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Briefing | Big shots

A new class of drugs for weight loss could end obesity

They promise riches for drugmakers, huge savings for health systems
and better lives for millions

[20230304_F]
Mar 2nd 2023
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How did Kim Kardashian, a reality tv star, lose enough weight to fit
into a slinky dress once worn by Marilyn Monroe? She has talked about
a diet and exercise, but lots of her fans think it could also be
thanks to new weight-loss drugs that many far-from-fat celebrities
are said to be taking to keep their figures supremely svelte. There
is no need to speculate about Elon Musk, a famed entrepreneur: he
readily admits that one such drug, Wegovy (semaglutide), has helped
him shed weight. In fact, social media are awash with pictures of
delighted patients flaunting before-and-after snaps that prove just
how effective these novel medicines are.

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Investors and analysts are as excited as the gossip columnists. Some
estimate that Novo Nordisk, the Danish pharmaceutical firm that makes
Wegovy, will sell $3bn-4bn of it in America alone this year. The firm
plans to launch the drug in many more countries in the coming months.
Its share price is up by 40% over the past year and has doubled over
the past two.

[20230304_F]

Eli Lilly, another pharmaceutical firm, hopes to start selling a
similar treatment for obesity, called Mounjaro (tirzepatide), as
early as this summer. In trials, recipients shed an astonishing 20%
of their weight on average. UBS, a bank, thinks it could become the
"biggest drug ever". Jefferies, an investment bank, says that by 2031
the market for these drugs, collectively known as GLP-1 agonists,
will exceed $150bn (see chart 1). That is on a par with all drugs to
treat cancer, sales of which amounted to about $185bn in 2021.

Even such head-turning numbers do not fully capture the drugs'
potential, however. Obesity is a problem of staggering global
proportions--and one that afflicts few celebrities, but legions of
ordinary people. In 2023 the World Obesity Federation (wof), an NGO,
says 1.1bn people aged older than five, or roughly 14% of all people
in that age bracket, were obese. A further 1.6bn, or 24% of all the
world's over-fives, were overweight. In a report to be published on
March 3rd, to mark World Obesity Day, the federation projects that
4bn people--half of everyone over five--are likely to be overweight or
obese by 2035 (see chart 2, left-hand panel).

[20230304_F]

The report estimates that the annual cost of humanity's growing
paunch will reach $4trn in 2035, of 2.9% of global gdp, in the form
both of spending on health care and of working time lost to illness
and premature deaths (see chart 2, right-hand panel). That is the
equivalent of another covid-19 pandemic every year.

Moreover, obesity is not just a first-world problem. The costs are
growing faster in poor and middle-income countries than they are in
rich ones. By 2035, the wof projects that 47% of Mexicans, 46% of
Iranians and South Africans and 42% of Malaysians will be obese.
Spiralling health-care costs in these countries will be a drag on
economic growth. Any treatment that can reduce these numbers could
potentially improve the health of billions, and also make the world
wealthier.

Tummy trouble

Obesity is typically determined using a ratio of weight to height
known as the body-mass index (BMI). A BMI over 25 is normally
considered overweight; one over 30 is the standard definition of
obesity. Thus an American man of average height (175cm or 5'9") is
considered overweight if he tips the scales at 77kg (170lbs) or more
and obese if his weight is 92kg (203lbs) or more. (There are
exceptions, such as bodybuilders, who weigh a lot thanks to copious
muscles.)

Excess weight is not simply a matter of appearance. Obesity is
associated with such grave illnesses as diabetes, strokes and heart
disease. John Speakman of the University of Aberdeen notes that women
with a BMI of 35 are 90 times more likely to have diabetes than those
with a BMI of 23. For men, the risk is five times greater. Obesity
also increases the risk of 13 types of cancer, including those of the
breast, bowel, womb and oesophagus. More recently, it was found to
raise the odds of a patient dying from covid-19. In these and other
ways, it causes the deaths of around 4m people a year.

The solution might seem obvious: to eat less and exercise more. To
those of a judgmental nature, the failure to lose weight reflects a
lack of willpower. But Louise Baur, a professor at the University of
Sydney and president of the wof, rejects the idea that the obesity
epidemic represents "the moral failure of hundreds of millions of
people". Fatima Stanford, who studies obesity at Massachusetts
General Hospital and Harvard Medical School, notes that attempts to
lose weight through diet and exercise work for only 10-20% of the
population: "For most people we don't see a dramatic drop."

Fat-linger error

The reason almost certainly lies in the evolutionary past. In a state
of nature food is rarely plentiful, so Homo sapiens has evolved to
hang on to fat. One adaptation is that, when a body's caloric intake
is reduced, its resting metabolism slows. Another is that it releases
extra ghrelin, a hormone which signals to the brain to increase food
intake.

