How Does Semaglutide Work? | A Comprehensive Overview

Seeking insights into how semaglutide works?

Then dive into this comprehensive guide as we elucidate the scientific mechanisms behind semaglutide's applications.

We break down the latest research on the peptide’s pharmacokinetics and pharmacodynamics, revealing the processes that drive its effects for:

• Glycemic control
• Chronic weight management
• Hormonal balance
• Cardiovascular health

For researchers planning to conduct semaglutide experimentation, this guide will provide insights to appropriately direct the studies.

We will also share details about our favored supplier of research-grade semaglutide and other research chemicals.

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What is Semaglutide?

Semaglutide is a synthetic peptide first developed in 2012 by global pharmaceutical firm Novo Nordisk. It is a 31-amino acid analog of the endogenous hormone glucagon-like peptide-1 (GLP-1). Semaglutide shares 94% homology with GLP-1’s active form, called GLP-1 (7-37) [1].

This allows semaglutide to bind to GLP-1 receptors throughout the body. In addition, the peptide has enhanced pharmacokinetics, prolonging its effects and extending its half-life to 7 days. The peptide is thus suitable for once-weekly subcutaneous injections [2].

This is thanks to several molecular modifications that enhance semaglutide’s ability to bind to plasma proteins, while making it more resistant to degradation by enzymes such as DPP-4 [3].

Based on impressive results from numerous phase-3 trials, semaglutide has gained clearance from the United States Food and Drug Administration (FDA) for several indications, including:

• In 2017, semaglutide was initially approved as an adjunct to diet and exercise in adult type 2 diabetics. The medication was marketed in doses of up to 1mg/weekly under the brand name Ozempic. In 2021, the FDA also authorized a higher dosage (2mg/weekly) for the same application [4].
• In 2019, an oral version of semaglutide, marketed under the brand name Rybelsus, was also approved for managing type 2 diabetes (T2D). Semaglutide is currently the only GLP-1 receptor agonist to be cleared by the FDA in oral form [5].
• In 2020, semaglutide (Ozempic) received FDA approval for use in reducing the risk of major adverse cardiovascular events (MACE) in diabetic patients [6].
• In 2021, a 2.4mg/weekly dosage of subcutaneous semaglutide was authorized for chronic weight management in adults with BMI≥30 or BMI≥27 and weight-related comorbidities. This product is available under the brand name Wegovy [4].
• In 2023, the 2.4mg/weekly dosage of semaglutide (Wegovy) was also approved for adolescents aged 12 years and older with a BMI for age/sex at ≥95th percentile [7].

Ozempic, Wegovy, and Rybelsus are all trade names of Novo Nordisk. In addition, semaglutide is available for online purchase by qualified researchers as a reference material.

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Mechanism of Action of Semaglutide

Semaglutide works by activating the GLP-1 receptors throughout the body, which results in various therapeutic effects. Keep reading to discover the latest evidence on its mechanisms.

How Semaglutide Works for Type 2 Diabetes

A primary use of semaglutide is improved glycemic control, achieved by the peptide’s interaction with the GLP-1 receptors in the exocrine pancreas.

Semaglutide mimics the function of the naturally occurring GLP-1 hormone, which is an incretin released by the digestive tract after food consumption to stimulate insulin release [8]

Semaglutide has a similar affinity to the GLP-1 receptors in the exocrine pancreas as native GLP-1(7-37), which results in [3]:

• Activation of pancreatic beta cell function and increased insulin production, and
• Suppression of pancreatic alpha cell function and reduced production of glucagon.

Increased insulin and suppressed glucagon production result in lower fasting and postprandial blood glucose levels as well as reduced gluconeogenesis. Moreover, the effect of semaglutide on the pancreas is glucose-dependent and does not significantly increase the risk of hypoglycemia [3].

The peptide may also help lower the postprandial glucose spike, which occurs right after a meal. It has been shown to slow down gastric emptying after a meal by up to 38%. The speed of gastric emptying decreases for the first four hours after a meal and then returns to normal [9].

