Scientific Poster Session III - Late-Breaking Original Research

Late Breaking Original Research
  Monday, October 14, 2024
  01:00 PM–02:30 PM

Abstract

Introduction:

SGLT2 inhibitors (SGLT2i) reduce the risk of major adverse cardiovascular and kidney outcomes in type 2 diabetes, heart failure and chronic kidney disease. Numerous genetic variants influence the efficacy and safety of medications, but none are identified for SGLT2i. The All of Us program conducted whole genome sequencing in a diverse cohort consisting of 80% participants from under-represented populations. Genomic research is essential for identifying novel variants linked to drug response.

Research Question or Hypothesis:

How does genetic variation in SLC5A2, the gene encoding the SGLT2 transporter, influence the effects of SGLT2i on glucose-lowering?

Study Design:

Retrospective cohort study

Methods:

All of Us participants who were taking an SGLT2i, had available short-read whole genome sequencing data and hemoglobin A1c (HbA1c) values were included. SGLT2i use was identified from linked health data. There were 14451 genetic variants within 200 kilobases of the SLC5A2 gene start and stop positions. Primary endpoint was the change in HbA1c from prior to SGLT2i initiation up to 60-150 days after initiation. Elastic net regression with adjustment for age, sex and the first 16 principal components and 10-fold cross-validation was used to identify SLC5A2 variants, significantly associated with HbA1c changes.

Results:

The cohort included 1,267 participants with mean age of 66 years, including 48% men, 51% women and 2% other gender, 54% White, 19% Black, 3% Asian and 25% other race/response. Mean baseline HbA1c was 7.8% and the mean change in HbA1c was -0.5% (mean time between baseline and follow-up: 115 days). Elastic net regression identified three variants, significantly associated with a greater reduction in HbA1c after starting an SGLT2i: chr16:31363214:C:G (minor allele frequency (MAF): 31%; beta coefficient: -0.005), chr16:31382223:C:T (MAF: 43%; beta coefficient: -0.029) and chr16:31382228:CT:C (MAF: 29%; beta coefficient: -0.026).

Conclusion:

Genetic variation in SLC5A2 may influence the effects of SGLT2i on HbA1c lowering. External validation of these findings is needed.

Presenting Author

Bhavya Chebrolu PharmD, MS
Brigham and Women's Hospital

Authors

Leo Buckley PharmD, MPH
Brigham and Women's Hospital

Subbaramireddy Remala BS
Brigham and Women's Hospital