Pharmacologic Weight Loss: An Underutilized Practice in the Fight Against Obesity Weight Loss: An Underutilized Practice in the Fight Against Obesity.

Obesity is considered one of the most contemporary threats to non-communicable disease such as cardiovascular disease, diabetes, musculoskeletal disorders and even some types of cancers. Its worldwide prevalence has nearly tripled between 1975 and 2016. In 2016, more than 1.9 billion adults aged 18 years and older were categorized as overweight, and of these over 650 million adults were obese. However, Weight management medications (WMM) are currently underutilized as an adjunct to behavioral and lifestyle interventions. By way of example, only 2% of eligible veterans received prescriptions for pharmacologic weight loss in the 2014-2015 fiscal years, and up to 1% of obese U.S. individuals filled a prescription for a WMM between 2009-2013. There are currently five FDA-approved medications for long-term weight loss medications. We analyzed 24 randomized clinical trials of the five drugs and interpreted findings. Of those 24, lorcaserin (Belviq®), naltrexone and bupropion (Contrave®), and phentermine and topiramate (Qsymia®) had four studies each, while liraglutide (Saxenda®), and orlistat (Xenical®) had six studies each. Underutilization of pharmacologic weight corrective therapies that have been statistically and clinically proven to be valuable tools in reducing obesity and its related risk factors. Studies of the five FDA-approved drugs have demonstrated clinically significant positive effects on weight loss with differing effects on both cardiovascular and glycemic markers/risk factors.


Limitations to current practice quantitative measurements of overweight and obesity
Body mass index (BMI), is used by WHO to measure body size and as an indicator of high body fatness. BMI is calculated using a person's weight in kilograms divided by the square of their height in meters. According to the WHO definition, overweight is a BMI greater than or equal to 25; and obesity is a BMI greater than or equal to 30. It is a quick and convenient population-level measure of overweight and obesity due to its universality: the calculation does not change between males and females, nor does it discriminate on age. However, despite its usefulness: BMI should be considered a rough guide rather than a true body fatness measure, as it is not powered to account for human variation in anatomy.

The concept of clinically meaningful weight loss
The idea of quantitative measurement of obesity came in stages. Quetelet introduced BMI, which was applied nearly a century later to the evaluation of degree of fatness in studies of familial inheritance of obesity [6]. Publication of average weight tables in the 1850s was expanded to "ideal" weight tables by the life insurance industry in the mid-20 th century. However, the relation of increasing weight to disease risk was extended by the Framingham Study from which Gordon and Kannel concluded that if everyone were at optimal weight, the incidence of coronary heart disease would be reduced by 25% and congestive failure and brain infarctions would be reduced by 35% [7]. By mid-1970's there had been many observations about the association of obesity and health issues. In 1973, the Fogarty Conference report suggested several criteria, including percent achieving 20-and 40-pound weight loss and a weight reduction index. Clearly the obvious question was, "What defines clinically significant weight loss?" Up to this point in time, few, if any, had suggested that modest weight losses might have important health benefits. In the 1980s, one approach to this question was based on defining clinically significant overweight as a body weight with a BMI>30. Thus, clinically significant weight loss would be reduction below a BMI of 30. By the early 1990s, Rossner interpreted outcomes of treatment by percent weight loss. He concluded that <5% weight loss may reduce risk but was unsatisfactory, whereas a weight loss of 5-10% was considered a "fair" response [8]. In 1992, Goldstein recommended ≤10% weight loss to define clinically meaningful weight loss [9]. Blackburn in 1995 suggested that 5% might be a valid "single" criterion to assess significant weight loss [10]. Two landmark studies of diabetes prevention supported this recommendation. An average weight loss of 5.5% reduced the incidence of diabetes by 58% in the American Diabetes Prevention Program (ADPP) trial [11]. A systematic analysis of clinical trials with outcome data observed for at least 2 years by Douketis et al. [12] provided convincing evidence that 5% weight loss produced important improvements in risk factors or incidence of disease in populations "at risk" from their obesity [12]. A statistical model of the weight loss data from the ADPP trial by Hamman et al. [13] showed that for every kilogram of weight lost there was a 16% reduction in risk for progression to diabetes and that 5% weight loss would produce about 50% reduction in the incidence of type 2 diabetes [13]. Furthermore, a categorical analysis of weight loss from the Look AHEAD trial demonstrated a strong relationship between glycemic measures and weight loss, with improvement beginning at 2.5% to 5% weight loss. For systolic and diastolic blood pressure, high density lipoprotein (HDL) cholesterol, and triglycerides, improvement began at 5% weight loss. In 2013, an expert panel formed by the National Institutes of Health (NIH) conducted an evidence based review of the literature around five critical questions [14]. Critical question one addressed the health benefits of weight loss: "What amount weight loss is necessary to achieve benefit with respect to cardiovascular disease (CVD) risk factors, morbidity, and mortality?" The graded evidence statements that resulted from this effort provide the strongest support for weight loss beginning at 3% for glycemic measures and triglycerides, and 5% for blood pressure and HDL and low density lipoprotein (LDL) cholesterol, to be considered clinically meaningful. The committee went on to conclude that increased amounts of weight loss provided even greater benefits. To achieve improvement in systolic and diastolic blood pressure, HDL and LDL cholesterol, 5% or more weight loss from baseline is considered meaningful, while for glycemic measures and triglycerides, ≥3% weight loss is considered clinically significant [15].

