The cardiovascular (CV) benefits of the diabetes mellitus (DM) drug dapagliflozin have been observed in the DECLARE-TIMI 58 trial. Dapagliflozin extends its benefits in type 2 DM (T2DM) patients with a wide spectrum of atherosclerotic cardiovascular disease (ASCVD).1 According to a new sub-analysis of the DECLARE-TIMI 58 trial, these benefits were especially pronounced in patients with a reduced ejection fraction and a history of heart failure (HFrEF).2 Related findings were presented at the American College of Cardiology’s (ACC) 68th Annual Scientific Session, March 16th-18th in New Orleans.
Cardio-protective effects of dapagliflozin in T2DM patients
ASCVD is one of the leading causes of death in patients with T2DM. Major adverse CV events (MACE) in patients with T2DM are more severe and occur 14.6 years earlier than individuals without T2DM.3 Consequently, the risk of developing ASCVD is increased twofold among patients with T2DM.3 Dapagliflozin is a sodium-glucose transport protein type 2 (SGLT2) inhibitor used to treat T2DM. It improves glycemic control in adults with T2DM as a monotherapy as well as in a combination therapy with metformin.4,5 In addition to the effective glycemic control, with its effects as a loop diuretic, dapagliflozin exhibits a wide range of cardio and renal-protection.6
The effects of dapagliflozin on CV events were further studied in the DECLARE-TIMI 58 trial investigating the use of dapagliflozin in patients with T2DM and established ASCVD or multiple risk factors for ASCVD.7 It was a randomized, double-blind, multinational, and placebo-controlled phase 3 trial, conducted at 882 sites with 17,000 patients recruited in 33 countries.7 Patients were randomized to receive dapagliflozin or placebo, and followed up for a median time of just over 4 years.7
To prevent new incidences of HF in T2DM patients
The initial findings stemming from the DECLARE-TIMI 58 trial were about T2DM patients with a broad range of variations in ASCVD.1 Treatment with dapagliflozin did not result in higher or lower rate of MACE than placebo, but showed a lower rate of CV death or hospitalization for HF (HR=0.83; 95% CI: 0.73-0.95; p=0.005) regardless of a history of ASCVD or HF.1 Also, the study showed that dapagliflozin could prevent new incidences of HF in a broad range of patients, regardless of a history of ASCVD or HF.1 Sub-analyses were further carried out to assess the CV outcomes of dapagliflozin in dedicated populations at risk for HF.
Reduction of CV death and all-cause mortality in T2DM patients with HFrEF
The new analysis of the DECLARE-TIMI 58 trial was the first to examine whether dapagliflozin’s benefits can be predicted based on the left ventricular ejection fraction (LVEF). LVEF is a measure of how effectively the heart’s left ventricle can squeeze blood out of its chamber. Ejection fraction (EF) is a tool for evaluating heart function objectively and has been shown to predict how well the patients could respond to various therapies and medications.8
Reduced EF can be evidence of HF, though many patients may have HF with normal, or preserved EF. In fact, reduced or preserved EF with previous HF among T2DM patients could lead to more signs of congestion in the heart vessels, worsen quality of life and poorer prognosis.9 In the current analysis, dapagliflozin was proven to decrease the occurrence of HF episodes across all patients regardless of EF or prior HF.2
“I want to emphasize that dapagliflozin reduced hospitalization for HF regardless of the EF or previous history of HF, which is a significant benefit for patients with T2DM” said Dr. Eri T. Kato, the principal investigator of the study from Kyoto Graduate School of Medicine, Japan.10
As HFrEF is a predisposing factor of further episodes of HF and hospitalization, it is regarded as an advanced risk factor for HF. In the subgroup of patients with HFrEF, dapagliflozin significantly reduced the hospitalization due to HF (HR=0.64; 95% CI: 0.43-0.95; p=0.45) (Figure 1A).2 The absolute risk reduction in HF among patients with HFrEF is greater than the wider population. In light of these findings, Dr. Kato remarked, “We all know there are only a few therapies that would improve cardiac outcomes in HFrEF patients, so the fact that we saw a reduction in hospitalization for HF in HFrEF patients is important and huge.”10
Additionally, patients with HFrEF could gain advanced benefits from dapagliflozin, for example, significant reduction of CV death in patients with HFrEF (HR=0.55; 95% CI: 0.34-0.90; p=0.02) compared to patients without HFrEF (Figure 1B).2 Moreover, all-cause mortality was seen to be reduced by dapagliflozin in patients with HFrEF (HR=0.59; 95% CI: 0.40-0.88; p=0.01), but not in those without HFrEF (Figure 1C).2
Given these specific outcomes on the subgroup of HFrEF patients, co-investigator of the study, Dr. Deepak L Bhatt, Bringham and Women’s Hospital, Boston, USA commented, “There is a reduction in all-cause mortality, largely confined to patients who have HFrEF, but that does not diminish the importance in those with HF without known EF or in those with no HF at all”.10 Dr. Bhatt further suggested that although the current study sheds light on the advantages achieved by dapagliflozin in those with worst heart condition, other T2DM patients with less ASCVD could also be benefited.
