Orlistat is a gastrointestinal lipase inhibitor that reduces the absorption of dietary fat. The recommended dose is 120 mg three times daily before meals. A lower dose (60 mg) is available as an over-the-counter preparation in the United States. One- and 2-year studies evaluating orlistat treatment for obesity have shown significant improvements in glycemic control and in blood pressure and lipid profiles [16]. In a large 4-year prospective study of 3,305 participants with BMI of ≥30 kg/m² and normal or impaired glucose tolerance (the Xenical in the Prevention of Diabetes in Obese subjects study), the orlistat-treated group exhibited significant mean weight loss (5.8 kg vs. 3.0 kg in the placebo group; P<0.001) and reduced progression to type 2 diabetes (risk reduction of 37.3% in the orlistat group; P=0.0032) [17]. A Korean study in which patients were administered orlistat for 24 weeks reported a modest but significant mean weight loss of -2.73 kg (mean weight change, -3.50%±0.38%) and significant improvements in lipid profiles, fasting insulin, waist circumference, blood pressure, fasting plasma glucose (-10.41±4.62 mg/dL), and glycosylated hemoglobin (HbA1c, -0.87%) [18].

The most common adverse effects of orlistat include flatus with discharge and oily spotting or fecal urgency, and the drug interferes with the absorption of fat soluble vitamins, although not tremendously [17,19]. Thus, subjects receiving orlistat are instructed to take vitamin supplements.

Lorcaserin is a selective serotonin 2C (5-HT2C) receptor agonist that suppresses appetite via stimulation of melanocortin receptor 4. The drug has low affinity for the 5-HT2B receptor, which is associated with the development of valvular heart disease and the cause of the withdrawal of agents such as dexfenfluramine [20].

In 2012, the FDA approved lorcaserin 10 mg twice daily based on the findings of the pivotal randomized, placebo-controlled trials: Behavioral Modification and Lorcaserin for Overweight and Obesity Management (BLOOM), Behavioral Modification and Lorcaserin Second Study for Obesity Management (BLOSSOM), and BLOOM-diabetes mellitus (BLOOM-DM) [21,22,23]. The BLOOM and BLOSSOM trials investigated the effect of lorcaserin on overweight or obese nondiabetic patients and found a ~3% placebo-corrected weight change in the group treated with lorcaserin (20 mg/day) (BLOOM, -3.6%; BLOSSOM, -2.9%; both P<0.05). Moreover, a significantly higher proportion of patients in the lorcaserin group lost ≥5% of their baseline body weight compared with the placebo group (approximately 47% vs. 20%, respectively in the BLOOM; 47% vs. 25%, respectively in the BLOSSOM trials). Furthermore, improvements in fasting glucose and triglyceride levels and blood pressure were observed in the lorcaserin groups.

The BLOOM-DM study included 604 overweight and obese patients with type 2 diabetes who were treated with metformin and/or sulfonylurea and randomized to lorcaserin 10 or 20 mg/day or placebo groups for 52 weeks [23]. Consistent with the results of the BLOOM and BLOSSOM trials, the lorcaserin-treated groups achieved weight losses of -3.4% (10 mg) and -3.1% (20 mg). A significantly higher proportion of patients in the lorcaserin groups lost ≥5% of their initial body weight (10 mg, 44.7%; 20 mg, 37.5%) compared with patients administered placebo (16.1%). The reduction in mean HbA1c was significantly greater in the lorcaserin-treated groups than in the placebo group (10 mg, -1.0% change from baseline; 20 mg, -0.9% change; and placebo, -0.4% change; P<0.001). A significantly higher proportion of patients in the lorcaserin groups achieved HbA1c ≤7% compared with patients treated with placebo (10 mg, 52.2%; 20 mg, 50.4%; and placebo, 26.3%). However, symptomatic hypoglycemia was more frequent in the lorcaserin groups (10 mg, 10.5%; 20 mg, 7.4%) than in the placebo group (6.3%).

The adverse events associated with lorcaserin include headache, dizziness, fatigue, nausea, dry-mouth, and constipation. No statistically significant difference in the occurrence of FDA-defined valvular disease was found between the lorcaserin and placebo groups. However, the postmarketing trials were required to evaluate the long-term cardiovascular effects of lorcaserin.

Phentermine/Topiramate (PT) extended-release (ER) is a combination of the FDA-approved medications phentermine and topiramate in an ER formulation. Phentermine is indicated for short-term weight loss in overweight or obese adults who exercise and eat a reduced calorie diet. Topiramate is indicated for the treatment of certain types of seizures in people who have epilepsy and to prevent migraine headaches. The weight loss effect of phentermine is mediated by catecholamine release in the hypothalamus. The exact mechanism underlying the weight loss action of topiramate is not known; however, it may be associated with a combination of features such as an effect on sodium channels, enhancement of GABA-activated chloride channels, and inhibition of carbonic anhydrase isoenzymes [24]. The recommended daily dose of PT is 7.5 mg phentermine/46 mg topiramate ER. PT is available at a higher dose (15 mg phentermine/92 mg topiramate ER) for select patients. Discontinuation or an increase in dosage is recommended for patients who have not lost 3% of their baseline weight. Treatment should be discontinued if a weight loss >5% of baseline is not achieved with 15/92 mg per day.

