Drugs alone won’t be enough to solve the obesity crisis

Semaglu­tide, Ozem­pic, Wegovy… The names of these drugs have been seen across many head­lines recent­ly as they have shown promis­ing results for peo­ple with obe­si­ty, in and out of the lab. These drugs—designed to mim­ic gut hor­mone glucagon-like pep­tide 1 (GLP‑1)—have been tout­ed as near-mir­a­cles at a time when the obe­si­ty epi­dem­ic is rag­ing, with about 1 in 8 now liv­ing with the dis­ease. But can they real­ly solve a med­ical prob­lem as com­plex obesity?

TRUE—When it comes to glucagon-like peptide 1 (GLP‑1) receptor agonist drugs, the health benefits are clear.

The land­mark STEP trials(2) showed that semaglu­tide, the anti-obe­si­ty drug that has been hit­ting the news, caus­es about 15% weight loss in just over a year (68 weeks) with a once-week­ly dose of 2.4 mg.

GLP‑1 drugs clear­ly also improve patients’ health beyond weight loss. GLP‑1 drugs can low­er blood pres­sure and triglyc­eride lev­els and aver­age blood sug­ar, as marked by gly­cat­ed haemo­glo­bin, of about 1.4%. They also alle­vi­ate car­dio­vas­cu­lar risks. In Type 2 dia­betes, GLP‑1 drugs are asso­ci­at­ed with a 12–14% reduction(3) in three-point com­pos­ite major adverse car­dio­vas­cu­lar events out­comes com­pared to place­bo. Inter­est­ing­ly, they only have a mod­est effect on cho­les­terol — much less than you might expect from the weight loss data.

FALSE—GLP‑1 drugs come with substantial side effects that can threaten a patient’s ability to continue taking them.

Gas­troin­testi­nal side effects are the most imme­di­ate. About 10 to 20% will expe­ri­ence uncom­fort­able nau­sea, only half of which will see those symp­toms sub­side after a year. The drugs also increase the heart rate — though the clin­i­cal con­se­quence of that is unclear.

GLP‑1 drug treat­ment also increas­es in the risk of gallstones(4), a side effect seen with rapid weight loss of any cause (e.g., very low-calo­rie diets). Anoth­er con­cern is that mus­cle could make up about 20 to 40% of that total weight. How best to pre­serve that mus­cle has been the sub­ject of a huge amount of research.

UNCERTAIN—To date, the clinical benefits clearly outweigh the potential risks.

Still, while these drugs have been around for some time, they have only been in wide­spread use in recent years. We’ll get greater clar­i­ty about long-term safe­ty in the com­ing years.

Some pre­clin­i­cal stud­ies in ani­mals have sug­gest­ed a slight­ly height­ened risk(5) of thy­roid can­cer, but there is no con­clu­sive evi­dence of this. Clin­i­cians may want to pro­ceed with cau­tion in some­body with a his­to­ry or fam­i­ly his­to­ry of thy­roid cancer.

We also need to under­stand our exit strat­e­gy. About two-thirds of peo­ple will put the weight back on after dis­con­tin­u­ing treat­ment. Wean­ing patients off the drugs may help them main­tain their health gains, or they may need to con­tin­ue tak­ing the drugs long-term.

TRUE—Our understanding of how body weight is maintained has come along enormously in the past 20 years.

What’s clear is that the old days of say­ing that obe­si­ty is just lazi­ness and poor atti­tude are over.

Weight main­te­nance mech­a­nisms fall out­side of our con­scious selves. This works sim­i­lar­ly to how the body sub­con­scious­ly reg­u­lates breath­ing — you can hold your breath in the short term, but even­tu­al­ly, the brain will take over. Sim­i­lar­ly, peo­ple can eas­i­ly lose weight with crash diets, but the body will drag itself back up in the long term. Time after time, dietary stud­ies have shown that most peo­ple regain their weight after about a year, no mat­ter what diet they’re on. It’s stag­ger­ing how people’s weight bare­ly shifts year in and year out.

