Insulin Aspart for 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: Tobacco use, Diabetes, Hypertension, others

Approved in 2 Jurisdictions This treatment is already approved in other countries

Compensation: Varies

Number of Visits: 1

Duration: 1 day

40 Participants Needed

Trial Summary

Will I have to stop taking my current medications?

The trial requires that you do not take statins, other cholesterol-lowering medications, or antihypertensive medications. If you are on these medications, you would need to stop taking them to participate.

What data supports the effectiveness of the drug insulin aspart for gestational diabetes?

Research shows that insulin aspart is effective in managing blood sugar levels in women with gestational diabetes, achieving target glucose levels similar to other insulin regimens without increasing adverse effects. ^{1 2 3 4 5}

Is insulin aspart safe for use in pregnant women with diabetes?

Insulin aspart is considered safe for use in pregnant women with diabetes, as studies show it does not increase insulin antibodies or appear in the fetal circulation, and it may lead to fewer severe low blood sugar episodes compared to regular human insulin. ^{1 3 6 7 8}

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

The drug for gestational diabetes, involving endothelin-1 modulation, is unique because it targets the endothelin system, which is linked to insulin resistance and glucose intolerance. This approach may improve insulin sensitivity and glucose metabolism, offering a novel mechanism compared to traditional treatments that primarily focus on insulin regulation. ^{9 10 11 12 13}

What is the purpose of this trial?

Women with a history of gestational diabetes mellitus (GDM) are at a 2-fold greater risk for the development of overt cardiovascular disease (CVD) following the effected pregnancy. While subsequent development of type II diabetes elevates this risk, prior GDM is an independent risk factor for CVD morbidity, particularly, within the first decade postpartum. GDM is associated with impaired endothelial function during pregnancy and decrements in macro- and microvascular function persist postpartum, despite the remission of insulin resistance following delivery. Collectively, while the association between GDM and elevated lifetime CVD risk is clear, and available evidence demonstrates a link between GDM and vascular dysfunction in the decade following pregnancy, the mechanisms mediating this persistent dysfunction remain unexamined. The purpose of this investigation is to examine the role of endothelin-1, a potent vasoconstrictor, in aberrant microvascular function in otherwise healthy women with a history of GDM and to identify whether this mechanism is influenced by physical activity and sedentary behavior.

Eligibility Criteria

This trial is for women who had a baby within the last 5 years and either had a healthy pregnancy or were diagnosed with gestational diabetes. They should meet the American College of Obstetricians and Gynecologists criteria for gestational diabetes.

Inclusion Criteria

I have not been pregnant in the last 5 years.

I had a healthy pregnancy or was diagnosed with gestational diabetes.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive local perfusion of ET-1 inhibitors and L-NAME through microdialysis fibers to study microvascular function

1 day

1 visit (in-person)

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

Treatment Details

Interventions

• Endothelin-1 Modulation

Trial Overview The study investigates how endothelin-1, which narrows blood vessels, affects small vessel function in women with past gestational diabetes. It also looks at whether physical activity or sitting too much can change this effect.

Participant Groups

Group I: local L-NAME perfusion Experimental Treatment 1 Intervention

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

Group II: local BQ-788 and BQ-123 perfusion Experimental Treatment 1 Intervention

local ET-1 inhibitors perfused through the microdialysis fiber to serve as the experimental treatment

Group III: local BQ-788 + BQ-123 + L-NAME perfusion Experimental Treatment 1 Intervention

local ET-1 inhibitors and L-NAME are perfused through the microdialysis fiber to inhibit nitric oxide synthase during the experimental treatment

Group IV: local lactated Ringer's perfusion Placebo Group 1 Intervention

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

Endothelin-1 Modulation is already approved in European Union, United States for the following indications:

Approved in European Union as Bosentan for:

• Pulmonary arterial hypertension

Approved in United States as Bosentan for:

• Pulmonary arterial hypertension

Approved in European Union as Macitentan for:

• Pulmonary arterial hypertension

Approved in United States as Macitentan for:

• Pulmonary arterial hypertension

Approved in European Union as Ambrisentan for:

• Pulmonary arterial hypertension

Approved in United States as Ambrisentan for:

• Pulmonary arterial hypertension

Approved in United States as Sparsentan for:

• Primary immunoglobulin A nephropathy

Who Is Running the Clinical Trial?

