Oxidative Stress Impact on Vascular Function After Gestational Diabetes

Overseen By Anna Reid-Stanhewicz, PHD

Age: 18 - 65

Sex: Female

Trial Phase: Phase < 1

Sponsor: Anna Stanhewicz, PhD

Must not be taking: Statins, Antihypertensives

Disqualifiers: Skin diseases, Tobacco use, Diabetes, others

Approved in 6 Jurisdictions This treatment is already approved in other countries

Compensation: Varies

Number of Visits: 1

28 Participants Needed

Trial Summary

Will I have to stop taking my current medications?

If you are currently taking statins, other cholesterol-lowering medications, or antihypertensive medications, you will need to stop taking them to participate in this trial.

What data supports the effectiveness of the drug for oxidative stress impact on vascular function after gestational diabetes?

Research shows that insulin aspart, a component of the drug, is effective in managing blood sugar levels in people with diabetes, including gestational diabetes. This suggests it may help improve vascular function by controlling blood sugar levels, which can reduce oxidative stress. ^{1 2 3 4 5}

Is insulin aspart safe for human use?

Insulin aspart, including its biosimilar versions like SAR341402, has been shown to be generally safe for human use in people with diabetes. Studies have demonstrated similar safety profiles, including low rates of adverse events and immunogenicity (the body's immune response to the drug), when compared to the original insulin aspart products like NovoLog and NovoRapid. ^{1 2 4 6 7}

How does the drug Insulin Aspart differ from other treatments for gestational diabetes?

Insulin Aspart is a fast-acting insulin that helps control blood sugar levels by mimicking the body's natural insulin response, which may be beneficial for managing gestational diabetes. Unlike other treatments, it specifically targets insulin-mediated vasorelaxation (widening of blood vessels) and may help improve vascular function affected by oxidative stress in women with a history of gestational diabetes. ^{8 9 10 11 12}

What is the purpose of this trial?

The purpose of this investigation is to examine the role of oxidative stress in aberrant microvascular function in otherwise healthy women with a history of GDM.

Eligibility Criteria

This trial is for healthy women aged 18-50 who had gestational diabetes within the last 5 years, as confirmed by ACOG criteria. It's not for those with liver or metabolic diseases, skin conditions, a history of preeclampsia or hypertension during pregnancy, current pregnancy, underweight individuals (BMI <18.5), latex allergies, drug allergies to study medications, statin users, smokers or e-cigarette users.

Inclusion Criteria

Female sex

You have been pregnant in the last 5 years.

You have never had gestational diabetes during a pregnancy.

Exclusion Criteria

Skin conditions

You have had preeclampsia or high blood pressure during pregnancy.

Current pregnancy

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Study Visit

Participants undergo microdialysis and endothelial cell collection to assess microvascular function and oxidative stress markers

1 day

1 visit (in-person)

Follow-up

Participants are monitored for any adverse effects and overall health status after the study visit

4 weeks

Treatment Details

Interventions

• Acetylcholine
• Insulin Aspart

Trial Overview The study is looking at how oxidative stress affects small blood vessel function in women who've had gestational diabetes. Participants will receive Acetylcholine and insulin aspart to see if these can improve vascular function by reducing oxidative stress.

Participant Groups

Group I: local ascorbate perfusion Experimental Treatment 2 Interventions

local ascorbate is perfused through the microdialysis fiber to serve as the antioxidant experimental treatment

Group II: local L-NAME perfusion Experimental Treatment 2 Interventions

local L-NAME is perfused through the microdialysis fiber to inhibit nitric oxide synthase

Group III: local lactated Ringer's perfusion Placebo Group 2 Interventions

lactated Ringer's is perfused through the microdialysis fiber to serve as the vehicle control

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

Approved in United States as NovoLog for:

• Type 1 Diabetes Mellitus
• Type 2 Diabetes Mellitus

Approved in European Union as Fiasp for:

• Type 1 Diabetes Mellitus
• Type 2 Diabetes Mellitus

Approved in Canada as NovoLog for:

• Type 1 Diabetes Mellitus
• Type 2 Diabetes Mellitus

Approved in Japan as NovoLog for:

• Type 1 Diabetes Mellitus
• Type 2 Diabetes Mellitus

Approved in China as NovoLog for:

• Type 1 Diabetes Mellitus
• Type 2 Diabetes Mellitus

Approved in Switzerland as NovoLog for:

• Type 1 Diabetes Mellitus
• Type 2 Diabetes Mellitus

Who Is Running the Clinical Trial?

