John Buse, MD, PhD Offers Wisdom, a Take on the ADA and FDA, and Weighs in on the Current Regulatory Environment

by adam brown and kelly close

We were honored to sit down with Dr. John Buse, Chief of the Division of Endocrinology, Director of the Diabetes Care Center, and the Executive Associate Dean for Clinical Research at the University of North Carolina School of Medicine. Dr. Buse has extensively researched both type 1 and type 2 diabetes, including involvement with many landmark diabetes research trials. He also recently concluded his term as President, Medicine and Science of the American Diabetes Association (ADA). Dr. Buse is widely recognized as an expert in the field, having received numerous awards over the years including recognition as one of the Best Doctors in America since 2001.

During our interview, Dr. Buse touched on a wide variety of topics in the world of diabetes, including the recent ADA (please see Learning Curve from this issue) and FDA meetings (please see New Now Next from this issue), his thoughts on treatment guidelines for people with diabetes, and the current regulatory and healthcare environment. Dr. Buse expressed skepticism over the necessity of the recent Avandia panel, noting that government resources may be much better spent focused on the prevention of diabetes. He also expressed excitement concerning the strong potential of the promising SGLT-2 compounds in development, as well as the continued success of the GLP-1s (Byetta and Victoza – see our Learning Curve from diaTribe #8 for more information). Notably, Dr. Buse was optimistic about the recent healthcare bill and discussed ways that it would help people with diabetes. Although he wasn’t willing to take on the job of “Diabetes Czar” for the United States (although we would love him to!), we were glad to hear how much he truly enjoys interacting with patients and working in academic medicine.

on the ada’s 70th scientific sessions

Kelly Close: Thanks so much for spending some time with us today, Dr. Buse! We’d love to start off by talking to you about ADA and some of the most important themes you drew from this year’s conference.

Dr. John Buse: As you know, the ADA is such a huge experience and everyone’s take on the conference will be influenced by the sessions that they attended. Many of the sessions that I attended were in support of the research teams that I work with including HEALTHY, ACCORD (see What We’re Reading from diaTribe #9), and STAR-3 (see this issue’s Learning Curve), which all ended up as New England Journal of Medicine papers. They all suggest continuing interval improvement in what we know and what we are capable of in diabetes care. HEALTHY suggested that an intensive intervention in middle schools focused on PE, the cafeteria, and basic understanding of nutrition and calorie balance can provide benefit for the obese kids in school without stigmatizing them. STAR-3 demonstrated a substantial benefit to sensor-augmented-pump therapy in comparison to multiple daily injection therapy in type 1 diabetes, on par with what we expect even for a drug therapy for diabetes. To my knowledge, that is the first time that a device in diabetes has been shown to provide a 0.6% reduction in A1c. Also, in an exenatide-glargine (Byetta-Lantus) combination study on the background of metformin and/or pioglitazone (Actos), we demonstrated a very impressive A1c lowering by that combination without increasing hypoglycemia and while producing moderate weight loss; for now at least, that combination looks to be the most powerful treatment for type 2 diabetes.

Adam Brown: What did you think of the continued focus on GLP-1s (e.g., Byetta and Victoza) at this year’s meeting?

Dr. Buse: There was a lot of news and I have always been excited about it. In 1999 we did a study that was the first study on Byetta in people with diabetes. The study involved six patients with advanced diabetes who were on insulin with difficulty controlling their blood sugar. They got a shot of Byetta and then a meal and we measured their blood glucose every 15 minutes. Byetta was like a steamroller for blood sugar in those patients. I remember the hair on the back of my neck standing up I was so excited. And I am still excited that the best days for this class are ahead.

Kelly: After seeing more data at ADA, how do you feel about SGLT-2 compounds?

Dr. Buse: I actually chaired a session on SGLT-2 inhibitors at ADA. I think the class looks very promising as a therapy that can lower A1c and promote modest weight loss in virtually all patients with diabetes. The paradigm of benefits beyond A1c lowering and the ability to combine with virtually any therapy in virtually any patient is compelling for drug development. Some criticize the class for not being too powerful with respect to A1c lowering. Some criticize the compounds for causing urinary tract infections. But they’re more or less on par with many agents developed recently in terms of A1c reduction. They seem to work in just about everyone. I’m optimistic that SGLT-2 compounds could have a major impact in populations where current treatments are ineffective. The metformin, GLP-1, and SGLT-2 combination could be a 1-2-3 punch that lowers A1c and weight.

