Genetic differences may help explain variation in type 2 diabetes treatment responses
Josephine Li, MD
Lukasz Szczerbinski, MD, PhD
Josep Mercader, PhD
Jose Florez, MD, PhD
One of the difficulties of treating type 2 diabetes (T2D) is that patients can respond differently to the same medications. For example, second-line therapies are commonly added when metformin alone is no longer sufficient, yet it can be difficult to predict how well they will work for any given patient. That's why a study published on behalf of the GRADE Research Group, led by researchers at Mass General Brigham and the Broad Institute of MIT and Harvard, investigated the role of genetics in patients' responses to second-line glucose-lowering therapies when added to metformin.
By conducting a genome-wide association study (GWAS) among participants in the GRADE trial, researchers identified a variant in SLC2A2, a gene involved in glucose transport, that was associated with reduced effectiveness of glimepiride, an oral medication belonging to a class of glucose-lowering medications called sulfonylureas. In fact, each copy of the risk allele was associated with a 38% increased risk of metabolic failure among participants assigned to glimepiride. The team followed up on the GWAS findings with additional analyses using data from GRADE participants, independent cohorts and a zebrafish model. The variant was more common in African/African American participants, and carriers showed reduced insulin secretion and pancreatic β-cell function.
Ultimately, the study highlights genetic differences as a potential contributor to variability in patients' responses to T2D medications. The researchers also homed in on SLC2A2 as a potentially important genetic factor influencing response to glimepiride and propose that future studies should examine whether alternative glucose-lowering medications may be more beneficial for carriers of these variants.
Published in Diabetes Care on November 5, 2026 | Read the paper: “Common Genetic Variants Near SLC2A2 and Glycemic Response to Glimepiride in the GRADE Comparative Effectiveness Clinical Trial”
Summary reviewed by: Josephine Li, MD, and Lukasz Szczerbinski, MD, PhD, co-lead authors; Josep Mercader, PhD, and Jose Florez, MD, PhD, co-senior authors
New Guidelines for the Treatment of Pulmonary Embolism
In 2026, the American Heart Association and American College of Cardiology (ACC) released the first comprehensive clinical guidelines dedicated to PE, marking a major shift in how the condition is evaluated and managed. Dr. Bikdeli was on the peer review committee for the new guidelines. Learn more about the guidelines and their implications in this Q&A.