Fish Oil + Salsalate for Diabetic Neuropathy

Recruiting at 1 trial location

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

Trial Summary

What is the purpose of this trial?

Diabetic peripheral neuropathy (DPN) is the most common chronic complication of diabetes, affecting about 50% of patients with diabetes and leading to severe morbidity, poor quality of life, high mortality, and high health care costs. Due to the complex structure and anatomy of the peripheral nervous system, DPN presents with a very broad spectrum of clinical symptoms and deficits, including severe pain, sensory deficits, foot ulcers and amputations. Presently there is no treatment for DPN and even with good blood glucose control DPN develops especially in patients with type 2 diabetes. There is a need to identify effective interventions for DPN. Preclinical studies have provided evidence that the combination of fish oil and salsalate is an effective treatment of DPN. 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 omega-3 polyunsaturated fatty acids (PUFA). Fish oil is an excellent source for the nutrition dependent omega-3 PUFA, primarily eicosapentaenoic acid (EPA; 20:5) and docosahexaenoic acid (DHA; 22:6). These fatty acids are the source of anti-inflammatory metabolites known as resolvin, neuroprotectin and maresin. Preclinical studies have also demonstrated that the metabolites of EPA and DHA are neuroprotective. Furthermore, when fish oil is combined with salsalate the production of these metabolites is increased in vivo. Thus, the investigators hypothesize that fish oil and salsalate will be an effective therapy of DPN. However, prior to doing a formal study of the effect of fish oil + salsalate on DPN there is a need to learn more about what concentration combination will provide the most efficacious effect on the omega-3 index (defined as the sum of EPA and DHA, as a percentage of total fatty acids in red blood cells) and that will safely increase the production of the anti-inflammatory metabolites. These studies will be performed at two sites the University of Iowa (Dr. Yorek) and University of Michigan (Dr. Pop-Busui) by treating human subjects with type 2 diabetes and DPN with either 2g or 4g of fish oil per day (capsules) for 4 months and then adding salsalate 1.5 g or 3g per day (tablets) to the fish oil treatments for an additional 2 months. At baseline and after treatment with fish oil alone and after treatment with the combination of fish oil and salsalate the omega-3 index and levels of circulating omega-3 PUFA metabolites will be determined as primary endpoints. Secondary endpoints will include determination of circulatory inflammatory markers and non-invasive measurements for DPN. The risks to subjects are minimal and are very reasonable in relation to the importance of the knowledge to be gained.

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.

What data supports the effectiveness of the drug Fish Oil + Salsalate for diabetic neuropathy?

Research on diabetic rats and mice suggests that combining fish oil with salsalate can improve nerve function and reduce symptoms of diabetic neuropathy more effectively than using fish oil alone. This combination was shown to protect nerve and blood vessel function, which are often impaired in diabetes. ^{1 2 3 4 5}

Is the combination of fish oil and salsalate safe for humans?

Research on animals suggests that fish oil and salsalate may help with nerve and blood vessel issues related to diabetes, but more studies are needed to confirm their safety and effectiveness in humans. ^{1 2 6 7 8}

How does the drug Fish Oil + Salsalate differ from other treatments for diabetic neuropathy?

The combination of fish oil and salsalate is unique because it may offer greater benefits for diabetic neuropathy by improving nerve function and reducing inflammation more effectively than using either component alone. This combination also increases levels of resolvin D1, a compound that helps resolve inflammation, which is not typically achieved with other treatments. ^{1 2 4 7 9}

Research Team

Mark A Yorek, PhD

Principal Investigator

Professor of Medicine

Rodica Pop-Busui, MD

Principal Investigator

Professor of Medicine

Eligibility Criteria

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

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

Treatment Details

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.

Participant Groups

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+

Findings from Research

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]

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 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]

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 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 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]

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]

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]

References

1. England 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. [2019]

2. United States 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. [2022]

3. England pubmed.ncbi.nlm.nih.gov

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

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

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

5. Netherlands 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. [2020]

6. England pubmed.ncbi.nlm.nih.gov

Effectiveness and tolerability of oral administration of low-dose salmon oil to HIV patients with HAART-associated dyslipidemia. [2013]

7. France pubmed.ncbi.nlm.nih.gov

Beneficial effects of deep sea fish oil on diabetic mice neurological injury. [2018]

8. Germany pubmed.ncbi.nlm.nih.gov

[Effect of olive oil and fish oil on parameters of lipids and antioxidants in hyperlipoproteinemia]. [2019]

9. United States 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. [2021]