Was it Worth the Weight? - Drug Review on Two New Weight Loss Agents: lorcaserin (Belviq®) and phentermine/topiramate ER (QsymiaTM)

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How to cite this editor-reviewed article (AMA format):
Crawford A, Kreys T-J. Was it Worth the Weight? - Drug Review on Two New Weight Loss Agents: lorcaserin (Belviq®) and phentermine/topiramate ER (QsymiaTM). ment Health Clin 2012;2(6):24. Available at: http://cpnp.org/resource/mhc/2012/12/was-it-worth-weight-drug-review-two-new-weight-loss-agents-lorcaserin-belviqr. Accessed January 31, 2015.

Aaron Crawford, PharmD Candidate 2013

Tiffany-Jade Kreys, PharmD
University of the Incarnate Word
Feik School of Pharmacy

JM is a 45 year old female who presents to your clinic with a past medical history significant for hyperlipidemia, new-onset diabetes, and obesity (BMI: 32). She reports taking weight loss supplements in conjunction with diet and exercise programs with minimal success in the past.  JM states that after a few months of taking the supplement(s) and trying a new exercise and/or diet routine, she returns to her original weight. JM’s primary care provider is wondering if there are any new weight loss agents available to assist her with weight loss.

  Belviq® (lorcaserin) Qsymia™ (phentermine/topiramate ER)
FDA approval date June 27, 2012 July 17, 2012
Indication Patients with a BMI > 30 kg/m2(obese) or BMI >27 kg/m2(overweight) with ≥1 comorbidity related to weight gain (e.g., hypertension, type II diabetes mellitus, and dyslipidemia).4,12
Mechanism of action 5-HT2C selective agonist5 Phentermine: sympathomimetic amine
Topiramate: GABA, glutamate, and voltage-gated ion channel activity13
Drug Scheduling DEA scheduling in progress Schedule IV
Dosing & Administration 10 mg twice a day with or without food
Recommended to discontinue medication if 5% weight loss is not achieved in 12 weeks6
Take once daily in the morning; evening dosing should be avoided to prevent insomnia
Recommended dose titration schedule:
3.75 mg/23 mg/day x 14 days then increase to 7.5 mg/46 mg/day
Reevaluate weight loss after 12 weeks of treatment with 7.5 mg/46 mg; if weight loss ≤ 3%, discontinue or increase dose to 11.25 mg/69 mg for 14 days followed by an additional increase to 15 mg/92 mg.  If > 5% weight loss is not achieved after 12 weeks of treatment with 15 mg/92mg daily dosing, discontinue treatment.13
Percentage of subjects that lost >5% of total body weight Lorcaserin:   37.5-47.5%
Placebo:         16.1-25%9,10,11
7.5 mg/46 mg dose:  62-75.2%
15 mg/92 mg dose:   66.7-79.3%
Placebo:                        17-30%14,15,16
Average amount of weight lost Lorcaserin:   4.7-5.8 kg (10.4-12.8 lbs)
Placebo:         1.6-2.9 kg ( 3.5-6.4 lbs)9,10,11
7.5 mg/46 mg dose:   8.1-9.6 kg (17.9-21.2 lbs)
15 mg/92 mg dose:   10.2-10.9 kg (22.5-24 lbs)
Placebo:                         1.4-2.1 kg (3.1-4.6 lbs) 14,15,16
Most common side effects
(≥5% incidence)
Non-diabetic patients:
Headache, dizziness, fatigue, nausea, dry mouth, constipation
Diabetic patients:
Hypoglycemia, headache, back pain, cough, fatigue6
Insomnia, paraesthesia, dizziness, constipation, dysgeusia, dry mouth13
Warnings /Precautions -Serotonin syndrome
-Neuroleptic malignant syndrome
- Valvular heart disease
- Cognitive impairment
- Psychiatric disorders (e.g., depression, suicidal thoughts)
- Use of anti-diabetic medications
- Priaprism
- Hematological changes
- Prolactin elevation6
- Fetal toxicity
- Nephrolithiasis
- Increased heart rate
- Suicidal behaviors and ideation
- Acute myopia and secondary angle closure glaucoma
- Mood and sleep disorders
- Use of anti-diabetic medications
- Cognitive impairment
- Metabolic acidosis
- Elevated creatinine13
Contraindications - Pregnancy6 - Pregnancy
- Glaucoma
- Hyperthyroidism
- Use during or within 14 days of taking a MAOI13
Drug interactions -Serotonergic drugs (e.g., SSRIs, SNRIs, MAOIs, bupropion, St. John’s Wort, dextromethorphan)
- Lorcaserin is a weak to moderate inhibitor of CYP2D66
- Oral contraceptives
- CNS depressants
- Non-potassium sparing diuretics
- MAOIs13

