,Bělohlávek Jan,Böhm Michael,Chiang Chern-En,Chopra Vijay K,de Boer Rudolf A,Desai Akshay S,Diez Mirta,Drozdz Jaroslaw,Dukát Andrej,Ge Junbo,Howlett Jonathan G,Katova Tzvetana,Kitakaze Masafumi,Ljungman Charlotta E A,Merkely Béla,Nicolau Jose C,O'Meara Eileen,Petrie Mark C,Vinh Pham N,Schou Morten,Tereshchenko Sergey,Verma Subodh,Held Claes,DeMets David L,Docherty Kieran F,Jhund Pardeep S,Bengtsson Olof,Sjöstrand Mikaela,Langkilde Anna-Maria, The New England journal of medicine 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. (Funded by AstraZeneca; DAPA-HF ClinicalTrials.gov number, NCT03036124.). 10.1056/NEJMoa1911303
    Prognosis of patients eligible for dapagliflozin in acute heart failure. Carballo Sebastian,Stirnemann Jérôme,Garin Nicolas,Darbellay Farhoumand Pauline,Serratrice Jacques,Carballo David European journal of clinical investigation BACKGROUND:Dapagliflozin, a sodium-glucose cotransporter 2 inhibitor, was shown in the DAPA-HF study to reduce the risk of worsening heart failure or death in symptomatic patients with left ejection fraction <40%, irrespective of diabetes. The aim of this study was to evaluate eligibility status for dapagliflozin in non-selected patients hospitalized for acute decompensated heart failure (ADHF), as well as prognostic implications of this status. MATERIALS AND METHODS:Analysis of 815 patients recruited in a prospective cohort of acute heart failure at the University Hospitals of Geneva, consisting of consecutive patients admitted with ADHF. Eligibility for dapagliflozin was determined using criteria described DAPA-HF. RESULTS:Of 815 patients, 220 (27%) were eligible for dapagliflozin treatment. In survival analysis, patients who were eligible for dapagliflozin had better clinical outcomes with respect to all-cause mortality and rehospitalization as compared to those who were not eligible. In multivariate analysis, the hazard ratio for all-cause mortality or readmission in patients eligible for dapagliflozin was 0.82 (95% CI 0.68-0.999, P = .049) as compared to the non-eligible. CONCLUSIONS:Using DAPA-HF criteria, only 27% of non-selected patients admitted for ADHF are theoretically eligible for dapagliflozin. This eligibility for dapagliflozin is associated with better outcomes. Further evaluation of the benefits of dapagliflozin in selected HF patients may be of interest. This may have implications for selection criteria in future randomized effectiveness studies. 10.1111/eci.13245
    Effects of dapagliflozin in DAPA-HF according to background heart failure therapy. Docherty Kieran F,Jhund Pardeep S,Inzucchi Silvio E,Køber Lars,Kosiborod Mikhail N,Martinez Felipe A,Ponikowski Piotr,DeMets David L,Sabatine Marc S,Bengtsson Olof,Sjöstrand Mikaela,Langkilde Anna Maria,Desai Akshay S,Diez Mirta,Howlett Jonathan G,Katova Tzvetana,Ljungman Charlotta E A,O'Meara Eileen,Petrie Mark C,Schou Morten,Verma Subodh,Vinh Pham Nguyen,Solomon Scott D,McMurray John J V European heart journal AIMS:In the DAPA-HF trial, the SGLT2 inhibitor dapagliflozin reduced the risk of worsening heart failure (HF) and death in patients with HF and reduced ejection fraction. We examined whether this benefit was consistent in relation to background HF therapy. METHODS AND RESULTS:In this post hoc analysis, we examined the effect of study treatment in the following yes/no subgroups: diuretic, digoxin, mineralocorticoid receptor antagonist (MRA), sacubitril/valsartan, ivabradine, implanted cardioverter-defibrillating (ICD) device, and cardiac resynchronization therapy. We also examined the effect of study drug according to angiotensin-converting enzyme inhibitor/angiotensin