The study to understand the genetics of the acute response to metformin and glipizide in humans (SUGAR-MGH): design of a pharmacogenetic resource for type 2 diabetes

Abstract

Objective: Genome-wide association studies have uncovered a large number of genetic variants associated with type 2 diabetes or related phenotypes. In many cases the causal gene or polymorphism has not been identified, and its impact on response to anti-hyperglycemic medications is unknown. The Study to Understand the Genetics of the Acute Response to Metformin and Glipizide in Humans (SUGAR-MGH, NCT01762046) is a novel resource of genetic and biochemical data following glipizide and metformin administration. We describe recruitment, enrollment, and phenotyping procedures and preliminary results for the first 668 of our planned 1,000 participants enriched for individuals at risk of requiring anti-diabetic therapy in the future.

Methods: All individuals are challenged with 5 mg glipizide × 1; twice daily 500 mg metformin × 2 days; and 75-g oral glucose tolerance test following metformin. Genetic variants associated with glycemic traits and blood glucose, insulin, and other hormones at baseline and following each intervention are measured.

Results: Approximately 50% of the cohort is female and 30% belong to an ethnic minority group. Following glipizide administration, peak insulin occurred at 60 minutes and trough glucose at 120 minutes. Thirty percent of participants experienced non-severe symptomatic hypoglycemia and required rescue with oral glucose. Following metformin administration, fasting glucose and insulin were reduced. Common genetic variants were associated with fasting glucose levels.

Conclusions: SUGAR-MGH represents a viable pharmacogenetic resource which, when completed, will serve to characterize genetic influences on pharmacological perturbations, and help establish the functional relevance of newly discovered genetic loci to therapy of type 2 diabetes.

Trial registration: ClinicalTrials.gov NCT01762046.

Fig 1. SUGAR-MGH protocol and schedule of events.

All events at Visit 1 and Visit 2 occur in the Clinical Research Center.

Fig 2. SUGAR-MGH Recruitment and study flow sheet.

Fig 3. Glucose and insulin changes during glipizide challenge.

Shown are A) mean ± standard deviation for blood glucose (mmol/L), B) median [IQR] for insulin (pmol/L), and C) median [IQR] for glucagon (ng/L) values prior to and during the glipizide challenge.

Fig 4. Glucose values during glipizide challenge stratified by time of challenge termination.

Shown are mean ± standard deviation for blood glucose (mmol/L) during the glipizide challenge stratified by the time of challenge termination: 60 minutes (blue solid line with blue circles), 90 minutes (green dashed line with green squares), 120 minutes (red dashed line with red triangles), 180 minutes (orange solid line with orange inverted triangles), and 240 minutes (black solid line with black diamonds).

Fig 5. Glucose values during oral glucose tolerance test (OGTT) in the presence and absence of metformin.

Shown are mean ± standard deviation for A) blood glucose (mmol/L) prior to and during the SUGAR-MGH oral glucose tolerance test (OGTT) stratified by participants who took no metformin doses (blue dashed line with blue circles) and participants who took any dose of metformin (black solid line with black squares); B) blood glucose (mmol/L) prior to and during an oral glucose tolerance test in the subset of participants who underwent an OGTT as part of the CAMP MGH study before receiving metformin (red dashed line with red circles) and after receiving four doses of metformin as part of the SUGAR-MGH study (black solid line with black squares).