Tirzepatide for Obesity

Overseen By Tracey McLaughlin, MD

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: Stanford University

Must not be taking: GLP1 analogs

Disqualifiers: Bariatric surgery, Major organ disease, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Prior Safety Data This treatment has passed at least one previous human trial

Approved in 5 Jurisdictions This treatment is already approved in other countries

Compensation: Varies

Number of Visits: 9

Duration: 22 weeks

66 Participants Needed

Trial Summary

Will I have to stop taking my current medications?

The trial does not specify if you need to stop taking your current medications, but you cannot participate if you have used diabetogenic or weight loss medications, including GLP1 analogs, in the past three months.

What data supports the effectiveness of the drug Tirzepatide for obesity?

Research shows that Tirzepatide, a drug that works on specific hormones in the body, helps people with obesity and type 2 diabetes lose weight effectively. Studies found that it leads to significant weight loss and improves other health factors like blood pressure and insulin sensitivity. ^{1 2 3 4 5}

Is tirzepatide safe for humans?

Tirzepatide has been tested in people with type 2 diabetes and is generally considered safe, with common side effects being mild to moderate stomach issues like nausea, vomiting, diarrhea, and constipation. It has also shown no increased risk of serious heart problems compared to other treatments. ^{6 7 8 9 10}

How is the drug tirzepatide unique for treating obesity?

Tirzepatide is unique because it combines two actions in one drug, targeting both the GLP-1 and GIP receptors, which helps with significant weight loss and improves other health markers like blood pressure and insulin sensitivity. This dual action makes it more effective than other treatments that only target one of these pathways. ^{1 2 9 11 12}

What is the purpose of this trial?

Obesity, affecting 40% of US adults and costing 173b annually, represents a significant health care burden (1). It is associated with increased risk for multiple chronic diseases including hypertension, type 2 diabetes (T2D), cardiovascular disease, and NAFLD, as well as cancer, osteoarthritis, and obstructive sleep apnea. The investigators plan to test the hypothesis that tirzepatide, a dual GLP/GIP agonist, improves metabolic health (insulin resistance and regional fat distribution and cardiovascular risk profile) not only by inducing weight loss via GLP1-agonism, but also via beneficial cellular and molecular changes in adipose tissue, given that GIP binds receptors in human fat cells. Based on studies in mice showing that GIP alone or tirzepitide treatment decreases inflammation, increases lipid buffering (fat storage in the fat cells instead of releasing it into the bloodstream), and improves glucose homeostasis. The investigators believe that the GIP component of tirzepatide will make fat cells healthier and reverse lipotoxicity, which is one of the mechanisms by which obesity leads to insulin resistance, disordered regional fat distribution, and type 2 diabetes. To date, the effect of dual GLP1 and GIP agonist treatment on adipose tissue has not been evaluated in humans. Given the existing but limited data, dual GIP/GLP-1 agonist treatment in obese humans with metabolic risk factors is an attractive pharmacologic candidate that would lead to both weight loss and healthier fat, potentially offering uniquely powerful synergistic clinical benefits. It is thus of tremendous importance to define the biological effects of dual-agonist treatment on human adipose tissue structure and function, as well as related improvements in regional fat distribution and systemic adipose and muscle insulin sensitivity. In this study, the investigators will randomize overweight (with risk factors) or obese nondiabetic individuals to hypocaloric diet or tirzepatide for 22 weeks with matched weight loss for the first 6 weeks. The investigators will quantify insulin resistance, fat and lean mass, including regional fat distribution, and changes in adipose tissue (needle biopsy from abdominal fat tissue) to see if tirzepatide effects differ from dietary weight loss.

Research Team

Tracey L McLaughlin, MD

Principal Investigator

Stanford School of Medicine

Eligibility Criteria

This trial is for adults aged 18-70 with obesity or overweight conditions. Overweight participants must have additional risk factors like hypertension, dyslipidemia, prediabetes, sleep apnea, fatty liver disease, gallstones, or osteoarthritis. Participants should not be diabetic and women can be pre or postmenopausal.

Inclusion Criteria

My fasting blood sugar is below 126 mg/dL without diabetes medication.

My BMI is between 27 and 39.9, and if it's under 30, I have a related health condition.

I am a woman and can provide details about my last menstrual period or hormone replacement.

