Steve Freed: Let’s start out with a little background about Qsymia and Belviq. What is the FDA allowing you to treat with the drugs?
Dr. Timothy Garvey: In 2012, the FDA approved two new weight loss medications. In 2014, another medication was approved. That is three new medications. We hope to be hearing any day now from the FDA on a fourth weight loss medication. In aggregate, these approvals give us new options for managing obesity and overweight in patients, tools that we just haven’t had previously. In fact, I think this is opening up a whole new field, Obesity Medicine, where we really manage obesity as the chronic disease that it is, and bring the full force of our medical model to help these patients. These medications are approved to treat obesity including diabetes patients with obesity. With respect to diabetes, there are existing clinical trial data in patients with type 2 diabetes for all of these medications. The pattern is very consistent. These medications when used in patients with type 2 diabetes lead to weight loss, over and above any weight loss that is achieved through lifestyle intervention program, while at the same time lowering hemoglobin A1c and decreasing the need for conventional diabetes medications; also lowering blood pressure and improving lipids. Of course, this is an outstanding profile of results in patients with type 2 diabetes….
SF: Do you have the names of the three drugs that have been approved, and the one that is coming up?
TG: The two approved in 2012 are phentermine-topiramate extended-release, which is a combination medication, brand name is Qsymia. The second medication is lorcaserin HCl, a single medication, and its brand name is Belviq. This year we’ve had another combination approved, a combination of extended release preparations of naltrexone and buproprion, which is called Contrave. We are hoping to hear soon regarding FDA approval for a higher dose of liraglutide, called Victoza for the lower-dose formulation approved to treat hyperglycemia in diabetes. (Note to our readers: this medication, brand name Saxenda, received FDA approval on December 23 after this interview.) When it is used to treat diabetes, the maximum dose is 1.8 mg a day, which is the maximum for controlling blood sugar, but at higher doses there is weight loss; the higher the dose, the more weight loss, up to about 3 mg per day. This higher dose of 3 mg per day is being developed for a weight loss or obesity indication. Those are the four new medicines, and they join another medication, Orlistat, which has been around since the late 1990s, as well as phentermine and other sympathomimetic amine anorectics approved for the short term treatment of obesity which have been around since the 1950s. These drugs constitute the pharmacotherapy of obesity as it now exists. Of course, other treatment modalities include lifestyle intervention therapy, which remains the cornerstone of therapy, and bariatric surgery. The medications are only to be considered an adjunct to lifestyle, and lifestyle modifications are important in bariatric surgery procedures as well.
SF: You listed possibly four medications, plus Orlistat and Victoza. If you put these into a chart, which would be your number one drug for reducing A1c, and which one for weight loss?
TG: We know with hemoglobin A1c lowering in diabetes, the more weight loss you have, the lower the hemoglobin A1c is going to go, so more weight loss provides better glycemic control. Assigning different levels of efficacy to these different weight loss medications is difficult because there have been no head to head comparisons. We just have the results from the clinical trials that were performed in the process of drug development, but we can compare them by looking at placebo subtracted weight loss. In all of these studies, everybody is put on lifestyle intervention, and then randomized to either placebo or the drug, but the intensity of the lifestyle intervention varies from trial to trial. If we look at how much more weight loss we get by adding medicine on top of the lifestyle intervention, the one that has the higher placebo subtracted weight loss is Qsymia. That gives you about a 9% loss of body weight; placebo subtracted, sustained over a two-year period. When combined with the lifestyle intervention, Qsymia provided approximately 12% total decrease in body weight. Next we have the high-dose liraglutide and the Contrave, which give you about a 6% placebo subtracted loss of body weight. Belviq and Orlistat allowed patients to achieve approximately 4-5% placebo subtracted loss of body weight. All of these medications do lower hemoglobin A1c while decreasing the need for other diabetes medications, and improve blood pressure and lipids.
SF: Were there any surprises in the final results of the trials?
TG: We’ve always known that weight loss is good for type 2 diabetes. The Look-AHEAD trial is an often quoted recent trial looking at lifestyle intervention, which showed good results in terms of managing glycemia and improving blood pressure and lipids. These medications now add additional options for even greater weight loss, and greater maintenance of the weight loss once it is achieved. There are really no surprises here. I think it is all good news. We just confirmed that weight loss, whatever way you can achieve it, is going to be good for patients with diabetes, whether it’s lifestyle, or the addition of medications, or even bariatric surgery in select patients.
SF: What about the concern which we’ve had for twenty-five years where every single heart medicine was taken off the market due to serious side effects such as heart irregularities? There is kind of a fear because people have died. I would imagine there is some hesitancy for medical professionals to prescribe these medications until they’ve been on the market for a while. Have they seen anything in the last year or two that could be a serious problem in the future?
