Dose escalation and side effects Phentermine/topiramate is prescribed for QD use. To prevent insomnia, its known side effect, it is recomm...
Dose escalation and side effects Phentermine/topiramate is prescribed for QD use. To prevent insomnia, its known side effect, it is recommended that this medication is taken in the morning. According to the package insert, the dose of phentermine/topiramate should be gradually escalated. After a starting dose of 3.75/23 mg QD is administered for 2 weeks, 7.5/46 mg is administered; this dose was best tolerated by the participants in the study. The dose should be administered for a minimum of 3 months before a further increase to the highest dose of 15/92 mg. Additionally, the dose is only increased if the patient fails to achieve a total body weight loss of 3% after 3 months. If the patient tolerates the medication poorly, a slow titration down or off (ideally over 3–5 days) is warranted to reduce the risk of seizure; this result was found in a study where patients with a history of seizures abruptly discontinued topiramate intake [18]
. Common side effects of phentermine/topiramate ER include insomnia, paresthesia, dizziness, dry mouth, dysgeusia, and constipation [38]. A fetal safety issue also exists with this medication: it increases the risk of oral clefts. Thus, advice on contraceptive planning is imperative before this medication is prescribed to women of child-bearing age. 3) Clinical efficacy Regarding weight loss efficacy, adequate assessments of phentermine/topiramate ER have been conducted via long-term studies. EQUIP and CONQUER were each one-year, randomized, double-blind, placebo-controlled studies comprising 1,267 and 2,487 participants, respectively [41,42]. The EQUIP trial included nondiabetic patients with a BMI ≥35 kg/m2 whereas the CONQUER study included patients with a BMI ranging from 27–45 kg/m2 and more than two obesity-related comorbid conditions. The study findings enabled the approval of phentermine/topiramate ER by the FDA. In the EQUIP study, the mean weight loss at 1 year for participants in the phentermine/topiramate ER 15/92 mg group was 10.9%, compared to 1.6% in the placebo group. Similarly, in the CONQUER trial, participants administered the same dose of phentermine/topiramate ER for 1 year achieved a 9.8% reduction in weight from baseline, compared to 1.2% in the placebo group. In the CONQUER trial, patients administered phentermine/ topiramate ER 7.5/46 mg for 1 year had a total body weight loss of 7.8%. Notably, both studies demonstrated an improvement in the cardiovascular risk factors. The SEQUEL study, a 2-year extension trial, was performed to assess the sustained weight loss of participants after completion of the CONQUER trial [43]. The study findings reinforced previous findings that phentermine/ topiramate ER intake can result in meaningful weight loss and significant improvements in BP, lipid profiles, fasting glucose, fasting insulin, and WC. 4. Naltrexone/bupropion Naltrexone/bupropion (Contrave® ) is a drug combination for the long-term management of weight loss. In 2014, this combination was approved the FDA (Mysimba® approved by the EMA). Each component of this medication has been used in other medical conditions since the 1980s [18]. As there is no potential of abuse with this medication, it is not a controlled substance. 1) Mechanism of action As an antidepressant, bupropion is used as a smoking cessation aide. Its anorectic mechanism of action involves the inhibition of dopamine and norepinephrine reuptake. Naltrexone was approved for the treatment of opioid and alcohol addiction and antagonizes an opioid‐dependent feedback loop that limits the effects of bupropion on the POMC neurons; hence, this drug combination works synergistically [44]. 2) Dose escalation and side effects A slow dose escalation of naltrexone/bupropion is recommended to minimize the side effect of nausea, with a starting dose of 8/90 mg (a single combination tablet)
QD for 1 week (at week 2; 1 tablet BID in the morning and evening, at week 3; 2 tablets in the morning and 1 tablet in the evening, at week two tablets BID (the maximum dose). Typical side effects include headache, dizziness, dry mouth, and gastrointestinal discomfort (i.e., nausea, vomiting, constipation, or diarrhea). Although naltrexone/bupropion results in significant weight reduction and long-term evidence to support its https://doi.org/10.5534/wjmh.200010 214 www.wjmh.org efficacy exists [18], its side effects of elevation of BP and heart rate make it challenging to prescribe to patients with significant CVD. 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].
No comments