Exclusion Criteria

Pregnancy/lactation

Active eating or psychiatric disorder

Heavy alcohol use (>2 drinks/day for women and > 3 drinks/day for men) will be excluded

Timeline

Screening

Participants are screened for eligibility to participate in the trial

1 week

1 visit (in-person)

Baseline Testing

Participants undergo baseline tests including insulin resistance test, Standardized Meal Tolerance Test, oral glucose tolerance test, DXA and MRI scans, and a subcutaneous periumbilical adipose tissue needle biopsy

1 week

1 visit (in-person)

Treatment

Participants are randomized to either tirzepatide or hypocaloric diet for weight loss, with matched weight loss for the first 6 weeks

22 weeks

Bi-weekly visits for the first 6 weeks, then every 4 weeks

Follow-up

Participants are monitored for safety and effectiveness after treatment, with repeat metabolic tests, regional fat scans, and biopsies

4 weeks

1 visit (in-person)

Treatment Details

Interventions

• Tirzepatide

Trial Overview The study tests Tirzepatide's effects on metabolic health in obese individuals by comparing it to a hypocaloric diet over 22 weeks. It aims to see if Tirzepatide improves fat distribution and insulin resistance beyond just weight loss through its dual action on GLP/GIP receptors in fat cells.

Participant Groups

Group I: 2.5 mg (up to 15 mg) Tirzepatide Experimental Treatment 1 Intervention

Patients assigned to tirzepatide will undergo dose titration starting with 2.5 mg per day with an increase every four weeks if tolerated by nausea. During the first 6 weeks, weight loss must be matched with the dietary weight loss arm at 0.6 kg/week. Participants will be seen every two weeks to review diet and physical activity, evaluate tolerability/side effects, and obtain morning weight. If weight loss is greater than 0.6 kg/week, recommendations to increase caloric intake will be made through the week 6 visits that repeat baseline testings (biopsy, metabolic tests, and regional fat scans). After the 6th week, weight loss can occur naturally without any restrictions (no further matching to the dietary weight loss group is required). Starting at week 8 the visits are decreased to every 4 weeks. Biopsies, metabolic tests, and regional fat scans are completed at baseline, week 6, and end of study (week 22).

Group II: Diet-controlled Active Control 1 Intervention

The group assigned to dietary weight loss will undergo intensive dietary counseling with initial 3 day food diary evaluation followed by specific dietary recommendations that include macronutrient balanced, healthful and calorie-restricted diet, weekly dietitian visits, alternating between video and in person, use of a mobile app for food logging, weekly weights at home and biweekly weights, and review of these data by the study dietitian who will give individualized feedback at the weekly visits in order to attain targeted weight loss of 0.6 kg per week. The goal is to match weight loss in the tirzepatide and diet groups for the first six weeks. Any residual differences in weight loss at 6 weeks will be adjusted statistically. At six weeks all baseline tests (biopsy, metabolic tests, and regional fat scans) will be repeated, after which no further attempts for matching for weight loss will occur. At the end of the study (week 22), all baseline testing will occur again.

Tirzepatide is already approved in United States, European Union, Canada, United Kingdom for the following indications:

Approved in United States as Mounjaro for:

• Type 2 diabetes

Approved in European Union as Mounjaro for:

• Type 2 diabetes

Approved in Canada as Mounjaro for:

• Type 2 diabetes

Approved in United States as Zepbound for:

• Weight loss
• Moderate to severe obstructive sleep apnea

Approved in United Kingdom as Zepbound for:

• Weight loss

Who Is Running the Clinical Trial?

Stanford University

Lead Sponsor

Trials

2,527

Recruited

17,430,000+

Eli Lilly and Company

Industry Sponsor

Trials

2,708

Recruited

3,720,000+

Dr. Daniel Skovronsky

Eli Lilly and Company

Chief Medical Officer since 2018

MD from Harvard Medical School

David A. Ricks

Eli Lilly and Company

Chief Executive Officer since 2017

BSc from Purdue University, MBA from Indiana University

Findings from Research

Tirzepatide significantly reduces body weight in patients with type 2 diabetes and obesity, with an average weight loss of -9.81 kg compared to placebo, based on a meta-analysis of 10 studies involving 9,873 patients.

While tirzepatide is effective for weight loss, it has a higher incidence of gastrointestinal side effects compared to placebo, although serious adverse events and hypoglycemia are less common, indicating a need for monitoring these reactions during treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Weight loss efficiency and safety of tirzepatide: A Systematic review. Lin, F., Yu, B., Ling, B., et al.[2023]

Tirzepatide, a once-weekly medication for type 2 diabetes, not only improves blood sugar control but also leads to significant weight loss and positive changes in cardiovascular health, such as reduced blood pressure and improved insulin sensitivity.