receptor blocker dose, beta-blocker (BB) dose, and MRA (≥50% and <50% of target dose). We analysed the primary composite endpoint of cardiovascular death or a worsening HF event. Most randomized patients (n = 4744) were treated with a diuretic (84%), renin-angiotensin system (RAS) blocker (94%), and BB (96%); 52% of those taking a BB and 38% taking a RAS blocker were treated with ≥50% of the recommended dose. Overall, the dapagliflozin vs. placebo hazard ratio (HR) was 0.74 [95% confidence interval (CI) 0.65-0.85] for the primary composite endpoint (P < 0.0001). The effect of dapagliflozin was consistent across all subgroups examined: the HR ranged from 0.57 to 0.86 for primary endpoint, with no significant randomized treatment-by-subgroup interaction. For example, the HR in patients taking a RAS blocker, BB, and MRA at baseline was 0.72 (95% CI 0.61-0.86) compared with 0.77 (95% CI 0.63-0.94) in those not on all three of these treatments (P-interaction 0.64). CONCLUSION:The benefit of dapagliflozin was consistent regardless of background therapy for HF. 10.1093/eurheartj/ehaa183
    Efficacy and Safety of Dapagliflozin in Heart Failure With Reduced Ejection Fraction According to Age: Insights From DAPA-HF. Martinez Felipe A,Serenelli Matteo,Nicolau Jose C,Petrie Mark C,Chiang Chern-En,Tereshchenko Sergey,Solomon Scott D,Inzucchi Silvio E,Køber Lars,Kosiborod Mikhail N,Ponikowski Piotr,Sabatine Marc S,DeMets David L,Dutkiewicz-Piasecka Monika,Bengtsson Olof,Sjöstrand Mikaela,Langkilde Anna Maria,Jhund Pardeep S,McMurray John J V Circulation BACKGROUND:The DAPA-HF trial (Dapagliflozin and Prevention of Adverse-Outcomes in Heart Failure) showed that dapagliflozin added to other guideline-recommended therapies reduced the risk of mortality and heart failure hospitalization and improved symptoms in patients with heart failure and reduced ejection fraction. We examined the effects of dapagliflozin according to age, given potential concerns about the efficacy and safety of therapies in the elderly. METHODS:Patients in New York Heart Association functional class II or greater with a left ventricular ejection fraction ≤40% and a modest elevation of NT-proBNP (N-terminal pro-B-type natriuretic peptide) were eligible. Key exclusion criteria included systolic blood pressure <95 mm Hg and estimated glomerular filtration rate <30 mL·min·1.73 m. The primary outcome was the composite of an episode of worsening heart failure (heart failure hospitalization or urgent heart failure visit) or cardiovascular death, whichever occurred first. RESULTS:A total of 4744 patients 22 to 94 years of age (mean age, 66.3 [SD 10.9] years) were randomized: 636 patients (13.4%) were <55 years of age, 1242 (26.2%) were 55 to 64 years of age, 1717 (36.2%) were 65 to 74 years of age, and 1149 (24.2%) were ≥75 years of age. The rate of the primary outcome (per 100 person-years, placebo arm) in each age group was 13.6 (95% CI, 10.4-17.9), 15.7 (95% CI, 13.2-18.7), 15.1 (95% CI, 13.1-17.5), and 18.0 (95% CI, 15.2-21.4) with corresponding dapagliflozin/placebo hazard ratios of 0.87 (95% CI, 0.60-1.28), 0.71 (95% CI, 0.55-0.93), 0.76 (95% CI, 0.61-0.95), and 0.68 (95% CI, 0.53-0.88; for interaction=0.76). Consistent benefits were observed for the components of the primary outcome, all-cause mortality, and symptoms. Although adverse events and study drug discontinuation increased with age, neither was significantly more common with dapagliflozin in any age group. CONCLUSIONS:Dapagliflozin reduced the risk of death and worsening heart failure and improved symptoms across the broad spectrum of age studied in DAPA-HF. There was no significant imbalance in tolerability or safety events between dapagliflozin and placebo, even in elderly individuals. CLINICAL TRIAL REGISTRATION:URL: https://www.clinicaltrials.gov. Unique identifier: NCT03036124. 10.1161/CIRCULATIONAHA.119.044133
