About Semaglutide: What Is It Exactly

Overview 

Semaglutide, the active ingredient in the medication known as Ozempic^® was originally introduced as a treatment for diabetes by the US Food and Drug Administration (FDA), but recently gained popularity as a treatment for chronic weight management. Cases of obesity are rising in the UK, with approximately 25.9% of adults in England classed as obese and 37.9% as overweight. Semaglutide provides a promising pathway in combating these health concerns, providing patients with greater options for weight management. Research has continued to highlight the effectiveness of using semaglutide as it demonstrated the largest weight loss of any obesity medication to date, with a 15% loss in initial weight at 68 weeks.¹ 

However, it is crucial to note that although it has benefits, semaglutide may not suit everyone.

Read on to find out more about semaglutide and why this is the case. 

What is semaglutide and how does it work in the body? 

Semaglutide belongs to a class of medications called glucagon-like peptide-1 receptor agonists (GLP-1RA). It mimics the naturally occurring glucagon-like peptide-1 (GLP-1) hormone, released in the gastrointestinal tract in response to eating. The role of GLP-1 is to prompt the body to produce more insulin, reducing blood glucose levels. Additionally, higher amounts of GLP-1 can interact with parts of the brain that reduce appetite and signal a feeling of fullness.

Semaglutide activates GLP-1 receptors by improving the efficiency of incretin function.² Incretins are gut-derived peptide hormones that are rapidly secreted in response to consuming a meal. Semaglutide acts as a GLP-1RA by selectively binding to the GLP-1 receptor in the brain and activating it. It can reduce blood glucose by stimulating and increasing insulin secretion and lowering glucagon secretion. Both are conducted in a glucose-dependent manner, therefore reducing the amount of unnecessary glucose produced by the liver. When blood glucose levels are high, insulin secretion is stimulated and glucagon secretion is inhibited. This mechanism of lowering blood glucose levels also causes a delay in postprandial gastric emptying and decreases the rate at which glucose appears in circulation.³  This delay in gastric emptying and subsequent reduced energy intake is associated with semaglutide’s effects on weight loss. 

Approved uses and medical conditions treated

There are currently three FDA-approved semaglutide products available on prescription:

• Semaglutide injection and tablets. These are approved to lower the blood sugar levels in adults with Type 2 Diabetes Mellitus (T2DM) in combination with diet and exercise. The injection was also approved to reduce the risk of stroke, heart attack, or death in adults with known heart disease and T2DM.
• Semaglutide injection for weight loss. This product is approved to aid adults and children aged 12 years and above with obesity or some adults who are overweight to lose weight and maintain it in addition to diet and exercise. 

Diabetes 

T2DM is a complex disease characterised by the progressive loss of pancreatic beta-cell insulin secretion and insulin resistance causing variable blood glucose levels.⁴ T2DM is the most common type of diabetes, making up an estimated 90% of total diabetes patients in high-income countries.⁵

Semaglutide injection for T2DM

This form is available as a self-injection pen. It is injected under the skin of the lower abdomen, the thigh, or the upper arm. The dosage is recommended by the National Institute for Healthcare and Excellence (NICE) to be a 0.25 mg or 1 mg prefilled pen for subcutaneous injection administered once weekly for four weeks. After four weeks, the 0.25 mg dose should be increased to 0.5 mg and if needed, can be increased to a maximum of 1 mg once weekly. ^6,7  The dosage is adjusted depending on individual patient needs and tolerability. 

Several studies have shown the efficiency of semaglutide injections in lowering the levels of HbA1c, the average blood glucose levels, by 1.2-1.8% over 10-13 months. Body weight was also reduced as compared with diet and exercise alone. It was also shown that a higher dose of 1 mg lowered body weight further compared to the 0.5 mg dose, with an estimated 1.3 kg difference in weight.⁷

Semaglutide tablets for T2DM

The first oral GLP-1RA and non-insulin treatment type for T2DM was approved by the FDA in 2019. This dosage form may be an attractive option for patients who are not interested in using injectable therapies, require improved glycaemic control, and want to lose weight.

Dosing strengths of the oral form include 3 mg, 7 mg and 14 mg tablets to be taken 30 minutes before eating, drinking, or taking other medication. Initially, a 3 mg tablet should be taken once a day for 30 days. After, the daily dose is then increased to 7 mg. If glycaemic targets have not been met after 30 days, the dose should be increased to a maximum of 14 mg orally once daily.³  

Obesity 

Semaglutide for anti-obesity exhibited significant weight loss compared to its predecessor, liraglutide. During clinical trials, a weight loss of 14.9% was achieved compared to 2.4% with a placebo, and participants who later switched to the placebo treatment gained weight.⁸  Semaglutide for T2DM has been shown to yield weight loss in patients who take them with lifestyle changes, however, they have not been approved for weight loss. 