TG: There have been instances in the past where weight loss medications have been observed to have serious adverse effects, and, in particular, three medicines have been taken off the market. One is sibutramine, which raises blood pressure. It was contraindicated in patients with heart disease but, in a trial where it was given to patients with heart disease, it seemed to increase events so it was taken off the market. The second one is rimonabant, which was never approved in the United States. It was approved in Europe. This medication led to psychiatric/psychological difficulties, and was subsequently withdrawn from the European market. Dexfenfluramine (or fenfluramine), which represents one component of the popular dual drug combination, fen-phen, was observed to induce heart valve abnormalities. Dexfenfluramine is a broad spectrum serotonin receptor agonist, which activated all members of the serotonin receptor family, including the 2B receptor which is on the heart valve. While the FDA never evaluated the fen-phen combination, the use of dexfenfluramine was removed from the market due to the associated valvulopathy. One of the new medications, lorcaserin HCl (Belviq), is a specific serotonin receptor agonist for the 2C receptor, which is not on the heart. There were plenty of echocardiograms done during clinical trials, and there was no signal for valve disease. It appears safe from that perspective. I think, yes, the discontinuations of sibutramine, rimonabant and dexfenfluramine are responsible for concern, and this has led to hesitancy by some clinicians in prescribing the newer agents. In my opinion, the uptake of these medications has been way below the level of benefit that patients could accrue by being prescribed these medications. It is understandable, nevertheless. Let me make a reassuring comment. These medications have been carefully reviewed by the FDA in a large number of trials during the exacting approval process for each of these medications. The data were critically reviewed by FDA advisory boards, and the FDA has been very cautious in approving these medications. The drugs were approved because there was a good track record of safety in the clinical trial process for all of these medications, with benefit far exceeding any risk. I think we should have some confidence in the regulatory process that we have for approving medicines in the United States at this point in time. All medicines have side effects and risks, and there is no perfect medication anywhere. Physicians have to use these medications judiciously, based upon benefit and risk. We know that obesity is a terrible disease, responsible for a large burden of patient suffering and social cost. It’s about time we start treating obesity like a disease with all the therapeutic options we have available. For example, there are excellent data showing that the weight loss achieved using these medications is highly effective in preventing progression to type 2 diabetes in high risk patients with prediabetes or metabolic syndrome. I was the lead author on a paper that showed Qsymia reduced progression to diabetes by nearly 80% over two years. We have the tools at our disposal to prevent or delay a significant fraction of diabetes in our country. I think we need to pay heed to that.
SF: That is interesting that you say it was able to prevent diabetes by 80%, which is mind-boggling. Yet, at this point in time, there is no treatment for prediabetes, according to the ADA and the FDA. It is my understanding that even metformin is not recommended for prediabetes. I guess we have to wait until the patients become diabetic and have complications before we can, technically, prescribe metformin to these patients. It would be off-label use.
TG: That’s kind of silly, isn’t it? The FDA has no disease category for prediabetes, and has not approved any medications for that indication. However, both the American Diabetes Association and the American Association of Clinical Endocrinologists have published position statements and guidelines for treatment of prediabetes and metabolic syndrome. In the case of AACE, it includes weight loss, including medicine-assisted weight loss, as a primary approach to treating the abnormal glucose tolerance, hypertension, and dyslipidemia. Both societies recommend the use of metformin, particularly in very high risk cases where there is a very high risk of developing diabetes in the future; so these societies have come out in favor use of medications in these patients, but you are right, there are no approved medications for diabetes prevention.
SF: According to the ADA, the definition of diabetes is an A1c of 7% but with AACE, the recommendation is an A1c of 6.5%. Which one is right?
TG: Well, these are the goals for hemoglobin A1c control if you can safely achieve it in patients. You are right that these societies have different recommendations. The closer to normal the better, and AACE advocates a slightly lower target in order to further minimize the risks of complications. However, what makes sense in clinical practice is you try to get it as low as you can, as long as you can do that safely. That is going to be an individual question in each patient. You can better control in some patients than you can in other patients. You just try to do it the best you can, and be safe about it, and avoid hypoglycemia. Both societies agree that the higher HbA1c targets will be necessary in patients at high risk of hypoglycemia.
SF: Whenever I ask a medical professional if you can have any A1c that you wanted (“Regardless of your health, what would you like your A1c to be?”), and I’ve asked this of many endocrinologists at the ADA, they all say the same thing: 5% or below. But you don’t see that offered to patients except by a very few doctors.
TG: We know that among patients with prediabetes in the DPP (Diabetes Prevention Project) 10 -11% had background retinopathy. Thus, even levels of hyperglycemia below the threshold for diabetes is sufficient to cause microvascular disease in some patients. It’s a continuum; even though we draw a line at A1c of 6.5 or 7%, the closer we get the glucose to normal, the less chance the patient will develop microvascular disease, and other complications. I think that explains the difference between the two societies, but both of them say to lower the A1c safely.
