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The long-term results of the Diabetes Prevention Program (DPP) tell us that the beneficial effect of metformin in terms of preventing or delaying the progression of diabetes persists over the entire 15 years of follow-up, and it’s looking to persist into the predictable future.

In the original publication of the DPP benefit from the first 3.2 years—that’s the way this study worked out—we saw that there was a particular beneficial effect of metformin among younger folks who were more overweight. Then in a subsequent analysis, we found that there was a particularly strong beneficial effect among women who reported a prior history of gestational diabetes before they entered the study. So, that was our expectation as we moved forward was that we would see this persisting benefit, at least in the subgroups. We’ve done the analysis now out to 15 years, and we don’t see a persisting benefit related to age or related to body mass index, obesity, but we do see a persisting benefit among women who came in with a prior history of gestational diabetes.

It may not be widely known, but women who have a history of gestational diabetes have the single highest risk of progressing to overt diabetes, so that’s a group who really do warrant some form of intervention. I don’t mean to minimize the effect of lifestyle—because lifestyle was also beneficial in that group and should certainly be a component of overall care—but when we look at the women who were randomized to metformin, they had an added benefit that was over and above what we could see otherwise with other therapies. So, metformin is a particularly beneficial therapy among women with gestational diabetes. That should equate to use in the general population. We haven’t seen a strong uptake in general of metformin for prevention, let alone in specific subgroups, and what we’re trying to get to with ongoing publications is to make sure that the world knows that not only was there benefit 15 years ago, but there’s a persisting benefit, and there are people who have a particularly strong benefit.

There’s a question about why we don’t see strong uptake among primary care providers, general medical providers, for metformin use in the prevention of type 2 diabetes. The question is “why?” and some of the thinking is that it’s because it’s officially an off-label use of the medication, and so we’ve been pushing an effort with the U.S. Food and Drug Administration to try and find some pathway to making a non-label use for prevention of diabetes with metformin, which has its own complications.

For people in primary care or general medical practice who are seeing someone with pre-diabetes who evidently has an elevated risk of progressing to diabetes—they’re overweight, it’s a woman with a history of gestational diabetes, they have high glucoses or rising glucoses that are being monitored over time—and the doctor wants to do something about that. There are two main choices that have been proven. One is a lifestyle intervention, and in many places across the country the Diabetes Prevention Program (DPP) curriculum has been implemented in various ways. Sometimes it’s the YMCA, sometimes it’s a local version of the National Diabetes Program that’s sponsored by the Centers for Disease Control and Prevention, so there are widely available, reasonably accessible—depending on where you live, largely—versions of the lifestyle intervention, and that’s certainly something that should come to mind. Metformin is a perfectly reasonable alternative. The fact that it’s off-label should not be a deterrent, in my mind. The effectiveness persists, the effectiveness is a known, and it has a known side effect profile, so the same things that happen for folks when we start metformin in diabetes happen for folks when we start metformin in pre-diabetes for prevention. We know how to manage that and it’s all a question of simply making the decision. The cost is low, and the barrier should be low.

The Diabetes Prevention Program (DPP) is now in follow-up stage 3, which is happening after more than 15 years of follow-up, and we’re continuing to follow those people. With the first 15 years of evaluation, we know that the original large benefit of lifestyle persists over time. We know that the original benefit of metformin persists over time and that there are persisting benefits in people who were originally randomized to one of the other groups, persisting benefit with taking the medication, and so we think that there’s a good argument for making an early assessment that determines someone to be at risk for diabetes and making at least one of those interventions happen.