A Clinician’s Plea for More Pragmatic Clinical Trials in Diabetes

It’s Monday morning, and your next patient is a 48-year-old Asian woman who was diagnosed with type 2 diabetes (T2D) 3 years ago. She performs self-monitored blood glucose (SMBG) tests regularly, and brings her readings with her most of the time when she sees you. She has been making dietary changes and has gradually increased her aerobic exercise and now averages approximately 150 minutes most weeks. 

The patient has been taking metformin 1000 mg twice a day consistently. Her hemoglobin A1c (HbA1c) measurements have been at or near goal, historically ranging from 6.3 to 7.3%. So far, she has not developed any microvascular or macrovascular complications of diabetes. As you absorb this data, you may very well be asking yourself, “Everything seems to be going well; what’s the problem?”

• Her HbA1cs have been trending upward.
• Despite her best efforts, her recent HbA1c was 8.6%.

What second medication would you recommend adding to her regimen? 

I have long been fascinated by the fact that no study has been conducted to try to tackle this question. Until 3 years ago, that is, when The Glycemia Reduction Approaches in Diabetes: A Comparative Effectiveness Study (GRADE) was launched. Funded by the National Institute of Health (NIH)’s National Institute of Diabetes and Digestive and Kidney Diseases, GRADE is a multicenter clinical trial that is investigating which of 4 FDA-approved therapeutic agents for T2D, when combined with metformin, has the most efficacy and fewest adverse effects.¹  

Study participants are randomly assigned to receive metformin along with: (1) a sulfonylurea (glimepiride); (2) a DPP-4 inhibitor (sitagliptin); (3) a GLP-1 receptor agonist (liraglutide); or (4) a long-acting insulin (glargine). These individuals will be followed for up to 7 years.

Throughout the United States, 45 sites are currently recruiting and enrolling study participants. According to the GRADE Study website (grade.bsc.gwu.edu), as of March 1, 2017, 4392 individuals have been randomly assigned to one of the study groups; the goal is a total of 5000 participants. 

Some of the inclusion criteria include: adults older than 30 who have been diagnosed with T2D for less than 10 years, have either never been on metformin or are only taking metformin, and have an HbA1c of 6.8 to 8.5%. Participants will undergo 4 follow-up visits per year for 4 to 7 years.

“What differentiates GRADE from previous studies is that it will perform a head-to-head comprehensive comparison of the most commonly used drugs over a long period of time,” observed David M. Nathan, MD, of Massachusetts General Hospital, Boston, a co-principal investigator along with John Lachin, ScD, of The George Washington University, Washington, DC. 

Dr Nathan also remarked, “In addition to determining which medications control blood glucose levels most effectively over time, we hope to examine individual factors that are associated with better or worse response to the different medications. This should provide understanding of how to personalize the treatment of diabetes.”²

Randomized placebo-controlled clinical trials (RCTs) are the gold standard, and I would feel reasonably confident in stating that very few — if any — individuals would dispute their critical importance. But, much like what a photo shows is in part a function of where the person who took it was standing, RCTs provide only a certain perspective. 

While we cannot completely replicate or account for all demographics, medication regimens, and other medical conditions of patients who may end up taking a new diabetes medication, we also need other types of studies to augment our knowledge about medications at a more patient-specific level. 

A commentary by Sheldon Greenfield, MD, delves more deeply into this concern.³ He states, “Comparative effectiveness research is, in essence, framed by asking the core question: for a doctor and a patient, what is the best treatment for that patient in terms of both benefits and harms?” 

Dr Greenfield goes on to consider whether the GRADE study is a comparative effectiveness trial — it is, and yet it isn’t. On one hand, GRADE is comparing 4 medications head-to-head. On the other, it may not have enough patients in certain, essential subgroups, such as patients who are older and have multiple chronic medical problems, especially patients with cardiovascular disease. And what about patients who are of low socioeconomic status?

While pharmaceutical companies do not compare medications in head-to-head trials, I would definitely want to see more of these types of studies designed to help shed more light on real-world challenges such as this one. These studies can, along with randomized controlled trials, arm both the patient and the physician with substantive information that can potentially lead to both better-informed decisions and improved clinical outcomes, including enhanced quality of life.

Dr Chao is a sub-investigator with the VA San Diego GRADE Study.