randomized controlled trial (RCT) that evaluated the effect of orlistat in 3,305 patients, orlistat was found to cause a total body weight ...
randomized controlled trial (RCT) that evaluated the effect of orlistat in 3,305 patients, orlistat was found to cause a total body weight loss of 2.4% after 4 years. More importantly, it significantly lowered the risk of type 2 diabetes mellitus (T2DM), compared to placebo (6.2% vs. 9.0%), over 4 years [21]. Orlistat also improved blood pressure (BP), insulin sensitivity, and lipid profiles owing to its primary action of decreasing intestinal fat absorption. However, in this study, 91% of participants administered orlistat experienced at least one gastrointestinal event and 8% withdrew from the study due to adverse events. Further, there are concerns regarding the potential risk of colorectal cancer due to the presence of excess fat in the colon. In animal models, orlistat was associated with clusters of apoptosis-resistant, neoplastic, premalignant colonic lesions [22].
However, a large retrospective matched cohort study (n=33,625 on orlistat; 160,374 on placebo) showed no evidence of an increased risk of colorectal cancer after the initiation of orlistat [23]. Meanwhile, a significant decrease in the absorption of vitamins A, D, E, and K was observed in participants administered orlistat [21]. To prevent possible deficiencies in fat-soluble vitamins (such as vitamin D), a supplement can be recommended. 2. Lorcaserin Lorcaserin (Belviq® and Belviq XR® ) is a selective agonist of the 5-hydroxytryptamine (5-HT) 2C receptors and a Drug Enforcement Administration (DEA) schedule IV-controlled medication. In 2016, its extended released (XR) form (once daily [QD] 20 mg of lorcaserin) was approved by the FDA following twice-daily (BID) 10 mg of lorcaserin in 2012. However, on February 13, 2020, the FDA requested that the drug manufacturer voluntarily withdraw lorcaserin from the US market because it was determined that potential risk of cancer associated lorcaserin outweighs the benefits [24]. It was an update to the FDA Drug Safety Communication: Safety clinical trial shows possible increased risk of cancer with weight-loss medicine Belviq, Belviq XR (lorcaserin) issued on January 14, 2020 [25]. This withdrawal came after the FDA’s reviewing data from the Cardiovascular and Metabolic Effects of Lorcaserin in Overweight and Obese Patients – Thrombolysis in Myocardial Infarction 61 (CAMELLIA-TIMI 61) clinical trial to evaluate the risk of CVD problems [26]. It was a randomized, double-blind, placebo-controlled, multicenter, parallel group trial conducted between January 2014 and June 2018 in the US, Canada, Mexico, the Bahamas, Europe, South America, Australia, and New Zealand. The study population consisted of 12,000 men and women who were overweight or obese. Patients were required to have either established CVD, or to be at least 50 years old for men or 55 years for women with T2DM plus at least one additional cardiovascular risk factor. Eligible patients were assigned randomly to either lorcaserin 10 mg BID or placebo. Approximately 96% of patients completed the study, and 62% who completed remained on treatment at the end of study. The median follow-up time was 3 years and 3 months. The primary safety analysis showed no meaningful difference between lorcaserin and placebo in the risk of major adverse cardiovascular events, demonstrating noninferiority. However, it was found that more patients taking lorcaserin (n=462; 7.7%) were diagnosed with cancer compared to those taking a placebo, which is an inactive treatment (n=423; 7.1%). A range of cancer types was reported, with several different types of cancers occurring more frequently in the lorcaserin group, including pancreatic, colorectal, and lung.
There was no apparent difference in the incidence of cancer over the initial months of treatment, but the imbalance increased with longer duration on lorcaserin. On the other hand, lorcaserin has failed to gain approval from the European Medical Agency (EMA) due to preclinical data that revealed the potential of breast cancer development and concerns regarding psychiatric issues—the aggravation of depression, suicidal ideation, and psychosis and valvulopathy. Moreover, phase III studies to determine the difference in adverse event incidence between groups were deemed underpowered [27]. 1) Mechanism of action Lorcaserin decreases food intake by increasing satiety through its serotonin anorectic effect by stimulating the proopiomelanocortin (POMC) receptors in the arcuate nucleus of the hypothalamus [28]. At least 14 serotonin receptor subtypes that modulate different physiological functions, ranging from hallucinations to muscle contraction, exist [29]. The side effects caused by non-specific serotonin agonists (i.e., fenfluramine and dexfenfluramine) are due to the stimulation of the peripheral serotonin 2B receptor. Fenfluramine is a predominant 5-
HT2b receptor agonist that is believed to cause adverse CVD effects by stimulating mitotic https://doi.org/10.5534/wjmh.200010 212 www.wjmh.org activity and subsequent cell overgrowth within the valve leaflets [30]. Owing to its high selectivity for 5-HT2c receptor (15-fold and 100-fold selectivity over the 5-HT2A and 5-HT2B receptors, respectively), lorcaserin can suppress appetite and hunger without triggering pulmonary hypertension or valvular heart defects [31]. Many studies suggest that lorcaserin has multiple psychological effects—reducing craving and impulsivity and elevating satiety), which contribute to weight loss.
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