*4.1.3 Semaglutide*

Approved in 2019, semaglutide is a long-acting GLP-1 analogue that mimics the effects of native GLP-1, stimulating WL by decreasing the energy intake and hunger, increasing satiety, and enhancing glycemic control [104]. It is approved for treatment of T2D using ≤1.0 mg once weekly subcutaneously or as tablets at a dosage of up to 14 mg. Side effects and contraindications are similar to liraglutide (**Table 3**). In STEP 1 trail, semaglutide 2.4 mg resulted in significant TWL% at 68 weeks compared to placebo (−14.9% vs. − 2.4%) [105]. More participants on semaglutide than placebo achieved ≥5% TWL% (86.4% vs. 31.5%), ≥10% (69.1% vs. 12.0%), and ≥ 15% (50.5% vs. 4.9%) [105]. Moreover, semaglutide led to more improvement in cardiometabolic risk and physical functioning than placebo [105]. In the STEP 4 trial, individuals completing a 20-week run-in period with semaglutide 2.4 mg once per week, maintenance with semaglutide resulted in continuous WL over the next 48 weeks compared to switching to placebo (−7.9% vs. +6.9%) [106].

### *4.1.4 Orlistat*

Approved in 1999, orlistat is the single anti-obesity medication that does not function via the CNS pathway. Instead, it inhibits pancreatic and gastric lipases, reducing absorption of 25–30% of ingested fat [101]. The recommended dose is 120 mg three times per day up to 1 hour after food intake. Side effects are related to fat malabsorption and include steatorrhea, oily spotting, flatulence, and fecal incontinence. The gastrointestinal symptoms can be reduced by a low-fat diet and increasing intake the dietary fiber [107]. Multivitamin supplementation is essential, as orlistat decreases absorption of fat-soluble vitamins (A, D, E, K). Orlistat resulted in a mean 2.9–3.4% weight loss at one year [107]. Long term WL (4 years) can reach 5.8 kg, where 53% of participants lost ≥5% of their weight, and 26.2% lost ≥10% of their weight [108]. Orlistat also reduces the serum glucose levels and increases insulin sensitivity. Individuals with T2DM prescribed orlistat 120 mg exhibited significantly more reduction in fasting blood glucose and HbA1c compared to placebo [109].

### **4.2 Combination medications**

### *4.2.1 Phentermine-topiramate ER*

This long-acting combination was approved in 2012. Phentermine is a shortterm appetite suppressant; topiramate is an antiepileptic and migraine medication [107]. The mechanisms of appetite suppression is not well understood, perhaps vis modulation of gamma-aminobutyric acid receptors [110]. Because of its anorexigenic properties, it is used off-label for obesity and binge eating, alone or combined with phentermine. Phentermine/topiramate ER is available as 4 doses daily (**Table 2**), taken in the morning, titrated every 2 weeks and stopped if 5% WL is not accomplished within 12 weeks on maximum daily dose 15/92 mg [111]. Phentermine/ topiramate ER, a schedule IV controlled substance. The FDA (Food and drug administration) requires a Risk Evaluation and Mitigation Strategy to inform physicians and women of reproductive age about potential increased likelihood of orofacial clefts in infants exposed to phentermine/topiramate ER during the first trimester of pregnancy [97]. The side effects are those of phentermine and topiramate. Topiramate has dose-dependent side effects and this include cognitive side effects such as psychomotor slowing, diminished concentration, memory impairment and language difficulties (**Table 3**) [111]. Many side effects of topiramate are due to the inhibition of carbonic anhydrase activity, such as metabolic acidosis, hypokalemia, renal stones, angleclosure glaucoma, myopia, and anhidrosis. Therefore, topiramate should not be given

with other medications that inhibit carbonic anhydrase [111]. Rare side effects also include increased suicidal thoughts or ideations, where the drug should be stopped immediately.

Phentermine/topiramate ER resulted in significantly greater WL compared to placebo where participants in the 3.75/23, and 15/92 groups lost 5.1%, and 10.9% of their baseline weight, respectively compared with 1.6% in the placebo group [112]. Moreover, 44.9% of 3.75/23 group, and 66.7% of 15/92 group, lost ≥5% of their weight after 56 weeks of treatment compared to 17.3% of the placebo group (p<0.0001) [112]. Phentermine/topiramate ER for 52 weeks also resulted in 76% reduction in the progression to diabetes in participants receiving 15/92 mg and a 54% reduction in participants receiving 7.5/46 mg compared with placebo [113].

### *4.2.2 Naltrexone-bupropion sustained release (SR)*

A combination approved in 2014, bupropion (dopamine and norepinephrine reuptake inhibitor) is used for depression and smoking cessation treatment while naltrexone is an opioid antagonist [97, 111]. Their combined use has synergistic effect on appetite suppression [111, 114]. Bupropion inhibits food consumption and increases energy expenditure by stimulating the neuropeptide pro-opiomelanocortin (POMC) and supplementing dopamine activation, which is lower among obese individuals [111]. Naltrexone is used for treating opioid and alcohol dependence [97]. It inhibits the appetite-enhancing influence of beta-endorphin caused by cannabinoid-1 receptor stimulation.

Starting with one tablet (8 mg ER naltrexone and 90 mg ER bupropion) daily, the dose is increased by one tablet per week to a therapeutic dosage of two tablets two times per day (32/360 mg). The medication should be discontinued if WL ≥ 5% is not achieved at 16 weeks [97]. The most common side effects are highlighted in **Table 3**. The medication is contraindicated with monoamine oxidase inhibitors and chronic opioids. It is also contraindicated in patients with uncontrolled HTN, and history of seizures. Bupropion increases the risk of suicidality in patients younger 24 years and therefore they need to be observed closely for mood changes [97].

Studies have shown that patients on naltrexone/bupropion 360/32 mg had a mean 6.1% WL in comparison to 1.3% for those on placebo; and 48% of naltrexone/bupropion individuals lost >5% body weight compared to 16% of placebo patients [114]. Others reported that 44.5% of patients on naltrexone/bupropion lost ≥5% of their body weight after 56 weeks vs. 18.9% on placebo [115]. Furthermore, the medication resulted in better glycemic control and improvements in triglycerides and HDL cholesterol when compared to those on placebo [115].
