Cardiovascular disease (CVD) is the leading cause of mortality among men and women in the United States,¹ with substantially higher rates in patients with diabetes mellitus.² However, until the 2008 FDA guidance mandating that new antidiabetic therapies be evaluated for increased cardiovascular risk, new therapies did not routinely present cardiovascular outcome data.³ As a -result, companies were urged to report cardiovascular events from appropriately sized phase 2 and phase 3 studies in order to demonstrate a "meaningful estimate of risk."³ Cardiovascular outcome trials (CVOTs) were thus only recently recommended and developed prior to approval for all new antidiabetic agents.³

Since 2008, findings of the ensuing CVOTs have shown differing ability to reduce CVD, with select drug classes exhibiting great potential to revolutionize the management of cardiovascular disease risk in diabetics. In addition to improvements in glycemic control, two classes of agents have produced reductions in major adverse cardiovascular events (MACE) and cardiovascular mortality, the occurrence and progression of renal disease and heart failure (HF) hospitalizations.⁴

Sodium-glucose co-transporter-2 (SGLT-2) inhibitors are a newer class of medications which exert their effect on glycemic control by inhibiting the resorption of glucose at the proximal tubule of the kidney, thus promoting glycosuria. Medications in this class have been extensively studied in CVOTs and include canagliflozin, empagliflozin, ertugliflozin and dapagliflozin. In this article, we review the new and emerging evidence for dapagliflozin and highlight its demonstrated cardiovascular health effects.

Dapagliflozin safety was studied in the Dapagliflozin and Cardiovascular Outcomes in Type 2 Diabetes (DECLARE-TIMI 58) CVOT, a randomized, placebo-controlled trial of over 17,000 patients with or at risk of atherosclerotic CVD (60% without ASCVD) randomized to 10mg of dapagliflozin or placebo.⁵ After a median follow-up of 4.2 years, the authors found non-inferiority for MACE across treatment arms, additionally noting a significant reduction in composite cardiovascular death and HF compared to placebo, a finding driven by reduction in HF hospitalizations.⁵ This difference in cardiovascular mortality or hospitalizations for HF did not differ between the primary prevention or secondary prevention subgroups.⁵

In a recent sub-analysis of the DECLARE-TIMI trial, Furtado et al. reported results for those with and without a prior history of myocardial infarction (MI).⁶ Approximately 20% of participants had a history of MI at baseline (3,584 patients).⁶ Contrary to the primary trial results of the DECLARE study, MACE was significantly lower in participants in the dapagliflozin arm whom had a history of prior MI (HR 0.84, 95% CI 0.72-0.99) compared to those without a prior history of MI (HR 1.00, 95% CI 0.88-1.13).⁶ This effect was largely due to the higher rates of recurrent MI in those with a prior history of MI, including history of Type I (HR 0.80, 95% CI 0.63-1.02) and Type II (HR 0.64, 95% CI 0.42-0.97) MI.⁶ There was no difference in HF hospitalizations or CV mortality based on prior MI status.⁶

The DECLARE-TIMI trial also demonstrated a reduction of incident HF, further raising questions regarding the interplay of dapagliflozin and HF. In a separate sub-analysis, Kato et al. assessed the effects of dapagliflozin according to HF status and baseline left ventricular ejection fraction (LVEF), defining HF with reduced LVEF as LVEF less than 45% (regardless of whether a patient had a history of HF).⁷ They found a large reduction in CVD mortality and HF hospitalizations in those with baseline reduced LVEF (HR 0.62, 95% CI 0.45-0.86) and reported no difference in these outcomes with dapagliflozin therapy in those with HF without reduced LVEF or those without a history of HF (HR 0.88, 95% CI 0.66-1.17 and HR 0.88, 95% CI 0.74-1.03, respectively).⁷ Furthermore, all-cause mortality and CVD mortality were significantly lower in the dapagliflozin arm for participants with HF with reduced LVEF but not in participants without a history of HF.⁷

Building on the findings of Kato et al., two upcoming trials, Study to Evaluate the Effect of Dapagliflozin on the Incidence of Worsening Heart Failure or Cardiovascular Death in Patients With Chronic Heart Failure (DAPA-HF) and Dapagliflozin Evaluation to Improve the LIVEs of Patients With PReserved Ejection Fraction Heart Failure (DELIVER), aim to better characterize the effects of SGLT-2 inhibitors, and dapagliflozin in particular, on HF.^8,9

Designed to assess the composite outcome of worsened HF or CV mortality, DAPA-HF enrolled 4700 participants and is expected to be completed in July of this year. It aims to determine the role of dapafliglozin as an adjunct to traditional goal directed medical therapy in those with HF with reduced LVEF (defined as LVEF ≤ 40%), regardless of diabetes mellitus status.⁸ This study will address important considerations for cardiologists and other clinicians alike, such as: 1) will previously described benefits of SGLT-2 inhibitor therapy extend to patients without diabetes mellitus; and 2) can SGLT-2 inhibitor therapy slow or reduce the progression of HF severity?

