Fish Oil + Salsalate for Diabetic Neuropathy

Recruiting at 2 trial locations

Overseen By Rodica Pop-Busui, MD

Age: 18+

Sex: Any

Trial Phase: Phase 1 & 2

Sponsor: University of Iowa

Must not be taking: Anticoagulants, Uricosurics, Lithium, others

Disqualifiers: Other neuropathies, Uncontrolled hypertension, Organ transplant, others

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

Compensation: Varies

Number of Visits: 16

100 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial explores a potential treatment for diabetic peripheral neuropathy (DPN), a common complication of type 2 diabetes that can cause severe pain and other issues. Researchers are testing the effects of fish oil, known for its anti-inflammatory properties, both alone and combined with salsalate, a non-steroidal anti-inflammatory drug (NSAID). Participants will help determine the best combination of these treatments to boost beneficial omega-3 fatty acids and reduce inflammation. This trial may suit individuals with type 2 diabetes who experience DPN symptoms and are not currently taking fish oil supplements. As a Phase 1, Phase 2 trial, the research focuses on understanding how the treatment works in people and measuring its effectiveness in an initial, smaller group.

Do I need to stop my current medications to join the trial?

You may need to stop certain medications to join the trial. Specifically, you cannot use anticoagulants like warfarin or high-dose aspirin, and you must not have taken fish oil supplements in the past 6 months. Daily low-dose aspirin (up to 81 mg) can be continued if prescribed.

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

Research shows that fish oil is generally safe and well-tolerated. Studies have found that omega-3 fatty acids from fish oil can improve heart health in people with type 2 diabetes. Most side effects are mild, such as a fishy aftertaste or an upset stomach.

When combined with salsalate, a drug that reduces inflammation, early findings suggest fish oil might be safe and helpful for treating diabetic neuropathy, which is nerve damage caused by diabetes. Although human data on this combination is limited, early lab studies are promising. The combination may help the body produce more substances that reduce inflammation.

This study is in the early stages of clinical trials, focusing on finding the best dosages and ensuring safety. So far, the risks seem small compared to the possible benefits. Prospective participants should discuss their health conditions with their doctor before joining the trial. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Fish oil and salsalate treatments for diabetic neuropathy are unique because they combine omega-3 fatty acids with a non-steroidal anti-inflammatory drug, potentially offering a dual-action approach that differs from standard treatments like gabapentin or duloxetine. Researchers are excited about these treatments because omega-3s are known for their nerve-protecting and anti-inflammatory properties, which might address nerve pain and inflammation simultaneously. Additionally, salsalate has anti-inflammatory effects without the gastrointestinal side effects common in other NSAIDs, offering a potentially safer option for long-term use.

What evidence suggests that this trial's treatments could be effective for diabetic neuropathy?

Research has shown that fish oil, rich in omega-3 fatty acids, might help treat diabetic peripheral neuropathy (DPN). Studies on diabetic animals have found that omega-3s from fish oil can heal nerves and slow the progression of DPN. In this trial, some participants will receive fish oil capsules alone, while others will receive a combination of fish oil and salsalate, an anti-inflammatory medication. Early studies found that this combination not only slows DPN but also repairs nerve damage. This suggests that using fish oil and salsalate together could improve nerve health in people with DPN. ^{6 7 8 9 10}

Who Is on the Research Team?

Rodica Pop-Busui, MD

Principal Investigator

Professor of Medicine

Mark A Yorek, PhD

Principal Investigator

Professor of Medicine

Are You a Good Fit for This Trial?

Adults over 18 with type 2 diabetes and diabetic peripheral neuropathy can join this trial. They should have an HbA1c level below 9.5% and be willing to use contraception if necessary. People with other types of neuropathy, severe kidney issues, recent transplants, or certain medical conditions that could interfere with the study cannot participate.

Inclusion Criteria

Be willing and capable of providing a written consent form and willing and able to cooperate with the medical procedures for the study duration

Your HbA1c level is less than 9.5%.

You have diabetic peripheral neuropathy as determined by the Michigan Neuropathy Screening Instrument.

Exclusion Criteria

Presence of any condition that in the opinion of the investigators would make it unlikely for the participant to complete study

You are allergic to salsalate or any of the inactive ingredients in the medication.

Participation in an experimental medication trial within 3 months of starting the study

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment - Fish Oil

Participants receive 2g or 4g of fish oil capsules daily for 16 weeks

16 weeks

Regular visits for monitoring and assessments

Treatment - Fish Oil and Salsalate

Participants continue fish oil treatment and add 1.5g or 3g of salsalate daily for an additional 8 weeks

8 weeks

Regular visits for monitoring and assessments

Follow-up

Participants are monitored for safety and effectiveness after treatment

8 weeks

Visits at 16 and 24 weeks for outcome measures

What Are the Treatments Tested in This Trial?

Interventions

• Fish Oil Concentrate
• Salsalate Oral Tablet

Trial Overview The trial is testing whether taking fish oil capsules (rich in omega-3 fatty acids) alone or combined with salsalate tablets can help people with diabetic nerve pain by changing their blood lipid profile and increasing anti-inflammatory metabolites.

