Cholesterol-Lowering Drugs for Type 1 Diabetes

(CHORD1 Trial)

Recruiting at 3 trial locations

Overseen By Zahi Fayad

Age: 18+

Sex: Any

Trial Phase: Phase 4

Sponsor: NYU Langone Health

Must not be taking: PCSK9 inhibitors, Antithrombotics, Aspirin, NSAIDs

Disqualifiers: Cardiovascular disease, Recent infection, Pregnancy, others

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

Prior Safety Data This treatment has passed at least one previous human trial

Compensation: Varies

Number of Visits: 1

Duration: 4 weeks

125 Participants Needed

Trial Summary

Will I have to stop taking my current medications?

The trial does not specify if you need to stop taking your current medications, but you cannot participate if you are using certain medications like antithrombotic therapy, aspirin, NSAIDs, or PCSK9 inhibitors.

What data supports the effectiveness of the drugs used in the clinical trial for cholesterol-lowering in type 1 diabetes?

Research shows that atorvastatin, a drug used in the trial, not only lowers cholesterol but may also help preserve some insulin-producing cells in people newly diagnosed with type 1 diabetes. Additionally, ezetimibe and evolocumab, other drugs in the trial, are effective in lowering bad cholesterol (LDL-C) and reducing heart disease risk, which is beneficial for managing diabetes-related complications. ^{1 2 3 4 5}

Is it safe to use cholesterol-lowering drugs like Atorvastatin, Evolocumab, and Ezetimibe in humans?

Cholesterol-lowering drugs such as Atorvastatin, Evolocumab, and Ezetimibe have been studied for safety in humans. Common side effects of statins like Atorvastatin include muscle symptoms and a risk of new-onset diabetes, but these do not outweigh the benefits. Evolocumab and Ezetimibe are generally safe, with Evolocumab being used for patients with high cholesterol not controlled by other drugs, and Ezetimibe showing no significant interactions with most other medications. ^{1 6 7 8 9}

How does the drug combination of Atorvastatin, Evolocumab, and Ezetimibe differ from other treatments for type 1 diabetes?

This drug combination is unique because it targets cholesterol management in type 1 diabetes, which is not commonly addressed. Atorvastatin may help preserve beta cell function, while Ezetimibe and Evolocumab are effective in lowering cholesterol absorption and LDL levels, respectively, offering a comprehensive approach to reducing cardiovascular risk in these patients. ^{2 3 10 11 12}

What is the purpose of this trial?

This is a prospective, interventional, cohort study, meaning that researchers will follow and observe a group of enrolled study participants over a period of time (one to two months) to gather information and record any developments of the outcomes in question. This study will recruit 125 participants with Type 1 Diabetes (T1D) to: 1. Analyze the effect of reducing the cholesterol levels in the blood on platelet function. (Platelets are small cells in the blood which help form blood clots to slow or stop bleeding and to help wounds heal 2. Analyze the effect of reducing the cholesterol levels in the blood on While Blood Cell (WBC) gene expression, (White Blood Cells are part of the body's immune system which help the body fight infection and other diseases) and 3. Analyze the effect of reducing the cholesterol levels in the blood on vascular or blood vessel function.

Research Team

Ira Goldberg, MD

Principal Investigator

NYU Langone Health

Eligibility Criteria

This trial is for adults aged 18 to 89 with Type 1 Diabetes and LDL cholesterol over 100mg/dl. They must have a confirmed diagnosis of T1D, not be pregnant, and cannot have been hospitalized or had an infection in the last month. Participants should not be on aspirin, NSAIDs within the past three days, immunosuppressives, antithrombotics, or PCSK9 inhibitors.

Inclusion Criteria

I have been diagnosed with diabetes based on blood sugar or A1C levels.

Your LDL cholesterol is higher than 100 milligrams per deciliter.

You have a history of type 1 diabetes, including a specific type called latent autoimmune diabetes of adulthood.

Exclusion Criteria

I have taken NSAID medication in the last 3 days.