The prevalence of obesity in the United States (U.S.) is currently at 34%.1 As obesity rates in the U.S. continue to rise, there is a constant search for new or beneficial combinations of approved drugs that can be used to treat obesity and help manage associated comorbidities.  Only a few FDA-approved drugs for weight loss currently exist, including phentermine (Adipex-P®) and orlistat (Alli®, Xenical®). Phentermine, a sympathomimetic agent, was approved in 1968 for short term use only at doses of 37 mg daily and has not been approved for use longer than a year duration.1 Phentermine has been shown in short-term studies of less than one year to produce weight loss up to 12 kg, but this medication carries the risk of addiction.1 Phentermine has not been FDA approved for long-term use due to the risk of developing tolerance to the medication and subsequent loss of efficacy.1 Orlistat, a gastric and pancreatic lipase inhibitor approved in 1998, is currently the only FDA-approved medication for long-term use in obese patients. Xenical®, the brand name of prescription orlistat, is dosed at 120 mg three times a day. Orlistat was approved in 2010 for over-the-counter use, under the brand name Alli®, and is dosed at 60 mg per day.1 In the XENDOS trial, a 4-year randomized, placebo controlled, double-blind trial comparing orlistat to placebo in combination with a reduction in diet of 800 kcal/day and encouragement of an additional kilometer walk to the subject’s regular routine, an average weight loss of 11.4 kg in the orlistat arm compared to 7.5 kg (p<0.001) for the placebo group was achieved after the first year, with a weight loss of 6.9 kg and 4.1 kg measured at the end of year 4 (p<0.001), respectively.2 This study also showed a decrease in the risk of developing diabetes with a 6.2% occurrence for the orlistat group versus 9% for placebo at 4 years, resulting in a 37.3% risk reduction.2 The side effects of orlistat relate to the gastric system and include diarrhea, fecal incontinence, bloating, oily spotting and the rare serious adverse effect of severe liver injury.3 In the past, other medications have been used to treat obesity such as sibutramine (Meridia®) and the combination fenfluramine/phentermine (Fen-Phen®).  Sibutramine was initially approved for weight loss by the FDA in 1997 and then withdrawn from the market in 2010 because of increased cardiovascular risk and strokes.3 The combination of fenfluramine/phentermine has produced significant weight loss compared to placebo of 15.5% and 4.9% from baseline (p<0.001), respectively, but was withdrawn from the market in 1997 due to heart valve malformation and damage as well as increased risk for pulmonary hypertension.3 These adverse effects are thought to originate from fenfluramine because of its non-selective activity at the 5-HT2B receptor.3 Some medications which are not FDA-approved for weight loss but have been shown to cause weight loss include metformin, topiramate, exenatide, and bupropion.1

Belviq® (lorcaserin)

What is the FDA-approved indication of lorcaserin?

Lorcaserin was approved by the FDA on June 27, 2012 as an adjunct to diet and exercise in obese patients with a BMI >30 kg/m2 or in overweight patients with a BMI >27 kg/m2 who also have at least one weight-related comorbidity, such as hypertension, type 2 diabetes mellitus, or dyslipidemia.4

What is the mechanism of action of lorcaserin?

