Before you take Ozempic (or Wegovy, or Rybelsus…)

The allure of a medication that enables people to lose weight quickly and easily is huge and has spawned a billion-dollar industry in products that are almost wholly ineffective. Semaglutide (the drug sold under the brand names Ozempic, Wegovy, and others) is different: It really works, and it works relatively quickly. This seemingly “holy grail” solution for an exceptionally large market demand has inspired a global frenzy for access to the drug. But there’s a catch, and it’s a big one: there is no research on long-term side effects of taking semaglutide for weight loss in otherwise-healthy people, and there are big reasons to suspect that the side effects could be dire. I am not an endocrinologist; I work at a business school and my expertise is in empirical research on innovation. You may thus take what I write below with that caveat in mind. However, in 2016, I published a large-scale review study of the relationship between diabetes and Alzheimer’s disease in the Journal of Alzheimer’s Disease. I began the study when I noticed some striking inconsistencies in the conclusions being drawn by different research groups and I wanted to understand how the differences in research designs had led to this strange outcome. I analyzed hundreds of published studies on Alzheimer’s disease and identified the choices researchers had made that led to conflicting results, which, in turn, highlighted which results were more likely to be true. The results of that review study suggest that it could be quite dangerous for otherwise-healthy people to take semaglutide-based drugs for weight loss.

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Semaglutide increases the secretion of both fasting and post-prandial (i.e., after eating) insulin. While we need insulin to survive, tinkering with the insulin machinery of the body is risky. First, one of the major causative mechanisms of Type 2 diabetes is insulin resistance. According to the American Diabetes Association, people with insulin resistance have built up a tolerance to insulin making them less sensitive to its effects, requiring them to secrete more and more insulin. As the insulin resistance gets worse, the pancreatic cells that produce insulin can wear out, leading to full-blown diabetes. Taking a drug that artificially increases your insulin above that needed for normal blood glucose management thus seems ill advised. That alone should probably be a reason for a healthy person to not take anything that increases their insulin secretion.

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Second, chronically elevated insulin is a highly suspected mechanism in Alzheimer’s Disease, as I describe at length in the study mentioned above. In brief, insulin and its co-secreted amylin, are amyloidogenic proteins (i.e., clumpy proteins that can gum up other cells such as neurons). Fortunately, the secretion of insulin stimulates the production of an enzyme that will eventually break it down (“insulin degrading enzyme”) so that it does not accumulate in the body and its constituent elements can be recycled. Insulin degrading enzyme also, however, is responsible for breaking down several other clumpy proteins, including amloid-β (one of the main clumpy proteins associated with Alzheimer’s) and amylin (another amyloidogenic protein that is often found clumped near amloid-β plaques in the brains of Alzheimer’s patients). If insulin degrading enzyme doesn’t get a chance to break down these other clumpy proteins, they can accumulate in damaging ways. Numerous studies have shown that elevated insulin competitively inhibits the breakdown of both amyloid-β and amylin – that is, because the enzyme is busy breaking down insulin it does not break down the other amyloidogenic proteins that it would normally break down. Furthermore, even though insulin upregulates the expression of insulin degrading enzyme, it has been shown that this ability diminishes at high levels .

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This suggests that when insulin is chronically elevated (as it is during prediabetes, early Type 2 diabetes, and obesity), insulin levels could outstrip insulin degrading enzyme’s ability to break insulin down and may prevent the breakdown of other clumpy proteins. This may explain the well-known association between Type 2 diabetes and Alzheimer’s disease. A large longitudinal study in the Netherlands , for example, found that people with diabetes are almost twice as likely to get Alzheimer’s, and diabetes patients taking insulin are more than four times as likely to get Alzheimer’s! If otherwise healthy people begin taking semaglutide for weight loss and as a result have chronically elevated insulin, they risk inducing an increase in their risk of Alzheimer’s disease. Alzheimer’s is a disease that unfolds slowly throughout one’s life, and we have little ability to detect it early. By the time a person has recognizable symptoms, it is nearly impossible to slow the disease.

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None of the above is conclusive evidence that the risks of taking semaglutide outweigh the benefits for people using the drug for weight loss. Obesity itself is a strong risk factor for numerous health problems, and for many patients the benefits may exceed the risks even if the above concerns turn out to be warranted. It does, however, suggest that for people for whom diabetes or obesity are not significant health concerns, the potential risks of taking semaglutide drugs should be seriously considered. Significantly more research on the potential long-term effects of taking semaglutide is needed, and its use should proceed with extreme caution. ?