Controversial Issues: A practical guide to the use of weight loss medications after bariatric surgery for weight regain or inadequate weight loss

Introduction

Obesity continues to be the most prevalent chronic disease in the United States with ~40% of the adult population and ~19% of the pediatric population with this diagnosis, and the prevalence of severe obesity in the adults and pediatrics is ~8% and ~6%, respectively.^{[1, 2]} In patients with moderate to severe obesity, bariatric surgery has the potential to provide significant and sustainable weight loss while also improving obesity related co-morbid conditions.^[3] Despite its overall relative high degree of efficacy compared to other treatment strategies, patients may experience inadequate weight loss (<50% of excess weight loss (EWL)) or weight regain after bariatric surgery which warrants consideration of alternate treatment modalities. warrants consideration of alternate treatment modalities. Current data suggest that between 25–35% of patients have inadequate weight loss or experience significant weight regain.[4–6] Inadequate weight loss and weight regain is multifactorial- it may secondary to genetics, sociodemographic factors, mental health co-morbid conditions, physical inactivity, poor diet quality or secondary to pathophysiology factors specific to the type of bariatric surgery performed.[7] While revision bariatric surgery and endoscopic procedures may be entertained,^{[8, 9]} studies have shown that weight loss medications may confer between 5– 15% of TWL after bariatric surgery without additional surgical intervention^{.[7, 10]}

The medical community has expressed interest in utilizing weight loss medications for achieving weight loss after bariatric surgery. Weight loss medications have emerged as an underutilized treatment strategy in this patient population. In our study which is the largest retrospective analysis of weight loss medications in bariatric surgery patients to date, of 15 medications evaluated, topiramate was the only medication which demonstrated statistical significance for ≥ 5% total body weight loss.[7] Yet in a recent analysis of this same patient cohort, topiramate, phentermine, and metformin appeared to be efficacious in young adults aged 21–30 years old.[6] Unfortunately, there is a paucity of research regarding the use of medications after weight loss surgery, and more research is needed to provide patients with tools to treat inadequate weight loss and weight regain. To date, there is no practical guide that provides guidance regarding this practice for practitioners who do not have specialized training (e.g. completion of an obesity medicine fellowship) in this treatment strategy. This article seeks to provide some guidance (based upon our clinical experience) to those with interest in exploring the use of weight loss medications in the population with inadequate weight loss or weight regain after weight loss surgery.

Methods

Prior to the consideration of weight loss medications after weight loss surgery, it is important to consider whether there is an anatomic reason for inadequate weight loss or weight regain after bariatric surgery, this can often be ascertained by taking a thorough medical history and ordering an upper GI to evaluate for issues such as staple line breakdown and post op leaks which would require revision surgery. Once anatomic issues have been ruled out, one might consider the addition of weight loss medications. It is important to emphasize that patients should not blame themselves for inadequate weight loss or weight regain after weight loss surgery. While patients might need to optimize patient specific factors (i.e. quality of diet, frequency and intensity of physical activity, sleep quality and duration), gut hormones after weight loss surgery (e.g. decrease in ghrelin) and genetics may be more likely to consider as reasons for a suboptimal response.[11] In our large retrospective analysis of weight loss medication use as an adjunct to bariatric surgery, we found that topiramate was statistically significant for conferring additional weight loss.^[7] As a result, we will choose topiramate as our initial drug to utilize in patients with excess weight after weight loss surgery. Topiramate has demonstrated efficacy for weight loss in pediatric and adult patients.[12, 13] Unfortunately, the mechanism of action of topiramate is largely unknown, but recent studies have shown that genetic variation in the INSR and HNF1A genes may differentially affect weight loss in individuals with obesity treated with topiramate and genes related to insulin action are implicated in modulating topiramate response.[14,15] However, we must note that while phentermine and topiramate are approved in combination by the Federal Drug Administration (FDA) for long term treatment of obesity, topiramate as standalone pharmacotherapy has not been approved for this purpose. If the patient has a history of nephrolithiasis, an alternate agent would be recommended secondary to the potential for nephrolithiasis with the use of topiramate. However if monitored by an obesity medicine physician, topiramate might be utilized with caution.

There is a potential for side effects with each weight loss medication, and it is important to monitor these closely in patients. For topiramate, the key side effects to notify patients about include cognitive changes (e.g. word finding difficulty) and paresthesias. Also, patients who regularly take topiramate should have their electrolytes monitored regularly secondary to this agent causing metabolic acidosis in some patients. Secondary to the need to reduce the likelihood of side effects and ensure that the medication is tolerable for chronic use, we start the medication very slowly and titrate up only when necessary. We utilize the principle: “Start Low and Go Slow”. Our strategy with how to utilize weight loss medications are delineated in a step by step fashion in Table 1.

Table 1.

Step-by-Step Guide for Utilization of Weight Loss Medications After Bariatric Surgery

Step 1. Ascertain whether there is anatomic reason for weight regain with a thorough history and physical and upper GI study (if needed).

