The weight-loss medication that acts by inhibiting the lipase enzyme in the small intestine is

Newer Approaches

Early in the 21st century there was optimism in Europe regarding the availability of treatments for obesity: in 1998 orlistat was introduced, followed by sibutramine in 2000 and rimonabant in 2006, but by the end of 2008 only orlistat remained (see Chapter 25). Although different in design, the orlistat and sibutramine registration trials provided the benchmarks for pharmacologic weight loss therapy, namely randomized placebo-controlled, parallel-group studies in overweight and obese patients noting placebo-subtracted weight loss at 12 months after randomization and number of patients achieving ≥5% and ≥10% decrease in body weight from baseline.4 These criteria are now included in the regulatory requirements for registration of a weight management drug in the European Union and the United States.5,6 Regulatory authorities also require (usually as a secondary end point) that a weight loss agent additionally benefits weight-related conditions, most notably type 2 diabetes, prediabetes, and other components of metabolic syndrome.

2.1.3.1 Orlistat

Orlistat is an oral gastrointestinal lipase inhibitor that reduces the intestinal absorption of dietary fat resulting in weight-reducing effects. Studies about the use of orlistat for the treatment of NAFLD and NASH generally demonstrated favorable effects such as promoting steatosis improvement (Harrison et al., 2003; Hussein et al., 2007; Zelber-Sagi et al., 2006). A randomized, double-blind, placebo-controlled trial assessed the efficacy of 120 mg TID orlistat for 24 weeks in adults with NAFLD (Zelber-Sagi et al., 2006). The study demonstrated significant reversal of fatty liver by US in the orlistat group only (P < 0.05) and a significant decrease in serum ALT and AST levels, with an almost twofold reduction in ALT in the orlistat group (48% vs 26.4%). Twenty-two of the subjects underwent biopsies at baseline and 24-weeks. The improvement in fibrosis was comparable in both groups and did not reach statistical significance. Weight loss in both groups was similar, suggesting orlistat improves serum ALT levels and steatosis on US in NAFLD patients, beyond its effect on weight reduction (Zelber-Sagi et al., 2006). A study randomized 50 overweight subjects with biopsy proven NASH to receive a 1400 kcal/day diet plus vitamin E (800 IU) daily with or without orlistat (120 mg three times a day) for 36 weeks (Harrison et al., 2009). The orlistat group lost a mean of 8.3% body weight compared to 6.0% in the diet plus vitamin E group (not significant). Both groups also had similarly improved serum aminotransferases, hepatic steatosis, necroinflammation, ballooning, and NAS. Stratified according to weight loss instead of treatment group, a loss of > 5% body weight (n = 24) compared to 9% of body weight (n = 16), to those that did not (n = 25), improved insulin sensitivity (P < 0.001), adiponectin (P = 0.03), steatosis (P = 0.005), ballooning (P = 0.04), inflammation (P = 0.045), and nonalcoholic fatty liver disease activity score (P = 0.009) were seen. Increases in adiponectin strongly correlated with improved ballooning and nonalcoholic fatty liver disease activity score (P = 0.03). Orlistat did not enhance weight loss or improve liver enzymes, measures of insulin resistance, and histopathology. However, subjects who lost > 5% of body weight over 9 months improved insulin resistance and steatosis, and those subjects who lost > 9% also achieved improved hepatic histologic changes (Harrison et al., 2009). Side effects of orlistat are mostly due to gastrointestinal side effects such as nausea, bloating, abdominal cramps, fecal urgency, and fecal incontinence. Its action on fat absorption can cause deficiency of fat-soluble vitamins. Despite its relative effectiveness, orlistat is not very well tolerated due to its unfavorable side effect profile and thus has high discontinuation rate among users (Sjöström et al., 1998).

Orlistat

Orlistat is a gastric and pancreatic lipase inhibitor that reduces the absorption of dietary fat in a dose-dependent manner. At the therapeutic dose of 120 mg three times a day, it blocks the absorption approximately about 30% of dietary triacylglycerol resulting in an energy deficit of 850 kJ day−1 (200 kcal day−1) for an individual on an average diet of 9240 kJ day−1 (2200 kcal day−1) with 40% of calories from fat.

