Dapagliflozin and Cardiovascular Outcomes in Patients with Type 2 Diabetes and Prior MI ACC 2019: A Sub-analysis From DECLARE TIMI-58 Trial

According to a presentation by Dr. Marc P. Bonaca at the American College of Cardiology Annual Scientific Session (ACC 2019), New Orleans, LA on March 18, 2019, patients with type 2 diabetes mellitus (T2DM) and prior MI are at high risk of major adverse cardiovascular events (MACE) and cardiovascular (CV) death/HHF. Dapagliflozin appears to robustly reduce the risk of both composite outcomes in these patients. These results were published online in Circulation.

Type 2 diabetes mellitus (T2DM) is a global epidemic, with a projected number of affected individuals to be around 640 million in 2040. Moreover, T2DM is strongly and independently associated with incident cardiovascular (CV) ischemic events and hospitalizations for heart failure (HF). Among patients with prior myocardial infarction (MI), those with T2DM comprise a higher risk subgroup. Even with contemporary standard-of-care treatment, residual risk is so heightened in this population that patients with T2DM derived a robust benefit in terms of major adverse cardiovascular events (MACE) reduction with more advanced secondary prevention therapies in the post-MI setting, like prolonged dual antiplatelet therapy and more aggressive lipid-lowering therapy. Also, patients with prior MI present with a higher risk of incident HF and subsequent lower survival in the long-term. Therefore, preventing both MACE and hospitalizations for HF in patients with T2DM and history of MI remain unmet clinical needs. Sodium-glucose transporter-2 inhibitors (SGLT2i) reduce the risk of major adverse cardiovascular events (MACE) in patients with type 2 diabetes mellitus (T2DM) and a history of atherosclerotic cardiovascular (CV) disease (ASCVD). Because of their baseline risk, patients with prior myocardial infarction (MI) may derive even greater benefit from SGLT2i therapy.

DECLARE TIMI-58 randomized 17,160 patients with T2DM and either established ASCVD (n = 6,974) or multiple risk factors (MRF) (n = 10,186) to dapagliflozin versus placebo. The two primary endpoints were composite of MACE (CV death, MI or ischemic stroke) and the composite of CV death or hospitalization for heart failure (HHF). Previous MI (n = 3,584) was a pre-specified subgroup of interest. The investigators found that in patients with prior MI (n=3,584), dapagliflozin reduced the relative risk of MACE by 16% and the absolute risk by 2.6 % (15.2% vs. 17.8%; HR 0.84; 95%CI 0.72-0.99; p=0.039) whereas there was no effect in patients without prior MI (7.1% vs. 7.1%; HR 1.00, 95%CI 0.88-1.13; p=0.97) (p-interaction for relative difference 0.11 and for absolute risk difference 0.048), including in patients with established ASCVD but no history of MI (12.6 % versus 12.8%, HR 0.98; 95% CI 0.81-1.19).  Moreover, there seemed to be a greater benefit for MACE within 2 years after the last acute event (p-interaction trend = 0.007). The relative risk reductions in CV death/HHF were more similar, but the absolute risk reductions tended to be greater: 1.9 % (8.6% vs. 10.5%; HR 0.81 95% CI 0.65-1.00, P=0.046) and 0.6% (3.9% vs. 4.5%; HR 0.85; 95% CI 0.72-1.00; P=0.055) in patients with and without prior MI, respectively (p-interaction for relative difference 0.69 and for absolute risk difference 0.010).

The investigators concluded that “Our results demonstrated that, in DECLARE TIMI 58 trial, dapagliflozin appeared to reduce both MACE and CV death or HF hospitalization in patients with type 2 diabetes mellitus (T2DM) and prior myocardial infarction (MI), with greater absolute benefit compared to patients without a history of MI. There was a robust decrease in type 2 MI’s, that is, those ones caused by mismatch between myocardial oxygen supply and demand rather than plaque rupture and atherothrombosis.” Enumerating the clinical implications, the authors believe that “These results bring new important data regarding the selection of therapies for treating T2DM aimed not only at glycemic control but also at cardiovascular events reduction. Whether this benefit could be expanded to the acute phase of MI or to patients with prior MI even if they do not have T2DM should be addressed in future studies. Lastly, the potential mechanisms which explain the CV benefits with SGLT2 inhibitors are not completely understood and should be a matter of intense research in the future, including possible myocardial protective effects.”