Worse, from the point of view of the would-be dieter, a body that has
lost weight appears to "remember" its previous level and fights to
regain it. "Your entire biology reacts in a way to make you want to
go back and eat," laments Ahmed Ahmed, a British bariatric surgeon. A
study of contestants in "The Biggest Loser", a television show in
which participants competed to lose the most weight, found that even
six years after their appearance, their metabolisms were still slower
than they had been before they started dieting. The amount they could
eat without prompting an increase in weight had, in effect,
diminished. Diets, in other words, get progressively harder to
sustain.

What is more, obesity has a sizeable genetic component, and so is
partly inherited. Dr Speakman says between 45% and 65% of an
individual's risk of becoming obese is passed down in this way. A
predisposition, though, needs encouragement to manifest itself. It is
not just people's genes, but also the "obesogenic" circumstances in
which so many of them live that is adding to the species' girth. As
Dr Baur puts it, obesity is "a physiological response to what has
become a pathological environment".

The most notable feature of that environment is an abundance not
simply of food but, more specifically, of processed food. Merely
grinding and reconstituting the food given to lab rats causes them to
put on weight. In 2019 a similar experiment on people by Kevin Hall
of America's National Institutes of Health and colleagues showed
that, under controlled conditions, people consume more calories if
offered mainly processed rather than unprocessed food.

And gaining fat is easy in a mechanised world. Work used to consist
of arduous manual labour for the vast majority of humanity--but not
any more. For most people in the rich world, and a fast-growing
proportion in developing countries, physical exercise is no longer a
necessity, but an entirely voluntary pastime, to be pursued in
leisure moments, if at all. A study published in 2011 looked at how
active people's work had been in America over the previous five
decades. Between 1960 and 2006 there was a reduction in energy
expended of 100 calories a day, on average--an amount that turned out
to account for much of the increase in Americans' weight over that
period.

Processed food and sedentary lifestyles are the principal elements of
today's obesogenic environment, but other things are involved as
well. Depression and other mental-health conditions--and some of the
drugs used to treat them--encourage weight gain. Dr Stanford says that
20% of America's obesity problems are tied to medications such as
lithium, antidepressants and anti-insomnia drugs. For women, the
menopause is also reckoned obesogenic.

The steady growth of human waistlines has defied the efforts of
doctors, dieticians, pharmacologists and policymakers for decades.
Ever more elaborate rules about how food is labelled or marketed have
not made a dent in the problem. Taxes on unhealthy ingredients are
unpopular, in part because they place a far higher burden on the poor
than on the rich. A good indication of how desperate so many people
are to lose weight is the nearly $250bn the world spent on dieting
last year, even though it tends not to work.

Drug companies have offered a series of ineffective and sometimes
dangerous treatments. There was dinitrophenol, used in diet pills
during the 1930s, which caused perhaps 25,000 people to lose their
sight. Later on amphetamines became popular (and effective) slimming
aids--until the risk of addiction and other side-effects became
apparent. Ephedra, a herbal medicine containing a substance like
amphetamines, was banned in America in 2004 after it was tied to
heart attacks and strokes. A few years later two other treatments,
rimonabant and sibutramine, were withdrawn from sale, amid concerns
about their safety.

Staple diet

In extremis, the seriously fat can turn to bariatric surgery, in
which their stomachs and small intestines are rearranged to reduce
the amount of food absorbed, and to accelerate the feeling of being
sated. This, says Dr Ahmed, can reduce body weight by 30% to 50% in
the first six months, and potentially more after that. It also brings
improvements in blood pressure, breathing, sleep, cholesterol and
back pain. And many patients will no longer be diabetic after
surgery.

Surgery, though, is a drastic response to the problem, and is limited
by the number of surgeons. Hence the excitement about GLP-1 agonists,
which can be administered by patients themselves as weekly
injections. The new drugs were first devised as treatment for
diabetics. They mimic hormones the body produces naturally after a
meal, which stimulates the release of more of a second hormone,
insulin, and less of a third, glucagon. Together, these effects
regulate the level of glucose in the blood.

In addition, however, GLP-1 agonists slow down the rate of "gastric
emptying", which means food stays in the stomach for longer, so
people feel fuller and want to eat less. The drug also affects the
hypothalamus, the part of the brain that controls hunger. What is
more, GLP-1 has an effect on fat, too, making the body more likely to
break it down.

Novo Nordisk began selling semaglutide, the first GLP-1 agonist, in
2017 under the brand name Ozempic, to treat diabetes. But having
noticed how many of the recipients slimmed down dramatically, it soon
began testing the drug as a weight-loss treatment. In a 40-week trial
a third of patients lost more than 10% of their body weight after
taking a weekly dose of 1mg. A second trial, of a 2.4mg weekly dose
for 68 weeks, brought an average weight loss of 15%. That is the dose
Wegovy provides; it has been on sale in America since 2021. In
December America's Food and Drug Administration approved its use for
12- to 18-year-olds as well.

