Belviq: A Novel Multipotential Therapeutic and Preventative Anti-Obesity Medication
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The new anti-obesity drugs such as Belviq are being evaluated by financial analysts whose vision is conditioned by the color of the lenses they choose to don. However, those who do not properly understand the underlying science and medicine can underestimate the potential clinical uses, and hence the future earnings potential, of any therapeutic drug. The purpose of this article is to provide a physician’s viewpoint on Belviq. After all, it is the medical community that will be writing the prescriptions! Belviq has the potential not only to drive weight reductions at a therapeutically beneficial level, but also to help prevent and treat obesity related co-morbidities. George Merck once said, "Medicine is for the people. Put patients first and the profits will follow." His wise words underpin why we need to view Belviq through a physician’s lenses to better understand the investment success of this multifaceted, novel new drug.
Obesity is associated with significant human and medical costs because it exacerbates many health problems. We are now experiencing a global obesity epidemic that is also associated with increases in co-morbidities such as metabolic syndrome and type 2 diabetes mellitus (T2DM). In a future paper, I will discuss the linkage between obesity and several other diseases, including diabetes. Here, my focus will be on metabolic syndrome, the common name for the combination of abdominal obesity, hyperglycemia, dyslipidemia, and hypertension.
Belviq, made by Arena Pharmaceuticals (NASDAQ: ARNA) is one of two anti-obesity drugs recently approved by the FDA (the other was Qsymia, from Vivus, Inc (NASDAQ: VVUS)). In my view, Belviq has the potential to be a blockbuster investment stock because it will be not only effective therapy for obesity but could also counter the associated co-morbidities such as metabolic syndrome. The largest study performed on the health care utilization and financial costs of metabolic syndrome risk factors compared patients with and without diabetes (Boudreau and al 2009). Of 170,000 men and women in the study, 58% had risk factors for metabolic syndrome. This group required more healthcare resources and incurred greater expenses ($5,732 versus $3, 581) than the comparison group who lacked the risk factors. Furthermore, patients who had both T2DM and metabolic syndrome risk factors incurred twice the costs of those who did not have diabetes but had the risk factors for metabolic syndrome ($8,067 vs. $4,638); here, obesity was the primary risk factor. This outcome was true even over a short period, two years. Of note is that this was the same time-frame in which Belviq was studied in the BLOOM trial I shall discuss below. Obesity co-morbidities clearly place a tremendous burden on healthcare costs. The beneficial effects that Belviq has on weight loss, which is the principle risk factor for metabolic syndrome, could therefore lead to very substantial financial benefits to patients and the nation's healthcare system. I will now discuss the potential use of Belviq in the treatment of metabolic syndrome, including the rationale and the existing scientific evidence.
Obesity, especially abdominal obesity, is associated with resistance to the effects insulin normally has on the peripheral utilization of glucose and fatty acids, which often leads to T2DM. About 85% of all US adults with diabetes are overweight or obese (MMWR 2004). Although both physical inactivity and obesity are significant predictors of developing diabetes, obesity is the strongest risk factor for T2DM. Insulin resistance is a marker of the development of diabetes. Both obesity and body fat distribution play a role here. Independent of total body fat, people with a large abdominal circumference are more insulin resistant and more likely to develop diabetes. Of note is that the BLOOM study showed that Belviq caused a significant decrease in abdominal circumference, as discussed below. Insulin resistance and the associated elevation in blood glucose can increase vascular abnormalities, elevate cholesterol levels, and raise high blood pressure - all of which lead to the development of atherosclerotic cardiovascular disease (Reaven 1988; DeFronzo and Ferrannini 1991). The combination of abdominal obesity, hyperglycemia, dyslipidemia, and hypertension is commonly known as the metabolic syndrome (Eckel and Grundy 2005).
The following discussion is based on information summarized from a recent update on metabolic syndrome
The most common definitions for the metabolic syndrome are the National Cholesterol Education Program (NCEP/ATPIII) and the International Diabetes Federation (IDF) and are the most widely used.
