ABSTRACT
Introduction
Studies examining preoperative weight loss using pharmacotherapy in metabolic and bariatric patients are limited. The objective was to investigate if patients taking a low‐dose formulation of phentermine had improved weight loss.
Methods
This study was a randomized, placebo‐controlled trial including patients undergoing laparoscopic Roux‐en‐Y gastric bypass and sleeve gastrectomy. Anthropometric and serological data were collected during the initial consult visit and again during two follow‐up visits. Lomaira is a low‐dose formulation of phentermine. Patients took 8‐mg tablets three times a day for 14 weeks. The primary outcome of this study was weight loss, which was measured as percentage total weight loss (%TWL) and change in body mass index (BMI).
Results
Among 53 participants randomized, 45 (85%) completed the trial. Participants were predominantly female (91%); the mean age was 41 years (SD = 11); and the mean initial BMI was 48.4 kg/m2 (SD = 8.2 kg/m2). Average weight loss was 6.2 kg (SD = 6) in the treatment group versus 1.1 kg (SD = 4.54) in the placebo group (p = 0.001). Average % TWL was greater in treatment Group 4.7 ± 4.3 versus placebo Group 1.1 ± 3.6, p = 0.001. Multivariate regression analysis demonstrated that preoperative medication use was significantly associated with greater %TWL (p = 0.004). There was no difference in OR time or post‐operative complications between the groups.
Conclusions
Low‐dose phentermine is efficacious and safe for preoperative weight loss in patients undergoing metabolic and bariatric surgery.
1. Introduction
Metabolic and bariatric surgery is a safe and efficacious intervention for the treatment of obesity that improves long‐term weight loss [1], promotes the remission of diabetes and hypertension [1], and improves survival [2]. However, some patients who undergo metabolic and bariatric surgery experience limited weight loss and/or weight regain over time [3]. Thus, previous studies have strived to identify characteristics predictive of successful postoperative weight loss [4, 5, 6, 7, 8]. A consistent predictor of lessened response to surgical therapy has been elevated BMI, namely greater than 50. All of this has led to the advocacy of preoperative weight loss to modify this negative weight loss risk factor.
The relationship between preoperative weight loss and metabolic and bariatric outcomes is generally favorable but variable [9, 10, 11, 12]. Changes in liver size [13, 14, 15] and reductions in complication rates [16] are additional outcomes improved in the pre‐operative weight loss literature. Studies suggest that reductions in liver volume resulting from weight loss during the pre‐operative period improve the technical ease of metabolic and bariatric surgery and potentially reduce the risk of surgical complications [15].
Some bariatric surgery programs have advocated for preoperative weight loss as a means of determining adherence to post‐operative dietary recommendations or to enhance the ease of technique. Rate limiting steps for technical proficiency in patients with higher BMI include hepatomegaly, greater omental fat, and thickened abdominal wall, which would all be improved with pre‐operative weight loss. In several meta‐analyses, demonstration of the utility of preoperative weight loss has been demonstrated in decreasing the technical burden of BMI [9, 10]. However, in these same studies, there has not been any demonstration of the long‐term effect of preoperative weight loss upon post‐operative weight loss. This finding has led some bariatric surgery programs to assert that preoperative weight loss, specifically those with time‐mandated preoperative weight loss, will only lead to delay of treatment or even lack of treatment [6, 7, 8, 9, 10, 11, 12].
Finally, previous studies examining the influence of preoperative weight loss on postoperative outcomes have predominantly implemented dietary and physical activity interventions for achieving preoperative weight loss [17, 18]. To our knowledge, no previous study has examined the possible benefit of using low‐dose phentermine (Lomaira) for achieving preoperative weight loss in metabolic and bariatric patients in a randomized trial. Thus, the purpose of this study was to investigate preoperative weight loss undergoing laparoscopic sleeve gastrectomy (SG) and laparoscopic Roux‐en‐Y gastric bypass (RYGB) who were randomized to Lomaira or a placebo.
2. Methods
2.1. Trial Design
This study was a double‐blind, prospective, randomized controlled trial conducted at an academic medical center. Patients who successfully completed standard of care evaluations by a surgeon and mental health professional during their initial consult visit were recruited for participation in this study. Patients were excluded from participation if they had a known contraindication to the study drug (cardiovascular disease, hyperthyroidism, glaucoma, history of substance abuse, current pregnancy or plans to become pregnant, presently nursing, active or recent use of monoamine oxidase inhibitors, and allergies to sympathomimetic amines). Randomization was performed using computer‐generated random numbers. Following the initial consult visit, patients were scheduled for study visits after 4 and 8 weeks, and all patients attended a standard of care preoperative clinic visit prior to surgery. This study was approved by the Institutional Review Board, and all patients provided written informed consent.
