The Ozempic Plateau: Time for a Course Correction?

As I find myself halfway through the initial three-month treatment course with Ozempic, I am experiencing a significant change. I am losing about two pounds a week, double what I lost while maintaining a diet and riding a Peloton for 30-40 minutes a day, five days a week. While I have continued to lose weight, and that feeling of early satiety has not really changed, I have, once again, begun to feel hungry. Why has this shift in my Ozempic trajectory changed? 

In a word, tachyphylaxis is the diminishing response to successive doses of a drug, making it less effective over time. Tachyphylaxis is a biological phenomenon; we see it in the escalating need for more substances among substance abusers and the sensory finding that the first bite is far more satisfying than the last. It should not be surprising that GLP-1s are subject to the same diminishing sensitivity to a continuous signal. Because repeated use of these medications results in achieving a "steady-state” blood concentration after about 6-7 weeks, I am right on schedule to begin to see diminishing returns to those weekly injections. 

There is little long-term literature on GLP-1 tachyphylaxis. Day-long short-term studies demonstrate reductions in the delay in gastric emptying and subsequent changes in glucose between two meals where GLP-1 is infused. In a longer-term study, GLP-1 showed no significant delay in gastric emptying at week 20. However, "reduced hunger and prospective food consumption, and increased fullness and satiety when compared with placebo” persisted. My experience differed, at least concerning hunger.

Other processes beyond tachyphylaxis keep me and others on a plateau. Most importantly, the mechanisms underlying homeostasis, our scientific way of describing balance, are crucial. Our bodies, faced with diminishing calories, take measures to preserve themselves—primarily a shift of energy from sugar to fats and a more efficient metabolism. Understanding these biological processes is crucial in our journey with weight loss or using a GLP-1. 

The shift in energy sources to fat is the basis of both the Atkins and Paleo diets; in the absence of glucose, the body mobilizes its fat stores, and the liver converts them into ketones, which can be utilized as cellular fuel. This conversion, ketosis, is responsible for the tell-tale odor some experience on their breath, a fruity, sweet, possibly metallic, "nail polish remover" smell of acetone, a fat-generated ketone. 

Our metabolism also becomes more efficient in utilizing the energy we have. This can be seen in our muscles, where weight loss has been associated with increased efficiency (At least in mice) of mitochondria, the true powerhouses of our muscles. Another group of mitochondria becoming more efficient in the presence of ketones are those in areas of the brain requiring high energy "due to their long-range neuronal projections and extensive synaptic connections, making them more susceptible to metabolic disturbances.” Among the susceptible neurons are those implicated in Alzheimer's, Parkinson's, and Huntington's Diseases, raising the intriguing question of whether ketosis may be beneficial in these patients. The studies are mixed. In one small randomized controlled trial, participants with mild cognitive impairment were given a daily medium-chain triglyceride (MCT) drink. They showed cognitive improvement in executive function and language compared with placebo controls at six months. In the largest trial to date, a different MCT mixture had no impact on cognition in the mildly cognitively impaired participants, although the researchers ascribed this to a dose of MCT that was too low to create a robust ketosis. 

Back to Ozempic

The use of Ozempic did play a role in my response to hunger – I ignored it, whereas just a few weeks ago, that feeling would have prompted a pantry drive-by in search of a treat. I know from prior reflection that I often eat when stressed or bored. Since leaving clinical practice, I have rarely been stressed, so much of my automatic, unthinking eating is from boredom. But now I recognize the urge and either ignore the feeling, which shortly after that leaves me having been denied attention, or I go ahead and eat or drink a standby substitute. Ozempic has given me the space to replace my prior bad acts with better decisions. 

The creation of this behavioral space is Ozempic's and the other GLP-1's great strength and weakness. The GLP-1s will provide that rapid weight loss; that is their strength. While the introduction of these medications to the general population has been relatively recent, there are studies showing that a majority of individuals are no longer taking these medications after a year; less than 25% are taking a GLP-1 for two years. Considering that roughly 40% of individuals taking a GLP-1 do so solely for weight loss, a weekly injection may be too arduous a treatment, or the medication might just be used as a "rescue drug" to rapidly lose weight for a special occasion or outfit. 

However, what about those on a plateau or electing to end their use of the GLP-1?If you return to your evil ways, the weight will surely return – the GLP-1s are not one and done; that is their weakness. For the 60% of individuals using the medication for chronic illness, we are looking at a high level of non-compliance (sorry, woke physicians no longer use that term; perhaps we might say patients who have made alternative decisions?). Any number of studies are underway replacing a weekly injection with a daily pill, which should increase long-term use.