The Weight-Loss Drug That Wasn't

Illustration for article titled The Weight-Loss Drug That Wasn't

Fibroblast growth factor 21 (FGF21 for short) was a hot prospect in anti-obesity research — and drug companies jumped into the fray, eager to capitalize. But now it appears that, like sticks and stones, FGF21 will break your bones. Here's the story of the hip new weight-loss drug that may never see the light of day.


FGF21 is a protein that acts on cell metabolism, affecting blood glucose, insulin, and lipid levels. It came on the scene as a possible drug in 2005, and scientists started getting really excited about it in the late aughts — one 2008 study, for instance, showed that elevated blood levels of the protein were associated with both obesity and metabolic syndrome. That doesn't mean FGF21 itself causes obesity, though — instead, researchers think obese people (and mice) are actually resistant to FGF21, meaning more of it ends up unused, floating around in their blood. Despite this resistance, FGF21 looked like a possible source for anti-obesity drugs. In 2007, pharmaceutical company Ambrx announced it would partner with Merck "to develop a novel therapeutic protein with biological properties similar to Fibroblast Growth Factor 21 (FGF-21) for the treatment of type 2 diabetes and related metabolic disorders such as obesity." And in 2009, a researcher at Eli Lilly wrote, "Recent evidence from several animal studies indicates that FGF21 induces numerous beneficial metabolic changes without apparent adverse effects. These results suggest that FGF21 could be a novel and attractive drug candidate for the treatment of cardiovascular disease, obesity and type 2 diabetes."

Yeah, that "without apparent adverse effects" part? Not so much — a new study shows that in addition to working with metabolism, FGF21 also has an effect on bones. A big one. ScienceDaily quotes lead study author Yihong Wan: "This hormone is a very potent regulator of bone mass. When we oversupply FGF21 in mice, it results in substantial bone loss." Mice that got an FGF21 drug for two weeks lost 78% of their spongy bone (that's the inside part of the bone). Basically, this means any good things FGF21-based drugs do might be outweighed by an increased risk of osteoporosis.

It's important to keep in mind here that research into FGF21 wasn't just about making money off fat-shaming (though the aggressive marketing of weight-loss drugs always has an element of this). Scientists were hoping FGF21 would be a key to lots of metabolic disorders, including diabetes. So this whole "rapid bone loss" thing is a setback for big pharma (Eli Lilly scientists published one of the first papers on FGF21, back in 2005), but also a setback for drug treatment of metabolic problems in general. That these problems are thorny is no surprise — glucose metabolism is how our cells run, after all, and its no surprise that it's linked with many organ systems. Just as FGF21 was getting big, scientists were discovering that bones could have a role in regulating blood sugar and fat — so the bone link in the new study shouldn't be a complete shock. What it should be is a reminder that developing drugs to change the way the body handles fat and sugar is fucking difficult — and when a company says they've got one, some healthy skepticism is in order.

Rapid Bone Loss as Possible Side Effect of Anti-Obesity Drug [ScienceDaily]

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I'm a biochemist, though not an expert in metabolic diseases, but this doesn't seem to suggest that studying FGF21 couldn't lead to drugs for metabolic disease, just that it isn't going to be as simple as injecting people with a hormone. For example, if researchers determined what causes FGF21 resistance in obese people, a drug might be developed that would prevent that resistance.

Many scientific advances work like this. Something new and exciting gets announced. Doctors and drug makers hype it as cure-all. And then a significant drawback is discovered, the public moves on to the next exciting thing, and researchers keep studying the effects in obscurity. Five to ten years later, what will likely emerge from all this is a better understanding of metabolism and, if we're lucky, a new drug with some pluses and some minuses that can be added to the toolbox for treating metabolic diseases.