SF: What do we know about the predominant side effects of these new drugs? I’ve read that there aren’t too many.
TG: They all have side effects, and they all have certain warnings and contraindications. It’s important for clinicians to be aware of these so that you can select medications in an informed way as you individualize therapy for each patient. I could go into detail, but different side effects and warnings would make one drug inappropriate for a given patient, while others would not be problematic. It’s just these considerations apply to any other chronic disease in which multiple treatment options are available, like diabetes. It’s important to know what the side effects are of each drug, so you can know when to optimally use them. Physicians have to read the prescribing information.
SF: Where has the ADA put these medications in relation to the different stages of diabetes, for example, first drug of choice, second drug, and so on? Has this been laid out yet?
TG: The ADA has not addressed this, at this point. They’ve not made any position statements or official announcements regarding recommended use of weight loss medications in diabetes. AACE, in its comprehensive diabetes treatment algorithms, includes an obesity algorithm, and in their diabetes algorithm, places weight loss, including medicine-assisted weight loss, right at the top of the chart. It can be something considered initially, or at any stage in the course of diabetes as an option for better glucose control. For example, when a patient fails metformin, and needs something else, consider a weight loss program, including medicine-assisted weight loss. If patients are at a stage where they require insulin, consider a weight loss program at that time. Medicine-assisted weight loss could also be considered early on as a first line therapy. We know that weight loss can be beneficial. In essence, the message is to consider these weight loss medications as an additional diabetes medication, something that can be used to get better glycemic control, while improving a lot of other risk factors at the same time. The clinical trials data support that approach.
SF: What kind of experiences have you had, personally, with patients, either through the studies, or from your own private practice, with these new weight loss drugs?
TG: I am in academic practice, and staff a clinic called UAB Weight Loss Medicine. We have a referral practice in which we use weight loss as a therapeutic intervention to treat weight-related complications, such as diabetes, prediabetes, sleep apnea, osteoarthritis, and other complications. We really emphasize a rigorous lifestyle intervention program, and also use weight loss medications in patients with and without diabetes. This is why these patients come to us. We’ve had a lot of success with this in patients of all stages of the diabetes, from early disease to chronic disease.
SF: In the drug package insert (for Qsymia), does it say “indicated for diabetes,” or “metabolic syndrome,” or just weight loss?
TG: That is an important question. None of these medications are approved to treat diabetes, or to treat any other obesity-related complications. Their indication is to treat overweight and obesity. Overweight if BMI is 27-29.9 with at least one complication, or 30 and above whether there are complications or not. However, promoting the weight loss will ameliorate the weight-related complications, such as diabetes, so weight loss can be used as a therapeutic intervention, in effect, to manage the obesity-related complication. This complications-centric approach to obesity management is the medical model that AACE has promoted, and I ascribe to.
SF: Has it also been shown to be effective for overweight type 1 diabetics, because it is an overweight drug?
TG: There haven’t been published studies in that patient group, but if you talk to any endocrinologist in this country who treats type 1 diabetes, there are many patients on insulin pumps, and obesity is an increasing problem. For overweight and obese adult patients with type 1 diabetes, weight loss medications with a lifestyle intervention program that reduces body weight by 10% will decrease insulin requirements, make it easier to control the glycemia with insulin. Unfortunately, no weight loss medications have been approved for use in obese children and adolescents.
SF: One of the big questions is, who is going to pay for these drugs?
TG: That is another good question. If a company develops a new diabetes drug that has shown to be efficacious, like the SGLT-2 inhibitors that have come on the market recently, insurance companies, payers, and benefits managers, readily bring the drug onto formulary if it has been shown to be effective. If it is an obesity medication, they want to know if it will lead to cost savings, or they wonder if they’ll have enough money to pay for the drugs. We look at obesity in a different way than we do other chronic diseases. Like any other chronic disease, obesity is the result of the interaction of susceptibility genes with the environment and behavior, just like diabetes, just like hypertension, just like asthma, etc…. I think we are in the midst of a cultural transition where more and more health practitioners, more payers, and society in general are beginning to regard obesity as a disease rather than a life-style choice. People do not want to be obese. Obesity is a chronic disease that should be treated like a chronic disease, again, using the full force of our medical model as we do with diabetes. That includes lifestyle, medications, and surgery in select patients in a way that optimizes benefit risk, and proceeds in a cost effective manner, and is based on evidence. The transformation of our thinking about obesity has been progressing slowly, but it’s happening.
SF: So would you say that, because insurance companies haven’t stepped up to the plate, there is going to be less usage of this drug for the individual only because it’s expensive?
