People at high risk for developing type 2 diabetes may be prescribed a variety of medications to lower their blood sugar levels; however, it is frequently unclear which patients will benefit most from which medications.
Researchers from Massachusetts General Hospital (MGH), a founding member of Mass General Brigham (MGB), identified genetic variants associated with response to two such drugs in a study that was published in Diabetologia: metformin and glipizide. The findings may assist in individualized diabetes treatment and prevention.
Accessible medicines for type 2 diabetes don’t consider a person’s basic hereditary qualities or illness pathophysiology, making it difficult to foster custom-fit interventions.
The team of researchers, led by endocrinologist Josephine Li, MD, who also teaches medicine at Harvard Medical School and works in the Diabetes Unit at MGH, looked into whether a genome-wide approach could uncover novel pharmacogenetic associations and provide insight into the significance of known genetic risk factors for type 2 diabetes.
“We conducted a genome-wide association study to identify genetic variants associated with drug response in great detail. We also investigated the impact of previously reported genetic variants for type 2 diabetes and glycemic traits on SUGAR-MGH outcomes,”
Josephine Li, MD, endocrinologist in the Diabetes Unit at MGH and an Instructor in Medicine at Harvard Medical School.
In the “Study to Understand the Genetics of the Acute Response to Metformin and Glipizide in Humans” (SUGAR-MGH), researchers gathered genetic information from 1,000 people who were at risk of developing type 2 diabetes and were prescribed metformin and glipizide for a brief period of time. Additionally, the team recorded the insulin and blood sugar levels of patients who received these medications.
“To comprehensively identify genetic variants associated with drug response, we conducted a genome-wide association study. We additionally tried the impact of recently announced hereditary variations for type 2 diabetes and glycemic attributes on SUGAR-MGH results,” says Dr. Li. “In contrast to previous pharmacogenetic genome-wide association studies, ours was unique in that over a third of SUGAR-MGH participants were not European.
The acute response to metformin or glipizide was significantly correlated with five genetic variants. African-American participants had a higher prevalence of three. In the Diabetes Prevention Program, participants with one of these African ancestry-specific variants (rs111770298) had a weaker response to metformin treatment than those without the variant.
Li writes, “Understanding the impact of ancestry-specific variants can assist in guiding and tailoring treatment selection for population subgroups in the future.”
In a separate study, another variant, rs703972, was found to be associated with higher levels of active glucagon-like peptide 1, a hormone that stimulates insulin secretion and reduces appetite. This variant was previously known to help protect against type 2 diabetes.
According to Li, “functional experiments will be the next step to confirm the implications of the novel genetic variants we’ve identified that are associated with the body’s response to these glucose-lowering therapies.”
According to co-senior author Jose C. Florez, MD, Ph.D., chief of the Endocrine Division and the Diabetes Unit at MGH and a professor of medicine at Harvard Medical School, “SUGAR-MGH is designed to allow investigators to use two commonly used drugs with different mechanisms of action to probe the role of specific genes on glucose regulation.”
In order to make it possible for other researchers to add value to their work, the researchers made their findings freely available as a resource.
Co-lead authors Varinderpal Kaur and Laura N. Brenner are among the additional authors; co-senior creator Josep M. Mercader; and furthermore, Katherine Figueroa, Philip Schroeder, Alicia Huerta-Chagoya, Miriam S. Udler, and Aaron Leong.
More information: Josephine H. Li et al, Genome-wide association analysis identifies ancestry-specific genetic variation associated with acute response to metformin and glipizide in SUGAR-MGH, Diabetologia (2023). DOI: 10.1007/s00125-023-05922-7
