New England Journal of Medicine January 24, 2019

Dapagliflozin and Cardiovascular Outcomes in Type 2 Diabetes

Stephen D. Wiviott, Itamar Raz, Marc P. Bonaca, Ofri Mosenzon, Eri T. Kato, Avivit Cahn, Michael G. Silverman, Thomas A. Zelniker, et al.

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Bottom Line

In a broad population of patients with type 2 diabetes, dapagliflozin did not reduce the rate of major adverse cardiovascular events compared to placebo but significantly lowered the risk of hospitalization for heart failure.

Key Findings

1. Dapagliflozin met the prespecified criterion for noninferiority to placebo regarding MACE (upper boundary of 95% CI <1.3; P<0.001) [1.1].

2. Dapagliflozin did not achieve superiority for MACE, which occurred in 8.8% of the dapagliflozin group versus 9.4% of the placebo group (HR 0.93; 95% CI 0.84-1.03; P=0.17).

3. Dapagliflozin significantly reduced the coprimary efficacy endpoint of cardiovascular death or hospitalization for heart failure (4.9% vs. 5.8%; HR 0.83; 95% CI 0.73-0.95; P=0.005).

4. The reduction in the CV death/HF composite was driven entirely by a lower rate of hospitalization for heart failure (2.5% vs. 3.3%; HR 0.73; 95% CI 0.61-0.88), as there was no difference in CV death (2.9% vs. 2.9%; HR 0.98; 95% CI 0.82-1.17).

5. A renal composite event occurred less frequently in the dapagliflozin group (4.3% vs. 5.6%; HR 0.76; 95% CI 0.67-0.87), alongside no difference in all-cause mortality (6.2% vs. 6.6%; HR 0.93; 95% CI 0.82-1.04).

6. Dapagliflozin was associated with higher rates of diabetic ketoacidosis (0.3% vs. 0.1%, P=0.02) and genital infections leading to discontinuation or serious adverse events (0.9% vs. 0.1%, P<0.001), but showed no imbalance in amputations or fractures.

Study Design

Design

Phase 3 RCT

Double-Blind

Sample

17,160

Patients

Duration

4.2 yr

Median

Setting

33 countries

Population Adults with type 2 diabetes (HbA1c 6.5-12.0%), creatinine clearance ≥60 mL/min, and either established atherosclerotic cardiovascular disease or multiple risk factors.

Intervention Dapagliflozin 10 mg once daily.

Comparator Matching placebo.

Outcome Dual primary efficacy: MACE (cardiovascular death, myocardial infarction, or ischemic stroke) and a composite of cardiovascular death or hospitalization for heart failure. Primary safety: MACE.

Study Limitations

• Because the trial did not show superiority for MACE, all secondary outcome analyses (such as the renal composite endpoint) were technically considered hypothesis-generating according to the prespecified hierarchical testing plan [1.3].

• The enrollment of a predominantly primary prevention cohort (nearly 60% had multiple risk factors but no established ASCVD) resulted in lower overall event rates, which may have reduced the statistical power to detect a significant difference in MACE.

• Systematic collection of echocardiographic data and baseline natriuretic peptide levels was not performed, limiting the ability to definitively stratify the heart failure benefit by ejection fraction or baseline severity.

• The inclusion criteria required a creatinine clearance of at least 60 mL/min, meaning the trial did not primarily assess outcomes in patients with established moderate-to-severe chronic kidney disease (a gap later addressed by DAPA-CKD).

Clinical Significance

DECLARE-TIMI 58 was a landmark cardiovascular outcome trial (CVOT) that extended the established benefits of SGLT2 inhibitors to a much broader population of patients with type 2 diabetes. Unlike earlier SGLT2i trials (EMPA-REG OUTCOME, CANVAS) that predominantly studied secondary prevention cohorts, DECLARE-TIMI 58 included a large majority of patients who had multiple risk factors but no established atherosclerotic cardiovascular disease. While it did not show a reduction in MACE or cardiovascular death in this lower-risk population, it definitively proved that the reduction in heart failure hospitalizations is a robust class effect that applies to primary prevention in type 2 diabetes. It also reinforced strong renal-protective signals, providing the foundational rationale for subsequent dedicated heart failure and chronic kidney disease trials (such as DAPA-HF and DAPA-CKD).

Historical Context

In 2008, following the rosiglitazone controversy, the FDA mandated that all new antihyperglycemic therapies for type 2 diabetes undergo dedicated cardiovascular outcome trials (CVOTs) to rule out unacceptable cardiovascular risk. The EMPA-REG OUTCOME (2015) and CANVAS (2017) trials dramatically shifted the treatment paradigm by demonstrating that empagliflozin and canagliflozin not only met safety criteria but actually reduced cardiovascular events and heart failure in patients with established ASCVD. Published in 2019, DECLARE-TIMI 58 was the largest of the SGLT2 inhibitor CVOTs and the first to include a predominantly primary prevention cohort. By demonstrating consistent heart failure benefits across a broad spectrum of risk profiles, it cemented SGLT2 inhibitors as foundational cardio-renal protective agents rather than merely glucose-lowering drugs.

Guided Discussion

High-yield insights from every perspective

Med Student

Medical Student

How does the physiological mechanism of action of SGLT2 inhibitors, like dapagliflozin, explain their ability to significantly lower the risk of hospitalization for heart failure despite not reducing atherothrombotic events like MI or stroke in this study?

Key Response

SGLT2 inhibitors block glucose and sodium reabsorption in the proximal tubule. This promotes osmotic diuresis and natriuresis, which reduces plasma volume, decreases cardiac preload, and lowers ventricular wall stress. This hemodynamic shift directly mitigates heart failure exacerbations, contrasting with traditional atherothrombotic mechanisms (plaque rupture) that lead to MI or stroke, which are less directly impacted by SGLT2 inhibition.