You have low hemoglobin or platelet levels in your blood.

I am on medication to prevent blood clots due to heart disease.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive weekly injections of PCSK9i (evolocumab) and daily oral pills of atorvastatin or ezetimibe for 1 month

4 weeks

1 visit (in-person) at baseline, 1 self-administered injection at 2 weeks

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

Treatment Details

Interventions

• Atorvastatin Calcium Tablets
• Evolocumab Cartridge
• Ezetimibe Tablets

Trial Overview The study tests how lowering cholesterol affects platelet function (which helps blood clot), White Blood Cell gene expression (important for fighting infections), and blood vessel function in people with Type 1 Diabetes using Evolocumab Cartridge combined with Atorvastatin Calcium Tablets or Ezetimibe Tablets.

Participant Groups

Group I: 4-Week LDL-Cholesterol (LDL-C)-Reduction Treatment Experimental Treatment 7 Interventions

Treatment consists of: Evolocumab (140 mg; 2 injections, one administered at baseline visit and another self-administered 2 weeks later), and; Atorvastatin (up to 80mg dose; 1 tab per day for 30 days, starting at baseline visit post-assessment). Participants with statin intolerance will be provided with a 1-month supply of ezetimibe 10 mg to replace Evolocumab and Atorvastatin. * Additional procedures: Blood draws. * Optional procedures: Glycocalyx testing, PET/CT, or Endothelial Cell Collection.

Atorvastatin Calcium Tablets is already approved in European Union, United States, Canada, Japan, China, Switzerland for the following indications:

Approved in European Union as Lipitor for:

• Hypercholesterolemia
• Mixed dyslipidemia
• Prevention of cardiovascular disease

Approved in United States as Lipitor for:

• Hypercholesterolemia
• Mixed dyslipidemia
• Prevention of cardiovascular disease
• Homozygous familial hypercholesterolemia

Approved in Canada as Lipitor for:

• Hypercholesterolemia
• Mixed dyslipidemia
• Prevention of cardiovascular disease

Approved in Japan as Lipitor for:

• Hypercholesterolemia
• Mixed dyslipidemia
• Prevention of cardiovascular disease

Approved in China as Lipitor for:

• Hypercholesterolemia
• Mixed dyslipidemia
• Prevention of cardiovascular disease

Approved in Switzerland as Lipitor for:

• Hypercholesterolemia
• Mixed dyslipidemia
• Prevention of cardiovascular disease

Who Is Running the Clinical Trial?

NYU Langone Health

Lead Sponsor

Trials

1,431

Recruited

838,000+

National Heart, Lung, and Blood Institute (NHLBI)

Collaborator

Trials

3,987

Recruited

47,860,000+

Findings from Research

Statin drugs effectively lower LDL-cholesterol and reduce cardiovascular risk, but can cause side effects like muscle symptoms and diabetes, which do not outweigh their benefits.

Evolocumab, a PCSK9 inhibitor, is an effective treatment for patients with familial hypercholesterolemia who do not respond adequately to statins or ezetimibe, highlighting the importance of tailored lipid therapy based on individual patient needs.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

An updated review of lipid-modifying therapy. Simons, LA.[2020]

In a study involving 89 patients with newly diagnosed type 1 diabetes, atorvastatin did not significantly preserve beta cell function compared to placebo over 18 months, although there was a nonsignificant slower decline in beta cell function in the atorvastatin group.

Atorvastatin treatment resulted in significant reductions in total cholesterol and C-reactive protein levels, indicating its effectiveness in lipid-lowering and anti-inflammatory effects, but metabolic control remained similar between both groups.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Residual beta cell function in newly diagnosed type 1 diabetes after treatment with atorvastatin: the Randomized DIATOR Trial. Martin, S., Herder, C., Schloot, NC., et al.[2022]

In a study comparing the effects of simvastatin and ezetimibe on cholesterol levels, simvastatin was significantly more effective in lowering total cholesterol (TC) and low-density lipoprotein cholesterol (LDL-C) in patients with type 2 diabetes (T2DM) than in those with type 1 diabetes (T1DM).

