Weight loss drugs: the wrong answer to the obesity problem

There is a place for weight loss drugs, such as Victoza (Saxenda in the United States), Contrave and Mysimba, which were recently approved in the European Union and the United States. But it is a small place. From a population health perspective, drugs for weight loss are not merely the wrong answer, they are the wrong answer to the wrong question.

The question weight loss drugs ostensibly answer is: what are some effective ways to facilitate weight loss? When correct answers may include serious illness, eating disorders, or even cocaine use, you are well into the realm of bad questions.

A better question is: what are some effective ways to facilitate sustainable weight loss? Unless “sustainable” is constrained within a span of 24 months or thereabouts, no weight loss drug has ever proven to be an answer to this question.

But frankly, even this better question is still not a good question. A good question is: what are some effective ways to lose weight sustainably and improve overall health? And an even better question is: what are ways to lose weight, find health, make it stick and share it all with others, such as family members? Drugs are clearly not the answer to this excellent question.

A changing relationship with food

Still, weight loss is hard, and harder for some than others^[1]
. In cases of particular weight loss resistance, drugs may serve as a springboard and, as such, an alternative to surgery.

The intent of pharmacotherapy to facilitate weight loss involves changing the relationship human metabolism has with food. That is a tall order. Throughout most of human history, the relevant threat was starvation, not obesity. We are only here because our ancestors had adequate, metabolic defenses against famine^[2]
.

Those defences do not go away just because modern civilisation makes them obsolete. Until or unless there is a genuine survival and procreative advantage attached to the avoidance of obesity, the traits favoured in the Stone Age will persist in the modern genome. They are of no benefit now, but old genotypes die hard.

Consequently, we remain endowed with not just a single, flighty defense against starvation. We have numerous, overlapping pathways of defence^[3]
. We would not be here to fret about it were it otherwise. And so it is that any drug that targets a single pathway ineluctably activates compensatory responses in other pathways. The demands of survival require nothing less.

What, then, of drugs that are powerful enough to address all of this at its origins, to affect “master” pathways or perhaps multiple pathways? I doubt we can say for sure, but the best example to date is a cautionary tale. Rimonabant, an endocannabinoid receptor blocker, looked to be an exceptionally effective weight loss drug in the Rio Trial, published in 2006^[4]
. The drug was approved for use in the EU in 2006, but never in the United States. It was subsequently withdrawn from the market in the EU in 2009. Why? A statistically significant and clinically meaningful uptick in, of all things, suicide. The drug affected a major brain pathway, and the law of unintended consequences prevailed.

And so it is we wind up relying on drugs with less calamitous, albeit not trivial, baggage, and lesser efficacy as well.

Latest weight loss drugs

Authorities in the EU recently approved the combination of naltrexone and bupropion for weight loss^[5]
. The combination, known as Contrave, will be marketed as Mysimba by Japanese pharmaceutical company Takeda and is approved by the US Food and Drug Administration (FDA) for use in the United States. An expert panel in Europe has recommended approval of liraglutide (marketed by Danish pharmaceutical company Novo Nordisk as Victoza in Europe and Saxenda in the United States) for weight loss^[6]
. It, too, is FDA approved for weight loss in the United States. Three other drugs are FDA approved for weight loss in the United States: lorcaserin, which is marketed as Belviq; the combination of phentermine and topiramate, marketed as Qsymia; and orlistat.

None of these is a great drug. Qsymia does produce a weight loss of roughly 10% of body weight over a year or two in clinical trials, and does outperform placebo, but so does every weight loss drug ever tested. Phentermine is an amfetamine-like stimulant and is unlikely to be safe or suitable for long-term use. Among its common side effects is an elevation of blood pressure — one of the complications of obesity itself. We gain little if a treatment causes the complications of the condition that we are trying to avoid.

Topiramate is an anti-seizure drug. It can, and often does, cause fatigue, brain fog and nausea. Contrave, the combination of the antidepressant bupropion and naltrexone, a drug used for treating addiction, appears to be slightly less effective than Qsymia, and perhaps slightly less encumbered by side effects, although nausea appears to be common enough to be rate-limiting.

Lorcaserin, which influences brain serotonin levels, produced a 5% or greater weight loss when combined with a lifestyle intervention more often than the lifestyle intervention alone^[7]
. But half of the study participants dropped out, and the rather modest weight loss achieved in those who remained lasted reliably only as long as they kept taking the drug. Half of those who stopped the drug gained back the weight, despite the lifestyle intervention. The drug company that sponsored the trial waxed optimistic but, honestly, I was pretty underwhelmed.

Liraglutide is a glucagon-like peptide (GLP)-1 receptor agonist. It increases insulin production, and may decrease gluconeogenesis. Its use in treating diabetes is clear; exactly how it works to facilitate weight loss is somewhat less so. Among the common side effects are nausea, diarrhoea, constipation, and headache. There is also concern that the drug may increase the risk of thyroid cancer in humans, as it has been seen to do in rodent studies.

Orlistat, which inhibits intestinal brush border lipase, is effective only when taken in conjunction with at least moderate dietary fat, and is then associated with the rather notorious side effect of “anal leakage”.

True effectiveness is elusive with drugs

The history of weight loss drugs is a litany of disappointments, large and small. From the infamous demise of “Fen-Phen” (fenfluramine/phentermine), a combination antidepressant and stimulant that caused heart valve damage, to the 2007 decision by the FDA to deny approval for rimonabant once the suicide risk emerged from the data.

So while there is, indeed, a role for pharmacotherapy in obesity treatment, as there clearly is for surgery (
The Pharmaceutical Journal 2015;294:79), that role should be small. It should be a small role because, overwhelmingly, the problem can and should be fixed with feet and forks^[8]
. It should be a small role on account of the high monetary and human costs of anatomy-altering operations and potentially toxic drugs. Those who need these options should certainly have access to them. But as a society, we should be doing all we can, and we are not^[9]
, to make sure very few of us ever need the options of surgery or drugs.

Throughout most of human history, calories were relatively scarce, and physical activity unavoidable. When calories in exceed calories out, it is normal for a human body to turn that surplus energy into body fat. What is not normal — at least in the context of time-honoured human experience — is that the rainy day never comes. A surplus today is followed by a surplus tomorrow, and the next day.

When one considers that the problem we are asking weight control drugs to fix — a body turning surplus calories into an energy reserve — is normal human physiology, the conclusion that effective drugs in this category may prove to be elusive not just now, but forever, is hard to avoid. Imagine trying to find the drug that would aid the fish out of water, gasping for air.

Stated differently, no drug can compensate for the peculiarities of gills in a creature gasping at the air. Little is to be gained by looking for the culpable genes, either, because they are the very genes that make it a fish. The modern world in which we live is nearly as great a departure from our native interactions with food and exercise as dry land is for a creature of the sea. Perhaps we will deal more effectively with epidemic obesity if we rely a bit less on pharmacotherapy, and give a bit more consideration to the environmental implications of our inner fish^[10]
.