What is the study, possibly the TRIMASTER trial, that compared a triple therapy regimen of metformin, a thiazolidinedione (TZD), and another oral hypoglycemic agent to the standard American Diabetes Association (ADA) approach for managing type 2 diabetes?

The ADOPT Trial: Comparing Metformin, TZD, and Sulfonylureas for Type 2 Diabetes Management

The study you are referring to is the ADOPT (A Diabetes Outcome Progression Trial) study, which was led by Dr. Ralph DeFronzo and compared metformin, rosiglitazone (a thiazolidinedione/TZD), and glyburide (a sulfonylurea) as initial monotherapy for type 2 diabetes. 1

Key Features of the ADOPT Trial

• Design: Long-term, randomized controlled trial comparing three oral antidiabetic medications as monotherapy
• Principal Investigator: Dr. Ralph DeFronzo (not Doranzo) was a key investigator
• Medications Studied:
  • Metformin (a biguanide)
  • Rosiglitazone (a thiazolidinedione/TZD)
  • Glyburide (a sulfonylurea)
• Primary Outcome: Time to monotherapy failure (defined as fasting plasma glucose >180 mg/dL)

Main Findings of ADOPT

The ADOPT trial demonstrated several important findings that have influenced diabetes management:

1. Durability of Glycemic Control: Rosiglitazone provided more durable glycemic control compared to both metformin and glyburide, with the lowest rate of monotherapy failure 1

2. Comparative Effects on HbA1c:

   • All three medications initially reduced HbA1c to similar degrees
   • Over time, glycemic control deteriorated most rapidly with glyburide, followed by metformin, and least with rosiglitazone 1

3. Side Effect Profiles:

   • Weight effects: Metformin was associated with weight loss, while rosiglitazone and glyburide were associated with weight gain 1
   • Hypoglycemia: Significantly higher with glyburide compared to metformin or rosiglitazone 1
   • Edema and fracture risk: Higher with rosiglitazone 1

Clinical Implications from ADOPT

The ADOPT trial provided important evidence that influenced ADA guidelines and clinical practice:

• Metformin remained first-line therapy despite not having the most durable glycemic effect, due to its weight neutrality, low hypoglycemia risk, and potential cardiovascular benefits 1

• TZDs demonstrated superior durability in maintaining glycemic control but had significant side effects including weight gain, fluid retention, and increased fracture risk 1

• Sulfonylureas showed the fastest deterioration in glycemic control, suggesting limitations in their ability to preserve beta-cell function long-term 1

Important Distinctions

The ADOPT trial should not be confused with:

1. The TODAY trial - which studied treatment options for youth with type 2 diabetes 1
2. The TriMaster trial - which is a more recent crossover study examining DPP-4 inhibitors, SGLT2 inhibitors, and thiazolidinediones as second or third-line therapy 2

Clinical Relevance Today

While the ADOPT trial was groundbreaking, it's important to note that:

• Rosiglitazone use became restricted due to cardiovascular safety concerns after the trial
• Newer medication classes (SGLT2 inhibitors, GLP-1 receptor agonists) have emerged with proven cardiovascular and renal benefits
• Current guidelines still recommend metformin as first-line therapy, with subsequent medication choices based on comorbidities and patient factors 1

The ADOPT trial remains a landmark study that demonstrated the importance of considering medication durability in addition to short-term efficacy when managing type 2 diabetes.