Dimitar Marinov, Ph.D.
Dimitar Marinov, Ph.D.Seeking evidence-based information on tirzepatide for weight loss?
For researchers exploring novel weight management options, this peptide may pique interest.
Tirzepatide is a first-in-class medication under active research for its chronic weight management potential in overweight and obese individuals. It is also approved by the United States Food and Drug Administration for diabetes treatment.
In this guide, we'll present the latest research on tirzepatide and weight loss, including the peptide's mechanism of action, benefits, and safety profile. We also provide insights into dosing and administering tirzepatide.
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What is Tirzepatide?
Tirzepatide (LY3298176) is a dual GIP/GLP-1 agonist developed by the American pharmaceutical company Eli Lilly and Co.f
It was patented in 2016 and received United States Food and Drug Administration (FDA) approval in 2022 as a treatment of type 2 diabetes (T2D) under the brand name Mounjaro [1].
The peptide combines the properties of two naturally occurring hormones, glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1).
Both GIP and GLP-1 are incretins released by the digestive tract to stimulate insulin release in response to food intake [2]. By mimicking their functions, tirzepatide activates both the GIP and GLP-1 receptors in the exocrine pancreas to lower blood sugar and improve glycemic control in T2D patients.
Tirzepatide is composed of 39 amino acids, with a modified GIP sequence at the N-terminus and a C-terminus sequence derived from the GLP-1 agonist exenatide.
This unique structure allows tirzepatide to have an affinity for both receptors, with a biased affinity towards GIP-R [3, 4].
Tirzepatide is conjugated to a hydrophilic linker and a C20 fatty di-acid moiety, which extends its half-life by enhancing its binding to plasma albumin. As a result, its half-life is roughly five days when administered subcutaneously [3, 4].
While Tirzepatide has been approved for clinical use in T2D patients, it is also available for purchase and study by qualified researchers and laboratory professionals. It is currently in clinical trials as a potential weight loss treatment, hence widespread interest in tirzepatide for weight loss.
What Does Tirzepatide Do?
Tirzepatide exerts its effects by activating the GLP-1 and GIP receptors in various organs, namely the pancreas, digestive system, central nervous system, and adipose tissue [5, 6].
In the pancreas, the peptide increases insulin secretion and decreases glucagon release, which helps lower blood sugar levels and reduce gluconeogenesis.
It also slows postprandial gastric emptying, which helps lower the glucose spikes that may occur right after a meal [7]. Both of these effects contribute to improving glycemic control in T2D patients.
Tirzepatide also acts on the brain and white adipose tissue, which results in an enhanced feeling of fullness and increased production of appetite-suppressing mediators.
Murine trials report that increased activation of the GIP receptors in the central nervous system, specifically the hypothalamus, can significantly decrease food intake [8]. This is likely because the hypothalamus is one of the primary appetite regulators of food intake.
Further, the researchers have reported a link between increased GIP receptor expression in adipose tissue and a notable downregulation of various genes associated with fatty acid synthesis, glyceroneogenesis, mitochondrial biogenesis, and inflammatory signaling [8].
GLP-1 receptors are also expressed in nervous and adipose tissues, and activating them has been shown to increase the expression of anorexigenic peptides such as peptide YY (PYY) while down-regulating the orexigenic neuropeptide Y (NPY) and agouti-related peptide (AgRP) [9, 10, 11]. This results in significantly suppressed hunger levels, reduced food intake and weight loss.
Tirzepatide For Weight Loss | What Researchers MUST Know
Extensive clinical data gathered from exploring the impact of tirzepatide on T2D reveals substantial weight loss benefits.
Depending on the dosage, tirzepatide's effectiveness in shedding excess pounds is believed to surpass that of potent GLP-1 receptor agonists such as semaglutide and dulaglutide.
One of the most extensive meta-analyses on weight loss in T2D patients taking tirzepatide was published in 2022 by Permana et al. and pooled data from 7293 patients [12].
The paper covered nine trials with durations ranging from 8-52 weeks and doses in the range of tirzepatide 5-15mg/weekly. The authors reported that the drug demonstrated considerable weight loss effectiveness at all three doses (5mg, 10mg, 15mg).
Compared to placebo, the peptide resulted in a mean weight loss of -11.66lb (-5.29kg) at 5mg, -16.16lb (-7.33kg) at 10mg, and -18.43lb (-8.36kg) at 15mg.
Even when compared to GLP-1 receptor agonists (dulaglutide and semaglutide), tirzepatide showed superior weight loss.