    Effect of Dapagliflozin on Outpatient Worsening of Patients with Heart Failure and Reduced Ejection Fraction: A Prespecified Analysis of DAPA-HF. Docherty Kieran F,Jhund Pardeep S,Anand Inder,Bengtsson Olof,Böhm Michael,de Boer Rudolf A,DeMets David L,Desai Akshay S,Drozdz Jaroslaw,Howlett Jonathan,Inzucchi Silvio E,Johanson Per,Katova Tzvetana,Køber Lars,Kosiborod Mikhail N,Langkilde Anna Maria,Lindholm Daniel,Martinez Felipe A,Merkely Béla,Nicolau José C,O'Meara Eileen,Ponikowski Piotr,Sabatine Marc S,Sjöstrand Mikaela,Solomon Scott D,Tereshchenko Sergey,Verma Subodh,McMurray John J V Circulation In the Dapagliflozin And Prevention of Adverse-outcomes in Heart Failure trial (DAPA-HF), dapagliflozin, added to guideline-recommended therapies, reduced the risk of mortality and HF hospitalization. We examined the frequency and significance of episodes of outpatient heart failure-worsening, requiring augmentation of oral therapy, and the effects of dapagliflozin on these additional events. Patients in New York Heart Association (NYHA) functional class II-IV, with a left ventricular ejection fraction ≤40%, and elevation of N-terminal pro-B-type natriuretic peptide (NT-proBNP) were eligible. The primary outcome was the composite of an episode of worsening heart failure (HF hospitalization or urgent HF visit requiring intravenous [IV] therapy) or cardiovascular (CV) death, whichever occurred first. An additional prespecified exploratory outcome was the primary outcome plus worsening HF symptoms/signs leading to initiation of new, or augmentation of existing, oral treatment. Overall, 36% more patients experienced the expanded, compared with the primary, composite outcome. In the placebo group, 684/2371 (28.8%) patients, and 527/2373 (22.2%) participants in the dapagliflozin group, experienced the expanded outcome (HR 0.73, 0.65-0.82; P<0.0001); each component of the composite was reduced significantly by dapagliflozin. Over the median follow-up of 18.2 months, the number of patients needed to treat (NNT) with dapagliflozin to prevent one experiencing an episode of fatal or non-fatal worsening was 16. Among the 4744 randomized patients, the first episode of worsening was outpatient augmentation of treatment in 407 participants (8.6%), an urgent HF visit with IV therapy in 20 (0.4%), HF hospitalization in 489 (10.3%) and CV death in 295 (6.2%) patients. The adjusted risk of death from any cause (compared with no event) following an outpatient worsening was HR 2.67 (95%CI 2.03-3.52), after an urgent HF visit 3.00 (1.39-6.48) and after a HF hospitalization 6.21 (5.07-7.62). In DAPA-HF, outpatient episodes of HF worsening were common, of prognostic importance and reduced by dapagliflozin. URL: https://clinicaltrials.gov Unique Identifier: NCT03036124. 10.1161/CIRCULATIONAHA.120.047480
    A trial to evaluate the effect of the sodium-glucose co-transporter 2 inhibitor dapagliflozin on morbidity and mortality in patients with heart failure and reduced left ventricular ejection fraction (DAPA-HF). McMurray John J V,DeMets David L,Inzucchi Silvio E,Køber Lars,Kosiborod Mikhail N,Langkilde Anna M,Martinez Felipe A,Bengtsson Olof,Ponikowski Piotr,Sabatine Marc S,Sjöstrand Mikaela,Solomon Scott D, European journal of heart failure BACKGROUND:Sodium-glucose co-transporter 2 (SGLT2) inhibitors have been shown to reduce the risk of incident heart