Effect of Dapagliflozin on Worsening Heart Failure and Cardiovascular Death in Patients With Heart Failure With and Without Diabetes

Petrie, Mark C.; Verma, Subodh; Docherty, Kieran F.; Inzucchi, Silvio E.; Anand, Inder; Bělohlávek, Jan; Böhm, Michael; Chiang, Chern‐En; Chopra, Vijay; Boer, Rudolf A. de; Desai, Akshay S.; Díez, Mirta; Dróżdż, Jarosław; Dukát, Andre; Ge, Junbo; Howlett, Jonathan G.; Katova, Tzvetana; Kitakaze, Masafumi; Ljungman, Charlotta; Merkely, Béla; Nicolau, José Carlos; O’Meara, Eileen; Vinh, Pham Nguyễn; Schou, Morten; Tereshchenko, S. N.; Køber, Lars; Kosiborod, Mikhail; Langkilde, Anna Maria; Martínez, Felipe A.; Ponikowski, Piotr; Sabatine, Marc S.; Sjöstrand, Mikaela; Solomon, Scott D.; Johanson, Per; Greasley, Peter J.; Boulton, David W.; Bengtsson, Olof; Jhund, Pardeep S.; McMurray, John J.V.

doi:10.1001/jama.2020.1906

Cited by 402 publications

(424 citation statements)

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“…However, the hypothesis that SGLT-2i might be an effective treatment for a broad range of patients with heart failure, including those with preserved ejection fraction (HFpEF), remains mysterious. Besides, trials assessing the effect of SGLT-2 inhibitors on cardiovascular outcomes may have different scales of effects on clinical outcomes [9][10][11][12][13]. Consistent with the results of the DAPA-HA trial, the CANVAS Program [10] found that canagli ozin signi cantly reduced the risk of cardiovascular death or hospitalization for heart failure in patients with HF concomitant with T2DM.…”

Section: Introductionmentioning

confidence: 74%

“…One study (the CREDENCE trial [13]) was described in an abstract but was eligible and included in this meta-analysis because the complete data were available. All of the studies were randomized, double-blind, placebo-controlled trials (the DECLARE-TIMI 58 trial [9], the CANVAS Program [10], the DAPA-HF trial [11], the EMPA-REG OUTCOME trial [12] and the CREDENCE trial [13]), involving a total of 6945 patients with HF and T2DM. Among the enrolled patients, 4686 (67.5%) were male and 2259 (32.5%) were female.…”

Section: Literature Search Results and Characteristics Of Identi Ed Smentioning

confidence: 99%

“…Alternatively, the DECLARE-TIMI 58 trial [9], DAPA-HF trial [11] and EMPA-REG OUTCOME trial [12] reported the frequency of different outcomes in the treatment and placebo groups. We thus extracted the data (supplementary table 1 Figure 3A), hospitalization for heart failure (weighted proportions: 10.9% vs 13.9%; RR 0.77, 95% CI 0.67-0.90, p=0•0009; Figure 3B) and all-cause mortality (weighted proportions: 12.8% vs 15.6%; RR 0.82, 95% CI 0.71-0.94, p=0•005; Figure 3D).…”

Section: Sensitivity Analysismentioning

confidence: 99%

“…Serious AEs were considered the safety outcome in this meta-analysis, and the incidence rate was reported in three trials [9,11,12]. The relatively common adverse events of interest were volume depletion and kidney impairment (less than 10%), but the incidence of these adverse events did not differ signi cantly between the SGLT-2i and placebo groups.…”

Section: Safety Outcomementioning

confidence: 99%

“…Impressively, the results from large-scale randomized clinical trials (RCTs), such as the EMPA-REG OUTCOME [7] Moreover, sub-analyses revealed that patients with HF at baseline appear to experience greater bene ts from those medications [9,10]. In addition, a very recent landmark trial (DAPA-HF trial) reported that a SGLT-2 inhibitor, namely, dapagli ozin, markedly reduced mortality and worsening heart failure in patients with heart failure with reduced ejection fraction (HFrEF) [11]. Of note, the bene ts were observed in both patients with T2DM and patients without T2DM.…”

Section: Introductionmentioning

confidence: 99%

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Effect of SGLT-2 Inhibitors on Cardiovascular Outcomes Among Patients With Heart Failure and Type 2 Diabetes Mellitus: A Systemic Review and Meta-Analysis of Randomized Controlled Trials