The benefits of dapagliflozin in reducing CV death, hospitalization due to HF and all-cause mortality in patients with HFrEF appeared early and continued to extend throughout the trial. The reduction of hospitalization due to HF was also observed early in patients with HFrEF, while taking a year or more to be observed in other groups. Nevertheless, the baseline diuretic use in different HF subgroups had no modification effect on the dapagliflozin efficacy. Noting that the interplay between T2DM and HF is complex and multifactorial, Dr. Kato said that further studies are needed to unravel the mechanisms of dapagliflozin on the cardio-protection.10
Dapagliflozin reduces MACE and CV death in T2DM patients with Prior MI
Patients with prior MI also present with a higher risk of incidence for HF and subsequent lower survival in the long-term.11 Another sub-analysis of Declare TIMI 58 trials found that patients with T2DM and prior MI were at increased risk for both MACE and HF events. In this analysis, dapagliflozin reduced MACE, CV death and hospitalization due to HF in patients with T2DM and past MI.12
In patients with a history of MI, dapagliflozin reduced the relative risk of MACE by 16% (HR=0.84; 95% CI: 0.72-0.99; p=0.039) compared to the patients without prior MI.12 Lower rates of MACE in patients with prior MI were driven by lower rates of recurrent MI, CV death, non-fatal or sudden cardiac death.12 Similar to those patients without prior MI, in patients with established ASCVD without a history of MI, there were no significant risk reduction of MACE.12
Patients with prior MI possess higher baseline risk for HF inherently compared to patients without previous MI. This adds to the importance of dapagliflozin in offering higher absolute CV risk reduction for patients with prior MI. In the current analysis, among patients with prior MI, the median time observed from last CV event was 5.4 years. Generally, MACE tended to be higher in patients who had a previous attack recently and dapagliflozin helped reduce the events among patients who were closer to last MI.12 These findings were built on the current guideline recommendations which highlighted that patients with T2DM and a history of MI should be strongly considered for SGLT2 inhibitor therapy in order to reduce the risk for HF.13
Patients who have HFrEF or a history of MI generally face a higher risk of CV events and death compared to those with normal EF or without a history of MI. In the sub analysis of DECLARE-TIMI 58 trial, T2DM patients with HFrEF or a history of MI tended to have greater cardioprotective effects by dapagliflozin. With the positive cardioprotective effects shown, a question is raised regarding whether dapagliflozin could be used in the patients without DM, but hospitalized for acute decompensation. The ongoing clinical trials will answer those questions and determine whether dapagliflozin could be incorporated in the treatment of HF patients without DM.
1. Wiviott SD, Raz I, Sabatine MS. Dapagliflozin and Cardiovascular Outcomes in Type 2 Diabetes. N Engl J Med. 2019;380(19):1881-1882.
2. 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].
3. Saeed A, Ballantyne C. Assessing Cardiovascular Risk and Testing in Type 2 Diabetes. Curr Cardiol Rep. 2017;19(3):19.
4. Rosenstock J, Mathieu C, Chen H et al. Garcia-Sanchez, R. & Saraiva, G. L. Dapagliflozin versus saxagliptin as add-on therapy in patients with type 2 diabetes inadequately controlled with metformin. Arch Endocrinol Metab. 2018;62(4):424-430.
5. Del Prato S, Rosenstock J, Garcia-Sanchez R et al. Safety and tolerability of dapagliflozin, saxagliptin and metformin in combination: Post‐hoc analysis of concomitant add‐on versus sequential add‐on to metformin and of triple versus dual therapy with metformin. Diabetes Obes Metab. 2018;20(6):1542-1546
6. Jabbour S, Seufert J, Scheen A et al. Dapagliflozin in patients with type 2 diabetes mellitus: A pooled analysis of safety data from phase IIb/III clinical trials. Diabetes Obes Metab. 2018;20(3):620-628.
7. Wiviott SD, Raz I, Bonaca MP et al. The design and rationale for the Dapagliflozin Effect on Cardiovascular Events (DECLARE)-TIMI 58 Trial. Am Heart J. 2018;200:83-89.
8. Bellenger NG, Burgess M, Ray SG et al. Comparison of left ventricular ejection fraction and volumes in heart failure by echocardiography, radionuclide ventriculography and cardiovascular magnetic resonance; are they interchangeable? Eur Heart J. 2000;21(16):1387-96.
9. Kristensen SL, Mogensen UM, Jhund PS et al. Clinical and Echocardiographic Characteristics and Cardiovascular Outcomes According to Diabetes Status in Patients With Heart Failure and Preserved Ejection Fraction: A Report From the I-Preserve Trial (Irbesartan in Heart Failure With Preserved Ejection Fraction). Circulation. 2017;135(8):724-735.
10.Less HF Hospitalization on Dapagliflozin in Diabetes at Any LVEF. Medscape (Accessed May 23 2019 at, http://www.medscape.com/viewarticle/911348.)
11.Torabi A, Cleland JG, Khan NK et al. The timing of development and subsequent clinical course of heart failure after a myocardial infarction. Eur Heart J. 2008;29(7):859-70.
12.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]
13.Das SR, Everett BM, Birtcher KK et al. 2018 ACC Expert Consensus Decision Pathway on Novel Therapies for Cardiovascular Risk Reduction in Patients With Type 2 Diabetes and Atherosclerotic Cardiovascular Disease: A Report of the American College of Cardiology Task Force on Expert Consensus Decision Pathways. J Am Coll Cardiol. 2018;72(24):3200-3223.