failure hospitalization in individuals with type 2 diabetes who have, or are at high risk of, cardiovascular disease. Most patients in these trials did not have heart failure at baseline and the effect of SGLT2 inhibitors on outcomes in individuals with established heart failure (with or without diabetes) is unknown. DESIGN AND METHODS:The Dapagliflozin And Prevention of Adverse-outcomes in Heart Failure trial (DAPA-HF) is an international, multicentre, parallel group, randomized, double-blind, study in patients with chronic heart failure, evaluating the effect of dapagliflozin 10 mg, compared with placebo, given once daily, in addition to standard care, on the primary composite outcome of a worsening heart failure event (hospitalization or equivalent event, i.e. an urgent heart failure visit) or cardiovascular death. Patients with and without diabetes are eligible and must have a left ventricular ejection fraction ≤ 40%, a moderately elevated N-terminal pro B-type natriuretic peptide level, and an estimated glomerular filtration rate ≥ 30 mL/min/1.73 m . The trial is event-driven, with a target of 844 primary outcomes. Secondary outcomes include the composite of total heart failure hospitalizations (including repeat episodes), and cardiovascular death and patient-reported outcomes. A total of 4744 patients have been randomized. CONCLUSIONS:DAPA-HF will determine the efficacy and safety of the SGLT2 inhibitor dapagliflozin, added to conventional therapy, in a broad spectrum of patients with heart failure and reduced ejection fraction. 10.1002/ejhf.1432
    Effect of dapagliflozin according to baseline systolic blood pressure in the Dapagliflozin and Prevention of Adverse Outcomes in Heart Failure trial (DAPA-HF). Serenelli Matteo,Böhm Michael,Inzucchi Silvio E,Køber Lars,Kosiborod Mikhail N,Martinez Felipe A,Ponikowski Piotr,Sabatine Marc S,Solomon Scott D,DeMets David L,Bengtsson Olof,Sjöstrand Mikaela,Langkilde Anna Maria,Anand Inder S,Chiang Chern-En,Chopra Vijay K,de Boer Rudolf A,Diez Mirta,Dukát Andrej,Ge Junbo,Howlett Jonathan G,Katova Tzvetana,Kitakaze Masafumi,Ljungman Charlotta E A,Verma Subodh,Docherty Kieran F,Jhund Pardeep S,McMurray John J V European heart journal AIMS:Concern about hypotension often leads to withholding of beneficial therapy in patients with heart failure and reduced ejection fraction (HFrEF). We evaluated the efficacy and safety of dapagliflozin, which lowers systolic blood pressure (SBP),according to baseline SBP in Dapagliflozin and Prevention of Adverse Outcomes in Heart Failure trial (DAPA-HF). METHODS AND RESULTS:Key inclusion criteria were: New York Heart Association Class II-IV, left ventricular ejection fraction ≤ 40%, elevated N-terminal pro-B-type natriuretic peptide level, and SBP ≥95 mmHg. The primary outcome was a composite of worsening heart failure or cardiovascular death. The efficacy and safety of dapagliflozin were examined using SBP as both a categorical and continuous variable. A total of 1205 patients had a baseline SBP <110 mmHg; 981 ≥ 110 < 120; 1149 ≥ 120 < 130; and 1409 ≥ 130 mmHg. The placebo-corrected reduction in SBP from baseline to 2 weeks with dapagliflozin was -2.54 (-3.33 to -1.76) mmHg (P < 0.001), with a smaller between-treatment difference in patients in the lowest compared to highest SBP category. Patients in the lowest SBP category had a much higher rate (per 100 person-years) of the primary outcome [20.6, 95% confidence interval (95% CI) 17.6-24.2] than those in the highest SBP category (13.8, 11.7-16.4). The benefit and safety of dapagliflozin was consistent across the range of SBP; hazard ratio (95% CI) in each SBP group, lowest to highest: 0.76 (0.60-0.97), 0.76 (0.57-1.02), 0.81 (0.61-1.08), and 0.67 (0.51-0.87), P interaction = 0.78. Study drug discontinuation did not differ between dapagliflozin and placebo across the SBP categories examined. CONCLUSION:Dapagliflozin had a small effect on SBP in patients with HFrEF and was superior to placebo in improving outcomes, and well tolerated, across the range of SBP included in DAPA-HF. CLINICAL TRIAL REGISTRATION:ClinicalTrials.gov NCT03036124. 10.1093/eurheartj/ehaa496