Lü¹,

Yu²,

Fan³

et al. 2020

Preprint

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Background Sodium-glucose cotransporter-2 inhibitors (SGLT-2i) are significantly effective in reducing cardiovascular events in patients with type 2 diabetes mellitus (T2DM). However, the magnitude of the effect of SGLT-2i on cardiovascular outcomes in established heart failure (HF) patients with T2DM remains undefined. Methods We systematically searched the PubMed, Embase, Cochrane Central and Web of Science databases for articles published prior to 09 April 2020 to identify randomized controlled trials that compared SGLT-2i with placebo in patients with heart failure concomitant with T2DM. Efficacy outcomes included the composite of cardiovascular death (CVD) or hospitalization for heart failure (HHF), individual CVD, individual HHF, and all-cause mortality (ACM). Hazard ratios (HRs) with 95% confidence intervals (95% CIs) were pooled across trials by using the generic inverse variance method. Sensitivity analyses were conducted by excluding specific studies or using risk ratios (RRs) with 95% CIs as measures of the effect size. Serious adverse events served as safety outcomes. Results A total of 5 large trials comprising 6945 patients with HF and T2DM were enrolled. Pooled data demonstrated that SGLT-2i significantly reduced the risk for the primary composite outcome of CVD or HHF by 13% (HR: 0.87, 95% CI: 0.83–0.91, I2: 0%, P < 0.00001) in patients with HF concomitant with T2DM. Similarly, the use of SGLT-2i was associated with a statistically significant 14% reduction in HHF (pooled HR: 0.86, 95% CI: 0.81–0.91, I2: 0%, P < 0.00001) and a 10% reduction in ACM (pooled HR: 0.90, 95% CI: 0.86–0.96, I2: 16%, P < 0.0005) but was not significantly associated with a reduction in CVD (HR: 0.91, 95% CI: 0.81–1.02, I2: 60%, P = 0.11). Sensitivity analyses indicted consistent results. Compared with placebo plus standard care, the SGLT-2i group had a lower proportion of serious adverse events (weighted proportions: 44.3% vs 50.3%; RR 0.88, 95% CI 0.82–0.95, I2: 22%, p = 0∙006). Conclusions SGLT-2i significantly reduced the risk of HHF and ACM in a broad range of HF patients concomitant with T2DM. Compared with standard care, SGLT-2i plus standard therapy was associated with a reduction in serious adverse events.

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Section: Introductionmentioning

confidence: 74%

Section: Literature Search Results and Characteristics Of Identi Ed Smentioning

confidence: 99%

Section: Sensitivity Analysismentioning

confidence: 99%

Section: Safety Outcomementioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Effect of SGLT-2 Inhibitors on Cardiovascular Outcomes Among Patients With Heart Failure and Type 2 Diabetes Mellitus: A Systemic Review and Meta-Analysis of Randomized Controlled Trials

Lü¹,

Yu²,

Fan³

et al. 2020

Preprint

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Heart Failure With Reduced Ejection Fraction

Murphy

Ibrahim

Januzzi

2020

JAMA

495

325

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ImportanceWorldwide, the burden of heart failure has increased to an estimated 23 million people, and approximately 50% of cases are HF with reduced ejection fraction (HFrEF).ObservationsHeart failure is a clinical syndrome characterized by dyspnea or exertional limitation due to impairment of ventricular filling or ejection of blood or both. HFrEF occurs when the left ventricular ejection fraction (LVEF) is 40% or less and is accompanied by progressive left ventricular dilatation and adverse cardiac remodeling. Assessment for heart failure begins with obtaining a medical history and physical examination. Also central to diagnosis are elevated natriuretic peptides above age- and context-specific thresholds and identification of left ventricular systolic dysfunction with LVEF of 40% or less as measured by echocardiography. Treatment strategies include the use of diuretics to relieve symptoms and application of an expanding armamentarium of disease-modifying drug and device therapies. Unless there are specific contraindications, patients with HFrEF should be treated with a β-blocker and one of an angiotensin receptor–neprilysin inhibitor, angiotensin-converting enzyme inhibitor, or angiotensin receptor blocker as foundational therapy, with addition of a mineralocorticoid receptor antagonist in patients with persistent symptoms. Ivabradine and hydralazine/isosorbide dinitrate also have a role in the care of certain patients with HFrEF. More recently, sodium-glucose cotransporter 2 (SGLT2) inhibitors have further improved disease outcomes, significantly reducing cardiovascular and all-cause mortality irrespective of diabetes status, and vericiguat, a soluble guanylate cyclase stimulator, reduces heart failure hospitalization in high-risk patients with HFrEF. Device therapies may be beneficial in specific subpopulations, such as cardiac resynchronization therapy in patients with interventricular dyssynchrony, transcatheter mitral valve repair in patients with severe secondary mitral regurgitation, and implantable cardiac defibrillators in patients with more severe left ventricular dysfunction particularly of ischemic etiology.Conclusions and RelevanceHFrEF is a major public health concern with substantial morbidity and mortality. The management of HFrEF has seen significant scientific breakthrough in recent decades, and the ability to alter the natural history of the disease has never been better. Recent developments include SGLT2 inhibitors, vericiguat, and transcatheter mitral valve repair, all of which incrementally improve prognosis beyond foundational neurohormonal therapies. Disease morbidity and mortality remain high, with a 5-year survival rate of 25% after hospitalization for HFrEF.

