Semaglutide vs. Tirzepatide | Best Weight Loss Peptides?

Seeking an evidence-based analysis of tirzepatide vs. semaglutide for weight reduction?

Our expert panel at Peptides.org has got it covered.

Both tirzepatide and semaglutide are incretin mimetics with similar benefits, side effects, and research prospects. They have been studied for similar uses, including:

• Type 2 diabetes (T2D) management
• Reducing cardiovascular risk in T2D
• Weight loss in overweight and obesity

Of the two, tirzepatide is the newer development and showcases a unique mechanism that seems to outperform other incretin mimetics.

Keep reading as we dive into the most recent findings on both peptides, offering a direct comparison between the two.

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What is Semaglutide?

Semaglutide is a synthetic GLP-1 receptor agonist that is 94% homologous to the amino acid structure of the native hormone glucagon-like peptide-1 (GLP-1) [1, 2].

GLP-1, which is naturally produced after meals, is a peptide hormone that is key to promoting insulin release, stabilizing blood sugar, and managing appetite [3].

Pharmaceutical firm Novo Nordisk introduced semaglutide in 2012, modifying the GLP-1 sequence to enhance its stability and half-life. The modifications in the peptide chain protect it from rapid breakdown. The addition of an 18-carbon fatty acid moiety further enhances its binding to serum proteins, allowing for an extended half-life and convenient once-weekly administration [4, 5].

Upon administration, semaglutide activates GLP-1 receptors throughout the body, increasing insulin synthesis, suppressing glucagon production, improving glycemic control, and suppressing appetite.

Based on rigorous phase-3 trials showcasing these benefits, the United States Food and Drug Administration (FDA) has granted approval for subcutaneous semaglutide for several indications:

• In 2017, it was authorized for T2D treatment as a 1mg/weekly injection under the trade name Ozempic [6].
• In 2020, it was also approved for the reduction of major adverse cardiovascular events (MACE), such as heart attacks, in T2D [6].
• A more potent 2mg/weekly dose was approved for T2D in 2022 [7].
• Marketed as Wegovy, 2.4mg/weekly semaglutide was approved for weight management in adults in 2021 and extended to adolescents (ages 12-17) in 2023 [7, 8].

In addition to its isubcutaneous formulations, semaglutide is the only oral GLP-1 receptor agonist the FDA has approved for managing blood sugar levels, available as Rybelsus since 2019 [9].

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What is Tirzepatide?

Tirzepatide is an innovative dual GIP/GLP-1 receptor agonist developed and patented by Eli Lilly in 2016. It activates the GLP-1 receptors and engages with the receptors of another hormone from the incretin family, glucose-dependent insulinotropic polypeptide (GIP) [10].

Like GLP-1, GIP is also released after eating to help stimulate insulin production, manage blood sugar levels, and control appetite [3, 11].

Tirzepatide's structure incorporates features from GIP and the GLP-1 receptor agonist exenatide. Tirzepatide is thus a dual GIP/GLP-1 agonist with a bias towards the GIP receptor [10, 12, 13].

It has a unique 39-amino acid makeup complemented by a C20 fatty di-acid component that increases its affinity to plasma proteins and extends its half-life [5]. This design allows for once-weekly dosing, similar to semaglutide [12, 13, 14].

By mimicking the function of the GIP and GLP-1 hormones and boasting improved pharmacokinetics, tirzepatide effectively:

• Increases insulin production
• Improves blood sugar management (in T2D)
• Suppresses appetite
• Induces weight loss

These benefits have all been demonstrated in phase-3 studies, which has led to tirzepatide's approval by the FDA for T2D treatment. It is marketed as prescription drug Mounjaro and available in doses of up to 15mg/weekly [10, 15].

Ongoing research also explores tirzepatide 15mg/weekly for weight management in non-diabetics and its ability to lower cardiovascular risk in T2D patients [16, 17].

The peptide is expected to receive FDA approval as an anti-obesity medication by the end of 2023, while its potential for reducing MACE risk is expected to be revealed in 2024.

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Tirzepatide vs. Semaglutide | Benefits

As mentioned, tirzepatide and semaglutide have similar benefits and therapeutic indications.

Several trials have directly pitted tirzepatide vs. semaglutide to compare their anti-diabetic and weight loss effects.