TG: They are expensive like new diabetes medications. Only about 30-35% of the prescriptions are covered by insurance with a copay for the patients, but the majority of patients still have to pay out of pocket for the total cost. Most companies producing weight loss medications have been providing some buy down and coupons, etc…. I think coverage of weight loss medications is slowly increasing as employers and benefits managers recognize the benefits of weight loss, and the fact that we have new tools to do this in a safe and effective way.
SF: My last question is, did you participate in the development of the educational tools that go along with these drugs?
TG: I did participate in continuing medical education programs around obesity and the pharmacotherapy that I developed independently as an educator, according to CME rules and practices. I have served on ad hoc advisory boards for a several companies, providing consultation on how to use their drug in the context of lifestyle interventions programs and the type of lifestyle intervention programs that might be highly effective.
SF: I’m a firm believer that, I don’t care what drug a patient is given, when it comes to diabetes and probably obesity, without the input of some education, like defining what carbohydrates are, they are doomed for failure, no matter what. You just can’t eat whatever you want, and take a diet pill. It just doesn’t work over the long period.
TG: You are so correct. These drugs act to inhibit appetite which enhances compliance to a reduced-calorie diet. If you do not have the lifestyle intervention program, and a reduced-calorie diet prescription, then you are essentially limiting the ability of the drug to promote weight loss. More weight loss will be achieved when the drug is combined with a lifestyle intervention program, with an improved benefit-to-risk ratio for the intervention. These are not magic pills, so that is critically important.
SF: I think the DPP showed that lifestyle alone actually out-performed any of the drugs that were used by a huge margin.
TG: Lifestyle intervention had more diabetes prevention than metformin as a single agent.
SF: I really appreciate your time. It was very educational. Thank you!
TG: Thank you, Steve, for thinking of me. I hope you can put together a good article here, and get the word out.
SF: We will. It’s great, because I think these drugs are so new that there’s a lot of information health professionals are looking for. Thank you, again.
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Dr. Timothy Garvey is Professor of Medicine and Chair of the Department of Nutrition Sciences at the University of Alabama at Birmingham. He obtained his MD degree, cum laude, from St. Louis University in 1978, and completed residency training in Internal Medicine at Barnes Hospital, Washington University, in 1981. He then was a clinical fellow in Endocrinology and Metabolism at the University of Colorado Health Sciences Center and University of California, San Diego School of Medicine. He subsequently held faculty posts at the University of California, School of Medicine (Assistant Professor), Indiana University School of Medicine (Associate and full Professor), and from 1994 to 2003 was the Director of the Division of Endocrinology, Diabetes, and Medical Genetics at the Medical University of South Carolina. Dr. Garvey moved to UAB on June 1, 2004.
Dr. Garvey has achieved international recognition for his research in the metabolic, molecular, and genetic pathogenesis of insulin resistance, Type 2 Diabetes, and obesity. His studies have involved the cellular and molecular biology of cell and animal models, metabolic investigations of human subjects on metabolic research wards, and the genetic basis of diseases in Gullah-speaking African Americans, Pima Indians, and national cohorts of diabetes patients. He has brought basic technology directly to the study of human patients, and the combined approach of human physiology, genetics, and basic cell and molecular biology has provided the laboratory with a flexible capability for hypothesis testing relevant to human disease. By studying molecular parameters and differential gene expression in muscle and fat tissue from metabolically characterized individuals, the Garvey laboratory has made important observations regarding the pathogenesis of human insulin resistance. He has been a principle contributor to our understanding of the role of the glucose transport system and glucose transporter proteins in human insulin resistance. The laboratory has also identified a polymorphisms in the uncoupling protein 3 gene as a “thrifty gene” and susceptibility gene for severe obesity in African Americans. He also served as the PI of an NIH-funded Program Project to study markers and mechanisms of diabetes vascular complications in collaboration with two national trial cohorts. Dr. Garvey has directed an independent laboratory since 1987 supported by the National Institutes of Health (NIDDK, NHLBI), the Department of Veterans Affairs, the AHA, JDFI, the ADA, and other agencies. Dr. Garvey also has a track record of community based research and outreach in the context of two initiatives, Project Sugar (a genetics study among Gullah-speaking African Americans) and MUSC/HBCU Partners in Wellness (a program in community health at 6 historically black colleges and universities in SC intended to challenge minority students towards careers in the health professions).
He has provided service as a member of national research review committees for the Juvenile Diabetes Research Foundation, the American Diabetes Association, the VA Merit Review Program, and the National Institutes of Health. He was a standing member of the Metabolism Study Section at NIH from 1998-2002, and has chaired several ad hoc NIH study sections. Dr. Garvey currently serves on the editorial boards of Diabetes, and has previously served in this capacity for the Journal of Clinical Endocrinology and Metabolism and Diabetes Reviews. He is a member of the American Society for Clinical Investigation, the Association of American Physicians, the Endocrine Society, and the American Diabetes Association, and the North American Association for the Study of Obesity.
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