I am wrapping up a course of tirzepatide, the GLP-1/GIP agonist drug from Eli Lilly. It has been an incredible, life-changing experience. I lost 25% of my body weight, regained vim, got healthier, and reversed a lifelong trend of slow-but-irreversible weight gain. I wrote this article as a way of organizing some of my thoughts on the experience, and am publishing it in case it is useful to someone.
For the last 25 years I've gradually gotten heavier, year on year. No one year was particularly awful. I'm a six-foot dude. In graduate school in the mid 1990s I was about 180 lbs. Each year I'd put on a couple of pounds. By spring of 2024 I was at 240 and developing knee issues. I'd worked on weight-loss over the years: trying to get better about exercise, paying some attention to what I ate. But that 1-2 lbs/year trend would always return, and after losing I'd bounce right back up to that increasing trendline.
Obesity runs in my family: a lot of us are "big people", as in 300+ lbs. I figured I was doomed to a personal Ragnarok, ratcheting up as nearly all my blood relatives have.
On the advice of family and physician, I started tirzepatide in June 2024, at 2.5mg/week. Eli Lilly recommends ramping up month-on-month. Neither I nor my physician wanted to do that unless needed. We decided I'd stay on the 2.5mg as long as it was working for me, and I never felt a need to increase.
You can read about tirzepatide, the GLP-1 endocrine system (and why the new drugs are effective) in lots of places. Tirzepatide differs from the more popular Novo Nordisk product semaglutide, in that it activates the same receptors as GLP-1 (reducing appetite and food ideation) but also activates the GIP system, aiding metabolism of fat. That's a big deal, especially for people who have had a cycle of weight loss/gain, because many bodies adapt to periodic "famine" and reduce overall metabolism rather than releasing fat calories.
Natural GLP-1 hormone is a peptide (a mini-protein) used by your body to regulate digestion. It's released by the small intestine during digestion, and signals that food has arrived. It has a metabolic half-life of about 2 minutes: appropriate for a digestion control signal. Tirzepatide has about a 5 day half-life. It can't survive passage through your digestive tract, so you inject it weekly.
Making the decision
Throughout 2023 – 2024, I kept noticing little things that bothered me about being heavy. It was growing uncomfortable to bend over and tie my shoes, because my belly would compress my lungs when I did. My knees complained when I walked more than a quarter-mile. I got winded going up stairs. Although I was never diagnosed with diabetes, I definitely felt some of the "food coma" and blood sugar swings that go with it.
At my annual physical, I mentioned to my physician that I knew I wanted to lose weight and would like tips. She mentioned semaglutide (Wegovy), and I said I wanted to think about it before moving forward. My lovely wife Lysandra had been studying the meds online, and had found a bunch of articles talking about tirzepatide and how effective it could be.
I asked my physician about Zepbound and she was enthusiastic – but talked about how expensive it was and how much trouble she had getting insurance to cover it. We talked about compounding pharmacies and the whole grey market that has arisen around the new drugs; unsurprisingly, she didn't trust the compounded stuff and recommended against it. In the end, Eli Lilly's "coupon" program convinced me to at least try. At the full retail price of over $1200/month, the medication is way too expensive in America (that is 8x the cost they sell it for in UK). Eli Lilly offered a coupon for $550/month, making it not too much more than a fancy gym membership, and the various testimonials were very promising.
Something that bugged me a little was the prospect of possible long-term side effects. Although GLP-1 agonists have been around in various forms for a long time, the blockbusters semaglutide and tirzepatide just haven't been around long enough to see how they'll play out in the long run. But ... we do know the long-term side effects of obesity, and they are dire.
My physician did put a prescription for Zepbound through my insurance (United Healthcare, who are famous for avoiding paying for medication whenever possible), but as expected they refused to cover it. I bit the bullet, paid my $550, and took my first dose at the end of June 2024.