Adverse effects of orlistat are predominantly related to its gastrointestinal action of fat malabsorption and can be associated with a modest reduction in fat-soluble vitamins (A, D, E, and K). However, clinical deficiency has not been reported in clinical trials. Nevertheless, it is recommended that patients taking orlistat receive vitamin supplements. Patients may complain of loose or liquid stool, fecal urgency, anal leakage, and infrequently fecal incontinence due to undigested fat. These adverse effects become less common with longer duration of treatment suggesting that patients learn to avoid high-fat meals to avoid these side effects hence enforcing behavioral change. This may well contribute to the therapeutic effects of orlistat treatment. Orlistat is minimally absorbed (less than 1%) and systemic events are negligible.

Lipase Inhibitors

Attempts have been made to develop novel lipase inhibitors that reduce body weight but have a lower propensity to cause gastrointestinal side-effects than orlistat (see above). The most advanced such compound in development is cetilistat which Alizyme and Takeda are preparing for Phase III clinical trials. In a recently published report of a Phase II clinical trial,164 cetilistat produced a significant weight loss and was well tolerated in 442 obese patients in a 12-week study. Alizyme has claimed that cetilistat and orlistat have similar efficacy but cetilistat is better tolerated and causes a lower incidence of gastrointestinal side-effects than orlistat.165 The superior tolerability and side-effect profile exhibited by cetilistat has been attributed by Alizyme to differences between the molecular structures of orlistat and cetilistat. Nevertheless, as both compounds act on the same molecular mechanism to cause weight loss and the gastrointestinal side-effects are thought to be mechanism based it is difficult to understand why there should be significant differences in the side-effect profile of the two compounds but no difference in efficacy. Therefore, the outcome of the planned Phase III clinical trials with cetilistat is awaited with interest.

International Brand Names

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Xenical (Hong Kong, Indonesia, Israel, Korea, Philippines, Singapore, Thailand)

Monoacylglycerol Lipase/2-Arachidonoylglycerol Modulation

The selective increase in brain levels of 2-AG with the MAGL inhibitor MJN110 produced opioid-sparing effects in mice (Wilkerson et al., 2016), suggesting that increasing 2-AG endogenous tone might affect the response to opiates in rodents. Previous studies have shown that an acute injection of morphine decreased tissue levels of 2-AG in the striatum but increased the levels of anandamide in several other brain structures including NAc, prefrontal cortex, caudate putamen, and hippocampus (Vigano et al., 2004). Additionally, in these studies, administration of rimonabant was able to attenuate the expression of morphine sensitization (Vigano et al., 2004), further suggesting the involvement of CB1 receptors in this process.

Some studies have suggested that 2-AG might also be involved in opiate withdrawal. Therefore similar to the effects of increasing the endogenous tone of anandamide (i.e., with FAAH inhibitors), the increase in 2-AG levels (e.g., with MAGL inhibitors or 2-AG administration) seems also effective in alleviating somatic opiate withdrawal symptoms. A study administering 2-AG (i.e., intracerobroventricular injection) found reduced signs of withdrawal (jumping and forepaw tremor) following naloxone challenge in morphine-dependent mice (Yamaguchi et al., 2001). Accordingly, the MAGL inhibitor JZL184 attenuated both spontaneous and naloxone-precipitated withdrawal in morphine-dependent mice (Ramesh et al., 2013, 2011). In contrast, in another study, JZL184 only reduced some withdrawal symptoms (e.g., jumping), but did not affect the acquisition of morphine withdrawal CPA in mice (Gamage et al., 2015).

Orlistat

One might expect the absorption of lipophilic drugs to be reduced by the lipase inhibitor orlistat. In a double-blind, placebo-controlled, randomized study in 32 healthy volunteers aged 18–65 years, body mass index 18–30 kg/m2, orlistat significantly reduced the Cmax and AUC of amiodarone by about 25%; the Cmax and AUC of desethylamiodarone were also significantly reduced [366]. However, orlistat did not affect the tmax or half-life of amiodarone. These results suggest that orlistat reduces the extent of absorption of amiodarone but not its rate of absorption. In parallel studies orlistat did not affect the pharmacokinetics of fluoxetine or simvastatin.