Resident

DECLARE-TIMI 58 included a large proportion of patients with multiple risk factors but without established atherosclerotic cardiovascular disease. How does this trial influence your decision to prescribe an SGLT2 inhibitor in a primary care setting compared to earlier trials like EMPA-REG OUTCOME?

Key Response

EMPA-REG OUTCOME studied a secondary prevention cohort (patients with established ASCVD) and showed MACE benefits. DECLARE-TIMI 58 showed that in a broader, lower-risk primary prevention cohort, MACE was not significantly reduced, but heart failure hospitalization was. Residents must recognize that dapagliflozin is highly effective for primary prevention of heart failure hospitalizations, guiding nuanced prescribing for diabetic patients who have risk factors but no prior cardiovascular events.

Fellow

The trial evaluated a dual primary efficacy endpoint of MACE and a composite of cardiovascular death or hospitalization for heart failure. How does the divergence in these endpoints inform our phenotyping of cardiometabolic risk in type 2 diabetes and our choice between SGLT2 inhibitors and GLP-1 receptor agonists?

Key Response

The failure to show superiority for MACE but success for the heart failure composite suggests SGLT2 inhibitors primarily modulate hemodynamic and renal pathways (reducing volume overload) rather than directly preventing atherothrombotic events. Fellows should use this to phenotype patients: prioritizing GLP-1 RAs for patients with high atherothrombotic risk (to reduce MACE) and SGLT2 inhibitors for patients with a high risk of heart failure or chronic kidney disease.

Attending

How do we reconcile the lack of MACE superiority in DECLARE-TIMI 58 with positive MACE findings in earlier SGLT2i trials, and what is the key teaching point to impart to trainees about interpreting negative primary endpoints in large cardiovascular outcome trials?

Key Response

The differing MACE results are driven by the baseline risk of the study populations; DECLARE had approximately 60 percent primary prevention patients, diluting the atherothrombotic event rate compared to secondary prevention trials. The teaching point is that a lack of superiority for MACE in a lower-risk population does not negate the drug class efficacy but highlights the statistical reality of lower event rates, while the robust heart failure benefit cements the drug's role in early disease intervention.

Scholarly Review

Critical appraisal through the lens of expert reviewers and guideline development

PhD

DECLARE-TIMI 58 utilized a time-to-first-event analysis for its primary composite endpoints. What are the statistical limitations of relying solely on time-to-first-event methods for outcomes like heart failure, and how might recurrent event models alter the interpretation of the drug's public health impact?

Key Response

Time-to-first-event ignores subsequent events, which are highly prevalent in heart failure where patients frequently experience multiple readmissions. Utilizing a recurrent event analysis (such as the Lin-Wei-Ying-Wei or negative binomial models) would likely capture a significantly larger total burden of disease prevented by dapagliflozin, providing a more comprehensive and statistically robust estimation of its true clinical efficacy and cost-effectiveness.

Journal Editor

As a critical reviewer evaluating the methodology of DECLARE-TIMI 58, how do you assess the investigators' use of alpha-splitting for the dual primary efficacy endpoints, and does the strong result in the heart failure composite offset the failure to achieve MACE superiority?

Key Response

Alpha-splitting allows the trial to test two hypotheses while controlling the family-wise error rate, but it sacrifices statistical power for each individual endpoint. A rigorous reviewer would question whether the trial was underpowered for MACE superiority specifically because the investigators intentionally enriched the trial with a lower-risk primary prevention cohort, making the dual endpoint a necessary strategic hedge rather than a purely clinical decision.

Guideline Committee

Based on the robust reduction in heart failure hospitalizations in the multiple risk factor cohort of DECLARE-TIMI 58, should current ADA and ACC/AHA guidelines upgrade the strength of recommendation for initiating SGLT2 inhibitors for the primary prevention of heart failure in type 2 diabetes?

Key Response

Current ADA guidelines strongly recommend SGLT2 inhibitors for patients with established ASCVD, heart failure, or CKD. DECLARE-TIMI 58 provides pivotal evidence that the heart failure benefit extends into the primary prevention cohort (multiple risk factors only). The committee must evaluate the absolute risk reduction and number needed to treat in this lower-risk population to determine if guidelines should explicitly recommend SGLT2 inhibitors earlier in the disease course specifically to prevent first-onset heart failure.

Clinical Landscape

Noteworthy Related Trials

2015

EMPA-REG OUTCOME

n = 7020 · NEJM

Tested

Empagliflozin 10 mg or 25 mg daily

Population

T2DM patients with established cardiovascular disease

Comparator

Placebo

Endpoint

3-point MACE

Key result: Empagliflozin significantly reduced the risk of the primary composite cardiovascular outcome and cardiovascular death compared to placebo.

2017

CANVAS Program

n = 10142 · NEJM

Tested

Canagliflozin

Population

T2DM patients with high cardiovascular risk

Comparator

Placebo

Endpoint

3-point MACE

Key result: Canagliflozin significantly reduced the risk of cardiovascular events but was associated with an increased risk of lower limb amputation.

2019

DAPA-HF

n = 4744 · NEJM

Tested

Dapagliflozin 10 mg daily

Population

Patients with heart failure and reduced ejection fraction with or without T2DM

Comparator

Placebo

Endpoint

Worsening heart failure or cardiovascular death

Key result: Dapagliflozin significantly reduced the risk of worsening heart failure or cardiovascular death regardless of the presence of diabetes.

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