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Cardiovascular, Renal, and Metabolic Outcomes of Dapagliflozin in Primary Cardiovascular Prevention
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Using data from the DECLARE-TIMI trial, authors evaluated the cardiovascular, renal, and metabolic effects of dapagliflozin in patients with type 2 diabetes and established atherosclerotic cardiovascular disease (ASCVD) or multiple risk factors for ASCVD. In total, 17,160 patients were randomly assigned to receive dapagliflozin or placebo. Dapagliflozin significantly lowered the risk of cardiovascular death or hospitalization for heart failure (HR, 0.84) and the risk of renal outcomes (HR, 0.51) over a median of 4.2 years of follow-up; effects were similar among patients with or without established ASCVD.
- In patients with type 2 diabetes and established ASCVD or multiple risk factors for ASCVD, dapagliflozin reduced the risk of cardiovascular death, hospitalization for heart failure, and adverse renal outcomes, indicating the beneficial effects of dapagliflozin for primary prevention.
abstract
This abstract is available on the publisher's site.
Access this abstract nowOBJECTIVE
International guidelines propose prescribing sodium-glucose cotransporter 2 (SGLT2) inhibitors to patients with type 2 diabetes (T2D) as secondary prevention in patients with established atherosclerotic cardiovascular disease (ASCVD) or for primary prevention of cardiovascular events in high-risk patients with multiple risk factors (MRF) for ASCVD. The current analyses expand on the cardiovascular renal and metabolic effects of SGLT2 inhibitors in MRF patients.
RESEARCH DESIGN AND METHODS
In DECLARE-TIMI 58, 17,160 patients with T2D and MRF (59.4%) or established ASCVD (40.6%) were randomized to dapagliflozin versus placebo; patients were followed for a median of 4.2 years. The cardiovascular and renal outcomes in the MRF cohort were studied across clinically relevant subgroups for treatment effect and subgroup-based treatment interaction.
RESULTS
Among patients with MRF, the reduction with dapagliflozin in risk of cardiovascular death or hospitalization for heart failure (CVD/HHF) (hazard ratio [HR] 0.84, 95% CI 0.67-1.04) and the renal-specific outcome (HR 0.51, 95% CI 0.37–0.69) did not differ from that for patients with ASCVD (Pinteraction 0.99 and 0.72, respectively). The effect on CVD/HHF was entirely driven by a reduction in HHF (HR 0.64, 95% CI 0.46–0.88). The benefits of dapagliflozin on HHF and on the renal-specific outcome, among the subset with MRF, were directionally consistent across clinically relevant subgroups. At 48 months, HbA1c, weight, systolic blood pressure, and urinary albumin-to-creatinine ratio were lower with dapagliflozin versus placebo and estimated glomerular filtration rate was higher (P < 0.001).
CONCLUSIONS
In patients with T2D and MRF, dapagliflozin reduced the risk of HHF and adverse renal outcomes regardless of baseline characteristics. These analyses support the benefit of dapagliflozin for important outcomes in a broad primary prevention population.
Additional Info
Disclosure statements are available on the authors' profiles:
Cardiovascular, Renal, and Metabolic Outcomes of Dapagliflozin Versus Placebo in a Primary Cardiovascular Prevention Cohort: Analyses From DECLARE-TIMI 58
Diabetes Care 2021 Mar 02;[EPub Ahead of Print], A Cahn, I Raz, LA Leiter, O Mosenzon, SA Murphy, EL Goodrich, I Yanuv, A Rozenberg, DL Bhatt, DK McGuire, JPH Wilding, IAM Gause-Nilsson, AM Langkilde, MS Sabatine, SD WiviottFrom MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
Primary Care
The DECLARE-TIMI 58 study had the largest group of primary prevention patients among the cardiovascular outcomes trials. This is important because approximately 75% of all diabetes patients are in the primary prevention camp. They have not had an event yet. That is why it is important to study what happens to these patients.
In the DECLARE study, there were just over 10,000 primary prevention patients who were randomized to either dapagliflozin or placebo, and they were followed up for a median of 4.2 years. There were two important findings. The first was that in these primary prevention patients there was a reduction in hospitalization for heart failure (HHF) by 36% (HR, 0.64; 95% CI, 0.46–0.88). Now the reason why this is a new finding is that we did not even know that primary prevention patients could get heart failure in the first place. Then to be able to reduce HHF was even more shocking.
Since these patients did not have heart attacks before, they were less likely to have heart failure with reduced ejection fraction (HFrEF). That means that they might have heart failure with preserved ejection fraction (HFpEF). So, there is hope that we may have a treatment for HFpEF.
The other interesting finding was the renal benefit. We have seen renal benefit in patients with renal disease, but it is rare that we get to study patients with normal renal function.
However, in the DECLARE study, the baseline eGFR was 85 mL per minute per 1.73 m2 of body surface area, which is pretty close to normal. This means that we can see what happens with near-normal renal function. The renal outcome was defined as ≥40% decrease in eGFR rate to <60 mL per minute per 1.73 m2 of body surface area, new end-stage renal disease, or death from renal causes. That outcome was reduced by 49% (HR, 0.51; 95% CI, 0.37–0.69). That means that, in patients with good renal function, we can prevent deterioration. This again is new information.
So, the reduction in HHF and reduction in renal outcomes in primary prevention patients means that we should be using these agents earlier. This means that the guidelines were correct when they promoted these agents to an earlier position. Prevention is key.
Reference
Diabetes
DECLARE-TIMI 58 included >17,000 participants with type 2 diabetes (T2DM) randomly assigned to dapagliflozin or to placebo. Although there were no differences in the composite outcome of major cardiovascular events (MACE), dapagliflozin use was associated with significant relative risk reductions in the composite outcome of cardiovascular death and hospitalization for heart failure and in the primary renal composite outcome. This study was unique in that the majority of the participants (59%) did not have established cardiovascular disease but did have multiple risk factors for disease, and it is this important subgroup that is the focus of the post hoc analysis by Cahn et al.
Participants in this primary prevention cohort (>10,000 participants) had at least one additional cardiovascular risk factor beyond T2DM, such as hyperlipidemia, hypertension, or current tobacco use. In this cohort, dapagliflozin treatment had no significant effect on MACE, but there were reductions in the cardiovascular composite outcome and renal composite outcome that were similar to the effects seen in patients with atherosclerotic cardiovascular disease. This cardioprotective and renoprotective effect of dapagliflozin was observed across all subgroups analyzed, including age, sex, diabetes duration and severity, smoking status, heart failure history, and other cardiovascular risk factors. Treatment with dapagliflozin also improved metabolic parameters like HbA1c, weight, blood pressure, microalbumin, and eGFR in those with multiple cardiovascular risk factors.
Robust data from the cardiovascular outcomes trials have led to the most recent diabetes treatment guidelines supporting the early use of SGLT2 inhibitors in patients with known cardiovascular or renal disease. The importance of this analysis is the implication that those with cardiovascular risk factors may also derive benefit from dapagliflozin, so early use of this agent may be considered for primary prevention of adverse cardiovascular and renal outcomes in this broader population.
Reference