Ezetimibe, a cholesterol absorption inhibitor, was found to be more effective than simvastatin in lowering LDL-C levels in T1DM patients, suggesting that cholesterol absorption inhibitors may be a better treatment option for this group.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Effects of simvastatin and ezetimibe in lowering low-density lipoprotein cholesterol in subjects with type 1 and type 2 diabetes mellitus. Ciriacks, K., Coly, G., Krishnaswami, S., et al.[2015]

In a study of 125,330 patients with clinical atherosclerotic cardiovascular disease (ASCVD) or heterozygous familial hypercholesterolemia (HeFH), only 1.05% added or switched to ezetimibe therapy, highlighting its limited uptake in real-world settings.

Among those who switched to ezetimibe, only 26% achieved the LDL-C goal of < 70 mg/dL within 90 days, indicating that while ezetimibe can help lower cholesterol, its effectiveness may be limited, especially in patients with higher baseline LDL-C levels.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Ezetimibe Use and LDL-C Goal Achievement: A Retrospective Database Analysis of Patients with Clinical Atherosclerotic Cardiovascular Disease or Probable Heterozygous Familial Hypercholesterolemia. Menzin, J., Aggarwal, J., Boatman, B., et al.[2023]

In a study of 31 patients with type 2 diabetes, high-dose simvastatin (80 mg) significantly reduced the activation of the proinflammatory transcription factor NF-κB and lowered inflammatory markers like hsCRP, indicating its strong anti-inflammatory effects.

In contrast, a combination of low-dose simvastatin (10 mg) and ezetimibe (10 mg) achieved similar LDL-cholesterol reduction but did not show any significant impact on NF-κB activation or inflammatory markers, suggesting that not all cholesterol-lowering therapies have the same anti-inflammatory benefits.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Identical LDL-cholesterol lowering but non-identical effects on NF-κB activity: High dose simvastatin vs combination therapy with ezetimibe. Rudofsky, G., Reismann, P., Groener, JB., et al.[2022]

In a study of 136 patients with extremely high-risk acute coronary syndrome (ACS), adding the PCSK9 inhibitor evolocumab to standard treatment significantly reduced LDL cholesterol levels compared to standard treatment alone, achieving an LDL-C compliance rate of 82.35% versus 22.06%.

The use of evolocumab also led to a lower incidence of major adverse cardiovascular events (MACEs) during a 3-month follow-up (8.82% in the evolocumab group vs. 24.59% in the control group), without increasing the risk of adverse reactions.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Effect of the Early Application of Evolocumab on Blood Lipid Profile and Cardiovascular Prognosis in Patients with Extremely High-Risk Acute Coronary Syndrome. Hao, Y., Yang, YL., Wang, YC., et al.[2022]

Ezetimibe is a selective cholesterol absorption inhibitor that effectively blocks the absorption of dietary and biliary cholesterol in the small intestine without affecting the absorption of bile acids, fatty acids, or fat-soluble vitamins.

It is approved for treating primary hypercholesterolemia, either alone or with statins, and is also used for homozygous familial hypercholesterolemia and homozygous sitosterolemia, highlighting its versatility in managing cholesterol-related conditions.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Ezetimibe for hypercholesterolemia. Morris, S., Tiller, R.[2015]

Ezetimibe effectively lowers cholesterol by inhibiting NPC1L1 transport proteins in the intestines, and it also has anti-inflammatory properties, making it a unique treatment option for hypercholesterolemia.

The drug is safe and effective for patients with various conditions, including those who have undergone cardiac, renal, and liver transplants, as well as HIV patients, and it shows no significant interactions with most other common medications.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Ezetimibe--a new approach in hypercholesterolemia management. Suchy, D., Łabuzek, K., Stadnicki, A., et al.[2020]

In a 12-week phase 3 study involving 981 patients with type 2 diabetes and high cholesterol, evolocumab significantly reduced LDL cholesterol levels by up to 74.9% when combined with atorvastatin, compared to placebo.