Kelly: What about the use of SGLT-2 compounds in type 1 diabetes? We’ve heard a lot of speculation on this but seen no data.

Dr. Buse: I think the potential for SGLT-2’s in type 1 diabetes is great. There is only so hard you can push with insulin. Lots of people can't get to the A1c they would like without incurring hypoglycemia. SGLT-2s might help lower glucose more effectively, especially when it is high like in the postprandial (after meal) state. We need studies, but there is a clear rationale why the SGLT-2s might be a substantial advance in type 1 diabetes.

on the fda panel on avandia

Kelly: Switching to the FDA meeting for Avandia, what’s your take on what happened there?

Dr. Buse: To me, this whole thing has been such a distraction. We had most of the high-powered diabetes investigators, most of the leadership of the clinical development programs from pharmaceutical companies, certainly the full attention of the FDA, and five days of media attention as a run-up. To me, it's been such a waste of time. It certainly seems that the level of attention has created a setting where it's very hard for a rational physician to prescribe Avandia. And so if we've gotten to that spot where a rational physician would not prescribe Avandia over Actos, I don't even understand why we had to discuss whether the drug should be marketed or not.

Kelly: We certainly see your point. The 2009 Avandia sales of $1 billion represented, of course, a major decline from 2008 but it still is a third more than global sales of Byetta and Victoza combined last year. What is your view on who is taking it and what will happen now? And is there an argument this should be kept on the market in case someone can’t take Actos for any reason? What about litigation – is that a reality for doctors to worry about? How politicized can this get?

Dr. Buse: I have never seen or heard of a documented case of someone that didn't respond to Actos that did respond to Avandia, but I'm sure it happens. I think the litigation concerns are really critical, both in how it's being prescribed as well as why it's not being withdrawn. I think politicians are entitled to make noise and rally the attention of the government in defense of their constituents. I don't deny them that right and that duty, in fact. But the FDA is a regulatory body and there are certain procedures that they follow. They don't have the authority to just take a drug off the market because they'd like to. Certainly I don’t know what the answer is, but I do not think it has been proven that Avandia is harmful and I don't think it's been proven that Avandia is inferior to Actos except with regards to lipids. Ultimately, I kind of hated to see a thousand very talented people focused on this for two days this month because there are much bigger fish to fry in the diabetes world than Avandia’s status. I’m sure every pharmaceutical company in America had six people there. You went, some of your team went, half of my colleagues went, and the other half was going to watch the webcast. It's the biggest thing since the World Cup.

treatment protocols in diabetes

Adam: Your perspective is so interesting to us as someone who has led the ADA in previous years; do you think that you might see the ADA guidelines for type 2 diabetes change to think about treatment combinations earlier or that you might see some more movement maybe when the GLP-1 compounds (e.g., Byetta and Victoza) have more safety data and history surrounding them?

Dr. Buse: The ADA has its "consensus statement," which to be fair, I remember it was eight or ten men and a woman locked in a hotel room for two days until basically everybody came out and said, “Okay, I can live with this.” [laughs] I do think it needs to be revisited. But my inclination would be to have as the final treatment option the combination of a long-acting insulin with a GLP-1 receptor agonist and metformin, plus or minus Actos. I think that's the most powerful combination that we have.

Kelly: Can you talk a little bit more about why you believe that – whether it is a strong belief in addressing insulin resistance early, etc?

Dr. Buse: Well I think part of it is when you're using a GLP-1 compound with insulin, you have the GLP-1 effect on appetite. Everybody experiences several pounds weight loss instead of several pounds of weight gain. But to be honest, it doesn't take much difference in weight to really make a big difference in the attitudes of patients about the benefit of therapy. And hopefully, a difference in weight will provide benefits on long-term outcomes.

The second benefit is that Byetta or Victoza stimulate insulin secretion at the times when glucose levels are high. And third, it's been my clinical impression that the combination of long-acting insulin (e.g., Lantus and Levemir) to get the fasting glucose down and GLP-1s to control post-prandial glucose excursions pretty much just does the trick for everybody. So it's just a very powerful combination.

