Making the Grade

Type 2 diabetes is a global epidemic. In the U.S. alone, 37 million people have diabetes, and approximately 90% to 95% of them have type 2. The Bronx community has been hit particularly hard with nearly one in three adults living with diabetes.  

This is an ongoing challenge for clinicians and one Dr. Jill Crandall is taking on. She is the site principal investigator of a large, multicenter trial studying the effectiveness of combination treatment for type 2 diabetes – the Glycemia Reduction Approaches in Diabetes: A Comparative Effectiveness (GRADE) Study.

Dr. Crandall, professor of medicine, and chief of the division of endocrinology at Einstein and Montefiore, recently spoke with us about the challenges of managing type 2 diabetes, the impetus for the study, and its results, which were recently published in The New England Journal of Medicine.

What’s the GRADE Study?

GRADE was a multicenter clinical trial comparing four commonly used drugs to treat type 2 diabetes. Einstein and Montefiore were among the 36 U.S. study sites. Approximately, 5,047 patients representing diverse racial and ethnic groups who were on metformin (the standard therapy for type 2 diabetes) were recruited and followed over five years. In addition to being on metformin, criteria included that participants were diagnosed no more than 10 years prior to the start of the trial and had an HbA1C of 6.8% to 8.5%.

Participants were randomized to one of four classes of commonly used diabetes medications: sitagliptin, liraglutide, glimepiride, and insulin glargine U-100, a long-acting insulin.

What was the rationale for starting the GRADE Study?

There was an explosion of medications for the treatment of type 2 diabetes, including the approval of eight new classes of medications in a 15-year period (1995-2010). And with that came a three-fold spike in costs – some $18 billion between 2001 and 2012.

This begged the question of how we should use these drugs. The standard monotherapy, metformin, generally fails in the majority of patients with type 2 diabetes. Most need multiple medications to achieve glycemic targets. Yet, with practically no comparison trials of which medications to add to metformin, there was little evidence-based data to guide individualized treatment. The trials that had been done were of short duration (less than two years), which could not provide clinicians with critical information needed for the treatment of a chronic, progressive disease that requires lifelong therapy.

In 2012, the American Diabetes Association and the European Association for the Study of Diabetes, took an official position, stating that “there was a significant need for high-quality comparative effectiveness research, not only regarding glycemic control, but also costs and the outcomes that matter most to patients – quality of life and the avoidance of morbid and life-limiting complications, especially cardiovascular disease.”

We began the GRADE trial in 2013 (though had been planning it for several years). It was funded by the National Institutes of Health/National Institute of Diabetes and Digestive and Kidney Diseases.

What were the results?

After an average of four years of follow-up the study found that participants taking metformin plus liraglutide or insulin glargine achieved and maintained their target blood levels for the longest time compared to sitagliptin or glimepiride. This translated into approximately six months more time with blood glucose levels in the target range compared with sitagliptin, which was the least effective in maintaining target levels. Treatment effects did not differ based on age, sex, race, or ethnicity. However, nearly 75% of participants were unable to maintain the glucose target over four years, underscoring how challenging it is to manage type 2 diabetes.

What were some of the challenges of the study?

Well, first there is the challenge of funding cycles, which are generally five years at most and we wanted to do a trial that would be able to follow people over a clinically significant period of time. And there is the challenge of how long you could keep a participant engaged in the study – five years is a long time. And finally, another consideration was the need for rescue therapy for participants who did not respond to the therapy that they were assigned to. It wouldn’t be ethical to allow someone to maintain an elevated HbA1C well above the target for a prolonged period of time. So, rescue therapy would need to be consistent among the 36 sites.

What would you say is the potential cost-benefit from the data you gleaned?

Formal cost benefit analysis from the trial is forthcoming. But it is interesting that glimepiride (a sulfonylurea), an inexpensive generic medication, was more effective in maintaining glucose control than sitagliptin, which is quite costly. On the other hand, the most effective agents, liraglutide and insulin, are expensive but they may be cost effective in the long run if they produce more durable glucose control.

What are the next steps in this research?

A lot more results will be published from GRADE, including metabolic and pharmacogenetic studies that may help decipher which medications work best for which patients – an advance for personalized medicine. We are also looking at the relationship between the burden of diabetes treatment and “diabetes distress,” a project led by Einstein’s Jeffrey Gonzalez, Ph.D.  

The field of diabetes pharmacotherapy in general has pivoted to focus more on the non-glycemic benefits of medications such as GLP-1 receptor agonists and SGLT2 inhibitors, which lower risk of cardiovascular disease and renal complications of diabetes. We can expect future studies to extend our current knowledge about which drugs and which drug combinations are best.