New Treatment for Lipoprotein Lipase Deficiency

(AGL12 Trial)

Overseen By Frédérique Frisch

Age: 18+

Sex: Any

Trial Phase: Academic

Sponsor: Université de Sherbrooke

Must not be taking: Fibrates, Thiazolidinediones, Beta-blockers, others

Disqualifiers: Cardiovascular disease, Liver disease, Renal disease, others

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

Approved in 3 Jurisdictions This treatment is already approved in other countries

Compensation: Varies

Number of Visits: 3

16 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial explores a new treatment for Lipoprotein Lipase Deficiency (LPLD). LPLD prevents the body from effectively removing certain fats from the blood, leading to painful symptoms and serious issues like pancreatitis. The study uses heparin, an anticoagulant medication, to determine if it can improve fat processing in the body. Individuals with LPLD, a history of high triglycerides, and a specific genetic mutation might be suitable for this trial. Participants will help researchers determine if the treatment can significantly improve condition management. As an unphased trial, this study offers a unique opportunity to contribute to groundbreaking research that could lead to new treatment options for LPLD.

Will I have to stop taking my current medications?

The trial requires participants to stop taking certain medications that affect lipid or carbohydrate metabolism, such as fibrates, thiazolidinediones, and beta-blockers. However, statins, metformin, and some antihypertensive medications can be safely interrupted. If you are on any of these medications, you may need to stop them to participate in the trial.

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

Research has shown that heparin, a medication that thins the blood, is generally safe for use. The FDA has approved heparin for other purposes, indicating it has passed many safety tests. Some studies have examined heparin's effect on an enzyme called lipoprotein lipase (LPL), which helps process fats in the blood. These studies indicate that heparin can safely alter this enzyme's function.

Although heparin is widely used, it can have side effects like any medication. It may cause bleeding due to its blood-thinning properties. However, heparin is considered very safe, and side effects are usually not serious. This makes it a promising option for further research in treating conditions related to LPL deficiency. ^{1 2 3 4 5}

Why are researchers excited about this trial?

Researchers are excited about using heparin for treating Lipoprotein Lipase Deficiency (LPLD) because it offers a unique approach compared to current treatments. While existing options like dietary management and gene therapy focus on reducing triglyceride levels indirectly or aim to fix genetic mutations, heparin directly stimulates the release of lipoprotein lipase, which helps break down triglycerides in the blood. This direct mechanism of action could lead to more immediate and effective control of triglyceride levels, offering new hope for managing this challenging condition. Additionally, heparin's administration via intravenous infusion allows for precise dosage control, which could enhance its effectiveness and safety.

What evidence suggests that this trial's treatments could be effective for lipoprotein lipase deficiency?

Research shows that heparin can release an enzyme called lipoprotein lipase (LPL), which is crucial for breaking down fats in the blood. Studies have found that after administering heparin, LPL activity increases, helping to lower fat levels, specifically triglycerides. This trial includes a treatment arm where participants with lipoprotein lipase deficiency (LPLD) will receive heparin to assess its effectiveness in improving fat breakdown. This is vital for people with LPLD, who often have very high triglyceride levels and related health issues. Animal studies also suggest that heparin effectively releases LPL. These findings offer hope that heparin may improve fat breakdown for those with LPLD. ^{1 3 6 7 8}

Who Is on the Research Team?

André Carpentier

Principal Investigator

Université de Sherbrooke

Are You a Good Fit for This Trial?

This trial is for adults aged 18-75 with Lipoprotein Lipase Deficiency (LPLD), evidenced by high fasting triglyceride levels and specific gene mutations. Healthy individuals with normal blood sugar and triglyceride levels can also join as controls. Participants must not have cardiovascular disease, a history of certain blood disorders or be on medications affecting lipid metabolism.

Inclusion Criteria

Control subjects must have normal glucose and triglyceride levels.

Willing and able to adhere to the specifications of the protocol

Signed an informed consent document indicating understanding of the purpose

Exclusion Criteria

I am under 18 years old.

You have been diagnosed with heparin-induced low platelet count before.

