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

ObjectiveGenome-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.MethodsAll 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.ResultsApproximately 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.ConclusionsSUGAR-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 RegistrationClinicalTrials.gov NCT01762046

Mexican Carriers of the HNF1A p.E508K Variant Do Not Experience an Enhanced Response to Sulfonylureas

“…The study was supported by the SIGMA Type 2 Diabetes Consortium and performed in accordance with the SUGAR-MGH protocol (10). The study protocol was approved by the Ethics Committee of the Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán.…”

“…The study consisted of two visits ( Fig. 1) (10). Prior to visit 1, participants with type 2 diabetes taking an oral antidiabetic agent underwent a 7-day washout period.…”

“…The aim of our study was to advance precision medicine by evaluating the insulin and glycemic responses to glipizide and metformin in p.E508K carriers and ageand sex-matched noncarriers. We followed the approach used in the Study to Understand the Genetics of the Acute Response to Metformin and Glipizide in Humans (SUGAR-MGH), a standardized pharmacogenetic protocol (10,11).…”

Pharmacogenetics in type 2 diabetes: precision medicine or discovery tool?

“…We have conducted the Study to Understand the Genetics of the Acute Response to Metformin and Glipizide in Humans (SUGAR-MGH), a pharmacogenetic resource in which 1000 participants who were naive to antihyperglycaemic medications were given a single dose of glipizide followed by a short course of metformin, and glycaemic responses were measured in the acute setting (Fig. 4) [56]. In addition, incretin hormones were measured after an OGTT.…”

The Application of Genomics in Diabetes: Barriers to Discovery and Implementation

“…There is surprisingly little information about the comparative benefits and harms for different drugs (51), and treatment guidelines for type 2 diabetes (52) permit the use of most approved drug classes as second-line therapy after metformin, which is the recommended first-line therapy for most patients because of its good safety profile and potential cardiovascular benefits (53,54). There is also substantial interindividual variability in drug response (55), and many patients eventually fail to achieve recommended levels of glycemic control with their initial therapy (56,57). For example, in the U.K. General Practice Research Database, only half of patients who initiated therapy with metformin or a sulfonylurea achieved an HbA 1c level of <7% (58).…”