The weight loss and metabolic benefits of tirzepatide are linked to its dual action as a GIP and GLP-1 receptor agonist, suggesting that these mechanisms play a crucial role in its effectiveness for managing type 2 diabetes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Perspectives on weight control in diabetes - Tirzepatide. Várkonyi, TT., Pósa, A., Pávó, N., et al.[2023]

Tirzepatide demonstrated a dose-dependent ability to lower HbA1c levels in adults with type 2 diabetes, with reductions ranging from -17.71 to -22.35 mmol/mol compared to placebo, and was also more effective in reducing body weight than other treatments.

While tirzepatide did not increase the risk of hypoglycaemia compared to placebo and showed lower rates than basal insulin, it was associated with a higher incidence of gastrointestinal side effects, particularly nausea and vomiting, especially at the 15 mg dose.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Management of type 2 diabetes with the dual GIP/GLP-1 receptor agonist tirzepatide: a systematic review and meta-analysis. Karagiannis, T., Avgerinos, I., Liakos, A., et al.[2023]

In a 72-week phase 3 trial involving 938 adults with obesity and type 2 diabetes, tirzepatide (10 mg and 15 mg) led to significant weight loss, with reductions of -12.8% and -14.7% respectively, compared to only -3.2% with placebo.

The safety profile of tirzepatide was generally favorable, with most adverse events being mild to moderate gastrointestinal issues, and serious adverse events were rare, indicating it is a safe option for weight management in this population.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Tirzepatide once weekly for the treatment of obesity in people with type 2 diabetes (SURMOUNT-2): a double-blind, randomised, multicentre, placebo-controlled, phase 3 trial. Garvey, WT., Frias, JP., Jastreboff, AM., et al.[2023]

In a systematic review of randomized controlled trials involving 5800 patients, tirzepatide was found to be highly effective for weight loss, with 78.22% achieving at least 5% weight loss and 32.28% achieving at least 15% weight loss.

Tirzepatide demonstrated superior weight loss compared to placebo and semaglutide, with a significant mean weight loss of -12.47 kg at the 5 mg dose, while showing a manageable safety profile with only a slight increase in gastrointestinal adverse events compared to placebo.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Efficacy and safety of tirzepatide for treatment of overweight or obesity. A systematic review and meta-analysis. Tan, B., Pan, XH., Chew, HSJ., et al.[2023]

Tirzepatide, the first dual GIP/GLP-1 receptor co-agonist approved for type 2 diabetes, significantly reduces HbA1c levels (by 1.24 to 2.58%) and body weight (by 5.4-11.7 kg) in clinical trials involving type 2 diabetic patients, outperforming the selective GLP-1 RA semaglutide.

The safety profile of tirzepatide is similar to that of other GLP-1 receptor agonists, with common side effects including nausea and diarrhea, and it shows potential cardiovascular safety, as no significant increase in major adverse cardiovascular events was observed during the trials.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Tirzepatide, a dual GIP/GLP-1 receptor co-agonist for the treatment of type 2 diabetes with unmatched effectiveness regrading glycaemic control and body weight reduction. Nauck, MA., D'Alessio, DA.[2022]

Tirzepatide, a dual GIP and GLP-1 receptor agonist, showed significant reductions in Hemoglobin A1c levels (up to 3.02%) and weight loss in adults with uncontrolled type 2 diabetes, outperforming both placebo and active comparators like semaglutide.

The safety profile of tirzepatide was comparable to semaglutide regarding gastrointestinal adverse effects, and it did not increase the incidence of major cardiovascular events compared to insulin glargine, indicating it may be a valuable addition to diabetes treatments.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Tirzepatide, the Newest Medication for Type 2 Diabetes: A Review of the Literature and Implications for Clinical Practice. Bradley, CL., McMillin, SM., Hwang, AY., et al.[2023]

Tirzepatide is a novel medication that acts on both GIP and GLP-1 receptors, enhancing insulin secretion and reducing glucagon levels, which helps improve glycemic control in adults with type 2 diabetes mellitus (T2DM).

