Clinical trial NCT05912621: Tirzepatide: Reversal of Lipotoxicity and Adipose Tissue Dysfunction in Humans With Overweight/Obesity
Official title: Tirzepatide: Reversal of Lipotoxicity and Adipose Tissue Dysfunction in Humans With Overweight/Obesity
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE2
Conditions: Obesity
Overweight and Obesity
Overweight
Lead sponsor: Stanford University
Sponsor class: OTHER
Collaborators: name: Eli Lilly and Company
First posted: 2023-06-22
Enrollment: 66
Sex: ALL
Minimum age (years): 18
Maximum age (years): 70
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: yes
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: 204 patients with BMI 27-39.9 kg/m2 and fasting plasma glucose \< 126 mg/dL will be screened to enroll 68 (to complete 60) who will be randomized 1:1 (computer generated randomization with blocking by sex and BMI category (27-29.9, 30-34.9, 35-39.9 kg/m2) to tirzepatide or dietary weight loss for 22 wks. Individuals with BMI 27-29.9 kg/m2 must have an additional cardiovascular risk factor or weight-related comorbidity.
Primary purpose: TREATMENT

Brief summary: 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.

Detailed description: All participants will come to the Stanford University campus for their baseline, week 6, and week 22 (end of study) tests. Prior to starting the assigned intervention, all participants will undergo a supervised (by study dietitian) week of weight maintenance, followed by baseline tests including insulin resistance test (SSPG), Standardized Meal Tolerance Test (for hormone and metabolite profiles), oral glucose tolerance test (OGTT), DXA and MRI scans (to quantify total, regional, and intrahepatic fat), and a subcutaneous periumbilical adipose tissue needle biopsy. Following baseline testing, participants begin tirzepatide vs diet. weight loss will be aggressive for the first six weeks with diet to match the tirzepatide weight loss that is expected. After week 6 weight loss will occur naturally on both without matching. Patients will see the dietitian and coordinator every two weeks to review diet and physical activity, and evaluate tolerability/side effects, and obtain morning weight at Stanford. The metabolic tests, regional fat scans, and biopsy will be repeated at week 6 and week 22.

Eligibility 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

Primary outcomes:
measure: Change in Adipocyte Size
timeFrame: Baseline and Week 22
measure: Change in Adipocyte Fat Storage Capacity
timeFrame: Baseline and Week 22
measure: Assess changes in Regional Fat
timeFrame: Baseline, week 6, and week 22
measure: Change from baseline on the 2-stage Steady State Plasma Glucose test
timeFrame: Baseline, week 6, and week 22
Secondary outcomes:
Other outcomes:
Locations:
city: Palo Alto
country: United States
facility: Clinical and Translational Research Unit
state: California
Study officials:
affiliation: Stanford School of Medicine
name: Tracey McLaughlin, MD
role: PRINCIPAL_INVESTIGATOR
References: