3) Clinical efficacy Naltrexone/bupropion was assessed in four phase III multicenter, long-term, double-blind placebo-controlled trials. Th...
3) Clinical efficacy Naltrexone/bupropion was assessed in four phase III multicenter, long-term, double-blind placebo-controlled trials. The COR (Contrave Obesity Research)-I (n=1,742), COR-II (n=1,496), and COR-BMOD (Behavior MODification) (n=793) trials included patients with a BMI ≥27 kg/m2 , at least one weight-related comorbid condition (i.e., hypertension [HTN]), and COR-DM (Diabetes Mellitus) [45-48]. The percent weight loss observed in CORI, COR-II, and COR-BMOD in patients administered naltrexone/bupropion 32/360 mg for 56 weeks compared to placebo was 6.1% vs. 1.3%, 6.4% vs. 1.2%, and 9.3% vs. 5.1%, respectively [49]. The final study, the CORDM trial, evaluated weight loss in 505 patients with T2DM who were either overweight or obese [48]. Here, patients administered naltrexone/bupropion 32/360 mg for 56 weeks vs. placebo lost 5.0% vs. 1.8%. Moreover, their HbA1c was reduced relative to the baseline value
(0.6% vs. 0.1%) [50]. These trials revealed improvements in high-density lipoprotein cholesterol and triglycerides in naltrexone/bupropion-treated patients. However, improvements in WC, fasting insulin, and insulin resistance index (homeostasis model assessment of insulin resistance, HOMA-IR) were only identified in participants in the COR-I, COR-II, and COR-BMOD studies [51]. 5. Liraglutide Liraglutide (Saxenda® ) is an injectable glucagon-like peptide 1 (GLP-1) derivative that was approved by the FDA in 2014 for weight management (dose, 3.0 mg subcutaneous [SC] daily).
This approval followed that of a lower dose (1.8 mg daily [Victoza® ]) in 2010 for T2DM management [52]. 1) Mechanism of action After meals, GLP-1 is secreted from the distal ileum, proximal colon, and the vagal nucleus of the solitary tract and exhibits multiple effects as an incretin hormone [53]. GLP-1 mainly regulates blood glucose by enhancing insulin secretion from the pancreatic beta-cells and inhibits glucagon secretion in a glucose-dependent manner. GLP-1 also induces postprandial satiety and fullness, slows gastric emptying, and decreases appetite and food consumption by acting on the hypothalamus, limbic/reward system, and cortex [54]. Unlike human GLP-1, liraglutide is more stable in plasma and binds strongly to plasma proteins, thereby enabling a much longer half-life (13 hours) than the human endogenous GLP-1 (a few minutes) [55]. 2) Dose escalation and side effects The optimal dose of liraglutide for weight loss is 3 mg daily; however, to prevent the side effects of nausea and vomiting, treatment should be initiated with 0.6 mg QD and gradually escalated each week by 0.6 mg up to 3 mg [38]. Previously, a meta-analysis revealed that among all FDA-approved anti-obesity medications, liraglutide had the highest discontinuation rate due to its side effects (13% of patients) [56]. The most frequent placebo-subtracted side effects were nausea (25.0%), vomiting (12.2%), diarrhea (11.6%), constipation (11.0%), and dyspepsia (6.4%), which were tolerated by most patients over time [57-59]. 3) Clinical efficacy Liraglutide was approved base on the results of three main RCTs; The SCALE Obesity and Prediabetes, the SCALE Diabetes and the SCALE Maintenance [58,60,61]. In the SCALE Obesity and Prediabetes, obese participants (n=2,487), including 61.2% of the prediabetic cohort, received liraglutide 3 mg QD or placebo. After 56 weeks, a weight loss of 8.0% was achieved in the liraglutide group (vs. 2.6% of placebo) and 63.2% and 33.1% of the participants in the liraglutide group achieved ≥5% and ≥10% weight reduction, respectively [58] (vs. 27.1% and 10.6% in the placebo group, respectively). Moreover, cardiovascular indicators, including BP and lipid profiles, were better improved in the treatment group. Particularly, HbA1c (-0.30%±0.28%) and fasting glucose levels (-7.1±0.8 mg/dL) were significantly reduced in subjects administered liraglutide 3.0 mg compared to placebo. The SCALE Diabetes assigned overweight or obese patients with T2DM (n=846) to receive liraglutide 3 mg QD or 1.8 mg QD or placebo for 56 weeks and reported a decrease in the weight of the patients (6.0%, 4.7%, and 2.0%, respectively) [58]. Early achievement of weight loss ≥4% with liraglutide 3 mg (at 16 weeks) was associated with greater weight reduction at the study’s termination [62]. Compared to the 1.8 mg SC daily group, the liraglutide 3.0 mg SC daily group had a greater improvement in the T2DM Young Jin Tak and Sang Yeoup Lee: An Updated Review on Anti-Obesity Drugs www.wjmh.org 215 measures, including HbA1c, fasting plasma glucose, HOMA-IR, and number of hypoglycemic agents. The SCALE Maintenance aimed to evaluate weight maintenance in non-diabetic participants who underwent a ≥4-week run-in with a low-calorie diet. Subjects who lost ≥5% of their body weight (n=422) were randomized to receive liraglutide 3.0 mg SC daily or placebo for 56 weeks. The liraglutide 3.0 mg SC daily group achieved an additional weight loss of 6.2% (0.2%, placebo) [61]. One of the main benefits of liraglutide, besides weight loss, is its favorable effects on CVD outcomes in obese patients with T2DM. Despite initial considerations of the risk of acute pancreatitis, long-term trials suggest that the risk of this disease does not significantly increase with liraglutide [63,64]
. Particularly, biomarkers of acute pancreatitis—amylase and mainly lipase—increase in a non-dose dependent manner during treatment with GLP-1 receptor analogs. However, their increase was not accompanied by symptoms; moreover, when monitored, acute pancreatitis could not be predicted [65]. Based on rodent studies that demonstrated the proliferative effect of liraglutide on thyroid C-cells, contraindications for liraglutide include patients with (or a family history of) medullary thyroid carcinoma or type 2 multiple endocrine neoplasia [27]. In rodents administered incretin-based medications, pancreatic, intestinal, and breast neoplasms were found to develop more frequently; however, these results were not found in human studies [66-68]. A phase IIIb RCT reported no difference in calcitonin levels and medullary thyroid carcinoma rates between liraglutide (≤1.8 mg) and placebo during a follow-up of 3.5–5 years [69]. Additionally, the total risk of malignant and benign neoplasms, including pancreatic cancer, was not found to increase in the liraglutide vs. placebo group [63,64,70]. However, these results should be interpreted cautiously and an intensive post-marketing surveillance of liraglutide should be performed as the studies were not designed to assess cancer risk and the incidence of medullary thyroid carcinoma was too low for detection in the trials. As no concern regarding neuropsychiatric safety was reported, this medication can serve as a good option for obese patients with mental disorders [71] if they can afford this costly medication (liraglutide 3.0 mg) and agree to a daily injection
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