My "regimen" and how it worked
I didn't do nothing -- but I didn't go overboard either. I tried to make tirzepatide part of a balanced lifestyle change. Going in, I saw it as a way to avoid obsessing over my caloric intake. After the first couple of weeks (when I lost 15 pounds in as many days), I recognized I would actually have to track calories: not to achieve weight loss, but to regulate it.
The drug profoundly affected the way I interacted with food. Throughout, I've had to consciously maintain dietary supplements (electrolytes, vitamins, hydration) as one would on a strict traditional weight-loss diet. At least at first, I also had to consciously work to take in enough calories to avoid actual starvation.
For the rest of the regimen, I've been making sure I "get my steps in": walking at least a mile, more typically 2-3, most days. My diet has changed, too, which is sort of the point of the drug. That's it -- my conscious lifestyle mods are very minimal. I'm paying a small amount of attention to what I eat but not regulating my intake in a way you'd call "being on a diet". In general, if I want food, I eat it. That's a little different from a "see-food" diet because seeing food isn't making me automatically want to eat it.
Tirzepatide's effects added up to a steadily decreasing weight through the late summer and winter, with expected bumps during holidays and/or business travel. Most importantly for my peace of mind: eating a single heavy meal, or snacking "too much" on a particular day, did not equate to "falling off the diet wagon", as I had come to expect. It meant that the next day I was less hungry, so that the overall weight-loss trend continued across weeks and months.
My results: This annotated plot shows my morning scale weights over six months, during which I lost 25% of my body weight.
The "internal experience"
The first, most incredible, part of the tirzepatide journey, for me, has been identifying food noise as a separable portion of my mind: something I can separate from myself. For over 20 years, there were very few times when I did not, in the back of my head, want a snack. Essentially all the time I was craving something to eat – even when full, I felt I could fit in a little bit of nosh. I completely normalized these feelings, and combating them became reflexive.
Tirzepatide completely shut off food cravings at first. In the first few weeks, I had to get used to managing hunger through secondary symptoms: I never "just felt like" eating and had to actively, consciously decide to eat or I'd find myself growing weak and stupid (while still not feeling hungry). That effect, especially early in the experience, was stark. The effort of constantly beating down impulses to grab a bite (or more) of food was so steady, and so long-lived, that I completely failed to notice it in everyday life. Turning off those impulses threw them into stark relief.
I like to compare it to the experience, occasionally repeated, of learning that some people have internal monologues and some don't. Everyone's experience of the human mind is dominated by how their own mind functions, so it comes as a surprise that other people's minds can work very differently from our own.
Although I didn't think much consciously about my daily struggle with food noise, the cognitive load was there: it takes mental effort to constantly beat back a chronic desire. The first result of shutting off the food noise was that I felt more spry and intelligent and productive, because I had more mental capacity available. That was surprising, but there was a noticeable uptick in my scientific productivity.
Even now, after nearly ten months on the drug, I find that I still sometimes have to decide it is time to eat. A little bit of noshiness has come back, but at levels much lower than before starting; and some days I just don't really feel like eating even though I know it's mealtime.
The second, almost as amazing, part of the journey was recognizing that, yes, the steady year-over-year weight gain and food orientation I'd experienced (as so many of us do) is a medical issue rather than a personal weakness.
Taking tirzepatide meant that I could actually do the things we all know we have to do, to control our weight and get in shape. I called my earlier weightloss experiences "white-knuckle dieting": most dieting boils down to "just" consciously overriding your whole endocrine system. There are lots of tricks, fad diets, and "pro tips" to try to manipulate appetite -- but in the end they are all small, secondary tweaks compared to the primary drive to consume more calories, and its associated cravings.
That second experience helps in surprising ways. By separating food intake from moral value, it allows better approaches to food and to dieting. It also highlighted to me the degree to which dieting is wrapped up in moral value, in our culture. The social connection between moral virtue and weight/food-intake management is so strong, so familiar, and so cliche that I don't need to expand it here. But direct experience makes everything look/feel different. Being able to separate the joy of eating (say) a cookie from the guilt of, well, eating a cookie is itself a gift.
