PracticeUpdate: Is there a correlation between the reduction in hemoglobin A1c and the improvement in cardiovascular risk?
Dr. Wexler: This is a very vexing question because in observational studies, it's been observed in every observational trial that lower A1c is associated with lower risk of cardiovascular events. In randomized controlled trials, such as ACCORD, ADVANCE, VADT, that directly tested the hypothesis that treating to very tight glycemic control versus moderately good glycemic control, when that hypothesis was tested in a randomized controlled trial, there was no cardiovascular benefit seen. And there have been people, we've been thinking about this for years and years and years, and what does this mean?
PracticeUpdate: What is a potential explanation for this?
Dr. Wexler: I think it means a couple of things. And my take-home message is this: First, the observational trials are riddled by stage bias. In other words, people with earlier diabetes have easier to control diabetes, have better A1cs, and have less established cardiovascular disease. People with long duration diabetes have more time to accumulate cardiovascular complications and have higher A1c. That correlation will always be there, and it's very hard to untangle that in any observational trial. So we'll set that aside.
PracticeUpdate: How would you incorporate these data into clinical recommendations?
Dr. Wexler: In the randomized control trials, I think what we can very strongly conclude is that certainly in people with established cardiovascular disease, treating people to intensive control versus moderate control has no cardiovascular benefit.
And what really matters for cardiovascular benefit is the management of cardiovascular risk factors, like hypertension, hyperlipidemia, smoking cessation, weight management. In addition, we now have specific diabetes medications that seem to have independent benefits for cardiovascular risk reduction, and those, of course, are among people, has been most strongly demonstrated among people with established cardiovascular disease, the GLP-1 receptor agonists and the SGLT-2 inhibitors. In the case of the SGLT-2 inhibitors, I think people pretty strongly feel those benefits are independent of the glucose-lowering effect. And in the GLP-1 receptor agonist, it can be hard to disentangle, because there's such potent glucose-lowering medications, and they also reduce cardiovascular events. But we think that there's probably some direct antiatherogenic benefit in those medications as well.
So the take-home message is, of all of this: For people with type 2 diabetes, their greatest risk of death is from cardiovascular complications. To manage that, we do all the usual: hypertension, statin, smoking cessation, weight management. And now, in people with established cardiovascular risk or high cardiovascular risk, we would preferentially choose the diabetes medications where you get not just glucose lowering, but two, three, or four, five sorts of benefits with one medication, and those would be the SGLT-2s and GLP-1s, which can cause cardiac benefit, weight loss, glucose lowering, no hypoglycemia, et cetera.