How Effective And Safe Are Peptides For Weight Loss?

In recent years, several peptides have shown great effectiveness as weight loss medications, with the promise to completely change weight loss therapy.

These peptides may be a promising solution for individuals complaining of unsatisfactory weight loss results with diet and exercise alone.

Nevertheless, weight loss peptides are not meant to replace these lifestyle changes but to be used alongside each other, facilitating faster weight loss and helping patients build healthier habits.

Currently, the use of peptides such as the GLP-1 receptor agonist semaglutide (trade names Ozempic and Wegovy) has become extremely common due to their potent appetite suppressant action and dramatic weight loss results.

Experts comment that as of 2023, U.S. doctors are writing more than 100,000 prescriptions per week for the weight loss peptide Wegovy (semaglutide).

Learn more about effective peptides to lose weight and the latest evidence on their effectiveness, mechanisms, and safety.

How do peptides help you lose weight?

Peptides may help with weight loss via a variety of mechanisms, which depend on their specific structure and class. The two groups of peptides which are most clinically researched regarding their weight loss effects are:

• Agonists of the receptors for the incretin hormones such as glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP).
• Agonists for the growth hormone-releasing hormone (GHRH) receptors.

These peptides work by suppressing appetite levels or stimulating fat mobilization in different body areas.

Regardless of the class, these peptides must be used at the right dosage and consistently over long periods of time to effectively burn fat. For example, GLP-1 receptor agonists are typically administered once daily or once weekly, and the majority of trials last between 12 and 104 weeks.

Furthermore, the dosage must be gradually titrated to minimize or prevent side effects such as nausea and vomiting. For example, semaglutide can be injected once weekly, with low starting doses (0.25 mg/week), and the dosage can be titrated gradually up to 2.4 mg/weekly for maximum weight loss effect.

GHRH-agonists such as tesamorelin are administered once daily due to their short half-life. Research reports of 1-2 mg administered subcutaneously for up to 12 months. Due to the GH-reducing effect of food, it may be optimal to administer the peptide at least 2-3 hours after your last meal for the day.

To get the best results for reducing body fat, patients must also combine peptide therapy with proper lifestyle changes such as weight loss diet and exercise.

How do GLP-1 receptor agonists work for weight loss?

GLP-1 and GIP are incretin hormones released by the gastrointestinal tract after food intake to stimulate insulin secretion and regulate appetite.

Peptides that mimic their function, such as GLP-1 agonists, activate the corresponding receptors throughout the body and exert similar effects.

GLP-1 receptor agonists regulate appetite

The weight loss effects of these peptides are thought to be mediated via the activation of the GLP-1 receptors in parts of the brain associated with appetite, such as the hypothalamus.

There, GLP-1 receptor agonists may activate a specific type of brain cells called proopiomelanocortin and cocaine- and amphetamine-regulated transcript (POMC/CART) neurons, which have appetite-suppressing functions.

The activation of the GLP-1 receptors in the brain, gut, and fat tissue may also influence other peptides that regulate hunger such as neuropeptide Y (NPY) and agouti-related peptide (AgRP), peptide YY (PYY) and leptin.

As a result, the GLP-1 receptor agonist semaglutide has been reported to significantly suppress appetite in clinical settings.

After 20 weeks of therapy with 2.4 mg/weekly semaglutide, the treatment group had a 35% lower ad libitum (unrestricted) intake than the placebo group. During a buffet-like meal, they ate only 415 kcal, compared to the placebo group, which consumed 640 kcal.

How do GHRH receptor agonists work for weight loss?

GHRH receptor agonists work for weight loss by upregulating the synthesis of the growth hormone (GH), which is catabolic for fat tissue. More specifically, GH activates an enzyme called hormone-sensitive lipase (HSL) that helps mobilize fat from adipose tissues.