The researchers compared tirzepatide to the average weight loss caused by the GLP-1 agonists and reported that tirzepatide was superior by -6.68lb (-3.03kg), -13.27lb (-6.02kg), and -18.32lb (-8.31kg) at doses of 5mg, 10mg, and 15 mg respectively [12].
A 2023 meta-analysis by Lin et al. also included data from trials in nondiabetic subjects with chronic weight management issues and reported even greater results.
The scientists pooled data from a total of 9873 participants and reported that both 10mg/weekly and 15mg/weekly of tirzepatide led to similar weight loss results, which were significantly greater when compared to placebo by -23lb (10.5kg) and -24lb (10.9kg) respectively.
The meta-analysis also included data from eligible studies comparing tirzepatide to GLP-1 receptor agonists. These trials showed that both 10mg/weekly and 15mg/weekly lead to greater weight loss results than GLP-1. In studies comparing tirzepatide to GLP-1 agonists, 15mg tirzepatide significantly outperformed 10mg/weekly for weight loss [13].
Tirzepatide for Diabetics
Tirzepatide's approval by the FDA for the treatment of T2D came after successful completion of the first five phase-3 trials within the clinical development program SURPASS, sponsored by Eli Lilly [14].
The trials compared various doses of tirzepatide (5mg, 10mg, and 15mg) to placebo, the GLP-1 agonist semaglutide (1mg), and insulin. All tirzepatide doses led to a significant reduction of glycated hemoglobin (HbA1c) across the five trials, which were in the range of 2-2.5% below baseline.
Two of the trials compared tirzepatide to placebo and reported that 15mg/weekly led to a 1.66%-2.11% greater HbA1c reduction over placebo. Further, the reductions were about 0.5% greater than semaglutide 1mg/weekly, 0.9% greater than insulin degludec, and 1.0% greater than insulin glargine [15, 16, 17, 18, 19].
There is also an ongoing phase-3 trial called SURPASS-CVOT, launched by Eli Lilly in 2020. The trial aims to investigate whether the peptide may also improve long-term cardiovascular outcomes in T2D patients.
In this trial, the cardioprotective effect of tirzepatide will be compared against dulaglutide, which is a GLP-1 agonist that is already FDA-approved for improving cardiovascular outcomes in T2D [20].
Tirzepatide for Obesity
Tirzepatide is currently under investigation as a potential treatment for obesity within the SURMOUNT development program launched by Eli Lilly and Co [21].
This program includes four global phase 3 trials, where participants with a BMI of 27kg/m² or higher are randomly assigned to receive either tirzepatide or a placebo in a double-blind manner.
The primary focus of these trials is to assess the percentage change in body weight from the beginning to the end of the treatment period.
The results of SURMOUNT-1 have been published in The New England Journal of Medicine and report data from more than 2500 subjects. The data thus far reveals that tirzepatide at 5mg, 10mg, and 15mg are all effective at achieving weight loss compared to placebo.
Within 72 weeks, the 5mg group lost a mean body weight of 15%, while the 10mg and 15mg lost about 20% (19.5% and 20.9%, respectively). The 10mg tirzepatide results appear rather impressive since the weight loss is almost identical to the higher dose.
Notably,the researchers also reported a higher discontinuation rate due to side effects in the 10mg group [22].
As of 2023, the results of SURMOUNT-2 have also been published in The Lancet. The trial investigated the weight loss potential of the peptide versus placebo in 938 individuals with chronic weight management issues and T2D.
According to the data, 10mg tirzepatide led to an average weight loss of 12.8% (28lb) from baseline, while 15mg led to weight loss of 14.7% (32.2lb) and placebo was associated with a 3.3% (7.0lb) weight reduction.
It was also revealed that 79% (10mg) and 83% (15mg) of trial volunteers taking tirzepatide achieved at least a 5% body weight reduction, compared to 32% of the placebo group [23].
Results from the remaining trials are anticipated to be released later in 2023 [21].
Tirzepatide for Fat Burning
Tirzepatide appears to induce significant fat loss, including by reducing both visceral and subcutaneous fat, while preserving lean body mass.
A substudy of SURPASS-3, termed SURPASS-3-MRI, was conducted to explore the specific impact of tirzepatide on organ and visceral fat, as well as abdominal subcutaneous adipose tissue in patients with type 2 diabetes (T2D). In comparison to insulin therapy, tirzepatide demonstrated superior results in a total of 502 participants.
