Clinical trial

Tirzepatide: Reversal of Lipotoxicity and Adipose Tissue Dysfunction in Humans With Overweight/Obesity

Recruiting now · Phase 2 · 1 countries · Registry ID NCT05912621

Recruiting nowPhase 2Interventional

What this study is about

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.

A promising-looking record is not the same as confirmed eligibility. The study team must review the full criteria and current recruitment status.

Basic eligibility

Age18 Years to 70 Years

SexAll

Healthy volunteersAccepted

ConditionObesity, Overweight and Obesity, Overweight

Full registry criteria

Inclusion Criteria: * nondiabetic as defined by fasting plasma glucose \< 126 mg/dL while off all glucose lowering medications * BMI 27-39.9 kg/m2. Individuals with obesity (BMI 30-39.9 kg/m2) are not required to have an additional risk factor but those who are overweight (27-29.9 kg/m2) must have at least one weight-related factor as follows: hypertension defined as physician-diagnosed and taking antihypertensive medication or SBP\> 130 or DBP \> 80 mm Hg; dyslipidemia defined as physician diagnosed and taking medication or LDL \> 160 mg/dL, TG \> 150 mg/dL, HDL \< 50 or \< 40 mg/dL for women and men, respectively; prediabetes defined as fasting glucose 100-125 mg/dL off all antidiabetic or diabetogenic medications, physician diagnosed obstructive sleep apnea, non-alcoholic fatty liver disease, history of gallstones, and osteoarthritis. * Age 18-70 * Pre and postmenopausal women will be eligible and details of last menstrual period and/or hormone replacement collected for statistical adjustment and formal testing for effect modification. Exclusion Criteria: * prior bariatric surgery or liposuction * unstable body weight defined as self-reported weight change \>2 kg over the past 6 weeks * unstable hypertension (defined as BP \>160/100 mm Hg) * major organ disease * chronic inflammatory conditions * pregnancy/lactation * active malignancy undergoing treatment * use (current or within the past three months) of diabetogenic or weight loss medications, including GLP1 analogs * active eating or psychiatric disorder * heavy alcohol use (\>2 drinks/day for women and \> 3 drinks/day for men) will be excluded

Treatments and study arms

Tirzepatide

Drug

Tirzepatide dose is titrated up by 2.5 mg every four weeks as per below, starting with 2.5 mg weekly and maxing out at 15 mg.

Primary outcomes

Change in Adipocyte SizeBaseline and Week 22

Using a multisizer, we will identify the size and distribution changes of fat cells from baseline to the end of the weight loss period to compare between tirzepatide administration and dietary restriction group

Change in Adipocyte Fat Storage CapacityBaseline and Week 22

Using a Oil Red O and rtPCR, we will identify the fat storage capacity of fat cells from baseline to the end of the weight loss period to compare between tirzepatide administration and dietary restriction group

Assess changes in Regional FatBaseline, week 6, and week 22

Using a DXA scan, we will measure the percentages of total, upper, lower, truncal, peripheral, and subcutaneous fat and compare it at baseline, 6 weeks, and 22 weeks for each participant

Change from baseline on the 2-stage Steady State Plasma Glucose testBaseline, week 6, and week 22

Compare direct measurement of insulin sensitivity after baseline, week 6, and week 22

Study locations

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Clinical and Translational Research Unit🇺🇸 Palo Alto, California, United States

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Nicole Turk, BSContact

Email · Call 650-888-0144

Tracey McLaughlin, MDPrincipal Investigator