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Updated: Jan 27, 2026
In Silico Clinical Trials for Cardiovascular Disease
Published on: May 27, 2022
Dapagliflozin and cardiovascular outcomes: anything else to DECLARE?
Emanuel Raschi1, Elisabetta Poluzzi1, Giulio Marchesini2
1a Pharmacology Unit, Department of Medical and Surgical Sciences , University of Bologna , Bologna , Italy.
Introduction:
Individuals with type 2 diabetes mellitus (T2DM) have increased cardiovascular risk with regulatory agencies requiring cardiovascular outcome trials (CVOTs) for the approval of new antidiabetic drugs. Areas covered: In this paper, the authors critically discuss the background, trial design, results and implications of a recent CVOT [NCT01730534; DECLARE-TIMI 58 study], which demonstrated that dapagliflozin was non-inferior to placebo in terms of major adverse cardiovascular events, and superior for the occurrence of hospitalization for heart failure (HF) and composite renal endpoints, thus confirming the cardiovascular benefit of sodium-glucose co-transporter-2 (SGLT2) inhibitors. No statistically-significant effects were found for amputations, fractures, and stroke (debated safety issues having emerged in previous CVOTs). Expert opinion: DECLARE-TIMI 58 is the longest (4.2 years of follow up), largest (>17,000 participants) and most inclusive (only 41% of individuals with established atherosclerotic cardiovascular disease) CVOT raising the debate towards SGLT2 inhibitor therapy in primary prevention and the potential use of these drugs also in patients with HF without T2DM and other subpopulations.
Insights
The DECLARE-TIMI 58 trial found that dapagliflozin, a sodium-glucose co-transporter-2 (SGLT2) inhibitor, did not increase major cardiovascular events in type 2 diabetes patients. It also showed benefits for heart failure hospitalizations and kidney endpoints.
Area of Science:
- Cardiology
- Endocrinology
- Nephrology
Background:
- Type 2 diabetes mellitus (T2DM) significantly elevates cardiovascular risk.
- Regulatory agencies mandate cardiovascular outcome trials (CVOTs) for new antidiabetic drug approvals.
- Sodium-glucose co-transporter-2 (SGLT2) inhibitors are a class of antidiabetic drugs with potential cardiovascular benefits.
Purpose of the Study:
- To critically discuss the background, design, results, and implications of the DECLARE-TIMI 58 CVOT.
- To evaluate the cardiovascular safety and efficacy of dapagliflozin in individuals with T2DM.
- To assess the impact of dapagliflozin on heart failure hospitalizations and renal outcomes.
Main Methods:
- Analysis of the DECLARE-TIMI 58 study (NCT01730534), a large-scale, long-term cardiovascular outcome trial.
- Inclusion of over 17,000 participants, with a significant proportion not having established atherosclerotic cardiovascular disease, making it highly inclusive.
- Comparison of dapagliflozin versus placebo for major adverse cardiovascular events and secondary endpoints including heart failure and renal outcomes.
Main Results:
- Dapagliflozin was non-inferior to placebo regarding major adverse cardiovascular events.
- Dapagliflozin demonstrated superiority in reducing hospitalizations for heart failure (HF).
- Composite renal endpoints were significantly improved with dapagliflozin; no significant effects on amputations, fractures, or stroke were observed.
Conclusions:
- The DECLARE-TIMI 58 study confirms the cardiovascular benefits of SGLT2 inhibitors, particularly for heart failure and renal protection.
- The trial's extensive follow-up and inclusive design support the investigation of SGLT2 inhibitors in primary prevention and in patients with HF, even without T2DM.
- Dapagliflozin presents a favorable risk-benefit profile for individuals with T2DM, extending potential therapeutic considerations to broader patient populations.
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