Weight main­te­nance is based on a com­plex neur­al cir­cuit­ry cen­tred in the mid­brain and hind­brain regions. These areas inte­grate sig­nals relat­ed to ener­gy bal­ance and mod­u­late feed­ing and ener­gy expen­di­ture. We now know that the oth­er piece of the puz­zle is gut sig­nalling. This knowl­edge comes in part from bariatric surgery. Research found it wasn’t food “mal­ab­sorp­tion” that caused the weight loss after the sur­gi­cal inter­ven­tion. Instead, the surgery trig­gered the release of gut hor­mones, like GLP‑1, which work togeth­er to sig­nalling sati­ety earlier.

Semaglu­tide har­ness­es that knowl­edge about gut sig­nals. It was devel­oped to mim­ic GLP‑1. It is more effec­tive than its pre­de­ces­sors, most of which led to a weight loss of about 5 to 8%, because it was engi­neered to bet­ter bind albu­min and resist enzy­mat­ic degra­da­tion so it can stay in the blood for longer.

Down the line, we may be able to achieve a cock­tail of drugs that per­fect­ly manip­u­lates these sig­nals and acts almost like a med­ical gas­tric bypass.

FALSE — While we know that semaglutide works, we’re not sure exactly how.

There’s a huge amount of redun­dan­cy in the weight main­te­nance sys­tem — if one bit is blocked, sig­nals get through a dif­fer­ent path­way. Because of that, it’s dif­fi­cult to know the rel­a­tive con­tri­bu­tion of each mech­a­nism and, in the case of obe­si­ty, exact­ly where and how sig­nals may be at fault.

GLP‑1 is no excep­tion. It acts on the brain, pan­creas, and stom­ach. None of these are “main”’ or “sub­sidiary” roles of the pep­tide. In obe­si­ty, we know that GLP‑1 delays gas­tric emp­ty­ing. We don’t quite know how much is con­tributed by that effect ver­sus the hypo­thal­a­m­ic sig­nalling effect. GLP‑1 recep­tors have also been found in oth­er tis­sues like the heart, lungs, and kidneys.

Anoth­er anti-obe­si­ty drug called tirzepatide, which com­bines GLP‑1 and gas­tric inhibito­ry polypep­tide (GIP) recep­tor ago­nists, also shows the com­plex­i­ty of the sys­tem. GIP on its own has an anti-fat-los­ing effect on the body. But when com­bined with GLP‑1, it has an addi­tive weight loss effect. About half of patients giv­en 10 or 15 mg of the drug week­ly lost about 20% of the body weight over 72 weeks in the SURMOUNT trial(6). It’s not clear why, though GIP seems to enable GLP‑1 to have greater recep­tor occupancy.

UNCERTAIN— We haven’t yet discovered all the effects of GLP‑1

While weight loss def­i­nite­ly plays a huge role in the health gains linked to GLP‑1, this doesn’t seem to be the full sto­ry. One pos­si­bil­i­ty is that GLP‑1 could have anti-inflam­ma­to­ry effects that act along­side the weight loss.

TRUE—There are definitely a number of genes that predispose to fat.

Epi­ge­net­ics may also be play­ing a role, so it’s not just the genes you car­ry, but how the genes are being read, that influ­ences the out­come. Anti-obe­si­ty drugs can help com­bat endoge­nous sig­nals bring­ing body weight back up.

FALSE—Obesity is not only genetics; many factors are at play.

The environment—including soci­etal pres­sures, socio-eco­nom­ic fac­tors, access to healthy food, and maybe even pollution—plays a huge role. A big thing across soci­eties has been a shift from man­u­al labour to com­put­er work and a much more seden­tary life.

UNCERTAIN—GLP‑1 drugs can’t do all the work.

There needs to be a soci­etal tack­ling of the obe­so­genic envi­ron­ment that we’ve man­aged to cre­ate in the last 30–40 years. If you’re get­ting to that point where lit­er­al­ly any­one and every­one with obe­si­ty and per­haps at the more upper over­weight spec­trum is on the drug, you would lose that focus.

Marianne Guenot