How does topiramate help with weight loss?

How does topiramate help with weight loss?

Comment by InpharmD Researcher

While the mechanism is not entirely understood, topiramate may promote weight loss through the suppression of appetite and alterations in metabolic pathways. Specifically, studies show topiramate decreases energy intake and lowers leptin levels, correlating with weight reduction by targeting appetite and reward centers in the brain as well as hormone signals involved in fat storage and metabolism.

Background

Topiramate is an anti-epileptic drug that has demonstrated weight loss effects in clinical trials. The biological mechanism behind topiramate’s weight loss effect is not completely understood; however, possible mechanisms include a reduction in appetite and decrease energy intake by altering appetite and reward pathways in the brain. Studies have also found topiramate may contribute to weight loss by lowering calorie intake, decreasing fat gain, and lowering triglyceride and cholesterol levels. Leptin is a hormone involved in fat storage and has observed reduced levels in patients taking topiramate, which has directly correlated with weight reduction. Leptin may also be involved in signal pathways regarding body weight and metabolism. As part of the medication phentermine-topiramate, a 56-week follow-up clinical trial demonstrated mean weight loss of 5.1% to 10.9% compared to 1.6% with placebo among individuals with obesity. Thus, the mechanism for weight loss may be related to a combination of appetite suppression and body metabolism, and has been linked to clinical weight loss. [1], [2]

Multiple meta-analyses have published the weight-loss benefit of topiramate as monotherapy or in combination with phentermine. In general, the meta-analyses found that phentermine-topiramate combination, glucagon-like peptide-1 receptor agonists (GLP-1 RAs) like liraglutide and semaglutide, naltrexone-bupropion, orlistat, and topiramate were effective at promoting clinically meaningful weight loss compared to placebo or lifestyle modification alone. Phentermine-topiramate, at higher doses, and semaglutide were identified as the most effective treatments based on measures such as odds of >5% weight loss and percentage body weight change reduced. While weight loss benefits increased with longer trial duration and higher drug doses, common side effects included taste alterations, numbness, dry mouth, and gastrointestinal issues, with phentermine-topiramate, naltrexone-bupropion, and GLP-1 RAs carrying a higher risk of discontinuation due to adverse effects. Beyond weight loss impacts, phentermine-topiramate was also shown to provide additional benefits of reducing waist circumference as well as lowering blood pressure and improving blood sugar and lipid levels. [3], [4], [5], [6]

Literature Review

A search of the published medical literature revealed 1 study investigating the researchable question:

How does topiramate help with weight loss?

Level of evidence

B - One high-quality study or multiple studies with limitations Read more→

Please see Table 1 for your response.