It received its first approval in the USA in May 2022 for T2DM treatment and is currently being studied for additional conditions like obesity, heart failure, and non-alcoholic steatohepatitis, indicating its potential for broader therapeutic applications.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Tirzepatide: First Approval. Syed, YY.[2022]

Tirzepatide, approved in 2022, is a novel treatment for type 2 diabetes that acts on both GLP-1 and GIP pathways, showing significant efficacy in lowering blood sugar levels and promoting weight loss in various patient groups.

Clinical trials, including the SURPASS and SURMOUNT studies, indicate that tirzepatide has a safety profile similar to traditional GLP-1 receptor agonists, with common gastrointestinal side effects, making it a promising option for patients needing better glycemic and weight management.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Tirzepatide: Clinical review of the "twincretin" injectable. Krauss, Z., Hintz, A., Fisk, R.[2023]

Tirzepatide, a novel GLP-1 receptor agonist, has been shown to significantly reduce A1C levels and body weight in patients with type 2 diabetes compared to placebo and other active treatments.

The safety profile of tirzepatide is similar to other GLP-1 receptor agonists, with the most common side effects being mild to moderate gastrointestinal issues, and it does not increase the risk of hypoglycemia, making it a promising treatment option.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Efficacy and Safety of Tirzepatide in Adults With Type 2 Diabetes: A Perspective for Primary Care Providers. Kushner, P., Anderson, JE., Simon, J., et al.[2023]

Tirzepatide, a new medication approved by the FDA, acts as an agonist for both GLP-1 and GIP receptors, which helps improve blood sugar control in patients with type II diabetes when combined with diet and exercise.

This drug represents a significant advancement in diabetes management, offering a new approach to treatment by targeting multiple pathways involved in glucose regulation.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Tirzepatide: A New Generation Therapeutic for Diabetes Type 2. Al-Horani, RA., Chedid, M.[2023]

Tirzepatide, a dual GIP and GLP-1 receptor agonist, has a safety profile similar to other GLP-1 receptor agonists, but higher doses (10mg and above) are associated with increased risks of hypoglycemia and treatment discontinuation.

In clinical trials involving 9818 patients, higher doses of tirzepatide led to more frequent gastrointestinal side effects like nausea, vomiting, and diarrhea, indicating that these adverse events are dose-dependent.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A systematic review of the safety of tirzepatide-a new dual GLP1 and GIP agonist - is its safety profile acceptable? Meng, Z., Yang, M., Wen, H., et al.[2023]

References

1. United States pubmed.ncbi.nlm.nih.gov

Weight loss efficiency and safety of tirzepatide: A Systematic review. [2023]

2. Ireland pubmed.ncbi.nlm.nih.gov

Perspectives on weight control in diabetes - Tirzepatide. [2023]

3. Germany pubmed.ncbi.nlm.nih.gov

Management of type 2 diabetes with the dual GIP/GLP-1 receptor agonist tirzepatide: a systematic review and meta-analysis. [2023]

4. England pubmed.ncbi.nlm.nih.gov

Tirzepatide once weekly for the treatment of obesity in people with type 2 diabetes (SURMOUNT-2): a double-blind, randomised, multicentre, placebo-controlled, phase 3 trial. [2023]

5. England pubmed.ncbi.nlm.nih.gov

Efficacy and safety of tirzepatide for treatment of overweight or obesity. A systematic review and meta-analysis. [2023]

6. England pubmed.ncbi.nlm.nih.gov

Tirzepatide, a dual GIP/GLP-1 receptor co-agonist for the treatment of type 2 diabetes with unmatched effectiveness regrading glycaemic control and body weight reduction. [2022]

7. United States pubmed.ncbi.nlm.nih.gov

Tirzepatide, the Newest Medication for Type 2 Diabetes: A Review of the Literature and Implications for Clinical Practice. [2023]

8. New Zealand pubmed.ncbi.nlm.nih.gov

Tirzepatide: First Approval. [2022]

9. England pubmed.ncbi.nlm.nih.gov

Tirzepatide: Clinical review of the "twincretin" injectable. [2023]

10. United States pubmed.ncbi.nlm.nih.gov

Efficacy and Safety of Tirzepatide in Adults With Type 2 Diabetes: A Perspective for Primary Care Providers. [2023]

11. United Arab Emirates pubmed.ncbi.nlm.nih.gov

Tirzepatide: A New Generation Therapeutic for Diabetes Type 2. [2023]

12. Switzerland pubmed.ncbi.nlm.nih.gov

A systematic review of the safety of tirzepatide-a new dual GLP1 and GIP agonist - is its safety profile acceptable? [2023]