By Saloni Dhaktode, Genetics and Genomics ’22
Author’s Note: My interest in research and biology began with understanding diabetes. This topic is close to my heart because my family is very susceptible to Type 2 diabetes, and many families of various ethnic groups in the U.S. are as well. Each patient has a unique background and lifestyle, which makes them unique in how their body handles both the condition and its treatments. My UWP 104E class with Dr. Nathaniel Williams gave me the opportunity to write this literature review and share one of the newest options available to Type 2 diabetic patients. I hope readers can learn more about how semaglutide is another step to best serving this uniqueness.
Introduction
The 2020 National Diabetes Statistics Report by the Centers of Disease Control (CDC) states that 34.2 million people in the United States have diabetes, either diagnosed or undiagnosed. Type 2 Diabetes Mellitus (T2D) accounts for about 90-95% of these cases. In healthy individuals, pancreatic β-cell insulin moves glucose into cells to be converted into energy, thus lowering glucose levels in the bloodstream. T2D is a chronic condition characterized by the body’s resistance to or inadequate production of β-cell insulin. This leads to uncontrolled hyperglycemia, or high blood glucose levels [1]. To compensate for rising blood glucose, the body may produce more insulin than normal, a condition known as hyperinsulinemia [8]. Since the body cannot properly respond to the accumulating insulin, hyperglycemia can persist alongside hyperinsulinemia.
Semaglutide, a medication used to treat T2D, falls under the class of glucagon-like peptide-1 receptor agonists (GLP-1RAs). An agonist is a chemical that activates a receptor. As an agonist, semaglutide activates receptors that prompt insulin release. Hence, these types of drugs regulate glycemic levels and are also linked to the treatments of obesity and cardiovascular disease, two conditions associated with T2D [2, 3, 6, 7, 9, 10]. Previously released medications of this class include liraglutide, dulaglutide, exenatide, and lixisenatide [6]. Semaglutide was added to the list in 2017 as a longer-acting alternative. GLP-1RAs were only administered through subcutaneous injection until 2019, when the first oral form, a pill version of semaglutide, was approved by the U.S. Food and Drug Administration. The SUSTAIN and PIONEER trials conducted by Novo Nordisk led to the release of semaglutide.
With semaglutide being a relatively recent development, further clinical trials are currently ongoing. This is why semaglutide is not recommended as the first choice for T2D treatment. But it still provides a substantial option for patients who do not see improvements with or have severe adverse reactions to previous treatments, such as Metformin (usually the first choice) or sulfonylureas (which also increase insulin secretion). The National Diabetes Statistics Report indicates an increase in total diabetes cases over the years [1], which calls for new medications that can benefit patients of diverse medical backgrounds. This review analyzes the function and effects of semaglutide using various clinical trials, in order to determine the scope of the drug’s ability to combat insulin resistance and other conditions associated with T2D.
What is Semaglutide?
Semaglutide is a GLP-1RA, a drug class that mimics the activity of the human glucagon-like peptide-1 (GLP-1) hormone. In particular, semaglutide has a 94% homology to GLP-1 [3, 5]. Glucagon, a hormone produced by pancreatic α-cells, raises blood glucose and induces insulin release to keep glycemic levels balanced. GLP-1 is called “glucagon-like” because it shares similarities with glucagon and enhances insulin secretion. GLP-1 is deficient in T2D patients, which is why semaglutide is designed as an agonist to mimic GLP-1. In this case, semaglutide activates GLP-1 receptors in the pancreas, promoting greater insulin release. By imitating GLP-1, semaglutide is able to lower glycemic levels, commonly indicated by decreased levels of Hemoglobin A1c (HbA1c), as glucose attaches to hemoglobin in the bloodstream [2, 4, 9, 10].
Novo Nordisk developed two forms of semaglutide: a subcutaneous injection and an oral pill. They were released and are being sold under the brand names Ozempic (injection) and Rybelsus (pill). Due to the half-life of semaglutide being 6-8 days, which is extended compared to earlier GLP-1RAs, the medication is administered once-weekly [3, 6, 7].
While there are no fatal safety issues with semaglutide, adverse effects must be considered. The most frequent effects are mild to moderate gastrointestinal events, such as nausea, vomiting and diarrhea [2, 3, 4, 5, 7, 9, 10] . A chance of hypoglycemia is always present, especially if semaglutide is taken with other antidiabetics. But most of the clinical trials reported low hypoglycemic rates [2, 4, 9, 10]. Significant increases in lipase were also reported [2, 4, 7]. Lipase is an enzyme that helps the body break down fats, but in high levels can be linked to pancreatitis. Semaglutide still requires testing with patients with histories of pancreatitis [3]. However, semaglutide exhibits a similar safety profile to other GLP-1RAs [2, 6, 7, 9, 10], so these effects are not unexpected.
