Fiber + Metformin for Severe Childhood Obesity and Insulin Resistance

Overseen By Andrea M Haqq, MD, MHS

Age: < 65

Sex: Any

Trial Phase: Phase 3

Sponsor: University of Alberta

Must not be taking: Insulin, Antibiotics, Probiotics, others

Disqualifiers: T2DM, Hypertension, Chronic disease, others

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

Pivotal Trial (Near Approval) This treatment is in the last trial phase before FDA approval

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

Compensation: Varies

Number of Visits: 6

Duration: 12 months

90 Participants Needed

Trial Summary

What is the purpose of this trial?

This is a 12-month, single center, three-arm parallel design, double-blind, randomized clinical trial, to compare the effects of supplemental dietary fiber and metformin (MET) alone and in combination over 12 months on glucose metabolism (insulin resistance \[IR\]), inflammation and BMI in adolescents with obesity and IR, and to assess the relationship between therapeutic intervention(s) and changes in gut microbiome composition and function. Since MET and FIBER have been shown to reduce weight and increase insulin sensitivity through distinct but overlapping mechanisms of action, our central hypothesis is that the combination of FIBER + MET will have a synergistic effect and be more effective than FIBER or MET alone in improving metabolic function (IR) and reducing BMI and inflammation in adolescents with obesity, IR and family history (FM) of T2DM. .

Will I have to stop taking my current medications?

The trial requires that you stop taking any medications known to affect body weight, as well as antibiotics, probiotics, prebiotics, lipid-lowering, and anti-inflammatory medications before participating.

What data supports the effectiveness of the treatment combining fiber and metformin for severe childhood obesity and insulin resistance?

Research suggests that high-fiber diets can improve carbohydrate metabolism and lower cholesterol in people with diabetes, and combining fiber with metformin has shown to reduce blood sugar levels in animal studies. This indicates that the combination of fiber and metformin might help manage insulin resistance and obesity. ^{1 2 3 4 5}

Is the combination of fiber and metformin safe for humans?

Research on the combination of fiber and metformin in animals suggests it can help manage blood sugar levels, but specific safety data for humans is not provided. However, both metformin and various dietary fibers are generally considered safe for human use individually, with metformin being a common diabetes medication and dietary fibers often used to aid digestion. ^{4 6 7 8 9}

How does the drug Metformin combined with fiber differ from other treatments for severe childhood obesity and insulin resistance?

This treatment is unique because it combines Metformin, a drug commonly used for diabetes, with a fiber mixture to enhance weight loss and improve insulin resistance in children. The addition of fiber may help increase the feeling of fullness and improve metabolic health, offering a potentially more effective approach than Metformin alone. ^{10 11 12 13 14}

Research Team

Andrea M Haqq, MD, MHS

Principal Investigator

University of Alberta

Eligibility Criteria

Adolescents aged 12-18 with severe obesity and insulin resistance can join this trial. They must have a family history of type 2 diabetes, be significantly overweight for their age/sex, and not have had major weight changes or taken certain medications recently.

Inclusion Criteria

Your HOMA-IR score is higher than 3.16.

Your weight has not changed by more than 10% in the past 6 months.

My family has a history of type 2 diabetes.

Exclusion Criteria

I currently have cancer.

I haven't had a serious infection or been in the hospital for more than 2 days in the last month.

I have not taken antibiotics in the last 60 days or probiotics/prebiotics and certain medications in the last 30 days.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive either fiber supplementation, metformin, or a combination of both over 12 months

12 months

Regular visits at baseline, 6, and 12 months

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

Treatment Details

Interventions

• Metformin
• Supplemental fiber mixture

Trial Overview The study is testing if a high-fiber supplement mix works better alone or combined with Metformin to improve blood sugar control, reduce body mass index (BMI), and lower inflammation in obese teens over one year.

Participant Groups

Group I: FIBER + MET Experimental Treatment 2 Interventions

Fiber supplementation \[35g fiber daily\] + MET 850 mg po bid

Group II: FIBER Active Control 1 Intervention

Fiber supplementation \[35g fiber daily\] + MET placebo po bid

Group III: MET Active Control 1 Intervention

MET (850 mg po bid - standard of care) + Fiber placebo daily

Metformin is already approved in European Union, United States, Canada, Japan, China, Switzerland for the following indications:

Approved in European Union as Glucophage for:

• Type 2 diabetes

Approved in United States as Glucophage for:

• Type 2 diabetes

Approved in Canada as Glucophage for:

• Type 2 diabetes

Approved in Japan as Glucophage for:

• Type 2 diabetes

Approved in China as Glucophage for:

• Type 2 diabetes

Approved in Switzerland as Glucophage for:

• Type 2 diabetes

Who Is Running the Clinical Trial?

