GRADE study

Last edited 09/2022 and last reviewed 09/2022

The GRADE study - Glycemia Reduction in Type 2 Diabetes - Glycemic Outcomes

A study to investigate the comparative effectiveness of glucose-lowering medications for use with metformin to maintain target glycated hemoglobin levels in persons with type 2 diabetes

Study methodology

• trial involving participants with type 2 diabetes of less than 10 years' duration who were receiving metformin and had glycated hemoglobin levels of 6.8 to 8.5%
• randomly assigned participants to receive either:
  • insulin glargine U-100 (hereafter, glargine),
  • glimepiride (a sulfonylurea)
  • the glucagon-like peptide-1 receptor agonist liraglutide,
  • or sitagliptin, a dipeptidyl peptidase 4 inhibitor
• primary metabolic outcome was a glycated hemoglobin level, measured quarterly, of 7.0% or higher that was subsequently confirmed, and the secondary metabolic outcome was a confirmed glycated hemoglobin level greater than 7.5%

Study results

• a total of 5047 participants (19.8% Black and 18.6% Hispanic or Latinx) who had received metformin for type 2 diabetes were followed for a mean of 5.0 years
• cumulative incidence of a glycated hemoglobin level of 7.0% or higher (the primary metabolic outcome) differed significantly among the four groups (P<0.001 for a global test of differences across groups)
  • all four medications, when added to metformin, decreased glycated hemoglobin levels. However, glargine and liraglutide were significantly, albeit modestly, more effective in achieving and maintaining target glycated hemoglobin levels
• participants who received liraglutide reported more frequent gastrointestinal side effects and lost more weight than those in the other treatment groups

The GRADE Study group also assessed the comparative effectiveness of commonly used glucose-lowering medications, when added to metformin, with respect to microvascular and cardiovascular disease outcomes in persons with type 2 diabetes (2):

• concluded:
  • participants with type 2 diabetes, the incidences of microvascular complications and death were not materially different among the four treatment groups. The findings indicated possible differences among the groups in the incidence of any cardiovascular disease

Reference:

• The GRADE Study Research Group. Glycemia Reduction in Type 2 Diabetes - Glycemic Outcomes. N Engl J Med 2022; 387:1063-1074
• The GRADE Study Research Group. Glycemia Reduction in Type 2 Diabetes - Microvascular and Cardiovascular Outcomes. N Engl J Med 2022; 387:1075-1088