Dealing with exploitative pricing
Tirzepatide is not cheap ... at least in the USA.
Tirzepatide is a great example of the shitty deal Americans are getting on healthcare. At (now) $650/month with the Eli Lilly coupon, a year of tirzepatide in America costs $7800 plus time and trouble (doctors' visits, insurance, etc.) to get and maintain the prescription – upwards of $8500 overall. For that price you can travel to UK for ten days' vacation (airfare $900, hotel + meals $4000), get a prescription for Zepbound there, and bring home a year's supply (￡1500 or about $2000) – and still have over $1000 left over to bring back gifts of shortbread and whiskey for your friends Stateside. Of course, you then have to deal with the uncertainty of taking an overseas trip and not being certain you can get (and fill) a yearlong prescription there.
Medical tourism by land
Going to UK to get medicine may seem extreme, but Mexico and Canada also have lower prices than the USA. In fact, so many Americans seek those lower prices that a whole market has sprung up to service them. It's difficult to google those prices, because the search results are clogged with exploitative companies that will offer to ship the drugs to you (or you to the drugs) across our land borders to our neighbors. I live in the middle of the country, so I didn't want to take this route.
Compounding pharmacies
Because all the GLP-1 agonists (including tirzepatide) are patented in the USA, nobody but their inventors is allowed to make and sell them at the moment. Except there is a loophole. Compounding pharmacies are licensed to produce tailored drug mixtures that are not economic to mass-produce, and (this is the important part) to fill in the production gaps for patented medicines, in times of shortage. Tirzepatide (and its predecessor, semaglutide) are extremely popular and have been in shortage for some time. So a whole slightly-shady industry and market have sprung up to supply compounded tirzepatide. Chemically, it should be identical to the substance Eli Lilly sells you, and therefore should have the same medical effect. Suppliers tend to run about half the cost of Eli Lilly's "official" stuff, but quality control has been variable. For example, in the fall of 2024 there were stories about visible unidentified precipitate (schmutz) being spotted in vials of injectable compounded tirzepatide. Although the facilities are FDA-inspected, quality control is not always as good and the supply is less certain. There are a lot of hype-heavy "grey market" websites and companies surrounding these products, which did not go far toward building confidence.
Pen arbitrage (dose splitting)
Pen arbitrage (also called "dose splitting") takes advantage of Eli Lilly's attempt to tailor prices to the market. In the USA, they sell tirzepatide in single-use auto-injector pens, at about $160 per pen. The pens looks like cylinders a little larger than a maxi tampon applicator. You put one end against your belly and push a button on the end of the cylinder. Ka-CHUNK, in about 2 seconds it auto-injects 0.5mL of solution subcutaneously, and withdraws the needle safely back into the pen.
Someone pretending to inject a dose of tirzepatide (with the pen locked and the grey protective cover still on)
Each injector pen contains a spring-loaded mechanism and 0.5 mL of tirzepatide solution. You can get them in doses of 2.5-15 milligrams. The concentration is what varies: they all have the same geometry, mechanism, and price. If you are on a low dose and work with your physician, you can buy large doses and inject smaller ones. At 2.5mg/week, you can split a 15mg pen to make 6 weeks of supply. That reduces your overall cost to under $125/month, rather than $650/month.
There are lots of tutorials online, showing people disassembling their pens and doing all manner of outlandish things. But by far the simplest way to split doses is to inject the pen's solution into a self-healing vial instead of directly into yourself.
The idea is simple: (1) "fire" the pen into a sterile, self-healing vial, through the rubber membrane at the top; (2) using an insulin syringe, withdraw bacteriostatic water from its own self-healing packaging, and inject a measured amount into the medicine, to make your chosen dose size 0.25-0.75 mL (your choice); (3) withdraw and administer a dose each week with a fresh insulin syringe. The last fractional dose can be tricky to get -- but you can "wash down" the inside of the vial with a little more bacteriostatic water to get the last little bit out. You have to remember some basics, like keeping things clean, not re-using anything, managing the air content inside the self-healing vials, and wiping everything down with isopropanol. Common sense stuff if you've ever worked in a lab. (The product links are informational, not medical grade stuff)
Insulin syringes are readily obtainable, and used by thousands of people daily.
