A randomized, open-label pilot of the combination of low-level laser therapy and lorcaserin for weight loss

In 2011–2012, approximately two-thirds of US adults were were either obese or overweight [1, 2]. Obesity significantly increases the risk for cardiovascular disease and is associated with poor quality of life (QOL). Weight reduction can modify both the risk and risk factors for cardiovascular disease [1, 3–6]. Weight reduction reduces blood pressure, triglycerides, and low-density lipoprotein (LDL) cholesterol; and increases high-density lipoprotein (HDL) cholesterol [7]. Reductions in waist circumference (WC) reduce the inflammatory biomarker C-reactive protein (CRP), LDL, diastolic blood pressure and overall cardiovascular risk [8].

Recent evidence has suggested that the distribution of adipose tissue (subcutaneous versus visceral) is more predictive of cardiovascular risk than body mass index (BMI) alone [9]. Central adiposity, which appears to be the best surrogate for estimating visceral adipose tissue, can be measured clinically as waist circumference (WC) and waist-to-hip ratio (WHR). Two large case–control studies have demonstrated that WC and WHR are independent risk factors for cardiovascular mortality [9, 10]; and measuring body composition is an important component of an effective weight loss program [11].

Unfortunately many obesity treatments are associated with poor adherence and high recidivism. Combining treatment modalities with different mechanisms of action to facilitate losing weight may hold the greatest potential for achieving meaningful weight loss, as individuals are provided with several approaches to successful weight management. Low-level laser therapy (LLLT) is a noninvasive body-contouring procedure designed to remove excess fat without emitting heat, sound, or vibrations. Originally designed to improve wound healing, reduce edema, and relieve pain [12, 13], LLLT has been utilized as an adjunct in Lipolysis (a process for removing fatty tissue) [12, 14–16], and was approved by the FDA in 2010 for fat reduction [17]. At that time the FDA identified this generic type of device as “a device using low level laser energy for the disruption of adipocyte cells within the fat layer for the release of fat and lipids from these cells for non-invasive aesthetic use.” [18]. It has also been shown to accelerate repair, stimulate cell proliferation, and promote vascularization in injured tissues [19]. Energy from the lasers (1.2 to 3.6 Joules/cm²) is proposed to permeabilize adipocyte membranes, resulting in extravasation of intra-adipocyte lipids. Lorcaserin is a selective serotonin 2C (5-HT_2C) receptor agonist. Activation of the 5-HT_2C receptor subtype in the hypothalamus increases pro-opiomelanocortin (POMC) production leading to weight loss through satiety [20–22]. Lorcaserin is FDA-approved for weight management [23] in individuals with a body mass index (BMI) of >27 kg/m² (overweight) when accompanied by a weight-related health condition such as type 2 diabetes or high blood pressure, or in people with a BMI >30 kg/m² (obese) [20–22].

The purpose of this study was to evaluate the safety, feasibility, and preliminary efficacy of LLLT alone or in combination with lorcaserin for reducing anthropomorphic meaures of obesity. Biomarkers and adherence to treatment were also measured to provide guidelines for potential future investigations.

A total of 122 individuals called with interest in this study,45 individuals were enrolled and randomized to study groups (15 LLLT, 15 lorcaserin, 15 combination therapy) and 44 went on to be treated according to their randomized assignment (15 LLLT, 14 lorcaserin, 15 combination therapy). This report is based on the 44 who went on to be treated in study (Fig. 1).

In this pilot project examing combined therapy for weight management, LLLT monotherapy, lorcaserin monotherapy, and combination therapy significantly reduced anthropomorphic measurements among overweight and obese adults. These interventions were also associated with improvements in body satisfaction and QOL. No side effects were reported related to LLLT and few side effects were reported related to lorcaserin. Satisfaction was higher with lorcaserin monotherapy and combination compared to LLLT alone.

