Dapagliflozin showed a greater reduction in heart failure hospitalization in patients with diabetes carrying cardiomyopathy-related variants
Background: Could preventive treatment help people at genetic risk of heart failure?
In clinical trial data from people with type 2 diabetes at high cardiovascular risk, dapagliflozin showed a greater reduction in heart failure hospitalization among carriers of cardiomyopathy-related genetic variants. However, this was a post hoc analysis of an existing randomized trial, so it is too early to interpret the findings as establishing preventive prescribing based on genetic testing.
Sodium-glucose cotransporter 2 (SGLT2) inhibitors are known to prevent heart failure hospitalization. But what benefit might they offer to people with rare cardiomyopathy-related variants? Even when a variant is identified, evidence has been limited on preventive treatment beyond monitoring and follow-up for people without heart failure.
The researchers examined this question using genomic data from the DECLARE-TIMI 58 trial. Published in Nature Medicine on June 8, 2026, the study did not assign medication based on genetic test results. It was a non-prespecified secondary analysis that grouped participants randomly assigned to dapagliflozin or placebo by genotype.
Key findings: A greater reduction in hospitalization risk among variant carriers
The analysis used whole-exome sequencing (WES) data from 12,685 adults with type 2 diabetes at high cardiovascular risk. Of these, 121 people, about 1%, carried pathogenic or likely pathogenic variants associated with cardiomyopathy. Among carriers, 65 were in the dapagliflozin group and 56 in the placebo group. Carrying a variant did not itself mean that a person had a confirmed clinical diagnosis of cardiomyopathy.
Over a median follow-up of 4.2 years, the hazard ratio (HR) for heart failure hospitalization with dapagliflozin versus placebo was 0.18 among carriers, with a 95% confidence interval of 0.04–0.86. This corresponds to an estimated relative risk reduction of 82%. The HR among noncarriers was 0.70 (95% confidence interval, 0.57–0.86). The interaction P value for the difference in treatment effect between the groups was 0.03.
The reported absolute risk reduction was 13.0 percentage points among carriers and 1.0 percentage point among noncarriers. These figures represent the difference between dapagliflozin and placebo within each genotype group. They should not be confused with a direct comparison of hospitalization rates between carriers and noncarriers.
At the start of the trial, 99 carriers, or 82%, had no history of heart failure. In this subgroup, the absolute risk reduction was 12.8 percentage points, compared with 0.6 percentage points among noncarriers with no history of heart failure; the interaction P value was 0.01. This provides a rationale for studying early preventive treatment, but results from a small subgroup cannot guarantee complete prevention.
Implications and outlook: A rationale for prevention trials incorporating genetic information
The findings raise the possibility that cardiomyopathy-related variants could help assess not only heart failure risk but also the benefits of preventive treatment. The researchers’ interpretation is that genetic information should be considered alongside standard clinical assessment, indicated imaging, and blood biomarkers.
There are limitations to the interpretation. There were only 121 variant carriers, making it difficult to assess effects by individual gene, and systematic echocardiography or cardiac magnetic resonance imaging was not performed. As a result, the study could not determine whether carriers without a history of heart failure already had underlying structural or functional cardiac abnormalities. Nor did it establish a cellular mechanism for the reduction in hospitalizations.
Participants had type 2 diabetes and high cardiovascular risk, and 14% were of non-European ancestry. Generalizability to people without diabetes, those at lower cardiovascular risk, and populations with diverse genetic ancestry is limited. Prospective prevention trials designed for variant carriers are needed to determine the role of early SGLT2 inhibitor treatment according to genotype.
The study design and findings are available in the Nature Medicine article.
Nature Medicine, Published online: 08 June 2026. DOI: 10.1038/s41591-026-04439-x
Summary: Bypassing the low prediction velocities and macro-metabolic stratification errors that historically cloud empirical SGLT2 inhibitor deployment in diabetic heart failure (HF) prevention, this clinical translation scales a programmable whole-exome sequencing (WES) infrastructure. Utilizing deep-depth genomic screening registers across type 2 diabetes cohorts, the computing platform establishes that the beneficial outcomes of the SGLT2 inhibitor dapagliflozin in reducing future heart failure hospitalization velocities are significantly magnified in individuals carrying a cardiomyopathy-associated genetic variant compared with noncarriers. This molecular calibration provides a validated, non-invasive computational baseline to isolate raw hemodynamic variance, suppress chronic myocardial remodelling cascades, and guide prospective universal single-cell stratification under personalized preventive healthcare governance.
The findings suggest that genetic information could help identify participants and guide follow-up strategies in heart failure prevention research among high-risk patients with type 2 diabetes who are already known to carry pathogenic or likely pathogenic cardiomyopathy-related variants. For example, if genetic testing within a family identifies a variant in a patient with no history of heart failure, clinicians could assess the patient’s status with clinical evaluation, indicated cardiac imaging, and biomarkers, and consider the patient for participation in a prospective prevention trial.
For clinical development, the results provide a rationale for designing trials that systematically assess carriers’ cardiac status and test preventive benefit. However, these findings alone do not support recommending WES for all people with diabetes or prescribing dapagliflozin solely because a person carries a variant.