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GLP-1 and Obesity

Let’s have a look at a paper that came out recently in the New England Journal of Medicine. It shows strong results in a therapeutic area that a lot of people have spent a lot of effort on: obesity.

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 phentermine (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.

46 comments on “GLP-1 and Obesity”

  1. Old Country Doctor says:

    The “phen” in fen-phen should be phentermine.

    1. Derek Lowe says:

      Thanks! Copy/paste error, fixed.

  2. Gene Dubowchik says:

    The area of permeation enhancement for large, polar molecules, like that of endosomal escape, is indeed fascinating and potentially transformational. A Sci. Transl. Med. paper from 2018 suggests that, at least in dog, SNAC-enhanced absorption of semaglutide takes place in the stomach, in an area close to the tablet surface (https://stm.sciencemag.org/content/10/467/eaar7047)

  3. 11 fingerssss says:

    SNAC in a diet drug. Snicker.

  4. Gary Cornell says:

    I wonder if, given these results, semaglutide becomes the obvious second drug to use for type 2 diabetes after Metformin? None of the second tier drugs are perfect as far as I know – so does this result make semaglutide the obvious second tier drug?

    1. base651 says:

      Check international guidelines as they speak to the rationale and place of varying classes. Disclaimer-I work in pharma-diabetes therapeutic area

  5. metaphysician says:

    I wonder if the similar hard time with developing non-addictive painkillers is part of a common cause: the entire human “motivational circuit” is well protected, because there is little or no evolutionary downside to “too much motivation” in our original natural heritage. So, turning it up is easy, but turning it down is hard. Might also explain why it really, really hard to convince people not to have sex, too, even when there are good reasons.

    ( Most immediate counterargument: depression. If up-motivation is strongly protected, then why is depression such a common disease? )

    1. Mo says:

      Depression might be the killer app for kin selection. If you feel useless you decrease food intake and reduce libido (anhedonia helps there). Sleep a lot. Possibly kill yourself. Of course that trait would have had to have been developed in a time where there was a much tighter coupling between feeling useless and actually being useless.

    2. confused says:

      A very good/interesting question.

      I really wonder how much of mental illness is a result of our environment having changed so much faster than evolution can adapt – would you find equivalent rates of depression, anxiety disorders, etc. among hunter-gatherers, or fishing villages in 1000 BC Japan, or Caddoan woodland farmers 1000 years before Columbus?

      Is there even a way to know, given that these diagnoses weren’t made in ancient times, and non-industrialized cultures today are generally under massive pressure from industrialized society, and have been mostly pushed into marginal areas?

    3. eub says:

      Median humans have a systematic optimism bias (or several of them), which is useful for the common need of “it’s not hopeless, keep trying”, but maladaptive for “this way is hopeless, try something else.” So if you have any group selection mechanism, it could make sense to sprinkle in some non-optimists to see if anyone will listen to them.

      (Or maybe brains are complicated and you get all kinds of diversity like it or not and some of it’s adaptive somewhere.)

      1. Some idiot says:

        Hmmm… Interesting hypothesis… That said, my own (N=1) experience suggests probably not… My reaction would have been less “this doesn’t work, should try something else” and more “this doesn’t work… nothing works, it’s hopeless, so I might as well continue in the same rut I have been in for a long time now…”.

        Depression is certainly a tough one. It cuts very deep; a lot deeper than much normal, conscious thought, which is one of the reasons it is tough to do something about…!

        1. metaphysician says:

          I think the theory here is that clinical depression is the maladaptive far end of a normal spectrum of pessimist behavior. Its not that depression is an advantage, but that the lesser manifestation is an advantage. Depression is just the acceptable collateral damage. Nature is entirely fine with “this trait will make the 10-25% most extreme ‘beneficiaries’ miserable before killing them young, but its an evolutionary advantage for the rest, so it stays”. Think sickle cell anemia.

    4. FoodScientist says:

      Depression seems like an evolutionarily positive thing for most animals. In unfavorable conditions; running around for no immediate reason would only burn through calories and get you eaten by a lion. The exception would be beavers, squirrels, ect (rodents have cached food for millions of years). Also feeling useless is a purely human societal problem. Discrimination/stigma against people with “silent disabilities”(no immediately obvious difference like missing a leg) is rampant.