Lorcaserin is a selective agonist at the serotonin 5-HT2C receptor.5 It is hypothesized that activation of the 5-HT2C receptor activates the pro-opiomelanocortin (POMC) neurons in the hypothalamus, which stimulates the release of α-melanocortin stimulating hormone (α-MSH).5 After the release of α-MSH in the hypothalamus, the hormone stimulates the melanocortin-4 receptors (MC4-R) triggering the feeling of satiety and causing weight loss.5

How is lorcaserin dosed and when are dosage adjustments recommended?

Lorcaserin is dosed at 10 mg orally twice daily and should be discontinued if the weight loss achieved is <5% from baseline after twelve weeks, as clinically significant weight loss is unlikely with continued treatment.6 It is advised to use lorcaserin with caution in patients with moderate renal impairment, while the use of lorcaserin in patients with severe renal impairment should be avoided.6 In the elderly population, the use of lorcaserin should be based on the patient’s renal function; increased sensitivity to lorcaserin in this specific patient population is unknown.6 In mild to moderate hepatic impairment, the CMAX was decreased by about 8% and 14% respectively, and the AUC was increased by 22% and 30%; however, these changes were not considered to be significant enough to necessitate a change in dosing.7 The use of lorcaserin in patients with severe hepatic impairment has not been studied.7

Are there any clinically significant drug interactions with lorcaserin?

Lorcaserin is metabolized by multiple cytochrome P450 enzymes and flavin-containing monooxygenase(FMO) enzymes to two inactive metabolites: lorcaserin sulfamate(M1) and N-carbamoyl glucuronide(M5).8 Lorcaserin is a weak to moderate inhibitor of the CYP2D6 enzyme, which may cause an increase in levels of medications that are metabolized by CYP2D6 when administered concomitantly with lorcaserin.7,8 Since lorcaserin affects the serotonin pathway, use of other serotonergic agents with lorcaserin may increase the risk of serotonin syndrome.7

How did lorcaserin perform in clinical trials?

Three trials evaluating the efficacy and safety of lorcaserin have been conducted, including a multicenter, placebo-controlled trial of lorcaserin for weight management (BLOOM), a randomized placebo-controlled clinical trial of lorcaserin for weight loss in type 2 diabetes mellitus (BLOOM-DM) and a one-year randomized trial of lorcaserin for weight loss in obese and overweight adults (BLOSSOM).9,10,11 The BLOOM trial was a 2-year randomized, double blind study (n=3182) of obese (BMI 30-45 kg/m2) or overweight patients (BMI 27-29.9 kg/m2 with at least one coexisting condition) randomized to either placebo or lorcaserin 10 mg BID with diet and exercise counseling.9 Patients were instructed at each monthly visit to decrease caloric intake to 600 kcal below the World Health Organization’s estimation for the patient’s daily energy requirements and to exercise moderately for at least 30 minutes a day, which was consistent with all three studies mentioned.9 The primary end-point of the BLOOM trial for the first year were the number of patients with >5% weight loss, the change in weight from baseline, and the percent of patients with >10% weight loss. For the second year, the primary endpoints were the number of patients with >5% weight loss from year one and the percentage of patients who maintained this loss in body weight.9 Fifty-two weeks into the trial, the lorcaserin arm was randomized in a 2:1 ratio to lorcaserin or placebo for an additional year.9  After the first year, 47% of the patients in the lorcaserin group and 20% of patients in the placebo lost greater than 5% of their total body weight (P<0.001), averaging 5.8 kg and 2.2 kg (p<0.001) respectively.9 About 23% and 8% of the lorcaserin and placebo arms lost ≥10% (p<0.001) from baseline, respectively.9 For the patients that completed the second year of the study, weight loss was maintained in 67% of the patients in the lorcaserin arm versus 50% of the patients in the placebo arm (p<0.001).9 The incidence of cardiac valvulopathy was 2.7% in the lorcaserin arm versus 2.3% in the placebo arm at the end of the first year, with a cumulative risk over the two years of 2.7% compared to 2.6% (p=0.70).9 The incidence of cardiac valvulopathy, which is caused by the activation of the serotonin 5-HT2B receptor leading to enlargement of the heart valves and valvular insufficiency, was not increased with prolonged treatment.9