2.2. Intervention and Follow Up
Participants in this study were randomized to a 14‐week course of Lomaira or placebo of similar size and shape. Lomaira is an FDA‐approved and low‐dose (8 mg/tablet) formulation of phentermine HCl. Control and treatment arm patients were instructed to take 1 tablet once a day for weeks 1 and 2, 1 tablet twice a day for weeks 3 and 4, and 1 tablet three times a day during weeks 5–14. Patients were instructed to take their medication within 30 min of a meal.
A member of the research team called patients to schedule for their follow‐up visits 1 week in advance. During follow‐up visits, research participants met with a member of the research team to discuss their experience in the trial and ensure adherence. A trained clinical staff member collected all follow‐up data during follow‐up appointments.
2.3. Measures
The primary outcome for this study was weight loss at the second study visit. Preoperative weight loss was defined using change in body mass index (BMI) and percentage total body weight loss (%TWL). Changes in BMI were calculated by taking the absolute difference between follow‐up and baseline BMI. Weights were obtained by trained clinic staff at baseline and during all follow‐up encounters. A power calculation was performed assuming two independent groups % TWL as a continuous variable, intervention mean 5% TBL, diet control 2% TBL, power of 80% and alpha level of 0.05 resulting in a sample size of 7 in each group.
Secondary outcomes included blood pressure and fasting serologic measures of glucose, insulin, HbA1C, total cholesterol (TC), high‐density lipoprotein (HDL) cholesterol, and low‐density lipoprotein (LDL) cholesterol. Blood pressure measures were obtained by trained clinic staff. Patients completed blood draws as part of the initial consult visit and again prior to surgery.
Additionally, OR time and post‐operative complications were recorded. This study was approved by the Institutional Review Board.
2.4. Statistical Analysis
Data were analyzed using means, standard deviations, counts, and percentage frequencies. The Chi‐Squared test of association was used to evaluate the relationship between categorical characteristics and treatment assignment. Two‐sample t‐tests and the Mann‐Whitney U test were used to evaluate the relationship between treatment assignment and continuous measures. Multi‐variate linear regression was used to evaluate the relationship between taking Lomaira versus the placebo on participants' %TWL. Models were adjusted for factors that were selected a priori and hypothesized to influence preoperative weight loss including age, gender, baseline weight, diabetes, and hypertension.
3. Results
Following recruitment, 53 participants were randomized to Lomaira or the placebo. The follow‐up rate at the first visit was 77.4%, whereas the follow‐up rate at the second visit was 84.9%. Participants in this study were predominantly female (90.6%), and the average age at the time of randomization was 40.8 years (SD = 10.9 years). Prior to intervention, the average participant weight and body mass index (BMI) were 129.5 kgs. (SD = 25.5 kgs.) and 48.4 kg/m2 (SD = 8.2 kg/m2), respectively (Table 1). At baseline, the average participant hemoglobin A1C (HbA1c), total cholesterol, HDL cholesterol, and LDL cholesterol were 6.2% (SD = 1.3%), 180 mg/dL (SD = 35.1 mg/dL), 46 mg/dL (SD = 9.8 mg/dL), and 106 mg/dL (SD = 30.6 mg/dL), respectively. Following randomization, the only statistically different characteristic different between the two groups was age. In patients assigned to take Lomaira, the average age was 37.8 years (SD = 10.7 years), compared to 45.4 years (SD = 9.8 years) in patients assigned to take the placebo (p = 0.012). This was statistically significant but not clinically significant as there is minimal physiologic difference between 38 and 45 years of age.
TABLE 1.
Participant characteristics by treatment assignment prior to intervention initiation.