    5. Michael says:

      I suspect that depression might be a trait useful for society rather than the individual. Having some members who quickly switch to not caring whether they live or die, and therefore more ready to sacrifice themselves when so directed, could improve group-survival chances at a time of crisis

      1. DataWatcher says:

        I seem to recall reading that religious/political sects that have used suicide bombers to spread terror have actually recruited depressive people, open to the idea of suicide, into their ranks. Does anyone else know whether this has been verified?

  6. Ken says:

    “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”

    After following the link to the wikipedia page, I’d have to say it’s even more risky than it sounds. It’s hard to pick which phrase stands out most: “instantaneous explosion hazard”, “non-selective bioaccumulating pesticide”, “severe side effects”, “high acute toxicity”, “close to cyanide in terms of toxicity.”

    It sounds like a candidate for Things I Won’t Work With, not a dietary aid.

    1. Crni says:

      Well, us chemists have a slightly higher bar for “Things I Won’t Work With”. Dinitrophenol synthesis is part of undergraduate lab courses in many university programs.

      https://www.coursehero.com/file/89723/Organic-II-lab-2/

  7. Stanislav Radl says:

    Recently, there have been reports of the development of some selective CB1 antagonists that would act exclusively peripherally and are developed for the obesity treatment.
    An example is TM-38837 or AM-6545, whose structures do not deny that they were derived from the structure of rimonabant.

    1. aairfccha says:

      This would sound more promising if rimonabant hadn’t been withdrawn from the market rather hastily due to side effects.

      1. metaphysician says:

        Did any of the -bants *not* have depression and suicidal ideation as side effects?

        1. In Vivo Veritas says:

          Only the ones that didn’t make it to the clinic! 🙂

    2. Anon says:

      Rimonabant was spectacularly successful in one measure: wildly overoptimistic pre-launch market valuations helped the minnow swallow the whale, which is how Sanofi-Aventis was born!

  8. In Vivo Veritas says:

    “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!”

    Oh, c’mon! You can’t tease us like that. I gave a good portion of my career to the field. Let’s just say that you didn’t even have to take rimonabant for it to induce suicidal ideation!

  9. Lambchops says:

    One of my projects in my final medchem job was working on small molecules targeting GLP-1, so having reading this piqued my interest.

    Back then it seemed a fruitful area to be researching (oral semaglutide wasn’t yet available and as Derek’s noted wasn’t necessarily something you’d have expected coming), but was made trickier as it was before the GLP receptor crystal structure had been published. Given that became available a few years ago it’s not surprising to me to see a few more potential candidates have been identified (and gratifyingly they look as unappealing as targets at first glance as some of the stuff I worked on!). Alas I don’t have access to the full articles on these, but from what I can tell some of these molecules bind at allosteric sites, which is rather interesting.

    Thanks for prompting a trip down memory lane (even if those memories are a mixed bag!).

  10. AnotherCommenter says:

    I wish semaglutide nothing but the best; there’s a serious health need that needs to be addressed. But I developed pancreatitis from it and that’s nothing to mess around with. My concern is that while there may (hopefully!) end up being few cases of it in the wider patient population, if just enough patients viral with having pancreatitis, the drug may be torpedoed.

    1. Derek Lowe says:

      That is definitely the weak point, and you’re absolutely right: pancreatitis is no joke at all (I’ve seen it in action on someone I knew).

  11. SM says:

    Why do many studies split people into 2:1 treatment to control from a statistical perspective ??

    1. Jd says:

      If I remember correctly, it is because the variance in the effect is expected to be larger for the treatment vs control groups

  12. flem says:

    On GoodRx Ozempic is priced at ~$900 for 2mg. The study used 2.4mg per week. That close to $8640/mth or $104,000 yr. When does the first GLP-1 patent expire?

    1. In Vivo Veritas says:

      And you can get a gastric bypass for less than 1/2 of a years supply of Sema.

