Dimitar Marinov, Ph.D.
Dimitar Marinov, Ph.D.When looking to explore weight loss peptides, researchers need to be aware of potential semaglutide side effects before deciding on whether to incorporate the peptide.
This comprehensive review will outline the primary side effects associated with semaglutide based on the current research.
Inside, we address questions like:
- What are the most common side effects of semaglutide?
- How are adverse reactions to semaglutide best managed?
- How should semaglutide be dosed to reduce side effect incidence?
Continue reading to also discover our most trusted resource for procuring research-grade semaglutide online.
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What is Semaglutide?
Semaglutide is a glucagon-like peptide-1 receptor agonist (GLP-1-RA) developed by the Danish pharmaceutical company Novo Nordisk. It is a synthetic 31-amino-acid peptide that shares 94% homology with native GLP-1 [1, 2, 3].
GLP-1 (7-37) is a truncated, active form of the incretin hormone glucagon-like peptide-1 (GLP-1) released by the intestines after food ingestion. GLP-1 (7-37) plays a crucial role in regulating glucose homeostasis and appetite [4].
Semaglutide mimics the GLP-1 hormone but possesses several structural modifications that provide comparative better stability and a longer half-life (about seven days), thereby enhancing semaglutide’s clinical potential [2, 3].
Initially formulated as a medication to reduce blood sugar levels, semaglutide showcases powerful benefits for type 2 diabetes (T2D) as shown by the SUSTAIN (Semaglutide Unabated Sustainability in Treatment of Type 2 Diabetes) clinical program [2].
Semaglutide's patent holder Novo Nordisk initiated this ongoing program that now consists of 15 published phase-3 trials. The already fruitful program is investigating the safety and efficacy of semaglutide on T2D in different settings and against different comparators [2].
Apart from the superior glucose-lowering effect of semaglutide vis-à-vis comparable drugs, the data has also indicated that semaglutide significantly reduces major adverse cardiovascular event (MACE) risk in T2D patients [2, 5].
This has led the United States Food and Drug Administration (FDA) to approve semaglutide as 1mg/weekly and 2mg/weekly subcutaneous injections for glycemic control and MACE risk reduction in T2D under the brand name Ozempic [5].
Due to semaglutide's notable effects on appetite suppression and weight loss in T2D, Novo Nordisk has also launched another ongoing clinical program called STEP (Semaglutide Treatment Effect in People with Obesity) [6].
It consists of several (STEP 1-10, STEP TEENS, etc.) phase-3 trials that have confirmed the long-term effectiveness and safety of semaglutide as a weight loss therapy in obese or overweight diabetics and nondiabetics [6, 7].
The peptide has shown remarkable results in the STEP program, earning FDA approval in doses of up to 2.4mg/weekly under the brand name Wegovy for chronic weight management in adults with overweight (BMI≥27kg/m2+ weight-related comorbidity) and obesity [7]. It has also received FDA approval for the treatment of obesity in pediatric patients aged 12-17 [8].
Semaglutide is also the only GLP-1-RA that is available and FDA-approved in tablet form under brand name Rybelsus. In this form, the peptide is attached to an absorption enhancer: sodium N-(8-[2-hydroxylbenzoyl] amino) caprylate (SNAC) [9]. Oral semaglutide is currently approved for T2D management thanks to the results of the ongoing PIONEER research program [2, 5, 9].
Semaglutide Side Effects
Numerous phase-3 clinical trials published as part of the STEP, SUSTAIN, and PIONEER clinical problems clearly demonstrate semaglutide’s excellent safety profile in subjects with and without T2D [2, 6, 10].
But the peptide is not free of side effects. The available clinical data reports that semaglutide is associated primarily with gastrointestinal issues, also the most common side effects among other GLP-1-RAs like liraglutide and tirzepatide [10].
Our readers may refer to the data published in the largest phase-3 trial to date that investigated the effects and safety of semaglutide at a maximum dose (2.4mg/weekly).
The STEP-1 trial included 1306 participants taking semaglutide and 655 participants receiving placebo. Overall, GI disorders were most common, affecting 969 participants on semaglutide (74.2%) and 314 participants on placebo (47.9%). The most common G.I. complaints in the semaglutide group were [11]:
- Nausea – 577 participants (44.2%)
- Diarrhea – 412 (31.5%)
- Vomiting – 324 (24.8%)
- Constipation – 306 (23.4%)
- Nasopharyngitis – 281 (21.5%)
- Dyspepsia – 135 (10.3%)
- Abdominal pain – 130 (10.0%)
Upper respiratory tract infections and headaches were common in both the semaglutide and placebo groups (8.7-15.2%) [11].
