Is there living pharmacogenovigilance behind Semaglutide drugs?

Last Updated on August 31, 2023 by Joseph Gut – thasso

August 04, 2023 – We at thasso recently had an article (blog) on the much discussed and recently throughout the social media as wonder compound (drug) for weight loss promoted active ingredient Semaglutide in the form of the newly marketed product Wegovy (Semaglutidee). While Semaglutide may work for some patients as promoted and intended, with some spectacular weight loss results in some mostly prominent individuals, we also expressed some reservations as to its safety and absence of known or of as yet unknown, if not even fatal, adverse drug reactions (ADRs) in individuals of the general population.

Semaglutide is a pharmacologically active ingredient of the antidiabetic medications Ozempic (Semaglutide) and Rybelsus (Semaglutide), approved for the   treatment of patients with type 2 diabetes  in order to help to control associated weigth reduction efforts. Wegovy (Semaglutide), on the other hand, is primarily intended and approved as an anti-obesity medication used for long-term weight management, It is a peptide similar to the hormone glucagon-like peptide-1 (GLP-1), modified with a side chain. Semaglutide is a GLP-1 receptor agonist, meaning that it mimics the action of the human incretin GLP-1, thereby increasing insulin secretion and increasing blood sugar disposal and improving glycemic control.

Unwanted drug reactions (side effects) of Semaglutide may include dizziness, fatigue, gastrointestinal issues, such as diarrhea, constipation and gassiness, headache, stomach issues including nausea, vomiting, abdominal pain, diarrhea, constipation, distension, and some more serious ones like suicidal thougts, anaphylaxis (a possibly life-threatening systemic allergic reaction characterized by acute onset and multiorgan involvement), and angioedema. Classical pharmacovigilance reveals postmarketing drug safety data such as those reported here for the marketed Semaglutide-based drugs. This concept applies until now more or less to all drugs and their postmarking safety surveillance. In some cases, a unwanted drug reaction (in the form of a resulting clinical phenotype) may be put into relation to an existing predisposition of a patient for the development of

the clinical phenotype in question under drug treatment. Unfortunately, the current pharmacovigilance reporting approach largely leaves out the causes of predisposition of patients for the development of the unwanted or adverse clinical phenotype under drug treatment. One, perhaps the most decisive reason for development of an ADR might be the genetic outfit of the affected patient. In the present case with Semaglitude-based drugs, you talk about a medication that acts on the GLP-1 receptor, of whom genetic variants are known and described in a way as to how they influence patients status/degree of diabetes and responses to therapies, such as, for example, HbA_1c reduction, even with considerable differences in populations of different gender and ethnic background. 

Such knowledge needs to go into the modern concept of pharmacogenovigilance which aims at integrating patient related pharmacogenomic and patient genomic data into pharmacovigilance reporting. The fact that genes play a vital role in variability in response to medicines makes pharmacogenomic data related to adverse drug reactions (ADRs) very essential. Genetic variations do significantly affected the drug action (indented or non-intended (i.e., adverse)) in many patients, and at times predisposes a fraction of patients to unforeseeable, sometimes even fatal ADRs that are not seen in a large majority of patients.

In the traditional way of pharmacovigilance, the European Medicines Agency (EMA) is investigating Ozempic (Semaglutide) after Iceland’s health regulator flagged three cases of patients thinking about suicide or self-harm. The EMA safety committee is looking closer into these adverse events raised by the Icelandic Medicines Agency, which include two cases of suicidal thoughts in patients who used Ozempic (Semaglutide), Another case was related to a patient on Saxenda (Liraglutide), an earlier and less effective weight-loss drug. Up to now, interestingly, suicidal thoughts are not listed as a side effect in the EU product information for either drug.

In the United States, however, prescribing instructions for Wegovy (Semaglutide) recommend that patients are monitored for suicidal thoughts or behaviour. According to the U.S. Food and Drug Administration Adverse Event Reporting System (FAERS) Public Dashboard, there have been at least 60 reports of suicidal ideation since 2018 from patients or from or their health care providers on Semaglutide drug-related cases. Apparently, FAERS has received also at least 70 such reports since 2010 from users of Liraglutide or their health care providers. This may indicate that drugs acting on the GLP-1 receptor may induce suicidal  ideation / thoughts in at least some patients.

Interestingly, and to some degree controversial in itself, the FDA said that it monitors safety of drugs throughout their life cycle. Wegovy (Semaglutide)’s clinical trials did not suggest increased risk of suicidal behaviour, but then, the drug’s label contains a warning for suicidal behaviour and ideation because of risks associated with other weight management drugs, the regulator said. And, in its clinical trial, the makers of Wegovy (Semaglutide) did explicitly exclude people with a history of psychiatric disorders or recent suicidal behaviour.

Although Iceland’s regulator has flagged only three cases, the issue of suicidal thoughts linked to weight-loss drugs is sensitive and has hobbled previous attempts by the drug industry to develop lucrative weight-loss drugs. The present events around Semaglutide illustrate that the time has come to include genetic background data of patients into pharmacovigilance reporting, giving rise to the all new concept of “Pharmacogenovigilance“. Pharmacogenovigilance aims at integrating patient related pharmacogenomic data into a pharmacovigilance reporting. The fact that genes play a vital role in variability in response to medicines makes pharmacogenomic data related to adverse drug reactions (ADRs) very essential. Genetic variations do significantly affected the drug action  (indented or non-intended (i.e., adverse)) in many patients, and at times predisposes a fraction of patients to unforeseeable, sometimes even fatal ADRs that are not seen in a large majority of patients. In the epoch of precision and personalized medicine, pharmacogenetics may provide a cleaner path to individualized use of medicines, making, among others, drug safety and efficacy studies more safe and effective when genetic polymorphism are taking into account.

In order to answer the question from the headline of this blog article: No, unfortunately, there does not exist a living pharmacogenovigilance concept around Semaglutide drugs nor any other drugs for that matter. Not yet.

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