Obesity Management: Clinical Review and Update of the Pharmacologic Treatment Options

The most common AEs noted were headache, nausea, and dizziness. Echocardiographic evidence of valvulopathy occurred in 2% of patients taking lorcaserin 10 mg twice daily and those taking the placebo. Lorcaserin administered in conjunction with a diet and exercise program was associated with an overall reduction in baseline BMI when compared with placebo over the year.

The BLOOM-DM study evaluated efficacy and safety of lorcaserin for weight loss in 604 patients with T2DM over the course of 1 year.²⁹ Patients had a hemoglobin A_1c (A_1c) of 7% to 10% and were treated with metformin, a sulfonylurea, or both. The primary endpoint was a 5% weight reduction from baseline at the end of 1 year. Patients were randomized into 3 groups: 1 group received lorcaserin 10 mg twice daily, 1 group took lorcaserin 10 mg daily, and 1 group received the placebo. A statistically significant 37.5% of patients taking lorcaserin 10 mg twice daily achieved > 5% body weight reduction, compared with 44.7% in the lorcaserin 10 mg daily group, and 16.1% in the placebo group. Overall reductions in A_1c and fasting glucose were observed in both lorcaserin groups taking as compared with placebo. Patient A_1c decreased 0.9 ± 0.06 with lorcaserin 10 mg bid, 1.0 ± 0.09 with lorcaserin 10 mg qd, and 0.4 ± 0.06 with the placebo (P < .001). Fasting glucose in the lorcaserin bid, lorcaserin qd, and placebo groups decreased 27.4 ± 2.5 mg/dL, 28.4 ± 3.8 mg/dL, and 11.9 ± 2.5 mg/dL, respectively (P < .001). Symptomatic hypoglycemia occurred in 7.4% of patients on lorcaserin bid, 10.5% on lorcaserin qd, and 6.3% on placebo. Headache, back pain, nasopharyngitis, and nausea were among the most commonly reported AEs.

As lorcaserin is a serotonergic agonist, potential interactions exist when used with other medications affecting serotonin. Most notably, serotonin syndrome and neuroleptic malignant syndrome-like reactions may occur. Because of this, it is recommended to avoid selective serotonin re-uptake inhibitors (SSRIs), selective norepinephrine reuptake inhibitors, tricyclic antidepressants, bupropion, triptans, monoamine oxidase inhibitors, lithium, dextromethorphan, and dopamine agonists. Lorcaserin seems to be safe in those patient populations with mild hepatic as well as mild renal impairment; however, it is not recommended for those with severe renal impairment. Given the multiple enzymatic pathways used to metabolize lorcaserin, there is a low probability for cytochrome drug interactions. Safety has not been well evaluated in patients aged < 18 years and those that are pregnant (pregnancy category X).

Adverse events include headache, dizziness, fatigue, nausea, and dry mouth. Other notable AEs include nasopharyngitis and URI. Hypoglycemia appeared to be more common in patients with DM taking lorcaserin. Cognitive impairment and psychiatric disorders including euphoria and hallucinations were also reported. Notably, valvular heart disease has been reported in patients who take medications with 5HT2b activity. In a 1-year clinical trial, a small number of patients were found to develop valvular regurgitation. Furthermore, bradycardia, priapism, leucopenia, elevated prolactin, and pulmonary hypertension have also been observed. Caution is recommended if symptoms of any of the aforementioned conditions are noticed.

Qsymia

The schedule IV controlled substance Qsymia (Vivus, Mountain View, CA) is a combination of phentermine, an anorexigenic agent, and topiramate extended-release, an antiepileptic drug. In July of 2012 it was approved for chronic weight management as an addition to a reduced-calorie diet and exercise. The drug is approved for adults with a BMI ≥ 30 kg/m² or adults with a BMI ≥ 27 kg/m² who have at least 1 weight-related condition such as hypertension, T2DM, or dyslipidemia.³⁰

In 1996 topiramate was approved by the FDA for the treatment of seizure disorders and was also approved for migraine prophylaxis in 2004. In patients who were treated with topiramate for seizure disorders and migraines, weight loss and a reduction in visceral body fat has been observed.³¹ The precise MOA of topiramate in regards to weight loss is not fully understood. It may be due to its effects on both appetite suppression and satiety enhancement. Topiramate exhibits a combination of properties including modulatory effects on sodium channels, enhancement of GABA-activated chloride channels, inhibition of excitatory neurotransmission through actions on kainite and AMPA receptors, and inhibition of carbonic anhydrase (CA) isoenzymes in particular CA II and IV.¹⁴

The combination of phentermine and topiramate is a once-daily formulation that is designed to provide an immediate release of phentermine and a delayed release of topiramate, allowing a peak exposure of the phentermine in the morning and a peak concentration of topiramate in the evening. It should be taken in the morning in order to avoid the possibility of insomnia that can occur if taken in the evening. It can be taken with or without food. The recommended dose is as follows: Start treatment with Qsymia 3.75 mg/23 mg extended-release daily for 14 days; after 14 days increase to the recommended dose of Qsymia 7.5 mg/46 mg once daily.

