African ancestry-specific genetic variant may influence response to metformin
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In a multiethnic genome study of response to diabetes drugs, researchers identified an African-ancestry genetic variant associated with favorable insulin response to metformin, according to a speaker.
A second novel variant was linked to reduced glucose response to glipizide, Josephine Li, MD, an endocrinologist in the diabetes unit at Massachusetts General Hospital and instructor in medicine at Harvard Medical School, said during her virtual presentation at the American Diabetes Association Scientific Sessions.
In the Study to Understand the Genetics of the Acute Response to Metformin and Glipizide in Humans, or SUGAR-MGH, Li and colleagues explored the functional mechanism of genetic variation associated with type 2 diabetes and its therapies and also sought to identify novel genomic regions associated with drug response.
“Clinicians currently do not consider the molecular target of the drug or a patient’s genetic profile when prescribing medications for type 2 diabetes,” Li told Healio. “We hope that our findings provide additional evidence to support tailored therapy in the future that incorporates genotype into clinical decision-making.”
The researchers enrolled 1,000 adults with type 2 diabetes controlled with lifestyle measures or at risk for the disease (mean age, 47.2 years; 54% women; 64% white; 21% Black; 7% Hispanic; 6% Asian; mean BMI, 30.2 kg/m2). Participants were not previously prescribed diabetes medications. On study day 1, participants received 5 mg glipizide; glucose and insulin measurements were taken at baseline (fasting) and six time points after glipizide administration. On days 6 and 7, participants received three 500 mg doses of metformin. On day 8, participants received 500 mg metformin and underwent a 75 g oral glucose tolerance test and glycemic measurements. Genome-wide genotyping with the Illumina multiethnic genotyping array was performed for 890 participants, and more than 12 million gene variants were imputed after quality control with the TOPMed reference panel.
Researchers identified five genome-wide significant variants associated with acute response to metformin or glipizide.
An African ancestry-specific variant, rs149403252, was associated with a 17 mg/dL greater decrease in fasting glucose level in response to metformin in GT carriers vs. non-GT carriers. GT carriers may be more insulin sensitive following metformin, Li said.
Researchers also identified rs150628520, which was associated with increased time and less steep slope to glucose trough and a higher 2-hour glucose level following glipizide, consistent with an attenuated response to the drug.
“SUGAR-MGH is a pharmacogenetic resource that continues to advance the genetics of type 2 diabetes,” Li told Healio. “In prior publications, SUGAR-MGH has characterized the influence of several genetic loci, such as TCF7L2 and CYP2C9, as well as a restricted-to-significant type 2 diabetes polygenic risk score on drug response. The addition of [genome-wide association study] data now permits us to not only identify novel pharmacogenetic variation, but also leverage the phenotypic outcomes constructed in this physiologic study to provide functional characterization of genes associated with type 2 diabetes.”
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Li JH, et al. 27-OR. Presented at: American Diabetes Association Scientific Sessions; June 25-29, 2021 (virtual meeting).
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