A New Drug Will Help You Shed 50 Pounds!

But is it really a good idea?

Photo by Diana Polekhina on Unsplash

Obesity medicines have greatly progressed in recent years. Being old fashioned, I’m not by nature much of a fan of a “diet in a pill” approach to weight loss. That said, I’m also a realist, and it’s quite clear that losing weight is well nigh impossible for many of my patients. Moreover, obesity is a super-sized risk factor for almost any problem that ails the human condition, whether it be diabetes, cancer, heart disease, or slim fit jeans.

In that context, this headline caught my attention:

True enough. This new med, tirzepatide, a once-weekly injectable, will probably be approved by the FDA for use in type 2 diabetics within months, and its use for obesity will likely follow. It sported some impressive results in a large (2,500 subjects) and long (72 weeks) multinational study, yet unpublished, looking at its ability to help obese people shed pounds, a separate indication from its known blood sugar lowering properties.

The results are not altogether shocking. A similar injectable diabetes medication, semaglutide, repurposed as a weight reduction drug at a higher dosage, was approved a year ago for obese and overweight (with a “weight-related health condition”) patients after a large study showed 15% weight loss over 62 weeks, a bit less but in the ballpark of tirzepatide’s 22% reduction.

Both medications have activity as a GLP-1 agonist, meaning they stimulate receptors for glucagon-like peptide-1; tirzepatide also acts on glucose-dependent insulinotropic polypeptide (“GIP”) receptors, making it the first “GIP/GLP-1 dual agonist” likely to be approved for use. Since this is word salad for most people — including most of us physicians — allow me a brief physiology break.

Managing exposures to carbohydrates is probably the single most important aspect of our health. The abbreviated version of the process is this: when we eat sugars and more complex carbohydrates, a hormonal response is triggered in the gut that leads to insulin release into the bloodstream from the pancreas, which in turn allows circulating sugars to be packed into our cells. Ideally, it gets burned off in metabolically active cells like muscle, rather than stored in hibernating cells like abdominal visceral fat. GLP-1 and GIP are the “incretin” hormones, helping to trigger insulin secretion, and a host of other things. (It’s far more complicated than that; true metabolic health nerds can read much, much more.)

Since a picture is worth a thousand words, here is a diagram from a Journal of Diabetes Investigations article on these incretin-mimicking medications that shows why so much R&D has been poured into this drug class in recent decades:

Lots of good things going on there, especially for metabolically-impaired people who have lost some incretin function over the years. The astute reader might notice the increased fat accumulation at the bottom left and wonder, “how is that good?” I had the same question. Added to the “things I thought I understood but didn’t” category: dropping carbohydrates into subcutaneous fat cells (“white adipose tissue”) and then burning them on demand is actually a healthy metabolic process - it helps prevent their deposition into visceral (i.e., around and in our organs) fatty tissue, which is strongly associated with bad things like poor hormonal function, heart attacks, and death.

At this point, it might seem like I am going against my grain and pumping up a new medication promising better living through chemistry. However, I have a few issues with broad adoption of a medication like this, or the already-approved semaglutide.

For one, we have to look at why people get fat. This has been an area of semi-hot controversy for over a century. The basic “energy balance” conceptualization generally has won the day: if we take in more calories than we burn, we put on fat to store the excess; burn more than we eat, we lose fat. A readable relation of the problems with this very simple explanation of a complex process was written by journalist and nutrition researcher, Gary Taubes, who, granted, has books to sell on the subject. He posits that the more accurate view is that the interaction between our insulin production and our carbohydrate consumption really drives our weight. I tend to side with Taubes, in that the “energy in minus energy out” model fails to explain what I see in my clinic, which is often filled with patients who genuinely eat like birds, exercise like squirrels in acorn season, and yet hoard fat like sea lions.

However, I doubt one explanation nails the root cause for obesity in everyone. Clearly, people have a set point at which their weight naturally settles. Changes in diet and activity will cause movement around this point, and maybe even re-set it under some circumstances, but something beyond mere energy balance is in play. I suspect for some people genes, environment and health conspire to indeed create a hormonally-mediated set point, whether the primary hormones be insulin, incretins, sex hormones, thyroid, etc.; for others, the gut biome; and maybe we’ll eventually figure out that the immune system runs the show for some overweight people.

For these groups, losing weight can be hard. Really hard. I am convinced with a high degree of certainty that doctors who tell all their overweight patients, “you just need to try harder, eat less, exercise more!” are really adding to the suffering of many of them without doing much good.