The PIONEER research program on oral semaglutide likewise showed an association with G.I. problems. For example, the PIONEER-4 trial, which compared oral semaglutide to subcutaneous liraglutide, reported the following side effects at 14mg/daily [12]:
- Nausea: 20%
- Diarrhea: 15%
- Vomiting: 9%
- Constipation: 8%
- Abdominal pain: 6%
- Dyspepsia: 6%
The SUSTAIN-6 trial, which investigated semaglutide doses of up to 1mg/weekly for 104 weeks, reports that the peptide may also lead to increased heart rate by 2.4bpm (beats per minute) from baseline. The increase in heart rate may lead to unpleasant sensations in some test subjects, but is not associated with any health risks [13].
STEP-1 also reported serious adverse events that affected the semaglutide group significantly more often than the placebo, including 23 patients with cholelithiasis and 3 patients with acute pancreatitis [11]. The PIONEER-4 also reported one case of pancreatitis in the semaglutide group [12].
Similar to other phase-3 trials, STEP-1 and PIONEER-4 trials did not report an increased risk of neoplasms [2, 10, 11].
Nevertheless, researchers must note that rat trials have reported an increased risk of thyroid C-cell carcinoma at high doses of semaglutide. Therefore, the peptide is contraindicated in individuals with a medical history of thyroid cancer or multiple endocrine neoplasia syndrome type 2 (MEN 2) [10].
Test subjects who are pregnant or lactating should also be excluded from semaglutide trials as per animal studies showing that GLP-1-RAs reduce embryo size and cause developmental abnormalities [14].
How to Manage Semaglutide Side Effects
Researchers should be aware of how to manage potentially serious side effects that may arise during semaglutide research. Such events may include:
- Hypoglycemia
- Allergic reactions
- Pancreatitis and gallbladder disease
In general, semaglutide carries a lower risk of hypoglycemia compared to other diabetes medications due to its glucose-dependent effects on insulin and glucagon secretion [2].
However, researchers should carefully monitor subjects who receive semaglutide alongside other anti-diabetic medications, such as injectable insulin, as the combination may lead to hypoglycemic events.
Given the immunogenic potential of peptides, researchers should also monitor allergic reactions with GLP-1-RAs like semaglutide. So far, no cases of anaphylactic reactions have been attributed to semaglutide [10].
As mentioned, serious side effects such as acute pancreatitis, cholecystitis, and cholelithiasis are possible during semaglutide therapy. The risk of these conditions may occur due to the inhibitory effect of GLP-1 towards cholecystokinin synthesis and gallbladder motility, which delays gallbladder emptying [15].
Acute pancreatitis, cholecystitis, and cholelithiasis can present with acute abdominal pain, fever, vomiting, and yellowing of the eyes (and the skin). Test subjects experiencing such symptoms should be referred for medical help immediately.
According to the available data from phase-3 trials, these side effects tend to have moderate severity and self-limiting progression, with all affected subjects fully recovering after discontinuing semaglutide [11].
Proper dosing and titration are also imperative for managing and minimizing semaglutide side effects. Keep reading to discover the recommended weight loss protocol for subcutaneous semaglutide based on the latest data.
Semaglutide Dosage and Administration
Semaglutide is available to qualified researchers and should be correctly dosed to minimize the risk of side effects.
In the case of weight loss research, this includes commencing with a lower dosage of 0.25mg/weekly and gradually increasing it every four weeks over a span of several months [6].
The maximum dosage of semaglutide is contingent on the research objective, with 2.4mg/weekly being the full dose for weight loss research [6].
Evidence from phase-3 trials recommends continuous administration of semaglutide, with most studies being conducted over a duration of 52-104 weeks at the 2.4mg/weekly dose [16, 17].
Here is the recommended weight loss dosing protocol for subcutaneous semaglutide [6, 16, 17]:
- Semaglutide Dosing Regime: 0.25mg/weekly for the first four weeks, 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: Do not exceed the maximum dose of 2.4mg/weekly. Missed doses are to be administered within 5 days or skipped.
Semaglutide Benefits
Semaglutide indicated for use in T2D and chronic weight management. Read on to learn about the peptide's science-backed benefits and associated mechanisms.
Treatment for Type 2 Diabetes
Semaglutide helps lower glucose levels in T2D subjects by interacting with the GLP-1 receptors in the pancreas. This interaction prompts pancreatic beta cells to produce insulin and inhibit glucagon synthesis by pancreatic alpha cells [2].
Consequently, this inhibits the process of hepatic gluconeogenesis and decreases both the fasting and postprandial blood glucose levels, thereby enhancing the blood sugar management in T2D [2].