Step 2. If there is no anatomic reason for inadequate weight loss or weight regain, ensure that lifestyle factors (diet quality, physical activity, sleep, and stress level) have been optimized.

Step 3. Add topiramate 25 mg at bedtime as soon as weight loss halts (once the patient reaches a plateau) or once weight regain has begun as adjuct to an optimal lifestyle.

Step 4. Ascertain if there are any side effects associated with the use of topiramate. If there are minimal side effects with good patient weight loss response, consider changing the topiramate to an extended release formulation OR consider a transition to zonisamide 100 mg in the evening.

Step 5. Titrate the medication up slowly, as needed (when weight loss halts), to reduce the likelihood of side effects. It is preferable to increase the dose of topiramate by 25 mg at each increase. If side effects ensue with topiramate, but the patient has achieved weight loss, one might consider transitioning to an extended release topiramate first before a switch to an alternate agent such as zonisamide. If zonisamide is used, we recommend to titrate up by 100 mg. If a patient begins to experience side effects, reduce the dose back to the previous dose and maintain the patient at that dose

Step 6. If the patient has additional weight loss to be conferred, consider the addition of a second medication (i.e. phentermine, bupropion, liraglutide, etc.) in addition to the first medication. It is important to use agents that are from different classes (e.g. phentermine/topiramate, bupropion/naltrexone, bupropion/zonisamide, liraglutide/topiramate).

Step 7. If more weight loss is desirable, one might consider the addition of phentermine in the morning. We choose to utilize an extended release of phentermine with an initial starting dose of 15 mg in the morning and an increase to 30 mg if the patient does not have side effects. If the patient has a desirable weight loss outcome from the addition of phentermine but notes side effects, one might consider the switch to a smaller dose of phentermine of 8 mg in the morning with titration to 8 mg a day, three times daily, as needed.

Step 8. For patients who have a history of psychotropic induced weight gain, one might consider the addition of metformin. Unlike the other medications where we use the lowest effective dose, we will most often titrate the patient to metformin 1000 mg by mouth twice daily. If the patient has GI side effects, consider a switch to an extended release format.

Discussion

The use of weight loss medications has been shown to help patients across a broad range of weight classes lose additional weight after bariatric procedures.^{[7, 16–21]} It is important to note that weight loss medications may be helpful for those with inadequate weight loss or weight regain after a patient has reached their nadir or plateau after bariatric surgery. Even for those persons who have attained an average amount of weight loss after a bariatric surgery, the patient often still has obesity. As such, these patients would meet criteria for weight loss medication consideration as weight loss medications may be utilized for patients with a Body Mass Index (BMI) ≥ 30 or a BMI ≥ 27 with a significant comorbidity such as type 2 diabetes, obstructive sleep apnea (OSA), or hypertension.^[16] Studies have demonstrated the efficacy of weight loss medications for additional weight loss in patients after several bariatric procedures with most studies demonstrating weight loss after Roux-en-Y Gastric Bypass (RYGB) and Sleeve Gastrectomy (SG), but there have been some studies that have demonstrated response after the adjustable gastric band (AGB).[7, 10, 18–21]

If one decides to utilize the strategy of adding medications to the care of the patient who has undergone bariatric surgery, there are several points that one should consider with all patients:

1. Make every effort to maximize lifestyle BEFORE the introduction of weight loss medication to a patient’s medical regimen. A patient would not need to introduce a weight loss medication if we can achieve a healthy weight without the use of medication.

2. Once you introduce a weight loss medication (and it works as denoted by 5–10% total body weight loss, but one might consider that in this special population that a patient has achieved success if they achieve weight maintenance or no further weight gain), you will need to use the medication indefinitely. If you discontinue a medication, the patient will regain weight loss (or may gain weight after weight maintenance has been achieved) that has been conferred with the addition of the medication. It is important to communicate the need for long term therapy with the patient prior to the initiation of the medication. Many believe that you can start the weight loss medication, achieve a desired amount of weight loss, and then stop the medication. This is not an effective strategy. Just as is the case when we treat other chronic diseases, when we discontinue the use of medication for obesity, weight regain will occur.

3. Several agents may be needed to help an individual lose weight, but it is important to engage in regular follow up (at least monthly on the initiation of a new agent or with dose adjustments) and to personalize care to the patient to ensure an optimal outcome.

4. Pay attention to the common side effects for medications, but patients may report other less common side effects. Since these medications will be used long term, it would not be advantageous to continue a medication which causes deleterious side effects just to achieve weight loss. While weight loss is desirable, this should not be at the expense of the patient’s overall health and quality of life.

5. Don’t be too aggressive with the speed of titration of the medication. We would recommend to titrate the medication monthly (as needed). Medications only need to be titrated if weight loss halts. It is important to recognize that the dose needed for each individual patient might vary. As a result, we encourage you to “personalize” the medication dose to each individual patient.

