I’ve been kicking around the idea of reviewing the history of anti-obesity drug discovery, but it’s just too much to face on a Monday morning! Put shortly, though, this has been, for the most part, a bottomless pit into which people shove money and time. The short guide is that most of the ideas that people come up with don’t work, and the few that really do work turn out to be hazardous. In that latter category I put dinitrophenol, which uncouples a key step in the metabolic production of ATP and is just as risky an idea as it sounds like, various amphetamines, whose effect on weight loss is just as clear as their severe side effects and risk of addiction, the combination of fenfluramine and dexfenfluramine (fen-phen), which leads to cardiac valve problems, sibutramine (which didn’t even work that well to start with), and more. There are weirdo mechanisms out there like Orlistat that continue on the market, but have the combination of not working much and having unpleasant side effects (but at least nonlethal ones, I’ll give ’em that).
And in the former category, we have various attempts at targets such as leptin, NPY5, galanin, CB-1, the D1 dopamine receptor, and plenty more besides. Here are some reviews that cover some of this ground (and people are still in there pitching), but believe me, there’s a lot to cover. Over the last 30 years there have been more development programs than I can count directed at such targets, and almost all that money has been incinerated as they failed one after the other. The general problem is that feeding behavior is, from an evolutionary perspective, extremely well guarded. We have multiple backup redundant overlapping mechanisms to make sure that we eat food, because every organism in the past that didn’t do an effective job of that is no longer with us. Our ancestors were the other guys.
The paper under discussion is part of a group of compounds that have been investigated for some years now: glucagon-like-peptide 1 (GLP-1) mimics. That’s a very powerful metabolic signaling peptide, and it’s been studied intensely in the diabetes field for its ability to stimulate insulin secretion. But it has effects on the kidneys, the liver, bone tissue, the cardiovascular system, the CNS, and more. Some of those CNS effects include inducing a feeling of satiety (that is, making you feel as if you’ve already eaten), and this is surely tied up with its effects on the gut of slowing gastric emptying.
GLP-1 has a very short half-life, under five minutes. This is often the case with proteins that have so many strong effects, because it’s under tight control. There’s a whole class of diabetes medications (the DPP-IV inhibitors) that work by blocking a key enzyme that degrades GLP-1, increasing its levels that way. And there are more direct methods. People have made a variety of versions of the actual GLP-1 peptide, modified in ways to extend its half-life. Those still have to be injected, because systemic oral delivery of peptide drugs is the very definition of an uphill fight (you’re throwing them right into a part of the body that is focused on ripping proteins to shreds). But via injection, dosing is typically once a day or even once a week, because they really did modify that half-life! There are a half-dozen or so of these approved now, and choosing between them is not always straightforward.
As these modified peptides went through clinical trials, a consistent effect seen in the treatment groups was weight loss, surely through the mechanisms mentioned above. That’s considered to be another feature of these drugs, because losing weight is one of the most important things that can be done to ameliorate Type II diabetes anyway. That naturally led to ideas about giving such drugs to people who didn’t have diabetes (or not yet) but needed to lose weight, and over the past ten years or so there have been a number of clinical trials. This area has been approached cautiously, for several really good reasons. First off, the GLP-1 analogs are not without side effects of their own (how could they not be?) Nausea, abdominal pain, and vomiting are a consequence of the gut motility effects in some people, just to name an obvious one right off the top. But there are rare side effects that are much worse: occasionally a person taking these will develop acute pancreatitis, so you have to watch out for that, and all of these drugs carry a warning about increased risk of medullary thyroid cancer as well. What these various risks are like for non-diabetic patients is something you’re only going to find out by dosing a lot of them, which is nerve-wracking, and then there’s the general experience of weight loss drugs failing over and over again, which doesn’t steady anyone’s hands, either.
But liraglutide (brand names Victoza and Saxenda) was approved by the FDA in 2014 specifically for weight loss (one injection daily), and has seen further approval in other patient populations since then. There’s evidence that a good amount of off-label prescription has been going on in this class as well. So far, there have been no show-stopping safety signals in the non-diabetic population. Other drugs in this class are in trials as well, but don’t get the idea that everything works: in 2019, a combination GLP-1/glucagon targeted drug failed in the clinic (weight loss was seen, but not enough glucose control).
Now, at long last, to the new paper. It’s a study of semaglutide (Ozempic, Rybelsus) in nearly 2000 patients without diabetes, but with BMI of at least 30 (or at least 27 with one other weight-related condition, which are the criteria under which liraglutide was approved). This group was divided 2:1 into treatment (one injection/week) and placebo groups, and all of them got lifestyle intervention (diet and exercise). After 68 weeks, the placebo group had lost about 2.4% body weight, while the treatment group had lost 14.9%, an impressive difference. The treatment group also showed greater improvement in other metabolic risk factors such as blood pressure as well as overall physical functioning. Adverse events were pretty similar across the two groups, with nausea and other GI symptoms resolving as the trial went on. There was an increased frequency of gallstones in the treatment group, which has been seen with GLP-1 analog treatment in general (and indeed, with relatively rapid loss of this kind by any means).
These look like very strong results – in fact, I don’t know if I’ve seen anything else that shows this level of weight loss so convincingly. Novo Nordisk (producer of semaglutide) is pressing ahead in the clinic with an eye to getting this approved for obesity, and given the record of liraglutide, they would seem to have a good case. One also wonders about another possibility. I mentioned two brand names above: the second one (Rybelsus) is, despite my earlier warnings about how hard it is to do this, an oral version of the drug. The modified peptide is co-formulated with sodium N-[8-(2-hydroxybenzoyl) amino] caprylate (SNAC), which has been studied for years now as an “absorption enhancer” that increases the permeability of the gut wall cells through mechanisms that are still being studied. Getting this to work for something like a GLP-1 mimetic was quite an accomplishment, and you wonder if this route of administration would be enough to show effects in an obesity trial as well. Rybelsus showed weight loss in its clinical trials for diabetes; it wouldn’t surprise me if this route is in the company’s long-terms plans as well.
Obesity drugs have blown up too many times in the past for me to proclaim that victory is at hand, but overall the GLP-1 field, for all its complications, looks like a serious contender. Long-term safety (and long-term efficacy) will have to be watched as semaglutide progresses, but so far, this is the most promising candidate I can recall ever seeing.
