Glycemia Reduction Approaches in Diabetes: A Comparative Effectiveness Study (GRADE)

General Description

Major human and economic costs are associated with the epidemic of type 2 diabetes (T2DM) in the United States, including long-term complications related to retinopathy, nephropathy, neuropathy, and cardiovascular disease (CVD). While research has resulted in the development of new classes of glucose-lowering medications, choosing the best means of maintaining an appropriate level of glycemic control from the array of medication options is a major challenge for practitioners. The Glycemia Reduction Approaches in Diabetes: A Comparative Effectiveness Study (GRADE) is a multicenter, parallel-group clinical trial designed to compare the major drug classes currently used to treat T2DM, with the ultimate goal of providing better guidance to practitioners in the choice of medications. Specifically, the GRADE study will compare the effects of four different glucose-lowering medications when combined with metformin, the standard therapy for T2DM, in patients with T2DM.

Individuals with duration of T2DM of less than 10 years and an age of at least 30 years at time of diagnosis are eligible for the study. Participants must complete a run-in phase to adjust metformin to a dose of at least 1,000 mg/day and a target dose of 2,000 mg/day. Following the run-in period, participants with baseline hemoglobin A1c values of 6.8-8.5% (51-69 mmol/mol) are randomized to treatment with metformin and one of four medications: sulfonylureas, dipeptidyl peptidase 4 inhibitors, glucagon-like receptor agonists, and insulin. All subjects will continue follow-up for a period of 4-7 years (depending on the time of entry), including those who reach the primary outcome. The primary outcome measure is the time to primary metabolic failure of the randomly assigned treatment, defined as the time to an initial HbA1c ≥ 7%, subsequently confirmed at the next quarterly visit. Secondary outcome measures include mean HbA1c and fasting glucose levels, frequency of hypoglycemia, cardiovascular events, estimated glomerular filtration rate (eGFR), albuminuria, adverse events, and mortality.

This study is ongoing.

Objectives

The primary objective of the study is to compare the major drug classes currently used to treat T2DM. Specifically, the GRADE study will compare the effects of four different glucose-lowering medications (sulfonylureas, dipeptidyl peptidase 4 inhibitors, glucagon-like receptor agonists, and insulin) when combined with metformin, the standard therapy for T2DM, in patients with T2DM.

Outcome Measure

The primary outcome measure is the time to primary metabolic failure of the randomly assigned treatment, defined as the time to an initial HbA1c ≥ 7%, subsequently confirmed at the next quarterly visit. Secondary outcome measures include mean HbA1c and fasting glucose levels, frequency of hypoglycemia, cardiovascular events, estimated glomerular filtration rate (eGFR), albuminuria, adverse events, and mortality.

Criteria

Individuals of at least 30 years of age with duration of diabetes of less than 10 years were eligible for the study. Participants are required to have an HbA1c value of 6.8-8.5% and to be taking a daily dose of at least 1000 mg/day of metformin at the conclusion of the run-in period.

Exclusion criteria are documented in the study protocol.

Outcome

This study is ongoing.