Is The Answer Finally Here?
If it was, you would give anything for it, right? Well, probably not anything. But you would likely agree to some things – you would eat more salads, spend more time at the gym.
- But how about giving up your physical strength?
- Your stamina?
- Your hard-earned muscle?
- What if you lost weight, but you felt sick all the time?
- What if in exchange for weight loss, your risk for cancer increased?
If you knew this weight loss miracle came at a tremendous cost to your overall health, would it be worth that?The potential solution for real, sustainable weight loss has been right in front of us for years – a game changer in the world of metabolic health and wellness. The realization of this major shift in metabolic health by the mainstream media would have been expected to be met by incredible pomp and circumstance, rainbows, the most beautiful of unicorns, and absolutely thrilling news coverage.
Well…
As it turns out – the coverage was late, at best. And it was more scathing than glowing, if I’m being perfectly honest. Now, the firestorm has reached a relative hysteria and is just plain ridiculous. So what’s behind the social media hate for these new weight loss peptides?
Let’s discuss.
What are GLP1s?
I don’t think there is a single drug currently on the market today getting anywhere near as much attention as the GLP1s. Why? Although originally developed to treat type 2 diabetes, the GLP1s have a convenient little side effect: they also have the best weight loss efficacy of anything on the market to date. Period. The public was made acutely aware of this in October of last year when the WSJ ran a story about how the Kardashians were using a specific GLP1, not for diabetes, but for weight loss. And that is when the controversy was born.
In recent months, I have been absolutely inundated with questions on the topic of these medications – their safety, their efficacy, their original intent, their cost, etc. Popular screaming headlines sound like –“They cause muscle loss!,” “You’ve gotta stay on them forever!”, “I stopped them and all the weight came back!”, “The side effects are awful!,” “You’re stealing life saving medications from diabetics who really need them!” Bahh.
To understand this social media frenzy, I think it is helpful to know some potential drivers of bias (Charlie Munger’s classic ‘show me the incentive and I’ll show you the outcome’):
- Insulin resistance is the largest contributor to obesity in developed countries.
- Insulin resistance is the largest contributor to type 2 diabetes.
- Illness related to obesity and type 2 diabetes = the largest revenue producing sector of the health care industry.
If GLPs fix insulin resistance in diabetics and non-diabetics alike, it would stand to reason that the dollars needed to treat obesity and diabetes related illness might go down…and might go down a LOT. Those numbers probably don’t make everyone happy.
You do the math.
When I say ‘GLP1s’, I am referring to a class of peptides (Glucagon Like Peptide-1 agonists) that were originally developed to treat type 2 diabetes – an extreme form of insulin resistance (IR). Type 2 diabetes occurs when overproduction of insulin by the pancreas results in ‘resistance’ of the insulin receptor. I’ve mentioned this in the weight loss section of our website, but I’ll summarize again here:
Every time you put food in your mouth, it triggers the pancreas to release a hormone called insulin. Insulin tells your body what to do with the food you eat. It tells your cells to do one of two things:
- Take the food you just ate and use it for fuel.
OR
- Take the food you just ate and store it as fat so that you can use it for fuel later.
TAKE AWAY… Too much insulin production = Too much fat storage
Insulin resistance (IR) is so common in developed countries partly because of what we eat (high glycemic index garbage), but also because of when we eat it. We have evolved from a society of hunter/gathers who ate “occasionally” to a society that eats all the time. We even invented an entirely new meal that never existed before. You’ve probably heard of it – called “breakfast” – and convinced Americans it was, ‘The most important meal the day!’ (spoiler alert: There is absolutely nothing physiologic about breakfast).
By eating through the day, year after year, decade after decade, the pancreas ends up making wayyy more insulin than it was ever designed to make. That ultimately results in a down regulation and ‘resistance’ of insulin receptors. Lazy, resistant insulin receptors are like your kids rolling their eyes when it’s time to take out the garbage. Same thing – Insulin receptors are told to control blood sugar, but they give you the eye roll instead. Trash cans sit in the garage, blood sugar remains high.
As IR progresses, the pancreas needs to make more and more insulin to maintain normal blood sugar levels. At some point, the pancreas becomes exhausted – sick and tired of making so much flipping insulin – and despite exceptionally high levels of insulin production, the ability of the pancreas to maintain normal blood sugar levels finally fails. As insulin receptors get lazier and lazier, the body goes from too much insulin but normal blood sugar levels, to too much insulin and too much circulating blood sugar. What then?