Anna Stanhewicz, PhD

Lead Sponsor

Trials

12

Recruited

460+

Findings from Research

In a 52-week study involving 597 adults with type 1 or type 2 diabetes, the biosimilar SAR341402 insulin aspart (SAR-Asp) demonstrated similar efficacy to the originator insulin aspart (NN-Asp) in reducing hemoglobin A1c (HbA1c) levels, regardless of whether participants switched from NovoLog/NovoRapid or Humalog/Liprolog.

Both SAR-Asp and NN-Asp showed comparable safety profiles, with similar rates of hypoglycemia, adverse events, and immunogenicity, indicating that SAR-Asp is a safe and effective alternative to NN-Asp for managing diabetes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Efficacy, Safety, and Immunogenicity of Insulin Aspart Biosimilar SAR341402 Compared with Originator Insulin Aspart in Adults with Diabetes (GEMELLI 1): A Subgroup Analysis by Prior Type of Mealtime Insulin. Shah, VN., Franek, E., Wernicke-Panten, K., et al.[2021]

SAR341402, a biosimilar insulin aspart, demonstrated stable insulin content and no significant impurities during a 13-day evaluation in insulin pump systems under stress conditions.

The study found that SAR341402 showed similar physicochemical stability to other insulin aspart products, with no occlusion events and acceptable levels of preservatives, making it a safe option for continuous subcutaneous insulin infusion.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

In vitro Stability of Biosimilar Insulin Aspart SAR341402 in the Medtronic MiniMed Insulin Pumps. Mohnicke, M., Blecher, A., Beichert, K., et al.[2023]

In a study of 15 women with gestational diabetes mellitus (GDM), insulin aspart was found to provide better post-meal blood sugar control compared to regular human insulin, as indicated by significantly lower glucose levels after meals.

Insulin aspart resulted in higher peak insulin concentrations and reduced the need for the body to produce its own insulin, suggesting it may be a more effective option for managing GDM in women who require insulin therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Comparison of an insulin analog, insulin aspart, and regular human insulin with no insulin in gestational diabetes mellitus. Pettitt, DJ., Ospina, P., Kolaczynski, JW., et al.[2019]

A study involving 30 adult males with type 1 diabetes showed that SAR341402, a biosimilar insulin aspart, has similar pharmacokinetic and pharmacodynamic profiles to both NovoLog and NovoRapid, indicating it works similarly in the body.

All three insulin treatments demonstrated comparable effectiveness in managing blood sugar levels, with SAR341402 being well tolerated, suggesting it could be a viable alternative to existing insulin products.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Single-Dose Euglycemic Clamp Study Demonstrating Pharmacokinetic and Pharmacodynamic Similarity Between SAR341402 Insulin Aspart and US- and EU-Approved Versions of Insulin Aspart in Subjects with Type 1 Diabetes. Kapitza, C., Nosek, L., Schmider, W., et al.[2021]

Long-acting insulin analogues for managing gestational diabetes mellitus (GDM) resulted in lower HbA1c levels during the second and third trimesters compared to intermediate acting NPH insulin, indicating better blood sugar control.

Despite the improved glycemic control, there were no significant differences in maternal or neonatal outcomes, such as birth weight, perinatal mortality, or complications, suggesting that long-acting insulin analogues are a safe alternative to NPH for GDM management.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Maternal and neonatal outcomes with the use of long acting, compared to intermediate acting basal insulin (NPH) for managing diabetes during pregnancy: a systematic review and meta-analysis. Wang, J., Ji, X., Liu, T., et al.[2022]

In a pilot study involving 19 adults using the MiniMed™ 670G system, both Novolog® and Fiasp® insulin showed similar effectiveness in managing blood sugar levels, with no significant differences in time spent within the target glucose range or hypoglycemia rates.

Fiasp® required a slightly higher daily insulin dose compared to Novolog®, but both insulins resulted in comparable glycemic outcomes, indicating that either can be effectively used in a hybrid closed-loop system.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Fast-Acting Insulin Aspart Use with the MiniMedTM 670G System. Hsu, L., Buckingham, B., Basina, M., et al.[2022]

In a 12-month study involving 597 participants with type 1 and type 2 diabetes, SAR341402 (SAR-Asp) showed sustained glycemic control similar to that of the originator insulin aspart (NN-Asp), with comparable reductions in HbA1c levels.

Both SAR-Asp and NN-Asp exhibited similar safety profiles, including rates of hypoglycemia and immunogenicity, indicating that SAR-Asp is a safe and effective alternative to NN-Asp for insulin therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Safety, Immunogenicity, and Glycemic Control of Insulin Aspart Biosimilar SAR341402 Versus Originator Insulin Aspart in People with Diabetes Also Using Insulin Glargine: 12-Month Results from the GEMELLI 1 Trial. Garg, SK., Wernicke-Panten, K., Wardecki, M., et al.[2022]

In pregnant women, insulin effectively reduces vasoconstriction caused by noradrenaline, indicating that its vasodilatory effects remain intact despite the presence of insulin resistance during pregnancy.

