BMJ protocol sets out a cardiovascular review of incretin drugs in heart failure and diabetes
Incretin-based drugs are moving deeper into routine care for type 2 diabetes and obesity, but their cardiovascular profile still carries important gaps, especially in people with a history of heart failure. A new BMJ Open protocol lays out a systematic review, meta-analysis, and trial sequential analysis designed to bring together randomized evidence on drugs that now sit at the center of metabolic treatment, including GLP-1 receptor agonists and the dual GIP/GLP-1 receptor agonist tirzepatide.
The protocol is notable for what it tries to answer and for what still remains unsettled. These agents already have a reputation for cardiovascular benefit in some settings, yet their effects on hard outcomes and on cardiac structure and function have not been fully resolved across patients with and without prior heart failure. For clinicians, that uncertainty matters at the bedside, where a treatment chosen for glycemic control or weight loss may also intersect with ventricular performance, fluid status, natriuretic peptide biology, and hospitalization risk.
One question sits at the center of the planned analysis: do these therapies reduce cardiovascular mortality in patients with heart failure history, or do they behave differently depending on the underlying cardiac phenotype?
Randomized trials will be pooled across major databases and registries
The review team plans to search major medical databases from inception onward, including CENTRAL, MEDLINE, EMBASE, LILACS, SCI-EXPANDED, and CPCI-S, alongside clinical trial registries. The search is scheduled for July 2025. Two reviewers will independently extract data and judge risk of bias, a standard safeguard that reduces single-reviewer error and helps prevent selective interpretation of trial results.
Eligibility is limited to randomized controlled trials evaluating cagrilintide/semaglutide, liraglutide, semaglutide, and tirzepatide in patients with and without a history of heart failure. The decision to focus on randomized data is clinically important because incretin therapies are already embedded in real-world care, where observational signals can be confounded by baseline weight, diabetes severity, kidney function, and background cardioprotective therapy.
The protocol does not attempt to answer every question surrounding incretin pharmacology. It is narrower than that. It focuses on cardiovascular endpoints that can be compared across trials and on a set of imaging and biomarker measures that may help explain why some patients improve while others do not.
Cardiovascular mortality is the primary endpoint, with heart failure and imaging measures secondary
The primary outcome is cardiovascular mortality. Secondary outcomes extend from clinical events to physiologic markers: heart failure hospitalization, myocardial infarction, stroke, heart rate, systolic blood pressure, N-terminal pro B-type natriuretic peptide, left ventricular ejection fraction, left ventricular end-diastolic volume, and left ventricular end-systolic volume.
That range of outcomes gives the review both breadth and clinical depth. Mortality and hospitalization address the outcomes that drive decisions in practice. The ventricular measurements and natriuretic peptide levels reach closer to mechanism, where reductions in afterload, weight, inflammation, neurohormonal stress, or myocardial remodeling might leave measurable traces. In a drug class used partly because of metabolic benefits, the question is whether cardiac effects are merely downstream noise or whether they reflect a consistent biologic signal.
The protocol also plans aggregate-data meta-analysis and trial sequential analysis. The latter is a useful addition because repeated pooling of small or sparse trials can overstate certainty. Trial sequential analysis can help determine whether the available evidence has already crossed a threshold for firm inference or whether more trial data are still needed before any confident conclusion can be drawn.
Why heart failure history changes the clinical stakes
Heart failure changes the meaning of almost every cardiovascular endpoint. A reduction in stroke or myocardial infarction is important, but in a patient with prior heart failure, a treatment’s influence on hospitalization, ventricular remodeling, and hemodynamics may be equally relevant. Some incretin drugs lower systolic blood pressure and body weight, both of which can ease cardiac workload. At the same time, heart rate effects and shifts in volume status may complicate interpretation, particularly if the heart failure phenotype is not uniform across trials.
The protocol’s structure reflects that complexity. By separating patients with and without prior heart failure, the investigators can examine whether the same drug class behaves differently once structural heart disease is already established. That distinction is essential because a therapy that appears broadly cardioprotective in one subgroup may not translate cleanly into benefit in another, especially when myocardial reserve, congestion risk, and baseline natriuretic peptide levels differ.
Evidence standards are built into the review design
Risk of bias will be assessed with the Cochrane Risk of Bias tool, version 2, and certainty of evidence will be graded using GRADE. Those methods matter because cardiovascular outcome studies vary in duration, background treatment, and endpoint collection. A review that intends to guide clinical interpretation has to separate a robust signal from a fragile one.
The planned combination of GRADE and trial sequential analysis should make the eventual synthesis more disciplined than a simple tally of positive or negative studies. If the evidence base is thin for ventricular remodeling or heart failure hospitalization, that limitation will surface clearly. If the mortality signal proves consistent across randomized trials, the review should be able to say so with a more defensible level of confidence.
The protocol also signals an important practical tension in contemporary diabetes and obesity care: drugs are often chosen for one indication, but the consequences spill across several organ systems. Incretin therapy may influence weight, glycemia, blood pressure, heart rate, and myocardial stress simultaneously. Parsing those effects separately is the only way to understand whether the cardiovascular benefit is direct, indirect, or concentrated in a particular phenotype.
A protocol, not a result, but a clinically useful one
This publication does not offer outcome data yet. It defines the question, the trial universe, the endpoints, and the analytic framework. That is still clinically meaningful because it sets the terms for how the field will judge a drug class that is expanding rapidly across endocrine and cardiovascular practice.
The review is registered in PROSPERO under CRD420251003374. Ethical approval is not required because the study uses published secondary data. Findings will be submitted to peer-reviewed journals once the analysis is complete.
For now, the most relevant issue is not whether incretin-based drugs work in general. The sharper question is how they perform in patients whose hearts are already vulnerable, and whether the same agents that improve metabolic risk can also alter the trajectory of heart failure-related events, ventricular function, and cardiovascular death.