The BLOOM-DM trial (n=604) evaluated patients for one year with diabetes mellitus and taking either metformin or a sulfonylurea with an HgA1c of 7-10%. The study used the same co-primary endpoints as the BLOOM study.10 Patients were randomized to receive lorcaserin once daily, twice daily, or placebo and showed a decrease in weight of >5% from baseline in 45%, 37%, and 16% respectively (p<0.001).10 It also demonstrated a decrease in HgA1c of 1% with lorcaserin once daily, 0.9% with lorcaserin twice daily, and 0.4% in the placebo arm (p<0.001).10 Additionally, a greater number of subjects in the lorcaserin arm achieved a goal HgA1c of < 7% (p<0.001) for once and twice daily dosing over placebo.10 The incidence of hypoglycemia was higher in the lorcaserin groups than in the placebo group at 7.4% (once daily) and 10.5% (twice daily) versus 6.3% (placebo)but no reports of severe hypoglycemia were observed in the study.10

The BLOSSOM study, a 52-week double-blind, placebo-controlled study with 3 parallel groups (n=4008), including patients with a BMI of 30-45 kg/m2 or 27-29.9 kg/m2 with either hypertension, sleep apnea, hyperlipidemia, impaired glucose tolerance, or cardiovascular disease, was performed to assess the efficacy and safety of lorcaserin at different dose ranges.  The primary endpoints included the percent of patients who obtained >5% weight loss, average weight loss, and percent of patients obtaining >10% weight loss.11 Sample size for the BLOSSOM study was determined based on the BLOOM study and the amount of patients needed to obtain a power of 80% to rule noninferiority in valvulopathy at week 52 for the primary echocardiographic endpoint.11 The BLOSSOM study produced similar results to the BLOOM study, with 40% and 47% of patients experiencing weight loss >5% with lorcaserin once and twice daily dosing, respectively, compared to 25% in the placebo arm (p<0.001).11  In this study, as compared to the BLOOM trial, the lorcaserin twice daily dosing arm achieved statistically significant greater weight loss compared to the once daily dosing arm (p<0.01).11  Weight loss of greater than 10% was achieved in 17.4%, 22.6%, and 9.7% of patients receiving lorcaserin once daily, twice daily, and placebo, respectively (p<0.001).11 The secondary endpoints were grouped into four families: lipids, blood pressure, body composition, and quality of life. Parameters that were found to improve significantly for twice daily dosing compared to placebo were HDL (p<0.001), triglycerides (p=0.02), systolic (p<0.001) and diastolic (p<0.001) blood pressure, total body fat percentage (p=0.018), lean body mass (p=0.02), and quality of life (p<0.001) as measured by the Impact of Weight on Quality Of Life-Lite (IWQOL-LITE) questionnaire.11 The study was unable to achieve the power desired to exclude a relative risk of 1.5 in developing valvulopathy, but was able to detect a significant difference in mitral and aortic regurgitation and pulmonary artery systolic pressure (PASP). A significant difference (p=0.014) was found in the percentage of patients that experienced an increase in mitral or aortic regurgitation between the lorcaserin BID (12.1%) and placebo arm (30.6%).11 Also the mean change in PASP at week 52 from baseline was significantly different between the lorcaserin BID (+0.04 mm Hg) and placebo (-0.4 mm Hg) arm but was not considered clinically significant (p=0.01).11

What adverse effects should I discuss with my patient?