The study found that this insulin-mediated vasorelaxation occurs through an endothelium-independent mechanism, suggesting that normal physiological insulin resistance in pregnancy does not lead to the vascular dysfunction seen in diabetes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Insulin-mediated vasorelaxation in pregnancy. Ang, C., Hillier, C., MacDonald, A., et al.[2019]

Women with gestational diabetes showed significantly poorer vascular relaxation in small arteries compared to normotensive nondiabetic pregnant women, indicating endothelial dysfunction.

The study suggests that this dysfunction may be due to a deficiency in dilator prostaglandin synthesis, which could contribute to higher cardiovascular risks in women with gestational diabetes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Association of gestational diabetes with abnormal maternal vascular endothelial function. Knock, GA., McCarthy, AL., Lowy, C., et al.[2019]

Women with gestational diabetes mellitus (GDM) showed significant alterations in markers of endothelial dysfunction, including decreased endothelial progenitor cell counts and increased soluble adhesion molecules, indicating a higher risk of vascular issues.

The study found that the molecular changes associated with oxidative stress in women with GDM and their fetuses resemble those seen in non-pregnant adults with type 2 diabetes, suggesting similar underlying mechanisms of endothelial dysfunction.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Alteration of endothelial function markers in women with gestational diabetes and their fetuses. Mordwinkin, NM., Ouzounian, JG., Yedigarova, L., et al.[2021]

Women with a history of gestational diabetes mellitus (GDM) show significantly reduced microvascular endothelial function compared to women with uncomplicated pregnancies, indicating a potential mechanism for their increased risk of cardiovascular disease and type 2 diabetes.

Oxidative stress appears to play a key role in this dysfunction, as the administration of l-ascorbate improved endothelial and nitric oxide-dependent dilation in women with GDM, suggesting that targeting oxidative stress may help mitigate these risks.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Oxidative stress contributes to reductions in microvascular endothelial- and nitric oxide-dependent dilation in women with a history of gestational diabetes. Stanhewicz, AE., Schlarmann, RL., Brustkern, KM., et al.[2023]

In a study of 248 singleton pregnancies, strong positive correlations were found between maternal and cord plasma biomarkers of oxidative stress, indicating that oxidative stress in mothers may impact fetal health.

The research suggests that oxidative stress negatively correlates with cord plasma ghrelin levels, which could have implications for fetal metabolic health and the risk of developing metabolic disorders later in life.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Perinatal Oxidative Stress May Affect Fetal Ghrelin Levels in Humans. Luo, ZC., Bilodeau, JF., Nuyt, AM., et al.[2018]

References

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

Efficacy, Safety, and Immunogenicity of Insulin Aspart Biosimilar SAR341402 Compared with Originator Insulin Aspart in Adults with Diabetes (GEMELLI 1): A Subgroup Analysis by Prior Type of Mealtime Insulin. [2021]

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

In vitro Stability of Biosimilar Insulin Aspart SAR341402 in the Medtronic MiniMed Insulin Pumps. [2023]

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

Comparison of an insulin analog, insulin aspart, and regular human insulin with no insulin in gestational diabetes mellitus. [2019]

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

Single-Dose Euglycemic Clamp Study Demonstrating Pharmacokinetic and Pharmacodynamic Similarity Between SAR341402 Insulin Aspart and US- and EU-Approved Versions of Insulin Aspart in Subjects with Type 1 Diabetes. [2021]

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

Maternal and neonatal outcomes with the use of long acting, compared to intermediate acting basal insulin (NPH) for managing diabetes during pregnancy: a systematic review and meta-analysis. [2022]

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

Fast-Acting Insulin Aspart Use with the MiniMedTM 670G System. [2022]

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

Safety, Immunogenicity, and Glycemic Control of Insulin Aspart Biosimilar SAR341402 Versus Originator Insulin Aspart in People with Diabetes Also Using Insulin Glargine: 12-Month Results from the GEMELLI 1 Trial. [2022]

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

Insulin-mediated vasorelaxation in pregnancy. [2019]

9. England pubmed.ncbi.nlm.nih.gov

Association of gestational diabetes with abnormal maternal vascular endothelial function. [2019]

10. England pubmed.ncbi.nlm.nih.gov

Alteration of endothelial function markers in women with gestational diabetes and their fetuses. [2021]

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

Oxidative stress contributes to reductions in microvascular endothelial- and nitric oxide-dependent dilation in women with a history of gestational diabetes. [2023]

12. England pubmed.ncbi.nlm.nih.gov

Perinatal Oxidative Stress May Affect Fetal Ghrelin Levels in Humans. [2018]