Type 2 Diabetes and Macrovascular Complications


John Anderson, MD: The pathophysiology in type 2 diabetes, which we’ve learned a lot about over the last 20 years, is a lot more complicated than we initially thought. When I started practice in 1989, we thought we knew that there was insufficient secretion of insulin from the beta cells to keep up with increased peripheral demand and insulin resistance in the muscle. We also knew that the liver produced too much glucose overnight. Well, we’ve learned a lot in that time. We now know that the failure to suppress glucagon after a meal is as much a pathophysiologic defect, maybe, as the inadequate secretion of insulin. We also know that there’s a huge incretin effect—a hormone secreted by the L cells of the intestine that helps with secretion of insulin, suppression of glucagon. We’ve got agents that we leverage with that.

We also know that insulin resistance at adipose or fat tissue… We used to think fat tissue is just this inert storage vehicle. Now we know that insulin resistance at adipose tissue produces free fatty acids that can actually cause inflammation in those places like the liver, the beta cells, the pancreas, and the muscle.

And we also know that there’s still this budding knowledge about what the role of the central nervous system is and what are the hormonal and neurologic centers that control peripheral glucose homeostasis. And then 1 other thing we’ve learned is that their increased glucose reabsorption from the kidney, which is really counterproductive for someone who’s already got a high glucose.

The macrovascular complications of type 2 diabetes are generally stroke, heart attack, and peripheral vascular disease; that is, diseases of the large vessels. And we know that in diabetes, things like smoking, high blood pressure, and high cholesterol all contribute to macrovascular disease. And it’s interesting to look at the United States. We’ve lowered the incidence of myocardial infarction and heart attack in patients with type 2 diabetes by about two-thirds over the last 20 years. We’ve lowered stroke by about 50%. But if you still look at age-matched controls, people with diabetes and people without diabetes, there’s still a 6- to 7-fold increased risk for the person with diabetes. So there’s still this gap that we need to bridge where we can do better for our patients.

John B. Buse, MD, PhD: In type 2 diabetes, patients have an extraordinary risk of cardiovascular disease. We don’t really fully understand why. Part of it is driven by the high blood sugar, but the biggest part is probably related to the underlying problem of obesity and insulin resistance, and its association with more high blood pressure, with a particular kind of lipid disorder with low HDL [high-density lipoprotein], high triglycerides, and small dense LDL [low-density lipoprotein] particles, as well as some sort of inflammatory and hypercoagulability states.

Exactly how this whole thing melds to create increased cardiovascular risk is still under investigation. But the risk is extraordinary. The estimate is that over 60% of patients with diabetes die of cardiovascular disease. And in general, cardiovascular events occur about 10 years earlier in patients with diabetes in the general population.

John Anderson, MD: Optimal glycemic control has to be individualized. In general, the American Diabetes Association recommends an A1C [glycated hemoglobin] goal for glycemic control of less than 7%. But they do say that in some cases, like in a younger patient with no comorbidities, you may want it to be closer to normal as possible. The American Association of Clinical Endocrinologists likes that goal of 6.5% or less, especially in younger people. But we also know that [with] regard to glycemic control in older patients, people who’ve had a long duration of diabetes, and people who have significant comorbidities—including cardiovascular comorbidities—you may be more interested in safety, and you may have to have a glycemic goal that’s less than aggressive.

Transcript edited for clarity.

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