| Overall | Treatment | Control | p‐value | |
|---|---|---|---|---|
| n (%) or x̄ ± SD | n (%) or x̄ ± SD | n (%) or x̄ ± SD | ||
| Gender | 0.3 | |||
| Male | 5 (9.4) | 2 (6.3) | 3 (14.3) | |
| Female | 48 (90.6) | 30 (93.8) | 18 (85.7) | |
| Diabetes | 0.5 | |||
| Non‐diabetic | 38 (71.7) | 24 (75.0) | 14 (66.7) | |
| Diabetic | 15 (28.3) | 8 (25.0) | 7 (33.3) | |
| Hypertension | 0.4 | |||
| Non‐hypertensive | 34 (64.2) | 22 (68.8) | 12 (57.1) | |
| Hypertensive | 19 (35.9) | 10 (31.3) | 9 (42.9) | |
| Age (yrs.) | 40.8 ± 10.9 | 37.8 ± 10.7 | 45.4 ± 9.8 | 0.01 |
| Weight (kgs.) | 130 ± 25.5 | 132 ± 25.0 | 126 ± 26.6 | 0.4 |
| Body mass index (kg/m2) | 48.4 ± 8.2 | 49.3 ± 7.9 | 47.1 ± 8.7 | 0.3 |
| Systolic blood pressure (mmHg) | 133 ± 17 | 130 ± 15 | 137 ± 20 | 0.1 |
| Diastolic blood pressure (mmHg) | 82 ± 11 | 80 ± 10 | 84 ± 13 | 0.6 |
| Hemoglobin A1C (%) | 6.2 ± 1.3 | 6.2 ± 1.2 | 6.2 ± 1.4 | 0.9 |
| Fasting glucose (mg/dL) | 108 ± 32.9 | 104 ± 26.4 | 114 ± 41.4 | 0.2 |
| Insulin* (uU/mL) | 26.0 ± 15.5 | 26.8 ± 17.2 | 24.5 ± 12.6 | 0.6 |
| Total cholesterol (mg/dL) | 180 ± 35.1 | 181 ± 36.5 | 177 ± 33.3 | 0.7 |
| HDL cholesterol (mg/dL) | 46 ± 9.8 | 46.2 ± 10.1 | 44 ± 9.3 | 0.5 |
| LDL cholesterol (mg/dL) | 106 ± 30.6 | 108 ± 31.4 | 103 ± 30.0 | 0.6 |
At visit 1, statistically significant differences were observed in the number of kilograms lost between the Lomaira and control groups. Patients taking Lomaira lost an average of 3.3 kgs. (SD = 2.9 kgs.), whereas patients taking the placebo lost 1.32 kgs. (SD = 2.0 kgs.; p = 0.044). Patients taking Lomaira experienced an average increase in diastolic blood pressure of 1.3 mmHg (SD = 9.4 mmHg), whereas patients taking the placebo experienced an average decrease in diastolic blood pressure of 6.6 mmHg (SD = 7.6 mmHg; p = 0.04).
At visit 2, statistically significant differences were observed between the Lomaira and placebo groups for all measures of weight. The average %TWL in patients taking Lomaira was 4.7% (SD = 4.3%), compared to 1.1% (SD = 3.6%) in patients taking the placebo (p = 0.001). On average, patients taking Lomaira lost 6.2 kgs. (SD = 6 kgs.) by visit 2, compared to 1.04 kgs. (SD = 4.5 kgs.) in patients taking the placebo (p = 0.001). On average, patients taking Lomaira experienced a decrease in their BMI of 2.3 kg/m2 (SD = 2.5 kg/m2) by visit 2 compared to a decrease of 0.5 kg/m2 (SD = 1.7 kg/m2) in patients taking the placebo (p = 0.002). There were no significant differences in systolic or diastolic blood pressures between the two groups by Visit 2 (Table 2). No difference in serologies, OR time or 30‐day post‐operative complications were noted (Table 3).
TABLE 2.
Participant characteristics after follow up.
| Follow up 1 | Follow up 2 | |||||
|---|---|---|---|---|---|---|
| Lomaira | Control | p‐value | Lomaira | Control | p‐value | |
| x̄ ± SD | x̄ ± SD | x̄ ± SD | x̄ ± SD | |||
| %TWL | 2.7 ± 2.6 | 1.1 ± 2.8 | 0.1 | 4.7 ± 4.3 | 1.1 ± 3.6 | 0.001 |
| ΔWeight (kgs.) | −3.3 ± 2.9 | −1.3 ± 2 | 0.04 | −6.2 ± 6 | −1.1 ± 4.5 | 0.001 |
| ΔBMI (kg/m2) | −1.2 ± 1.1 | −0.5 ± 0.8 | 0.09 | −2.3 ± 2.5 | −0.46 ± 1.7 | 0.002 |
| ΔSBP (mmHg) | −0.62 ± 16.9 | −5.2 ± 9.9 | 0.4 | −2.1 ± 15.8 | −6.8 ± 12.2 | 0.3 |
| ΔDBP (mmHg) | 1.3 ± 9.4 | −6.6 ± 7.6 | 0.04 | −0.5 ± 6.3 | −2.7 ± 11.2 | 0.5 |
TABLE 3.