Here are the latest data on the main benefits of the two peptides:

Tirzepatide vs. Semaglutide for Fat Loss in Overweight and Obesity

Unfortunately, no studies directly compare the weight loss effectiveness of 2.4mg/weekly semaglutide against 15mg/weekly tirzepatide in subjects with overweight or obesity.

Semaglutide and tirzepatide have however been separately studied in large-scale phase-3 trials for their weight loss potential:

• Semaglutide is already FDA-approved for weight loss therapy in overweight and obesity in non-diabetics based on a phase-3 clinical development program called STEP. This ongoing program includes 10 trials. As of writing, trial results indicate a body weight reduction from baseline of up to 17.4% within 68 weeks of administration [7, 18].
• Tirzepatide is currently under investigation as a weight loss medication in a phase-3 clinical development program called SURMOUNT, sponsored by Eli Lilly [16].

Here is detailed information on some of the most impressive trials from each clinical development program:

• The SURMOUNT-1 study included over 2500 non-diabetics who were overweight or obese. Study authors reported a mean weight reduction of 20.9% from baseline at the highest 15mg/weekly dose after 72 weeks. Considering that the volunteers’ initial body weight in this subgroup was 233lb on average, the mean weight loss was over 45lb [19].
• STEP-1 involved over 1900 overweight and obese subjects without T2D, two-thirds of whom received semaglutide 2.4mg/weekly. The treatment group experienced a 15.0% (32.2lb) weight loss from baseline within 68 weeks. The investigators also utilized DXA scans on 140 semaglutide recipients, showing that the participants lost about 18lb of fat mass, equal to 3.0% of their body fat percentage [20, 21].

Clearly, both tirzepatide and semaglutide can significantly help overweight and obese individuals lose weight. Based on the findings thus far, tirzepatide seems to be slightly more effective at reducing body weight.

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Tirzepatide vs. Semaglutide for Weight Loss and Glycemic Control in T2D

Both tirzepatide and semaglutide are FDA-approved for glycemic control in T2D.

• Semaglutide was approved in doses of up to 2mg/weekly for T2D based on the success of the SUSTAIN phase-3 clinical development program [6, 7].
• Tirzepatide has been approved for T2D in doses of up to 15mg/weekly based on favorable results from the SURPASS phase-3 clinical development program [10].

SURPASS-2 pitted tirzepatide (5mg, 10mg, and 15mg/weekly) against semaglutide (1mg/weekly) and directly compared their effectiveness for T2D management in almost 2000 study volunteers for 40 weeks [22].

The trial used glycated hemoglobin (HbA1c) to measure long-term glycemic control. Glycemic control was poor at baseline, as indicated by the high mean glycated hemoglobin level of 8.28%. Here are some of the most notable findings [22]:

• From baseline, tirzepatide at doses of 5mg, 10mg, and 15mg/weekly led to mean reductions of -2.01% HbA1c points, -2.24%, and -2.30%, respectively, while the 1mg/weekly semaglutide lowered mean HbA1c by -1.86% points.
• In addition, tirzepatide 15mg/weekly led to a -24.7lb weight reduction among T2D subjects, almost double the weight loss observed with 1mg/weekly semaglutide (-12.6lb).

Vadher et al. (2022) performed an adjusted indirect treatment comparison of the results of SURPASS-2 and the SUSTAIN FORTE trial, which involved 2mg/weekly semaglutide. Here are the most notable findings [23]:

• 15mg/weekly tirzepatide led to a -0.4% greater HbA1c reduction from baseline than 2mg/weekly semaglutide.
• T2D subjects receiving tirzepatide 10mg/weekly lost -6.93lb, and the 15mg/weekly group lost -11.35lb more weight from baseline than the 2mg/weekly semaglutide group.

These trials show that tirzepatide at 15mg/weekly appears to induce greater weight loss and better glycemic control in T2D than 2mg/weekly semaglutide.

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Tirzepatide vs. Semaglutide for Cardiovascular Health in T2D

Several incretin mimetics have shown benefits for cardiovascular health in T2D subjects, including semaglutide and tirzepatide. Semaglutide is already FDA-approved for lowering MACE risk in T2D [6].

On the other hand, tirzepatide is still under investigation for MACE risk reduction in T2D as part of SURPASS-CVOT, with completion anticipated by late 2024 [17].