Semaglutide is further known to mitigate postprandial glucose surges by slowing down gastric emptying by as much as 38% within a few hours post-meal [18]. Apart from its hypoglycemic effects, the weight loss benefits of semaglutide help reduce insulin resistance, further improving glycemic control in T2D [19].
As mentioned, numerous phase-3 studies within the SUSTAIN and PIONEER programs confirm semaglutide's benefits in clinical settings. Overall, the trials report a glycated hemoglobin (HbA1c) reduction of 0.6% to 1.6% points greater than comparators such as placebo, oral antidiabetics, insulin, and other GLP-1-RAs [20].
Semaglutide for Weight Loss
Research indicates that semaglutide aids in weight reduction by suppressing appetite, primarily through the activation of GLP-1 receptors in key brain regions like the hypothalamus. This action increases satiety and dampens food cravings, leading to lower energy intake and gradual weight reduction [21].
Moreover, GLP-1-RAs such as semaglutide may prompt the production of satiety-inducing hormones like leptin and PYY3-36 to further support long-term weight management [22].
According to STEP-1, weekly semaglutide doses of 2.4mg resulted in an average 14.9% body weight reduction over 68 weeks. The placebo group, however, only saw a 2.4% decrease, despite both groups adhering to a semaglutide dosage [11].
The more recent STEP-8 trial compared the weight reduction effects of semaglutide (2.4 mg/weekly) with those of liraglutide (3.0 mg/day), another GLP-1-RA approved for weight management [23].
After 68 weeks, semaglutide subjects saw a notable average weight loss of 15.8%, while liraglutide users achieved only a 6.4% reduction. This amounts to an average weight loss of 33.7lb (15.3kg) with semaglutide, compared to 15lb (6.8kg) with liraglutide [23].
Apart from the STEP 1-10 trials, ongoing studies such as STEP UP and STEP UP T2D are evaluating the weight reduction impact of a yet-to-be-approved 7.2mg weekly semaglutide dosage in patients with and without T2D, comparing it to the standard 2.4mg weekly dosage. These studies are projected to finish by late 2024 [24, 25].
Where to Buy Semaglutide Online? | 2024 Edition
Eligible researchers can acquire semaglutide for scientific and educational pursuits from a reliable online vendor.
To ensure purchases of high-grade semaglutide, it is advisable to rely only on vetted sources.
Our peptide review team has made purchases from multiple vendors, and the following two vendors consistently meet high standards in peptide purity, delivery, and customer support.
Limitless Life
Limitless Life provides research-grade semaglutide through its exclusive VIP club. Here's how this vendor surpasses its competition:
- Third-Party Tested Semaglutide: Limitless Life guarantees the quality of their peptides, working only with certified sourcing partneres and subjecting all peptides to HPLC-MS testing by reputable independent laboratories to guarantee 99% purity.
- Quick Delivery: Limitless Life offers rapid, dependable, and cost-effective delivery options. They waive shipping charges for orders of $350+ within the U.S., with orders usually delivered within two to three working days.
- Outstanding Customer Service: This vendor’s knowledgeable and professional support team typically responds to queries within 24 hours to ensure a smooth purchasing experience.
- Community Support: Limitless Life consistently earns high customer satisfaction ratings on platforms like Trustpilot and Sitejabber, which reflects their dedication to serving the research community.
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Research Chemical
We also recommend Research Chemical for their competitive pricing and superior quality semaglutide.
Here’s why they earn our endorsement:
- Third-Party Testing: All Research Chemical peptides are tested by an esteemed third-party laboratory and backed by Certificates of Analysis published on its website.
- Competitive Prices: Research Chemical’s pricing is fair and reflects their reference grade products. Semaglutide 5mg currently retails for just under $150.
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Bacteriostatic Water and Semaglutide
Semaglutide for educational purposes is typically shipped as a lyophilized powder.
This requires a suitable solvent and other materials, which must be obtained from a reliable source that guarantees their quality. Further, procuring all required items from one source can save time and effort during research studies.
This is why we highly recommend this supplier as one of the most trusted online retailers of peptide supplies.
Side Effects of Semaglutide | Overall
Semaglutide is a GLP-1-RA and weight loss agent that stands out for its potency, superior pharmacokinetics, and variety of formulations.
While semaglutide displays a favorable safety profile, researchers must be aware of semaglutide's potential adverse effects, including gastrointestinal complaints and hepatobiliary disorders. Rare events of acute pancreatitis and cholelithiasis require immediate medical attention.
By being aware of potential side effects and following recommended dosing protocols and hygiene standards, researchers can guarantee safety and success in research.
When looking to order semaglutide for research purposes, we highly recommend Limitless Life and Research Chemical as reputable suppliers of exceptionally pure research chemicals.
Luis Daniel López Murillo, PhD