Obesity, a major public health concern worldwide, is associated with a growing list of comorbidities and complications. The morbidity, mortality, and reduced productivity linked to obesity and its complications place a significant burden on healthcare costs. Managing obesity long-term remains challenging, often requiring a multifaceted approach that includes lifestyle and behavioral modifications, increased physical activity, and adjunctive pharmacotherapy. While bariatric surgery is considered a safe and effective treatment for most patients with obesity, it's often a last resort.
The Challenge of Post-Bariatric Surgery Weight Management
After bariatric surgery, some patients struggle with inadequate weight loss or weight regain, leading to the return of obesity-related comorbidities. This highlights the need for effective strategies to augment and sustain weight loss following surgical intervention.
The Stanford Team's Evaluation
Dr. Stanford's team evaluated 37 patients who met the eligibility criteria from two academic medical centers on 5,110 patients who underwent Roux-en-Y gastric bypass (RYGB) or sleeve gastrectomy between November 2000 and June 2014. Of these participants, 28 underwent RYGB and nine underwent sleeve gastrectomy. The addition of medication to treatment proved beneficial for the majority of participants, helping 20 patients (54%) lose ≥5% of their postsurgical weight. These results were similar to those from a previous study led by Dr. Stanford, which reviewed 319 patients between the ages of 21 and 73. Patients in the RYGB group lost more of their postsurgical weight on medications (8.1%) than patients who underwent sleeve gastrectomy (3.3%), and the difference approached statistical significance (P = .0515).
Investigating Common Weight-Loss Medications
A review of commonly used weight-loss medications, including orlistat (Xenical), lorcaserin (Belviq), phentermine/topiramate (Qsymia), bupropion (Wellbutrin), metformin (Glucophage), and zonisamide (Zonegran), reported an average weight loss for participants of 2.5 to 8.0 kg (5.5 to 17.5 lb) relative to placebo after one year of therapy, with improvements noted in cardiovascular risk factors, including reduced lipid, glucose, and blood pressure levels. However, there is no evidence yet that any of these treatments have improved patient-oriented cardiovascular outcomes, including reduced morbidity or mortality. These investigators searched clinicaltrials.gov and PubMed, and examined expert recommendation reports and bibliographic references of included studies for English language-only randomized controlled clinical trials. The trials must have lasted at least one year with at least 50 participants per group at baseline, and must have had a 50% retention rate or better. Studies meeting eligibility criteria included 15 trials of orlistat (N = 9,561), three trials of lorcaserin (N = 6,638), and two trials of phentermine/topiramate (N = 3,544), all compared with placebo.
The Role of Metformin
Metformin, a biguanide commonly used to treat type 2 diabetes, has also been investigated for its potential role in weight loss.
Read also: Berberine and Metformin
Metformin and Weight Loss After Bariatric Surgery
Patients who took metformin after bariatric surgery had a significantly lower percentage of weight loss (2.9%) compared with the rest of the study cohort (7.7%) (P = .02). The researchers find it likely that metformin was associated with less weight loss because the medical conditions it is used to treat (such as insulin resistance, type 2 diabetes and metabolic syndrome) can make weight loss more difficult.
Metformin's Mechanisms of Action
Metformin's effect to decrease dietary energy intake may involve more than one mechanism. Metformin has an AMP kinase-dependent effect on glucagon-like peptide-1 (GLP-1)-secreting L cells and increases postprandial GLP-1 secretion, which seems to contribute to its glucose-lowering effect and weight loss effects. Also, studies in rodents have shown increasing expression and secretion of growth differentiating factor 15 (GDF15) in hepatocytes leading to decreased appetite and subsequent weight loss.
Phentermine and Topiramate: A Powerful Combination
Phentermine, the most widely prescribed obesity medication in the United States, and topiramate, an anticonvulsant, have shown promise as a combination therapy for weight loss.
Phentermine: An Appetite Suppressant
Phentermine is an appetite suppressant. However, there are no clinical trials evaluating outcomes of monotherapy at 12 months or longer.
Topiramate: Beyond Seizure Control
Topiramate (Topamax®, Janssen Pharmaceuticals, Inc, Titusville, NJ, USA) has a long and checkered history in clinical therapeutics. Topiramate is a sulfamate-substituted monosaccharide marketed since 1996, and initially approved by the FDA for management of seizure disorders. Weight loss was noted as a side effect as topiramate was being investigated for other uses such as migraine prevention, seizures and bipolar disorder. Topiramate, which is clinically prescribed for migraine prophylaxis and treatment of seizures, induces weight loss via appetite suppression.
