Cardiology · Medical Literature
Effects of SGLT2 inhibition on incident heart failure in carriers of cardiomyopathy-associated genetic variants.
Abstract
Although the beneficial effects of sodium-glucose cotransporter 2 (SGLT2) inhibition in heart failure (HF) have been well established, it is unknown whether SGLT2 inhibition confers benefit in carriers of rare variants in cardiomyopathy-associated genes. Here we evaluated whole-exome sequencing data from the randomized DECLARE-TIMI 58 trial, in which adults with type 2 diabetes and increased cardiovascular risk were randomized to dapagliflozin or placebo treatment. Pathogenic or likely pathogenic variants (P/LP) in high-confidence cardiomyopathy genes were identified, and treatment effects on hospitalization for HF (HHF) were compared between carriers of such variants and noncarriers. Among 12,685 patients for whom sequence data were obtained, 121 carried a cardiomyopathy variant (76 dilated cardiomyopathy, 25 hypertrophic cardiomyopathy and 25 arrhythmogenic cardiomyopathy). Over a median follow-up of 4.2 years, dapagliflozin lowered the risk of HHF more strongly in carriers (hazard ratio 0.18, 95% confidence interval 0.04-0.86) than in noncarriers (hazard ratio 0.70, 95% confidence interval 0.57-0.86; P interaction 0.03). Absolute risk reduction was 13.0% in carriers and 1.0% in noncarriers (P interaction 0.03). Most carriers (82%) had no prior HF, and in carriers without prior HF, treatment with dapagliflozin reduced the absolute risk of HHF by 12.8%, compared with a reduction of 0.6% in noncarriers (P interaction 0.01). The findings from this cohort of older and high-risk patients raise the possibility that SGLT2 inhibitor treatment should be started early to prevent HF in individuals who carry P/LP cardiomyopathy variants. These results need to be confirmed in a prospective, dedicated trial of preventive HF treatments in carriers of P/LP cardiomyopathy-associated variants.
Clinical relevance
Among adults with type 2 diabetes and elevated cardiovascular risk enrolled in the DECLARE-TIMI 58 trial, does dapagliflozin reduce the risk of hospitalization for heart failure (HHF) differentially in carriers of pathogenic or likely pathogenic variants in cardiomyopathy-associated genes compared with noncarriers? __SNAPSHOT__ {"studyDesign":"Pre-specified whole-exome sequencing substudy of a randomized, double-blind, placebo-controlled cardiovascular outcomes trial (DECLARE-TIMI 58)","setting":"International, multicenter; conducted within the DECLARE-TIMI 58 phase 3 trial infrastructure (NCT01730534)","sampleSize":"n=12,685 (patients with available exome sequencing data); cardiomyopathy variant carriers: n=121; noncarriers: n=12,564","population":"Adults with type 2 diabetes and increased cardiovascular risk. Among the 121 carriers: 76 dilated cardiomyopathy (DCM), 25 hypertrophic cardiomyopathy (HCM), and 25 arrhythmogenic cardiomyopathy (ACM) variant carriers; 82% of carriers had no prior heart failure at baseline","intervention":"Dapagliflozin (SGLT2 inhibitor) added to standard care","comparator":"Placebo","primaryOutcome":"Hospitalization for heart failure (HHF); treatment effect compared between pathogenic/likely pathogenic (P/LP) cardiomyopathy variant carriers and noncarriers","followUp":"Median 4.2 years","fundingSource":"Industry (DECLARE-TIMI 58 was funded by AstraZeneca); certain investigators also received NIH and non-profit support"}
Key findings
Among cardiomyopathy variant carriers, dapagliflozin was associated with a markedly lower risk of HHF (HR 0.18, 95% CI 0.04–0.86) compared with a more modest reduction in noncarriers (HR 0.70, 95% CI 0.57–0.86; P interaction = 0.03). The absolute risk reduction (ARR) for HHF was 13.0% in carriers versus 1.0% in noncarriers (P interaction = 0.03), yielding an NNT of approximately 8 in carriers versus 100 in noncarriers (both calculated). In the placebo arm, 16% of variant carriers were hospitalized for heart failure over follow-up, compared with approximately 3% in dapagliflozin-treated carriers — an 82% relative risk reduction in this subgroup. In the clinically critical subgroup of carriers without prior HF (82% of all carriers), dapagliflozin reduced the absolute risk of HHF by 12.8%, versus only 0.6% in noncarriers without prior HF (P interaction = 0.01); notably, no carrier without prior HF who received dapagliflozin was hospitalized for heart failure during follow-up. Adverse event data specific to the carrier subgroup were not reported in available sources.