6. Every patient has a different response to weight loss medications. However, a person is considered to have success with weight loss medication if they achieve a 5–10% total body weight loss. If weight loss is less than 5%, an alternative agent should be considered. While this is our standard practice which reflects utilization of weight loss medications in non-surgical patients, clinicians might also consider that a medication is successful after weight loss surgery if the patient achieves weight maintenance. Since it is often a challenge to get weight loss medications approved by insurers, the 5–10% target may be necessary for weight loss medication insurance coverage to continue for many agents by health care insurers.

7. Patients will reach a nadir weight and will have a slight rebound from the nadir. This is a normal phenomenon. An additional agent might be added when the patient reaches weight stability or once a rebound is noted.

8. If topiramate is utilized as the weight loss medication, we often do not exceed a dose of 100 mg at bedtime. There are some patients that require higher doses, but we generally do not exceed 150 mg for the purposes of weight loss. For patients that develop issues such as word finding difficulty or parasthesias but HAVE ALSO achieved weight loss, one might consider a switch to an extended release topiramate in lieu of the regular formulation. If side effects still persist, one might consider an alternate agent such as zonisamide,[22–24] which has a similar mode of action to topiramate. If zonisamide is utilized, we find that a 100 mg dose is equivalent to a 25 mg dose of topiramate. As such, we can titrate up to a maximum of 400 mg in the evening for weight loss purposes.

9. Since topiramate and zonisamide are anti-epileptic medications, rapid cessation may induce seizures. As a result, we recommend a gradual titration off of these medications if they need to be discontinued. We recommend a taper from one dose to another dose to occur every 3 days (e.g. a patient is on 100 mg of topiramate in the evening, but they need to discontinue the medication- we might taper the patient as follows- 75 mg in the evening for 3 nights, 50 mg in the evening for 3 nights, 25 mg in the evening for 3 nights, then stop.)

10. We prefer to dose topiramate and zonisamide in the evening to reduce the impact of cognitive slowing. For some patients, these agents lead to better quality sleep (i.e the patient is able to fall asleep and stay asleep). Many also note that these agents reduce cravings for food in the evening hours.

11. There are special considerations to note in women of childbearing age. Many medications are linked to fetal anomalies and not safe to utilize during pregnancy. We would recommend that persons discontinue the use of medication prior to conception. Concurrently, we would recommend appropriate and consistent birth control in women to prevent conception while taking these medications.

12. Patients might achieve additional weight loss with topiramate when combined with phentermine. We titrate topiramate/zonisamide to the appropriate dose for the patient (a dose in which weight loss occurs but side effects are minimal). Once this dose has been achieved, we add phentermine 15 mg extended release capsule in the morning with a titration to a dose of 30 mg if additional weight loss is desirable.[10, 19, 25] Common side effects include insomnia and dry mouth, but we are most vigilant to have the patient obtain ambulatory blood pressure and pulse readings on Monday mornings, Wednesday middays, and Friday evenings at the start of the medication and whenever a dose adjustment is needed. If a patient has consistent readings which are greater than a blood pressure of 140/90 and pulse of 96, then the medication might not be suitable for the medication.

13. Many patients who undergo weight loss surgery have a history of co-morbid mental health diagnoses such as bipolar disorder. For patients who have excess weight who are concurrently being treated with psychotropic medications, we recommend the addition of metformin to topiramate.[26, 27] Unlike with other medications for weight loss in which we use the lowest effective dose, most patients on metformin are titrated to a dose of 1000 mg by mouth twice daily. For patients who have gastrointestinal side effects such as loose stool, we encourage a switch to an extended release version of metformin which often mitigates these issues.

14. For patients in which topiramate, topiramate XR, zonisamide, phentermine, or metformin have not been efficacious, one might consider the addition of agents commonly prescribed for weight loss such as bupropion/naltrexone,[28] lorcaserin,[29] liraglutide,[30] etc. We recommend following label instructions for the use of these medications, but in our practice, other off label options such as bupropion/zonisamide[31] might also be considered.

Conclusions

Weight loss medications are an effective strategy to confer additional weight loss following inadequate weight loss or weight regain after bariatric surgery. This paper demonstrates how to use topiramate, a medication which has been previously demonstrated to help patients achieve clinically meaningful weight loss in bariatric surgery patients with inadequate weight loss or weight regain.^[7] Clinicians should consider the use of a step-by-step approach to introduce weight loss medications in the post-operative setting. In order to treat the chronic disease of obesity in patients with a history of moderate to severe obesity, long term use of weight loss medications is often necessary to provide a multifaceted approach (i.e. behavioral, pharmacotherapy, and surgery) to the patient with moderate to severe obesity.

Highlights.

• Weight loss medications may be utilized as an adjunct to weight loss surgery in patients with inadequate weight loss or weight regain.

• Both FDA and non-FDA approved medications have shown to be beneficial in treating patients with excess weight after bariatric surgery.

• We provide guidance on how to initiate several medications after weight loss surgery in patients.