Underutilization of pharmacologic corrective therapies
Weight management medications (WMM) are currently underutilized as an adjunct to behavioral and lifestyle interventions. By way of example, only 2% of eligible veterans received prescriptions for pharmacologic weight loss in the 2014-2015 fiscal years, and up to 1% of obese U.S. individuals filled a prescription for a WMM between 2009-2013. In addition, physician prescribing patterns have been declining, with the exception of phentermine, since 1991. Possible explanations for the WMM prescribing downtrend include absence of physician training

Examine the five US FDA-approved medications for longterm weight loss
There are five FDA-approved weight loss medications for longterm use. See Table 1 for detail.

Indications
For obesity management including weight loss and weight maintenance when used in conjunction with a reduced-calorie diet To reduce the risk for weight regain after prior weight loss Adjunct to a reduced-caloric diet and increased physical activity for chronic weight management in adults with an initial BMI of ≥30kg/ m 2 or ≥27kg/m 2 in the presence of at least one weight-related co-morbidity such as HTN, T2DM or DLD Adjunct to a reduced-caloric diet and increased physical activity for chronic weight management in adults with an initial BMI of ≥30kg/m 2 or ≥27kg/m 2 in the presence of at least one weight-related co-morbidity such as HTN, T2DM or DLD Adjunct to a reduced-caloric diet and increased physical activity for chronic weight management in adults with an initial BMI of ≥30kg/ m 2 or ≥27kg/m 2 in the presence of at least one weight-related co-morbidity such as HTN, T2DM or DLD Adjunct to a reduced-caloric diet and increased physical activity for chronic weight management in adults with an initial BMI of ≥30kg/ m 2 or ≥27kg/m 2 in the presence of at least one weight-related co-morbidity such as HTN, T2DM or DLD

Xenical® (orlistat)
We selected six Xenical ® studies for review, conducted by Davidson et al. [23][24][25][26][27][28] respectively (Table 2). 23-28 Five out of 6 studies demonstrated statistically significant weight loss and four out of six Xenical studies demonstrated clinically significant weight loss. For waist circumference measurement, two out of three Xenical studies led to statistically significant values versus control. Two out of two studies demonstrated statistically significant reduction in blood pressure while one out of two studies demonstrated statistically significant differences in fasting blood sugar versus control. In regard to cholesterol, four out of four studies demonstrated statistically significant reductions in total and LDL cholesterol, however, non-statistically significant variation was noted with triglycerides. Unfavorable yet statistically significant increase in HDL cholesterol was seen in comparison of Xenical and control group (Table 3).

Belviq (lorcaserin)
We reviewed four Belviq ® clinical studies conducted by Fidler et al. [33][34][35][36] & (Table 6). Three out of four studies demonstrated statistically and clinically significant weight loss, and two out of three studies measuring waist circumference led to statistically significant values versus control. One out of four studies demonstrated statistically significant reductions in blood pressure and significant fasting blood sugar. No difference has been seen on C-reactive protein value while one out of three studies demonstrated statistically significant differences in triglycerides. Results are shown in Table 7.

Discussion
Twenty-four studies of the five FDA-approved weight loss drugs demonstrated clinically significant effects on weight loss with differing effects on both cardiovascular and glycemic markers/risk factors. Saxenda ® , Belviq ® , Contrave ® and Qsymia ® all positively affect fasting plasma glucose while Xenical ® have no effect. Xenical ® , Qsymia ® and Contrave ® demonstrated to have largely impacted cholesterol levels versus Belviq ® and Saxenda ® having minimal effects. Regarding systolic and diastolic blood pressure, Xenical ® , Qsymia ® and Saxenda ® all showed positive effects compared to diet and exercise alone. According to Guideline for the Management of Overweight and Obesity in Adults, adjunctive pharmacotherapy should be considered for people who have either a BMI of 30 and over, or 27 and over with at least one comorbid conditions such as hypertension, dyslipidemia, type 2 diabetes or obstructive sleep apnea [14]. Even though it has been demonstrated that pharmacotherapy can enhance the likelihood of clinically meaningful weight loss and improve health, it is largely underutilized [17]. There is a potential role for pharmacist to be involved in primary care and serve as a liason between prescriber and weight management resources. Further research is needed to identify the cost effectiveness, most effective adjunctive behavioral treatments, the role of intermittent vs. continuous therapy as well as duration of treatment.

Conclusion
Underutilization of pharmacologic weight corrective therapies that have been statistically and clinically proven to be valuable tools in reducing obesity and its related risk factors [24]. Studies of the five FDA-approved drugs have demonstrated clinically significant effects on weight loss with differing effects on both cardiovascular and glycemic markers/risk factors.