Can weight-loss drugs tackle the obesity crisis?

Sir Simon Stevens, NHS Eng­land chief exec­u­tive, described obe­si­ty as “the new smok­ing” when cal­cu­la­tions fore­cast 360,000 peo­ple will have weight-relat­ed can­cers by 2030, a rise of 62 per cent.  

Diet and exer­cise alone will not resolve the mul­ti-bil­lion-pound obe­si­ty epi­dem­ic. Bariatric surgery, which reduces stom­ach size, is the most effec­tive treat­ment. It has even been acclaimed as the most effec­tive inter­ven­tion in health­care, but only 0.1 per cent of eli­gi­ble UK patients opt for it, accord­ing to the Nation­al Insti­tute for Health and Care Excel­lence (NICE). This has cre­at­ed a huge, unmet need for weight-loss drugs.

An effec­tive, safe, cheap, anti-obe­si­ty pill could become one of the biggest-ever phar­ma block­busters. In 2014–15 obe­si­ty cost the NHS £6.1 bil­lion. The bill is pro­ject­ed to reach £9.7 bil­lion a year by 2050, with over­all costs to soci­ety of near­ly £50 bil­lion annu­al­ly.

But the mul­ti-bil­lion-dol­lar game of phar­ma­ceu­ti­cal roulette gen­er­ates many more losers than win­ners. The his­to­ry of weight-loss drugs is lit­tered by dis­as­ter and drugs tak­en off the mar­ket amid safe­ty con­cerns, from heart attacks to depres­sion and sui­cide. 

Only two years after being acclaimed the holy grail of obe­si­ty drugs, lor­caserin was with­drawn this year. Oth­er weight-loss drugs had been found to increase the risk of heart attack, which is a threat to obese patients even before they take any drugs. A US tri­al of 12,000 patients con­clud­ed lor­caserin patients were not sim­i­lar­ly at risk, but they were judged to be at increased risk from can­cer.

Irre­spec­tive of can­cer fears, the chances of lor­caserin being licensed for the NHS were lim­it­ed by costs rang­ing from £1,860 to £2,700 per patient a year. Oth­er notable drugs tak­en off the mar­ket includ­ed rimon­a­bant in 2008 and sibu­tramine two years lat­er.

Sibu­tramine worked by boost­ing lev­els of nor­ep­i­nepher­ine and sero­tonin, two chem­i­cal mes­sen­gers in the brain, and induc­ing feel­ings of full­ness after eat­ing. But the Euro­pean Med­i­cines Agency sus­pend­ed all its Euro­pean licens­es, rul­ing that poten­tial side-effects, includ­ing stroke and heart attack, out­stripped any ben­e­fits.

Weight-loss drugs only a quarter as effective as surgery

This left the NHS with only one offi­cial­ly approved weight-loss drug. Sold under the band name Xeni­cal, orli­s­tat helps to avoid weight gain and pro­duces weight loss, but it is only about a quar­ter as effec­tive as bariatric surgery. It pre­vents absorp­tion of a third of fat in food. Undi­gest­ed fat is excret­ed. Many patients strug­gle to tol­er­ate orlistat’s unpleas­ant side-effects which include diar­rhoea. 

A major plus of orli­s­tat is cost at about £18 a month. In con­trast, the so called list price of the gen­tler liraglu­tide is £196.20 a month or more than £2,350 a year. Liraglu­tide mim­ics a nat­ur­al hor­mone, glucagon-like pep­tide (GLP‑1), that helps to reg­u­late hunger.

Last week, NICE rec­om­mend­ed mak­ing liraglu­tide avail­able on the NHS after a con­fi­den­tial dis­count had been agreed with man­u­fac­tur­ers Novo Nordisk.

But the new licence is restrict­ed to only about 3,000 patients who are at high risk of car­dio­vas­cu­lar dis­ease, have pre-dia­betes and a body mass index (BMI) of at least 35kg. A person’s BMI is their weight in kilo­grams divid­ed by the square of their height in metres. Nor­mal BMI ranges from 18.5 to 24.9kg.

Anoth­er form of liraglu­tide, with the brand name Vic­toza, has a low­er dose and is approved to treat dia­betes, but not obe­si­ty alone. 

Why has NICE lim­it­ed liraglu­tide pre­scrib­ing? Its unen­vi­able job is to bal­ance infi­nite demand with finite, scarce resources. In 2018 the Nuffield Trust report­ed that 28 per cent of the UK pop­u­la­tion was obese. As Pro­fes­sor John Wild­ing, of the Uni­ver­si­ty of Liv­er­pool and pres­i­dent of the World Obe­si­ty Fed­er­a­tion, says: “We can­not treat a quar­ter of the pop­u­la­tion with liraglu­tide.”