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Weight loss should be evaluated after 12 weeks at the higher dose. If at least 3% of baseline body weight has not been lost at that time, discontinue or escalate the dose. To escalate the dose: Increase to Qsymia 11.25 mg/69 mg daily for 14 days; followed by Qsymia 15 mg/92 mg daily. Evaluate weight loss following dose escalation to Qsymia 15 mg/92 mg after an additional 12 weeks of treatment. If at least 5% of baseline body weight has not been lost on Qsymia 15 mg/92 mg, discontinue as directed. It is important not to suddenly discontinue, as this may cause seizures. Patients should be slowly titrated off the medication.

In vitro studies of phentermine and topiramate indicate that these drugs are not likely to cause clinically significant interactions with drugs using the cytochrome P450 enzyme pathways, or those involved in plasma protein binding displacement; however there is evidence suggesting that ethinyl estradiol levels may be decreased by 16%, thus raising a concern about the possibility of decreased contraceptive efficacy.³¹ In patients with moderate (creatine clearance ≥ 30 mL/min to < 50 mL/min) and severe renal dysfunction (< 30 mL/min), the maximum dose of should not exceed 7.5 mg/46 mg.

Qsymia was evaluated in 3 phase 3 trials for its long-term efficacy and safety. In all trials, diet and lifestyle counseling were provided for all patients. The first of these studies was OB-301, a 28-week confirmatory trial with a factorial design involving 7 treatment arms, tested 2 fixed-dose Qsymia combinations—regular dose (7.5 mg/46 mg) and maximum dose (15 mg/92 mg)—as well as regular and maximum doses of the individual constituent drugs vs placebo.³² The study randomized 756 obese patients with a BMI range of 30 kg/m² to 45 kg/m² to 1 of the 7 treatment arms for 28 weeks. Patients treated with maximum-dose Qsymia achieved an average weight change of -9.0%, vs -1.5% with placebo (P < .0001). Weight change with regular-dose Qsymia was -8.2%. Weight changes with monotherapies were: -6.1% with topiramate 92 mg, -4.9% with topiramate 46 mg, -5.8% with phentermine 15 mg, and -5.2% with phentermine 7.5 mg.

OB-302 was a 56-week trial that randomized 1,267 morbidly obese patients with a BMI ≥ 35 kg/m² without significant comorbidities to low-dose Qsymia (3.7 mg/23 mg), maximum-dose Qsymia (15 mg/92 mg), or placebo.33 At baseline, the mean BMI for the entire study cohort was 42 kg/m². Mean weight changes were -1.6% with placebo, -5.1% with low-dose Qsymia, and -10.9% with maximum-dose Qsymia. The proportions of patients achieving ≥ 5% weight loss were: 17% with placebo, 45% with low-dose Qsymia, and 67% with maximum-dose Qsymia.

CONQUER was the largest of the phase 3 trials. It randomized 2,487 overweight or obese patients with a BMI of 27 kg/m² to 45 kg/m² and ≥ 2 obesity-related comorbidities (hypertension, dyslipidemia, T2DM, prediabetes or abdominal obesity) to receive a placebo, regular-dose Qsymia, or maximum-dose Qsymia for 56 weeks.34 In the completer population, mean weight changes in the placebo, regular dose Qsymia, and maximum-dose Qsymia groups were -1.6%, -9.6% (P <.0001), and -12.4% (P < .0001); and weight loss of ≥ 5% was achieved by 21%, 62%, and 70%, respectively. Relative to placebo, there were greater reductions in systolic BP, triglycerides, and fasting insulin with both doses of Qsymia.

Patients should not take Qsymia if they are pregnant, planning to become pregnant, or become pregnant during Qsymia treatment as there is an increased risk of birth defects, namely cleft lip and cleft palate. Women who can become pregnant should have a negative pregnancy test before taking Qsymia and every month while on the medication. They should use effective birth control consistently while taking Qsymia.

Qsymia is contraindicated in patients with glaucoma and patients who have hyperthyroidism. Qsymia can cause an increase in resting heart rate and regular monitoring of resting heart rate is recommended, especially in patients with cardiac or cerebrovascular disease. It has not been studied in patients with recent or unstable cardiac or cerebrovascular disease and therefore use is not recommended.

Qsymia can cause mood disorders such as anxiety and depression and can increase the risk of suicidal thoughts. Patients should be monitored for worsening depression, suicidal thoughts or behavior, or any unusual changes in mood or behavior. It is not recommended in patients with a history of suicidal attempts or active suicidal ideation. Qsymia can cause cognitive dysfunction. It can cause confusion, problems with concentration, attention, memory, or speech. Patients should be cautioned about operating automobiles and hazardous machinery.

Normal anion gap hyperchloremic metabolic acidosis has been reported in patients treated with Qsymia. If this does develop and persists, consideration should be given to either reduce the dose or discontinue Qsymia.