Lorcaserin trials have shown that 8.6% of patients discontinue the medication due to side effects.6 The most commonly occurring adverse effects with lorcaserin compared to placebo resulting in discontinuation included headache (1.3% vs. 0.8%), depression (0.9% vs. 0.5%) and dizziness (0.7% vs. 0.2%).6 For non-diabetic patients, the most common side effects were headache (16.7%), dizziness (8.5%), fatigue (7.2%), nausea (8.3%), dry mouth (5.3%), and constipation (5.8%), while the most common side effects in patients with diabetes included hypoglycemia (29.3%), headache (14.5%), back pain (11.7%), cough (8.2%), and fatigue (7.4%).6,7 Lorcaserin’s approval was delayed by the FDA due to the potential risks associated with the use of lorcaserin outweighing the benefits. Some potential  serious adverse effects associated with lorcaserin use include an increased risk of hypoglycemia in diabetics (7.4%), prolactinemia (up to 6.7%), valvular heart disease (2.4%), psychiatric disorders (2.2%), such as depression and suicidal ideation, cognitive impairment (1.9%), hematological changes (0.4%), a theoretical increased risk of serotonin syndrome or neuroleptic malignant syndrome-like reactions, and priaprism.6 In the studies assessing lorcaserin , medications such as SSRIs, SNRIs, MAOIs, TCAs, and bupropion were excluded while triptans and dextromethorphan were allowed.6 Possible serotonin syndrome symptoms were seen in two patients.6 In pregnancy, the recommendation is for a weight gain versus weight loss for all patients. In animal trials (i.e., rats), births resulted in lower viability and lower birth weight, resulting in lorcaserin being labeled as Pregnancy Category X.6

What place does lorcaserin have in the treatment of overweight and obese patients?

Lorcaserin has shown to be effective in causing weight loss up to 13 lbs, in conjunction with a diet that consists of a decrease in 600 calories and exercise counseling, but it is not without its fair share of side effects. The drug has also been shown to lower cholesterol, blood pressure, and body fat percentage along with lowering HgA1c by up to 1% in diabetic patients in a period of one year. Thus, patients with diabetes may derive additional benefit from lorcaserin, due to its ability to induce weight loss and as well as reduce HgA1c.

Qsymia™ (phentermine/topiramate)

What is the FDA-approved indication of phentermine/topiramate?

Phentermine/topiramate was approved July 17, 2012 and is to be administered in conjunction with a reduced-calorie diet (exact caloric reduction not specified) and exercise for patients with a BMI >30 kg/m2, or a BMI > 27 kg/m with at least one weight-related comorbidity, including hypertension, type II diabetes, or hyperlipidemia.12 This medication was previously known as Qnexa, but the FDA required a name change to avoid confusion with other medications prior to its approval.

What is the mechanism of action of phentermine/topiramate?

Phentermine/topiramate is an oral medication comprised of immediate release phentermine and extended release topiramate, both of which have been on the market individually for several years.12 The exact mechanisms of both medications are currently unknown. Phentermine is hypothesized to mimic sympathomimetic amines, which act in the hypothalamus causing decreased appetite and food intake.13 The proposed mechanism of topiramate in terms of weight loss is its effect on multiple pathways including the activity of gamma-aminobutyrate (GABA), modulation of the voltage-gated ion channels, inhibition of AMPA/kainite excitatory glutamate receptors, and/or inhibition of carbonic anhydrase.13 Topiramate has been shown to have positive effects on appetite suppression and satiety.13

How is phentermine/topiramate dosed and when are dose adjustments recommended?

Phentermine/topiramate is initiated at a dose of 3.75 mg/23 mg of phentermine/topiramate once daily, given during the day to avoid insomnia, and titrated after 14 days to a dose of 7.5 mg/46 mg once daily.13 After 12 weeks at a dose of 7.5 mg/46 mg per day, the patient’s weight should be reassessed, and if the patient has not lost more than 3% of their baseline body weight, phentermine/topiramate should be discontinued or increased to phentermine/topiramate 11.25 mg/69 mg.13 After another 14 days, the dose should be titrated up to a daily dose of 15 mg/92 mg.13 Weight loss should be reevaluated in another 12 weeks to assess outcomes, and if the patient has not lost more than 5% of their baseline body weight then the medication should be discontinued since further benefit from phentermine/topiramate is unlikely to be achieved.13 The doses of phentermine/topiramate 3.75 mg/23 mg and 11.25 mg/69 mg should be used for titrating purposes only.13 When discontinuing phentermine/topiramate 15 mg/92 mg daily, the dose should be taken every other day for at least one week to avoid precipitating seizures; however, no seizures have occurred in clinical trials but have been seen with discontinuation of topiramate alone.13 For patients with moderate to severe renal impairment with a creatinine clearance of <50 ml/min or moderate hepatic impairment with a Child-Pugh score of ≥7, phentermine/topiramate should not exceed a dose of 7.5 mg/46 mg daily.13

Are there any clinically significant drug interactions with phentermine/topiramate?