    SGLT2 inhibitors in patients with heart failure with reduced ejection fraction: a meta-analysis of the EMPEROR-Reduced and DAPA-HF trials. Zannad Faiez,Ferreira João Pedro,Pocock Stuart J,Anker Stefan D,Butler Javed,Filippatos Gerasimos,Brueckmann Martina,Ofstad Anne Pernille,Pfarr Egon,Jamal Waheed,Packer Milton Lancet (London, England) BACKGROUND:Both DAPA-HF (assessing dapagliflozin) and EMPEROR-Reduced (assessing empagliflozin) trials showed that sodium-glucose co-transporter-2 (SGLT2) inhibition reduced the combined risk of cardiovascular death or hospitalisation for heart failure in patients with heart failure with reduced ejection fraction (HFrEF) with or without diabetes. However, neither trial was powered to assess effects on cardiovascular death or all-cause death or to characterise effects in clinically important subgroups. Using study-level published data from DAPA-HF and patient-level data from EMPEROR-Reduced, we aimed to estimate the effect of SGLT2 inhibition on fatal and non-fatal heart failure events and renal outcomes in all randomly assigned patients with HFrEF and in relevant subgroups from DAPA-HF and EMPEROR-Reduced trials. METHODS:We did a prespecified meta-analysis of the two single large-scale trials assessing the effects of SGLT2 inhibitors on cardiovascular outcomes in patients with HFrEF with or without diabetes: DAPA-HF (assessing dapagliflozin) and EMPEROR-Reduced (assessing empagliflozin). The primary endpoint was time to all-cause death. Additionally, we assessed the effects of treatment in prespecified subgroups on the combined risk of cardiovascular death or hospitalisation for heart failure. These subgroups were based on type 2 diabetes status, age, sex, angiotensin receptor neprilysin inhibitor (ARNI) treatment, New York Heart Association (NYHA) functional class, race, history of hospitalisation for heart failure, estimated glomerular filtration rate (eGFR), body-mass index, and region (post-hoc). We used hazard ratios (HRs) derived from Cox proportional hazard models for time-to-first event endpoints and Cochran's Q test for treatment interactions; the analysis of recurrent events was based on rate ratios derived from the Lin-Wei-Yang-Ying model. FINDINGS:Among 8474 patients combined from both trials, the estimated treatment effect was a 13% reduction in all-cause death (pooled HR 0·87, 95% CI 0·77-0·98; p=0·018) and 14% reduction in cardiovascular death (0·86, 0·76-0·98; p=0·027). SGLT2 inhibition was accompanied by a 26% relative reduction in the combined risk of cardiovascular death or first hospitalisation for heart failure (0·74, 0·68-0·82; p<0·0001), and by a 25% decrease in the composite of recurrent hospitalisations for heart failure or cardiovascular death (0·75, 0·68-0·84; p<0·0001). The risk of the composite renal endpoint was also reduced (0·62, 0·43-0·90; p=0·013). All tests for heterogeneity of effect size between trials were not significant. The pooled treatment effects showed consistent benefits for subgroups based on age, sex, diabetes, treatment with an ARNI and baseline eGFR, but suggested treatment-by-subgroup interactions for subgroups based on NYHA functional class and race. INTERPRETATION:The effects of empagliflozin and dapagliflozin on hospitalisations for heart failure were consistent in the two independent trials and suggest that these agents also improve renal outcomes and reduce all-cause and cardiovascular death in patients with HFrEF. FUNDING:Boehringer Ingelheim. 10.1016/S0140-6736(20)31824-9