Bariatric surgery: the key to new drugs 

The pic­ture might sound gloomy, but bariatric surgery is play­ing an unfore­seen role in fill­ing the ther­a­peu­tic vac­u­um.

Wild­ing explains: “Bariatric surgery has giv­en us new insights into the phys­i­ol­o­gy of the gut. We now know that by alter­ing the anato­my of the gut and alter­ing the way gut hor­mones work, we can over­come the prob­lems peo­ple have when they diet.

“The big prob­lem with a diet is that how­ev­er hard you try, your body is going to fight you, by mak­ing you feel hun­gri­er and slow­ing your meta­bol­ic rate. This is why it is so hard to lose weight and why peo­ple inevitably lose the bat­tle.”

It is also why Wild­ing insists obe­si­ty should be treat­ed as a dis­ease. He chal­lenges the pop­u­lar idea that obe­si­ty reflects per­son­al irre­spon­si­bil­i­ty rather than poli­cies pur­sued by the food indus­try to pro­mote cheap, high-fat, high-sug­ar food with super-siz­ing, meal deals and buy-one, get-one-free offers. Last month more than 800 food and drink man­u­fac­tur­ers signed a let­ter attack­ing gov­ern­ment pro­pos­als to ban online adver­tis­ing for prod­ucts high in salt, sug­ar and fat.

“The ‘per­son­al respon­si­bil­i­ty’ argu­ment is incor­rect as it fails to recog­nise the pow­er­ful genet­ic and envi­ron­men­tal pres­sures that cause obe­si­ty in the first place,” says Wild­ing.

“If you told peo­ple with asth­ma they need­ed to work hard­er at breath­ing, or those with depres­sion to pull them­selves togeth­er, it would be con­sid­ered inap­pro­pri­ate. This is what those advo­cat­ing that obese peo­ple should eat less and move more are doing. It’s far more com­pli­cat­ed than that.”

Research aris­ing from bariatric surgery is high­light­ing this com­plex­i­ty. Much of it is focused on so-called incretin hor­mones, includ­ing GLP‑1, the hor­mone liraglutin so effec­tive­ly mim­ics. Stim­u­lat­ing a decrease in blood glu­cose lev­els, incretins are released after eat­ing and enhance secre­tion of insulin, help­ing glu­cose enter the body’s cells.

Tomorrow’s prescription medications

Even though liraglu­tide has just been licensed by NICE as an obe­si­ty treat­ment, its days may be num­bered. It has been sur­passed by semaglu­tide, a once-week­ly injec­tion used to treat type‑2 dia­betes.

Wild­ing says: “Semaglu­tide is cheap­er than liraglu­tide even though it is made by the same com­pa­ny. It is not approved for treat­ing obe­si­ty, but it has been test­ed as an obe­si­ty treat­ment. The aver­age weight loss in the one-year tri­al was 16.9kg, which is more than dou­ble what we’ve seen with liraglu­tide. It may become avail­able to treat obe­si­ty in the next 18 months.”

In future, pow­er­ful com­bi­na­tion ther­a­pies could match bariatric surgery. These include tirzepatide which tar­gets GLP‑1 and anoth­er hor­mone, glu­cose-depen­dent insulinotrop­ic polypep­tide (GIP), released by the small intes­tine to con­trol diges­tion.

The Lancet med­ical jour­nal report­ed in 2018 that patients tak­ing tirzepatide lost sig­nif­i­cant­ly more weight than those tak­ing just a GLP‑1 drug alone. But it will take sev­er­al years for tirzepatide to reach the mar­ket, if it is licensed. Clin­i­cal tri­als are due to end in 2024.

There is even the prospect of a triple-action ther­a­py that could out­match bariatric surgery, tar­get­ing GLP‑1, GIP and glucagon, a hor­mone con­trol­ling blood sug­ar: this real­ly could be the holy grail of weight-loss drugs.

There could be anoth­er major ben­e­fit to this holy grail. It could help to kill the boom­ing mar­ket in unli­censed, dan­ger­ous and fake diet pills. The Phar­ma­ceu­ti­cal Jour­nal recent­ly report­ed that a pill known as DNP had killed a 21-year-old stu­dent. Wide­ly avail­able on the inter­net from sites which seem to be legit­i­mate, DNP was first used on an indus­tri­al scale to make bombs. Almost cer­tain­ly the stu­dent nev­er knew that.