Secondary effects
Secondary medical effects are between you and your doctor. But there were a lot of non-medical things I didn't expect.
Be ready for your clothes to get loose
I've "pro-actively" bought clothes to shrink into before, but generally that hasn't lasted. I'm used to clothes gradually growing tighter over time. Not fast, but enough that my old stuff always feels slightly tight and my new stuff feels more comfortable. It was a surprise to feel stuff -- rapidly! -- getting too big. Pants that fit tightly turned loose, then baggy. I went from a 42 inch waist to a 34-36 inch waist in under six months. That's pretty drastic, and I ended up buying two small-but-complete wardrobes on the way down. I still have one pair of pants from last spring. They look like clown pants now.
Make sure to stay hydrated
This is no joke! In addition to not feeling hungry, you may not feel thirsty. You will dehydrate unless you actively drink a surprisingly large amount of water. My lovely wife laid in (and maintained) a large supply of heatlhy electrolyte drink mix, which made it easy to get down enough fluid. The major electrolyte turned out to be magnesium salts, which was good because...
Unless you are proactive, you will get constipated
The tirzepatide slows down all digestive activity. Your bowels exist to dehydrate poop, and they do so at a more-or-less fixed rate. If everything slows down, it also gets firmer and drier. Practically everyone I've spoken to who has used these drugs has experienced difficulty keeping things moving. Drink your electrolytes, keep magnesium supplements on hand, keep track, and take the supplements if you're slowing down and miss your regular time. You're welcome.
Cold hands
Especially after about 30 lbs down, I started to feel a lot more cold-susceptible, and to dress more warmly. It turns out not to be "just" an insulation effect. The body does short-term thermoregulation with "brown fat" that can burn calories to create heat. Something about tirzepatide in particular messes with that. It's not clear (to me) whether the brown fat just atrophies with the white fat, or undergoes fatigue effects, or gets shut down in some other way. But my body lost much of the ability to do short-term thermoregulation. As a result, the main heat-preserving step it can take is restricting bloodflow to extremities – which exacerbates the problem in any cold part of the body. So my hands and feet get cold very easily. I don't know whether that is an acute effect of being on tirzepatide, or a chronic effect of being lighter. But it's new to me, and surprised me when it came on.
Be ready for comments
Losing a large amount of weight in a matter of months will make your friends and acquaintances nervous. They'll notice but not say anything or, worse, will say that you look gaunt or drawn. Some will ask if you have cancer. Everyone will treat you differently. I've heard the stories from others, but this was the first time I had to deal with it personally. The social aspects of weight loss were surprising to me. They're more drastic for women, but still present for men (or at least for me).
Looking forward: maintenance, tapering, and the future
Lots of clinical trials (including the famous SURMOUNT-3) show that tirzepatide is effective in increasing weight loss. But what happens after? In the SURMOUNT-4 clinical trials of tirzepatide, most folks who quit the drug gained back at least some weight: participants averaged 20% weight loss during tirzepatide treatment and 14% weight regain in the first six months after quitting (i.e. they still ended up 9% lighter overall, but were presumably still gradually rebounding). Semaglutide has similar results -- one study cohort gained 80% of their weight back in one year.
My attitude is that I never want to go back to the weight I was. I'm willing to stay on this drug for the rest of my life if that turns out to be necessary. But I also hope that I don't have to. I'm tapering off tirzepatide gradually: I'm on 2.0 mg right now, and so far so good. If that holds for a couple of weeks I'll drop further to 1.5mg, etc. I'm coordinating with (and reporting to) my physician regularly.
I'm hoping that being more active, being even slightly mindful of my intake, and generally having good habits will keep me here even as the food noise comes back and the dose drops to zero. Time will tell.