That said, a lot of people really do get fat simply by eating too much. The remarkable rise in obesity rates in this country are unlikely to reflect “shifting set points” for everyone but rather an increase in calorie consumption exacerbated by an increasingly sedentary lifestyle. Another picture, this time from a Vox article on why it’s so easy to become obese in America:

We eat too much! I think that’s the real caveat to the lure of GLP-1 and GIP agonists and their ilk: the first step is always adjusting what we eat. My overweight patients with a daily 6-pack of Coke habit don’t need a $1500/mo drug; they need to start drinking free water.

For those who have genuinely made lifestyle adjustments and failed to lose weight — or simply can not or will not make changes — jumping into a medication like this is still not a simple decision. For one, there is the cost. When I discussed semaglutide/Ozempic with a patient recently, their monthly cost with full Blue Cross/Blue Shield coverage was still over $500. This is for a “covered” medication on their formulary, at a lower dose than the Wegovy weight loss dose, which is not covered at all. I don’t expect tirzepatide will be cheaper.

We also have concern for safety and tolerance with a new class of medication. Pushing the doses in these drugs to max out weight loss predictably leads to more side effects. From Medscape, observe the high rate of gut adverse reactions rising from Ozempic (diabetes dosing) to Wegovy (weight loss dosing):

Being that one of the mechanisms of action of these medicines is to slow down stomach emptying, nausea is an almost intentional side effect. It does help weight loss by making people not want to eat very long or very much, or snack soon after a meal. It can also feel pretty crappy. I’ve had a number of patients bail out of the covered, earlier GLP-1 agonists like exenatide/Byetta for this reason. Tirzepatide reported somewhat lower rates of gastrointestinal reactions than Wegovy, in the 20-25% range. On the sunnier side, placebo patients complained of nausea 10% of the time, too; and most patients tend to improve in this regard with more time on these medications — only about 6-7% of those receiving tirzepatide actually stopping taking it altogether due to side effects.

The other concern is safety. GLP-1 agonists have been around almost 20 years, and have a fairly clean track record. For high-risk diabetics, they appear to have a modest effect reducing all-cause deaths. The concerns floated since their inception were based on animal models showing higher rates of pancreatitis and pancreatic cancer, dangers with biological plausibility since part of the activity of these medications involves stimulating the pancreas to make more of the insulin-producing beta islet cells.

Pancreatitis is terrible, unless you enjoy being hooked up to an IV for days or weeks, with biting abdominal pain, and being told you cannot eat anything at all. This is “mild” pancreatitis, the category under which 90% of GLP-1-induced pancreatitis falls; “severe” pancreatitis is life-threatening. Pancreatic cancer is an even greater concern. However, recent meta-analyses of GLP-1 trials both for cardiac outcomes and diabetes showed only a modest (5-25%) increase in risk of these two problems, neither reaching statistical significance.

It’s also worth noting that much of the increase in pancreatic cancers in both meta-analyses was driven by one trial, the 2016 LEADER study on liraglutide, and despite 13 pancreatic cancers in the study group vs 5 in placebo, even that study showed a mortality benefit among those taking liraglutide. What’s more, even if future trials show an actual, statistically-significant increase in risk of unwanted pancreatic outcomes in the 5-25% range, that’s relative risk; since the absolute risk of either outcome ran around 0.5% over multi-year trials, adding a tiny fraction of bad outcomes to a small number like 0.5% is unlikely to outweigh the benefits of weight loss and improved blood sugar regulation.

So… is this the future of weight loss management for those who can afford it?

Hold on, there’s one big problems left to discuss: it’s probably a fantasy to think you could melt away those extra 50 pounds in a year or two of tirzepatide, drop the med, and then have those 50 pounds stay away. None of the trials on these medications follow what happens to people’s weight after a few months or years off the meds. I’ve never seen research, or met a patient, to suggest that weight loss is a one-time event, followed by a nice, even plateau after reverting back to the conditions that led to the weight gain in the first place. Never.

Tirzepatide, or semaglutide, or whatever variant of GLP-1 or GIP/GLP-1 agonists comes next, are a lifelong commitment. An expensive one. One which is essentially an experiment in very long-term use of a very high dose of medications which have never been studied in quite this way. Given that the alternative for this level of weight loss is bariatric surgery — which tends to trigger about a 50% loss of body weight (a number which drops into the 25-30% range a decade after surgery), but is invasive, not truly reversible, and can lead to unpredictable long-term problems — I do think these medications will find a market, and rightfully so.

For me, though, I’d need to be convinced my patients have tried and failed every other avenue of weight loss before addressing these medications — and that’s before even considering their impressive cost. We are still a long way from the answer to the average person’s battle with their waistline.