Anna Stanhewicz, PhD

Lead Sponsor

Trials

12

Recruited

460+

Findings from Research

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]

In a study of 361 pregnant women with gestational diabetes, over 40% achieved target glucose levels using a simple insulin injection regimen (SII) without increasing adverse perinatal outcomes.

The SII regimen was as effective as a more complex multiple daily injection (MDI) regimen in controlling blood glucose levels, indicating that a simpler treatment approach can be safe and effective for managing gestational diabetes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Achievement of Target Glycemic Goal with Simple Basal Insulin Regimen in Women with Gestational Diabetes: A Prospective Cohort Study. Fukuoka, M., Yasuhi, I., Yamashita, H., et al.[2023]

In a study involving 80 women with gestational diabetes, both human aspart and regular human insulin showed comparable efficacy and safety in managing glucose levels during pregnancy.

No significant differences were found in insulin dosage, glucose control, or delivery outcomes between the two insulin types, indicating that either can be effectively used for treating gestational diabetes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Efficacy and safety of insulin aspart versus regular human insulin for women with gestational diabetes mellitus]. Zhou, L., Fan, L.[2013]

Gestational diabetes (GD) significantly increases the risk of adverse outcomes for both mothers and their babies, including higher chances of type 2 diabetes later in life and complications like macrosomia and neonatal hypoglycemia.

While insulin has traditionally been used to manage GD, recent studies indicate that glyburide may be an effective alternative, and metformin shows promise in potentially preventing the development of GD.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The contentious nature of gestational diabetes: diet, insulin, glyburide and metformin. Glueck, CJ., Goldenberg, N., Streicher, P., et al.[2019]

In a study of 102 patients with spleen deficiency type gestational diabetes mellitus, combining insulin aspart with exercise therapy significantly lowered blood glucose levels and improved overall treatment efficacy (96.08% vs. 74.51% for insulin alone).

The combination therapy also resulted in fewer adverse pregnancy outcomes (3.92% vs. 37.25%) and complications (5.88% vs. 41.17%), suggesting it is a safer and more effective treatment option for these patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Insulin Aspart Combined with Exercise Therapy in Spleen Deficiency Type Gestational Diabetes Mellitus: The Effect on Disease Control and Pregnancy Outcomes. Shi, Y., Meng, X.[2023]

Insulin aspart (IAsp) is at least as safe and effective as regular human insulin (HI) for managing type 1 diabetes in pregnant women, with a lower risk of major hypoglycemia (1.4 vs. 2.1 episodes/year) and a 52% reduction in major nocturnal hypoglycemia risk.

IAsp showed better postprandial glucose control compared to HI, with significantly lower plasma glucose levels after meals, while maintaining comparable A1C levels, indicating it may be a preferable option for meal-time insulin in this population.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Maternal glycemic control and hypoglycemia in type 1 diabetic pregnancy: a randomized trial of insulin aspart versus human insulin in 322 pregnant women. Mathiesen, ER., Kinsley, B., Amiel, SA., et al.[2022]

Insulin aspart, a fast-acting insulin analogue, has been shown to improve postprandial blood sugar control in pregnant women with Type 1 diabetes, potentially leading to fewer severe hypoglycemia episodes compared to traditional human insulin.

The use of insulin aspart during pregnancy is considered safe, as it does not appear in fetal circulation and does not increase insulin antibodies, while also being associated with lower rates of fetal losses and preterm deliveries.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Insulin aspart in diabetic pregnancy: state of the art. Mathiesen, ER.[2022]

Insulin aspart was found to be safe for use in pregnant women with gestational and pregestational diabetes, with no significant difference in the incidence of macrosomia (large babies) between the two groups studied (5.1% in gestational diabetes and 8.9% in pregestational diabetes).

The study involved 355 patients and monitored their blood glucose levels and insulin dosages over several weeks, indicating that insulin therapy was effective in managing blood glucose levels after medical nutrition therapy failed.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Insulin aspart in patients with gestational diabetes mellitus and pregestational diabetes mellitus. Deepaklal, MC., Joseph, K., Rekha, K., et al.[2020]

The study found that using an endothelin-B (ET(B)) receptor antagonist in pregnant rats led to significantly lower fetal and placental weights at higher doses (10 and 15 mg/kg per day), indicating a negative impact on fetal growth.

