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

Weight loss may increase the risk of hypoglycemia in patients with T2DM treated with insulin and/or insulin secretagogues (eg, sulfonylureas). Qsymia has not been studied in combination with insulin. A reduction in the dose of antidiabetic medications, which are nonglucose dependent, should be considered to reduce the risk of hypoglycemia.

The most common AEs in controlled clinical studies (≥ 5% and at least 1.5 times placebo) included paraesthesia in the hands, arms, feet or face, dizziness, dysgeusia, insomnia, constipation, and dry mouth.

Contrave

In 2014, the FDA approved Contrave (Takeda, Deerfield, IL) as treatment option for chronic weight management in addition to reduced-calorie diet and physical activity. The combination of naltrexone hydrochloride and bupropion hydrochloride was originally introduced for the treatment of opioid addiction and later expanded to include the treatment of alcoholism. The antidepressant bupropion was approved in the U.S. in 1989. It is structurally different from all other marketed antidepressants (ie, tricyclics, tetracyclics, and SSRIs), but closely resembles the structure of diethylpropion, an appetite depressant with minimal CNS effects.³⁵

This drug is approved for adults with BMI ≥ 30 kg/m² and for adults with BMI ≥ 27 kg/m2 with at least 1 weight-related risk factors such as hypertension, T2DM, or dyslipidemia. It should be used as an adjunct to diet and exercise and is not approved for use for depression even though it contains bupropion.

Naltrexone is a pure opioid antagonist with high affinity to μ-opioid receptor, which is implicated in eating behavior. Naltrexone is rapidly and nearly completely absorbed from the GI tract after oral administration. The time to peak plasma concentration is about 1 hour. Naltrexone is well absorbed but first pass extraction and metabolism by the liver decreases oral bioavailability to between 5% to 40%. Primary elimination of naltrexone and its metabolites is renal excretion.

Bupropion is a weak inhibitor of neuronal reuptake of dopamine and norepinephrine. This drug is used to treat depression and seasonal affective disorder, and aid in smoking cessation. Bupropion is absorbed rapidly after oral administration, but the absolute oral bioavailability of bupropion is not known because an IV preparation is not available. The time to peak plasma concentrations of bupropion is within 2 hours of oral administration. Bupropion is extensively metabolized by the liver to multiple metabolites. Primary elimination of bupropion is urinary excretion. However, hepatic and renal impairment may affect the elimination of bupropion and its metabolites. Patients with hepatic or renal impairment should use a reduced dosage.

Combination therapy has been found to have complementary actions on CNS to reduce food intake. They are believed to dampen CNS reward pathways, taking away the compulsive feeding behavior and pleasure of feeding, ultimately leading to weight loss. Bupropion stimulates hypothalamic pro-opiomelanocortin neurons (POMC), which results in reduced food intake and increased energy expenditure. Naltrexone blocks opioid-receptor mediated POMC auto-inhibition, blocks the increase in dopamine in nucleus accumbens that occurs when eating, and acting synergistically with bupropion in augmenting POMC firing.

The COR-I and COR-II trials compared Contrave to diet and exercise in patients who did not have DM. The COR-Diabetes trial included the same study design but focused on patients with DM. In all the studies the participants had a 4-week titration to Contrave (naltrexone 8 mg/bupropion 90 mg) to decrease nausea. The first week dosing was 1 tablet in the morning. Week 2 was 1 tablet in morning and 1 tablet in the evening. In week 3, patients took 2 tablets in the morning and 1 tablet in the evening. The final titration step was 2 tablets in the morning and 2 tablets in the evening.

The COR-1 study was a 56-week randomized, double-blind, placebo-controlled study. It compared Contrave 32 mg naltrexone/360 mg bupropion (NB32/360) with an active placebo of diet and exercise.³⁶ To be included adults must be aged 18 to 65 years with a BMI 30 kg/m² to 45 kg/m² or a BMI 27 kg/m² to 45 kg/m² with dyslipidemia or hypertension. Patients were instructed on a hypocaloric diet that was a 500 kcal per day deficit based on World Health Organization algorithm for calculating metabolic rate and they were urged to increase physical activity.

The completer population results showed 8.0% weight loss in the NB32/360 group and 1.9% weight loss in the placebo group (P < .001). For the NB32/360 and placebo groups, weight loss of ≥ 5% was achieved by 48% and 16% (P <.001), respectively; and weight loss of ≥ 10% by 25% and 7% (P < .001), respectively. The most common AE was nausea—29.8% with NB32/360 vs 5.3% with placebo. Nausea generally occurred early and then diminished and the discontinuation rate from nausea was significantly lower (6.3%) then the overall reported nausea rates.