Evolocumab was well tolerated, showing a similar incidence of adverse events as placebo, and did not adversely affect blood sugar levels, indicating it is a safe option for lipid management in diabetic patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Randomised study of evolocumab in patients with type 2 diabetes and dyslipidaemia on background statin: Primary results of the BERSON clinical trial. Lorenzatti, AJ., Eliaschewitz, FG., Chen, Y., et al.[2021]

Statin therapy is the first-line treatment for lowering cholesterol in diabetes patients, significantly reducing their cardiovascular disease (CVD) risk, regardless of whether they have a history of CVD.

Patients with diabetes should aim for specific cholesterol levels: LDL cholesterol below 2.6 mmol/L (100 mg/dL) for those with CVD and below 2.6 mmol/L for those without, while also managing triglycerides and HDL cholesterol to further reduce CVD risk.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Treatment of lipid disorders in patients with diabetes. Colhoun, HM., Betteridge, DJ.[2020]

Lipid-lowering therapy is important for reducing cardiovascular risk in individuals with type 1 diabetes (T1D), but many patients are not adequately treated for dyslipidaemia.

Surveys revealed key barriers to effective lipid management in T1D, such as a lack of awareness about cardiovascular risks, a focus on blood sugar control over cholesterol management, and concerns about statin side effects.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Patient perceptions of cardiovascular risk, lipid management and statins in type 1 diabetes. Lan, NSR., Hong, RSY., Ryan, C., et al.[2023]

Statin therapy remains the primary treatment for lowering LDL cholesterol and preventing atherosclerotic cardiovascular disease (ASCVD) in patients with type 2 diabetes, supported by nearly 30 years of clinical use.

Ezetimibe, PCSK9 inhibitors (alirocumab and evolocumab), and high-dose icosapent ethyl are effective add-on therapies for further reducing ASCVD risk in statin-treated patients with diabetes, particularly those with elevated triglyceride levels.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Dyslipidemia Management in Adults With Diabetes. Lazarte, J., Hegele, RA.[2020]

References

1. Australia pubmed.ncbi.nlm.nih.gov

An updated review of lipid-modifying therapy. [2020]

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

Residual beta cell function in newly diagnosed type 1 diabetes after treatment with atorvastatin: the Randomized DIATOR Trial. [2022]

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

Effects of simvastatin and ezetimibe in lowering low-density lipoprotein cholesterol in subjects with type 1 and type 2 diabetes mellitus. [2015]

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

Ezetimibe Use and LDL-C Goal Achievement: A Retrospective Database Analysis of Patients with Clinical Atherosclerotic Cardiovascular Disease or Probable Heterozygous Familial Hypercholesterolemia. [2023]

5. Ireland pubmed.ncbi.nlm.nih.gov

Identical LDL-cholesterol lowering but non-identical effects on NF-κB activity: High dose simvastatin vs combination therapy with ezetimibe. [2022]

6. Japan pubmed.ncbi.nlm.nih.gov

Effect of the Early Application of Evolocumab on Blood Lipid Profile and Cardiovascular Prognosis in Patients with Extremely High-Risk Acute Coronary Syndrome. [2022]

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

Ezetimibe for hypercholesterolemia. [2015]

8. Switzerland pubmed.ncbi.nlm.nih.gov

Ezetimibe--a new approach in hypercholesterolemia management. [2020]

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

Randomised study of evolocumab in patients with type 2 diabetes and dyslipidaemia on background statin: Primary results of the BERSON clinical trial. [2021]

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

Treatment of lipid disorders in patients with diabetes. [2020]

11. England pubmed.ncbi.nlm.nih.gov

Patient perceptions of cardiovascular risk, lipid management and statins in type 1 diabetes. [2023]

12. Canada pubmed.ncbi.nlm.nih.gov

Dyslipidemia Management in Adults With Diabetes. [2020]