GLP-1 Agonists for the Treatment of Type 2 Diabetes - Episode 5
John Anderson, MD: One of the great debates about what is the best first injectable for a patient with type 2 diabetes has been around for a while. And this past year, the American Diabetes Association and the European Association for the Study of Diabetes were very, very firm. In almost all conditions, unless the patient happens to be glucose-toxic, catabolic, is losing weight, has blurred vision, a very high A1C [glycated hemoglobin], or very high glucose, in general, the GLP-1 [glucagon-like peptide-1] receptor agonist should always be your first choice of an injectable for patients with type 2 diabetes. Let me tell you why.
Even the original exenatide, used twice a day, which is not used as much anymore because we have longer-acting agents, still was non-inferior to basal insulin glargine titrated to a pretty aggressive goal in add-on to oral therapy with patients with type 2 diabetes. And now what we’re seeing with the longer-acting GLP-1 receptor agonists—and I include liraglutide, even though it’s a once-a-day option, along with the once-a-week therapies—they’re superior to basal insulin.
When you try to titrate basal insulin in a lot of these studies to a fasting glucose of less than 100, a lot of these patients can’t quite get to a fasting of less than 100, And in general, the A1C-lowering is more potent with the GLP-1 receptor agonist than it is with the insulin. In addition, when you add a GLP-1 receptor agonist, you’re usually going to get a non-glycemic benefit of weight reduction. You tend not to have hypoglycemia, unless you’re using it with insulin, or with a secretagogue; whereas the insulin is definitely going to cause some weight gain. It’s going to definitely increase the risk of hypotension. You’re going to definitely have to monitor more, at least once-a-day fasting glucoses to titrate the dose. So it’s just more complex. Those are all the arguments that go into using a GLP-1 receptor agonist first, as the first injectable in patients with type 2 diabetes.
John B. Buse, MD, PhD: The issue of how aggressive to be in pursuing glycemic control is an area of ongoing controversy. Through the clinical trials that have looked specifically at how low to go—there’s the DCCT trial in type 1 diabetes and the UKPDS trial in type 2 diabetes—it’s often misunderstood that these trials basically try to normalize glucose. They got to an A1C of about 7%, on average, for the period of follow up and showed clinically meaningful reductions in microvascular complications—eye, kidney, and nerve disease; and with long-term follow up improvements in cardiovascular outcomes.
In those trials, patients achieved an average A1C of about 7%. The American Diabetes Association says you should aim for an A1C of less than 7% in many patients with diabetes. And I agree with that 100%. The people that I would aim for less than 7% are particularly patients early in the course of their disease, younger patients with long life expectancies, and patients who don’t have multiple comorbidities and complications. So basically, early in the course of the disease.
Other organizations like the American College of Physicians say that the general goal should be 7% to 8%. I don’t really quibble with that much. I think in an older patient that clearly is a reasonable goal. But you have to sort of decide how old is old. I have lots of extremely vigorous 80-year-old patients who are golfing 3 times a week and going line-dancing with their wife and their children and grandchildren every Saturday night—people who are living vibrant lives, even if they’re 80. They’re actually likely to live another 10 years, and they may live 20 years or more.
In those patients I will develop a reasonable plan to try and get the A1C to less than 7%, or as close to 7% as we can, but I’m not going to do anything crazy unless the A1C is more than 8%. So I think that guidance has a ring of truth to it. And in fact, there is data from Scandinavia that in patients who have a 25-year history of type 1 diabetes, if their average A1C over that 25-year period is 7.6% or less, essentially none of them developed advanced microvascular complications—eye disease requiring laser treatment or clinical proteinuria.
So I think there’s even some data to suggest that 7% to 7.5% is probably OK, particularly as patients get older.
Vanita Aroda, MD: One of the questions that’s been up for debate is what the general glycemic goal should be for patients with type 2 diabetes.
Our current guidance suggests that the goal should be less than 7% for A1C, or as close to normal as possible, as safely as possible, without the untoward [adverse] effects of polypharmacy. And these recommendations stem from early studies from the UKPDS, but we’re actually seeing follow-up studies to demonstrate the role of early, good glycemic control and the legacy effect of this good glycemic control.
For example, a recent publication in Diabetes Care looked at patients in the Kaiser [Permanente] Northern California health system and found that those who were able to achieve and maintain a hemoglobin A1C on average of less than 6.5% in that first year of diagnosis did better in terms of microvascular complications and macrovascular complications than those who were not. And those who were able to achieve and maintain an A1C of less than 7% in that first year had less mortality than those who could not. So we’re seeing even contemporary evidence that getting to goal, getting to goal safely, and keeping patients at goal helps prevent long-term consequences and complications.
John Anderson, MD: When I’m trying to discuss with a patient where we need to get to, it’s about an individualized therapy. Are you an older person? Am I much more worried about safety? Or like this woman in this case, who’s age 46 and has already had a stent, I’m really aggressive. I think there is a reason to be aggressive, not necessarily for the macrovascular risk reduction. But we also know that microvascular risk reduction, both from UKPDS, and in type 1 patients, the DCCT, that if we can get them down to goal early and keep them there very safely, we really make a difference—not just 8 years later, but 10, 20, 30 years later you may have less microvascular complications.
So I think it’s really incumbent on all of us, and I’m a primary care physician, to understand: Let’s don’t spend months and years getting them to goal. Let’s get them to goal early, and let’s keep them there. And let’s stop this step-edit-treat-to-failure sort of approach that we’ve had. And what that may require in a lot of patients is combination therapy from the very beginning, not waiting and always failing.
Transcript edited for clarity.