Weight Loss Interventions for Obesity

Overseen By Roz De Leon

Age: 18 - 65

Sex: Any

Trial Phase: Academic

Sponsor: University of Washington

Must not be taking: Insulin, DPP-4 inhibitors

Disqualifiers: Hypertension, Coronary artery disease, Cancer, others

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

Compensation: Varies

Number of Visits: Unknown

112 Participants Needed

Trial Summary

Will I have to stop taking my current medications?

The trial requires that participants stop using insulin (except for the Surgical Weight Loss group), DPP-4 inhibitors, thiazolidinediones, or medications known to alter metabolic function, such as atypical antipsychotics and corticosteroids.

What data supports the effectiveness of the treatment Roux-en-Y Gastric Bypass or Sleeve Gastrectomy for weight loss?

Roux-en-Y gastric bypass is shown to be one of the most effective treatments for long-term weight loss in severely obese individuals, achieving 60% to 70% excess body weight loss. It works by reducing food intake and absorption, and it has multiple effects on the body's hormones and feelings of fullness. ^{1 2 3 4 5}

Is Roux-en-Y gastric bypass generally safe for humans?

Roux-en-Y gastric bypass (RYGB) is widely reported to be safe and effective for weight loss, but it may lead to long-term nutritional deficiencies if supplements are not taken regularly, especially in adolescents. ^{2 3 4 6 7}

How is the Behavioral Weight Loss Program, Roux-en-Y Gastric Bypass, or Sleeve Gastrectomy treatment different from other obesity treatments?

This treatment is unique because it combines surgical options like Roux-en-Y Gastric Bypass, which changes how your body processes food, with a Behavioral Weight Loss Program that includes lifestyle changes and support. This comprehensive approach not only targets physical weight loss but also addresses psychological and social factors, offering long-term benefits and maintenance of weight loss. ^{2 3 4 8 9}

What is the purpose of this trial?

Patients and clinicians need better options to prevent the weight regain that almost universally follows a weight loss intervention. In lay terms, a new, higher "set point" seems to occur after people gain weight. Evidence from some research studies reinforces these observations, showing that processes of energy homeostasis vigorously defend the higher level of adiposity for years, if not permanently. Only bariatric surgery appears to "re-set" to a lower level of adiposity. No clear mechanism has been elucidated to date that explains these phenomena. The current proposal endeavors to address this crucial scientific gap by translating preclinical data into human studies testing novel mechanistic hypotheses. Prior studies in rodents show that a high-fat diet causes inflammation and a cellular response, known as gliosis, within hypothalamic regions regulating energy balance and glucose homeostasis. Evidence further suggests that gliosis might play a pathogenic role in obesity and type 2 diabetes mellitus (T2D) because its development precedes weight gain and impaired glucose homeostasis and its inhibition improves metabolic health. Importantly, gliosis is detectable in mice and humans by magnetic resonance imaging (MRI). Using MRI, the investigators discovered the first evidence of gliosis in obese humans and went on to show associations of gliosis with insulin resistance in humans, independent of the level of adiposity. New findings suggest that people with T2D have more extensive gliosis than is seen in nondiabetic obese subjects. Further findings reveal that gliosis improves, but is not completely reversed, 8 mo. after Roux-en-Y gastric bypass (RYGB) surgery in T2D patients. It remains unknown whether gliosis improves similarly when weight loss occurs by lifestyle change or if the efficacy and durability of weight loss via bariatric surgery is partially explained by its ability to reverse gliosis via an as yet unknown mechanism of action. We therefore propose three studies in humans to discover 1) if hypothalamic gliosis is reversed by a standard behavioral weight loss intervention, 2) if the extent of gliosis predicts successful weight loss during, or weight regain after, behavioral weight loss, and 3) the time course of improvement in gliosis after RYGB and the relation of its improvement to the short- and long-term efficacy of RYGB. Future research would define dietary, environmental, or other risk factors for the development of hypothalamic gliosis in humans. Achieving a better understanding of the role of the brain in obesity and its treatment could open new avenues for research, intervention, and prevention.

Research Team

Ellen Schur, MD, MS

Principal Investigator

University of Washington

Eligibility Criteria

This trial is for adults aged 25-64 with obesity, who are eligible for weight loss surgery (Roux-en-Y Gastric Bypass or Sleeve Gastrectomy) and have a BMI of 30-<56 kg/m². Healthy individuals with a BMI of 18.5-24.9 can also participate as controls. Exclusions include poorly controlled hypertension, severe chronic diseases, certain medication use, pregnancy, MRI contraindications, smokers or heavy alcohol users.

Inclusion Criteria

My BMI is between 30 and less than 56 kg/m².

Healthy Weight Controls (HWC): BMI 18.5-24.9 kg/m²

I am between 25 and 64 years old.

Exclusion Criteria

Current smoking/daily use of nicotine containing products (cigarettes, e-cigarettes, vaping or other nicotine containing products) or heavy alcohol use

Severe food allergies

Pregnancy or breastfeeding

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Behavioral Weight Loss Intervention

Participants undergo a standard behavioral weight loss program to assess if hypothalamic gliosis is reversed

8 months

Surgical Intervention

Participants undergo Roux-en-Y Gastric Bypass Surgery to evaluate the time course of improvement in gliosis

8 months

Follow-up

Participants are monitored for safety and effectiveness after interventions, focusing on gliosis improvement and weight regain

6 months

Treatment Details

Interventions

• Behavioral Weight Loss Program
• Roux-en-Y Gastric Bypass or Sleeve Gastrectomy

Trial Overview The study tests if hypothalamic gliosis related to obesity and diabetes can be reversed by behavioral weight loss programs or bariatric surgery (Roux-en-Y Gastric Bypass or Sleeve Gastrectomy). It will examine the role of brain inflammation in maintaining higher body weights after initial weight loss.