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How Semaglutide Works for Weight Loss

Research demonstrates that GLP-1 receptor agonists like semaglutide work for weight loss primarily by suppressing appetite.

In fact, clinical data reveals that a weekly dose of semaglutide 2.4mg could lead to a 35% cut in mean ad libitum (unrestricted) energy consumption within a 20-week treatment course compared to placebo [10].

Semaglutide’s potent appetite suppression is likely due to the stimulation of GLP-1 receptors within various body parts, more specifically:

• GLP-1 receptors in brain regions associated with appetite and cravings, like the hypothalamus [11, 12].
• GLP-1 receptors in white fat tissue, which may upregulate the satiety hormone leptin [12].
• GLP-1 receptors in intestinal endocrine cells, which upregulates the production of the satiety-promoting Peptide YY(3-36) [12].

For example, scientists theorize that GLP-1 receptor agonists like semaglutide interact with neurons located in the arcuate nucleus of the hypothalamus and upregulate the expression of proopiomelanocortin/cocaine- and amphetamine-regulated transcript (POMC/CART) [12].

Likewise, activation of POMC/CART neurons promotes a sense of fullness and indirectly hinders the secretion of two peptides known for stimulating hunger: neuropeptide Y (NPY) and agouti-related peptide (AgRP) [12].

Research further indicates that GLP-1 receptor agonists like semaglutide mitigate the reduction of free leptin amid weight loss and elevate Peptide YY(3-36) levels. Leptin and Peptide YY(3-36) are hormones created respectively in fat tissue and the small intestine, and both facilitate satiety and potentially aid long-term weight reduction [12].

How Semaglutide Affects Inflammation and Metabolic Health

Semaglutide has favorable effects on inflammatory and metabolic markers in both diabetics and non-diabetics. For example, semaglutide can induce significant weight loss and improve both fasting glucose and fasting insulin, which are valuable markers for improved insulin resistance [13].

Addressing insulin resistance is crucial in the context of obesity, given its key contribution to the onset of numerous chronic conditions, including T2D, atherosclerosis, non-alcoholic fatty liver disease (NAFLD), and polycystic ovary syndrome (PCOS), among others [14]. Here is a summary of the relevant research.

• Semaglutide is highly effective at reducing intraorgan fat and potentially improving NAFLD. In an investigation comprising 48 diabetics receiving semaglutide 1mg/weekly, researchers observed a reduction in liver fat in 70% of the subjects over the course of 52 weeks. Liver enzyme levels and biomarkers of hepatic steatosis also saw significant improvements [15].
• A study conducted in obese mice documented that semaglutide significantly curtailed the expression of proinflammatory genes, leading to a decrease in plasmatic cytokine levels and a reduction in macrophage infiltration [16].
• Clinical studies indicate that semaglutide is also effective in reducing inflammation markers such as C-reactive protein (CRP) levels [17]. Results from murine studies also suggest that these anti-inflammatory effects could contribute to a reduction in atherosclerosis [18].
• The peptide's potent anti-inflammatory and metabolic benefits are thought to contribute to its cardioprotective potential, as well [19]. Semaglutide is already approved for reducing MACE risk in T2D, and is currently under investigation as a potential cardioprotective medication for cardiovascular risk reduction in non-diabetics under the ongoing SELECT trial [20].

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Benefits of Semaglutide

Broad scientific investigations have highlighted the multifaceted advantages of semaglutide.
Below, we will focus on the most significant and well-established benefits observed thus far, including its effectiveness in weight reduction, controlling blood sugar levels, and reducing cardiovascular risk.

Semaglutide for Type 2 Diabetes

The FDA’s clearance as a therapeutic agent for type 2 diabetes was underpinned by positive results from the SUSTAIN (Semaglutide Unabated Sustainability in Treatment of Type 2 Diabetes) clinical trials.

SUSTAIN was launched by Novo Nordisk to determine the safety and efficacy of the peptide in T2D. The research compared the effects of semaglutide 1mg/weekly with placebo and various glycemic control medications [21].

