Dimitar Marinov, Ph.D.
Dimitar Marinov, Ph.D.Does semaglutide make you tired?
This question often arises when researching the effects of this potent weight loss peptide.
Side effects such as tiredness and fatigue, while not relatively common, are still of significant interest to researchers looking to incorporate semaglutide into their weight loss studies.
For researchers looking to do the same, then this comprehensive review will help discover the latest clinical data on whether semaglutide may lead to fatigue, as well as what other potential side effects to expect.
We’ll also break down semaglutide’s mechanism of action, dosing recommendations, and contraindications. Plus, we reveal our most trusted online source of research-grade semaglutide and other GLP-1-R agonists.
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What is Semaglutide?
Semaglutide is a 31-amino acid peptide classified as a glucagon-like peptide-1 receptor agonist (GLP-1-RA). It is a synthetic analog of the endogenous hormone glucagon-like peptide-1 (GLP-1) and shares 94% homology with GLP-1 in active form [1].
GLP-1 is an incretin hormone released by the digestive tract after food consumption and plays a crucial role in regulating metabolic processes such as glucose homeostasis and appetite [2].
Semaglutide works by mimicking the hormone but possesses several structural modifications that give it enhanced stability and a longer half-life compared to native GLP-1. This makes it clinically efficacious in numerous settings [3, 4].
Semaglutide was originally developed by Novo Nordisk and quickly gained attention for its potent hypoglycemic effects in type 2 diabetes (T2D). But it also showed remarkable effectiveness as an appetite suppressant and medication for chronic weight management [3, 4].
Clinical studies involving both diabetics and non-diabetics have provided evidence of its sustained weight loss action. Recent research has also highlighted additional benefits, including its potential to reduce the risk of cardiovascular incidents (MACE) in susceptible populations such as diabetics [5, 6, 7].
Subcutaneous semaglutide is approved by the United States Food and Drug Agency (FDA) for numerous indications, including [5, 6, 7]:
- Glycemic control and MACE risk reduction in T2D under the brand name Ozempic (up to 2mg/week subcutaneously).
- Chronic weight management along with diet and exercise in adults (BMI≥30 or BMI≥27 and weight-related comorbidities) and adolescents (12 years and older with a BMI for age/sex at ≥95th percentile) under the brand name Wegovy (up to 2.4mg/week subcutaneously).
Semaglutide is also approved by the FDA in an oral version, and it is the only incretin mimetic on the market in tablet form. Semaglutide tablets are available for T2D therapy under the brand name Rybelsus [8].
Ozempic, Wegovy, and Rybelsus are available for purchase with a valid prescription issued by a licensed healthcare provider.
In addition, qualified researchers may obtain semaglutide powder for scientific or educational purposes.
How Does Semaglutide Work?
Semaglutide (previously known as A10BJ06) is indicated for type 2 diabetes (T2D) due to its ability to lower blood glucose levels and improve glycemic control when combined with exercise and proper nutrition [3].
It achieves these effects by increasing insulin secretion and reducing glucagon production in a glucose-dependent manner. As a result, semaglutide carries a lower risk of hypoglycemia compared to other diabetes medications [3].
Semaglutide for T2D Management
Extensive trials in T2D patients have demonstrated semaglutide's effectiveness in restoring glucose balance.
In the phase 3 studies making up the SUSTAIN (Semaglutide Unabated Sustainability in Treatment of Type 2 Diabetes) clinical program, semaglutide caused demonstrated significant reductions in HbA1c levels and fasting plasma glucose (FPG) at the 1mg/weekly and 2mg/weekly doses [3].
Even the 1mg/weekly dose showed greater impact on glycemic control compared to other antidiabetic medications (oral antidiabetics, injectable insulin, and other GLP-1 RAs) and placebo [9, 10, 11, 12, 13, 14].
In addition to its hypoglycemic properties, semaglutide reduces appetite and aids in weight loss, reinforcing its use in type 2 diabetes management [15].
Semaglutide for Weight Management
Another ongoing research program called STEP (Semaglutide Treatment Effect in People with Obesity) consists of ten phase-3 trials that have also confirmed the long-term effectiveness and safety of 2.4mg/weekly semaglutide in managing weight in non-diabetics [16].