To me, there's no reason not to throw metformin in the mix because it's so cheap and so effective, and again, may have many modest off-target effects that are of benefit to people with diabetes. I guess then the big question is what the role of TZDs (e.g., Actos and Avandia) is in this ultimate cocktail? I think many patients just need a bit more help with insulin resistance and the TZDs can really be a life-altering therapy. For some patients, weight gain seems to be the predominant effect of throwing it in the combination. I don't have a dogma of who should be on a TZD and who shouldn’t, but I think it's always worth trying and seeing how people respond to them. TZDs have the best data for beta cell-preservation; really the only data is for beta cell-preservation.

Kelly: What about dosing for TZDs? Where do you think TZDs should be placed in the type 2 lineup?

Dr. Buse: So I am a believer that if you use a TZD, you should always start it after metformin and maybe even after metformin and Byetta or Victoza, with the idea that you're hopefully going to minimize the weight gain associated with it. I am also a big believer that for the average patient, you don't get a whole lot more glycemic benefits in going from a half maximum dose of a TZD to the full maximum dose. In some patients, you need the big dose, but in the average patient, it doesn't seem to make a big difference. And so my most common dose is a half of the 45 mg Actos tablet.

Kelly: That’s interesting – it would be great to see data on this since it seems side effects are higher with the full dose – this is a very useful alternative, a lower dose and we wondered how often that’s being done by doctors more broadly? Even a guess would be great.

Dr. Buse: I think relatively few people use half of a 45 mg tablet of Actos, as it is not in the label of the drug at all. At least several years ago, my understanding was that the vast majority of patients were treated with sub maximal doses of TZD’s, 30 mg or less of Actos or 4 mg or less of Avandia. But, you are right, most of the long-term studies that have looked at outcomes have used the highest dose.

Kelly: What about claims that Byetta and Victoza can prevent decline in beta cell function? Or, what about the notion that going on these medications sooner will prompt a longer life overall – more time in the normal zone?

Dr. Buse: I’m not sure. I’m less of a believer that these medications will dramatically alter the natural history of diabetes and ensure beta cell survival. I hope it does, but I think the jury is still out. But if you are on insulin and gain five pounds the first year, and you can lose a few pounds with Byetta or Victoza, that could dramatically alter the disease over 10 years. It’s just a very compelling story - in general great glycemic control with weight loss. This could potentially have a life altering effect.

Adam: Dr. Buse, we’d love to ask about other tools for people with diabetes. What about continuous glucose monitoring (CGM), broadly speaking? And what are your thoughts the use of software for managing blood glucose?

Dr. Buse: Good question on software – this represents another advance that we haven't taken full advantage of. More people have internet access at home. Why don’t we have a quickly accessible website that is used by most patients with diabetes? They upload their meter and/or pump and then all of their data is available to me when they come to the office. It’s remarkable with all the competition between the various meter companies that some of the software is so poor. I think CGM will become more and more commonly used in type 1 diabetes. It takes an engaged patient to benefit and even tolerate CGM. The engaged patient is going to do fairly well regardless of CGM though. We need CGM to evolve to the point that the unengaged patient can benefit and closing the loop is the huge, huge, huge opportunity.

the diabetes industry and current regulatory environment

Kelly: If you could say there's another pressing need out there, something that you would much rather see all these people focusing on, what would it be?

Dr. Buse: I think agreeing to screening strategies to detect and intervene early in diabetes is very, very important.If the government got a thousand people to do their homework for a year in preparation for a two-day conference on prevention, it could literally change the world. Can you imagine if every pharmaceutical company had multiple executives going and congressmen were pounding their shoes on the table agitating about prevention in diabetes? Wow, that would be really something.

Kelly: Right on, Dr. Buse. We actually don't understand why there aren't more congress people that are behind earlier diagnosis. Do you have a sense for this?

Dr. Buse: Just statistically, chances are there are several dozen people in Congress with type 2 diabetes, but it is absolutely certain that there are a hundred or more House and Senate members with pre-diabetes. I think that's probably the biggest opportunity that we have. I'm not talking about selling drugs to people with pre-diabetes, I'm talking about counseling about lifestyle change and encouraging them to be more physically active and lose weight. Our healthcare system apparently is going to have a tax or incentivize, I don't know exactly if it's a carrot or a stick, for people with a BMI over 30 to help them get and keep themselves in shape. I don't know the details that I would propose, but I do like the idea of paying people to take care of themselves within the healthcare system.

