In April 2026, the New York Times printed an article entitled “The Great Ozempic Experiment” (1). Perhaps a better title for the article might have been “How Can One Minor Hormone Do So Many Things?” Sometimes the answer is hiding in plain sight.

First, hormones are signaling agents that allow one organ to communicate with another. Once the receiving organ gets its hormonal signal, it then alters the metabolism within that target organ. The real physiological action takes place in these complex metabolic pathways.

In the NY Times article, Richard DiMarchi, one of the early pioneers in GLP-1 research, states that “many diseases may share the same root causes, even though we label them and treat them as distinct.” I contend that virtually all chronic diseases are caused by constant metabolic disruption. If there is one candidate that fits that bill to explain my description, it would be inhibition of AMPK, the master regulator of metabolism (2). AMPK directly or indirectly controls inflammation, immune response, and neurotransmitter action. I would restate Dr. DiMarchi’s quote as follows: “Many diseases share the same root causes, which is inhibition of AMPK activity leading to disruption of many metabolic pathways.”

GLP-1 drugs activate AMPK primarily through reducing calorie intake. I am not the only one who has articulated this thinking (3). However, I believe a far more effective way to activate AMPK is using Metabolic Engineering®, not only to avoid the side effects of current GLP-1 drugs, but also to achieve far greater metabolic control.

I discussed the roles of the three dietary components of Metabolic Engineering® (i.e., Zone diet, omega-3 fatty acids, and polyphenols) in increasing AMPK activity in two of my most recent books, The Mediterranean Zone and The Resolution Zone (4,5). That is why these three dietary components used in Metabolic Engineering® can have many of the same clinical benefits as current GLP-1 drugs. Like GLP-1 drugs, a calorie-restricted diet with the same macronutrient composition as the Zone diet is very effective at reducing hunger (6). A recent small pilot study using the same calorie-restricted diet with a macronutrient composition identical to that of the Zone diet resulted in complete disease remission in all six diabetic patients within 6 months (7). In the control group of type 2 diabetic patients with the same level of calorie restriction, but following a lower protein-to-carbohydrate ratio, only one of the six patients had remission. In neither group was there any indication of ketosis.

Furthermore, in the group following the Zone diet, their markers of inflammation, cardiovascular, and oxidative stress were significantly lower than in the other group. As the authors stated, “To our knowledge this is the first lifestyle intervention study where remission of T2D has been studied with 100% remission with a feeding study using meals and food obtained from local grocery stores.” However, unlike GLP-1 drugs, a calorie-restricted diet with the same macronutrient composition as the Zone diet causes weight loss without loss of lean body mass in both individuals with type 2 diabetes (7) as well as those with pre-diabetes (8).

Metabolic Engineering® addresses a broader range of inflammatory triggers that cause metabolic damage than do GLP-1 drugs. There are three types of inflammation: (a) cytokine-based, (b) eicosanoid-based, and (c) free-radical-based. GLP-1 drugs are effective at reducing cytokine-driven inflammation because they activate AMPK, which, in turn, inhibits NF-kB activity, thereby decreasing cytokine production (9). This may explain their benefits in treating the long-term complications associated with long COVID-19, as well as other autoimmune conditions mentioned in the article.

However, GLP-1 drugs are far less effective than high-dose omega-3 fatty acids in reducing eicosanoid-driven inflammation or increasing levels of resolvins, which are necessary to stop inflammation (10,11). The third type of inflammation (free-radical damage) is best reduced by the transcription factor Nrf-2, which is activated by polyphenols (12). This is why Metabolic Engineering® provides a more comprehensive metabolic intervention than GLP-1 drugs do, without their side effects. However, if you really want to take GLP-1 drugs for a lifetime, then adding high-dose omega-3 and polyphenols will make them work even better and will likely reduce some of their side effects.

One last item to add is that there is much discussion of the upcoming new oral GLP-1 drugs. Although an earlier oral GLP-1 drug (i.e., Rybelsus) for treating diabetes was introduced in 2019, its daily dosing schedule was more onerous than a weekly injection. Oral GLP-1 drugs are largely destroyed in the stomach before they enter the bloodstream. To increase GLP-1 uptake, these oral formulations use a chemical enhancer (i.e., sodium salcaprozate, or SNAC) to increase the amount of the drug that enters the bloodstream, thus making compliance easier. In a recent 21-day study in rats, SNAC was associated with the loss of beneficial gut bacteria, lower butyric acid levels, and elevated levels of inflammatory markers (13). Hopefully, these potential adverse effects observed in animal studies will be addressed in clinical trials of these new, higher-dose oral GLP-1 drugs using SNAC before their widespread introduction. That’s why it is always good to read the fine print of the drug inserts. You don’t have that problem when following Metabolic Engineering®.