University of Alberta

Lead Sponsor

Trials

957

Recruited

437,000+

Findings from Research

In a randomized, double-blind, placebo-controlled trial involving 96 children aged 6-17, glucomannan supplementation did not lead to a significant reduction in body mass index (BMI) after 12 weeks compared to a placebo.

While glucomannan did not affect weight loss, it was associated with lower total and low-density lipoprotein cholesterol levels, although it also resulted in increased blood pressure in the participants.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

No Effect of Glucomannan on Body Weight Reduction in Children and Adolescents with Overweight and Obesity: A Randomized Controlled Trial. Zalewski, BM., Szajewska, H.[2020]

High-fiber diets, particularly those rich in soluble fiber, can improve carbohydrate metabolism and lower cholesterol levels in patients with non-insulin-dependent diabetes mellitus (NIDDM), with reductions in serum cholesterol and LDL cholesterol observed in both normal and high cholesterol individuals.

While fiber intake is generally beneficial, especially for those with diabetes, caution is advised for individuals with gastrointestinal issues and those on insulin, as changes in fiber intake can affect blood sugar levels and may require adjustments in insulin dosage.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Dietary fiber in management of diabetes. Vinik, AI., Jenkins, DJ.[2019]

In a randomized crossover trial with 20 postmenopausal women, high-fiber rye bread significantly increased acute insulin response compared to white-wheat bread, suggesting it may enhance insulin secretion.

Despite the increase in insulin response, high-fiber rye bread did not change insulin sensitivity, indicating that while it may improve beta cell function, it does not affect how the body responds to insulin in this population.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

High-fiber rye bread and insulin secretion and sensitivity in healthy postmenopausal women. Juntunen, KS., Laaksonen, DE., Poutanen, KS., et al.[2022]

Combining the polysaccharide PolyGlycopleX (PGX) with metformin or sitagliptin/metformin significantly reduced blood sugar levels in Zucker diabetic fatty rats compared to monotherapy, indicating enhanced efficacy of the combination treatments.

The combination of PGX with sitagliptin/metformin not only lowered blood glucose levels but also improved β-cell mass and reduced fat mass, suggesting it may be a more effective treatment for diabetes management than PGX with metformin alone.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Combining sitagliptin/metformin with a functional fiber delays diabetes progression in Zucker rats. Reimer, RA., Grover, GJ., Koetzner, L., et al.[2015]

Plantago ovata husk significantly increased the oral bioavailability of metformin by 34.42% in rabbits, suggesting that dietary fiber can enhance the effectiveness of this diabetes medication.

When taken simultaneously with metformin, Plantago ovata husk delayed the absorption of the drug, indicating that the timing of fiber intake can influence how quickly metformin enters the bloodstream.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Influence of Plantago ovata husk (dietary fiber) on the bioavailability and other pharmacokinetic parameters of metformin in diabetic rabbits. Díez, R., García, JJ., Diez, MJ., et al.[2018]

Dietary fibers like pectin and sodium alginate can significantly reduce the levels of the hypoglycemic agent biguanide in solution, indicating potential interactions that could affect drug efficacy.

Glimepiride levels were also reduced when mixed with certain dietary fibers, suggesting that the type of dietary fiber and the pH of the solution can influence the availability of these medications in the body.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Effect of Dietary Fiber on the Level of Free Hypoglycemic Agents in Vitro. Iwazaki, A., Imai, K.[2022]

In a study involving eight insulin-dependent diabetics, pure pectin significantly reduced post-meal blood glucose levels compared to a meal without any added fiber.

In contrast, a mixture of barley and citrus fiber (Dumovital) did not have the same effect on blood glucose control, highlighting the importance of selecting specific types of dietary fiber for managing diabetes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Effect of different kinds of fibre on postprandial blood glucose in insulin-dependent diabetics. Vaaler, S., Hanssen, KF., Aagenaes, O.[2019]

In a study involving groups of four to six volunteers, various types of dietary fibers were tested for their effects on blood glucose levels during glucose tolerance tests, with guar showing the most significant reduction in blood glucose and insulin levels.

The effectiveness of these fibers in controlling blood sugar was closely linked to their viscosity, suggesting that viscous fibers are the most beneficial for managing post-meal blood sugar spikes in diabetic treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Dietary fibres, fibre analogues, and glucose tolerance: importance of viscosity. Jenkins, DJ., Wolever, TM., Leeds, AR., et al.[2022]

In a study involving 12 healthy adults, the nonfermentable fiber UHV-HPMC significantly reduced post-meal blood glucose levels compared to a placebo, indicating its potential effectiveness in managing glycemic response.