Mounjaro, meanwhile, activates the same GLP-1 receptors as Wegovy,
but also mimics a second hormone involved in the regulation of
appetite. In trials it stimulated an astonishing 20% reduction in
body weight on average. Many other drug companies, sensing a possible
bonanza, are working on similar products.

Not to everyone's taste

The new treatments are not without their flaws. For one thing, there
are side-effects, including vomiting and diarrhoea, which were severe
enough to cause 3% of patients to stop using them in a survey
conducted by the Mayo Clinic, an American hospital. In addition, they
are supposed to be taken as part of a broader programme of dieting
and exercise--although it is not clear how essential this is to the
weight loss. Semaglutide, specifically, appears to increase the risk
of a rare type of pancreatitis. There are also concerns over the use
of the drugs during or just before pregnancy. And studies in animals
have shown a higher incidence of thyroid cancer.

[20230304_F]

For many these risks will be worth running. A bigger drawback,
however, is that those who start taking the new drugs are likely to
depend on them for life. Stop, and the weight piles back on, just as
with most conventional diets. In the first year after stopping a
2.4mg dose of semaglutide, people regain two-thirds of the weight
they lost (see chart 3). And, as with dieting, some people even put
on more weight than they started with.

The need to keep injecting is fine with drug companies, but it makes
doctors more cautious, given the lack of data on the effects of
lifelong use. Britain's draft national guidelines say semaglutide
should not be taken for more than two years for weight loss. But as
more data on the drugs' long-term effects become available, it is
possible that they will become like statins, a medicine to lower
cholesterol that is commonly prescribed for life.

[20230304_F]

Lifelong commitments can be expensive, however. Taking Wegovy costs
around $1,300 a month in America and Ozempic about $900. The market
will clearly bear this: so great is the demand for the drugs for
weight loss, many diabetics complain, that they cannot get hold of
them for their original purpose. Novo Nordisk has set up a page on
its website to reassure potential customers who are struggling to
find any Wegovy. "We are taking significant measures to increase our
production capacity," it declares. The firm has hired a second
contract manufacturer to make the drug; the first is expanding its
output.

Insurers and governments will presumably be able to negotiate
discounts to drugmakers' list prices. And as rival products come to
market, prices should come down eventually. In the very long run the
new drugs will lose their patents, and become available in generic
form.

But at the moment, in America, relatively few insurance policies
cover Wegovy--mainly those backed by employers. (This still leaves
Wegovy a potential American market of 40m patients, notes Lars
Jorgensen, Novo Nordisk's chief executive.) Governments are even more
hesitant. Although the drug has been licensed in Denmark and Norway,
it is not provided through the state health system in either country.
Britain's National Health Service has been reviewing the drug; it
seems likely to make it available soon, but only to the most obese
patients and only through specialised clinics.

This caution will presumably evaporate if it becomes clear that
widespread use of the drugs will bring big cost savings to insurers
or governments in the form of avoided treatments for conditions
related to obesity. Daniel Chancellor of Citeline, a market-research
firm, says GLP-1 agonists have reduced strokes and heart attacks in
those taking them for diabetes by 14%, deaths from all causes by 12%
and hospital admissions for heart problems by 11%. Novo Nordisk is
sponsoring a formal trial looking at semaglutide's impact on
cardiovascular disease among overweight and obese patients. It
started in 2018 and is due to conclude later this year.

A frantic spate of haggling will doubtless follow. Insurers and
health systems will need to weigh the massive cost of treating
diseases linked to obesity, and the improved quality of life the new
drugs will bring, against the prices drugmakers are demanding,
multiplied across the lifetimes of likely recipients. But the scope
for savings is enormous.

Reducing the global numbers of the overweight and obese by five
percentage points below the current trend would bring annual savings
of $429bn, according to a study published inBMJ Global Health, a
medical journal (that figure includes the benefits of the obese
living longer, more productive working lives). The potential benefits
would extend to middle-income countries, too. The study expects the
costs of obesity to rise by 3.6% a year between now and 2060 in
Australia, but by 6.6% in Thailand and 7.6% in India.

The fact that a growing share of humanity has more than enough to eat
and no need to exhaust itself through constant, gruelling physical
labour should be cause for celebration. Indeed, to most people, it
would seem an obvious sign of progress. Yet those same heartening
trends are also entombing billions of people in a shroud of fat. The
misery associated with this global epidemic of obesity is vast. It
kills millions, makes many more sick, costs huge sums--and is an
unfathomable well of stigma and shame for those afflicted. If the new
drugs being deployed against obesity can reduce this unhappy tally by
even a small amount, they should be welcomed with open arms. #

This article appeared in the Briefing section of the print edition
under the headline "Big shots"

Eat, inject, repeatEat, inject, repeat

From the March 4th 2023 edition

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