Several STEP trials have already been published, and all showcase the superior weight loss benefits of semaglutide compared to other GLP-1-RAs. STEP-5 is the longest trial published to date, and lasted two full years at the 2.4mg/weekly semaglutide dose [16, 17].
STEP-5 trial subjects taking semaglutide progressively lost weight over the first 60 weeks, after which they maintained their progress over the total 104-week study period. The weight loss from baseline was −15.2% in the semaglutide group versus −2.6% in the placebo group [17].
Semaglutide reduces weight through multiple pathways, primarily by suppressing appetite through its action on the GLP-1 receptors in the hypothalamus. This leads to modified eating patterns and reduced cravings [18].
The peptide may also interact with the GLP-1 receptors in the small intestine and white adipose tissue. This may upregulate the production of leptin by fat cells and Peptide YY3-36 from endocrine intestinal cells. Both hormones are associated with increased satiety and sustained weight loss [19].
Semaglutide has also been shown to slow postprandial gastric motility by up to 38%, which may also contribute to increased feelings of satiety [20]. As a result of semaglutide's effects on appetite, food intake is reduced, leading to weight loss and improved body composition [21].
Does Semaglutide Make You Tired?
Although it has shown great effectiveness and a favorable safety profile in numerous phase-3 trials, semaglutide is not free of side effects. Adverse reactions observed in clinical trial subjects have included tiredness and fatigue.
According to the Wegovy (up to 2.4mg/weekly semaglutide injections) package insert, semaglutide was associated with fatigue in about 11% of the volunteers receiving 2.4mg/weekly in the STEP 1-3 phase-3 trials, while the same complaint was reported by 5% of those receiving placebo [22].
By contrast, many of the phase-3 trials in T2D patients involving 1mg/weekly and 2mg/weekly semaglutide do not report this side effect at all. Further, the Ozempic package insert (1mg/weekly and 2mg/weekly semaglutide injections) states that the incidence of tiredness and fatigue is under 0.4% [23].
Side effects like tiredness and fatigue have also been reported with other GLP-1 RAs. For example, the STEP-8 clinical trial, which compared the weight loss effectiveness of 2.4mg/weekly semaglutide vs. 3.0mg/daily liraglutide, reported that both peptides can lead to fatigue as a side effect [24].
This 68-week trial reported that semaglutide caused tiredness and fatigue in 9.5% of participants, while liraglutide may have induced the symptom in 11%. Notably, semaglutide led to -15.8% weight loss in participants while the average weight reduction for liraglutide was -6.4% [24].
Another trial involving semaglutide 1.7mg-2.4mg/weekly for six months has also reported that fatigue may occur in about 6.3% of patients (both with and without T2D). This side effect was significantly less frequent compared to gastrointestinal (GI) symptoms such as nausea (36.6%) and diarrhea (8.6%) [25].
Why Does Semaglutide Cause Fatigue?
Although scientists have observed tiredness or fatigue as a side effect in test subjects receiving GLP-1 RAs such as semaglutide, the precise mechanism behind these complaints remains uncertain.
One possible explanation for semaglutide’s fatigue-inducing effect is related to its effect on appetite. It has been shown to decrease appetite and reduce caloric intake, which is also why the peptide can induce weight loss [26].
When subjects consume fewer calories, their bodies receive less energy from food, which could contribute to feelings of tiredness. Notably, the energy obtained from nutrients in foods such as carbohydrates is vital for sustaining daily activities and bodily functions.
A low energy intake that is associated with low intake of carbohydrates have been reported to increase feelings of fatigue in certain individuals [27]. The reduced total amount of food consumed also increases the risk of vitamin and mineral deficiencies that are associated with increased tiredness [28].
Additionally, semaglutide affects glucose metabolism by increasing the production of insulin. It is conceivable that the altered insulin levels and potentially lower glucose levels throughout the day might also contribute to feelings of tiredness.
Glucose serves as a primary energy source for the body, and fluctuations in its availability can impact overall energy levels.
However, it is crucial to emphasize that currently, there is insufficient scientific evidence to definitively establish the exact cause of fatigue in those receiving semaglutide. It is also important to note that the fatigue observed in the research is likely temporary and diminishes as subjects adjust to potential changes in their diet and metabolic processes.