Based on these definitions, 34.5% to 39% of US adult participants met the definition for metabolic syndrome according to data used from the National Health and Nutrition Examination Survey (NHANES) 1999 to 2002 database. By contrast, using the same database only 22% of the study subjects met the definition for metabolic syndrome in the period from 1988 to 1994. The incidence of the metabolic syndrome is therefore increasing at an alarming rate. As another example, metabolic syndrome was assessed in 3323 Framingham Heart Study participants, ages 22 to 81, who did not have diabetes or cardiovascular disease at a baseline examination in the early 1990's (Wilson, et al. 2005). At baseline, the prevalence of the metabolic syndrome was 26.8% in men and 16.6% in women but after eight years of follow-up, there was an age-adjusted 56% increase in prevalence among men and a 47% increase among women.
Why is this important with regard to Belviq? The prevalence of obesity is increasing in all US population segments, including adults of all ages and both genders and also, sadly, children. The findings in the US population are a reflection of a global epidemic. The prevalence of metabolic disease increases with age; it exceeds 30% in adults older than 40 years, and is more than 40% for those over 60. Body weight is a major risk factor for the metabolic syndrome. Thus, in the NHANES III (1988-1994) study of 8814 adults the metabolic syndrome was present in 5 per cent of those at normal weight, 22 percent of those who were overweight, but 60 per cent of those who were obese (Wilson, D'Agostino, et al. 2005). In the Framingham Heart Study cohort, an increase in weight of 2.25 kg or more over 16 years was associated with a 21 to 45 percent increase in the risk for developing the syndrome (Wilson, Kannel, et al. 1999). A large waist circumference alone identifies up to 46 percent of individuals who will develop the metabolic syndrome within 5 years (Palaniappan, et al. 2004), again highlighting the importance of the findings in the BLOOM study below.
The rapidly increasing prevalence of obesity among adults in the United States is likely to lead to even higher rates of the metabolic syndrome in the near future, which again highlights the importance of obesity prevention and the need to improve physical activity. Studies have consistently demonstrated a strong association between the metabolic syndrome and the risk for subsequent development of serious chronic diseases such as T2DM. Metabolic Syndrome also increases the risk for all-cause mortality. So what are the treatment options for such a devastating syndrome?
The importance of weight reduction and decrease in abdominal circumference cannot be overstated. Weight reduction is critical to reducing co-morbidities and metabolic disorders such as hyperglycemia, hypertension, and dyslipidemia that are associated with increased weight. The importance of weight management in preventing the progression of metabolic syndrome is illustrated by The Coronary Artery Risk Development in Young Adults (CARDIA) study (Lloyd-Jones, et al. 2007). In this observational study of 5115 young adults (ages 18-30 years), an increase in body mass index (BMI) over 15 years was associated with adverse progression of metabolic syndrome components, when compared with young adults who maintained stable BMI over the study period, regardless of what that BMI value actually was.
Although Belviq is considered an 'anti-obesity' agent what is more important for the physicians who will be writing the prescriptions are the benefits that this 'anti-obesity' medication will have on the metabolic disorders associated with obesity (and in particular, abdominal obesity). Again, the emphasis will be on improving the overall health of the patients, not just the weight of the patients (Bays 2009).
The indications and usage are outlined in the prescribing information for Belviq. Belviq may be given to patients with a BMI of 27 kg/m2 or greater in the presence of AT LEAST ONE weight-related co-morbid condition. I will present an argument that Belviq may be beneficial as an adjunct treatment for metabolic syndrome.