Here is a direct comparison of published data on the potential of tripeptide vs. semaglutide in lowering cardiovascular risk in T2D:

• The SUSTAIN-6 phase-3 trial, involving over 3,200 diabetics, showed that weekly doses of 0.5mg and 1mg semaglutide reduced the risk of cardiovascular-related death, nonfatal myocardial infarction, and nonfatal stroke by 26%. This significant decrease was primarily attributed to a 39% drop in nonfatal stroke rates [24].]
• A meta-analysis of the SURPASS trials pooled safety data from all three tirzepatide doses (5mg, 10mg, and 15mg/weekly) and reported that the peptide does not increase the risk of cardiovascular events in T2D subjects compared to controls.

  Conversely, the analysis reported a hazard ratio (HR) of 0.8 for MACE risk compared to placebo, which can be interpreted as 20% lower cardiovascular risk. The risk of cardiovascular death was also lower in the tirzepatide group compared to placebo by 10% (HR=0.9) [25].

Based on available data, semaglutide appears to be the more reliable option for reducing cardiovascular risk, as the results from SURPASS CVOT are still pending.

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Semaglutide vs. Tirzepatide | Cycle Length and Dosing

The specific dose of semaglutide and tirzepatide that researchers should administer to test subjects depends primarily on the research objective.

Yet dosage considerations are similar for both peptides, including cycle length, titration, frequency, and route of administration. Here is an overview on how to dose semaglutide and tirzepatide:

• Incretin mimetics, including semaglutide and tirzepatide, are not meant to be cycled on/off when taken for weight loss. Most studies have applied both compounds for over 52 weeks, and trials with semaglutide report maximum weight loss effectiveness after 60 weeks of therapy [26].
• Tirzepatide and semaglutide are dosed once weekly due to their favorable pharmacokinetics and extended half-lives of 5-7 days [5, 15].
• Experiments with both peptides should be initiated at low doses (0.25mg/weekly for semaglutide and 2.5mg/weekly for tirzepatide) and increased gradually every four weeks until reaching the maintenance dose to minimize the incidence of side effects.

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Tirzepatide Dosing Protocol

Initiate tirzepatide at a dose of 2.5 mg/weekly, increasing by 2.5mg every four weeks until reaching a maximum of 15mg/weekly [16, 22].

For weight loss studies involving tirzepatide, non-diabetic participants have exhibited comparable outcomes at both the 10mg and 15mg/weekly doses. Hence, it's recommended to titrate up to 10mg/weekly and then modify dosing based on each subject’s tolerance and reaction [19].

Here is a tirzepatide dosing regimen grounded in current research:

• Tirzepatide Dose: Start with 2.5mg weekly for the initial four weeks. Progress to 5mg for weeks 5-8, 7.5mg for weeks 9-12, and 10mg for weeks 13-16. Depending on individual reactions, consider advancing to 12.5mg in weeks 17-20 and 15mg from week 21 onward.
• Frequency: Once weekly; subcutaneously.
• Study Span: 24 to 72 weeks.
• Notes: The 15mg weekly tirzepatide dose should not be surpassed. If a dose is missed, it should be given within five days or skipped, and the remaining doses must be delivered according to schedule.

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Semaglutide Dosing Protocol

Here's a concise dosing guideline for semaglutide based on recent findings regarding the peptide's use for weight loss [18]:

• Semaglutide Dose: 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 for weeks 9-12, 1.7mg/weekly for weeks 13-16 and 2.4mg for weeks 17 and beyond.
• Frequency: Once weekly; subcutaneously.
• Study Duration: 52-104 weeks.
• Notes: The 2.4mg weekly semaglutide dose should not be surpassed. If a dose is missed, it should be given within five days or skipped. Then, the remaining doses must be delivered according to schedule.

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Tirzepatide and Semaglutide | Side Effects and Risks

In trials involving both tirzepatide and semaglutide, gastrointestinal problems such as nausea, dyspepsia, and diarrhea are frequently observed, with the likelihood rising as the dosage increases.

Semaglutide and tirzepatide may also lead to rare but potentially serious side effects related to pancreatitis, gallstones (cholelithiasis), and other hepatobiliary disorders.

It's crucial to highlight that these peptides should not be used during pregnancy or breastfeeding due to a lack of human research and preclinical studies suggesting teratogenic potential.

