Lifestyle Changes + Metformin for Frailty in Obese Seniors

(DEMFOS Trial)

Overseen By Arjun Paudyal, MS

Age: 65+

Sex: Any

Trial Phase: Phase 3

Sponsor: VA Office of Research and Development

Must be taking: Metformin

Must not be taking: Bone acting drugs

Disqualifiers: Diabetes, Cardiopulmonary disease, Renal impairment, others

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: Unknown

Duration: 6 months

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial explores how combining lifestyle changes with metformin (a medication commonly used to treat type 2 diabetes) can reduce frailty and improve health in older individuals who are obese. Researchers aim to determine if this combination is more effective than lifestyle changes alone or a healthy lifestyle paired with metformin. It is ideal for seniors dealing with obesity, who are not very active, and have maintained a stable weight recently. Participants should be ready to commit to diet changes and exercise as part of the study. As a Phase 3 trial, this study represents the final step before FDA approval, offering a chance to contribute to a potentially groundbreaking treatment.

Do I have to stop taking my current medications for the trial?

The trial protocol does not specify if you need to stop taking your current medications. However, you cannot participate if you are taking metformin, any other glucose-lowering drugs, or bone-acting drugs like estrogen or bisphosphonates.

Will I have to stop taking my current medications?

The trial requires that participants do not take metformin or any other glucose-lowering drugs. If you are currently taking these medications, you would need to stop before joining the trial.

Is there any evidence suggesting that this trial's treatments are likely to be safe?

Research has shown that metformin is generally safe and well-tolerated. One study found that metformin may lower the risk of frailty in older adults with diabetes, suggesting it could help reduce frailty. Another study demonstrated that metformin is safe for long-term use and can aid in weight loss, with effects lasting at least 10 years.

Metformin is often used to prevent diabetes and is considered safe for this purpose. This trial also includes lifestyle changes like diet and exercise, which are usually safe and aim to improve overall health.

Overall, evidence suggests that metformin, when combined with lifestyle changes, is safe for older adults dealing with obesity. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about these treatments because they combine lifestyle changes with Metformin, a medication typically used for diabetes, to tackle frailty in obese seniors. Unlike standard care options that might focus solely on lifestyle modifications or medications for weight loss, this approach uses Metformin to potentially enhance the effects of diet and exercise. Metformin is known for its role in improving insulin sensitivity and metabolic health, which could offer additional benefits in reducing frailty. By integrating a proven medication with lifestyle therapy, this treatment has the potential to improve mobility and overall health more effectively than either strategy alone.

What evidence suggests that this trial's treatments could be effective for frailty in obese seniors?

Research has shown that combining lifestyle changes with the medication metformin may help reduce frailty in older adults. In this trial, participants will join different treatment arms to evaluate these approaches. One study found that people with diabetes who took metformin were less likely to become frail, suggesting that metformin might also help reduce frailty in those without diabetes. Additionally, lifestyle changes like healthy eating and regular exercise are known to aid weight loss and improve overall health. Together, these approaches could effectively address muscle loss, obesity, and frailty in older adults. ^{1 2 5 6 7}

Who Is on the Research Team?

Dennis T Villareal, MD

Principal Investigator

Michael E. DeBakey VA Medical Center, Houston, TX

Are You a Good Fit for This Trial?

This trial is for sedentary obese seniors with a BMI of 30 or higher who've maintained a stable weight recently and are willing to consent. It's not for those on glucose-lowering drugs, with severe cardiopulmonary disease, renal impairment, uncontrolled hypertension, recent cancer (except skin), using bone drugs, osteoporosis sufferers, diabetics, terminal illness patients or those with conditions that limit exercise/diet/metformin use.

Inclusion Criteria

BMI = or > 30 kg/m2

Sedentary (regular exercise <1 h/wk or <2 x/wk for the last 6 months)

Stable body weight (plus/minus 2 kg) during the past 6 months

Exclusion Criteria

My kidney function is low, and I cannot take metformin.

I have not had any cancer except for non-melanoma skin cancer in the last 5 years.

Lives outside of the study site or is planning to move out of the area in the next 2 years

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive lifestyle therapy (diet-induced weight loss and exercise training) plus metformin or placebo for six months

6 months

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

What Are the Treatments Tested in This Trial?

Interventions

• Lifestyle therapy
• Metformin Hydrochloride

Trial Overview The study tests if combining lifestyle therapy (diet and exercise) with metformin is more effective than diet and exercise alone in reversing frailty due to obesity in older adults. Participants will be randomly assigned to receive either the drug plus lifestyle changes or a placebo alongside the same lifestyle interventions.