Semaglutide for weight loss

Semaglutide is FDA-approved for chronic weight management in adults with an initial Body Max Index (BMI) of ≥30 kg/m² (classed as obesity), or ≥27 kg/m² to <30 kg/m² (classed as overweight) in the presence of at least one weight-related comorbidity. 

It can be administered with or without food. In the first month, the starting dose is 0.25 mg once weekly and is gradually increased over 16 weeks until the maintenance dose of 2.4 mg is reached to reduce gastrointestinal side effects. It has been approved for long-term use in overweight and obese adults. This means it can be taken as long as it remains beneficial for weight loss without causing intolerable side effects.⁹

In the UK, there are currently shortages of semaglutide to treat T2DM, partly caused by off-label prescribing and use for weight loss, therefore stressing the importance of using this medication for its licensed indication only. 

Other potential uses

Semaglutide has shown promise for other potential uses, including:

• Cardiovascular Disease (CVD) prevention. Approximately one-third of T2DM patients are or will be affected by CVD as insulin resistance may cause heart failure, stroke, or myocardial dysfunction.² Phase III clinical trials reported that patients receiving semaglutide had a 26% lower risk of death from CV causes, nonfatal stroke, and nonfatal myocardial infarction compared with patients taking a placebo after 2 years.⁷ Further research is needed but current evidence suggests that semaglutide may be an option to lower CVD risk in T2DM patients.
• Non-alcoholic steatohepatitis (NASH). NASH is a type of non-alcoholic fatty liver disease (NAFLD) with no clinically approved treatment available except for changes to diet and exercise. T2DM, insulin resistance and obesity are attributed to the risk of developing NASH. Those with NASH have impaired GLP-1 secretion and semaglutide was found to decrease hepatic steatosis via stimulation of GLP-1 receptors and reducing inflammation. Phase II clinical trials showed the highest impact in NAFLD activity with semaglutide as a combination regimen.⁸
• Neurological disorders. Insulin resistance in the brain is responsible for impaired cognitive functions and neurodegeneration. In Alzheimer’s Disease (AD), GLP-1RAs have been reported to regulate the aggregation of amyloid beta-peptides, which are hallmarks of AD. Human studies have shown the neuroprotective property of semaglutide against amyloid beta-plaques and several phase II trial reports support the dosage of 14 mg oral semaglutide on Alzheimer’s patients. In Parkinson’s Disease (PD), GLP-1RAs have been shown to regulate dopamine levels. A placebo-controlled, phase II clinical study has been designed to study the anti-inflammatory and neuroprotective effect of semaglutide on cognitive function in PD.⁸ 

Adverse effects 

Semaglutide is well tolerated but can show some of the following adverse effects:^2,7

Common side effects:

• Mild to moderately severe gastrointestinal symptoms that usually improve within 2 weeks of starting treatment. These include vomiting, nausea, constipation, diarrhoea, and dyspepsia. Clinical trials reported that these side effects were higher in the oral form rather than subcutaneous.
• Fatigue
• Dizziness
• Reactions at injection sites. 
• Slower digestion and an early feeling of fullness
• As semaglutide delays gastric emptying, the absorption of other oral medications can be affected.

Serious side effects

• Hypoglycaemia (low sugar levels). This occurs when semaglutide is combined with other medications like insulin or sulfonylurea. Symptoms include sweating, dizziness, and shaking.
• Thyroid tumours. Animal studies showed that semaglutide caused thyroid tumours and cancer. A 2022 study found a higher risk of thyroid cancer in those who used semaglutide. Thus, people should look out for symptoms such as a lump or swelling in the neck, shortness of breath and trouble swallowing. Anyone with a family history of thyroid cancer shouldn’t use semaglutide. 
• Acute pancreatitis, although rare, a few studies have shown that GLP-1RAs induce pancreatic inflammation. Noticeable symptoms include severe pain from the abdomen to the back. 
• Clinical trials found that subjects had a 76% higher risk of retinopathy complications, including blindness.

Summary 

Semaglutide has garnered significant attention since its approval to treat T2DM, due to its efficacy in improving glycaemic control and facilitating weight loss, which have established its position as a breakthrough therapeutic agent. However, the medication poses side effects which range from common gastrointestinal symptoms, fatigue and interference with other medication, to serious effects such as hypoglycemia, thyroid cancers and pancreatitis. It can be noted that ongoing research is required to explore its applicability in other medical conditions like CVD, NASH and neurological disorders, as well as further confirmation of its adverse effects.