Semaglutide Administration
Subcutaneous Injection
Subcutaneous injection is the most common form of GLP-1RA medications. The injection is commercially available as Ozempic. It is applied under the patient’s skin, into the tissue layer that lies between the skin and the muscle. The tissue layer has lower blood supply, which allows the medication to enter the bloodstream slowly and in a controlled manner.
The SUSTAIN 1 clinical trial conducted by Sorli et al. (2017) of Novo Nordisk tested the efficacy of subcutaneous semaglutide monotherapy versus placebo in T2D patients. Participants of 18 years or older with T2D were randomly assigned once-weekly subcutaneous semaglutide (0.5 mg or 1.0 mg) or volume-matched placebos. The testing period was 30 weeks. Results show that HbA1c levels significantly decreased by 1.45% with 0.5 mg and 1.55% with 1.0 mg [9]. The trial confirms subcutaneous semaglutide’s superiority versus the placebo. The Ozempic patient site prescribes a starting dose of 0.25 mg, which increases to 0.5 mg and 1.0 mg if needed. This is in accordance with the doses tested in SUSTAIN 1.
Oral Pill
The oral pill form of semaglutide is the first oral version of all GLP-1RAs [2, 4]. Since semaglutide is peptide-based, it is prone to proteolytic damage in the stomach. To overcome this issue, the tablet is co-formulated with sodium N-[8 (2-hydroxybenzoyl) amino] caprylate (SNAC). SNAC enhances the absorption of semaglutide across the stomach’s mucus layer and protects it from proteolytic degradation [2, 4, 6, 9].
The PIONEER 1 clinical trial conducted by Aroda et al. (2019) of Novo Nordisk tested the efficacy of oral semaglutide monotherapy against placebo in T2D patients. Participants of 18 years or older with T2D were randomly assigned once-daily oral semaglutide (3 mg, 7 mg, or 14 mg) or a placebo. The testing period was 26 weeks. Results indicate that the largest dose, 14 mg, led to HbA1c levels decreasing by an average of 1.5% [2]. The trial confirms oral semaglutide’s superiority at all dose levels versus the placebo. The Rybelsus patient site prescribes 7 mg or 14 mg tablets, corresponding to the doses tested in PIONEER 1.
Oral vs. Injection
The availability of two semaglutide products raises the question of which form of administration is more effective in enhancing insulin secretion. The 1.45% to 1.55% HbA1c reductions seen in the SUSTAIN 1 trial are comparable to the 1.5% HbA1c reduction in the PIONEER 1 trial. Each of the trials differed in methods and testing duration, but the percent reductions of HbA1c are very similar, with respect to the doses each trial’s researchers deemed most effective.
A clinical trial by Davies et al. (2017) assessed the efficacy of oral semaglutide versus subcutaneous semaglutide or placebo in T2D patients. Participants 18 years or older with T2D were randomly assigned to one of five oral semaglutide groups, an oral placebo group, or a subcutaneous semaglutide group. The oral groups’ HbA1c levels significantly reduced by an average of 1.8% and the subcutaneous group’s HbA1c levels by 1.9%. Evidently, there is very little difference between the percent reductions in both group types. [4]. This supports the similarity in HbA1c reduction between the SUSTAIN 1 and PIONEER 1 trials observed earlier. Therefore, it can be concluded that there is no significant difference between either form’s ability to effectively secrete insulin.
Since there is no obvious advantage or disadvantage between the two forms, the choice between an injection and a pill is open to patients, according to their preference or compatibility with their bodies. The subcutaneous tissue layer has a lower blood supply, which allows semaglutide to enter the bloodstream slowly. Similarly, a semaglutide pill must be metabolized by the gastrointestinal system before entering the bloodstream. The slow absorption of both forms lowers the risk of sudden hypoglycemia in patients. Patients can also take into account (using the Rybelsus and Ozempic patient sites) that the pill (Rybelsus) must be taken once-daily on an empty stomach, as food can hinder its absorption in the stomach. In contrast, the injection (Ozempic) must be administered once-weekly with or without food.