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A Novel Cardioprotective Therapy That Also Improves Glycemia

Neal

Arnott

2020

JAMA

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The profound effects of sodium-glucose transporter 2 (SGLT2) inhibition on the risks of cardiovascular complications in patients with hyperglycemia have provided for rapid and substantive changes to diabetes guidelines from various countries. In this issue of JAMA, Petrie and colleagues 1 report findings from a highly informative exploratory analysis of the most recent large-scale clinical trial of an SGLT2 inhibitor that may suggest the next chapter for this drug class-the transition from a glucose-lowering therapy that provides cardioprotection to a cardioprotective agent that happens to lower blood glucose.The main results of the Dapagliflozin and Prevention of Adverse Outcomes in Heart Failure (DAPA-HF) trial were reported in 2019, and it was the first large-scale trial of an SGLT2 inhibitor designed specifically to assess the effects of the drug on clinical cardiovascular end points in patients with heart failure. 2 The high-quality trial showed definitive evidence of protection against a broad range of cardiovascular and kidney complications for patients with heart failure and reduced ejection fraction (HFrEF). The results confirmed and extended benefits anticipated from secondary analyses of the 4 prior large-scale outcome trials conducted in a broader set of patients with diabetes. 3 In addition to the specific focus on patients with heart failure at baseline, the design feature of the DAPA-HF trial that distinguished it from its predecessors was the inclusion, for the first time, of patients without diabetes at enrollment. In the present report in JAMA, Petrie et al 1 defined the effects of SGLT2 inhibition on various outcomes among patients with diabetes vs those without diabetes. The investigators enrolled 4744 patients with HFrEF from 410 sites in 20 countries. 1 Patients were eligible if they met the following criteria: aged 18 years or older; New York Heart Association class II, III, or IV symptoms; an ejection fraction of 40% or less; and an elevated level of plasma N-terminal pro-B-type natriuretic peptide (NT-proBNP). The majority of participants (2605 [55%]) had no history of diabetes at baseline.Patients were randomized to receive 10 mg of dapagliflozin daily (n = 2373 [1075 with type 2 diabetes]) or matched placebo (n = 2371 [1064 with type 2 diabetes]). Patients were followed up for a median of 18 months, and the primary outcome was a composite of worsening heart failure or cardiovascular death. Among patients with diabetes, the primary outcome occurred in 215 of 1075 patients (20.0%) in the dapagliflozin group and 271 of 1064 patients (25.5%) in the placebo group (hazard ratio, 0.75 [95% CI, 0.63-0.90]); among participants without diabetes, the primary outcome occurred in 171 of 1298 (13.2%) patients in the dapagliflozin group and 231

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Effect of Dapagliflozin on Worsening Heart Failure and Cardiovascular Death in Patients With Heart Failure With and Without Diabetes

Cited by 402 publications

References 36 publications

Effect of SGLT-2 Inhibitors on Cardiovascular Outcomes Among Patients With Heart Failure and Type 2 Diabetes Mellitus: A Systemic Review and Meta-Analysis of Randomized Controlled Trials

Effect of SGLT-2 Inhibitors on Cardiovascular Outcomes Among Patients With Heart Failure and Type 2 Diabetes Mellitus: A Systemic Review and Meta-Analysis of Randomized Controlled Trials

Heart Failure With Reduced Ejection Fraction

A Novel Cardioprotective Therapy That Also Improves Glycemia

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