I do not have liver, kidney diseases, or uncontrolled thyroid issues.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

1 visit

1 visit (in-person)

Metabolic Study A0

Participants undergo a postprandial metabolic study without heparin administration, including PET and stable isotopic tracer methods

9 hours

1 visit (in-person)

Metabolic Study A1

Participants undergo a postprandial metabolic study with heparin administration, including PET and stable isotopic tracer methods

9 hours

1 visit (in-person)

Follow-up

Participants are monitored for safety and effectiveness after metabolic studies

6 months

What Are the Treatments Tested in This Trial?

Interventions

• Heparin

Trial Overview The study investigates how LPLD affects the body's handling of dietary fats after eating, specifically looking at fat storage in tissues and its use as fuel for heart function. It involves administering heparin and a liquid meal to understand these metabolic processes in both LPLD patients and healthy controls.

How Is the Trial Designed?

Group I: LPLD group-A1 Experimental Treatment 2 Interventions

LPLD group: LPL deficient subjects with history of fasting TG \> 5 mmol/l and homozygote or compound heterozygote for a LPL-gene mutation; A1: with an intravenous (i.v.) heparin bolus (50 IU/kg i.v.) followed by 250 IU/h i.v. during 6 hours starting 15 minutes before ingestion of liquid meal.

Group II: LPLD group-A0 Experimental Treatment 1 Intervention

LPLD group: LPL deficient subjects with history of fasting TG \> 5 mmol/l and homozygote or compound heterozygote for a LPL-gene mutation; A0: without heparin administered

Group III: Control group-A1 Experimental Treatment 2 Interventions

Control group: Healthy subjects with fasting glucose \< 5.6, 2-hour post 75g OGTT glucose \< 7.8 mmol/l and HbA1c \< 5.8%; fasting TG \< 1.5 mmol/l); A1: with an intravenous (i.v.) heparin bolus (50 IU/kg i.v.) followed by 250 IU/h i.v. during 6 hours starting 15 minutes before ingestion of liquid meal.

Group IV: Control group- A0 Experimental Treatment 1 Intervention

Control group: Healthy subjects with fasting glucose \< 5.6, 2-hour post 75g Oral Glucose Tolerance Test (OGTT) glucose \< 7.8 mmol/l and HbA1c \< 5.8%; fasting TG \< 1.5 mmol/l); A0: without heparin administered

Who Is Running the Clinical Trial?

Université de Sherbrooke

Lead Sponsor

Trials

317

Recruited

79,300+

Institut de Recherches Cliniques de Montreal

Collaborator

Trials

72

Recruited

10,300+

Published Research Related to This Trial

The study identified specific regions in the N-terminal domain of lipoprotein lipase (LPL) that are crucial for binding to heparin, with mutations in these areas significantly reducing binding affinity and catalytic activity.

In contrast, mutations in the C-terminal domain did not affect heparin binding or enzyme activity, indicating that the N-terminal domain is essential for LPL's interaction with membrane-associated polyanions.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Mutagenesis in four candidate heparin binding regions (residues 279-282, 291-304, 390-393, and 439-448) and identification of residues affecting heparin binding of human lipoprotein lipase. Ma, Y., Henderson, HE., Liu, MS., et al.[2021]

Unfractionated heparin (UFH) is a high-alert medication with a significant risk of drug-related problems, including harmful medication errors that account for 4.5-5.5% of reported cases, highlighting the need for improved safety measures in its administration.

UFH therapy can lead to serious complications such as heparin-induced thrombocytopenia, bleeding events, and osteopenia, with safer alternatives like low-molecular-weight heparins offering equivalent or superior efficacy for many conditions.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Unfractionated heparin: focus on a high-alert drug. Niccolai, CS., Hicks, RW., Oertel, L., et al.[2019]

In a study involving 52 horses with colic, low molecular weight heparin (LMWH) was found to have significantly fewer side effects compared to unfractionated heparin (UFH), particularly regarding changes in jugular veins and blood parameters.

