Heart failure outcomes with empagliflozin in patients with type 2 diabetes at high cardiovascular risk: results of the EMPA-REG OUTCOME<sup>®</sup>trial

Fitchett, David; Zinman, Bernard; Wanner, Christoph; Lachin, John M.; Hantel, Stefan; Salsali, Afshin; Johansen, Odd Erik; Woerle, HJ; Broedl, Uli C.; Inzucchi, Silvio E.

doi:10.1093/eurheartj/ehv728

Cited by 867 publications

(766 citation statements)

References 29 publications

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“…78 In the liraglutide effect and action in diabetes: Evaluation Of Cardiovascular Outcome Results (LEADER) trial, which randomized 9340 T2DM patients with high cardiovascular risk, liraglutide reduced the primary composite endpoint of cardiovascular death, non-fatal MI or non-fatal stroke compared to placebo after a median follow-up of 3years. 79,80 Although not currently FDA approved, semaglutide, a once-weekly GLP-1 agonist, was non-inferior to placebo after 26 months follow up among 3297 patients with T2DM in the Trial to Evaluate Cardiovascular and Other Long-term Outcomes with Semaglutide in Subjects with Type 2 Diabetes (SUSTAIN-6) with regards to the primary composite endpoint of cardiovascular death, non-fatal MI and nonfatal stroke. 81 Notably, majority of the trial patients had established cardiovascular disease, stage 3 or higher chronic kidney disease, or both at baseline.…”

Section: Cardiovascular Safetymentioning

confidence: 99%

“…75,79,81,82 Inhibition of SGLT-2 lowers blood glucose by promoting renal glucose excretion, which is independent of β-cell function and thus carries a low risk for hypoglycemia. 77,78,80,82 Currently, 3 agents are approved in the United States and Europe: dapagliflozin, canagliflozin, and empagliflozin.…”

Section: Sodium Glucose Cotransporter-2 Inhibitorsmentioning

confidence: 99%

“…SGLT-2 inhibitors reduce HbA1c by 0.5-0.7% compared with placebo. [75][76][77][78][79][80][81][82] and promotes weight loss of 2-3 kg over 12 weeks. It has a modest beneficial effect on the lipid profile through an increase in high density lipoprotein cholesterol and decrease in triglycerides.…”

Section: Sodium Glucose Cotransporter-2 Inhibitorsmentioning

confidence: 99%

“…[79][80][81][82] Further analysis showed a 34% relative risk reduction of a composite of heart failure hospitalization or cardiovascular death with empagliflozin. Driven mainly by these results, a metaanalysis of data from regulatory submissions and published trials suggested net protection of SGLT-2 inhibitors against cardiovascular outcomes and death.…”

Section: Cardiovascular Safetymentioning

confidence: 99%

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Cardiovascular safety of oral antidiabetic therapy in type 2 diabetes mellitus- review article

et al. 2017

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Cardiovascular disease is the leading cause of morbidity and mortality among patients with type 2 diabetes mellitus (DM). There is twofold increased risk of cardiovascular (CV) mortality among diabetic patients as compared with nondiabetic patients. The glycemic efficacy of anti-diabetic drugs does not necessarily provide cardiovascular safety. Since 2008, US Food and Drug Administration has recommended that new drugs for type 2 DM should undergo clinical trials to demonstrate cardiovascular safety in addition to glycemic benefit. In 2012, European medicine agencies issued a similar recommendation. In this review, we have tried to examine the cardiovascular safety of oral antidiabetic agents in major published trials. Metformin remains the initial drug of choice in type2 DM till date. The sulfonylureas, one of oldest oral anti-diabetic drugs, have adverse cardiovascular events and are gradually being out classed by other second line drugs. The glitazones have been found to have adverse outcome in heart failure. The incretin based drugs have been found to have cardiovascular safety in various trials in recent past and their performances have been reassuring. There is lack of enough cardiovascular outcome data for meglitinides and glucosidase inhibitors. Various current trials have found sodium glucose cotransporter-2 inhibitors to have a potential for cardiovascular benefit. Careful selection of drug therapy with special attention for cardiovascular risk is important in selection and optimization of diabetic therapy.