GH and GHRH receptor agonists are most effective for abdominal and visceral fat loss

Most interestingly, GH selectively targets central fat, which is deposited around the abdomen and internal organs, rather than fat in other areas, such as the limbs. Thus, GH and GHRH receptor agonists are most effective for abdominal and visceral fat loss.

Additionally, GH selectively blocks another enzyme, lipoprotein lipase (LPL), from allowing fatty acids to re-enter cells. However, it blocks LPL in fat without affecting muscle LPL activity. As a result, fatty acids are available for energy use by muscles but cannot be stored back in fat cells.

List of the best peptides for weight loss

Here is a list of the most prominent peptides for weight loss:

• Semaglutide – This is a GLP-1 receptor agonist with a long half-life and once-weekly dosing regime. It is a 31 amino acid peptide that shares 94% similar structure with the native GLP-1 hormone. The peptide is currently FDA-approved for glycemic control and reduction of cardiovascular risk in type 2 diabetes, as well as management of overweight and obesity in adolescents (aged 12-17) and adults.
• Liraglutide – This is a GLP-1 receptor agonist with a once-daily dosing regime (up to 3 mg/daily given subcutaneously). It is one of the most extensively researched incretin mimetics, since its development in the 1990s. It shares 97% homology with the native GLP-1. It is approved by the FDA for the same indications as semaglutide. Additionally, it is researched for its potential neuroprotective effects.
• Tirzepatide – This is a novel dual GLP-1/GIP receptor agonist which has a peptide structure that incorporates fragments from both the GIP hormone and another GLP-1 receptor agonist called exenatide. It is currently FDA-approved for glycemic control in type 2 diabetes, and its still in phase-3 trials as a weight loss medication and as a potential tool for reducing cardiovascular risk in diabetes.
• Tesamorelin – This is a GHRH receptor agonist which is made of 44 amino acids, identical to the native GHRH and a 6-carbon chain moiety attached at the N-terminus to improve its stability and half-life. Tesamorelin is FDA-approved for the treatment of abnormal fat distribution in HIV/AIDS patients. The condition is called lipodystrophy and is likely related to the infection itself as well as side effects from the antiviral therapy.
• Sermorelin – This is a GHRH receptor agonist which is made of only 29 amino acids and is considered the smallest functional analog of the native hormone that is effective in stimulating GH synthesis. Sermorelin was FDA-approved for stimulating growth in children with idiopathic short stature and for diagnostic purposes in growth hormone deficiency (GHD).

How effective are weight loss peptides?

Some of the most popular peptides for fat loss on the market are the GLP-1 receptor agonists such as semaglutide.

Semaglutide was initially developed and approved by the Food and Drug Administration (FDA) for therapy in patients with type 2 diabetes under the brand name Ozempic. For this indication, the peptide can be administered in doses of up to 2 mg per week. At this dose, semaglutide leads to -15.2 lbs weight loss for 40 weeks in diabetic patients.

In addition, semaglutide has been reported to cause between 9.6% and 17.4% weight reduction within 68 weeks of therapy at the highest FDA-approved dose of 2.4mg/weekly.

As mentioned, GHRH receptor agonists upregulate GH levels, which target specific areas of fatty tissue, such as the fat around the waist and internal organs. Studies report that the GHRH mimetic tesamorelin can lead to -3.7 lbs fat reduction compared to placebo in healthy obese individuals.

Tesamorelin also led to about an 8% reduction in visceral fat compared to baseline levels in the tesamorelin group. Moreover, the patients receiving tesamorelin ended up with 19% less visceral fat at the end of the study, compared to those on a placebo.

Currently, tesamorelin is FDA-approved only for reducing visceral fat in HIV patients who are suffering from abnormal fat distribution (lipodystrophy). The peptide is highly effective in this group of patients, with trials reporting up to about 25% reduction in visceral fat from baseline within 12 months.

How long does it take to see results from peptides?

Research in HIV-infected patients reports that daily injections of 2 mg of tesamorelin can lead to an 11.3% greater reduction in visceral fat compared to a placebo, with the initial effects of the therapy observable as early as 12 weeks.