Laboratory animal research also implies a potential increased risk of thyroid cancer, specifically medullary thyroid carcinoma, with both peptides. Yet, there’s no evidence to date to suggest this risk in humans of this type of thyroid cancer, which moreover has a fairly high long-term survival rate.

Nevertheless, in subjects with a history of thyroid malignancy, including those with multiple endocrine neoplasia type 2 (MEN-2), research involving tirzepatide or semaglutide is contraindicated [15, 27].

Keep reading to find detailed information on the rate of side effects for each peptide.

Tirzepatide Side Effects Incidence

According to a meta-analysis that pooled data from ten tirzepatide trials and over 6800 participants, 15mg/weekly tirzepatide was associated with a 10% discontinuation rate due to adverse events. The most notable events were [28]:

• Nausea (24.08%)
• Diarrhea (20.79%)
• Vomiting (13.98%)
• Constipation (7.57%)
• Dyspepsia (6.79%)
• Cholelithiasis (<1%)
• Pancreatitis (<1%)

The gastrointestinal issues were mild-to-moderate in severity. Hypersensitivity reactions affected approximately 2-4% of study participants [28].

Semaglutide Side Effects Incidence

STEP-1, one of the most extensive 2.4mg/weekly semaglutide phase-3 trials involving nearly 2,000 individuals, reported a 7% discontinuation rate due to adverse events. The most notable adverse reactions were [20]:

• Nausea (44.2%)
• Diarrhea (31.5%)
• Vomiting (24.8%)
• Constipation (23.4%)
• Dyspepsia (10.3%)
• Cholelithiasis (1.2%)
• Pancreatitis (<1%)

Most gastrointestinal events were mild or moderate. Similarly to that observed with other incretin mimetics, side effects are transient and resolve without treatment cessation.

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Where to Buy Weight Loss Peptides Online? | 2024 Edition

Qualified researchers can obtain tirzepatide or semaglutide for educational or investigational purposes. However, it's essential to choose vendors wisely to guarantee experimental success.

Here are our two favorite sources:

Limitless Life

We highly endorse Limitless Life, a top-tier supplier of both tirzepatide and semaglutide, available to members of its VIP Peptide Club.

Here are just a few of the advantages that make this vendor globally recognized by esteemed researchers:

• Exceptional Quality: Limitless Life ensures over 99% purity in their compounds, including tirzepatide and semaglutide. Each peptide batch undergoes rigorous third-party HPLC-MS analysis.
• Comprehensive Insights: The vendor provides in-depth research summaries for each peptide, along with guidance on reconstitution, storage, and usage.
• Affordability and Discounts: Tirzepatide and semaglutide are both fairly priced, and orders of $350+ include free shipping.
• Unparalleled Support and Service: Limitless Life’s friendly support representatives are available during business hours by email and phone to address any questions or concerns.

Click the below link to enroll in the Limitless VIP Club for exclusive access to semaglutide and tirzepatide. Sign up is simple and instant:

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Xcel Peptides

For high-purity semaglutide, Xcel Peptides is another reputable vendor who offers the following benefits:

• Peptide Quality: The vendor provides lab-tested peptides that are held to high standards of potency and purity.
• Quick Checkout: Xcel Peptides offers streamlined checkout and a range of payment options, including credit cards, cryptocurrencies, and e-checks.
• Excellent Support and Service: Xcel Peptides' friendly customer service team is available during business hours to address any questions about products or orders.

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Bacteriostatic Water for Research Peptides

For optimal research results with peptides like semaglutide and tirzepatide, it's vital to use bacteriostatic water.

This solvent ensures sterility after reconstitution, excellent solubility, and peptide stability.

For those in need of bacteriostatic water, consider our highly recommended supplier.

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Comparing Semaglutide vs. Tirzepatide | Verdict

Tirzepartide and semaglutide are peptides known for their weight loss properties. They have similar pharmacokinetics and safety characteristics. Both have demonstrated enhanced glycemic control and other metabolic advantages, in addition to weight loss.

Tirzepatide appears to edge semaglutide out in chronic weight management settings compared to semaglutide.

Yet, this GLP-1/GIP receptor agonist is yet to be researched in depth regarding its potential for other benefits like lowering cardiovascular risk.

To purchase tirzepatide or semaglutide for research, we strongly recommend turning to a trusted supplier like the ones listed above.

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