UNC’s John B. Buse on Developments in Diabetes

Scientist Interview: November 2011

John B. Buse If you’re looking for a place to cheer yourself up after reading the latest economic news, Science Watch does not recommend you turn to recent reports on diabetes incidence and mortality worldwide. According to calculations released in September at the European Association for the Study of Diabetes congress in Lisbon, over 360 million people worldwide are living with diabetes and almost five million a year dying from it—one every seven seconds on average. In the U.S., the incidence of diabetes, both diagnosed and undiagnosed, has quadrupled since 1970—from 2% of the population to 8%.

If there’s any good news in this picture, it’s that diabetes therapy has improved dramatically over that same period, as has understanding of the disease itself. Among the most influential clinical researchers in the field is John B. Buse of the University of North Carolina, Chapel Hill.

According to the latest update of the Thomson Reuters Hot Papers Database, in the last two years Buse has contributed to seven diabetes papers that are currently collecting markedly high numbers of citations. These include two reports, from July 2009, on the new diabetes drug liraglutide.

One of these, published in The Lancet (J.B. Buse, et al., 374[9683]: 39-47, 2009), has now been cited nearly 170 times, while the other, from Diabetes Care (B. Zinman, et al., 32[7]: 1224-30, 2009), has attracted upwards of 120 cites. In the last decade, Buse has published 20 papers with more than 100 citations each. During that time, he has also co-authored two articles each cited more than 1,000 citations times—including the results from the ACCORD (Action to Control Cardiovascular Risk in Diabetes) trial, published in June 2008 in the New England Journal of Medicine, with upwards of 1,200 citations. (See table below, paper #1.)

Buse, 53, obtained his A.B. degree at Dartmouth College in New Hampshire in 1979 and then moved on to Duke University, where he received both his M.D. and Ph.D. in physiology/immunology in 1986. While studying at Duke, he also spent three years as a pre-doctoral fellow at the Joslin Diabetes Center in Boston. In 1986, Buse joined the University of Chicago as an intern and progressed through residency, fellowship, and chief residency before appointment to the faculty in the Department of Medicine. In 1994, he moved to the University of North Carolina School of Medicine, where he is now a full professor in the Division of Endocrinology & Metabolism, also serving as Chief of the Division of Endocrinology, and Executive Associate Dean for Clinical Research.

BUSE SPOKE TO SCIENCE WATCH FROM HIS OFFICE IN CHAPEL HILL.


SW: You’ve been doing clinical research on diabetes for over 20 years. How has the research and treatment changed in that time?

It’s amazing how different diabetes management is today from what it was when I started in 1989. Back then, before any demonstration that improving blood-sugar control was associated with improvements in anything—retinopathy, kidney disease, nerve disease, heart disease, and so on—the only pills available were sulfonylureas (the second generation were considered new then), and the commonly used insulin at the time was animal insulin. We now have better sulfonylureas, better insulins, and approximately ten other classes of drugs to treat type 2 diabetes.

Also, back then, diabetes insurance plans didn’t cover education or glucose monitoring or supplies. We had little in the way of intervention to either prevent or delay the progression of complications. Today we screen for early complications with the idea that we can intervene to prevent their progression. Back in 1992, we basically would send patients to the Society for the Blind to learn how to use a white cane or how to obtain a seeing-eye dog. We’d send patients to the hospital to have their legs removed. I distinctly remember early in my career, every minute of every day, seeing patients in the lobby sitting in wheelchairs with missing limbs or with seeing-eye dogs or white canes, and now I cannot remember the last time I’ve seen that in our outpatient center. It’s been many years.

SW: You were a co-author on the ACCORD Trial that received a lot of interest from journals and the press when it failed to show any benefit of intensive glucose lowering on mortality. What is your take on the ACCORD results?

I think people misunderstand ACCORD. It wasn’t fundamentally a trial to validate glucose management, blood-pressure management, and lipid management in diabetes care. It was really an effort to establish what the diabetes treatment of the 21st century should look like. The way we saw it, the value of blood-pressure management, lipid management, and glucose management had been established in many prior studies. When we were putting together the ACCORD proposal in the late 1990s, we were thinking that the evolving technologies at the time gave us the possibility of getting even lower targets for blood glucose, blood pressure, and lipids than researchers had attempted to get in the past. So we were exploring whether new, lower targets were associated with benefits compared to what the standard of care had become in the late 1990s.