While the antagonist increased maternal blood pressure initially, this effect was not sustained throughout the pregnancy, suggesting that ET(B) receptor antagonism is harmful to pregnancy outcomes in rats.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Influence of ET(B) receptor antagonism on pregnancy outcome in rats. Madsen, KM., Neerhof, MG., Wessale, JL., et al.[2019]

Long-term treatment with the endothelin antagonist atrasentan significantly improved whole body glucose metabolism in insulin-resistant Zucker fatty rats compared to control, indicating its potential efficacy in managing insulin resistance.

Atrasentan treatment enhanced insulin signaling in the liver by normalizing the expression of the regulatory subunit of PI-3 kinase, suggesting a mechanism through which it may help correct insulin resistance, although it did not have the same effect in muscle tissue.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Endothelin antagonism improves hepatic insulin sensitivity associated with insulin signaling in Zucker fatty rats. Berthiaume, N., Carlson, CJ., Rondinone, CM., et al.[2018]

Chronic activation of the endothelin-1 (ET-1) system can lead to insulin resistance and cardiovascular issues by disrupting insulin signaling pathways and reducing insulin delivery to tissues, which may result in glucose intolerance and hyperinsulinemia.

ET-1 antagonists show promise in improving heart function and glucose tolerance in obese individuals and those with early insulin sensitivity, suggesting they could be a beneficial treatment option, especially when combined with other therapies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Insulin resistance, obesity and the metabolic syndrome. Is there a therapeutic role for endothelin-1 antagonists? Shaw, SG., Boden, PJ.[2019]

Endothelin peptides, discovered in the 1980s, are linked to insulin resistance, suggesting they play a role beyond just causing blood vessels to constrict.

The review highlights how endothelin interacts with insulin signaling at various physiological levels, potentially contributing to vascular and metabolic issues associated with insulin resistance.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Interactions of endothelin and insulin: expanding parameters of insulin resistance. Strawbridge, AB., Elmendorf, JS., Mather, KJ.[2019]

Endothelin-1 (ET-1) reduces insulin-stimulated glucose uptake in skeletal muscle by suppressing the phosphorylation of Akt, a key protein in insulin signaling, indicating a mechanism for insulin resistance.

The negative effects of ET-1 on insulin signaling can be countered by blocking ETA receptors or inhibiting GRK2, suggesting that targeting these pathways may help improve insulin sensitivity in muscle cells.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Endothelin-1 suppresses insulin-stimulated Akt phosphorylation and glucose uptake via GPCR kinase 2 in skeletal muscle cells. Horinouchi, T., Hoshi, A., Harada, T., et al.[2021]

References

1. 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]

2. England pubmed.ncbi.nlm.nih.gov

Achievement of Target Glycemic Goal with Simple Basal Insulin Regimen in Women with Gestational Diabetes: A Prospective Cohort Study. [2023]

3. China pubmed.ncbi.nlm.nih.gov

[Efficacy and safety of insulin aspart versus regular human insulin for women with gestational diabetes mellitus]. [2013]

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

The contentious nature of gestational diabetes: diet, insulin, glyburide and metformin. [2019]

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

Insulin Aspart Combined with Exercise Therapy in Spleen Deficiency Type Gestational Diabetes Mellitus: The Effect on Disease Control and Pregnancy Outcomes. [2023]

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

Maternal glycemic control and hypoglycemia in type 1 diabetic pregnancy: a randomized trial of insulin aspart versus human insulin in 322 pregnant women. [2022]

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

Insulin aspart in diabetic pregnancy: state of the art. [2022]

8. India pubmed.ncbi.nlm.nih.gov

Insulin aspart in patients with gestational diabetes mellitus and pregestational diabetes mellitus. [2020]

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

Influence of ET(B) receptor antagonism on pregnancy outcome in rats. [2019]

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

Endothelin antagonism improves hepatic insulin sensitivity associated with insulin signaling in Zucker fatty rats. [2018]

11. United Arab Emirates pubmed.ncbi.nlm.nih.gov

Insulin resistance, obesity and the metabolic syndrome. Is there a therapeutic role for endothelin-1 antagonists? [2019]

12. United Arab Emirates pubmed.ncbi.nlm.nih.gov

Interactions of endothelin and insulin: expanding parameters of insulin resistance. [2019]

13. England pubmed.ncbi.nlm.nih.gov

Endothelin-1 suppresses insulin-stimulated Akt phosphorylation and glucose uptake via GPCR kinase 2 in skeletal muscle cells. [2021]