FDA approval of PT was based on three phase III clinical trials performed to evaluate the efficacy of the drug (EQUIP, CONQUER, SEQUEL) [25,26,27]. In the EQUIP trial, 1,276 obese adults without diabetes were assigned randomly to a low- (3.75/23 mg/day) or high- (15/92 mg/day) dose PT or placebo group for 56 weeks. At the conclusion of the study, the patients in the low- and high-dose PT and placebo groups lost 5.1%, 10.9%, and 1.6% of their baseline body weight, respectively (P<0.0001). Moreover, the results revealed improvements in waist circumference, triglyceride levels, and blood pressure.

The CONQUER trial included 2,487 overweight and obese patients with two or more weight-related comorbidities such as hypertension, prediabetes, type 2 diabetes, dyslipidemia, and abdominal adiposity. The participants were assigned to PT (7.5/46 or 15/92 mg) or placebo groups for 56 weeks. At the conclusion of the trial, the subjects in the 7.5/46 mg group achieved a -8.1kg change in body weight (mean change -7.8%), those in the 15/92 mg group a -10.2 kg change (mean change -9.8%), and those in the placebo group a -1.4 kg change (mean change -1.2%). A higher percentage of subjects in the PT groups achieved a ≥5% weight loss after 1 year compared with those receiving placebo (62%, 70%, and 21% in the 7.5/46, 15/92 mg, and placebo groups, respectively; P<0.001 for both groups vs. placebo). Moreover, weight loss was maintained for a second year in the SEQUEL trial, a 52-week extension of the CONQUER trial. The CONQUER trial revealed an overall significant improvement in HbA1c (% change from baseline: 0%, -0.1%, and 0.1% in the 7.5/46, 15/92 mg, and placebo groups, respectively; P<0.0001 for both groups vs. placebo) and in fasting glucose levels (% change from baseline: -0.01%, -0.07%, and 0.13% in the 7.5/46, 15/92 mg, and placebo groups, respectively; P=0.0047 for 7.5/46 mg vs. placebo and P<0.0001 for 15/92 mg vs. placebo) at week 56. The progression to type 2 diabetes among participants without diabetes was lower in the PT-treated patients (2.8% in the 7.5/46 mg and 1.7% in the 15/92 mg) compared with those receiving the placebo (3.6%). The relative risk of type 2 diabetes versus placebo was 0.78 (95% confidence interval [CI], 0.40 to 1.50) for the 7.5/46 mg and 0.47 (95% CI, 0.25 to 0.88) for the 15/92 mg doses of PT.

An improvement in glycemic control was observed in the SEQUEL trial. At the conclusion of the trial (108 weeks), fasting glucose levels were significantly reduced from baseline in the 15/92 mg dose group (the least-squared change in fasting glucose was 0.1 in the 7.5/46 mg, -1.2 in the 15/92 mg, and 3.7 in the placebo groups; P=0.0048 for 15/92 mg vs. placebo).

In the participants without type 2 diabetes at baseline, the progression of type 2 diabetes decreased during the 1-year extension. The annualized incidence rates for progression to type 2 diabetes were 0.9%, 1.7%, and 3.7% in the 7.5/46, 15/92 mg, and placebo groups, respectively, among the study participants without diabetes at baseline. These results revealed a 54% reduction in the progression to type 2 diabetes in the low- (7.5/46 mg) and a 76% reduction in the high-dose (15/92 mg) groups compared with the placebo group [28]. Among participants with type 2 diabetes at baseline, HbA1c did not change markedly from baseline in the placebo group (0%), whereas treatment with 7.5/46 and 15/92 mg PT led to 0.4% and 0.2% reductions in HbA1c, respectively. However, the results of the SEQUEL trial should be interpreted with caution because, as an extension of the CONQUER trial, it may be subject to selection bias.

Common drug-related side effects include paresthesias, nausea, dizziness, constipation, and dry mouth. The reported neuropsychiatric adverse events include depression, anxiety, insomnia, and disturbances in attention. PT is contraindicated in pregnancy because of concerns about the teratogenicity of topiramate. Furthermore, PT may increase heart rate by two beats per minute; however, the FDA judged that the potential risk posed by an elevated heartbeat was outweighed by improvements in cardiovascular risk factors such as blood pressure [29].

In September 2014, the FDA approved Naltrexone/bupropion (NB) sustained-release (SR) tablets as a treatment option for chronic weight management. Naltrexone was approved previously to treat alcohol and opioid dependence, and bupropion was approved for the treatment of depression or as an aid for smoking cessation. Naltrexone is an opioid receptor antagonist, and bupropion acts on adrenergic and dopaminergic receptors in the hypothalamus. Bupropion reduces energy intake and increases expenditure through neuronal effects. The combining of bupropion and naltrexone was based on the theory that naltrexone may block the compensatory mechanisms associated with bupropion that prevent sustained weight loss.