Contrave was also studied in patients with T2DM. The COR-Diabetes Trial was a 56-week randomized, double blind, placebo-controlled study. The trial compared Contrave 32 mg naltrexone/360 mg bupropion (NB32/360) with an active placebo of diet and exercise.³⁷ Inclusion criteria for the trial were patients aged 18 to 70 years with T2DM and a BMI from 27 kg/m² to 45 kg/m², A_1c between 7% and 10%, and fasting blood glucose < 270 mg/dL. Participants either were not taking a DM medication or were on stable doses of oral antidiabetes drugs ≥ 3 months prior to randomization. Patients were placed on a 500 kcal hypocaloric diet and advised to increase physical activity.

The results showed 5.0% weight loss in the NB32/360 group and 1.8% weight loss in the placebo group (P < .001). Weight loss of ≥ 5% and ≥ 10% was achieved by 44.5% and 18.5% of the NB32/360 group, respectively, and 18.9% and 5.7%, respectively (P < .001) of the placebo group. The NB32/360 and placebo showed a reduction of A_1c of 0.6% and 0.1% respectively (P < .001). The most common AE was nausea (42.3% with NB32/360 vs 7.1% with placebo). Nausea generally occurred early and then diminished and the discontinuation rate from nausea was significantly lower (9.6%) then the overall reported nausea rates.³⁷

Due to potential nausea caused by naltrexone, Contrave should be titrated over 4 weeks as described earlier. At maintenance dose, patients should be evaluated after 12 weeks to determine treatment benefits. If a patient has not lost at least 5% of baseline body weight, Contrave should be discontinued, because it would be unlikely that the patient will achieve and sustain clinically meaningful weight loss with continued treatment. Contrave should not be taken with high-fat meals that may result in significant increase in bupropion and naltrexone systemic exposure.

Since Contrave contains the antidepressant bupropion, it has a boxed warning similar to other antidepressants in its class of increased risk of suicidal thoughts and behaviors, especially in children, adolescents, and young adults.³⁸Contrave can lower the seizure threshold; therefore it should not be used in people with a seizure disorder. It can also raise BP and heart rate; however the clinical significance of hypertension and elevated heart rate observed with Contrave treatment is unclear. Blood pressure rose on average by 1 point during the first 8 weeks of treatment and then returned to baseline.³⁸ The heart rate also increased by about 1.7 beats per minute.³⁸ Patients with uncontrolled hypertension should avoid Contrave.

Contrave should not be taken with products contain bupropion or naltrexone. It should not be taken by patient who are regularly taking opioids or who are opioid dependent, or who are experiencing opiate withdrawal. Pregnant women should also avoid Contrave. In patients with renal impairment the maximum dose is 1 tablet twice a day and in patients with hepatic impairment the maximum dose is 1 tablet a day.

Liraglutide

Liraglutide is the newest weight loss medication to be approved by the FDA for chronic weight management as an adjunct to a reduced calorie diet and increased physical activity in adult patients with BMI ≥ 30 kg/m² or ≥ 27 kg/m² with hypertension, diabetes, or dyslipidemia. The recommended dose of liraglutide is 3 mg daily. The initial dose is 0.6 mg daily for the first week, then titrated up by 0.6 each week for 4 weeks, until reaching 3 mg daily.

Liraglutide is an acylated human glucagon-like peptide-1 (GLP-1) receptor agonist, which are expressed in the brain and is involved in the control of appetite. It is also found in the beta cells of the pancreas, where GLP-1 receptors stimulate insulin release in response to elevated blood glucose concentrations and suppress glucagon secretion. Endogenous GLP-1 has a half-life of 1.5 to 2 minutes due to degradation by the DDP-4 enzyme, but liraglutide is stable against degradation by peptidases and has a half- life of 13 hours.

Liraglutide was studied in a 56-week randomized, double-blind, placebo-controlled trial, which compared liraglutide 3 mg with an active placebo of diet and physical activity.³⁹ Inclusion criteria were adults aged ≥ 18 years old with a BMI 30 kg/m² to 45 kg/m² or BMI 27 kg/m² to 45 kg/m² with dyslipidemia and/or hypertension. Both groups received lifestyle modification counseling. Patients were excluded if they had DM.

In the trial, 3,731 participants enrolled, 2,487 in the liraglutide group and 1,244 in the placebo group; 78.7% of the participants were female and the average age was 45 years. Subjects in the liraglutide group had a weekly titration regimen. The starting dose at week 1 was 0.6 mg, week 2 was 1.2 mg, week 3 was 1.8 mg, week 4 was 2.4 mg, and week 5 was 3.0 kg.