Who Should Not Take Semaglutide

What is Semaglutide?

Belonging to a group of medications that help in reducing your sugar (blood glucose) levels in the body, Semaglutide falls under a class of receptor agonists classified as glucagon-like peptide-1 (GLP-1) that imitates the action of GLP-1 hormones. These hormones are usually released after the consumption of food, in the gastrointestinal tract and prompt the body to produce more insulin.¹

Figure 1: The lock-and-key mechanistic action of GLP-1, a peptide hormone. The activated receptor has a strong effect on the management of type 2 diabetes mellitus and obesity, including glucose homeostasis and regulation of gastric motility and food intake.²

A receptor is a substance found on the surface of cells and possesses a certain feature that enables it to act as a lock. An agonist is another cell that binds to this lock (receptor) and acts as its key. This binding mechanism helps in the activation and inhibition of hormones or cellular responses based on their specific effects and conformations.³

Semaglutide has garnered its name as a promising therapeutic drug for type 2 diabetes mellitus (T2DM). Although, when taken in high doses, it mimics the effects of hormones in the brain, such as ghrelin and leptin, decreases appetite and promotes the feeling of fullness. 

Further benefits of semaglutide

GLP-1 receptor agonist therapy may have certain benefits, such as:¹²

• Low risk of hypoglycemia
• Postprandial (after a meal) glucose control
• Decrease energy intake
• Delayed emptying of gastric content
• Glucose-dependant insulin secretion
• Glucose-dependant glucagon secretion
• Possible weight loss
• Feeling satiated quicker

How can one acquire semaglutide?

Owing to this, there are at present, three FDA-approved products that consist of semaglutide. 

• In adults afflicted with type 2 diabetes mellitus, GLP-1 agonist medication is prescribed. Rybelsus tablets [5] or Ozempic, orally or via subcutaneous injection [4] are the approved methods of trying to regulate blood sugar levels and reduce the chances of developing further heart disease. This is usually recommended in relation to following a healthy lifestyle of regular exercise and a good diet
• Also, used as a weight loss treatment in the form of a Wegovy injection⁶ in children aged 12 years or older and adults to help lose and keep it off. Again, effective when paired with exercise and a balanced diet, it helps patients suffering from weight-related problems and in lowering it

The above-mentioned medications are only available upon prescription, to be administered once weekly. 

Ozempicis also used as an “off-label” drug for weight loss and has garnered popularity for it.⁷ Wegovy is an FDA-approved weight loss drug made from the same compound, usually prescribed to people who are medically obese. Although derived from Semaglutide as well, Wegovy is medically recommended for use for weight loss and not to be replaced with Ozempic.⁸ Although offering two health-related benefits, semaglutide is not suitable for consumption by everyone. This article discusses the precautions as well as contradictions that are associated with semaglutide use. 

Who cannot take semaglutide?

• Drug-drug interactions: Since semaglutide works as a receptor agonist, it can interact with other similar medications and lead to adverse reactions or inhibition in their action. Medications such as opioids, ones affecting gastrointestinal motility, or anticholinergic agents will not particularly benefit from combining semaglutide with their current administration without prior advice from their healthcare providers⁹

• Potential non-responders: There might be certain individuals who might be afflicted with other underlying diseases, who might not respond accurately to semaglutide therapy. By consulting your healthcare provider, they may be able to assess and examine whether one qualifies to be put on semaglutide therapy. This could evade unnecessary administration and alternative approaches could be explored that would be comparatively beneficial

• Underlying medical conditions: Patients afflicted with certain severe illnesses such as pancreatitis, gastrointestinal disease, or a history of thyroid cancer could result in receiving adverse effects and would require close and careful administering if prescribed

• Risk of adverse effects: Individuals who are more prone to vomiting or nausea or even at high risk of experiencing gastrointestinal discomfort are not well-suited to receiving semaglutide and must always consult their healthcare providers for advice

Overall, identifying the symptoms and characteristics that do not qualify for semaglutide therapy through consultation with a local GP surgery or healthcare providers will help prevent unnecessary treatment. Planning and assessing the individual thoroughly will enable the healthcare provider tailoring a personalised and efficient track in prescribing the right course of action with regards to semaglutide medication. 

When can semaglutide be harmful?