The efficacy of NB was evaluated by the Contrave Obesity Research (COR) program consisting of the COR-I, COR-II, COR trial with intensive behavior modification (COR-BMOD), and COR-Diabetes trials (Table 1) [30,31,32,33]. The COR-I, COR-II, and COR-BMOD trials evaluated overweight/obese patients without diabetes. Following treatment for 1 year, the group receiving naltrexone 32 mg/bupropion 360 mg lost 4 to 5 kg (approximately -4% weight loss from baseline body weight) more than the placebo group, and 48% to 66% of the patients in the NB group lost ≥5% of their baseline body weight.

The COR-Diabetes trial evaluated the safety and efficacy of NB in 505 overweight or obese patients with type 2 diabetes over a 56-week period [34]. Participants were assigned to the naltrexone 32 mg SR/bupropion 360 mg SR or placebo group. Compared with the placebo group, the patients treated with NB lost significantly more weight (-5.0% vs. -1.8%; P<0.001), and a higher proportion lost ≥5% of their body weight (44.5% vs. 18.9%; P<0.001). Furthermore, baseline HbA1c was significantly reduced in the patients receiving NB compared with the placebo group (-0.6% vs. -0.1%, respectively; P<0.001), and 44.1% of patients receiving NB achieved <7% HbA1c compared with 26.3% in the placebo group (P<0.001). The incidence of hypoglycemia did not differ between groups. The cardiovascular safety of naltrexone 32 mg SR/bupropion 360 mg SR is currently under investigation (Clinical trial reg No. NCT01601704, clinicaltrials.gov).

The most common adverse events include nausea, constipation or diarrhea, headache, vomiting, dizziness, insomnia, and dry mouth. The NB provides a boxed warning to alert users to the increased risk of suicidal thoughts and behaviors associated with bupropion. The NB has a dose-related risk of seizures and may elevate blood pressure and heart rate.

Liraglutide is a human glucagon-like peptide 1 analog that may be administered once a day because of its prolonged half-life of 13 hours [35]. Liraglutide was developed to improve glycemic control in patients with type 2 diabetes. The efficacy of the drug was well established in the Liraglutide Effect and Action in Diabetes (LEAD) studies, a series of phase III randomized, controlled trials [36,37]. The approved doses for the treatment of diabetes are 1.2 and 1.8 mg in the United States and 0.6 and 0.9 mg in Japan [38]. The LEAD-3 trial comprised 746 patients with type 2 diabetes assigned to liraglutide (1.2 or 1.8 mg) or glimepiride (8 mg) treatment groups for 52 weeks [36]. The HbA1c reductions from baseline were -0.84% and -1.14% in the 1.2 and 1.8 mg groups, respectively, and body weight was reduced by -2.05 kg from baseline in the 1.2 mg group and -2.45 kg in the 1.8 mg group, whereas a significant weight gain (1.12 kg) was observed in patients treated with glimepiride. A consistent reduction in body weight was observed across the LEAD trials.

Liraglutide is pending FDA approval for the treatment of obesity. The recommend dose is 3 mg in contrast to 1.2 or 1.8 mg for diabetes. The Satiety and Clinical Adiposity-Liraglutide Evidence in Nondiabetic and Diabetic Subjects (SCALE) trial consists of four clinical trials designed to demonstrate the safety and efficacy of liraglutide 3 mg for weight management. The SCALE Obesity and Prediabetes phase IIIa trial involving 3,731 patients found that patients treated with liraglutide lost an average of 8% of their body weight in 56 weeks compared with 2.6% in the placebo group. Moreover, significantly more patients in the liraglutide group lost ≥5% of their baseline body weight compared with those taking the placebo (63.5% vs. 26.6%, respectively), and 32.8% of the liraglutide group lost >10% of their baseline body weight (10.1% in the placebo group).

The SCALE-Diabetes trial was a 56-week randomized, placebo-controlled trial designed to investigate the potential of liraglutide 3 mg in obese or overweight patients with type 2 diabetes. In this trial, 846 overweight or obese patients with diabetes were assigned randomly to liraglutide 3 mg or 1.8 mg or placebo groups. After 56 weeks, the 3 and 1.8 mg liraglutide groups achieved weight loses of 6% and 5%, respectively, compared with 2% in the placebo group. Furthermore, 50% of the patients in the 3 mg group and 35% of those in the 1.8 mg group achieved ≥5% weight loss compared with 13% in the placebo group, and approximately 69% of the patients treated with liraglutide 3 mg achieved the HbA1c target of <7% (Clinical trial reg No. NCT01272232, clinicaltrials.gov).

Concerned by the lack of long-term data for liraglutide in the treatment of obesity and a variety of safety issues, such as gallbladder disease, pancreatitis, breast and thyroid cancers, and increased heart rate, the FDA advisory panel recommended that these issues be addressed in postmarketing studies. However, the panel agreed that the ongoing cardiovascular outcomes trial of the Liraglutide Effect and Action in Diabetes: Evaluation of Cardiovascular Outcome Results study would be sufficient to characterize the cardiovascular risk of the liraglutide.