4.4 PERIPHERALLY ACTING MEDICATION

Orlistat (Xenical) is a synthetic hydrogenated derivative of a naturally occurring lipase inhibitor, lipostatin. Orlistat is a potent slowly reversible inhibitor of pancreatic and gastric lipases which are required for the hydrolysis of dietary fat in the gastrointestinal tract. The drug’s activity takes place in the lumen of the stomach and small intestine by forming a covalent bond with the active serine residue site of these lipases. Taken at a therapeutic dose of 120 mg tid, orlistat blocks the digestion and absorption of about 30% of dietary fat. On discontinuation of the drug, fecal fat usually returns to normal concentrations within 48–72 hours.

Multiple randomized, 1- to 2-year double-blind, placebo-controlled studies have shown that after 1 year, orlistat produces a weight loss of about 9–10% compared with a 4–6% weight loss in the placebo-treated groups. Since orlistat is minimally (<1%) absorbed from the gastrointestinal tract, it has no systemic side effects. Tolerability to the drug is related to the malabsorption of dietary fat and subsequent passage of fat in the feces. Six gastrointestinal tract adverse effects have been reported to occur in at least 10% of orlistat-treated patients; oily spotting, flatus with discharge, fecal urgency, fatty/oily stool, oily evacuation, and increased defecation. The events are generally experienced early, diminish as patients control their dietary fat intake, and infrequently cause patients to withdraw from clinical trials. Psyllium mucilloid is helpful in controlling the orlistat-induced GI side effects when taken concomitantly with the medication. The manufacturer’s package insert for orlistat recommends that patients take a vitamin supplement along with the drug to prevent potential deficiencies. Orlistat was approved for over-the-counter (OTC) use in 2007.

Pharmacotherapy

Several medications are currently FDA approved for the treatment of obesity including the pancreatic and gastric lipase inhibitor orlistat, the selective 5HT2C agonist Lorcaserin, GLP-1 agonist Liraglutide, a phenteramine–topiramate combination, and a naltrexone–bupropion combination.5 Of these, Lorcaserin, phenteramine–topiramate combination, and naltrexone–bupropion combination are CNS acting. The naltrexone–bupropion combination might target pathways involved in the reward deficit (i.e., food addiction) model of obesity including a bupropion-mediated attenuated hypothalamic response to food cues and enhanced activation in areas associated with inhibitory control (anterior cingulate cortex), internal awareness (superior frontal gyrus, insular cortex, superior parietal lobe), and memory (hippocampus) regions.57 Additionally, preclinical work has shown that a high-dose baclofen–naltrexone combination significantly decreases (compared to either drug alone or vehicle) consumption of highly palatable foods without changing consumption of standard, laboratory chow.58 Whether this combination, too, is useful for food addiction requires rigorous testing in human populations.

We note that these preclinical and clinical studies highlight superior efficacy of and increased response to combination pharmacotherapy rather than a single agent. Addiction is a complex disease, affecting many neurotransmitter systems and an array of neural circuits.25 In the case of food addiction, both preclinical and clinical evidence suggests that the different macronutrients in highly palatable foods may synergistically contribute to the food addiction phenotype through both independent and overlapping mechanisms.59 Thus, that a single agent modulating a single neurotransmitter or targeting one neuropeptide would have marginal efficacy is a foregone conclusion, and a neuroscience-informed, multitargeted approach appears more ideal.

2.2 Anti-obesity natural products from microbial sources

Microorganisms have great potential as natural sources of drugs for the treatment and prevention of infections and diseases like cancer, anemia, diarrhea, obesity, atopic dermatitis and Crohn's disease's. They are also potential sources of natural antioxidants, colors, immuno-suppressants, enzyme inhibitors, hypocholesterolemic agents, vitamins, enzymes, and obviously antibiotics.62 The discovery of penicillin from Penicillium notatum by Alexander Fleming in 1928 marked a significant shift from plants to microorganisms as a source of bioactive natural products for new drug discovery.63 Since then, microorganism-derived compounds have been utilized in medicine, agriculture and food industries.64 Some examples of anti-obesity agents from microbial sources are discussed below.

2.2.1 Lipstatin

Microbial natural products also function as enzyme inhibitors. Lipstatin (Fig. 4) is a pancreatic lipase inhibitor produced by Streptomyces toxytricini that is used to combat obesity and diabetes by interfering with the gastrointestinal absorption of fat. It contains a beta-lactone structure that is likely responsible for irreversibly binding to the active site of lipase.65

Fig. 4. Lipstatin, an anti-obesity agent from Streptomyces toxytricini.