    Dapagliflozin and Diuretic Use in Patients With Heart Failure and Reduced Ejection Fraction in DAPA-HF. Jackson Alice M,Dewan Pooja,Anand Inder S,Bělohlávek Jan,Bengtsson Olof,de Boer Rudolf A,Böhm Michael,Boulton David W,Chopra Vijay K,DeMets David L,Docherty Kieran F,Dukát Andrej,Greasley Peter J,Howlett Jonathan G,Inzucchi Silvio E,Katova Tzvetana,Køber Lars,Kosiborod Mikhail N,Langkilde Anna Maria,Lindholm Daniel,Ljungman Charlotta E A,Martinez Felipe A,O'Meara Eileen,Sabatine Marc S,Sjöstrand Mikaela,Solomon Scott D,Tereshchenko Sergey,Verma Subodh,Jhund Pardeep S,McMurray John J V Circulation 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 ( 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. 10.1161/CIRCULATIONAHA.120.047077
    Efficacy and safety of sodium-glucose co-transporter 2 inhibition according to left ventricular ejection fraction in DAPA-HF. Dewan Pooja,Solomon Scott D,Jhund Pardeep S,Inzucchi Silvio E,Køber Lars,Kosiborod Mikhail N,Martinez Felipe A,Ponikowski Piotr,DeMets David L,Sabatine Marc S,Bengtsson Olof,Sjöstrand Mikaela,Langkilde Anna Maria,Anand Inder S,Bělohlávek Jan,Chopra Vijay K,Dukát Andrej,Kitakaze Masafumi,Merkely Béla,O'Meara Eileen,Schou Morten,Vinh Pham Nguyen,McMurray John J V, European journal of heart failure AIMS:The aim of this study was to examine whether left ventricular ejection fraction (LVEF) modified efficacy and safety of dapagliflozin 10 mg compared with placebo in the 4744 patients with LVEF ≤40% randomized in the Dapagliflozin And Prevention of Adverse-outcomes in Heart Failure trial (DAPA-HF). METHODS AND RESULTS:We examined whether LVEF, analysed categorically or continuously, modified the effect of dapagliflozin. The primary efficacy outcome was the composite of a worsening heart failure (HF) event (unplanned HF hospitalization/an urgent HF visit requiring intravenous therapy) or cardiovascular death. Mean LVEF was 31.1% and LVEF categories analysed were: <26% (n = 1143), 26-30% (n = 1018), 31-35% (n = 1187), and >35% (n = 1396). Each 5% decrease in LVEF was associated with a higher risk of the primary outcome [hazard ratio (HR) 1.18; 95% confidence interval (CI) 1.13-1.24]. The benefit of dapagliflozin was consistent across the spectrum of LVEF: the dapagliflozin vs. placebo HR was 0.75 (95% CI 0.59-0.95) for LVEF <26%, 0.75 (0.57-0.98) for LVEF 26-30%, 0.67 (0.51-0.89) for LVEF 31-35%, and 0.83 (0.63-1.09) for LVEF >35% (P for interaction = 0.762). Similarly, the effect of dapagliflozin on the components of the primary endpoint was not modified by baseline LVEF (P for interaction for cardiovascular death = 0.974, and for worsening HF = 0.161). Safety of dapagliflozin was also consistent across the range of LVEF and neither efficacy nor safety were modified by diabetes status. CONCLUSION:Left ventricular ejection fraction was a significant predictor of hospitalization and mortality in patients with HF with reduced ejection fraction but did not modify the beneficial effect of dapagliflozin, overall or separately, in patients with and without diabetes. CLINICAL TRIAL REGISTRATION:ClinicalTrials.gov Identifier NCT03036124. 10.1002/ejhf.1867