Read also: Health Benefits of Metformin
Clinical Evidence for Phentermine/Topiramate Combination
The initial clinical approval trials offer evidence that this fixed drug combination offers synergistic potential for effective, robust and sustained weight loss with mean weight loss of at least 10% of baseline achieved and sustained for up to 2 years in over 50% of subjects treated.
Pre-Operative Weight Loss with Metformin and Topiramate
For patients with severe obesity, whose body mass index (BMI) exceeds 50 kg/m2, the benefits of bariatric surgery must be weighed against perioperative complication risks which are known to be higher independent of surgical technique (1-3). The primary strategy for minimizing complications in such patients is to decrease the BMI before surgery. Preoperative weight loss through dietary modification has demonstrated reduced surgical morbidity for patients with severe obesity (4).
Case Studies: Metformin and Topiramate in Action
- Patient A: A 32-year-old female with a BMI of 51.2 kg/m2 was prescribed topiramate 25 mg daily. After 12 weeks, she experienced a 14.97 kg weight loss (8.2% total body weight loss).
- Patient B: A 58-year-old female with a BMI of 52.2 kg/m2 was prescribed metformin 500 mg twice daily and topiramate 50 mg nightly. After six months, she experienced a 20.41 kg weight loss (15.0% TBWL), resulting in a BMI of 45.9 kg/m2 at the time of LSG surgery.
- Patient C: A 39-year-old female with a BMI of 55.5 kg/m2 was started on topiramate 25 mg. After 22 months on topiramate, total weight loss was 56.70 kg (36% TBWL), resulting in a BMI of 35.4 kg/m2. As a result of this robust weight loss, her surgical work up was placed on hold.
In our series, metformin and topiramate were selected to modify hunger drive, including reduction of cravings and increasing feelings of satiety. The drugs can be used alone or in combination to facilitate pre-operative weight loss.
Advantages of Pre-Operative Weight Loss
Regardless of preoperative weight loss continuing to be a debated topic due to contradictory publications, clinically there are multiple advantages of implementing pre-operative weight loss in patients with obesity. Preoperative weight loss has demonstrated decrease in the size of the liver and the thickness of the abdominal wall, allowing the surgery to be technically easier. Excess visceral fat and a high liver volume are known to complicate the technical aspects of bariatric surgery because they can increase the blood loss volume, operating time, and risk of complications. There may also be significant 30-day mortality risk reduction postoperatively associated with moderate weight loss of <5%. Pre-operative weight loss in patients with obesity may reduce the increased likelihood of hypoxemic complication due to reduction in apneic oxygenation reserve.
Potential Side Effects and Considerations
Phentermine
According to the package insert, phentermine therapy is associated with cardiovascular complications including primary pulmonary hypertension +/− regurgitant cardiovascular disease, palpitations, tachycardia, increased blood pressure, and ischemic events. Therefore, it is contraindicated for use in patients with a history of cardiovascular disease, including uncontrolled hypertension. However, data suggest that phentermine may not be associated with serious adverse events and that use may actually cause blood pressure lowering associated with the resultant weight loss. The potential for abuse with phentermine is a major concern among providers which may preclude prescribing this agent for weight loss.
Read also: Antipsychotic-Induced Obesity Treatment
Topiramate
Several of the adverse effects of topiramate may be related to its inhibitory effect of carbonic anhydrase.65,66 Paresthesias of the distal extremities and periorbitally are a potential side effect as they are with other drugs with carbonic anhydrase inhibiting activity, and may possibly be relieved by potassium supplementation. In addition to paresthesias, the carbonic anhydrase inhibitor activity of topiramate can contribute to a metabolic acidosis and type 3 renal tubular acidosis.62,64-66 However in the metabolic acidosis, plasma bicarbonate levels are seldom less than 18 mM. The acidosis can usually be resolved by reducing the dose of topiramate and administration of sodium bicarbonate if needed. Topiramate has been shown to be teratogenic in animal studies.70 In humans there is an increased risk of oral clefts, and because of this the medication has a category D designation and should absolutely not be used in pregnant women.
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