Although no significant differences were observed between groups, consistent with previous literature, all three interventions were associated with reductions in at least one anthroporphic measurement. In a double-blind, placebo-controlled study (active vs. “sham” LLLT), 67 overweight patients were randomized to LLLT (17 mW) or sham-LLLT (2.5 mW) and received 6 treatments over 2 weeks. Sixty-three percent (22/35) of subjects in the LLLT group participants achieved individual success, defined as at least 3.0 in. reduction in combined circumference measurements for waist, hip, and bilateral thighs from baseline to after treatment phase completion, compared with 6 % (2/32) of participants in the sham group [40]. A larger study (N = 689) from the same investigative team indicated that the reductions in circumference were not attributable to fluid loss or fat relocation [41]. Retrospective studies have supported the body measurement reductions achieved (e.g., waist, hips, thighs) with this therapy and reported concomitant decreases in weight [42].

The treatment and efficacy of lorcaserin for weight loss has been evaluated in three large phase III clinical trials, with over 8,000 overweight and obese subjects, in which a weight loss of 3 % to almost 4 % was found at 1 year. The Behavioral Modification and Lorcaserin for Overweight and Obesity Management (BLOOM) trial enrolled 3,182 subjects and observed an average weight loss of 5.8 ± 0.2 kg with lorcaserin and 2.2 ± 0.1 kg with placebo during year 1 (P < .001) [20]. The Behavioral Modification and Lorcaserin Second Study of Obesity Management (BLOSSOM) trial enrolled 4,008 patients and showed that more people lost at least 5 % of their body weight at one year compared to placebo (47 %, 40 %, vs. 25 %; P < .001, lorcaserin twice daily, lorcaserin once daily, vs. placebo, respectively) [21]. The Behavioral Modification and Lorcaserin for Obesity and Overweight Management in Diabetes Mellitus (BLOOM-DM) trial, which enrolled 604 obese/overweight individuals with diabetes observed that more patients lost ≥5 % body weight with lorcaserin twice daily (38 %; P < .001) or lorcaserin daily (45 %; P < .001) compared with placebo (16 %) [22]. In our study, we observed an average weight loss of 3.5 to 3.7 kg (combination and lorcaserin group, respectively) by end of 12 weeks of treatment; whereby, similarly to these past studies, 57 % (8/14) in the lorcaserin group and 33 % (5/15) in the combination therapy lost at least 5 % or more of their baseline weight by end of treatment.

Because QOL is so important and many obese adults report having a negative QOL [43], it is crucial to assess the QOL of participants in weight-loss programs as it has been reported that weight loss can improve QOL [44]. In this study we observed that participants in the LLLT conditions improved their QOL, which suggests that there may be an important psychosocial dimension of this treatment. We hypothesize that participants may have anticipated that the LLLT would improve their health and well-being. Given the importance of QOL to the individual, further exploration of this QOL finding is warranted.

Unlike the previous LLLT studies, in this study satisfaction with LLLT was low; we hypothesize that this may be related to unrealistically high expectations surrounding its utility. Several participants expressed dissatisfaction in not receiving LLLT and one participant went as far as refusing to continue with the study after finding out that her randomized assignment was lorcaserin monotherapy. Less than half of the subjects assigned LLLT adhered with the behavioral intervention instructions related to their behavior changes (i.e., wearing the restrictive undergarments during the treatment weeks and drinking plenty of water) leading the investigators to hypothesize that, as unrealistic as it seems, study participants assumed that the LLLT would take care of their weight loss with little or no lifestyle changes on their part.

The behavior change phenomenon of setting unrealistic expectations and becoming disappointed when those expectations are not met is not unusual in weight loss programs where setting unrealistic expectations is a barrier to actual weight loss [45]. For example, a study of 60 obese females (mean BMI of 36.3 kg/m²), where subjects set a goal of 32 % reduction in body weight the average weight loss was a little less than 17 % from their baseline weight and the subjects deemed the program a failure [46]. Two other studies with individuals who had a BMI of 40 kg/m² or higher also found this same phenomenon [47, 48]. Leading us to conclude that individuals with higher baseline weight may have more unrealistic goals for weight loss and high unrealistic expectations set prior to the program lead to poor compliance with the program and worse outcomes [45]. This phenomenon was also observed in our study, where subjects expected a large weight loss while not adhering to the behavioral interventions provided by study staff, indicating that in future studies behavioral intervention should include an initial intake discussion whereby subjects can set realistic expectations with the study staff in order for the study to have the most impact. Individuals trying to lose weight should receive valid information at this time about the expected outcomes of the intervention they are receiving and this, in turn, may improve adherence with the program.