The list of comparative drugs included oral antidiabetics, injectable insulin, and other GLP-1 receptor agonists such as exenatide, dulaglutide, and liraglutide. Semaglutide demonstrated superior capability in reducing glycated hemoglobin (HbA1c) and fasting plasma glucose (FPG) levels versus all comparators [22. 23, 24, 25, 26, 27].

One of the latest trials (SUSTAIN FORTE) led to the approval of a higher semaglutide dose (2mg/weekly) for T2D, also reported a reduction in glycated hemoglobin of up to 2.2% from baseline [28].

Sermorelin for Weight Loss

For high-quality data on semaglutide for weight loss, researchers may refer to the STEP clinical development program, comprising ten phase-3 trials (STEP 1-10) focused on assessing the benefits of semaglutide 2.4mg/weekly for patients struggling with weight [29].

At present, findings from STEP 1-6 and STEP-8 trials are available in peer-reviewed scientific publications. Here’s a summary of some of the more notable published STEP trials [29]:

• STEP-1 is the biggest of the STEP trials, as it involved 1961 obese or overweight nondiabetics and reported an average body weight reduction of 14.9% during the 68-week semaglutide 2.4mg treatment course. By contrast, the placebo group lost a mere 2.4% in body weight even though it involved the same lifestyle interventions as the semaglutide group [29].
• STEP-5 is the longest of the STEP trials, which spanned two years at semaglutide 2.4mg and reported gradual weight loss over the initial 60 weeks. This progress was sustained throughout the 104-week trial. The net placebo-adjusted weight loss was 12.6% [13].
• STEP-8 is the most recently published trial as of writing. It compared semaglutide 2.4mg/weekly and liraglutide 3.0mg/daily over 68 weeks, demonstrating a substantial mean body weight reduction of 15.8% with semaglutide, relative to 6.4% with liraglutide [29].

Apart from STEP 1-10, there are ongoing STEP UP and STEP UP T2D trials evaluating the efficacy of a yet unapproved semaglutide 7.2mg/weekly dose against 2.4mg/weekly in patients with and without T2D, expected to be completed by end of 2024 [30, 31].

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Semaglutide Dosage For Research

For research purposes, semaglutide is available in freeze-dried powder form that requires reconstitution and careful dosage.

The optimal dosage for semaglutide research will vary based on objectives like the goal of the study and its duration. Researchers studying weight loss with semaglutide may refer to data from phase 3 trials involving T2D patients with chronic weight management problems [32].

According to this data, semaglutide should be administered subcutaneously once weekly on the same day. Studies should start with a low dose of 0.25mg, which should be increased gradually every four weeks to a maintenance dose of 2.4mg, based on the subject's tolerance [32].

Published studies suggest that semaglutide may be safely administered at 2.4mg/weekly for extended periods without cycling. The available studies have spanned anywhere from 52 to 104 weeks, with maximum effectiveness observed beyond 60 weeks [13, 33].

Here is a sample weight loss protocol for semaglutide based on existing scientific data:

• Semaglutide Dose Titration. 0.25mg/weekly for the first four weeks of the study period, followed by an increase to 0.5mg/weekly in weeks 5-8, 1mg/weekly in weeks 9-12, 1.7mg/weekly in weeks 13-16 and 2.4mg in weeks 17 and beyond.
• Frequency. Once weekly; subcutaneously.
• Study Duration. 52-104 weeks.
• Notes. Missed doses should be administered within 5 days, with the following dose delivered according to schedule. Do not exceed the maximum dose of 2.4mg/weekly.

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Side Effects and Safety

According to clinical data, semaglutide’s side effects are primarily gastrointestinal-related, similar to other drugs in its class [34].

The largest phase 3 trial to date studied semaglutide's effects and safety at a maximum dose of 2.4mg/weekly and offered crucial insights into the frequency of side effects [14].

The 1961 participants in the study were separated into two groups: semaglutide (1306) and placebo (655). The authors reported that GI disorders were almost twice as frequent in the semaglutide group, impacting 74.2% (969) of semaglutide users and 47.9% (314) of placebo users [14].