The study findings revealed an 8% absolute reduction in liver fat in the combined tirzepatide groups (10mg and 15mg), nearly 5% higher than the insulin group after 12 months. Additionally, significant reductions were observed in both subcutaneous and visceral adiposity [24].
Further, a trial conducted by Yabe et al. (2023) in Japan focused on 10mg/weekly and 15mg/weekly tirzepatide and the effects of these doses on body weight, lean body mass, and body fat mass. The study indicated notable reductions in these parameters, with the decline in lean body mass primarily attributed to decreased body water.
When analyzing body composition percentages, both the 10mg/weekly and 15mg/weekly groups experienced a decrease in body fat percentage by approximately 5%, accompanied by increases in body water (3.7%), protein (2%), and minerals (0.4%) as assessed through bioelectric impedance analysis [25].
Tirzepatide Side Effects | A-Z Guide
Scientists who plan on incorporating tirzepatide into their weight loss research should be aware of its potential adverse effects.
The data from phase 3 clinical trials and post-marketing surveillance reveals that gastrointestinal complaints, including nausea and diarrhea, are the most commonly reported side effects, with higher incidences observed at higher doses.
The latest meta-analysis on Tirzepatide side effects, conducted by Mishra et al. (2023), reports that the rates of gastrointestinal adverse events were 39%, 46%, and 49% for the 5mg, 10mg, and 15mg doses, respectively [26].
Nausea and diarrhea rates were similar and occurred in 10-25% of subjects depending on the dose. The discontinuation rate due to adverse events was highest at the 15mg dose (10%).
Other relatively common side effects included indigestion, headache, constipation, abdominal pain, dyspepsia, and vomiting. Injection site reactions were rare.
Serious adverse events are rare, occurring in less than 1% of test subjects, and may include cholelithiasis, cholecystitis, pancreatitis, and hypersensitivity reactions affecting 2-4% of subjects [26].
Pregnant and lactating women are advised to avoid tirzepatide use. Further, a risk of medullary thyroid carcinoma has been linked to tirzepatide based on animal research, though none has been linked to human use [27]. Nevertheless, subjects with a history of medullary thyroid cancer or multiple endocrine neoplasia syndrome type 2 should be excluded from tirzepatide research.
Tirzepatide Dosage Guide
The available data on SURMOUNT-1 and SURMOUNT-2 trials regarding the weight loss potential of tirzepatide can also be used as a useful reference for weight loss research.
According to SURMOUNT-1, the evidence suggests a maximum weekly dose of 15mg for chronic weight management, with significant weight loss also occurring at 10mg/weekly [21, 22].
Researchers may accordingly consider aiming for 10mg/weekly and exceeding it only in specific cases related to the individual test subject’s response and tolerance.
It is likewise advisable to start with a low weekly dose and gradually increase it over several months to minimize the risk of side effects. The recommended initial dosage is 2.5mg once weekly, with increases by 2.5mg increments every four weeks.
Here is a sample tirzepatide weight loss protocol according to these recommendations:
- Tirzepatide Dose: Initiate at 2.5mg/weekly for the first four weeks of the study period, followed by an increase to 5mg/weekly in weeks 5-8, 7.5mg/weekly in weeks 9-12, and 10mg/daily in weeks 13-16. Consider increasing further to 12.5mg/weekly in weeks 17-20, and 15mg in weeks 21 and beyond, depending on the test subjects' response and tolerance.
- Frequency: Once weekly; subcutaneous.
- Study Duration: Studies using this protocol have lasted 24-72 weeks.
- Notes: Do not exceed a weekly dose of 15mg tirzepatide.
Where to Buy Tirzepatide Online? | 2024 Edition
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Limitless Life
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Bacteriostatic Water and Tirzepatide
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Weight Loss and Tirzepatide | Verdict
Tirzepatide is a novel dual-incretin agonist that activates both the GIP and GLP-1 receptors to produce superior glycemic control and weight loss results compared to even the most popular GLP-1 agonists.
It is currently approved by the FDA as a T2D medication, and there are several ongoing studies regarding its effect on fat loss and chronic weight management in overweight and obese individuals.
Tirzepatide for weight loss can be legally purchased by researchers looking to incorporate it into their studies. The peptide's half-life of five days allows for a weekly administration and requires a specific weight loss dosing regime to minimize side effects.
We wholeheartedly recommend this top-rated vendor to any qualified professional interested in exploring the effects of tirzepatide on weight loss.
Luis Daniel López Murillo, PhD