PhaRmacogenetics Of the Glycemic RESponse to SGLT2 Inhibitors
PROGRESS is studying dapagliflozin (Farxiga) to understand the role of a patient’s genetic makeup in choosing what diabetes drug to prescribe. It’s one of the first pharmacogenetic investigations of SGLT2 inhibitors involving the acute response.
Aims & What Study Visits Involve
Aims
- Use integrated multi-omic analyses — genetics, metabolomics, and proteomics — to predict the effects of SGLT2 inhibitors.
- Tailor type 2 diabetes treatment by considering a patient’s genetic profile in drug choices.
- Identify patients across the spectrum of type 2 diabetes genetic risk and carriers of variants within SLC5A2, the gene encoding the molecular target of SGLT2 inhibitors.
- Assess whether the change in blood sugar due to SGLT2 inhibitors differs by genetic risk or SLC5A2 variation.
- Assess whether SGLT2 inhibitor effects on glycemic control and complications are modified by genetic risk or SLC5A2 variation.
What Study Visits Involve
- A brief screening visit and blood draw, if recent bloodwork isn’t on file.
- Two five-hour visits, a week apart.
- If you have diabetes, pausing your home diabetes medication for 5 days before the first five-hour visit.
- At each visit: height and weight, glucose checks, blood draws, and urine collections.
- Taking the study drug daily for 5 days at home, and once during the second visit.
The track record PROGRESS is built on.
PROGRESS hasn’t published primary results yet — it’s still enrolling. But its acute drug-challenge design isn’t new for this team: these two prior studies used the same basic approach (a supervised drug challenge, followed by genetic association testing) for other diabetes medications, and PROGRESS applies that same playbook to SGLT2 inhibitors.
SUGAR-MGH is this team’s blueprint for exactly the kind of study PROGRESS now is: 1,000 participants of diverse ancestries, naive to diabetes medication, underwent sequential glipizide and metformin drug challenges, with genome-wide association testing against their glycemic responses. The study found five genome-wide significant variants tied to drug response — the strongest an African-ancestry-specific variant associated with a stronger fasting glucose reduction after metformin — demonstrating that acute challenge designs in diverse cohorts can surface pharmacogenetic signal that larger, less carefully designed studies miss.
Variants in GLP1R, the gene for the glucagon-like peptide-1 receptor, are associated with type 2 diabetes risk, but it wasn’t clear whether they act by changing how the body responds to interventions that raise incretin hormones. This study evaluated the physiologic and hormonal effects of GLP1R genotypes before and after glucose-raising interventions — a design template PROGRESS mirrors closely, just testing a different drug target (SLC5A2/SGLT2 instead of GLP1R).