Now, you have type 2 diabetes (T2D).
*Side note* I don’t want to derail too much here, but I need to say this:
Type 2 diabetes is 100% preventable and 100% curable. The best way to identify the problem early is to STOP relying on fasting blood sugars greater than 100 as a warning sign for diabetes. We need to start using fasting insulin and HgbA1c levels instead. While we’re at it, let’s redefine a target for fasting glucose. Fasting blood sugar levels start to predict the development of diabetes by a certain number of percentage points per year once they’re over 85! The early warning signs of T2D are easy to measure with simple blood tests. These levels should be checked every year. By the time fasting glucose levels start to rise, the pancreas has already been on insulin production overdrive for years. T2D is still treatable in later stages, but it simply doesn’t need to exist if we screen for IR regularly and manage it early instead.
Back to the GLP1s…
The GLP1s are unique in that they work to improve insulin resistance, and in so doing, generally suppress production of insulin – this is one of the mechanisms by which they result in weight loss. Recall – one of the key roles of insulin is fat storage.
The GLP1s seem to have many, many metabolic benefits – only some of which we understand:
- Improved blood sugar control
- Improved insulin resistance
- Weight loss
- Improved lipid profiles
- Lower blood pressure
- Decreased risk for ASCVD (atherosclerosis/heart disease)
GLPs In The News: Semaglutide & Tirzepatide
GLP1 is a hormone (peptide) made by the gut. There are several peptides in this class, but I will keep this discussion to the two at the center of the current hoopla:
Semaglutide
- Ozempic (brand name) for diabetes
- Wegovy (brand name) for weight loss
(Both are semaglutide, just different brand names and different dosing.)
Tirzepatide
- Mounjaro (brand name) currently indicated only for diabetes, soon to be branded for weight loss (most certainly under a different name).
Semaglutide is a pure GLP1 agonist. Tirzepatide is a “co-agonist” – a GLP1/GIP agonist (glucose-dependent insulinotropic peptide– so technically a novel class of peptide). I won’t get lost in the weeds of the differences between the two, but in general, tirzepatide is superior to semaglutide for the following reasons:
- Fewer side effects
- Significantly more weight loss
- General sparing of lean tissue, weight lost is mostly fat
- Better glycemic control
- Superior effects on lipids/ASCVD risk
In essence, the “GIP” component of tirzepatide corrected all the known shortcomings of the straight GLP1s making it better, cleaner, stronger, and safer.
* All patients of Lindgren Functional Medicine using any injectable weight loss medications (Mounjaro, Tirzepatide, Ozempic, Victoza, Semaglutide, etc.) are REQUIRED to have a weight and blood pressure check by a clinical staff member or provide proper signed documentation from their General Practitioner EVERY THREE MONTHS.
Why are physicians prescribing diabetic medications for weight loss in non-diabetic patients?
Insulin suppression. That’s the primary reason I endorse this therapy – it very efficiently suppresses insulin production. Remember, high insulin levels don’t just cause weight gain, they increase risk for ASCVD, T2D, dementia, and cancer.
Quite frankly, weight loss is just a nice side effect.
Why do people lose weight on GLP1s? Do they keep it off?
Good questions. The general misconception is that these peptides cause massive appetite suppression and that’s what causes the weight loss. They do suppress appetite – at least initially. But any insulin resistant person will tell you that it doesn’t matter HOW many calories they eat – they CAN NOT LOSE WEIGHT. They are effectively locked in a fat storage mode.
The entire mechanism of action by which patients treated with GLP1s experience reliable weight loss is not completely understood. Part of the mechanism is most certainly related to the improvement in insulin sensitivity and the subsequent decrease in insulin production. Remember, insulin is a hormone that promotes fat storage and weight gain. This is a tricky area to explain because at least initially, both of these medications actually cause an increase in insulin production. In spite of this increase in insulin, patients lose weight, underscoring the fact that metabolism is far more complex than we originally thought.
*Side note*
If you’re still using a phone app to log your calorie intake and exercise output in order to predict your weight loss, delete it. Metabolism is extremely complicated – don’t be insulted by some uneducated code writer who doesn’t understand a thing about it.
Side effects?
No medication is without side effects. Prior to tirzepatide, the GLP1s were notorious for GI side effects – mostly loss of appetite and nausea. These are definitely more pronounced with semaglutide but can occur with any peptide in this class. Thankfully, those side effects largely soften overtime – and overall this is MUCH less pronounced with tirzepatide.