Several interactions exist for phentermine/topiramate that should be avoided.  Phentermine/topiramate should be avoided within 14 days of the use of MAOIs to reduce the risk of a hypertensive crisis.13 Phentermine/topiramate has also been shown to alter the levels of oral contraceptives by decreasing the estrogen component of the drug by 16% and increasing the progestin component by 22%, which may alter the efficacy of oral contraceptives.13 Please see adverse effects section below for more information regarding pregnancy and the use of phentermine/topiramate.

If the patient consumes alcohol or takes CNS depressants, he/she should be counseled on the increased risk of CNS depression and potential side effects from the interaction with phentermine/topiramate.13 Phentermine/topiramate can interact with non-potassium sparing diuretics, like hydrochlorothiazide and chlorthalidone, by increasing the amount of potassium excreted, resulting in an increased risk of hypokalemia.13 This interaction can possibly result in an increased AUC and CMAX of topiramate by 29% and 27%, respectively.13 The phentermine component of the phentermine/topiramate is metabolized primarily by CYP3A4 enzymes but not extensively. The topiramate portion of the drug is metabolized through multiple enzymes by hydroxylation, hydrolysis and glucuronidation and serves as a mild inhibitor of CYP2C19 and inducer of CYP3A4. Since topiramate goes through this metabolic pathway, the concentration of topiramate can be decreased from 14-48% by phenytoin, carbamazepine, valproic acid, and lamotrigine; topiramate’s effect can increase phenytoin serum levels and decrease the concentration of valproic acid.

How did phentermine/topiramate perform in clinical trials?

Phentermine/topiramate was studied primarily in 3 trials before receiving FDA-approval. The first trial evaluated the effects of low-dose, controlled-release, phentermine plus topiramate combination on weight gain and associated comorbidities in overweight and obese adults (CONQUER). The second trial was a randomized controlled trial that assessed the use of controlled-release phentermine/topiramate in severely obese adults (EQUIP). The third trial focused on weight loss sustained at two years and the metabolic benefits associated with controlled-release phentermine/topiramate in obese and overweight adults(SEQUEL).14, 15, 16

The effects of low-dose, controlled-release, phentermine/topiramate combination on weight gain and associated comorbidities in overweight and obese adults trial (CONQUER) (N=2487) was a 56-week phase 3, randomized 2:1:1 (placebo, phentermine/topiramate 7.5 mg/46 mg, and 15 mg/92 mg) double-blind, placebo controlled, multi-center study including overweight or obese patients with a BMI of 27-45 kg/m2 and two or more comorbidities (hypertension, dyslipidemia, diabetes, prediabetes, or pre-abdominal obesity).14 The co-primary outcomes in the CONQUER trial included the average percent change in body weight from baseline and the percentage of patients with >5% weight loss from baseline at week 56, with significant weight loss defined as a loss >4.4% with intention-to-treat.14  Patients on phentermine/topiramate 7.5 mg/46 mg and 15 mg/96 mg lost an average of 8.1 kg and 10.2 kg, respectively, compared to placebo (1.4kg, p<0.0001).14 About 62% and 37% of patients in the phentermine/topiramate 7.5 mg/46 mg arm, and 70% and 48% in the 15 mg/92 mg, lost greater than 5% and 10% of their body weight, respectively, compared to 21% and 7% of patients in the placebo arm (p<0.0001).14 Besides weight loss, significant differences in favor of secondary outcomes were found for the 15 mg/92 mg arm versus placebo in systolic blood pressure, diastolic blood pressure, HDL, LDL, total cholesterol, triglycerides, fasting glucose, glycosylated hemoglobin, and C-RP (p<0.0001).14 These same significant differences over placebo were also found in the 7.5 mg/46 mg arm except for total cholesterol, LDL cholesterol, and diastolic blood pressure.14

