Redefining Prediabetes to Prevent Complications
Can treating prediabetes like diabetes lead to better outcomes?
Ralph DeFronzo, MD
Chief of the Diabetes Division at the University of Texas Health Science Center
Type 2 Diabetes
ADA Research Funding
Clinical Science and Epidemiology
Ralph DeFronzo, MD, wants to redefine prediabetes. The American Diabetes Association identifies the condition as blood glucose levels that are higher than normal, raising the risk for type 2 diabetes and cardiovascular disease. What’s normal, according to the ADA, is an A1C (an estimate of average blood glucose over a period of time) below 5.7 percent. Anything in the gray zone above that but below 6.5, the official threshold for a diagnosis of type 2 diabetes, is labeled prediabetes.
Many people seem to believe that prediabetes is a separate illness—and that’s what DeFronzo, an endocrinologist and chief of the Diabetes Division at the University of Texas Health Science Center, wants to change. He argues that prediabetes is just type 2 diabetes that isn’t far enough along to meet the definition. “The development of type 2 is a gradual process that occurs over years,” he says. “People with prediabetes, in my opinion, have diabetes—they just don’t meet the cutoff points set by the ADA yet.”
An estimated 86 million Americans have prediabetes, according to the Centers for Disease Control and Prevention. The standard treatment is diet and exercise, with a focus on losing at least 5 to 7 percent of body weight. Some doctors also prescribe metformin, the drug typically used first to treat type 2 diabetes. In 2002, a nationwide study found that modest weight loss and regular exercise reduced the risk of developing type 2 diabetes by almost 60 percent. Metformin lowered the risk by 30 percent.
Yet DeFronzo thinks it’s still critical to find the most effective pharmaceutical treatment for prediabetes, not because drugs yield better results than weight loss but because they’re more realistic. “The best treatment is to get people to lose weight and exercise,” DeFronzo says. “The problem is that most people fail to lose weight and to stick with an exercise program.”
DeFronzo argues that the debate over the best way to treat prediabetes contributes to the diabetes epidemic because doctors aren’t treating people with prediabetes early enough or aggressively enough. His belief: The best course is to recommend diet and exercise but treat with a drug as insurance. “We need to identify people with prediabetes and treat them,” DeFronzo says. “I believe you should treat early. If you keep the A1C from going up, that will protect people from microvascular complications [eye, kidney, and nerve problems] later on.”
Based on earlier research, DeFronzo says there are two different types of prediabetes, depending on when the body fails to produce insulin, the hormone that signals body tissues to use glucose: impaired glucose tolerance and impaired fasting glucose.
Following a meal, insulin is released in two phases: an early burst that occurs 30 minutes after eating and a late phase that happens a half hour to two hours after a meal. Some people with prediabetes have trouble producing that late-phase insulin. Their blood glucose level is normal after fasting overnight and between meals but rises progressively after meals and remains elevated two hours after eating. This is referred to as “impaired glucose tolerance” because blood glucose levels are high after eating carbohydrate. This problem is compounded by the fact that muscle tissues are resistant to the action of insulin, which usually stimulates muscle to remove glucose from the bloodstream after a meal.
The other group has elevated fasting blood glucose when they wake up in the morning because the liver is resistant to the action of insulin, allowing it to release too much glucose into the bloodstream. They also do not produce the early burst of insulin that occurs within 30 minutes of a meal. This allows the liver to release too much glucose into the bloodstream in the hour after eating, causing the blood glucose level to skyrocket. The late insulin response after the meal is normal, so blood glucose returns to its usual (albeit elevated) fasting level two hours after the meal. These individuals have “impaired fasting glucose.”
With the help of a grant from the ADA, DeFronzo is looking at how those types of beta cell dysfunction might respond to four different kinds of medicines. He recruited 60 people with both types of prediabetes and randomly assigned them to four different drugs: metformin, dapagliflozin, pioglitazone, and saxagliptin. Over the course of four months, he and his team monitored participants to see how their bodies responded.
Now the researchers are analyzing the data to understand what effects the different drugs had on the two different types of prediabetes. He hopes to have results early next year. “For physicians who like to be aggressive, hopefully this will show us which drugs are best to treat people early,” DeFronzo says. When combined with tests to see which type of prediabetes patients have, the drugs could be targeted to have the maximum impact. And effective treatment early would reduce the risk of developing type 2 diabetes and its costly complications later.
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