Horses treated with UFH experienced a decrease in packed cell volume and prolonged coagulation times, while those treated with LMWH showed stable blood parameters, suggesting that LMWH is a safer option for preventing coagulation disorders in colic-affected horses.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Comparison of unfractioned and low molecular weight heparin for prophylaxis of coagulopathies in 52 horses with colic: a randomised double-blind clinical trial. Feige, K., Schwarzwald, CC., Bombeli, T.[2019]

In a study involving seven chronic haemodialysis patients, switching from unfractionated heparin (UH) to low molecular weight heparin (LMWH) resulted in a significant increase in tissue releasable lipoprotein lipase activity after 6 months, suggesting improved lipid metabolism over time.

Hepatic lipase activity remained unchanged regardless of the type of heparin used, indicating that LMWH specifically benefits lipoprotein lipase stores without affecting hepatic lipase levels.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Different types of heparin in haemodialysis: long-term effects on post-heparin lipases. Arnadottir, M., Kurkus, J., Nilsson-Ehle, P.[2019]

A Phase I pharmacokinetic study showed that oral heparin/SNAC reaches peak anti-factor Xa activity within 45-60 minutes and returns to baseline after 4 hours, indicating effective absorption and action.

In a randomized trial with 123 patients undergoing total hip arthroplasty, oral heparin/SNAC demonstrated a safety profile similar to subcutaneous unfractionated heparin, with no significant differences in venous thromboembolic events or major bleeding, supporting its potential for thromboprophylaxis.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Oral heparin administration with a novel drug delivery agent (SNAC) in healthy volunteers and patients undergoing elective total hip arthroplasty. Berkowitz, SD., Marder, VJ., Kosutic, G., et al.[2023]

Enoxaparin was found to be more effective than unfractionated heparin (UFH) in reducing the combined risk of death, myocardial infarction, and urgent revascularization in both obese and non-obese patients, as well as those without severe renal impairment.

Patients with severe renal impairment showed a higher risk of adverse clinical events and major hemorrhages, indicating that while enoxaparin is effective, this population may require closer monitoring due to increased risks.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Safety and efficacy of unfractionated heparin versus enoxaparin in patients who are obese and patients with severe renal impairment: analysis from the ESSENCE and TIMI 11B studies. Spinler, SA., Inverso, SM., Cohen, M., et al.[2014]

In a study involving 26 hemodialysis patients, switching from unfractionated heparin (UFH) to low molecular weight heparin (LMWH) resulted in less reduction of triglycerides during dialysis, indicating that UFH may worsen hyperlipidemia in these patients.

While LMWH treatment led to significant decreases in total cholesterol and triglycerides in Type IIb hyperlipidemic patients over 6 months, it did not affect lipoprotein lipase activity, suggesting that UFH's impact on hyperlipidemia is not due to its effect on this enzyme.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Long-term use of low molecular weight heparin ameliorates hyperlipidemia in patients on hemodialysis. Akiba, T., Tachibana, K., Ozawa, K., et al.[2019]

In a study involving rats, low-molecular-weight heparin (LMWH) caused a rapid decline in lipoprotein lipase (LPL) activity within 30 minutes after injection, decreasing by over 80%, while unfractionated heparin (UFH) maintained LPL levels during the same period.

Both heparins released LPL from vascular sites, but LMWH was less effective at delaying its removal by the liver compared to UFH, suggesting that LMWH may lead to faster catabolism of functional LPL.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Depletion of lipoprotein lipase after heparin administration. Chevreuil, O., Hultin, M., Ostergaard, P., et al.[2019]

PK 10169, a low molecular weight heparin with a molecular weight of 4000-6000, has a significantly reduced anticoagulant effect in vitro compared to standard heparin.

Despite its lower anticoagulant capacity, PK 10169 effectively retains the ability to enhance lipoprotein lipase and hepatic lipase activity after intravenous injection, suggesting potential therapeutic benefits in lipid metabolism.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Release of LPL activity after intravenous injection of a low molecular weight heparin. Etienne, J., Millot, F., Pieron, R., et al.[2019]

In a study of 720 patients with acute venous thromboembolism (VTE), subcutaneous unfractionated heparin (UFH) was found to be as effective as fixed-dose nadroparin for preventing recurrent thromboembolic events, with similar rates of recurrence (4.2% for UFH vs. 3.9% for nadroparin).