Kelly: Do you have any thoughts on the recent healthcare bill?

Dr. Buse: Our healthcare system will be increasingly value-driven. Right now it is not. I can't tell you how often I am flabbergasted by what doctors do or what patients demand. Testing is so expensive and so often unnecessary or at least overdone. In evaluating every aspect of access, diagnosis and treatment, outcomes will need to have similar weight to the financial issues. That is what value is all about.

Adam: How will healthcare reform specifically affect those with diabetes?

Dr. Buse: I think the healthcare bill will be great for people with diabetes mostly because it will improve access to care. But maybe I suffer from too much optimism. In our current system, people who do not have good access to care get eaten alive by diabetes. If you are poor, you are eaten alive. Those with perfect access to care don’t have nearly the rates of amputations and blindness complications. Here at UNC, our patients have great access to care, so disabling complications aren’t much of a problem. It’s horrifying to see some of this in a nation as wealthy as ours. People who are well-insured over the last five to ten years have done pretty well in avoiding end-stage complications. Increasingly though, the way that most insurance plans are moving, people are paying more today. Co-pays are really piling up and even the insured are putting off care that would really provide benefit. Chronic disease management will certainly do better in a national healthcare system. More of the concerns are about how much of a damper there will be on innovation, but I think inspired leadership and the demands of the public will make sure that is not the case.

Kelly: It’s such a shame when we can prevent all these complications by just spending a little more on monitoring.

Dr. Buse: Exactly. We need to examine the relationship of cost to benefit. The $10/year that it costs our healthcare system to track down patient’s eye test results is probably worth it for the downstream benefits of avoiding cases of blindness from missed opportunities to intervene early. The question is would the $30-50 that it costs to take photographs in the office and have them evaluated by our ophthalmologist when we don’t have access to the report of an exam done elsewhere, is that of similar value. 

Kelly: I’m wondering about how you’re feeling about the incentives for people to go into diabetes. Are there enough to persuade more students in medical school to specialize in diabetes? How has your thinking on this evolved?

Dr. Buse: That’s a great question. I feel really good about the national trends toward greater focus on chronic disease in medical education in the primary care setting. But I’m a little more unsettled about endocrinology as a specialty. But these things always have a way of working themselves out. We’re seeing more and more people going into medicine in the last twenty years with a focus on balancing their personal and professional lives. Those of us in the over-fifty crowd learned how to do that in a different way than people today. It’s no longer like the old days when people would willingly work 80 and 100 hours a week. If you want to accomplish a lot, you really have to put in the time.

Thankfully, there has been an uptick in interest in diabetes among students and residents and fellows. We really need that as there are so many of the best minds in diabetes that are 65 or older. We have had some spectacular young people come through UNC in the last few years and I just hope that they can keep the flame burning for their academic careers. Personally, I love my job. I cannot imagine that people would not jump at the opportunity to do what I do, to be an academic clinician-investigator. When I advise young people, I tell them that no one starves as a doctor. It's a fabulous way to spend your life, especially in an academic setting. You can really do all kinds of things. It is a fabulous, fabulous life. And you do not have to be a rocket scientist to do this. You have to work hard and be focused and be patient, but you don't have to be the number one kid in your class to have a very fulfilling career.

Kelly: Dr. Buse, you have so much incredible research that you have done, such a great understanding of patients and physicians, and there must be no one you can’t talk to. If you were asked, would you consider being the Diabetes Czar for the country?

Dr. Buse: I like doing research, I like taking care of patients, and I like helping investigators. The further up the food chain you go, the less real work you do. And I’m not sure how effective czars have been. I think the main issue that everyone has with the government is how long it takes to make decisions. The FDA has had to deal with 700+ pages on Avandia and this isn’t anywhere near all the data. I think the process is slow, but it usually gets to the right place.

Kelly: Dr. Buse, you’ve been incredible to spend so much time with us. What would be your advice for those trying to improve their own diabetes management or the management of someone they know?

Dr. Buse: Do your best. Do not make unreasonable sacrifices in lifestyle because you only get to live it once as far as I know. Demand inspired care from your providers. Their role is not to take care of your diabetes but to help you live well with your diabetes. You should live well with your diabetes; if you are not happy, find someone to help you find the way. And be balanced in your approach - avoiding serious or severe hypoglycemia is an equally or maybe more important goal to the goal of getting the A1c around 7%.