Participant Groups

Group I: Lifestyle Cohort Active Control 1 Intervention

Participants Undergoing Behavioral Weight Loss Program

Group II: Surgical Cohort Active Control 1 Intervention

Participants Scheduled for Roux-en-Y Gastric Bypass Surgery

Group III: Healthy Weight Control Cohort Active Control 1 Intervention

Healthy Weight Controls With No Intervention

Behavioral Weight Loss Program is already approved in United States, European Union for the following indications:

Approved in United States as Behavioral Weight Loss Program for:

• Obesity
• Weight Loss
• Type 2 Diabetes Prevention

Approved in European Union as Behavioral Weight Loss Interventions for:

• Obesity
• Weight Loss
• Type 2 Diabetes Prevention

Who Is Running the Clinical Trial?

University of Washington

Lead Sponsor

Trials

1,858

Recruited

2,023,000+

National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)

Collaborator

Trials

2,513

Recruited

4,366,000+

National Heart, Lung, and Blood Institute (NHLBI)

Collaborator

Trials

3,987

Recruited

47,860,000+

Findings from Research

Bariatric surgery, such as Roux-en-Y gastric bypass and biliopancreatic diversion, is effective for long-term weight loss and reducing health risks in morbidly obese individuals, but it can lead to serious nutritional complications that may require revisional surgery.

In a study of four patients who underwent revisional surgery due to complications, one patient died, highlighting that while revision surgery is rare, it carries increased risks and can involve different surgical approaches depending on the patient's condition.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Revisional surgery in severe nutritional complications after bariatric surgical procedures: report of four cases from a single institution and review of the literature. Braga, JGR., Concon, MM., Lima, AP., et al.[2021]

In a study of 617 patients who underwent Roux-en-Y gastric bypass, Medicare beneficiaries experienced similar long-term weight loss and comorbidity resolution as non-Medicare patients after 10 years, indicating the procedure's effectiveness across different insurance statuses.

Despite Medicare patients being older and having a higher preoperative body mass index, their outcomes were equivalent to those of non-Medicare patients, supporting the case for continued Medicare coverage of bariatric surgery.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Ten-year outcomes of Roux-en-Y gastric bypass are equivalent in patients with Medicare disability and non-Medicare patients. Michaels, AD., Mehaffey, JH., Hawkins, RB., et al.[2019]

In a study of 213 type 2 diabetes patients with a BMI of 25 to 32.5 kg/m2, Roux-en-Y gastric bypass (RYGB) was found to be more effective than medical treatment in achieving significant metabolic improvements, with 23.9% of RYGB patients meeting the triple endpoint compared to only 7.0% in the medical group.

However, RYGB was associated with a higher rate of complications (36 vs. 22), highlighting the need to weigh the benefits of improved metabolic outcomes against the risks of surgical complications when considering treatment options for patients with lower BMI.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Two-year outcomes of Roux-en-Y gastric bypass vs medical treatment in type 2 diabetes with a body mass index lower than 32.5&#160;kg/m2: a multicenter propensity score-matched analysis. Ling, J., Tang, H., Meng, H., et al.[2022]

In a study of 85 adolescents who underwent Roux-en-Y gastric bypass (RYGB), adherence to prescribed micronutrient supplementation was only 44-61% over 5 years, leading to significant long-term deficiencies, particularly in iron and vitamin D.

Adolescents who did not adhere to supplementation had lower levels of essential nutrients and a higher prevalence of anemia and deficiencies, highlighting the need for ongoing monitoring and potentially increased supplementation post-surgery.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Micronutrient intake and biochemistry in adolescents adherent or nonadherent to supplements 5 years after Roux-en-Y gastric bypass surgery. Henfridsson, P., Laurenius, A., Wallengren, O., et al.[2020]

An interdisciplinary comprehensive weight loss program, combined with a biweekly behavioral maintenance program, helped participants maintain 83% of their initial weight loss after 18 months.

This multi-disciplinary approach, which includes social support and aerobic exercise, is considered the best current treatment for obesity, providing significant long-term health benefits.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Current treatment of obesity: a behavioral medicine perspective. Pera, V., Clark, MM., Abrams, DB.[2005]

References

1. Brazil pubmed.ncbi.nlm.nih.gov

Revisional surgery in severe nutritional complications after bariatric surgical procedures: report of four cases from a single institution and review of the literature. [2021]

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

Quality of life and psychosocial adjustment in patients after Roux-en-Y gastric bypass: a brief report. [2019]

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

Melanocortin-4 receptor signaling is required for weight loss after gastric bypass surgery. [2022]

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

Bariatric surgery: 1-year weight loss outcomes in patients with bipolar and other psychiatric disorders. [2021]

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

Ten-year outcomes of Roux-en-Y gastric bypass are equivalent in patients with Medicare disability and non-Medicare patients. [2019]

6. Italy pubmed.ncbi.nlm.nih.gov

Two-year outcomes of Roux-en-Y gastric bypass vs medical treatment in type 2 diabetes with a body mass index lower than 32.5&#160;kg/m2: a multicenter propensity score-matched analysis. [2022]

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

Micronutrient intake and biochemistry in adolescents adherent or nonadherent to supplements 5 years after Roux-en-Y gastric bypass surgery. [2020]

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

Band versus bypass: influence of an educational seminar and surgeon visit on patient preference. [2015]

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

Current treatment of obesity: a behavioral medicine perspective. [2005]