The controlled-release phentermine/topiramate in severely obese adults: a randomized controlled trial (EQUIP) was a 56-week double-blind, parallel group trial (N= 1267) that produced results similar to the CONQUER trial.15 EQUIP included patients aged 18-70 years with a BMI > 35 kg/m2 and had a goal of maximizing the dose and minimizing adverse effects.  Primary outcomes were percent, absolute, and categorical weight loss with significance defined as > 2-3% difference from placebo, with secondary outcomes being multiple metabolic and cardiovascular outcomes.15 The EQUIP trial results in patients with greater than 5% and 10% weight loss were 45% and 19% in the phentermine/topiramate 3.75 mg/23 mg arm (p<0.0001), 67% and 47% in the phentermine/topiramate 15 mg/92 mg arm(p<0.0001), and 17% and 7% for placebo.13,15 Statistical significance occurred for 15 mg/92 mg versus 3.75 mg/23 mg for the number of patients that achieved >5%, >10% and >15% weight loss (p<0.0001).15 The average weight loss for the phentermine/topiramate 7.5 mg/46 mg was 6.8 kg, phentermine/topiramate 15 mg/92 mg was 13.5 kg, and placebo group was 2.4 kg.15 The patients of EQUIP in the intention-to-treat analysis experienced a weight loss of 5.1% for 7.5 mg/46 mg, 10.9% for 15 mg/92 mg, and 1.6% for placebo from baseline body weight (p<0.0001).15 When examining only the patients that completed the study the percent weight loss from baseline was 6.7% for 7.5 mg/46 mg, 14.4% for 15 mg/92 mg, and 2.1% for placebo (p<0.0001).15

The EQUIP and CONQUER trial lasted only one year and the two-year sustained weight loss and metabolic benefits with controlled-release phentermine/topiramate in obese and overweight adults trial (SEQUEL) was a one year extension of the CONQUER trial, designed to evaluate the long-term efficacy of phentermine/topirmate. The SEQUEL trial was a double-blind, placebo controlled trial (N=676) with the same co-primary outcomes as the CONQUER trial. The patients in the three trials assessing phentermine/topiramate were counseled on lifestyle changes based on the LEARN manual and directed to follow a 500 kcal reduction in food intake with increased water intake and exercise. The SEQUEL trial showed that patients had a greater weight loss and maintained the weight loss they achieved with phentermine/topiramate in the first year than placebo at all time points assessed (p<0.0001), though weight loss seemed to have plateaued after the first 52 weeks.16 In this study the dose of phentermine/topiramate 15 mg/96 mg showed significance in weight loss over 7.5 mg/46 mg for severely obese patients with BMIs 40-45 (p=0.0016).16 The patients of the SEQUEL arms were all representative of the CONQUER study except an increased number of diabetic patients comprised the SEQUEL trial (21.5% versus 15.8%).16 In the SEQUEL trial the rate of adverse events were less in the second year at 2.6%, 4.1%, 4%, for 7.5 mg/46 mg, 15 mg/92 mg, and placebo, respectively, compared to the end of the first year at 5.9% and 8.1%, 6.2%.16  At the end of the second year, the rate of diabetes was decreased versus placebo by 54% in the 7.5 mg/46 mg arm (p=0.1514) and by 76% in the 15 mg/92 mg arm (p=0.0078).16

What adverse effects should I discuss with my patient?

Phentermine/topiramate has been studied across three different trials, including the CONQUER, EQUIP, and SEQUEL trial.  In the CONQUER trial, the patients were split into placebo, 7.5 mg/46 mg, and 15 mg/92 mg. Discontinuations from adverse effects due to the increased dose of the medication was the highest in the 7.5 mg/46 mg (12%) arm and 15 mg/92 mg (19%) arm compared to the placebo (9%), with most treatment discontinuations being secondary to insomnia.13,14 The three trials showed the overall adverse events approximately doubled when increased to the 15 mg/92 mg dose, but in clinical practice the dose can be tapered down to minimize adverse effects.14 The most common adverse effects for the phentermine/topiramate 7.5mg/46mg and 15mg/92mg were paresthesisa (13.7%, 20%), dizziness (7.2%, 8.6%), dysgeusia (7.4%, 9.4%), insomnia (5.8%, 9.4%), constipation (15.1%, 16.1%), and dry mouth (13.5%, 19.1%).13 A decrease in serum bicarbonate below the normal range of 22 mEq/L occurred in 12.8% of the patients in the phentermine/topiramate 15mg/92mg arm.13 Across all three trials, phentermine/topiramate was associated with a greater number of patients experiencing heart rate increases, ranging from 5 to 20 beats per minute, compared to placebo.13