Practice implications
This study establishes that among adults with type 2 diabetes and elevated cardiovascular risk, carriers of pathogenic or likely pathogenic variants in high-confidence cardiomyopathy genes derive substantially larger absolute and relative reductions in HHF from dapagliflozin than noncarriers, with a statistically significant interaction. The most clinically compelling finding is the apparent near-elimination of incident HHF in genetically at-risk individuals without pre-existing heart failure — a population in whom SGLT2 inhibitors are not routinely initiated. However, several important limitations constrain the interpretation: (1) the carrier group is very small (n=121), making the HR in carriers (0.18) statistically wide and potentially unstable; (2) this is a post-hoc genomic substudy — the original trial was not powered to detect a gene-treatment interaction, and the interaction p-value of 0.03 should be interpreted cautiously given the multiple comparisons inherent in such analyses; (3) all participants had type 2 diabetes, so findings cannot be extrapolated to cardiomyopathy variant carriers without diabetes; (4) the study does not establish the mechanism by which cardiomyopathy variant status modifies SGLT2i efficacy; (5) only abstract-level data were available for this summary, limiting full appraisal of covariate adjustment, variant classification methodology, and safety data; (6) industry sponsorship (AstraZeneca) of the parent trial warrants acknowledgment. The findings are hypothesis-generating and clinically provocative, supporting the concept of genetically guided SGLT2 inhibitor initiation, but prospective confirmation in dedicated genetic cohorts — including non-diabetic cardiomyopathy carriers — is needed before this represents a formal practice change. __LIMITATIONS__ Very small carrier subgroup (n=121), yielding a wide 95% CI for the carrier HR (0.04–0.86) and limited statistical power for the interaction test.,Post-hoc genomic subgroup analysis of a trial not prospectively powered to detect a gene-treatment interaction; the P interaction of 0.03 is nominally significant but must be interpreted in the context of multiple testing and exploratory design.,Exclusive enrollment of adults with type 2 diabetes limits generalizability to cardiomyopathy variant carriers without diabetes — a major gap given that most genetically identified carriers will not have diabetes.,Heterogeneity across cardiomyopathy subtypes (DCM, HCM, ACM) is clinically important but the subgroup sizes are too small to draw subtype-specific conclusions.,Variant classification relied on ClinVar-like pathogenicity criteria applied to exome data; variant reclassification over time could affect findings.,Only abstract-level data publicly available at summary preparation; full appraisal of statistical methods, covariate adjustment, and safety reporting is not possible.,Industry sponsorship of the parent trial (AstraZeneca) introduces potential for publication and analysis bias.,HHF is a clinically meaningful but composite-adjacent endpoint; effects on mortality, LVEF, and quality of life in carriers were not reported.,Absence of echocardiographic or biomarker data at baseline in carriers limits understanding of the phenotypic spectrum represented. __BOTTOM_LINE_CATEGORY__ promising_but_preliminary __BOTTOM_LINE__ In this whole-exome sequencing substudy of DECLARE-TIMI 58, dapagliflozin produced a substantially larger absolute risk reduction in HHF among cardiomyopathy variant carriers (ARR 13.0%, NNT ~8 [calculated]) compared with noncarriers (ARR 1.0%), with a significant interaction, driven largely by a near-complete prevention of HHF in carriers without prior heart failure. These findings are clinically provocative and support the hypothesis that genetic cardiomyopathy variant status identifies a high-yield target population for early SGLT2 inhibitor therapy, but the small carrier sample, post-hoc design, and restriction to patients with type 2 diabetes mandate prospective validation before genetically guided SGLT2 inhibitor initiation can be adopted into clinical practice.