How Is the Trial Designed?

Group I: Lifestyle Therapy plus Metformin Experimental Treatment 2 Interventions

Diet-induced weight loss and Exercise Training plus Metformin 1500 mg daily

Group II: Healthy lifestyle plus Metformin Active Control 2 Interventions

Healthy lifestyle and Metformin 1500 mg daily

Group III: Lifestyle Therapy plus Placebo Placebo Group 2 Interventions

Diet-induced weight loss and Exercise Training plus Placebo

Lifestyle therapy is already approved in United States, European Union for the following indications:

Approved in United States as Lifestyle therapy for:

• Childhood obesity
• Weight management

Approved in European Union as Lifestyle therapy for:

• Childhood obesity
• Weight management

Who Is Running the Clinical Trial?

VA Office of Research and Development

Lead Sponsor

Trials

1,691

Recruited

3,759,000+

Michael E. DeBakey VA Medical Center

Collaborator

Trials

68

Recruited

17,200+

Baylor College of Medicine

Collaborator

Trials

1,044

Recruited

6,031,000+

Published Research Related to This Trial

In a study of veterans aged 65 and older with type 2 diabetes, metformin exposure was linked to a significantly lower risk of frailty, with an adjusted odds ratio of 0.55, indicating a protective effect.

The study included 783 veterans, with a frailty index constructed from 44 variables, highlighting that nearly half of the participants were classified as frail, emphasizing the importance of managing frailty in this population.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Is There an Association Between Metformin Exposure and Frailty? Baskaran, D., Aparicio-Ugarriza, R., Ferri-Guerra, J., et al.[2020]

In a long-term follow-up study of 2,979 adults with type 2 diabetes, the prevalence of frailty was similar between those who received a multidomain intensive lifestyle intervention (ILI) and those who received diabetes support and education (DSE), with rates of 10.9% and 11.6% respectively after a median follow-up of 14 years.

Factors such as older age, female gender, non-White ethnicity, lower socioeconomic status, and higher baseline body mass index were associated with a higher prevalence of frailty, indicating that these demographic and health factors may play a significant role in frailty among older adults with obesity and diabetes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The Association of Prior Intensive Lifestyle Intervention and Diabetes Support and Education With Frailty Prevalence at Long-Term Follow-Up in the Action for Health in Diabetes Extension Study. [2022]

A systematic review of 11 randomized clinical trials involving individuals with prediabetes and type 2 diabetes found that intensive lifestyle interventions did not significantly reduce cardiovascular or all-cause mortality compared to usual care.

The analysis showed no differences in outcomes based on the type of intervention or other factors, indicating that current lifestyle interventions may not provide additional mortality benefits for this population.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Long-term Effect of Lifestyle Interventions on the Cardiovascular and All-Cause Mortality of Subjects With Prediabetes and Type 2 Diabetes: A Systematic Review and Meta-analysis. Zucatti, KP., Teixeira, PP., Wayerbacher, LF., et al.[2023]

In a 30-month follow-up study of 16 frail, obese older adults, significant long-term weight loss was maintained after a 1-year lifestyle intervention, with weight dropping from 101.5 kg to 94.5 kg and BMI from 36.0 to 33.5 kg/m².

Improvements in physical performance, insulin sensitivity, and reduced waist circumference and blood pressure were sustained, indicating that lifestyle changes can lead to lasting health benefits without adverse effects on liver or renal function.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Long-term maintenance of weight loss after lifestyle intervention in frail, obese older adults. Waters, DL., Vawter, R., Qualls, C., et al.[2022]

In a study of 6,758 matched patients with type 2 diabetes, those on DPP-4 inhibitors showed slightly better adherence (65.5%) and persistence (52.5%) compared to those on sulfonylureas (63.3% adherence and 48.0% persistence) over 12 months.

Patients on sulfonylureas were more likely to remain untreated after discontinuation of their initial therapy, while those on DPP-4 inhibitors were more likely to use multiple oral antidiabetic drugs, indicating different treatment progression patterns between the two groups.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Treatment progression in sulfonylurea and dipeptidyl peptidase-4 inhibitor cohorts of type 2 diabetes patients on metformin. Peng, X., Jiang, D., Liu, D., et al.[2020]

A randomized clinical trial involving 694 patients with diabetes showed that a multicomponent intervention improved adherence to the Mediterranean diet but did not significantly affect glycemic control (HbA1c) or other lifestyle factors like physical activity and smoking cessation.

