Semaglutide is an agonist of the glucagon-like peptide-1 receptor (GLP-1R), and is available as an injectable (Ozempic and Wegovy) or oral tablet (Rybelsus) [1]. Off-label prescriptions for these drugs have skyrocketed of late due to endorsements by moronic celebrities and social media influencers working on behalf of Novo Nordisk, the manufacturer of semaglutide [2]. The problem is the above trio is nowhere near as safe as they are being marketed as, and healthcare providers are prescribing them like candy without informing their patients of the side effects. Following is an honest listing of these, as given in the current medical literature.
GLP-1 is a pleiotropic hormone formed by cleaving of the proglucagon protein released by the intestines and pancreas [3]. As an incretin, GLP-1 stimulates insulin secretion upon glucose intake, but it also lowers glucagon (a hormone that raises blood sugar), delays gastric emptying, and suppresses appetite [4]. Being a synthetic analog, the sequence of semaglutide is not identical to that of native GLP-1 [5]. This homology deficit brings a potential for immunogenicity, and indeed patients on semaglutide have formed antidrug antibodies which were cross-reactive toward the endogenous peptide [6]. Because native GLP-1 has a half-life of only a few minutes at best, while semaglutide has a half-life of about a week, lingering of this immunogenic analog might engender more serious reactions relating to hypersensitivity or autoimmunity [7] [8] [9]. Although rare, the autoimmune blistering disease bullous pemphigoid, anaphylaxis, and drug-induced liver injury have all been reported with semaglutide use [10] [11] [12] [13]. Add to this the fact that inconsistent manufacturing processes can create impurity profiles that contribute to immunogenicity (this has been demonstrated with follow-on versions of semaglutide), and we get a bigger drug safety problem [14] [15]. Weight regain is nothing new for obesity pharmacotherapy, and in an observational study by Wilding et al., participants going off the drug “led to most of the weight loss being regained within 1 year, and a similar change in some cardiometabolic variables back to baseline, reinforcing the need for continued treatment to maintain weight loss…” [16]. The authors also noted that “participants in the semaglutide arm with greater weight loss during the 68-week treatment period tended to have greater regain in body weight after semaglutide withdrawal,” illustrating how powerful the rebound effect is with these drugs. And of course, with rapid weight loss, not all of the weight lost is fat [17]. Ozempic face is now a popular term used to describe the gauntness of sagging skin, more prominent wrinkles, and changes to the lips, chin, and cheeks caused by the drug [18]. The loss of elastin, collagen, and nutrients for the skin barrier can accelerate the appearance of facial aging [19]. Signs of facial aging can persist when fat regained does not get distributed in the manner it did before the medication was started, and body fat redistribution is a consequence of many pharmaceuticals – visceral fat accumulation being the chief concern with this [20]. In a clinical trial published in 2021, out of 535 participants who continued to receive subcutaneous semaglutide after 20 weeks, 435 reported an adverse event, with 41 being serious [21]. In the group that switched to a placebo after 20 weeks (n = 268), 201 reported an adverse event, with 15 being serious. These are not great odds. Gastrointestinal symptoms such as nausea and vomiting are frequently experienced by semaglutide users, but concerns over induced pancreatitis have been raised, and in the SUSTAIN 5 trial, one patient developed metastatic pancreatic cancer after treatment [22] [23]. An increased risk for pancreatitis and pancreatic cancer has been observed with other GLP-1R agonists [24]. In the SUSTAIN 6 trial, rates of vitreous hemorrhage or bleeding in the eye and diabetes-related blindness were “significantly higher” in the group that received semaglutide versus a placebo [25]. Blurred vision is a listed side effect for semaglutide too [26]. The GLP-1 receptor appears to be marginally expressed in the normal human thyroid, and Bezin et al. found a heightened risk of thyroid cancer with the use of GLP-1R agonists, not including semaglutide [27] [28]. However, both semaglutide formulations come with a box warning for thyroid tumors, and in both the SUSTAIN and PIONEER trials, thyroid malignancies were more prevalent in semaglutide-treated patients versus comparator groups [29]. Worry exists over cardiovascular complications with GLP-1R agonists, as these pharmaceuticals can increase resting heart rate [30] [31]. An uptick of 5 beats per minute associates with a 17% elevation in the risk of cardiovascular mortality according to Hozawa et al., and semaglutide raises the pulse rate by roughly 3 beats per minute [32] [33]. A higher likelihood of gallbladder disease seems to be par for the course with incretin-based medications, and a meta-analysis by Nreu et al. saw the chance of cholelithiasis (gallstones) go up by 28% with GLP-1R agonist treatment [34] [35]. In the STEP and SUSTAIN programs, gallbladder events occurred more often in those given semaglutide [36] [37]. Acute kidney injury has been reported after starting semaglutide with normal kidney function prior [38]. Leukocytoclastic vasculitis (blood vessel inflammation) has also been seen with the oral form of the drug [39]. Semaglutide may bring about psychiatric symptoms in some individuals, as Li et al. recently gave two cases of semaglutide-associated depression, with one appearing in a 54-year-old man with no previous history of depression [40]. Other adverse effects such as suicidal ideation and anxiety have been linked to a GLP-1 receptor agonist previously [41]. Since semaglutide interacts with neural pathways in the brain relating to food preference and appetite regulation, one wonders what the long-term effect of GLP-1 receptor hyperactivation on eating behavior might be [42] [43]. Lastly, another potential but serious outcome of taking GLP-1RAs is intestinal obstruction, as these medications were tied to a nearly 2-fold increase in bowel obstruction risk that rose to 3.48 after 1.6 years of use, per the cohort study by Faillie et al. [44]. A hazard ratio of 3.48 means the users were 348% more likely to experience an obstruction after taking semaglutide or another drug of the same class for over a year and a half. Speaking to the same danger, Lu et al. said the following in their 2023 paper: “Because GLP-1RAs could cause continuous increases in the intestinal length and villus height, the small intestine may become as inelastic and fibrotic as a loose spring…leading to long-term upper intestinal obstruction…” [45]. Untreated bowel obstructions can be life-threatening, so this is an unsettling issue [46]. In conclusion, there are natural and safe means of helping the body lose weight healthfully, obesity medications are not the only option. With so many clinics and spas offering semaglutide right now, please do your homework and be informed before taking the advice of a practitioner who may be all too eager to write a script for Ozempic. References:
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AuthorDenton Coleman is an Exercise Physiologist and Medical Researcher. Archives
October 2023
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