What is the name of the trial that compared 5 different classes of diabetes medications, including Dipeptidyl Peptidase-4 (DPP-4) inhibitors, Glucagon-Like Peptide-1 (GLP-1) receptor agonists, and Sodium-Glucose Cotransporter 2 (SGLT2) inhibitors, in addition to metformin?

The GRADE Trial: Comparing Five Diabetes Medication Classes with Metformin

The Glycemia Reduction Approaches in Diabetes: A Comparative Effectiveness Study (GRADE) is the landmark trial that compared four different classes of diabetes medications added to metformin in patients with type 2 diabetes. 1

Trial Design and Medications Compared

The GRADE trial was a 36-center unmasked, parallel treatment group, randomized controlled trial that evaluated four diabetes medication classes when added to metformin:

1. Sulfonylureas (glimepiride)
2. Dipeptidyl Peptidase-4 (DPP-4) inhibitors (sitagliptin)
3. Glucagon-Like Peptide-1 (GLP-1) receptor agonists (liraglutide)
4. Basal insulin (insulin glargine)

1, 2, 3

Key Characteristics of the GRADE Trial

• Study Population: 5,047 participants with type 2 diabetes
• Inclusion Criteria: Adults with type 2 diabetes for less than 10 years, HbA1c between 6.8-8.5%, on metformin monotherapy
• Mean Follow-up: 5.0 years
• Primary Outcome: Ability to maintain HbA1c <7.0%
• Secondary Outcomes: Microvascular complications, cardiovascular events, mortality, and other diabetes-related outcomes

1, 2, 3

Key Findings from GRADE

Glycemic Control

• All four medication classes improved glycemic control when added to metformin
• Liraglutide and insulin glargine demonstrated greater durability in maintaining glycemic control compared to sitagliptin and glimepiride 3

Cardiovascular Outcomes

• No significant differences among the four treatment groups for major adverse cardiovascular events (MACE) or hospitalization for heart failure
• Liraglutide showed a possible reduction in the incidence of any cardiovascular disease (hazard ratio 0.7,95% CI 0.6-0.9) compared to the other three treatments combined 3

Renal Outcomes

• No significant differences in kidney outcomes among the four medication classes
• Mean chronic eGFR slope was similar across all treatment groups (approximately -2.0 mL/min/1.73 m² per year) 2

Important Context

While the GRADE trial compared these four medication classes, it's important to note that it did not include SGLT2 inhibitors, which have shown significant cardiovascular and renal benefits in other trials 4. The ongoing research continues to evaluate the comparative effectiveness of newer diabetes medications, including SGLT2 inhibitors and the dual GIP/GLP-1 receptor agonist tirzepatide 5.

The GRADE trial provides valuable information on the comparative effectiveness of commonly used diabetes medications when added to metformin, helping clinicians make evidence-based decisions for glycemic management in patients with type 2 diabetes.