The ever increasing issue of world obesity is constantly in the news and with the statistics illustrating a frightening upwards trend it is now a critical illness it terms of cost to the health services worldwide. In fact in 2012 it was calculated that more than a third of Americans—34.9% or 78 million—were obese. In 2008 the cost on U.S. healthcare due to treatment of obesity was $147 billion. More recent data suggests that if the current trend continues the prevalence of obesity will rise to 43% in adults by 2018 with the cost of treatment destined to top $344 billion.

Although the population in general accepts that a regimen of exercise and healthy eating should allow us to control and indeed lose weight, the harsh reality of the situation is that a large percentage of obese and morbidly obese people either ignore this advice, or for various reason feel that they are either unable or incapable of controlling their weight without either pharmaceutical or surgical intervention.

The pharma industry has been trying to find the miracle weight-loss pill for decades. Indeed pharmaceutics have been used for over a century to assist in shedding pounds. In terms of history, the drug Thyroxin (or Thyroid Extract) has been used since before 1900 and is still used today, unregulated in the U.S. by body builders even though it is known to cause potentially serious side effects. DNP (2,4 Dinitrophenol), an industrial chemical used in wood preservatives and pesticides, was used for weight loss throughout the 1930s. It was indeed banned but is still used illegally to assist in fat loss even though it has been associated with over 50 deaths of U.S. body builders.

Phentermine (Adipex-P, Suprenza and Lonamin) is a psychostimulant, pharmacologically similar to amphetamine, and is available in the U.S. for short-term weight management. Although these drugs are not illegal in the UK and Europe, they are not prescribed on the NHS. Phentermine should only be prescribed for short-term use alongside a managed diet regime and exercise, however due to the potential habit-forming effect of the drug it shouldn’t be used long-term. The same goes for Diethylpropion, another potentially addictive medication available in the U.S. There has been much controversy in the UK with regards to these two medications with a legal battle aiming to ban them 10 years ago, which failed when in 1995 the Medicines Control Agency argued that there was insufficient evidence to do so.

But the quest for the miracle cure for obesity has continued through the 90s, 00s and into the second decade of the 21st Century. Many of the previously used and discontinued drugs have targeted appetite in order suppress the urge to binge. A newer generation of drugs have been researched and trialed focusing more on regulating metabolism or interfering with processes of selective absorption in the GI tract.

Sibutramine (Meridia, Reductil and Sibutrex) is a neurotransmitter re-uptake inhibitor, which acts as an appetite suppressant. It was launched onto the market in 1997 but was withdrawn in the U.S. and Europe in 2010 due to cardiovascular risk factors. Closely following the release of Sibutramine, Orlistat (Xenical and Alli) was launched in 1999. Alli is a lower dose formulation of Orlistat available OTC. Orlistat works differently to previously marketed anti-obesity medications whereby it targets intestinal fat absorption via inhibition of pancreatic lipase. Sounding simplistic in terms of how it works, Orlistat has a tendency to cause fatty diarrhoea (steatorrhea) as well as flatulence and other gastric problems. Regardless, following the non-launch of Rimonabant (Acomplia and Zimulti), a cannabinoid (CB1) receptor antagonist in 2007 due to potential psychiatric issues, Orlistat remains the only long-term pharmacological agent licensed to treat gross obesity in the UK and U.S.

And so the journey goes on, and maybe another chapter is yet to open? The anti-diabetic medications have become a newer area of interest. It is well acknowledged that patients who take metformin for Type II Diabetes may be able to lose weight—this is thought to be related to the fact that its action decreases the amount of glucose excreted by the liver while increasing absorption of the same substance by muscles.

Another anti-diabetic drug is Exenatide (Byetta), which is a glucagon-like peptide-1 analogue (GLP-1). It is known to delay gastric-emptying, promote and prolong satiety and some patients taking the medication have been observed to show a large degree of weight loss. Currently, Exenatide is only indicated for Type II Diabetes and is a subcutaneous injection, which can be associated with severe nausea; however this group of drugs is certainly of interest in weight management as research suggests that some obese people are deficient in the hormone.

The world of anti-obesity drugs does just seem to be all boom and bust. Every time a new hopeful appears on the stage the question gets asked, “Could this be the one?” But the figures suggest that the Holy Grail has yet to be found. And this seems to have had an effect on R&D time and spend in that therapeutic area. After almost a decade it looks likely that two new drugs will be licensed for use in Europe. A combination therapy of nor-adrenaline reuptake inhibitor Bupropion HCl and the selective opioid antagonist Naltrexone HCl will be marketed as Mysimbia, and the second is an injectable human GLP-1 analogue Liraglutide, to be marketed as Saxenda. Liragultide is already licensed under the name Victoza for the treatment of Type II Diabetes at much lower doses. Both of these drugs rely on modified calorific intake and increased exercise.

The question remains though: Is it the drug, or is it the illness? Regardless of the pharmacological action of the drugs, successful weight loss must be accompanied by a lifetime of changes in both diet and exercise. Whichever way we look at it, obesity occurs due to over indulgence and no matter how clinically effective a drug is, consuming thousands of calories on a daily basis will render any drug therapy obsolete regardless of how pharmacologically efficacious it is. Accompanied by the fact that many of these drugs are associated most commonly with addictiveness, cardiovascular risk and psychiatric effects, it seems many of these APIs are doomed to failure simply because of the patient group and lack of predictability.

Furthermore all the licensed products have a limited period of usage if adequate weight loss is not achieved; therefore a stage-gated, weight focused system can mean treatment is discontinued even if the patient is heading in the right direction.

It will be interesting to see how the future pans out for anti-obesity medication. Could we finally have newer drugs that can combat the slippery slope into morbid obesity, or will it be another failed start out of the blocks? Only time will tell, but if the outcomes are not seen as being strongly positive then pharma may well decide to call it a day and walk away as some have already done. It could well be the last chance saloon for anti-obesity drugs.