1794 In Table I, the potential approaches have been catego- rized into the most important areas of research and development. Basically, the first three categories primarily target body weight, which is the focus of this review. However, there is not always a sharp division between reduction of weight or reduction of complications as primary goal, while combin- ing these objectives also offers advantages. Specifically modulating metabolic or immunological processes associat- ed with adiposity is considered potentially effective to reduce health complications. An interesting example is the approach to reduce the pro-inflammatory state in over- weight and obese persons using anti-inflammatory com- pounds such as salsalate (17–19). In addition, strategies aiming to modulate body fat distribution and not primarily total body fat are being investigated. This is based on the observation that persons with a predominant android (“apple”) body shape are at higher risk for cardiovascular disease than persons having a more gynaeoid (“pear”) body shape. Obviously, genetic and hormonal factors play a role (20,21). Furthermore, fat cell size may be of importance (22). Finally, the discovery that regular physical exercise significantly reduces health risks even in the absence of direct weight reduction (1,23–25) has stimulated the research on an “exercise pill” (24,26–28). WEIGHT MANAGEMENT DRUGS—ISSUES AND NEEDS While keeping in mind that health risks are not simply determined by body weight or even total body fat mass, losing weight is still commonly regarded as effective in overweight people who are developing symptoms of the (pre-)metabolic syndrome. Ideally, weight management should be based on lifestyle modification, including the reduction of caloric intake, increased activity, and physical exercise. Unfortunately, long-term effects of diet or exercise on weight are often disappointing. The desire to eat is one of the strongest instincts, and humans have developed powerful mechanisms to guard against starvation during Table I General Pharmacological Strategies to Combat Overweight or Complications of Adiposity Reducing energy absorption from the GI tract or peripheral tissues Decreasing food consumption by increasing satiety or satiation, reducing appetite, increasing feelings of reward, etc. Reducing body fat by stimulating energy expenditure or inhibiting energy supply of adipose tissue Reducing inflammatory activity of adipose tissues Modulating body fat distribution, energy fluxes or mimicking physical exercise Witkamp periods of food scarcity. Our brains do not only generate sensations of hunger as a result of direct metabolic stimulation. Instead, human eating behavior is a combina- tion of liking (hedonic impact), wanting (incentive motivation), and learning (associations and predictions) (29–31). Non-homeostatic overeating is regulated by central dopaminergic, serotonergic, opioid and cannabinoid sys- tems that show many interconnections and overlaps with other important regulatory pathways (32,33). As a result, the development of effective drugs with acceptable side- effects can be very cumbersome. With respect to durable weight reduction, bariatric surgery is the most effective long-term treatment for severe obesity with the greatest chances for amelioration and even resolution of obesity- associated complications, including diabetes (34,35). How- ever, depending on the technique used, it is not without surgical risks or metabolic complications (35) and involves high costs. Pharmacological options are to be considered as an adjunct to dietary measures and physical exercise, and long-term weight management by drug treatment alone does not seem realistic at present. However, there will be situations where the use of drugs or possibly even vaccines to reduce weight is medically rational and justified. Criteria for FDA approval of anti-obesity drugs prescribe that 35% of treated persons must lose at least 5% of their body weight, and that group should include at least twice as many individuals as the number of patients who achieve a similar weight loss on placebo. Alternatively, the therapy must result in at least 5% placebo-corrected weight loss. On a population level, such figures will contribute to a lower incidence of complications. The history of development and application of weight loss drugs has shown to be trouble- some and characterized by many failures and withdrawals. The most recent example of this occurred in January 2010, when subitramine was suspended from the European market by EMA (www.ema.europe.eu) because of potential cardiovascular risks in certain patients. The compound has remained available in the US, but the FDA issued a safety notification and requested a new contraindication stating that sibutramine should not be used in patients with a history of cardiovascular disease. Another recent case was the suspension of the cannabinoid receptor type 1 (CB1) inverse agonist rimonabant from the EU market in October 2008. At that time, FDA had not given approval for the compound because of doubts regarding its CNS risk-benefit profile. While preparing this review (October 2010) the FDA raised serious concerns on the new applications for lorcaserin and the new phentermine/topiramate combina- tion. In 1997, fenfluramine and dexfenfluramine, particu- larly popular with phentermine in fen-phen combinations, were withdrawn after reports of negative effects on heart valves and primary pulmonary hypertension (36). The historical list of failures and withdrawals further continues