Other Semaglutide Side Effects
Semaglutide therapy can lead to other, relatively more common side effects, such as GI complaints. In fact, GI problems are the most frequently reported adverse reactions linked to GLP-1-RAs [29].
For example, STEP-1 (the largest of the STEP trials) involved almost 2000 participants and reported the following side effects in the 2.4mg/weekly semaglutide group [30]:
- Nausea: 44.2%
- Diarrhea: 31.5%
- Vomiting: 24.8%
- Constipation: 23.4%
- Nasopharyngitis: 21.5%
- Headache: 15.2%
- Dyspepsia: 10.3%
- Abdominal pain: 10.0%
These side effects appear to be dose-dependent, mild-to-moderate in severity, and self-limiting. Overall, the study dropout rate due to side effects was ~7% for the semaglutide group and ~3% for the placebo group [30].
Serious adverse events included mainly gastrointestinal and hepatobiliary disorders. They occurred in 9.8% of semaglutide participants and 6.4% of placebo participants.
Gallbladder-related disorders, specifically cholelithiasis, were reported in 2.6% of semaglutide participants and 1.2% of placebo participants. Three semaglutide participants also experienced mild acute pancreatitis and recovered during the trial.
Notably, there was no significant difference in the incidence of neoplasms between the subjects receiving semaglutide and placebo [30].
Is Semaglutide Safe?
Overall, the available phase 3 trials on semaglutide and its FDA approval for numerous indications indicate that semaglutide is safe when used for chronic weight management issues and T2D [3, 16].
The peptide has a few contraindications, which include pregnancy, breastfeeding, and a history of certain malignancies.
More specifically, semaglutide is contraindicated in those with a history of thyroid cancer or multiple endocrine neoplasia syndrome type 2 (MEN 2). These concerns are based on preclinical data from rat studies which have shown an increased incidence of thyroid C-cell carcinoma. This risk has not been confirmed in human trials [29].
Semaglutide Dosage Guide
Semaglutide is commercially available in two prescription-only forms, subcutaneous and oral, for treating patients with type 2 diabetes (T2D) and other FDA-approved uses.
In addition, qualified researchers can obtain the peptide without a prescription for educational purposes. When sold to researchers as a reference material, semaglutide is provided in powder form that needs to be reconstituted and dosed correctly.
Researchers should determine the appropriate dosage of the peptide depending on their research objective.
According to the available data from phase-3 trials conducted to test semaglutide’s safety and efficacy for weight loss, semaglutide should be administered subcutaneously once a week [16].
Therapy should start with a low initial dose of 0.25mg/weekly, and the dose can be gradually increased every four weeks until reaching maintenance at 2.4mg/weekly. This is important for minimizing side effects such as GI complaints [16].
Semaglutide Dosing Schedule for Weight Loss
Here's a sample weight loss protocol for semaglutide based on the aforementioned scientific findings [16, 17, 31]:
- Semaglutide Dosing Regime: 0.25mg/weekly during weeks 1-4 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 at consistent times.
- Study Duration: 52-104 weeks; semaglutide should not be cycled.
- Notes: Do not exceed 2.4mg/weekly. Administer missed doses within five days, and deliver the following doses according to the dosing schedule.
Where to Buy Semaglutide Online? | 2024 Edition
Qualified researchers and laboratory professionals who aim to acquire semaglutide can legally purchase it from a reputable online vendor.
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Semaglutide and Fatigue | Verdict
In summation, semaglutide is a GLP-1 receptor agonist that has gained significant attention for its effectiveness in glycemic control and weight management, in both diabetics and nondiabetics.
It stands out from other medications in its class with its superior pharmacokinetics, and is also the only GLP-1-RA currently available in oral form.
While fatigue and tiredness have been reported as potential side effects in clinical trials, the exact mechanism behind this phenomenon remains uncertain. Reduced caloric intake and altered glucose metabolism due to semaglutide's effects on appetite and insulin production are possible explanations.
Semaglutide also carries other side effects, with gastrointestinal complaints being the most common. Nevertheless, these tend to be dose-dependent, mild, and transitory.
For qualified researchers looking to buy semaglutide for educational purposes, we highly recommend this top-rated vendor for their pure peptides and secure buying experience.
Luis Daniel López Murillo, PhD