One debate the pharmaceutical world is definitely going to have is “what constitutes a longevity drug?”

I’m getting ahead of the curve here by debating the longevity status of one of the most popular drugs on the market at the moment: Ozempic. The first part of this post delves into what the drug is, how it works, and why/how it was developed. If you are someone who looks up the ending of a movie before watching it, you can just scroll down straight to the takeaway.

Note: Ozempic has been prescribed off-label by doctors for weight loss. Novo Nordisk, the company which makes Ozempic, has received FDA clearance for a weight loss specific version of the drug which they are now marketing as Wegovy (along with a pill form, Rybelsus). To avoid confusion, I’ll refer to all these drugs from here on out as “semaglutide” which is the generic term for the drug. Ozempic, Wegovy, and Rybelsus are all semaglutide.

Good ol’ GLP-1s

First, a very brief overview of what these weight loss drugs do.

Most people know about insulin, the hormone which causes cells to increase glucose uptake. Glucagon is the lesser known hormone which, like any good sibling, counterbalances the effects of insulin. Glucagon is primarily a response to low blood glucose levels. These two hormones work to keep your blood sugar in balance.

GLP-1 stands for “glucagon-like-peptide-1” and it has a regulatory effect on the amount of insulin and glucose present in the blood. GLP-1 has a range of effects on the body, from decreasing gastric emptying (i.e. keeping food in the stomach longer) to stimulating insulin secretion. One important effect in the context of weight loss is increasing the feeling of satiety, i.e. “fullness”.

Development

Studies on GLP-1 began in the ‘70s when Dr. Joel Habener started research on diabetes, specifically what contributed to insulin production in the body. Over the following years, various features of the hormone were unveiled including it’s genetic sequence, structure, and preeminent functions.

A series of scientists at various labs around the world - including Jens Juul Holst, Dan Drucker, and Svetlana Mojsov - continued research on GLP-1 but ran into a significant therapeutic problem. The peptide, when injected, would not last long enough in the body to be useful; the body would quickly break it down before it had time to act.

A decade of research and a couple Gila Monsters later, Dr. John Eng discovered a stable version with the desired properties: increased glucose secretion only when glucose levels in the blood were high. GLP-1 had a way of self-regulating, making it a terrific partner to those with type 2 diabetes.

Eng licensed the patent for to Amylin Pharmaceuticals who marketed the new, stable GLP-1 analog as Exenatide or Byetta which was longer lasting but had to be injected 2x/day.

Chemists at Novo Nordisk latched on to the idea, aiming to develop an even longer lasting version of Byetta. They used a well-known trick, loosely attaching GLP-1 to a blood protein. This kept it stable in the body for at least 24 hours. After altering the hormone’s structure, liraglutide (sold as Victroza beginning in 2010) was born. It lasted long enough to reduce injections to 1x/day.

The bonus indication

Liraglutide had an unintended side effect: weight loss.

In 2014, Novo Nordisk received FDA approval to begin marketing it’s first weight loss drug, saxenda. In 2017, the company received approval for semaglutide. This is a 1x/week injection and what became Ozempic. Wegovy received its own FDA approval in 2021 (as mentioned above, they are the same drug).

If you’re unfamiliar with the term “indication” in medicine, it refers to the specific disease target of a drug. In the case of Ozempic, the disease target is diabetes. When Novo Nordisk discovered the happy side effect of weight loss, they immediately had a second indication for the same drug: obesity.

This is an important point in the world of longevity therapeutics. The FDA does not recognize aging as a disease target and therefore no company can develop a purely anti-aging drug. In other words, aging is not an indication. Any company which wants to develop an anti-aging drug must bundle it with some other indication to get FDA approval. This means (for the time being) any longevity drug will actually be an alzheimers drug, cardiac drug, liver drug, etc. At least in the eyes of the FDA.

Sales

Wegovy alone has estimated sales of over $1.5b per year.¹

For comparison, the top 3 grossing drugs in the US in 2022 were Humira ($18.6b), Keytruda ($12.7b), and Eliquis ($11.6b). Humira has been on the market since 2002, Keytuda since 2014, and Eliquis since 2012. Wegovy is still very much in its infancy.

Initially, nobody was interested in Dr. Eng’s (the Gila Monster guy) finding. Most pharma execs thought that obesity was a willpower disease, not a medical one. It’s amazing how much $1.5b in sales can change the biology of a disease.

So, is it longevity?

The technical case

We’ve covered the Hallmarks of Aging which lay out the technical definitions for longevity treatments. Obesity itself isn’t really an age-related disease - incidence doesn’t correlate with age.² But obesity does affect longevity.

For one, it is a major contributor to heart disease and cancer:

One cause of this could be inflammation: adipose tissue (i.e. fat) tends to release cytokines which are inflammatory molecules. As we know from the hallmarks post, inflammation is, to put it simply, bad. Especially bad is the visceral adipose tissue which surrounds the organs. This is not the fat that most people think of because it isn’t visible like subcutaneous version. With my level of vanity, I’d probably think this is the preferable type. Visceral fat, however, is extremely harmful because it releases those inflammatory molecules in direct contact with vital organs. This leads to a myriad of diseases.

So, from a technical perspective, if a drug reduces inflammation it could be considered a longevity drug. Semaglutide, through the process of decreasing the amount of adipose tissue in the body, could be said to promote longevity even if it isn’t necessarily marketed as an “anti-aging drug”.

The literal case

Anything that increases lifespan could be considered a longevity therapeutic. Semaglutide does increase lifespan by virtue of decreasing diabetes which decreases lifespan. In this sense, aspirin could also be considered a longevity drug because it can help reduce the incidence of heart attacks.

When thinking about it this way, it probably makes sense to differentiate between longevity drugs and drugs with longevity side effects. At the end of the day, semaglutide is only going to prevent the age-promoting side effects of obesity. It’s not going to help anyone who isn’t suffering from obesity live longer.

There are two sides to this coin:

• Every drug is a longevity drug because the point of drugs is to keep people alive and healthy for a longer period of time

• No drug is a longevity drug because they only mitigate the downside effects of diseases people may have. In other words, they don’t add years to otherwise healthy people.

  
  Also:

• No drug is a longevity drug because the FDA doesn’t recognize aging as a disease so any pro-longevity clinical outcome is merely a nice side effect.

What is clear is the market opportunity. Novo Nordisk unlocked billions in additional revenue using a therapeutic they already had on the market. Imagine the opportunities for a hypertension drug which actually reverses cardiac aging to the point where people no longer need the drug.

The inevitable conspiratorial argument will be that drug companies don’t want these types of drugs because they want to sell more drugs. This is incorrect. Drug companies want to make more money. Think about the case above: Novo Nordisk only unlocked the Ozempic market when they reduced the dosing from 1x/day to 1x/week. They sold 1/7th as much of the drug but made more money than they ever would have otherwise.

That’s all for now. My semaglutide Sweetgreen salad is here.

Cheers,

[1] Wegovy costs ~$1,350 per month with ~98,000 active prescriptions as of October ‘23.
[2] NHANES 2021, page 14

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