History of pancreatitis

There have been certain clinical trials that demonstrate that the GLP-1 agonist receptor therapy might be associated with an increased risk of drug-related pancreatitis.¹⁰ Although originating in individuals as a result of drug-induced illnesses, hypertriglyceridemia,¹² and other idiopathic causes, it is mainly seen in patients with T2DM in comparison to the overall general population.¹³ The symptoms include severe and persistent abdominal pain, at times, radiating down to the back that could also be followed by vomiting. If there is a suspicion of pancreatitis, this drug must be promptly discontinued. Furthermore, restarting semaglutide in these patients must be discouraged. 

This reaction could potentially be caused since GLP-1 receptors are present in the islet cells of the pancreas, which, when exposed to semaglutide therapy, are stimulated, leading to their overgrowth, causing acute inflammation that could progress into acute pancreatitis.¹⁴

Severe gastrointestinal issues

Patients with severe gastrointestinal issues - inflammatory bowel disease, gastroparesis, history of gastrointestinal surgery.¹⁵ These conditions impact the function, motility, and absorption of the gastrointestinal tract, and cause adverse effects such as nausea, diarrhoea, and vomiting due to decrease in intestinal functioning and delay in gastric emptying.¹⁶

Renal impairment

Since semaglutide is a drug, it undergoes metabolising and filtration in the renal system within the body. The kidney plays an important role in this process in eliminating and filtering out drugs from the bloodstream. Although the liver carries out most of the metabolising of drugs that enter the system, the renal system must also function properly in order to clear out the semaglutide from the body, leading to reduced systemic exposure to the drug. If there is an impairment in renal functioning, it could lead to increase in exposure to the drug in the body, causing adverse effect, eg. a hypoglycemic attack.¹⁷

History of medullary thyroid carcinoma (MTC)

Although occurring sporadically in most cases, a subgroup of patients could be afflicted with medullary thyroid carcinoma (MTC) due to a hereditarily acquired mutation of their RET proto-oncogene, resulting in a loss of its functioning. That particularly happens in the thyroid gland’s parafollicular C (calcitonin) cells, which lead to the development of MTC.¹⁸ Animal studies have demonstrated a positive relationship between the uptake of GLP-1 receptor agonists - like semaglutide - and the increase in risk of onset of MTC.¹⁹

The thyroid hormone influences the pancreatic cells which are responsible for maintaining glucose homeostasis [20]. Several studies have been conducted that show an increase in prevalence of thyroid disorders in patients suffering with T2DM as well as vice versa.²¹ Owing to this potentially positive association between administration of semaglutide and T2DM, it is recommended to focus on individuals with a familial history of MTC or multiple endocrine neoplasia type 2 (MEN2). Screening for this could consist of genetic testing for RET gene mutations, as well as periodic monitoring of the MTC biomarker, calcitonin, found on a full blood count panel. 

Who should take precautions?

Individuals with these conditions, mentioned below, should take pre-caution when administering semaglutide, and monitor their hormone levels routinely to ensure there is no onset of a disease occurring as an adverse effect of semaglutide in combination with a contraindication. Individuals with:

• Cardiovascular diseases
• Renal impairment
• Geriartic patients
• Pregnant and Lactating mothers²²

Those people should take extreme pre-caution or try and utilise alternate methods to control their T2DM levels. 

Semaglutide is usually prescribed as a medication for the control of high blood pressure and management of T2DM. Individuals with type 2 diabetes mellitus are more prone to developing heart-related illnesses. T2DM often presents itself with other comorbidities such as hypertension, obesity, dislipidemia (high cholesterol). It also can lead to alteration in kidney function, impairing proper renal functioning as well as hepatic impairment. Improper liver activity can result in incorrect metabolism of the drug administered, in some cases not filtering out the drug causing it to remain in the body’s circulation. This could lead to adverse effects such as pancreatitis or severe gastrointestinal symptoms. 

In older individuals, age-related changes in hepatic and renal functioning, cognitive functioning, presence of various comorbidities, administration of different drugs, and pharmacokinetics can potentially affect drug-drug interactions and exacerbate underlying medical conditions leading to side effects. 

Pregnant and lactating mothers are not advised to take semaglutide as it can increase the chances of birth defects in the foetus as well as miscarriages. Although not studied extensively, there have been traces of semaglutide found in the breast milk, through animal studies. But further studies need to be conducted to back the latter claims. 

Summary

Semaglutide therapy, although FDA-approved and recommended in obese and/or diabetic patients and is subjected to adverse effects in certain individuals. Careful administration for those presenting with heart, kidney or liver impairments; severe gastrointestinal issues, or older individuals and pregnant people is advisable. Routine blood panels and consultations with one's healthcare provider are necessary to ensure a personalised plan that benefits the individual.