First we must review some important findings in the randomized, placebo controlled trial of Belviq (then called lorcaserin), the BLOOM trial, that were reported in the New England Journal of Medicine in July of 2010 (N Engl J Med 2010; 363:245-56). This trial provides information on the possible benefits Belviq may have as an adjunct therapeutic option in the treatment of metabolic syndrome. Thus, in year 1, lorcaserin use was associated with a significant decrease in waist circumference (baseline 109.6 cm) of 6.8 cm versus a decrease of 3.9 cm in the placebo arm and a decrease in BMI of 2.09 versus 0.78. Fasting blood glucose, insulin, and glycated hemoglobin (HBA1C) levels and the homeostasis model assessment of insulin resistance (HOMA-IR, a calculation used to estimate insulin resistance) also all decreased significantly more during year 1 in the lorcaserin group than in the placebo arm. Furthermore, NEJM article stated, "In year 2, patients who continued to take lorcaserin were significantly better able to maintain their year 1 weight loss than those who were switched to placebo, demonstrating a weight maintenance benefit of long term lorcaserin use."
BMI is a function of both muscle mass and peripheral and abdominal adipose tissue. However, abdominal adipose tissue appears to be the main mediator of cardiovascular risk. Waist circumference correlates highly with abdominal adiposity. In one study, a graded and increased mortality risk was noted across increasing waist circumference categories after adjustment for BMI and other covariates. Overall, it is not only weight loss but also decrease in body fat content and waist circumference that are key influences on cardiovascular disease, findings that are supported in several studies. Abdominal obesity is associated strongly with multiple cardiovascular risk factors, including hypertension, diabetes, and hyperlipidemia, in adults with BMI <35 kg/m2 (Janssen et al. 2002).
In 2001, ATP III (Adult Treatment Panel III) recommended two major therapeutic goals in patients with the metabolic syndrome. These goals were reinforced by a report from the American Heart Association and the National Institutes of Health.
The key to treatment of metabolic syndrome is to treat the underlying causes (overweight/obesity and physical inactivity) by intensifying weight management and increasing physical activity.
To reiterate, the KEY element in the treatment of metabolic syndrome is weight loss, especially abdominal fat. Belviq will be a useful adjunct therapeutic measure in the treatment of this chronic and devastating disease, because in the BLOOM trial it was shown to significantly decrease abdominal fat, as measured by abdominal circumference. In the BLOSSOM clinical trial (Steve R. Smith et al. a One-Year Randomized Trial of Lorcaserin for Weight Loss in Obese and Overweight Adults: The BLOSSOM Trial. Journal of Clinical Endocrinology and Metabolism, Oct 2011, Vol 96) are the following results:
MITT-LOCF results (this statistic provides a conservative estimate of the treatment’s effect -generally the effect of the treatment is underestimated):
- Lorcaserin 10 mg BID: 47.2% lost at least 5% of baseline body weight; 22.6% lost at least 10% of baseline body weight
- Lorcaserin 10mg QD: 40.2% lost at least 5% of baseline body weight; 17.4% lost at least 10% of baseline body weight
We can also get the per-protocol results reported in this study (Lorcaserin 10 mg BID):
- 63.2% of patients lost at least 5% of their body weight
- 35.1% of patients lost at least 10% of their body weight
- Patients lost an average of 17.0 lbs. or 7.9% of their body weight
- The quartile of lorcaserin in patients with the greatest weight loss (among those with a week 52 weight recorded) lost an average of 35.1 lbs. or 16.3% of their body weight
These per protocol subjects were the most compliant patients; they therefore achieved a greater weight loss than the MITT-LOCF population. It must be noted that the per-protocol subjects reflect a population more akin to those in the 'real world'. However, for the purposes of statistical analysis it would be inappropriate to use only these patients, because randomization would be lost.
It is reasonable to assume that patients who have metabolic syndrome, or are at risk for it, and who understand the increased risks of tT2DM and cardiovascular morbidity and mortality would be more motivated to continue on the medication for a longer period of time. Extrapolating from the BLOSSOM clinical trial, the results expected for a 'real world' population would be more in line with the per protocol subjects than the outcome of the MITT-LOCF analysis.