How Is the Trial Designed?

Group I: Fish oil capsules Experimental Treatment 1 Intervention

Subjects will be randomized for the treatment of fish oil capsules. Subjects will take daily supplements of two or four fish oil capsules per day, 2 and 4 g respectively. Treatment will continue for 16 weeks. Fish oil capsules are enriched in omega-3 polyunsaturated fatty acids.

Group II: Fish oil and Salsalate Experimental Treatment 2 Interventions

Salsalate is a non-steroid anti-inflammatory drug. Subjects taking 2 or 4g of fish oil capsules will be randomized to take in addition 1.5 or 3.0 g of salsalate per day. The combined treatment of fish oil and salsalate will continue for 8 weeks.

Fish Oil Concentrate is already approved in United States, European Union for the following indications:

Approved in United States as Lovaza for:

• Severe hypertriglyceridemia

Approved in European Union as Lovaza for:

• Severe hypertriglyceridemia

Approved in United States as Omtryg for:

• Severe hypertriglyceridemia

Approved in United States as Vascazen for:

• Omega-3 fatty acid deficiency in cardiovascular patients

Who Is Running the Clinical Trial?

University of Iowa

Lead Sponsor

Trials

486

Recruited

934,000+

University of Michigan

Collaborator

Trials

1,891

Recruited

6,458,000+

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

Collaborator

Trials

2,513

Recruited

4,366,000+

Oregon Health and Science University

Collaborator

Trials

1,024

Recruited

7,420,000+

Published Research Related to This Trial

In a study of 22 patients with distal diabetic polyneuropathy, those who received 360 mg of gamma-linolenic acid for 6 months showed significant improvements in neuropathy symptoms and nerve function compared to a placebo group.

Gamma-linolenic acid supplementation led to better scores in nerve conduction velocities and sensory nerve action potentials, suggesting it could be an effective treatment for managing diabetic neuropathy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The effect of gamma-linolenic acid on human diabetic peripheral neuropathy: a double-blind placebo-controlled trial. Jamal, GA., Carmichael, H.[2022]

Pre-clinical studies indicate that omega-3 fatty acids, particularly eicosapentaenoic and docosahexaenoic acids, can improve and potentially reverse nerve and blood vessel damage in diabetic rodents, suggesting a promising treatment for diabetic peripheral neuropathy.

Metabolites of omega-3 fatty acids, known as resolvins, have been shown to promote nerve growth in cell cultures and provide similar benefits for peripheral neuropathy in diabetic mice, highlighting their potential therapeutic role, although further clinical trials are necessary to confirm these effects in humans.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The Potential Role of Fatty Acids in Treating Diabetic Neuropathy. Yorek, MA.[2019]

In a study involving diabetic rats, a diet high in menhaden oil (up to 45% kcal) significantly improved vascular and neural function, showing the potential of fish oil in managing diabetes-related complications.

The combination of salsalate with lower amounts of menhaden oil enhanced vascular reactivity and nerve function more effectively than menhaden oil alone, although salsalate did not provide additional benefits at higher oil concentrations.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Effect of Dietary Content of Menhaden Oil with or without Salsalate on Neuropathic Endpoints in High-Fat-Fed/Low-Dose Streptozotocin-Treated Sprague Dawley Rats. Davidson, EP., Coppey, LJ., Shevalye, H., et al.[2019]

Evening primrose oil (EPO) significantly improves nerve function in diabetic rats, with effects seen within 7 days, indicating its potential efficacy in treating peripheral nerve dysfunction.

The active component responsible for EPO's benefits is di-linolein mono-gamma-linolenate (DLMG), and both DLMG and tri-gamma-linolenate (TGLA) showed similar effects, suggesting that the specific triglyceride structure of gamma-linolenic acid (GLA) is not critical for its therapeutic action.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Comparison of the effects of evening primrose oil and triglycerides containing gamma-linolenic acid on nerve conduction and blood flow in diabetic rats. Dines, KC., Cameron, NE., Cotter, MA.[2021]

In a study of 58 HIV-infected patients, low-dose salmon oil (3 g/day) significantly reduced triglyceride levels after 12 weeks of treatment, demonstrating its effectiveness in managing HAART-induced dyslipidemia.

The treatment was well-tolerated, with only mild nonserious adverse events reported in 33.3% of patients, indicating a favorable safety profile for salmon oil in this population.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Effectiveness and tolerability of oral administration of low-dose salmon oil to HIV patients with HAART-associated dyslipidemia. Baril, JG., Kovacs, CM., Trottier, S., et al.[2013]

In a study using a type 1 diabetes mouse model, treatments with salsalate, menhaden oil, and resolvin D1 showed effectiveness in reducing symptoms of diabetic neuropathy, such as slowed nerve conduction and reduced thermal sensitivity.