Phentermine/topiramate is contraindicated in pregnancy, glaucoma, hyperthyroidism, use within 14 days of a MAOI, and in patients with hypersensitivity to sympathomimetic amines.13 Since phentermine/topiramate is teratogenic and labeled as Pregnancy Category X, the drug is only available through a Risk Evaluation and Mitigation Strategy (REMS) program, in which the physician is required to register if planning to dispense the medication.13 Patients with reproductive potential should have a pregnancy test performed before the start of therapy and monthly thereafter to ensure pregnancy doesn’t occur. If pregnancy does occur, phentermine/topiramate should be discontinued immediately due to the risk of cleft palate associated with its use during the first trimester of pregnancy. Phentermine/topiramate has also been associated with low infant birth weights.13 Patients should be counseled on proper contraceptive methods (e.g., intrauterine device/system, a progestin implant, a combination of hormonal contraception along with a barrier method, or two different barrier methods) to ensure pregnancy does not occur.13 Topiramate has been known to increase the risk of depression and suicidal thoughts and should be avoided in high risk populations, such as patients with a history of suicide attempts and active suicidal ideation.13 When taking the medication, abrupt discontinuation should be avoided to minimize the risk of seizures secondary to topiramate discontinuation.13

What place does phentermine/topiramate have in the treatment of overweight and obesity patients?

Similar to lorcaserin, phentermine/topiramate has produced a significant amount of weight loss in overweight and obese patients, in conjunction with diet and exercise. Unlike lorcaserin, the dose of phentermine/topiramate can be adjusted based on efficacy and tolerability.  Phentermine/topiramate also has been shown to decrease the incidence of diabetes, LDL, HDL, blood pressure, and HgA1C.

Revisiting Our Patient

JM should be reassessed on her dieting practices and exercise routine, as these medications have only been studied and shown to produce a significant amount of weight loss when used concurrently with a diet and exercise program. Additionally, the potential for drug interactions associated with the use of orlistat, lorcaserin, or phentermine/topiramate should be assessed. Of the FDA-approved medications, the agent producing the greatest amount of weight loss compared to placebo was the 15 mg/92 mg dose of phentermine/topiramate; however, the discontinuation rate of phentermine/topiramate due to adverse effects was almost double that of placebo (13% versus 7%, respectively). However, when assessed at week 108, discontinuation rates were similar (4.4% versus 3.1%, respectively).13 The discontinuation rate due to adverse events for lorcaserin was up to 7.2% versus 4.6% in the placebo arm.9,11 Before initiating any of these medications, the patient should be educated on potential side effects. It should be noted that these subjects were on a fixed-dose regimen of phentermine/topirmate in the clinical trials and adverse effects may be lower in real treatment settings because of the ability to decrease the dose. When phentermine/topiramate and lorcaserin are compared directly, the 15 mg/92 mg dose of phentermine/topiramate and lorcaserin 10 mg BID both demonstrated statistical significant decreases in many characteristics that can lead to cardiovascular disease (i.e ., high blood pressure, elevated lipids, HgA1c). Both of the medications discussed have been proven efficacious and approved for long-term use for at least two years. In our patient JM, she would likely derive the most benefit from phentermine/topiramate because of a greater likelihood of losing weight than lorcaserin at both dose ranges. Also, phentermine/topiramate can be dosed once daily compared to lorcaserin which requires twice daily. In addition, JM is less likely to experience hypoglycemic episodes with phentermine/topiramate than lorcaserin, and may even be able to eventually decrease her anti-diabetic medication use.


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