Nuts and Bolts of the New Anti-Obesity Drugs Pharmacology, Drug-Drug Interactions and Efficacy In this ACCEL interview, David Dixon, PharmD, AACC, a pharmacist at Virginia Commonwealth University School of Pharmacy in Richmond, VA, shares perspectives on new anti-obesity drugs, including pharmacology, drug-drug interactions and efficacy, and deciding which drug is best for a patient. C. Noel Bairey-Merz, MD, FACC, led the conversation. Dr. Bairey-Merz: Cardiologists in general are likely to shy away from prescribing anti-obesity drugs, because of the memory of the fen-phen situation. Why should they prescribe these drugs? Dr. Dixon: The current anti-obesity agents might be a way to help patients lose enough weight that they can become more physically active. This increase in physical activity is good for heart health in any patient. In particular, these drugs may be beneficial for patients who have finished cardiac rehab and have not achieved their personal weight loss goal, despite making lifestyle modifications. Would you use anti-obesity drugs for a patient who has incorporated some lifestyle changes? Absolutely. If you look at the clinical trials, all the participants had fairly intensive lifestyle education and lifestyle modification. These drugs are simply an adjunct to this. The anti-obesity drugs are indicated for a BMI of 40, 35, 30, 25? What is the cut-off for using these drugs? The current recommendation says these drugs are worth considering for patients with a BMI of 30 or greater. This is especially true for patients with an elevated BMI and at least one additional risk factor, such as hypertension, diabetes or dyslipidemia. Are there contraindications for cardiac patients for the anti-obesity drugs? Again, we cardiologists remember the previous formulations and are cautious. That’s an interesting question. For the naltrexone and bupropion product, as well as the phentermine-topiramate combination, the blood pressure should be closely monitored. An increase in blood pressure, particularly with the phentermine and bupropion components, can be seen because these agents have a stimulatory effect. Clearly, monitoring blood pressure and heart rate would be critical. Let’s talk about fen-phen, because that is what will be on the minds of most cardiologists. Why should we be thinking about using the new anti-obesity drugs? The fen-phen product, which was removed from the market in 1997, caused valvulopathies. It was really the pulmonary hypertension that caused some deaths and was concerning. A key difference with the lorcaserin product is that it targets the serotonin 2B receptor, which is found only or mostly in the hypothalamus, whereas the fenfluramine product targeted 5-HT2C, which is in the valves. The lorcaserin product that is highly selective for the 2B receptor, appears, at least based on the data available, to be safe. Looking at the incidence of valvulopathies in the studies that have been completed, there has been no statistically significant difference between the placebo group and those patients receiving lorcaserin. There is a large cardiovascular trial under way with lorcaserin – CAMELLIA-TIMI – so in 2018 I would say we would feel much more comfortable prescribing that particular agent once we see the data. Lorcaserin is available now and approved for weight loss. Presumably the big clinical trial will not only show safety but maybe efficacy for reducing cardiovascular disease? That is the hope. New products are available. They are approved by the Food and Drug Administration. They are found to be effective for weight loss. What could we expect to see? Five pounds, 10 pounds, 20 pounds? The combination phentermine and topiramate product at the highest dose actually is considered to be the most efficacious. Over half of the patients who take that higher dose will achieve at least a five percent weight loss. The naltrexone and buproprion product would be considered the next best in terms of weight loss. It’s really about setting the goal with the patient and understanding what they’re trying to do. If a patient comes into your office and says, “I would love to lose 100 pounds, and that’s my goal,” these drugs are not going to do that. They may be adjuncts to get patients started, but really, it’s going to be about them taking responsibility and making some permanent lifestyle changes to maintain weight loss and achieve such a high goal. Let’s talk a bit more about side effects. I would say lorcaserin is fairly well tolerated. There are more patients who discontinue the medicine due to adverse effects compared to placebo. Around what percent? Close to about 10 percent of patients. Not bad. However, for the naltrexone and buproprion product, you’re really looking at a discontinuation rate of almost one-quarter of patients, and that’s going to be due to side effects. So again, tolerability is key. For liraglutide for weight loss, which has been reformulated at a higher dose compared to the liraglutide we use for diabetes, nausea is a huge side effect, and about 40 percent of patients will experience that. The nausea does improve within two to four weeks. So it’s about coaching patients through that, because the data do show that tolerability of that agent improves dramatically. There are definitely some issues in terms of gastrointestinal side effects with that product. Another concern with liraglutide is the potential risk for acute pancreatitis, and there is the blackbox warning for medullary thyroid cancers. Clearly, there are some big things that you want to look at, and make sure that the drugs are appropriate for these patients. In cardiology, we are evaluating patients for chest pain, shortness of breath and hypertension. Many cardiac patients have hypertension. Would you rank-order these drugs in terms of which ones are going be a stimulant and which have less of that? Phentermine is a sympathomimetic amine, and you’re definitely going get a stimulatory effect, with an increase in blood pressure and heart rate. That’s the product I would watch closely. In addition, the bupropion in the bupropion and naltrexone combination can increase blood pressure and is an antidepressant. Like the other selective serotonin reuptake inhibitors can do sometimes. Correct, and it [bupropion] has an effect on norepinephrine. It inhibits the reuptake of norepinephrine, you’ll get a little bit of increase in blood pressure and heart rate. So, with lorcaserin, not much of an effect on blood pressure. Maybe it will go down a few