Changes in serology between consult and pre‐operative visits.
| Lomaira | Control | p‐value | |
|---|---|---|---|
| x̄ ± SD | x̄ ± SD | ||
| ΔHemoglobin A1c (%) | −0.4 ± 0.4 | −0.4 ± 1.3 | 0.1 |
| ΔGlucose (mg/dL) | 1.0 ± 38.1 | −15.2 ± 58.6 | 0.8 |
| ΔInsulin (uU/mL) | −12.4 ± 19.0 | −9.7 ± 10.2 | 0.7 |
| ΔHDL (mg/dL) | −1.2 ± 4.7 | −0.3 ± 4.9 | 0.7 |
| ΔLDL (mg/dL) | −0.3 ± 20.9 | −3.1 ± 16.0 | 0.8 |
| ΔCholesterol (mg/dL) | −7.2 ± 23.3 | −9.9 ± 23.1 | 0.8 |
Following multivariate adjustment, taking Lomaira was significantly and positively associated with greater % TWL (Estimate 4.04, Standard Error 1.33, p = 0.004), Table 4.
TABLE 4.
Multiple linear regression for characteristics predicting participant total body weight loss (TWL).
| Variable | %TWL | ||
|---|---|---|---|
| Estimate | Standard error | p‐value | |
| Lomaira | 4.04 | 1.33 | 0.004 |
| Female | 2.13 | 2.22 | 0.3 |
| Age | 0.08 | 0.07 | 0.3 |
| Baseline weight | −0.01 | 0.01 | 0.6 |
| Diabetes | −0.87 | 1.61 | 0.6 |
| Hypertension | 0.16 | 1.61 | 0.9 |
4. Discussion
This study investigated the impact of a low‐dose phentermine (Lomaira) on the pre‐operative weight loss of patients undergoing metabolic and bariatric surgery. The results of this study suggest that patients assigned to a 14‐week course of Lomaira were able to achieve greater weight loss compared with patients taking a placebo.
This study contributes to a growing body of literature regarding the use of pharmacotherapy for weight management in persons with overweight and obesity. In dietary intervention trials, patients typically achieve < 5% weight loss after 12 months [19]. In contrast, patients in this study assigned to Lomaira achieved 4.7% weight loss following a 14‐week course of treatment. These results are consistent with previous data demonstrating significant weight loss in patients using pharmacotherapy [20, 21]. Furthermore, previous studies have suggested possible blood pressure increases in patients taking phentermine [22, 23], but no statistically different changes in blood pressure were observed by the second follow up visit between patients taking Lomaira and those taking the placebo.
While this study did demonstrate greater preoperative weight loss with medication than dietary counseling, the result was modest with an incremental difference of 3.6% TWL between the groups. With the advent of the GLP‐1 class of anti‐obesity medications and their significantly more powerful effect, future trials will perhaps lead to greater preoperative treatment effect. This continue to be a source of interest as the strongest negative predictor of post‐operative weight loss is elevated BMI. Given that BMI is a modifiable risk factor, efforts to enhance preoperative BMI to improve postoperative weight loss will continue. An analogy can be made to neoadjuvant chemotherapy prior to surgical resection of cancer. Utilizing this cancer model to obesity could yield enhanced surgical outcomes with combination therapy.
Strengths of this study include a randomized, placebo‐controlled study design and consistent definitions of outcomes. Limitations of this study include the lack of postoperative data, moderate loss to follow up, and a sample comprised predominantly of females. The lack of long‐term postoperative data limits analysis of postoperative outcomes, including weight loss and comorbidity remission. Loss to follow up in the sample was modest but may introduce bias, and the lack of males in the study sample limits the generalizability of these results.
Future research is necessary to investigate the influence of a preoperative course of low‐dose phentermine on long‐term metabolic and bariatric outcomes, including weight loss and comorbidity remission. One study found an enduring effect of preoperative weight loss augmented with anti‐obesity medication [24].
5. Conclusion
The improved weight loss and lack of blood pressure effects observed between the treatment and placebo groups in this study provide evidence to support the efficacy and safety of low dose phentermine as an adjunctive preoperative weight loss intervention for patients undergoing metabolic and bariatric surgery.
Conflicts of Interest
The authors received a research grant from KVK Tech. There were no other relevant relationships.
Acknowledgments
The authors received a grant to fund the cost of the study including drug and placebo costs from KVK Tech.
Funding: This study was supported by KVK Tech.
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