Effects of Semaglutide on Conditions Associated with T2D
On Obesity
People with obesity are at a higher risk of being diagnosed with T2D. Thus, it is important to note that semaglutide’s benefits include weight loss. GLP-1RA has been shown to stimulate satiety and reduce hunger and energy intake. These effects may be due to activation of GLP-1 receptors in the hypothalamus, the part of the brain that controls appetite. A study conducted by Blundell et al. (2017) investigated the effects of semaglutide on appetite, energy intake, and body weight in patients with obesity. The study made sure to exclude participants diagnosed with diabetes. Subjects of 18 years or older were randomized to once-weekly subcutaneous semaglutide or a placebo, both 1.0 mg doses, for 12 weeks. Subjects were allowed ad libitum (i.e. unrestricted) meals. The study shows energy intake lowered by 24% across all ad libitum meals with semaglutide versus placebo. Results also indicate lower preferences for high-fat foods and better portion control with semaglutide. Body weight was lowered by about 5.0 kg, which can be attributed to the changes in appetite [3]. Weight loss was also observed in SUSTAIN 1 and PIONEER 1 [2, 9]. These effects in conjunction with enhanced insulin secretion would particularly help obese T2D patients, who are more likely to deal with higher glycemic levels.
It is worth noting that it is possible to have T2D without being overweight or obese. For example, the Body Mass Index (BMI) cutoff for diabetes screening is lower in some ethnic groups than others. This may be due to genetic factors rather than dietary factors. However, the PIONEER and SUSTAIN trials’ subjects were undergoing diet and exercise prior to screening, indicating that weight loss was a goal. The subjects’ mean BMI was also greater than 30. Because T2D in non-overweight individuals is less common and harder to detect, there remains a need for more research on how T2D treatments promoting weight loss can affect them.
On Cardiovascular Disease
T2D increases the chances of developing cardiovascular disease. In fact, it is the leading cause of death in T2D patients [7]. According to the CDC, excess blood glucose damages blood vessels over time, preventing oxygen-rich blood from reaching the heart. A study by Marso et al. (2016) for the SUSTAIN 6 trial investigated the effects of semaglutide on Major Adverse Cardiovascular Events (MACE) versus placebo. The doses administered were the same as in SUSTAIN 1. The trial confirmed the researchers’ hypothesis that semaglutide would be non-inferior to placebo. This is evidenced by a significant 26% decrease in MACE, which are a composite of cardiovascular death, non-fatal stroke, and non-fatal myocardial infarction [7].
Semaglutide with Metformin
Metformin is the preferred first-line treatment for T2D, because it has been well-studied and successfully used as such since the 1950s. It is classified as a biguanide, an oral drug that prevents glucose production in the liver and lowers insulin resistance. Dual therapy of semaglutide (both oral and subcutaneous) added to metformin is of interest because there are many T2D patients who do not see satisfactory results with metformin monotherapy. Semaglutide may be able to provide additional glycemic control.
The PIONEER 8 trial, conducted by Zinman et al. (2019) investigated the efficacy of oral semaglutide versus placebo in T2D patients taking insulin with or without metformin. The doses administered were the same as in PIONEER 1. Results show that 14 mg of semaglutide with insulin, regardless of the presence of metformin, reduced HbA1c levels by 1.3%, which is significantly greater than the placebo’s effects [10]. An older study by Hausner et al. (2017) explored the effects of subcutaneous semaglutide on metformin in healthy subjects. No significant interactions between the two medications were found [5]. Further research must be conducted to determine whether metformin works better with semaglutide as opposed to on its own. Nevertheless, it is evident that semaglutide can be used in conjunction with metformin safely and without adjustments in dosage.
Conclusion
The clinical trials referenced in this review have demonstrated that both subcutaneous and oral semaglutide are significantly effective in lowering Hb1Ac levels in T2D patients [2, 4, 9, 10]. In addition, semaglutide has also been proven effective in weight loss and reducing the risk of MACE [3, 7]. Semaglutide’s efficacy is a major advancement in T2D treatment and GLP-1-based therapies because of its diverse functions. Its ability to treat hyperglycemia, obesity, and cardiovascular disease; availability in oral and injection forms; and compatibility with metformin caters to T2D patients with various needs.
Semaglutide was only recently approved, with more clinical trials being run by Novo Nordisk and other institutions today. Future research should focus on investigating the advantages of oral over subcutaneous forms and metformin-semaglutide dual therapy over metformin monotherapy. These studies would provide deeper insight into determining the best possible treatments for T2D.
References:
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- Blundell, J., Finlayson, G., Axelsen, M., Flint, A., Gibbons, C., Kvist, T., & Hjerpsted, J. 2017. Effects of once‐weekly semaglutide on appetite, energy intake, control of eating, food preference and body weight in subjects with obesity. Diabetes, Obesity and Metabolism [Internet]. 19(9):1242–1251. doi:10.1111/dom.12932
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