As indicated by the prescribing label, BELVIQ is indicated as an adjunct to a reduced-calorie diet and increased physical activity for chronic weight management in adults. The reduction of obesity, especially abdominal obesity, is the main therapeutic goal for patients with the metabolic syndrome. Belviq not only significantly decreases body mass, the BLOOM trial demonstrated that it also significantly reduces abdominal obesity. Weight reduction is optimally achieved with a multimodality approach including diet, exercise, and pharmacologic therapy, such as with Belviq. The decrease in appetite as a result of the pharmacologic action of Belviq would help patients remain more compliant with their recommended diet.
The key to the treatment of metabolic syndrome, regardless of multiple risk factors, which should be treated individually, is to prescribe lifestyle changes and weight management. Weight management can be achieved through diet, exercise, and by using medications like Belviq. This new, important drug should help decrease the incidence of the multiple risk factors for the metabolic syndrome.
In summary, obesity is a major component of the metabolic syndrome, which is also present in 80-90% of T2DM patients. The increased insulin resistance, dyslipidemia, and hypertension that so often are seen in these patients lead to increased cardiovascular morbidity and mortality. Even a modest weight loss of 5% to 10% - the scale induced by Belviq in the BLOOM, BLOSSOM, and BLOOM-DM trials - leads to improved glycemic control, increased insulin sensitivity, improvement in blood lipid markers, and a lowering of blood pressure. This was demonstrated in the BLOOM, BLOSSOM, and BLOOM-DM trials. Furthermore, Belviq significantly decreased abdominal circumference, a major risk factor for the development of metabolic syndrome. The potential healthcare cost savings and decrease in human suffering need to be taken into consideration when determining the investment potential of this multipotential drug.
The gravest errors financial analysts make when evaluating the therapeutic potential of Belviq are threefold:
- The benefits should not be measured solely on percentage of weight lost, but should also take into account the therapeutic effects that even modest weight loss (a 5-10% decrease) has on the co-morbidities of obesity, and hence the substantial healthcare cost savings that can be incurred. Numerous scholarly articles in the literature speak to these points. It is also incorrect to assess how long Belviq would be used, based on weight loss alone. The important endpoints (improvement in obesity co-morbidities) are achieved with a longer duration of use. Furthermore, in the Framingham Heart Study, risk of death within 26 years increased by 1% for each extra pound increase in weight between the ages of 30 years and 42 years, by 2% between the ages of 50 years and 62 years. When analysts focus on efficacy, based on weight loss alone, they are overlooking the many benefits derived from even a modest loss of weight.
- Belviq will probably be prescribed not only by family practice physicians but also by bariatric surgeons, endocrinologists, internists, and obstetrician/gynecologists. And if proven safe for children, it will be used by pediatricians who have no other therapies for metabolic syndrome apart from exercise and diet, approaches that have not been successful because of noncompliance.
- Finally, physicians can legally prescribe medications off-label. The Federal Food, Drug, and Cosmetic Act (FD&C) does not limit the manner in which a physician may use an approved drug. Not only is it not illegal to prescribe drugs for unlabeled purposes, it is a very common practice to do so. Furthermore, the FDA cannot prohibit drug companies from distributing information to physicians about off-label use of drugs or devices, applications other than what has been specifically FDA-approved. The FDA also cannot prevent manufacturers from distributing articles (i.e., the BLOOM DM study results) or portions of studies on unapproved uses published in bona fide, peer-reviewed professional journals. This becomes important when physicians are evaluating their options for treating metabolic syndrome. It should be noted that conscientious physicians do not prescribe medications based on advertisements; they rely on evidence published in the peer reviewed medical literature.
Daniel P. Lopez, M.D., F.A.C.O.G. (BruinMD) has a long position in ARNA but has no position in VVUS. The Motley Fool has no positions in the stocks mentioned above. Try any of our Foolish newsletter services free for 30 days. We Fools may not all hold the same opinions, but we all believe that considering a diverse range of insights makes us better investors. The Motley Fool has a disclosure policy.If you have questions about this post or the Fool’s blog network, click here for information.