Will I need to take this forever to keep the weight off?
The short answer is, we just don’t know. Certainly, the GLP1s seem to have the ability to not just improve insulin resistance in the short term but to restore insulin sensitivity in the long term as well. In the SURMOUNT trial, examining tirzepatide and obesity, patients taken OFF tirzepatide regained weight far slower, then they initially lost it – suggesting a corrective effect of insulin receptors.
My Question:
How long did it take you to become this IR and overweight in the first place??
Let’s see….carry the 1, move the decimal point … by my calculations, AT LEAST THE MAJORITY OF YOUR ENTIRE ADULT LIFE!
Should we expect a medication to correct this over night? It only makes sense that improving and sustaining insulin sensitivity will take more than 6 months – and probably more than a year. It is hilarious to me listening to people scream about losing weight on GLP1s, who then gain every single pound right back when they openly admit to not making A SINGLE SOLITARY LIFESTYLE CHANGE to keep that weight off.
Some day, you may get to have your cake and eat it too – but that day just isn’t here yet.
Do the GLP/GIPs cause muscle loss?
Yes. Everyone who loses weight loses muscle. We know this. It doesn’t matter how you lose it, weight loss is part fat, part muscle. Period. The question I have as a provider recommending a GLP1, is whether there is a disproportionate amount of muscle lost when patients use these peptides for weight optimization. This has been, and will continue to be, studied.
Results from a new 72-week trial demonstrated a 46.2% loss of total body fat, and a clear 38.5% INCREASE in lean muscle mass in patients using tirzepatide – a finding we have not seen clinically in the pure GLP1s. This is in support of the claim that the GLP1/GIP combination functions as a ‘thermodynamic uncoupler’, providing protection to lean tissue but not to fat.
Whether there is a true trend towards muscle loss or not, patients using these peptides should be very mindful of their macronutrient caloric intake while working towards optimizing weight. When patients start therapy with GLP1/GIP peptides, they often have marked appetite suppression, making it difficult for some to consume adequate amounts of protein to protect lean tissue. If you don’t eat anything, guess what. You can’t maintain a healthy body composition!
Monitoring body composition with change in weight is useful in monitoring for any unwanted shifts in fatty/lean tissue. As we gain more experience with the newer GLP1s, we will learn how best to manage macro and micronutrient intake recommendations.
Do the GLP1s cause thyroid cancer? There is no clear data suggesting any real relationship between semaglutide/tirzepatide and cancer. Long before the current GLP1s, GLP1/GIP, there was an earlier GLP1 called liraglutide. There was one French study on liraglutide suggesting there may be a small increase in incidence of a rare type of thyroid cancer – and ever since that time, this ‘medullary thyroid cancer’ warning was attached to all the other GLP1s, despite a speck of evidence to substantiate this claim (guilty by association).
This rare thyroid cancer increase claim has been argued ad nauseam. Many researchers state the finding in the study was simply a change in baseline and not a finding applicable to real-world change in risk whatsoever. Without sounding dismissive, I want to say this – there is a well-known INCREASED risk in cancer across the board in patients with IR. If the data on the medullary thyroid cancer risk is real, it is likely dwarfed by the overall decrease in cancer risk realized when IR is reversed.
This is not medical advice. Everyone is different. If you think this therapy might be helpful for you, please have this risk/benefit discussion with your doctor.
What do these peptides cost?
A LOT.
This therapy is cost prohibitive for many patients. Without insurance assistance, these peptides cost roughly $1000-1200/month. Yikes. Weight loss surgery might be sounding more attractive now as you’re doing the math, but surgery will not correct IR. This is why so many patients who have had weight loss surgeries, gain their weight back – their metabolic issue wasn’t reversed. They were still ‘locked in fat storage mode’. We have ways of being creative about cost to make it less horrifying, but peptide intervention here is still expensive.
In Conclusion
-Weight loss does not have a ‘one-size fits all’ solution
-Insulin resistance plays a key role in age related weight gain
-GLP1s can be an extremely powerful tool – in conjunction with a comprehensive weight loss strategy – for optimizing metabolic goals and body weight
The content contained in this blog is for informational purposes only. Every individual is different and should consult with their own physician to formulate a customized health care program that can be tailored to their unique metabolic, genetic, and epigenetic needs.
Best Regards, Kristen Lindgren, MD