GLP-1 drugs restrict calorie intake, leading to rapid metabolic benefits. So does Metabolic Engineering®. The critical question is whether those benefits can be sustained long-term without continuous reliance on GLP-1 drugs.
GLP-1 drugs are hailed as wonder drugs. They cause weight loss, reduce the risk of diabetes, improve cardiovascular health, decrease cravings, etc. Unfortunately, all those benefits rapidly disappear once you stop using the drug. And why would anyone stop using such a wonder drug? The answer is the side effects, as nearly 50 percent of the patients stop using the drugs within a year after starting (1, 2).
Side effects rarely emerge during the initial clinical trials run by the drug company marketing the drug. However, they begin to develop after the drug is introduced into the general population once it is approved. GLP-1 drugs are no different, but 50 percent is an exceptionally high discontinuation rate considering the media hype and extensive television marketing of these drugs.
Now two new articles have come out indicating that the weight regain after stopping these GLP-1 drugs is twice as rapid compared to those who lost weight via diet and exercise (3, 4). Furthermore, the metabolic and cardiovascular benefits observed with GLP-1 drugs were also rapidly lost (3).
The reason for the rapid loss of all GLP-1 benefits is more complex. One theory is that constant injection of GLP-1 drugs downregulates the natural release of GLP-1 from the gut in response to dietary protein. This reduced natural GLP-1 signaling could explain the more rapid weight regain after stopping the drugs. It also suggests a potential solution: changing the macronutrient composition of your diet while maintaining the same level of calorie restriction induced by GLP-1 drugs, without hunger. That is the foundation of the Zone diet.
The Zone diet was developed based on drug delivery principles, not dietary beliefs. The starting point is determining the amount of protein you need daily to maintain your lean body mass, but not your total weight, but your lean body mass. The typical American diet provides about 16% of total calories coming from protein. A safe protein intake for adults is between 10 and 35% of total calories. The Zone diet starts with increasing your daily protein intake to 30% of total calories, not only to maintain lean body mass, but also to stimulate the natural release of GLP-1 from the gut more effectively.
Your protein intake should be spread evenly throughout the day to maintain a steady release of GLP-1 from the gut, so you aren’t hungry. That is the secret to successful lifetime calorie restriction. On an individual meal basis, that is about 30-35 grams of protein per meal. Add to that amount of protein a slightly higher level of low glycemic carbohydrates (non-starchy vegetables are the best, with limited amounts of fruits) and a dash of fat, and you will get the same degree of appetite suppression as any GLP-1 drug, but without any loss of lean body mass (5, 6).
What does this mean practically? At each meal, use your plate as a guide. One third of the plate should consist of low-fat protein, approximately the size of the palm of your hand. Half of the plate should consist of non-starchy vegetables, and one-sixth of your plate should consist of fruits, primarily small berries (no more than half a cup). Then add a dash of monounsaturated fat, such as olive oil or nuts. That’s it. No complicated mathematical calculations. How do you know if it’s working? You shouldn’t be hungry after five hours. If you are, you probably added too much fruit since it is rich in simple sugars like glucose and fructose.
At the molecular level, both GLP-1 drugs and the Zone diet use calorie restriction to activate AMPK, the master regulator of metabolism. If AMPK is activated, you burn fat faster, which leads to weight loss. However, both the Zone diet and lifelong GLP-1 use can be enhanced to provide even greater metabolic benefits by increasing omega-3 fatty acid intake and reducing oxidative stress through increased polyphenol intake, thereby further increasing AMPK activity (7). This total dietary system is Metabolic Engineering®. Metabolic Engineering® is a lifelong intervention. But if you prefer taking weekly injections of GLP-1 drugs with their associated side-effects, at least consider adding these adequate levels of omega-3 fatty acids and polyphenols as supplements to those GLP-1 injections to get the full benefits that automatically come from Metabolic Engineering®.
References
1. Do D, Lee T, Peasah SK, Good CB, Inneh A, Patel U. GLP-1 receptor agonist discontinuation among patients with obesity and/or type 2 diabetes. JAMA Netw Open 7:e2413172 (2024). doi: 10.1001/jamanetworkopen.2024.13172.
2. Rodriguez PJ, Zhang V, Gratzl S, Do D, Goodwin Cartwright B, Baker C, Gluckman TJ, Stucky N, Emanuel EJ. Discontinuation and reinitiation of dual-labeled GLP-1 receptor agonists among US adults with overweight or obesity. JAMA Netw Open. 8:e2457349 (2025). doi: 10.1001/jamanetworkopen.2024.57349.
3. Horn DB, Linetzky B, Davies MJ, Laffin LJ, Wang H, Murphy MA, Zimner-Rapuch S, Lau E, Arad AD, Lee CJ. Cardiometabolic parameter change by weight regain on tirzepatide withdrawal in adults with obesity: A post hoc analysis of the SURMOUNT-4 trial. JAMA Intern Med. Nov 24:e256112 (2025). doi: 10.1001/jamainternmed.2025.6112.
4. West S, Scragg J, Aveyard P, Oke JL, Willis L, Haffner SJP, Knight H, Wang D, Morrow S, Heath L, Jebb SA, Koutoukidis DA. Weight regain after cessation of medication for weight management: systematic review and meta-analysis. BMJ. 392:e085304 (2026). doi: 10.1136/bmj-2025-085304.
5. Stentz FB, Brewer A, Wan J, Garber C, Daniels B, Sands C, Kitabchi AE. Remission of pre-diabetes to normal glucose tolerance in obese adults with high protein versus high carbohydrate diet: randomized control trial. BMJ Open Diabetes Res Care. 4:e000258 (2016). doi: 10.1136/bmjdrc-2016-000258.
6. Stentz FB, Lawson D, Tucker S, Christman J, Sands C. Decreased cardiovascular risk factors and inflammation with remission of type 2 diabetes in adults with obesity using a high protein diet: Randomized control trial. Obes Pillars. 4:100047 (2022). doi: 10.1016/j.obpill.2022.100047.
7. Sears B, Saha AK. Dietary control of inflammation and resolution. Front Nutr. 8:709435 (2021) doi: 10.3389/fnut.2021.709435..