Similarly, the DELIVER study aims to recruit 4700 participants and is scheduled to be completed in June 2021. It aims to assess the effects of dapafliglozin as an adjunct to standard of care in patients with HF without reduced LVEF (defined as LVEF >40%) to determine the effects on worsened heart failure events or CV mortality.⁹ This study will elucidate what role, if any, SGLT-2 inhibitors have in patients with functional cardiovascular impairment who may or may not suffer from glucose intolerance or frank diabetes mellitus.

In summary, current data strongly supports considering dapagliflozin or alternate SGLT-2 inhibitors early in the management of diabetes mellitus in patients at cardiovascular risk broadly, and in particular those with HF with reduced LVEF or a prior history of MI. Research on the role of SGLT-2 inhibitors in patients with HF with or without diabetes mellitus is ongoing. While extensive heterogeneity exists among patients with HF and much remains unknown on which patients derive the most benefit from SGLT-2 inhibitor therapy, the data to date highlight major potential strides in CVD prevention in general and hold great promise for the treatment of patients at risk of heart failure and cardiovascular disease mortality.¹⁰

The authors are deeply indebted to Drs. Blumenthal and Blaha for the critical review of this piece.

References

1. US Department of Health and Human Services Centers for Disease Control and Prevention. Heart Disease Facts: United States, 2017. Accessed May 10, 2019.
2. Campbell PT, Newton CC, Patel AV, Jacobs EJ, Gapstur SM. Diabetes and cause-specific mortality in a prospective cohort of one million U.S. adults. Diabetes Care 2012;35:1835-44.
3. US Department of Health and Human Services Food and Drug Administration Center for Drug Evaluation and Research. Guidance for Industry on Diabetes Mellitus-Evaluating Cardiovascular RIsk in New Antidiabetic Therapies to Treat Type 2 Diabetes: United States, 2008. Accessed May 10, 2019.
4. Ferraro RA, Nass CM, Dudum R, Blumenthal RS, Sarkar S. What clinicians need to know about the cardiovascular effects of the most recent classes of drugs used for type 2 diabetes. Am J Med 2019. [Epub ahead of print]
5. Wiviott SD, Raz I, Bonaca MP, et al. Dapagliflozin and cardiovascular outcomes in type 2 diabetes. N Engl J Med 2019;380:347-57.
6. Furtado RHM, Bonaca MP, Raz I, et al. Dapagliflozin and cardiovascular outcomes in patients with type 2 diabetes and prior myocardial infarction: a sub-analysis from DECLARE-TIMI-58 trial. Circulation 2019. [Epub ahead of print]
7. Kato ET, Silverman MG, Mosenzon O, et al. Effect of dapagliflozin on heart failure and mortality in type 2 diabetes mellitus. Circulation 2019. [Epub ahead of print]
8. McMurray JJV, DeMets DL, Inzucchi SE, et al. 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 fractino (DAPA-HF). Eur J Heart Fail 2019;21:665-75.
9. ClinicalTrials.gov, Identifier: NCT03619213. Dapagliflozin Evaluation to Improve the LIVEs of Patients With PReserved Ejection Fraction Heart Failure. (DELIVER). Bethesda, MD: National Library of Medicine, 2019.
10. Triposkiadis F, Butler J, Abboud FM. The continuous heart failure spectrum: moving beyond an ejection fraction classification. Eur Heart J 2019. [Epub ahead of print]

Keywords: Hypoglycemic Agents, Diabetes Mellitus, Type 2, Glucose Intolerance, Stroke Volume, Glucose, Secondary Prevention, Cardiovascular Diseases, Risk Factors, Glucosides, Benzhydryl Compounds, Glycosuria, Heart Failure, Myocardial Infarction, Primary Prevention, Diabetes Mellitus, Metabolic Syndrome

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