Similarly, studies report significant weight loss with GLP-1 agonists such as semaglutide as soon as the 12th week of therapy, and the treatment effect was equal to about 6% weight loss.

Furthermore, long-term research (104 weeks) suggests that maximum weight loss with semaglutide (about 15-16% reduction from baseline) may be achieved within the first 60 weeks.

Another peptide called tirzepatide, which activates the receptors for both the GLP-1 and GIP can cause about 21% weight loss at the highest dose (15 mg per week).

Based on the average weight in the treatment group that received 15 mg of tirzepatide per week, the peptide has led to about -48 lbs of body weight loss.

However, tirzepatide is still in phase 3 trials as a weight loss medication. It will likely be FDA-approved for this indication by the end of 2023.

Are peptides safe for weight loss?

The safety of peptides for fat loss depends on several factors, such as the specific compound, the available research on it, and its current approval status.

Peptides such as the GLP-1 receptor agonist semaglutide and the GHRH mimetic tesemorelin are extensively researched and already approved by the FDA as safe for human use.

For example, tesamorelin is FDA-approved for treating lipodystrophy in HIV/AIDS after a couple of phase-3 trials that involved over 800 participants with HIV.

Clinically significant side effects of tesamorelin compared to placebo include:

• Injection site reactions – 24.5%
• Peripheral edema – 6.1%
• Worsened glycemic control (elevated glycated hemoglobin) – 4.5%
• Hypersensitivity (allergic reactions) – 3.6%

Tesamorelin is contraindicated in individuals with active malignancies due to the known proliferative effect of GH.

Furthermore, semaglutide is approved by the FDA based on extensive phase-3 trials conducted as part of the STEP clinical program, showcasing that the peptide is safe and well-tolerated.

The clinical program included thousands of patients, with the largest of the trials (STEP-1) reporting data from nearly 2000 individuals.

The study indicated a roughly 4% higher discontinuation rate than the placebo group, which was primarily due to adverse events such as gastrointestinal issues. In fact, gastrointestinal problems are the most common side effects during GLP-1 agonist use.

Specifically, for patients administered with a weekly dose of 2.4 mg of semaglutide, the most frequently reported complaints and their corresponding incidence rates were as follows:

• Nausea (44.2% of subjects)
• Diarrhea (31.5%)
• Vomiting (24.8%)
• Constipation (23.4%)
• Dyspepsia (10.3%)

In addition, the peptide can also lead to pancreatitis and gallbladder disorders, which are potentially serious adverse reactions that affect less than 3% of subjects.

In order to minimize the risk of these side effects, it’s important that peptides such as GLP-1 agonists are administered under medical supervision.

An experienced medical doctor will help minimize or completely avoid the side effects by titrating the dose properly and monitoring various indicators throughout the course of the therapy, such as pancreatic and liver enzymes.

Can you get peptides for weight loss over the counter?

Peptides for weight loss such as semaglutide and tesamorelin are not available over the counter (OTC). They are FDA-approved medications that can be purchased only from licensed pharmacies after presenting a valid medical prescription.

Thus, the only way to legally purchase peptides that help lose weight is to first obtain a valid prescription from a healthcare professional. A medical doctor will offer you a prescription after examining your symptoms, medical history, and potential contraindications.

Over-the-counter products, such as dietary supplements, do not contain therapeutic peptides and may only contain peptide-based compounds that are naturally found in foods, such as collagen.

Yet, there are no naturally-occurring peptides that work for weight loss when taken as supplements. Moreover, most peptides become inactivated and destroyed in the gastrointestinal system when taken orally.

In order to prevent this, the peptide must be modified, such as the anti-diabetic drug Rybelsus, which contains semaglutide attached to an absorption enhancer called sodium N-(8-[2-hydroxylbenzoyl] amino) caprylate (SNAC). Yet, this peptide is a prescription-only medication, and incorporating it in OTC products would be illegal.