The combination of salsalate and menhaden oil not only alleviated neuropathic symptoms but also increased plasma levels of resolvin D1, suggesting a potential enhanced efficacy over individual treatments, warranting further investigation.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Effect of Treatment with Salsalate, Menhaden Oil, Combination of Salsalate and Menhaden Oil, or Resolvin D1 of C57Bl/6J Type 1 Diabetic Mouse on Neuropathic Endpoints. Yorek, MS., Coppey, LJ., Shevalye, H., et al.[2022]

In a study using diabetic mice, treatment with deep sea fish oil significantly improved memory and exploration abilities compared to untreated diabetic mice, suggesting its potential therapeutic effects on neurosensory impairment.

Fish oil also reduced oxidative stress, as indicated by lower malondialdehyde levels and increased antioxidant levels in the brain tissue of treated mice, highlighting its role in protecting against nerve damage caused by diabetes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Beneficial effects of deep sea fish oil on diabetic mice neurological injury. Qiao, Z., Chen, Y., Zhang, Y., et al.[2018]

Omega-3 polyunsaturated fatty acids (ω-3 PUFAs), including fish oil, eicosapentaenoic acid (EPA), and docosahexaenoic acid (DHA), significantly reduced mechanical allodynia in diabetic rats without affecting blood sugar levels or weight gain, indicating their potential as a safe treatment for diabetic neuropathic pain.

The antinociceptive effects of ω-3 PUFAs were sustained with sub-chronic treatment and were shown to involve the activation of central μ-opioid receptors, suggesting a specific mechanism of action for pain relief.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Acute antinociceptive effect of fish oil or its major compounds, eicosapentaenoic and docosahexaenoic acids on diabetic neuropathic pain depends on opioid system activation. Redivo, DDB., Jesus, CHA., Sotomaior, BB., et al.[2020]

In a study of 56 patients with different types of hyperlipidemia, salmon-oil capsules effectively reduced triglyceride levels in those with hypertriglyceridemia and mixed hyperlipidemia, but increased cholesterol levels in patients with hypercholesterolemia.

The increase in malondialdehyde, a marker of lipid peroxidation, suggests that antioxidant supplementation may be needed during salmon-oil treatment, indicating potential side effects that require further investigation before recommending widespread use.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Effect of olive oil and fish oil on parameters of lipids and antioxidants in hyperlipoproteinemia]. Reuter, W., Vorberg, B., Krumpolt, K., et al.[2019]

Citations

1. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/28530530/

Is Fish Oil a Potential Treatment for Diabetic Peripheral ... Existing data suggests that dietary enrichment with omega-3 fatty acids contained in fish oil may be beneficial treatment for diabetic neuropathy.

2. reporter.nih.gov reporter.nih.gov/project-details/10854778

Omega-3 Polyunsaturated Fatty Acids in the ... - NIH RePORTER Our studies have demonstrated that treating diabetic rodents with DPN with omega-3 polyunsaturated fatty acids (PUFA) derived from menhaden (fish) oil initiates ...

3. clinicaltrials.gov clinicaltrials.gov/study/NCT05169060

Omega-3 Fatty Acid Lipidomics in Diabetes Peripheral ... The human subject study to be performed will examine the effect of fish oil with and without salsalate on the blood lipid profile and circulating metabolites of ...

4. mdpi.com mdpi.com/2227-9059/13/7/1607

Omega-3 Polyunsaturated Fatty Acids (PUFAs) and ... Fatty acid composition of the diets, serum and liver were measured after the lipid fraction was extracted using chloroform/methanol, followed by ...

5. sciencedirect.com sciencedirect.com/science/article/pii/S0022316623019077

Fish Oil Supplementation Prevents Diabetes-Induced ... The aim of this study was to evaluate the potential effect of a dietary supplementation with fish oil [(n-3) fatty acids] on the sciatic nerve of diabetic rats.

6. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC12292556/

Omega-3 Polyunsaturated Fatty Acids (PUFAs) and ... Conclusions: We confirm that omega-3 PUFAs are an effective treatment for DPN and sources other than fish oil are similarly effective. Keywords: ...

7. mayoclinic.org mayoclinic.org/drugs-supplements/omega-3-acid-ethyl-esters-oral-route/description/drg-20066973

Omega-3-acid ethyl esters (oral route) - Side effects & ... Omega-3-acid ethyl esters are used together with a proper diet to lower very high triglyceride (fat-like substance) levels in the blood.

8. webmd.com webmd.com/vitamins/ai/ingredientmono-993/fish-oil

Fish Oil: Uses, Side Effects and More Fish oil comes from many types of fish. It is rich in two important omega-3 fatty acids called eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA).

9. diabetesjournals.org diabetesjournals.org/diabetes/article/70/8/1794/137901/Investigating-the-Neuroprotective-Effect-of-Oral

Investigating the Neuroprotective Effect of Oral Omega-3 Fatty ... Safety assessments included diabetic retinopathy grade and adverse events. Between July 2017 and September 2019, 43 participants received n-3 (n ...

10. sciencedirect.com sciencedirect.com/science/article/abs/pii/S0952327822000680

The effects of omega-3 fatty acids in type 2 diabetes The results of this systematic review suggest that n-3 PUFAs can improve cardiovascular risk factors in type 2 diabetes.