GLP-1 receptor agonists and SGLT2 inhibitors significantly reduced cardiovascular events in people with type 2 diabetes, while DPP-4 inhibitors showed cardiovascular neutrality.
3 drug classes, divergent CV outcomesGLP-1 receptor agonists and SGLT2 inhibitors reduced major adverse cardiac events, while DPP-4 inhibitors showed neither benefit nor harm in large randomized trials.
What the researchers found
This review of major cardiovascular outcome trials found that GLP-1 receptor agonists (liraglutide in the LEADER trial, semaglutide in the SUSTAIN-6 trial) significantly reduced major adverse cardiac events (MACE) in people with type 2 diabetes. SGLT2 inhibitors (empagliflozin in EMPA-REG OUTCOME, canagliflozin in CANVAS) also significantly reduced MACE and hospitalizations for heart failure. DPP-4 inhibitors showed cardiovascular neutrality — they neither increased nor decreased MACE — though a small increased risk of heart failure with some members of the class could not be ruled out.
Importantly, the review notes that most trial participants had already experienced cardiovascular events, meaning these results primarily reflect secondary prevention. The majority of people with type 2 diabetes who take these medications have not had prior cardiovascular events, so how these benefits translate to primary prevention remains an open question.
Why it matters
Heart disease is the leading cause of death among people with type 2 diabetes. For years, diabetes drugs were evaluated primarily on their ability to lower blood sugar, with cardiovascular effects largely unknown. This generation of outcome trials — mandated by regulators after safety concerns with earlier drugs — shifted the landscape by showing that some newer glucose-lowering therapies actively protect the heart, not just avoid harming it. These findings have reshaped diabetes treatment guidelines worldwide.
How the study worked
The authors reviewed data from multiple large, randomized controlled cardiovascular outcome trials, including LEADER (liraglutide), SUSTAIN-6 (semaglutide), EMPA-REG OUTCOME (empagliflozin), and CANVAS (canagliflozin), as well as trials of DPP-4 inhibitors. They examined composite MACE outcomes (cardiovascular death, non-fatal heart attack, and non-fatal stroke) and heart failure hospitalization across these trials.
Who was studied
People with type 2 diabetes enrolled in major cardiovascular outcome trials, mostly with established cardiovascular disease
What this study cannot tell us
As a narrative review, this study did not perform independent meta-analysis. Direct comparisons between trials are limited by differences in patient populations, cardiovascular risk at enrollment, trial designs, and analytical methods. Most trial participants had pre-existing cardiovascular disease, so results may not apply to lower-risk patients who make up the majority of the type 2 diabetes population.
How to read the evidence
This review synthesizes findings from multiple large, randomized controlled trials — the gold standard for clinical evidence — each enrolling thousands of participants and designed to assess cardiovascular outcomes. The trials themselves are individually high-quality, and this review provides a comprehensive overview.
When this study was published
Published in 2019, this review captures the first wave of cardiovascular outcome trials. Since then, additional trials and real-world data have further confirmed the cardiovascular benefits of GLP-1 receptor agonists and SGLT2 inhibitors, making these findings well-validated and still clinically relevant.
The bigger picture
These cardiovascular outcome trials marked a turning point in diabetes care. Before them, glucose-lowering drugs were approved primarily based on their ability to reduce blood sugar. The regulatory mandate for cardiovascular safety trials — introduced after the rosiglitazone controversy — inadvertently revealed that some newer peptide-based therapies actively protect the heart. This has led to a paradigm shift where cardiovascular benefit, not just glucose control, now drives treatment selection in type 2 diabetes guidelines worldwide.
Questions still open
- Do these cardiovascular benefits extend to people with type 2 diabetes who have not yet experienced a heart attack or stroke?
- What are the specific mechanisms by which GLP-1 receptor agonists and SGLT2 inhibitors reduce cardiovascular events — and are these effects independent of glucose lowering?
- Could combining a GLP-1 receptor agonist with an SGLT2 inhibitor provide additive cardiovascular protection?
Common questions
Do all diabetes drugs protect the heart?
Should people without heart disease still take these medications?
Read the original research
Cardiovascular protection in type 2 diabetes: Insights from recent outcome trials.
Diabetes, obesity & metabolism, 21(1), 3-14
Citation
Bailey, Clifford J; Marx, Nikolaus. (2019). Cardiovascular protection in type 2 diabetes: Insights from recent outcome trials.. Diabetes, obesity & metabolism, 21(1), 3-14. https://doi.org/10.1111/dom.13492