    2. Tony says:

      The first Ozempic patents start expiring in 2022, though quite a few go into the 2030s it seems.

    3. Gary Cornell says:

      The poster is confusing the cost of a pen (which can last 56 days) with the daily dose. The yearly cost of Ozympic lists for around 10k but nobody pays that. ICER estimates the “real” cost at about 6500/year which in line with most other second tier type 2 drugs

      1. flem says:

        the indicated dose for diabetes control is 0.25mg/wk for 4 weeks ; then 0.5mg/wk or titrated to max dose of 1mg/wk. a 2mg pen list price is ~$900. I’m sure NND is discounting their product heavily to remain competitive with other GLP-1’s. It will be interesting if they do anything with pricing for obesity. Of course they may soon be competing with Lilly’s tirzepatide GIP/GLP-1 receptor agonist.

  13. lizzy says:

    The NEJM article certainly was very impressive and hit all the right endpoints. It showed not only an impressive weight loss, but the right type of weight loss. Blood pressure went down, lipids went down, Hs-Crp went down, waist circumference went down, lean muscle mass percentage went up on DEXA, physical functioning improved. WOW!

    Just a few sticking points. This population wasn’t just slightly overweight. Their mean BMI was 38. That’s almost morbidly obese. Many such individuals have gained and lost weight through the years many times. For example, OverEaters Anonymous has 100 pounders meetings. They are led by people who have lost 100 pounds and KEPT IT OFF. It’s not so much the losing that’s hard for many of these people, it’s the maintaining the weight loss. That said, I’d love to see a one year followup on this crowd after they are off semaglutide. No I don’t expect Novo Nordisc to fund that trial.

    I’d love to see a similar trial in the BMI 29 – 35 group with follow up.

    Also, look at the price of this drug! With such a large segment of the population eligible here, I can’t see insurers authorizing it for the masses.

    1. Lambchops says:

      Anecdotal obviously, but the BBC article reporting on the trial had some quotes from one participant who started putting weight on again after the trial: https://www.bbc.co.uk/news/health-56011979

      The article also mentions a 5 year study to see if weight loss can be sustained in the long-term – but couldn’t find details on what type of study this is/who is funding it/how long they are taking semaglutide.

      From a UK perspective given the high costs of semaglutide and the lack of data on whether weight loss is sustained I wouldn’t be surprised to see some tight starting criteria and/or some sort of managed access agreement in place to get more data on whether weight loss is sustained.

  14. Aaron says:

    Is the goal of this to use it short term to help people lose the first amount of weight and get into less dangerous area, and then stop using it and continue on with diet and exercise? Or is this something they’re looking to keep people on long term?

    Personally I don’t know if i’d be open to something like this long term just for weight loss, but as part of a re-work of habits and to help get past the first hurdle of getting started it seems, if the safety risks are low, as a reasonable thing.

  15. albatross says:

    I wonder how the risk profile compares to gastric bypass surgery.

  16. I believe this drug will be positioned against bariatric surgery rather than other treatment approaches. Bariatric surgery has a similar benefit although different risks, but in general, these two modalities would be comparable for the groups initially targetted the very and morbidly obese.

  17. Eugene says:

    I am currently taking Ozempic. It comes packaged in a 2 pen box, 2ml per pen. I inject 1 ml once a week so a 2 pen box lasts a month. I am required to refill by my plan a 3 month supply. I pay a $40.00 copay and the label printed by the pharmacy claims my plan saved me ~$2900 dollars. Getting access to the true cost of some of these medications has proved difficult to say the least. In regards to GLP-1 agonists in general, they all resulted in weight loss for myself (330 to 220 lbs) and over the years I have gone from Byetta to Victoza to Ozempic. Between Victoza and Ozempic their was a 1 year pause in which I regained ~40 ibs. The Victoza also proved to be problematic due to the never-ending diarrhea. Ozempic is much less severe in that respect.

    1. flem says:

      If ever I need to go beyond metformin I would definitely opt for Ozempic instead of Lantus.
      In fact if I was on a low to moderate dose of a basal insulin I would ask to be switched to Ozempic ASAP.

  18. CET says:

    “In that latter category I put dinitrophenol….”