The small sample size limited the ability to detect significant differences between groups. The open label design limits our study due to patient selection bias [49], participant retention bias [50], and participant performance bias [51]. In this study, participants who entered the study had a preference for LLLT. We observed that although they had no choice in what they were assigned, some subjects dropped out of the study after a few treatments, if it was not the treatment they wanted; while we hypothesize that other subjects did not adhere to the behavioral changes recommended if they received the intervention they did not expect/prefer, we did not track adherence to preferences and cannot confirm this at this time.

Another potential limitation was the LLLT administration. Both in a clinical setting and in research trials, LLLT can be provided at three different frequencies: 40 min (20 min on each side-front and back 3 times a week (every 48 h); 60 min (30 min on each side) 2 times a week; and 60 min (30 min on each side) once a week. The contemporary theory postulates that the lysing of fat cells should be continuous and the fat cells should not be allowed to recover. When we designed the study we sought expert opinion and it was recommended that if we increase the duration from 20 min on each side to 30 min on each side, once a week would be adequate. Taking into consideration the participant burden and study attrition, we decided that this preliminary study would focus on the last option (once per week). While reducing the visits to once a week may have led to improved treatment adherence, we suspect that the treatment of the LLLT was not frequent enough to result in clinical benefit. The study outcomes did not substantiate that this was the correct decision. Another study is currently being designed to determine the best frequency, which will address the lysing of cells and the subject burden.

In order to open recruitment to a larger number of individuals, the BMI inclusion criteria was expanded to include anyone with a BMI of 27–39.9, which included those categorized as overweight (BMI 25–29.9), obese level 1 (BMI 30–34.9), and obese level II (BMI 35–39.9). At the time that the study started, only the Zerona™ 2.0 LLLT option was available for anyone with a BMI of ≥25. After completion of the study, a second type of LLLT was approved by the FDA. Two LLLTs are now approved by the FDA for body sculpting: a 6-headed green laser (K130922) for adults with a BMI of 25–29.9 kg/m² (NCT01702259) and a 10-headed green laser (K142042) for patients with a BMI of 30–40 kg/m² (NCT01821352). If indeed the 10-headed green laser provides greater treatment effect for those individuals with a BMI between 30–40 kg/m², as the marketing implies, then we are undertreating our patients who fall in this range.

Another potential limitation is related to variability in the behavioral counseling and lack of tailoring of the behavioral intervention to LLLT. Since LLLT is a new weight loss intervention it is not known if healthy lifestyle recommendations should be tailored for LLLT, such as more focus on strength training, use of form fitting clothing, or nutritional guideline. In terms of the variability of the behavioral intervention, in order to accommodate the study participants, a large coordinating staff was used. No study participant was guaranteed the same staff member at all visits. While, the study staff was uniformly trained on the behavioral intervention approach, the behavioral intervention had to target the subjects personal needs and therefore varied between subjects and staff members. As a result, the counseling approach varied depending on the staff member. In addition, the study staff was trained using an established protocol for collecting body measurements. We did not perform a formal study to assess variability of the measurement process. Although variability in the measurement process contributes to the variability seen in body measurements, each study subject was seen by different staff throughout the course of the study and therefore the variability of the measurement process should not introduce any bias when comparing across treatments.

Future studies will need to consider another approach to providing uniform counseling (e.g., identifying key behavioral topics for each session, or the use of online programs), collecting body measurements uniformally (e.g., iDEX), and investigating potential tailoring of a behavioral weight management intervention to LLLT.

While there has been some concern regarding the safety of LLLT, in this small pilot study we did not find any indication of harmful effects based on the biomarkers or self-reported side effects, which provides some initial support for LLLT being a safe intervention. It appears that LLLT targets central adiposity, and our finding of reduction in waist circumference supports this premise. Further exploration utilizing a larger sample size with longer duration of treatment and follow-up is warranted to assess the safety and efficacy of LLLT in the treatment of obesity.