Anti-Obesity Drugs: How Safe Are They?

Lifestyle modifications are just not enough to reduce and maintain weight in obese people. New anti-obesity drugs are being developed for long term use. But how safe are they? How do they intend to treat obesity? Can they be a substitute for lifestyle modification programs? To find out the answers to these questions, Gilbert W Kim and colleagues from Thomas Jefferson University, Philadelphia, USA, reviewed the various researches done in this area and discussed the efficacy and safety of these anti-obesity drugs in the journal Expert Reviews on Clinical Pharmacology.

So far, medical treatment for obese patients focused on the co-morbidities of obesity such as diabetes and high blood pressure. Lifestyle modifications alone could successfully reduce 10 per cent of the weight in 6 months. Unfortunately, the lost weight is regained within 1 year following treatment in most patients.

The medical community felt that anti-obesity pharmacotherapy could be an alternative for obese patients to achieve long-term weight reduction. However, many anti-obesity medications such as fenfluramine-phentermine (Fen-Phen) and sibutramine showed potentially fatal adverse effects and they had to be withdrawn from the market. So much so, that orlistat remained the only drug approved by the US FDA for long-term use in weight management.

Reviewers say, ‘Newer researches focus on the regulation of appetite and energy consumption. Hormonal regulators serve as endogenous mediators of energy balance. By targeting these pathways, drug development programs aim to minimize central or peripheral adverse effects, while driving appetite reduction and weight loss.’

The following is an analysis of the therapeutic approaches to regulating food intake:

Cholecystokinin (CCK) is an intestinal peptide found in the gut, which helps in digestion. Chronic administration of CCK has been found to eliminate its ability to reduce weight. Researches have, however, pointed out that CCK potentiates appetite and weight reduction by the use of leptin, suggesting that combination therapy may be more useful.

 

Glucagon-like Peptide 1 (GLP-1) is a gut hormone that increases secretion of insulin by pancreatic â-cells. It is an anorexigenic that has shown good results in inducing satiety and weight loss in humans. However, GLP-1 has limited therapeutic utility because of its ‘short circulating half-life’. So, GLP-1 analogues such as liraglutide, exenatide, and orally active analogues (vildagliptin and sitagliptin) were developed. Although severe adverse reactions were rare, hypoglycemia was common in patients receiving GLP-1. Again, exenatide should not be used by patients with renal disease.

Similarly other gut hormones such as Oxyntomodulin (OXM) and Peptide YY (PYY) and Ghrelin showed positive results for weight reduction. Pancreatic hormones – pancreatic polypeptide and amylin – may also be efficacious in long-term appetite control and weight loss, but they are still in the pre-clinical test stage. Unlike the above, adipose tissue hormones such as leptin and adinopectin acting alone have not been that successful in the clinical tests.

Combination therapy with Pramlintide and Leptin, however, showed very good results. According to the study investigators, ‘In a Phase II study, overweight and obese individuals treated with combination therapy twice daily lost approximately 11 percent of bodyweight, which was significantly greater than patients receiving either agent alone. In a continuation of this study, patients receiving cotherapy exhibited sustained weight loss, while those receiving placebo regained almost all their weight. Based on these results, pramlintide/leptin cotherapy is advancing into Phase III trials’.

In the study, investigators found the following limitation for use of therapeutic approaches to treat obesity:

1. The morbidity and mortality risks accompanying anti-obesity medications make it difficult for the physician to prescribe these, especially in cases of the drugs used to treat the comorbidities of obesity. Further, most of these drugs are delivered via injection, which is a major impediment to patient compliance. So, orally active drugs have to be developed to succeed in this therapy.

2. Most physicians address obesity through lifestyle modification programs and prescribe anti-obesity drugs as a last resort. So the patients struggle unsuccessfully for months or years to achieve and maintain weight loss. Introducing anti-obesity pharmacotherapy early in the treatment could provide significant benefits, both in terms of weight loss and the risk of development of comorbidities.

3. Although regulatory guidelines for anti-obesity drugs promote drug safety and efficacy, and are essential for worthwhile development of pharmacotherapy, they ‘demand an enormous investment of time and resources from biopharmaceutical companies, and have contributed to the waning of approved anti-obesity drugs that are currently available to physicians and their patients’.

4. Financial barrier is another obstacle for patients going in for anti-obesity therapy. Since obesity without comorbidities is not classified as a disease, insurance companies decline reimbursement for anti-obesity medications and the patient ends up paying out of his/her pocket for treatment.

The authors concluded that ‘In the context of the pandemic into which obesity has evolved, recent efforts have focused on the development of combination therapeutics for the treatment of obesity, and based on the positive results achieved with these agents, and the effectiveness of combination drug therapy in treating a variety of other pathologies, new combinations of anti-obesity drugs can be expected’. However, they go on to say, ‘scientific, regulatory and economic hurdles must be overcome to permit the rapid entry of anti-obesity pharmacotherapeutics into mainstream clinical care’.

Source: Regulation of Appetite to Treat Obesity. http://www.medscape.com/viewarticle/739374

Source-Medindia