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Section: Cardiovascular Safetymentioning

confidence: 99%

Section: Sodium Glucose Cotransporter-2 Inhibitorsmentioning

confidence: 99%

Section: Sodium Glucose Cotransporter-2 Inhibitorsmentioning

confidence: 99%

Section: Cardiovascular Safetymentioning

confidence: 99%

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Cardiovascular safety of oral antidiabetic therapy in type 2 diabetes mellitus- review article

et al. 2017

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“…Recently, some concerns have also been raised with the dipeptidyl peptidase (DPP)-4 inhibitor saxagliptin, following the publication of the Saxagliptin Assessment of Vascular Outcomes Recorded in Patients with Diabetes Mellitus (SAVOR) -Thrombolysis in Myocardial Infarction (TIMI) 53 trial [7], a finding that casts some suspicion on the entire incretin-based pharmacological class [8][9][10]. In contrast, a marked, significant reduction in hospitalizations for HF has been reported with the sodium -glucose cotransporter type 2 (SGLT2) inhibitor empagliflozin in the Empagliflozin Cardiovascular Outcome Event Trial in Type 2 Diabetes Mellitus Patients (EMPA-REG OUTCOME) [11,12]. Because hospital admission for HF is a common and serious factor associated with a higher risk of death, HF is a cardiovascular outcome that can no longer be ignored in diabetic patients, especially when choosing a glucose-lowering agent [13].…”

Section: Introductionmentioning

confidence: 99%

GLP-1 receptor agonists and heart failure in diabetes

Scheen

2017

Diabetes & Metabolism

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The prevalence of heart failure (HF) is increasing in patients with type 2 diabetes (T2D), and glucose-lowering agents have distinctive effects on the risk of developing HF that requires hospitalization. Such an increased risk has been consistently reported with thiazolidinediones (glitazones) and perhaps also with the dipeptidyl peptidase (DPP)-4 inhibitor saxagliptin (at least in SAVOR -TIMI 53), whereas a markedly decreased risk was highlighted with the sodium -glucose cotransporter type 2 (SGLT2) inhibitor empagliflozin in EMPA-REG OUTCOME. Yet, the effects of glucagon-like peptide-1 receptor agonists (GLP-1RAs) on myocardial function remain controversial. Whereas some promising observations have been reported in various animal models, the effects of GLP-1RAs on myocardial function in humans are more heterogeneous, while the positive effect on left ventricular ejection fraction (LVEF), if any, appears to be inconsistent and rather modest in most patients with HF. However, no increased risk of hospitalization for HF has been reported with GLP-1RAs in meta-analyses of phase-II/III trials (exenatide, albiglutide, dulaglutide, liraglutide), demonstrating the safety of this pharmacological class, and such findings have been confirmed by three large prospective cardiovascular outcome trials (ELIXA with lixisenatide, LEADER with liraglutide and SUSTAIN-6 with semaglutide). In particular, LEADER reported a trend towards a reduction in HF hospitalization (-13%, P = 0.14), together with a significant reduction in cardiovascular and all-cause mortality in patients with T2D at risk of cardiovascular disease. These results are reassuring in the face of the somewhat negative results of the FIGHT trial, which evaluated the effects of liraglutide in patients with advanced HF and low LVEF, such that further studies and caution are now required when using this agent to treat such patients in clinical practice.

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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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Heart failure outcomes with empagliflozin in patients with type 2 diabetes at high cardiovascular risk: results of the EMPA-REG OUTCOME^®trial

Cited by 867 publications

References 29 publications

Cardiovascular safety of oral antidiabetic therapy in type 2 diabetes mellitus- review article

Cardiovascular safety of oral antidiabetic therapy in type 2 diabetes mellitus- review article

GLP-1 receptor agonists and heart failure in diabetes

A Novel Cardioprotective Therapy That Also Improves Glycemia

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Heart failure outcomes with empagliflozin in patients with type 2 diabetes at high cardiovascular risk: results of the EMPA-REG OUTCOME®trial

Cited by 867 publications

References 29 publications

Cardiovascular safety of oral antidiabetic therapy in type 2 diabetes mellitus- review article

Cardiovascular safety of oral antidiabetic therapy in type 2 diabetes mellitus- review article

GLP-1 receptor agonists and heart failure in diabetes

A Novel Cardioprotective Therapy That Also Improves Glycemia

Contact Info

Product

Resources

About

Heart failure outcomes with empagliflozin in patients with type 2 diabetes at high cardiovascular risk: results of the EMPA-REG OUTCOME^®trial