Highly Cited Papers by John B. Buse and Colleagues,
Published Since 2000
(Listed by citations)
Rank Paper Citations
1 H.C. Gerstein, et al., "Effects of intensive glucose lowering in type 2 diabetes," New Engl. J. Med., 358(24): 2545-59, 2008.  1,218
2 S. Genuth, et al., "Follow-up report on the diagnosis of diabetes mellitus," Diabetes Care, 26(11): 3160-7, 2003. 1,215
3 R. Kahn, et al., "The metabolic syndrome: Time for a critical appraisal. Joint statement from the American Diabetes Association and the European Association for the Study of Diabetes," Diabetes Care, 28(9): 2289-2304, 2005. 830
4 D.M. Nathan, et al., "Medical management of hyperglycemia in type 2 diabetes: A consensus algorithm for the initiation and adjustment of therapy. A consensus statement of the American Diabetes Association and the European Association for the Study of Diabetes," Diabetes Care, 32(1): 193-203, January 2009. 476
5 J.B. Buse, et al., "Effects of exenatide (exendin-4) on glycemic control over 30 weeks in sulfonylurea-treated patients with type 2 diabetes," Diabetes Care, 27(11): 2628-35, 2004. 471
SOURCE: Thomson Reuters Web of Knowledge®

For me, the outcome of ACCORD was straightforward: It suggested that by attempting to lower glucose more than we’d suggested in the past, by attempting to lower blood pressure more aggressively than we’d suggested in the past, and by using a combination therapy for lipids, we didn’t provide much in the way of an advantage to patients at substantial cost and burden. So, at the least, we now know that we really can’t do much better in the way of improving diabetes outcomes than we were already doing when we started the trial.

On the other hand, what’s often forgotten is that the outcome we obtained in ACCORD just by doing what we have recommended for nearly a decade is really quite good. The rates for cardiovascular events were quite low—lower than anticipated. I’m just stunned at how well patients are doing—at least those with good access to care—living out basically normal life expectancies without disabling complications.

SW: What do you see as the major advances of this century that are going to be the standard of care in the years to come?

The GLP-1 receptor agonists like exenatide—the brand name is Byetta, and the second generation version is liraglutide, brand name Victoza—are as powerful glucose-lowering drugs as we’ve ever had. In head-to-head studies, they either beat or tied all other classes of diabetes medicines in lowering glucose, and they’re associated with weight loss and not with hypoglycemia. They also provide some modest improvements in blood pressure and cholesterol. We really see those as revolutionary, life-altering therapies.

SW: What happens when you use the GLP-1 that provides the glucose-lowering effect of these drugs?

Broadly, these drugs do at least four things. One is stimulate insulin secretion in a glucose-dependent fashion—meaning that if blood sugar is low, they don’t stimulate insulin secretion. Another is that they reduce glucagon in a glucose-dependent fashion. Then they work in the brain to promote satiety, thereby reducing food intake. Byetta, which is the rapid-acting version of these drugs, also seems to slow gastric emptying, which slows the delivery of carbohydrates to the circulation. It’s also been proposed, but not yet really well demonstrated with humans, to perhaps slow or delay the progression of beta-cell defects in type 2 diabetes, and it’s the beta-cell defects that really make diabetes more difficult to treat over time. Researchers have also proposed, with data that’s a little bit better in humans, but not really well defined, that these drugs have cardiovascular- and neuro-protective effects that also might reduce cardiovascular and stroke risks.

There are also GLP-1 agonist-like drugs, known as DPP4 inhibitors. They’re tablets that slow the breakdown of the body’s own production of GLP-1. So they result in a smaller increase of GLP-1, as well as a whole host of other things. While they’re not very powerful blood sugar-lowering agents, they’re the best-tolerated pills we’ve ever had for diabetes. And well-tolerated is an important characteristic when you’re treating a disease that is generally asymptomatic to begin with.

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