    Effect of Dapagliflozin in Patients With HFrEF Treated With Sacubitril/Valsartan: The DAPA-HF Trial. Solomon Scott D,Jhund Pardeep S,Claggett Brian L,Dewan Pooja,Køber Lars,Kosiborod Mikhail N,Martinez Felipe A,Ponikowski Piotr,Sabatine Marc S,Inzucchi Silvio E,Desai Akshay S,Bengtsson Olof,Lindholm Daniel,Sjostrand Mikaela,Langkilde Anna Maria,McMurray John J V JACC. Heart failure OBJECTIVES:This study assessed the efficacy and safety of dapagliflozin in patients who were or were not taking sacubitril/valsartan at baseline in the DAPA-HF (Study to Evaluate the Effect of Dapagliflozin on the Incidence of Worsening Heart Failure or Cardiovascular Death in Patients With Chronic Heart Failure) trial. BACKGROUND:Both the angiotensin receptor neprilysin-inhibitor sacubitril/valsartan and the sodium glucose co-transporter 2 inhibitor dapagliflozin reduced cardiovascular death and heart failure (HF) hospitalization in patients with HF with reduced ejection fraction (HFrEF). Whether either of these classes of drugs influences the effectiveness or safety of the other remains unknown. METHODS:DAPA-HF was a 4,744 patient trial that compared dapagliflozin with placebo in patients with HFrEF. Patients were analyzed according to whether they were taking sacubitril/valsartan at randomization. The efficacy of dapagliflozin on the primary composite outcome (CV death or episode of worsening heart failure), its components, and all-cause death was examined according to sacubitril/valsartan and the interaction tested. Predefined safety outcomes were examined by sacubitril/valsartan group. RESULTS:A total of 508 patients (10.7%) enrolled in DAPA-HF were treated with sacubitril/valsartan at baseline. Patients prescribed sacubitril/valsartan were more likely to be from North America or Europe, to have lower ejection fractions and systolic and diastolic blood pressures, but were similar with respect to age, New York Heart Association functional class, history of diabetes, and use of other evidence-based HF therapies. The benefit of dapagliflozin compared with placebo was similar in patients taking sacubitril/valsartan (hazard ratio: 0.75; 95% confidence interval 0.50 to 1.13) compared with those not taking sacubitril/valsartan (hazard ratio: 0.74; 95% confidence interval 0.65 to 0.86) for the primary endpoint of cardiovascular death or worsening HF; similar findings were observed for secondary endpoints. All measures of safety, including episodes related to hypovolemia, were similar among patients randomized to dapagliflozin or placebo, whether they received background sacubitril/valsartan. CONCLUSIONS:Dapagliflozin was similarly efficacious and safe in patients who were and who were not taking sacubitril/valsartan in the DAPA-HF trial, which suggested that the use of both agents together could further lower morbidity and mortality in patients with HFrEF. (Dapagliflozin And Prevention of Adverse outcomes in Heart Failure [DAPA-HF]; NCT03036124). 10.1016/j.jchf.2020.04.008
    The Dapagliflozin And Prevention of Adverse-outcomes in Heart Failure (DAPA-HF) trial: baseline characteristics. McMurray John J V,DeMets David L,Inzucchi Silvio E,Køber Lars,Kosiborod Mikhail N,Langkilde Anna Maria,Martinez Felipe A,Bengtsson Olof,Ponikowski Piotr,Sabatine Marc S,Sjöstrand Mikaela,Solomon Scott D, European journal of heart failure BACKGROUND:The aims of this study were to: (i) report the baseline characteristics of patients enrolled in the Dapagliflozin And Prevention of Adverse-outcomes in Heart Failure (DAPA-HF) trial, (ii) compare DAPA-HF patients to participants in contemporary heart failure (HF) registries and in other recent HF trials, and (iii) compare individuals with diabetes, pre-diabetes