Despite the lack of overall significant changes in health outcomes, the study highlights the potential of dietary interventions, suggesting that further research is needed to explore their effectiveness in managing diabetes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Effectiveness of a Multicomponent Intervention in Primary Care That Addresses Patients with Diabetes Mellitus with Two or More Unhealthy Habits, Such as Diet, Physical Activity or Smoking: Multicenter Randomized Cluster Trial (EIRA Study). Represas-Carrera, F., Couso-Viana, S., Méndez-López, F., et al.[2021]

Older adults with diabetes face increased risks of frailty and cognitive impairment due to shared mechanisms like insulin resistance and chronic inflammation, highlighting the need for targeted interventions.

Nutritional therapy, combined with exercise and social support, is essential for preventing frailty in older adults with diabetes, emphasizing the importance of proper glycemic control and a healthy diet to extend healthy life expectancy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Nutrition Management in Older Adults with Diabetes: A Review on the Importance of Shifting Prevention Strategies from Metabolic Syndrome to Frailty. Tamura, Y., Omura, T., Toyoshima, K., et al.[2021]

Metformin is the first-line treatment for type 2 diabetes but often has limited efficacy over time, leading to the need for additional medications due to its gastrointestinal side effects and contraindications in certain patients.

Incretin-based therapies, particularly GLP-1 receptor agonists, are emerging as effective add-on treatments that can help achieve glycemic control while potentially offering cardiovascular benefits and improving β-cell function.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pharmacological management of type 2 diabetes: the potential of incretin-based therapies. Charbonnel, B., Cariou, B.[2022]

The Active Steps for Diabetes (ASD) program effectively reduced blood glucose levels (A1C) and frailty in 50 older women with type 2 diabetes, regardless of whether they used a walking aid.

Participants using a walking aid experienced a greater reduction in frailty, highlighting the program's adaptability and potential to enhance physical activity among frail older adults.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Active steps for diabetes: a community-campus partnership addressing frailty and diabetes. Pariser, G., Hager, K., Gillette, P., et al.[2022]

Older adults with diabetes should have their treatment goals adjusted based on their level of frailty, as they are more susceptible to complications like hypoglycemia, which can lead to serious health issues such as falls and hospitalizations.

There is a common trend of over-treatment in older adults with type 2 diabetes, often leading to unnecessary intensification of therapy; therefore, simplifying or de-escalating treatment regimens is recommended to improve safety and adherence, particularly for those at higher risk of hypoglycemia.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Diabetes and Frailty: An Expert Consensus Statement on the Management of Older Adults with Type 2 Diabetes. Strain, WD., Down, S., Brown, P., et al.[2021]

Citations

1. clinicaltrials.gov clinicaltrials.gov/study/NCT04221750

Diet and Exercise Plus Metformin to Treat Frailty in Obese ... The clinical trial will test the central hypothesis that a multicomponent intervention consisting of lifestyle therapy (diet-induced weight loss and exercise ...

2. withpower.com withpower.com/trial/phase-3-obesity-2-2021-3f37c

Lifestyle Changes + Metformin for Frailty in Obese Seniors One study found that exposure to metformin was linked to a lower risk of frailty in older adults with diabetes, suggesting that metformin helps reduce frailty.

3. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC1360736/

Within-Trial Cost-Effectiveness of Lifestyle Intervention or ... The aim of this study was to assess the cost-effectiveness of the lifestyle and metformin interventions relative to the placebo intervention.

4. ctv.veeva.com ctv.veeva.com/study/diet-and-exercise-plus-metformin-to-treat-frailty-in-obese-seniors

Diet and Exercise Plus Metformin to Treat Frailty in Obese ... The clinical trial will test the central hypothesis that a multicomponent intervention consisting of lifestyle therapy (diet-induced weight loss ...

5. ccjm.org ccjm.org/content/90/9/545

Should I consider metformin therapy for weight loss in ... In the DPP trial, the incidence of diabetes was 58% lower (95% CI 48% to 66%) in the lifestyle intervention group and 31% lower (95% CI 17% to ...

6. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC3308305/

Long-Term Safety, Tolerability, and Weight Loss Associated ... Metformin used for diabetes prevention is safe and well tolerated. Weight loss is related to adherence to metformin and is durable for at least 10 years of ...

7. grantome.com grantome.com/grant/NIH/I01-CX002161-01

Lifestyle Intervention plus Metformin to Treat Frailty in Older ... We reported not only that frailty is common in obese older adults due to sarcopenic obesity but also that lifestyle therapy resulting in weight loss in this ...