After Metformin, Which Drug Makes the GRADE?

Deborah J. Wexler, MD, MSc; Mark Harmel, MPH


July 09, 2021

This transcript has been edited for clarity.

Hi. I'm delighted to be here today to tell you about the results of the GRADE diabetes study.

Back in [2013], when GRADE launched, it was very clear that the first glucose-lowering medication to use in people with type 2 diabetes was metformin, but it really wasn't clear which medication to add to metformin. GRADE aimed to fill this evidence gap.

How Is GRADE Different?

GRADE aimed to be different from the other trials out there. We wanted to follow people for a very long time, since people with type 2 diabetes take medications for a really long time. And unlike many other trials that compare medications to placebo, GRADE was a comparative effectiveness trial, which meant that it compared four active treatments to each other, with no placebo arm.

Another very different thing about GRADE from the recent trials that we've seen published in diabetes is that GRADE is not a cardiovascular outcomes trial. The recent cardiovascular outcomes trials from which we've learned so much have enrolled people with longstanding diabetes, with very high cardiovascular risk or established cardiovascular disease. GRADE enrolled people with an average duration of diabetes of almost 5 years, and very few people, around 6%, had cardiovascular disease at baseline. So this is a very different population from many of the trials that we've seen in recent years.

GRADE aimed to be diverse and representative of people with type 2 diabetes in America. We enrolled a highly diverse population of 20% African American and 18% Latino patients, and we followed them for an average of 5 years. And we finally have our results.

Injection Over Pills for A1c Control

The results of GRADE have demonstrated that liraglutide was more effective in keeping the A1c < 7%. Glimepiride had an intermediate effect, and sitagliptin resulted in the fastest development of A1c levels > 7%. So, GRADE found that among the four glucose-lowering medications, the two taken by injection — glargine insulin and liraglutide — were slightly better at reaching and keeping the A1c level < 7% over the course of the study than either of the two pills, glimepiride or sitagliptin.

GRADE also aimed to evaluate the comparative effectiveness of these medications with respect to side effects, adverse outcomes, microvascular outcomes, macrovascular outcomes, quality of life, cost-effectiveness, and a range of other outcomes.

Patients treated with liraglutide and sitagliptin had more weight loss than those treated with glimepiride. All participants treated with glargine had stable weight over time. Severe hypoglycemia was very rare in GRADE, but hypoglycemia requiring assistance from other people was slightly more common in people treated with glimepiride than with other medications. In terms of side effects, liraglutide had more gastrointestinal side effects, such as nausea, abdominal pain, and diarrhea, than the other three medications.

We also examined complications. There was no difference in microvascular complications measured by kidney outcomes or neuropathy outcomes in any of the four treatment groups of GRADE. But there was an interesting finding with respect to macrovascular outcome. On the basis of preliminary results, liraglutide had a relative benefit for a broad composite outcome of heart attacks, stroke, and other heart and vascular complications compared with the other medications used in GRADE. However, that result is not final, and more data on cardiovascular events are yet to come.

What About SGLT2 Inhibitors?

Lots of questions come up when we think about this study. Over the months and years to come, we're going to learn a lot from GRADE about how to individualize treatment and how each of these medications work. We're going to be able to look at things like insulin resistance and genotypic and phenotypic characteristics that correlate with response to outcome. And we're going to learn a ton about how to individualize treatments for patients with type 2 diabetes.

GRADE didn't include an SGLT2 inhibitor. One of the reasons for that is that GRADE was started before SGLT2 inhibitors were even approved in the United States. This is a very long-term trial that looked at outcomes in a low-risk population over time, and we unfortunately don't have the comparison between SGLT2 inhibitors and the medications included in GRADE.

One thing we feel good about is that all four of these medications are commonly used and will continue to be commonly used, and the wealth of information that we'll gain from this trial will allow us to better use them in all of our patients with type 2 diabetes.

Deborah J. Wexler, MD, is an associate professor of medicine at Harvard Medical School, the associate clinical chief of the MGH Diabetes Unit, and clinical director of the MGH Diabetes Center. She is the MGH site principal investigator and is on the executive committee of the GRADE study.

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