The most prevalent GI symptoms in the semaglutide group were:

• Nausea (44.2%)
• Diarrhea (31.5%)
• Vomiting (24.8%)
• Constipation (23.4%)
• Nasopharyngitis (21.5%)
• Dyspepsia (10.3%)
• Abdominal pain (10.0%)

Both the semaglutide and placebo groups commonly experienced upper respiratory tract infections and headaches, indicating that these complaints were not linked to semaglutide use.

The trial also identified potentially serious side effects in the semaglutide group, which are also typical for GLP-1 receptor agonists. Semaglutide caused 23 cases of cholelithiasis and 3 instances of acute pancreatitis. These cases were mild to moderate in severity and self-limiting [14].

Researchers should also note that there are specific contraindications for semaglutide, which include:

• History of thyroid cancer
• Multiple endocrine neoplasia syndrome type 2 (MEN 2)
• Pregnancy
• Lactation

Subjects with a history of thyroid cancer and MEN 2 are contraindicated for semaglutide based on data from rat trials showing an elevated risk of thyroid C-cell carcinoma with high semaglutide doses. This risk has not been confirmed in human trials [34].

Safety information is lacking in regard to breastfeeding women, so the peptide should not be administered to lactating subjects. Pregnant subjects should also avoid semaglutide, based on animal studies that reveal GLP-1-RAs could reduce embryo size and cause developmental abnormalities [35].

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Where to Buy Semaglutide Online? | 2024 Edition

While the cost of semaglutide may intimidate some researchers, it is also important to consider the peptide’s cost-effectiveness relative to other anti-diabetic and anti-obesity compounds.

For example, studies conducted in the United States showcase that subcutaneous semaglutide is considerably more potent and therefore more cost-effective than other FDA-approved therapies like dulaglutide [36].

However, researchers should exercise caution when procuring semaglutide online for their experiments, as many research chemical vendors offer low-quality products that may impede success in research.

We’re often asked about where to buy semaglutide online, and we always confidently recommend the following two vendors.

Limitless Life

Limitless Life offers research-grade semaglutide through their online member’s only club.

We continually recommend this vendor to researchers for a number of reasons:

• High-Quality Semaglutide: Limitless Life provides quality peptides backed by HPLC-MS test results from reputable third-party laboratories.
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• Helpful Service and Support: Their friendly support and service staff is always on hand to answer questions and address concerns.
• Fast, Affordable Shipping: Limitless Life offers fast, reliable, and affordable shipping options, and US orders of $350+ ship free.

Click the link below to enroll as a Limitless VIP Club member to gain access to semaglutide. Sign up is quick and instant:

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Research Chemical

For another highly recommended source of semaglutide for research, visit Research Chemical, a semaglutide vendor that stands out for the following reasons:

• Lab-Tested Semaglutide: All Research Chemical products undergo rigorous third-party purity testing conducted by MZ Biolabs.
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• Top-Notch Customer Service: The vendor’s customer service team is available by phone and email to assist customers with their questions.

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Bacteriostatic Water for Semaglutide

Semaglutide research requires proper handling and storage supplies.

Bacteriostatic water is the key ingredient needed to prepare semaglutide and keep it stable.

At Peptides.org, we recognize the need for high-quality research materials and recommend a leading provider.

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How Does Semaglutide Work? | Overall

Semaglutide is a powerful GLP-1 agonist that is designed appropriate for once-weekly use. It holds FDA approvals for T2D management, MACE risk in diabetics, and chronic weight control in adolescents and adults.

The peptide works by activating GLP-1 receptors throughout the body. Its glycemic control capability is thanks to its interaction with the GLP-1 receptors in the pancreas. Its appetite-suppressing and weight loss effects are thanks to its interaction with receptors in the brain, adipose tissue, and endocrine intestinal cells.

Researchers looking to use semaglutide in their work should turn to our top-rated vendor for research-grade reference materials.

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