and a normal glycated haemoglobin (HbA1c) in DAPA-HF. METHODS AND RESULTS:Adults with HF in New York Heart Association functional class ≥ II, a left ventricular ejection fraction ≤ 40%, an elevated N-terminal pro-B-type natriuretic peptide concentration and receiving standard treatment were eligible for DAPA-HF, which is comparing dapagliflozin 10 mg once daily to matching placebo. In patients without a history of diabetes, previously undiagnosed diabetes was defined as a confirmed HbA1c ≥ 6.5%. Among patients without known or undiagnosed diabetes, pre-diabetes was defined as a HbA1c ≥ 5.7% The remainder of patients, with a HbA1c < 5.7%, were defined as normoglycaemic. Of the 4744 patients (mean age 66 years; 23% women) randomized, 42% had known diabetes and 3% undiagnosed diabetes. Of the remainder, 67% had pre-diabetes and 33% normal HbA1c. Overall, DAPA-HF patients were generally similar to those in recent registries and in relevant trials and had high levels of background therapy: 94% angiotensin-converting enzyme inhibitor/angiotensin receptor blocker/angiotensin receptor-neprilysin inhibitor, 96% beta-blocker, and 71% mineralocorticoid receptor antagonist; 26% had a defibrillator. Patients with diabetes had worse HF status, more co-morbidity, and greater renal impairment but received similar HF therapy. Patients with diabetes received non-insulin hypoglycaemic therapy alone in 49%, insulin alone in 11%, both in 14%, and none in 26%. CONCLUSIONS:Patients randomized in DAPA-HF were similar to those in other contemporary HF with reduced ejection fraction (HFrEF) registries and trials. These patients were receiving recommended HFrEF therapy and those with diabetes were also treated with conventional glucose-lowering therapy. Consequently, DAPA-HF will test the incremental efficacy and safety of dapagliflozin in HFrEF patients with and without diabetes. CLINICAL TRIAL REGISTRATION:ClinicalTrials.gov Identifier NCT03036124. 10.1002/ejhf.1548
    Estimated Population Prevalence of Heart Failure with Reduced Ejection Fraction in Spain, According to DAPA-HF Study Criteria. Camps-Vilaró Anna,Delgado-Jiménez Juan F,Farré Núria,Tizón-Marcos Helena,Álvarez-García Jesús,Cinca Juan,Dégano Irene R,Marrugat Jaume Journal of clinical medicine Heart failure (HF) is one of the main causes of morbidity, mortality, and high healthcare costs. Dapagliflozin, a sodium-glucose cotransporter-2 (SGLT2) inhibitor, reduced cardiovascular mortality and hospitalization for HF compared to placebo in patients with chronic HF, and reduced ejection fraction (EF) in the Dapagliflozin and Prevention of Adverse Outcomes in Heart Failure (DAPA-HF) study. Our aim was to estimate the number of patients with DAPA-HF characteristics in Spain. Our literature review identified epidemiological studies whose objective was to quantify the prevalence of HF and its comorbidities in Spain. We estimated the prevalence of HF with reduced EF, of New York Heart Association (NYHA) functional class II-IV, and with a glomerular filtration rate (GFR) ≥ 30 mL/min/1.73 m². In this population, we analysed the prevalence of diabetes using data from the REDINSCOR (Spanish Network for Heart Failure) registry. Our estimations indicate there are 594,684 patients ≥45 years old with HF in Spain (2.6% of this population age group), of which 52.4%, 84.0%, and 93.9% have reduced EF, are NYHA II-IV, and have a GFR ≥ 30 mL/min/1.73 m², respectively. By our calculations, approximately 245,789 Spanish patients would meet the DAPA-HF patient profile, and therefore could benefit from the protective cardiovascular effects of dapagliflozin. 10.3390/jcm9072089