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