In another analysis of the DECLARE-TIMI 58 trial, baseline HF status was collected from all patients and EF where available. HF with reduced EF (HFrEF) was defined as EF <45%. Outcomes of interest were the composite of CV death/HHF, its components, and all-cause mortality (ACM). It was found that of 17,160 patients, 671 (3.9%) had HFrEF, 1316 (7.7%) had HF without known reduced EF and 15,173 (88.4%) had no history of HF at baseline. Dapagliflozin reduced CV death/HHF more in patients with HFrEF (HR 0.62, 95% CI 0.45-0.86) than in those without HFrEF (HR 0.88, 95% CI 0.76-1.02; P-interaction 0.046), in whom the treatment effect of dapagliflozin was similar in those with HF without known reduced EF (HR 0.88, 95% CI 0.66-1.17) and those without HF (HR 0.88, 95% CI 0.74-1.03). Whereas dapagliflozin reduced HHF both in those with (HR 0.64, 95%CI 0.43-0.95) and without HFrEF (HR 0.76, 95%CI 0.62-0.92), it reduced CV death only in patients with HFrEF (HR 0.55, 95% CI 0.34-0.90) but not in those without HFrEF (HR 1.08, 95% CI 0.89-1.31, P-interaction 0.012). Likewise, dapagliflozin reduced ACM in patients with HFrEF (HR 0.59, 95% CI 0.40-0.88), but not in those without HFrEF (HR 0.97, 95% CI 0.86-1.10, P-interaction 0.016). From these results, the conclusion could be drawn that in the first SGLT2i CV outcome trial to evaluate T2DM patients stratified by EF,  dapagliflozin reduced HHF in patients with and without HFrEF, and reduced CV death and ACM in patients with HFrEF.

The serendipitous story of SGLT2 inhibitors and heart failure stems from the EMPAREG OUTCOME trial, which unexpectedly demonstrated a profound 35% relative risk reduction in hospitalization for heart failure in patients with type 2 diabetes and established atherosclerotic vascular disease (ASCVD) who were treated with empagliflozin. Two additional SGLT2 inhibitors, canagliflozin and dapagliflozin, have been studied in large cardiovascular outcome trials (the CANVAS Program6 and DECLARE-TIMI 58, respectively). Both confirmed the benefit of SGLT2 inhibitors on hospitalization for heart failure (HHF), the composite of HHF or cardiovascular death (HHF/CV death), and renal composite outcomes. Importantly, these latter studies included people with type 2 diabetes with and without established ASCVD. By contrast to the clear benefit on HHF, none of the three trials showed a convincing effect of SGLT2 inhibition on atherothrombotic events. Taking these findings into perspective, Dr. Subodh Verma remarked, “In general, physicians should be aware that diabetes adversely affects the pump (heart failure), pipes (atherosclerosis) and filter (renal disease), and that these effects can occur independently. In patients with diabetes who have had a prior MI, the use of an SGLT2 inhibitor should be strongly considered as part of routine secondary prevention. In these individuals, SGLT2 inhibitors will reduce ischemic, heart failure and renal events, benefits which appear to be mediated largely via glucose-independent mechanisms. The absolute risk reduction for MACE in post-MI patients are similar and additive to what are observed with antiplatelet therapies and intensive LDL-C lowering in recent trials. Whether patients with a recent acute coronary syndrome can also be treated safely and effectively with a SGLT2 inhibitor has not been studied, and a definitive recommendation cannot be given. This may be a useful area for further investigation.”