Abbreviations: AGB – adjustable gastric binding; BMI – body mass index; ESRD – end-stage renal disease; EMA – European Medicines Agency; EPI – exocrine pancreatic insufficiency; GLP-1 – glucagon-like peptide-1; GLUT2 – glucose transporter-2; PYY – peptide YY; RYGB – Roux-en-Y gastric bypass; SG – sleeve gastrectomy; SGLT2 – sodium-dependent glucose co-transporter-2; WHO – World Health Organization

Overweight and obesity are major health problems in today’s society, especially in the westernized countries. The western diet, together with a sedentary lifestyle with a lack of physical activity, is suggested to be the main reasons for the epidemic of these conditions (1). Overweight is defined by the World Health Organization (WHO) as a body mass index (BMI) > 25 kg/m² and obesity as a BMI > 30 kg/m². In 2008, around 35% of the global adult population was overweight and 11% obese. Huge differences can however be seen between westernized and non-westernized countries. Overweight and obesity are associated with comorbid conditions such as type 2 diabetes, cardiovascular diseases, and cancer. This might explain why overweight and obesity are linked to more deaths worldwide than underweight (2).

Lifestyle changes such as the introduction of a healthier diet and increased physical activity should be considered a first step in the management of overweight and obesity (3). However, for many overweight and obese patients it is difficult to loose weight and maintain this weight loss over a long period of time (4). For patients who have failed to achieve weight loss through lifestyle interventions, pharmacological or surgical treatments may be an option (3).

The most commonly used pharmaceutical and surgical approaches to treat obesity are based on the creation of functional exocrine pancreatic insufficiency (EPI) (1, 5). Orlistat, an inhibitor of pancreatic lipase, is currently the only drug approved by the European Medicines Agency (EMA) for treatment of obesity (1). However, several plant-derived phytochemicals has been identified as potent inhibitors of both pancreatic lipase and pancreatic α-amylase, and the clinical potential of these agents are widely investigated (6). In addition, Roux-en-Y gastric bypass (RYGB), the most commonly preformed bariatric surgery worldwide (7), is designed to induce weight loss through a combination of malabsorption and gastric restriction (5). Nevertheless, one should remember that these types of interventions usually are associated with nutritional (4) and metabolic (8) complications. It is therefore of great importance that both medical doctors and patient are well informed about the risks that come with various therapies.

Pancreatic lipase is an important enzyme in the digestion of dietary fat. It is produced and secreted from acinar cells of the exocrine pancreas, and enters the duodenum via the common bile duct. In the intestinal lumen, pancreatic lipase act on triglycerides to generate free fatty acids and monoglycerides. These digestive products are then absorbed by the enterocytes lining the small intestine (9). By inhibiting the action of pancreatic lipase, the digestion of triglycerides in the intestinal lumen will be reduced. This will in turn result in a decreased absorption of free fatty acids and monoglycerides and, thus, a reduced caloric uptake (1).

The pharmaceutical and nutraceutical industry has proposed various inhibitors of pancreatic lipase for the management of weight loss. A few of these agents have after successful clinical trials been able to reach the market, however, the majority are still under investigation (6).

Orlistat is a potent, specific and irreversible inhibitor of pancreatic lipase (10) that is approved by the EMA for long-term use in two forms: as a prescriptive drug in 120 mg capsules under the trade name Xenical, and as a non-prescriptive drug in 60 mg capsules under the trade name Alli (1). Orlistat acts by forming a covalent bond to the active site of pancreatic lipase, thus preventing catabolism of luminal triglycerides into absorbable free fatty acids and monoglycerides (10). Studies have shown that the action of orlistat is not only associated with weight loss, but also reduced blood pressure and lowered plasma levels of low-density lipoprotein cholesterol (11). However, numerous adverse effects have been reported following treatment with orlistat, such as intestinal cramps, oily rectal spotting, flatus with discharge, and fecal incontinence. These are usually detected during the first week of treatment, but are reduced once the patients learn how do avoid high-fat diets. In addition, treatment with orlistat is associated with decreased absorption of fat-soluble vitamins, such as vitamin D, vitamin E, and β-carotene. Therefore, multivitamin supplementation should be recommended to patients treated with this agent (12).

Cetilistat is a pancreatic lipase inhibitor that recently was approved in Japan for the treatment of obese patients with comorbid conditions (13). Its mechanism of action is similar to that of orlistat (14). However, due to structural differences, it has been suggested that the safety profile of certilistat is superior to that of orlistat (15).

A novel approach for the treatment of obesity is the use of plant-derived phytochemicals (6). These agents are hybrids between nutrients and pharmaceuticals, and are therefore referred to as nutraceuticals (16). It has been shown that several phytochemicals that belong to the chemical classes saponins, polyphenols, and terpenes are able to inhibit the activity of pancreatic lipase. For some of these, the inhibitory activity can reach as high as 70%. However, more research is needed to further evaluate the clinical potential of these agents (6).

Carbohydrates are the main energy source of the human diet, accounting for about 40-80% of the total caloric intake. These are either digestible or non-digestible. The most frequently consumed digestible carbohydrates are disaccharides, such as sucrose and lactose, and larger polysaccharides, such as starch. These are comprised of monosaccharides, which are joined together by glycoside bonds. The digestion of carbohydrates is initiated in the mouth, were salivary α-amylase hydrolyzes the α-1,4 bonds in starch. The products of this process include maltose, maltotriose and dextrins. The digestion of starch is continued in the small intestine by the action of pancreatic α-amylase, and completed by enzymes located at the brush border membrane. The action of these enzymes yields the monosaccharides glucose, fructose, and galactose, which are absorbed by the enterocytes lining the small intestine. Non-digestible carbohydrates, such as fibers and cellulose, as well as digestible carbohydrates that manage to escape the action of the digestive enzymes in the small intestine, enter the colon where they are fermented by the colonic microbiota. Fermentation yields short chain fatty acids, which can be absorbed in the colon, used as bacterial substrate, or excreted in the feces (6).

Since a high amount of consumed calories are ascribed to carbohydrates, it is of great interest to limit the uptake of these nutrients in the management of obesity. Inhibitors of pancreatic α-amylase have been suggested as potential anti-obesity agents, and numerous α-amylase inhibitors have been isolated from a number of different plant sources (6). These include Phaseolus vulgaris (17), Cinnamomum cassia (18), Rosmarinus officinalis (19), and black, green, and mulberry teas (20). Administration of α-amylase inhibitors causes reduced luminal activity of pancreatic α-amylase, resulting in limited absorption of carbohydrates. This in turn leads to decrease postprandial plasma glucose and insulin levels, and increased activity of the colonic microbiota (6).

Bariatric surgery, or weight loss surgery, is a possible treatment for obese patients who do not manage to lose weight and maintain this weight loss with lifestyle interventions such as increased exercise and diet modifications (5). In 2011, a total number of 340 768 bariatric surgeries worldwide were reported. This is more than twice as many compared to 2003 (7).

To be considered a candidate for bariatric surgery, the patient must meet the criteria of a BMI > 40 kg/m² or a BMI > 35 kg/m² with an obesity-related comorbid condition (5). Different surgical procedures can be preformed on these patients, where the most common include RYGB, sleeve gastrectomy (SG), and adjustable gastric binding (AGB) (7). RYGB is designed to induce weight loss through a combination of gastric restriction, creating early satiety, and malabsorption. On the contrary, SG and AGB are solely restrictive procedures and, because they do not aim to induce weight loss by affecting the function of exocrine pancreatic enzymes, they will not be further discussed (5).