While psyllium fiber also showed a trend towards lower glucose levels, it did not achieve statistical significance, and neither fiber had a lasting effect on blood glucose levels during the second meal.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Ultrahigh-viscosity hydroxypropylmethylcellulose blunts postprandial glucose after a breakfast meal in women. Dow, S., Pritchett, KL., Hawk, S., et al.[2019]

In a study involving 28 children and adolescents with obesity, metformin treatment led to significant reductions in weight, body mass index, waist circumference, and abdominal fat compared to placebo, indicating its efficacy in improving body composition.

While metformin improved insulin sensitivity in 45% of participants, the overall group analysis showed less clear benefits, suggesting that individual responses may vary, especially during puberty.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Randomized, controlled trial of metformin for obesity and insulin resistance in children and adolescents: improvement in body composition and fasting insulin. Srinivasan, S., Ambler, GR., Baur, LA., et al.[2022]

Metformin has been effectively used for 15 years to treat children with type 2 diabetes in the U.S., and its clinical applications in pediatrics are expanding, including potential uses in type 1 diabetes.

The medication's mechanisms of action are being better understood, particularly its effects on the gastrointestinal tract, which may contribute to its efficacy and safety profile.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Metformin; a review of its history and future: from lilac to longevity. Thomas, I., Gregg, B.[2018]

High-fiber diets, which include non-starchy vegetables, fruits, whole grains, legumes, and nuts, are linked to better body-weight regulation and increased feelings of fullness, making them potentially effective for preventing and treating obesity in children.

In addition to aiding in weight management, fiber-rich diets may also help prevent cardiovascular disease and type 2 diabetes, offering further health benefits beyond just weight control.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Dietary fiber and body-weight regulation. Observations and mechanisms. Pereira, MA., Ludwig, DS.[2022]

In the TODAY study involving 626 adolescents with type 2 diabetes, the combination of metformin and rosiglitazone (M + R) was more effective in maintaining glycemic control compared to metformin alone (M) or metformin plus lifestyle changes (M + L).

M + R led to a greater increase in both visceral adipose tissue (VAT) and subcutaneous adipose tissue (SAT) compared to the other treatment groups, but these changes did not explain the differences in glycemic control, indicating that the mechanism of action for rosiglitazone may differ in youth compared to adults.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Changes in Visceral and Subcutaneous Fat in Youth With Type 2 Diabetes in the TODAY Study. Dhaliwal, R., Shepherd, JA., El Ghormli, L., et al.[2020]

In a study of 129 obese children and adolescents with metabolic syndrome, metformin significantly reduced body mass index (BMI) and improved insulin resistance and glucose levels over two years.

Adding a polysaccharide complex (Policaptil Gel Retard®, PGR) to metformin treatment further enhanced weight loss and metabolic improvements, indicating that this combination may be more effective than metformin alone.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Retrospective Evaluation of Metformin and/or Metformin Plus a New Polysaccharide Complex in Treating Severe Hyperinsulinism and Insulin Resistance in Obese Children and Adolescents with Metabolic Syndrome. Stagi, S., Ricci, F., Bianconi, M., et al.[2018]

References

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

No Effect of Glucomannan on Body Weight Reduction in Children and Adolescents with Overweight and Obesity: A Randomized Controlled Trial. [2020]

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

Dietary fiber in management of diabetes. [2019]

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

High-fiber rye bread and insulin secretion and sensitivity in healthy postmenopausal women. [2022]

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

Combining sitagliptin/metformin with a functional fiber delays diabetes progression in Zucker rats. [2015]

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

Influence of Plantago ovata husk (dietary fiber) on the bioavailability and other pharmacokinetic parameters of metformin in diabetic rabbits. [2018]

6. Japan pubmed.ncbi.nlm.nih.gov

Effect of Dietary Fiber on the Level of Free Hypoglycemic Agents in Vitro. [2022]

7. Sweden pubmed.ncbi.nlm.nih.gov

Effect of different kinds of fibre on postprandial blood glucose in insulin-dependent diabetics. [2019]

8. England pubmed.ncbi.nlm.nih.gov

Dietary fibres, fibre analogues, and glucose tolerance: importance of viscosity. [2022]

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

Ultrahigh-viscosity hydroxypropylmethylcellulose blunts postprandial glucose after a breakfast meal in women. [2019]

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

Randomized, controlled trial of metformin for obesity and insulin resistance in children and adolescents: improvement in body composition and fasting insulin. [2022]

11. Denmark pubmed.ncbi.nlm.nih.gov

Metformin; a review of its history and future: from lilac to longevity. [2018]

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

Dietary fiber and body-weight regulation. Observations and mechanisms. [2022]

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

Changes in Visceral and Subcutaneous Fat in Youth With Type 2 Diabetes in the TODAY Study. [2020]

14. Switzerland pubmed.ncbi.nlm.nih.gov

Retrospective Evaluation of Metformin and/or Metformin Plus a New Polysaccharide Complex in Treating Severe Hyperinsulinism and Insulin Resistance in Obese Children and Adolescents with Metabolic Syndrome. [2018]