    One of my students surprised me by mentioning offhand that a lot of folks around here take chromium picolinate for weight loss. I had never heard of such a thing, and it seems ill-advised.

    1. flem says:

      that’s what Adkins was advocating very strongly. Not sure if any clinical data supports this but its cheap.

  19. Yuri K. says:

    2,4-dinitrophenol does wonders for the health of obese macaques (n=6) and it is dirt cheap.

    The trick is to give it in small doses as sustained-release tablets, and use DNP-methyl ether instead of plain DNP (methyl ether is liver targeted).

    (2019) https://pubmed.ncbi.nlm.nih.gov/31578240
    “Cynomolgus monkeys were fed a high-fat diet for 1 year. Following a baseline characterization, monkeys were treated with DNP-methyl ether (0.8 mg/kg body weight b.i.d.) for 6 weeks. . 0.8 mg/kg DNP-methyl ether treatment resulted in peak plasma DNP (the active moiety of DNP-methyl ether) concentrations of 10–15 uM. This is well below the lower plasma concentration threshold for DNP toxicity in rodents (~400 uM/L), and slightly above the concentration needed to promote a sustained increase in hepatic mitochondrial fat oxidation (5 uM/L) [27, 28]. Importantly 6-weeks of DNP-methyl ether treatment was not associated with any appreciable differences in body temperature [a known on-target side-effect of DNP
    https://pubmed.ncbi.nlm.nih.gov/?term=Shulman+GI%5Bau%5D+protonophore&sort=pubdate&size=50
    https://patents.google.com/patent/US20200352879A1/en
    2013. The present invention also includes a multi-layer tablet comprising a layer providing for the delayed release of one or more compounds of the invention (2,4-dinitrophenol) .. Example 1: reversal of hypertriglyceridemia, fatty liver and insulin resistance by a novel liver-targeted mitochondrial uncoupler (rats).
    https://patents.google.com/patent/US20200354306A1/en
    2013. Therapeutic DNP derivatives (DNP-methyl ether) and methods using same. Example 1: Reversal of hypertriglyceridemia, fatty liver and insulin resistance by a novel liver-targeted mitochondrial uncoupler. DNP-methyl ether (DNPME) was examined further to determine if it could safely decrease hypertriglyceridemia, NAFLD and insulin resistance without systemic toxicities. Treatment with DNPME both prevented and reversed hypertriglyceridemia, fatty liver and whole-body insulin resistance in high-fat fed rats.

  20. In the obesity drug context, does anyone know more details about what happened to the San people’s Pfizer’s P57 drug from hoodia gordonii?

    ‘Jasjit Bindra, lead researcher for hoodia at Pfizer, stated that components of the plant could raise liver enzymes and affect liver function. Even in its purified form, many of these compounds are not easily removed during processing.‘

    ( https://www.verywellhealth.com/side-effects-of-hoodia-89657 )

    Won’t the liver raise neutralizing enzyme levels in response to many approved small-molecule drugs?

    (Corollary – wondering whether the San people are known to develop liver issues?)

  21. Michael says:

    Three more medications that aren’t approved for obesity might be suitable for inclusion. Metformin is well established to cause weight-loss, and has generally beneficial effects upon health. It does often produce uncomfortable side-effects at the regular dose for diabetes though.

    Another diabetes drug: Miglitol, seems to cause slight weight-loss and again is probably beneficial to general heath due to lowering post-prandial glucose. Miglitol has no side-effects of note. Bizarely, it is unavailable in much of the world.

    Salbutamol is a little like amphetamine without the downsides. The side-effects of high doses are generally mild: tremor, headaches, insomnia etc. It can occasionally produce more serious side-effects like arrythmia, but these do lift quickly upon cessation due to the short half-life.

    I suspect PPARg antagonism would be effective for weight-loss, given that agonists – which are everywhere – reliably cause weight-gain.

  22. Walter Sobchak says:

    It took me a couple of weeks to verify this, but, my daughter had become obese after several spinal operations led to lots of physical and digestive problems. She was put on a course of Ozempic and lost 100 (not a typo, one hundred) pounds.

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