Dr. Wexler: Hi, my name is Deborah Wexler, and I'm the clinical director of the Massachusetts General Hospital Diabetes Center and an associate professor at Harvard Medical School. I'm also one of the GRADE investigators, and it was extremely exciting after many years of conducting the great trial that we presented the preliminary results of the GRADE study at the American Diabetes Association Scientific Sessions in June of 2021. I just want to say a little bit about GRADE. GRADE is a comparative effectiveness study, which is comparing which second glucose-lowering medication added to metformin is most effective over time for people with diabetes.
PracticeUpdate: What makes GRADE such a uniquely useful trial for clinical practice?
Dr. Wexler: The vast majority of medication trials are placebo-controlled. Very rarely are there active competitors. And in a placebo controlled trial, there's often a very clean message coming out of the study. That's partially because an active medication is being compared against the placebo. And it's partially because, often when it's a registration trial, the trial is really designed to highlight the benefit of the new medication. GRADE was completely different. Comparative effectiveness trials compare multiple, one or two or more, active medications against each other. And GRADE actually compared 4 medications head-to-head.
The rationale for this, of course, was that people with type 2 diabetes have a number of medications to choose from. At the time that GRADE was designed, and up until the publication of GRADE, it really wasn't clear which second glucose-lowering medication was best for type 2 diabetes. And people take these medications for a very long time. GRADE was designed to answer the question: In an apples-to-apples comparison, when you line up a DPP-4 inhibitor (we used sitagliptin), a sulfonylurea (we used glimepiride), a GLP-1 receptor (we used liraglutide), or basal insulin glargine, when you compare those head-to-head in people who are at the same stage of diabetes, which one performs best over time? And we have a result, and I'm going to share that result with you in a minute, but I just want to point out that the results are a little bit like, a little bit of this is better, a little bit of that is better. It's not just one take-home message.
And in fact, from GRADE, we're not going to have one take-home message. We're going to have a number of papers that come out over years that really help all of us understand how these medications play out in diverse people with type 2 diabetes.
GRADE study population
So GRADE included a highly diverse population: 20% black and 18% Latino patients. That was deliberately designed to recruit from the populations disproportionately impacted by diabetes. And we did perform that head-to-head comparison among people with type 2 diabetes. When they enrolled in the trial, they had to have a hemoglobin A1c between 6.8 and 8.5, and they had to have diabetes for less than 10 years. And they had to be tolerating metformin, at least 1000 mg daily, but most people were very close to 2000 mg daily of metformin. And we enrolled 5000 people. On average, people were about 57 years old and had diabetes for about 4 years. And we assigned 1250 to each of those medications and followed people on average for 5 years, but at the most up to 8 years.
So what we found in GRADE was that the two injectable medications, liraglutide and insulin, were most effective in keeping A1c levels less than 7. Glimepiride was slightly less effective than insulin and liraglutide. And sitagliptin was the least effective and had the fastest progression to a development of an A1c greater than 7. We also then followed people on the assigned medication until the A1c hit 7.5, and glargine was the most effective in keeping the A1c less than 7.5, which was a secondary outcome. Liraglutide was a close second there.
GRADE adverse effect signals
Now, one of the other really interesting things about this study was that the adverse effects really differed. So we found that weight changes really differed. So on average, participants treated with liraglutide and sitagliptin had more weight loss than those treated with glimepiride. And actually, the glimepiride group had the most weight gain over time, whereas patients assigned to basal insulin, glargine, had stable weight over time. That was a little bit of a surprise. I think we might've expected that patients treated with basal insulin would have had more weight gain than people with sulfonylureas, but that was not what we found. In terms of side effects, liraglutide, as might be expected for a GLP-1 receptor agonist, did have more GI side effects, such as nausea, abdominal pain, and diarrhea than the other medications. And interestingly, when it came to hypoglycemia, glimepiride actually had the highest risk for hypoglycemia than the other medications, followed, of course, by insulin. But again, it was a bit of a surprise that the glimepiride did a little worse than the insulin with respect to hypoglycemia.
GRADE cardiovascular outcomes
Now, one of the most interesting findings coming out of GRADE was the cardiovascular outcomes. So GRADE enrolled a very low risk population as listeners and watchers probably know. Most cardiovascular outcome trials with all the diabetes meds have enrolled people who have a history of cardiovascular disease or people at very high risk of cardiovascular disease. That was not the case in GRADE. In GRADE we enrolled people, like I said with only 4 years duration of diabetes. The rate of established cardiovascular disease at baseline was around 6%. This was a relatively healthy, early diabetes population. And we actually did not expect to see any differences in cardiovascular outcomes because we didn't expect to have enough numbers of cardiovascular outcomes to be able to detect a benefit.
But what we reported at American Diabetes Association is when we looked at the composite outcome of all of the adjudicated cardiovascular events put together, all of the heart attacks, all of the strokes, all of the heart failure, all of the vascular complications, not just MACE, but sort of the big, every cardiac event together, there did seem to be a relative benefit for liraglutide. Now that is not a final result, and we're going to have to see. We wanted to get the results out as quickly as possible for ADA, but we also want to confirm that result. So I don't want people to say that that's a hundred percent certain, but I think what's going to be important since we hadn't yet adjudicated all the cardiovascular outcomes, is when the final papers come out this fall, keep an eye out to see what were the final cardiovascular results of GRADE. What happened to MACE? What happened to heart failure? What happened to the composite of cardiovascular events? I think that's a very intriguing finding that people are going to want to know more about.