Weight Loss And Metabolic Effects Of Topiramate In Overweight And Obese Type 2 Diabetic Patients: Randomized Double-Blind Placebo-Controlled Trial
Design	Randomized, double-blind, placebo-controlled N= 38
Objective	To examine the metabolic effects, including glycemic control, insulin sensitivity, postprandial glycemia and lipaemia, as well as body composition changes, after topiramate treatment of obese type 2 diabetic patients (DM2) for 11 months.
Study Groups	Placebo (n= 19) Topiramate (n= 19)
Inclusion Criteria	Non-smoking men aged 35-75 years, postmenopausal women aged 45-75 years, DM2 for at least 6 months before enrollment, controlled diabetes by either diet alone or by a stable dose of a sulfonylurea in the monotherapy for a minimum of 6 months, HbA1c between 6.5-10%, body mass index (BMI) between 27-50 kg/m2, and weight stable
Exclusion Criteria	Not specified
Methods	Eligible patients were randomized either to treatment with topiramate 96 mg PO BID or placebo (6-week run-in phase, 2-months titration phase, 9-month maintenance phase). After the maintenance phase, topiramate was tapered over 2 weeks and subjects were followed up a further 4 weeks off-drug, concluded by a final visit. The patients were instructed to not start a diet or exercise program during the course of the study. HbA1c, fasting plasma glucose (FPG), blood lipid profile, and circulating cytokine levels were measured regularly. Three-day food diaries of the quantity and types of food consumed were also collected. All laboratory measurements were taken after an 8 hour overnight fast and analyzed by an accredited central laboratory.
Duration	May 2000 to May 2002 Screening phase: 6 weeks Double-blind titration phase: 8 weeks Double-blind maintenance phase: 9 months
Outcome Measures	Primary: Change in insulin sensitivity (as measured with the euglycemic hyperinsulinemic clamp) Secondary: Mean change in body weight, body composition, and visceral and subcutaneous abdominal adipose tissue areas.
Baseline Characteristics		Placebo (n= 19)	Topiramate (n= 19)	p-value
	Age, years	60.2 ± 76.6	57.1 ± 7.6	0.2
	Male	11 (57.9%)	14 (73.7%)	0.3
	Weight, kg	95.8 ± 10.9	100.4 ± 20.1	0.4
	BMI, kg/m2	33.7 ± 3.9	32.3 ± 5.0	0.4
	HbA1c, %	7.05 ± 0.71	7.61 ± 1.03	0.06
	Fasting plasma glucose (FPG), mmol/L	8.29 ± 1.51	9.56 ± 2.56	0.07
Results		Placebo (n= 13)	Topiramate (n= 9)	Adjusted p-value for age and gender
	HbA1c, %	Mean: 0.31 ± 0.79 95% CI: -0.17, 0.78	Mean: -1.11 ± 0.91 95% CI: -1.81, -0.41	0.0033
	FPG, mmol/L	Mean: 0.54 ± 0.88 95% CI: 0.01, 1.07	Mean: -1.31 ± 1.12 95% CI: -2.18, -0.45	0.0008
	Fasting insulin, U/mL	Mean: -1.40 ± 7.50 95% CI: -5.92, 3.12	Mean: -0.1 ± 7.6 95% CI: -6.0, 5.71	0.9
	Weight, kg	Mean Change: 0.01 ± 2.54 95% CI Change: -1.5, 1.5	Mean Change: -7.24 ± 4.26 95% CI Change: -10.5, -4.0	0.001
	BMI, kg/m2	Mean Change: 0.045 ± 0.86 95% CI Change: -0.47, 0.56	Mean Change: -2.28 ± 1.30 95% CI Change: -3.28, -1.27	0.001
	SAT, cm2	Mean Change: -5.50 ± 14.5 95% CI Change: -14.3, 3.25	Mean Change: -48.8 ± 27.5 95% CI Change: -70.0, -27.6	0.0012
	VAT, cm2	Mean Change: -3.85 ± 34.6 95% CI Change: -24.8, 17.1	Mean Change: -37.3 ± 28.7 95% CI Change: -59.4, -15.3	0.021
	TAT, cm2	Mean Change: -9.35 ± 42.3 95% CI Change: -34.9, 16.3	Mean Change: -86.1 ± 45.5 95% CI Change: -121.1, -51.1	0.0024
	Abbreviations: BMI= body mass index; CI= confidence interval; SAT= subcutaeneous adbdominal adipose tissue; VAT= visceral abdominal adipose tissue; TAT= total abdominal tissue
Adverse Events	Common Adverse Events: Paresthesia (15 topiramate-treated vs. 4 placebo-treated), headache (6 vs. 4), fatigue (6 vs. 4), dizziness (3 vs. 2), anorexia (3 vs. 0), depression (2 vs. 1), difficulty with concentration/attention (2 vs. 0), insomnia (2 vs. 1), nervousness (2 vs. 0), nausea (3 vs. 1), gastritis (2 vs. 0), dry mouth (2 vs. 0), muscle weakness (2 vs. 0), tooth caries (2 vs. 0).
	Serious Adverse Events: Occured in 3 topiramate-treated patients (atrial fibrillation, pulmonary hamartoma, and malignant breast neoplasm). All three of these were classified by the investigators as not related to the study treatment.
	Percentage that Discontinued due to Adverse Events: Eight patients discontinued due to an adverse event (vs one in placebo-treated).
Study Author Conclusions	Topiramate treatment of overweight DM2 patients results in significant weight reductions and reductions in body fat as well as a marked improvement in glycaemic control. Interestingly, no improvement in peripheral insulin sensitivity was demonstrated, although we cannot exclude such an effect in the liver. Although frequent side effects were associated with topiramate treatment, limiting its use in obese DM2 patients, novel therapeutic possibilities may emerge from additional studies addressing the mechanisms through which it improves glycaemic control.
InpharmD Researcher Critique	This was a small size study conducted in Sweden. The study only included obese DM2 patients with controlled diabetes, limiting the generalizability of study findings to a broader T2DM population.

References:

Eliasson B, Gudbjörnsdottir S, Cederholm J, et al. Weight loss and metabolic effects of topiramate in overweight and obese type 2 diabetic patients: randomized double-blind placebo-controlled trial. Int J Obes (Lond). 2007;31(7):1140-1147. doi: 10.1038/sj.ijo.0803548.