Thin Drugs, Fat Profits

So, at one extreme, we have genetically determined problems with hormones or their pathways as a cause of gross obesity, mostly commencing in childhood. Then there is the middle ground as it were, where the response of our hormones to the things that we do (or don’t do), like exercise and overeat, makes us fat — and sometimes very, very fat. There are relatively small numbers of people in the first category — possibly 5 per cent of those who are obese — but the numbers in the second category run to tens of millions. Knowing this has drug companies rubbing their hands in glee. For if hormones make you fat, can they not also be used to make you thin?

In 1893 thyroid extracts began to be marketed for weight loss under brand names like ‘Safe Fat Reducer’ and `Corpulin’. As you now know, thyroid extract is the one hormone that can safely navigate the gut, but safe it ain’t. Given in excess it can cause sudden death, not to mention bone loss, palpitations and weakness, as muscles are burned up in its all-consuming quest for fuel to increase metabolism. In order to avoid these alarming side effects, patients were advised to take ‘chasers’ of arsenic or even strychnine.

Hormones were not the only diet fixes. Laxatives too were very popular as was a particularly nasty chemical called dinitrophenol, a diet aid of the 1920s. An ingredient of explosives and weed killers, it too had a nasty habit of killing people. The idea of increasing metabolism persisted, however, and in the 1940s, digitalis, better known as a heart medication, was introduced as a treatment for weight loss. Amphetamines were touted for the same purpose at around the same time and were prescribed indiscriminately to two thirds of those seeking advice on weight control. Their side effects — psychiatric disorders, addiction, withdrawal problems, heart failure, sudden death — were well known but largely swept under the carpet. It wasn’t a lesson learned. Fenfluramine and phentermine, both licensed individually for dieters in the 1970s by the FDA, began to be used together and by 1996, despite media scares, 18 million prescriptions a year were issued for illegal ‘off label’ (i.e. not for indications licensed by regulators) use of what came to be known as fen-phen. It caused long lingering deaths from primary pulmonary hypertension and valvular heart disease. By the late 1990s, fen and phen and another similar drug, dexfenfluramine, had finally disappeared.

This illustrates two things: first, the intense desire for such products by the overweight, even with knowledge of their potential side effects; and second, nothing that is both really effective and relatively free of side effects has yet been invented, even though a fortune awaits its inventors.

A successful obesity drug is top of every drug company’s wish list. At the time of writing, there are two, neither of which are particularly effective (weight loss with proper use of around 5 per cent), and both have side effects. The drug orlistat (Xenical) attempts to stop food being absorbed by altering the action of a fat- busting enzyme, which prevents fats from being broken down and thus absorbed. About a third of dietary fat exits via the stools. If you don’t cut down the level of fat in your diet whilst taking Xenical, you get what the company euphemistically calls ‘anal leakage’. Nice. Sibutramine (Reductil) works in a different way in that it affects neurotransmitters in the brain involved in appetite. One of its side effects is an increase in blood pressure, the very last thing you want in the seriously obese, who usually already have blood pressure problems.

So why don’t the companies just target the neurotransmitters involved in switching off appetite — by developing an anti-NPY molecule, for example? The problem here is that this neurotransmitter is found all over the brain and does far more than just regulate appetite. Thus the likelihood of an anti-NPY drug causing side effects is very high and on this rocky shore have foundered many attempts which target the brain circuits controlling appetite. Of 114 anti-fat products that began development, just four have made it all the way through to clinical trials.

The discovery of leptin has led to an explosion of new hormonal discovery and a plethora of potential new anti-fat targets for the pharmaceutical companies. For instance, oxyntomodulin is a newly discovered pre-hormone, which inhibits appetite and is released in the gut in proportion to meal size. It is found in high quantities in those conditions associated with low bodyweight, such as anorexia. But knowing what these things do and understanding how to develop them as effective drugs are very different. An example would be giving people PYY so that they would constantly feel too full to eat much. The problem here is that PYY is a peptide, which means that it would be destroyed by the gut if taken orally, so would have to be injected — and on a daily basis to be effective. Daily injections are just not practical for the purposes of mass medication.

Ghrelin is proving to be a shining star, endocrinologically speaking. It’s been discovered that it is what’s called a secretagogue for growth hormone — triggering its production. Far from just acting in the stomach and in the brain, ghrelin receptors have been found in the heart, pancreas, testis and placenta. What on earth is it doing there?

One of the best ways to find out what something does in the body is to breed mice engineered not to have the gene that makes whatever it is that you are interested in. These are called knockout mice. From all you’ve heard so far, you’d think ghrelin-deficient mice would be teeny and ever so skinny. Actually they’re not, they’re of normal size and weight but interestingly they do seem to have cardiovascular problems as they age. This suggests ghrelin might have a role in maintaining metabolism during ageing. Ghrelin also seems to be implicated in sleep and in the regulation of anxiety. Truth to tell, there’s decades of research left in ghrelin. If there was one hormone that I would tip as the one to watch, it’s this one. I suspect that you may possibly see the first use of ghrelin, not in the obese but as a weight controller in cancer patients who have lost too much weight.

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