The safety profiles were comparable, with only 1.1% of patients on UFH and 0.8% on nadroparin experiencing major bleeding, indicating that both treatments are safe options for initial VTE management.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Subcutaneous adjusted-dose unfractionated heparin vs fixed-dose low-molecular-weight heparin in the initial treatment of venous thromboembolism. Prandoni, P., Carnovali, M., Marchiori, A.[2006]

In patients with abetalipoproteinemia, the absence of triglyceride-rich lipoproteins is linked to significantly reduced activity of both hepatic lipase and lipoprotein lipase after heparin administration, indicating a potential mechanism for lipid metabolism impairment.

In contrast, patients with heterozygous hypobetalipoproteinemia exhibited normal enzyme activity, suggesting that not all lipid disorders affect lipase activity in the same way.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Lipoprotein lipase and hepatic lipase activity after heparin administration in abetalipoproteinemia and hypobetalipoproteinemia. Illingworth, DR., Alam, SS., Alam, NA.[2019]

Heparin injection leads to a quick rise in serum lipoprotein lipase levels, which are believed to circulate as a complex with heparin, indicating a potential mechanism for enhancing lipolysis.

The study in unanesthetized dogs shows that the liver plays a crucial role in removing lipoprotein lipase activity from circulation, and high doses of heparin can inhibit this removal process, suggesting a two-step inactivation mechanism involving heparin breakdown.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Effect of heparin on the inactivation of serum lipoprotein lipase by the liver in unanesthetized dogs. Whayne, TF., Felts, JM., Harris, PA.[2018]

Citations

1. clinicaltrials.gov clinicaltrials.gov/study/NCT02656095?term=lipase&viewType=Table&rank=6&checkSpell=

Lipoprotein Lipase Enzyme Activity Assay Validation and ... This study plans to learn more about measuring Lipoprotein lipase (LPL) activity in humans. LPL is an enzyme in the breakdown of certain types of fats into ...

2. ahajournals.org ahajournals.org/doi/pdf/10.1161/01.atv.13.10.1391

Depletion of lipoprotein lipase after heparin administration. The low dose (50 U/kg) led to lower initial levels of LPL activity with LMWH in spite of slower elimination of heparin activity from the blood. These results ...

3. sciencedirect.com sciencedirect.com/science/article/abs/pii/S1933287423000223

Role of lipoprotein lipase activity measurement in the ... Results. All post-heparin plasma LPL activity in the FCS patients were below 25.1 mU/mL, that was cut-off with best performance.

4. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC534784/

Effects of heparin on the uptake of lipoprotein lipase in rat liver This study shows that there are heparin-insensitive binding sites for LPL on both hepatocytes and Kupffer cells.

5. researchgate.net researchgate.net/publication/353712966_Effects_of_Low_Molecular_Weight_and_Unfractionated_Heparin_on_Lipoprotein_Lipase_and_Lipid_Profile_in_haemodialysis_patients/download

(PDF) Effects of Low Molecular Weight and Unfractionated ... Studies in animals have shown that LMW-heparins release lipoprotein lipase (LPL) as efficiently as unfractionated (UF) heparin, but are less ...

6. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC209279/

Heparin-binding defective lipoprotein lipase is unstable and ... Heparin-binding defective lipoprotein lipase is unstable and causes abnormalities in lipid delivery to tissues.

7. pubs.acs.org pubs.acs.org/doi/10.1021/bi960008e

Interaction of Lipoprotein Lipase with Heparin Fragments and ... Our results show that LPL has very high affinity for heparan sulfate and for heparin. The Kd values were remarkably lower than those previously presented ( ...

8. apm.amegroups.org apm.amegroups.org/article/view/83380/html

Systematic review and meta-analysis of the safety and ... LMH intervention can dramatically reduce the average hospital stay and complications of patients with SAP, improve treatment efficacy, and has high safety.