points, and same thing with liraglutide. I think, generally, from a blood-pressure perspective, those’d be the considerations. I wouldn’t start a patient on the buproprion or phentermine products who had highly uncontrolled blood pressure. Obviously, [we’d first be] getting the blood pressure controlled, and then consider the addition of those agents. Endovascular Repair Compared with Medical Management of Patients With Uncomplicated Type B Acute Aortic Dissection Valentin Fuster, MD, PhD, MACC, physician-in-chief at Mount Sinai Health System in New York City, discusses here the implications of a recent study by Qin et al., published in the Journal of the American College of Cardiology, of which he is the editor-in-chief. Dr. Fuster: In their introduction, the authors point out that the morbidity and mortality rate in type B acute aortic dissection (AAD) is highest within the first 10 to 14 days after acute onset. Current consensus calls for patients with complicated type B-AAD to be treated with thoracic endovascular aortic repair (TEVAR), leading to better in-hospital survival than open surgery. Patients with uncomplicated type B-AAD are commonly treated with conservative therapy, although the long-term outcome of medical therapy alone is suboptimal, with a reported 30-50 percent mortality rate at five years, and a delayed expansion of the false lumen in 20-50 percent at four years. According to Qin and colleagues, with improved operator skills and better technology, TEVAR may emerge as the first-line therapy for uncomplicated type B-AAD. Perhaps not perfect, as discussed later. I believe this is an important study. The study objective was to clarify the early and long-term outcomes, a minimum of 5 years and up to 11 years, with TEVAR compared with medical treatment in patients with uncomplicated type B-AAD. Three tertiary medical centers in China were involved, and between 2003 and 2014, a total of 338 patients with uncomplicated type B-AAD were retrospectively identified. Information about baseline characteristics was collected from medical records. Images were retrieved from the imaging archiving system, and the thrombosis status of the false lumen and extent of the dissection were evaluated via CT angiography. Early and late outcomes were recorded and analyzed. Although retrospective, I believe this is a unique study. First, TEVAR procedures were performed in 184 patients and medical therapy alone was provided for 154 patients. Second, early events and 30-day mortality were not significantly different between the two groups; however, the early event rate in the TEVAR group was 10. 3 percent (usually related to transient endoleaks), while in the optimal medical-treated group, the event rate was only 4.5 percent (although it’s noted the differences were not significant). Third, in a long-term follow-up, patients receiving medical therapy had significantly higher aortic-related adverse event rates compared with those in the TEVAR group. Most of the events in the medically treated group were tabulated as vascular in origin (either aortic enlargement or aortic rupture), while the lower number of events in the TEVAR group was also mostly vascular (but over 50 percent related to a transient or not perpetual endoleak). And, finally, what about mortality? Long-term mortality in the TEVAR group was significantly lower than in the medically treated group (specifically, 10 percent versus 20 percent). Certainly, a large proportion of patients in both groups had mortality related to vascular causes such as aortic rupture or dissection. The authors conclude the study confirms the feasibility of TEVAR for uncomplicated type B-AAD in the acute setting with fewer aortic-related adverse events and a lower mortality rate compared with best medical therapy. They also point out, however, that uncomplicated dissection is better to be considered than potentially complicated dissection. Why? Because in the total analysis, 71 percent of patients treated medically had an aortic event. This is 46 percent after TEVAR, so this is not a benign disease. Four points are made in the editorial comment. The first is that patient management for complicated type B dissection enjoys complete agreement in what to do in terms of the complicated cases, and this is class I level of the European Society of Cardiology guidelines. That is the primary endovascular approach. For uncomplicated cases of dissection, the cardiovascular community continues to struggle on whether to embrace TEVAR as a first-line of therapy, or rather just medical therapy alone. The second point is of interest and relates to the statement made by the authors of the paper. They say that uncomplicated dissection in a way should be looked as potentially complicated, since the number of events in the uncomplicated group was very significant in the study, particularly in the medically treated group. Here, a concern of the author is why the incidence rate of events was so high. I don’t know what the response from the authors would be. Long follow-up? Good surveillance system? We don’t know. This leads to point number three of this editorial comment, which really boils down to the limitations of this study. First, it is a retrospective analysis. Second, over the years, five different stent graphs were used. Third, there is a question of why TEVAR is used in the acute phase rather than waiting more than 14 days when the patient is more stabilized. I suspect that the answer by the authors would be that in their study, a number of events occurred within the first 14 days. I suspect that the answer to study authors by the editorialist would be that the number of events was higher in the TEVAR group within the first two weeks than in the medically treated group. Other limitations include the relative lack of information about crossovers and the question about offering TEVAR to young adults with connective tissue disorders, which perhaps would be problematic. The fourth point of this editorial is quite insightful. Rather than defining Type B dissection as complicated or uncomplicated, why not define the uncomplicated as “high risk” or “low risk?” For example, high risk would be a post-dissection-resistant hypertension, a large and single entry tier, a partial false-lumen thrombosis, a total diameter of more than 35 mm of dissected aorta, etc. The point, according to the editorial, is that uncomplicated cases may be high risk and low risk. I think the concept is fair.
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