Effect of Alirocumab on Postprandial Hyperlipemia in Patients With Type 2 Diabetes

NCT ID: NCT03344692

Last Updated: 2022-09-27

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE3
• Total Enrollment: 22 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2019-02-12
• Study Completion Date: 2022-04-28

Brief Summary

Proprotein convertase subtilisin/kexin type 9 (PCSK9) has emerged over the past decade as a post-transcriptional regulator of the LDL receptor (LDL-R). PCSK9 acts as an endogenous natural inhibitor of the LDL-R pathway. Monoclonal antibodies (mAb) directed against PCSK9, such as Alirocumab, are the most common method of PCSK9 inhibition.

The goal of the present study is to assess, in the context of type 2 diabetes, a situation associated with an increased post-prandial hyperlipemia, whether PCSK9 inhibition with Alirocumab affects postprandial intestinal lipoprotein metabolism.

Detailed Description

Recently, human monoclonal antibodies directed against PCSK9 have been shown to be effective in reducing LDL cholesterol. Besides the liver, little is known about the role of PCSK9 in the small intestine, a tissue where it is expressed at a high level. Preclinical studies in mice indicate that PCSK9 inhibition reduces post-prandial hyperlipemia.

Here, the investigators will test the effect of PCSK9 inhibition with alirocumab, a PCSK9 mAb, on post-prandial hyperlipemia in 24 patients with type 2 diabetes. The investigators will perform a randomized, double-blind, placebo-controlled, cross-over trial with alirocumab 75 mg every two weeks.

In the cross-over design, two periods of 10-weeks treatment (i.e. 5 injections) will be separated by a 10-week wash-out period to avoid carry-over effect. The primary endpoint will be the total area under the post-prandial triglycerides concentration-time curve from meal-time until 8h (AUC0-8h) after a standardized meal test. As secondary endpoints, the investigators will explore the effect of alirocumab on plasma lipids, markers of cholesterol absorption and synthesis, and glycemic parameters.

This study will help to decipher the function of PCSK9 on intestinal lipoprotein metabolism in human and to determine whether alirocumab can reduce post-prandial hyperlipemia, which is an independent cardiovascular risk factor. From a patient perspective, this study will give some important clues for the management of cardiovascular disease.

Conditions

Type2 Diabetes

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: CROSSOVER
• Primary Study Purpose: TREATMENT
• Blinding Strategy: QUADRUPLE

Study Groups

Alirocumab

Alirocumab 75 mg for subcutaneous injection via a pre-filled pen. One injection every 2 weeks during a 10-weeks period (5 injections in total)

Group Type: EXPERIMENTAL

Alirocumab

Intervention Type: DRUG

prefilled pen containing 75 mg of Praluent (Alirocumab) in 1 ml of solution

Placebo

Placebo matching alirocumab is prepared in the same formulation as alirocumab, without the addition of protein, for subcutaneous injection via a pre-filled pen.

One injection every 2 weeks during a 10-weeks period (5 injections in total)

Group Type: PLACEBO_COMPARATOR

Placebo

Intervention Type: OTHER

prefilled pen containing 1 ml of solution without Praluent

Interventions

Alirocumab

prefilled pen containing 75 mg of Praluent (Alirocumab) in 1 ml of solution

Intervention Type: DRUG

Placebo

prefilled pen containing 1 ml of solution without Praluent

Intervention Type: OTHER

Eligibility Criteria

Inclusion Criteria

• Men with type 2 diabetes diagnosed since ≥ 6 months
• HbA1C <9.0%
• Men with primary hypercholesterolemia and/or mixed dyslipidemia
• Aged 18-75 years (limits inclusive)
• Patient could be treated for type 2 diabetes when diet and physical activity are not sufficient to restore glycemic control. The treatment must be stable 1 month before the inclusion and have to remain unchanged all along the study. The only authorized treatments are:
• Metformin
• And/or Sulphonylureas (SUs)
• And/or Repaglinide
• And/or DPP-4 inhibitors
• And/or GLP1 receptor agonists: exenatide, liraglutide, dulaglutide
• Fasting serum TG ≥ 150 mg/dl and < 500 mg/dl
• BMI: 20-45 kg/m2
• Use of statins or ezetimibe is allowed if treatment is stable for ≥ 1 month before the screening

Exclusion Criteria

• Any secondary causes of hypercholesterolemia or of mixed dyslipidemia (nephrotic syndrome, hypothyroidism…)
• impaired liver function (AST and/or ALT ≥ 3ULN)
• impaired renal function (eGFR with CKD-EPI formula < 30 ml/min)
• Alcohol abuse (> 2 standard alcoholic drink per day; 1 standard alcoholic drink is the equivalent of 10g of alcohol)
• History of myocardial infarction, acute coronary syndrome, unstable angina pectoris, stroke, transient ischemic attack, or cardiac revascularization within the 6 months before the screening visit.
• History of PCSK9 mAb use
• Known sensitivity to monoclonal antibody therapeutics or to their excipients
• Lipid lowering therapies (other than statins), including fibrates, omega-3 fatty acids, bile acid sequestrants, niacin.
• Insulin-treated patients
• History of bariatric surgery
• Inflammatory bowel diseases and gastrointestinal malabsorption diseases
• Uncontrolled hypothyroidism (TSH > ULN and Free T4 < ULN) or hyperthyroidism (TSH < ULN)
• Active cancer: progressive cancer or remission ≤ 3 years, except for basal or squamous cell carcinoma of the skin that has been successfully treated
• Known history of positive test for HIV, hepatitis C or chronic hepatitis B
• Corticosteroids therapy
• Minors
• Adults under guardianship or trusteeship

• Minimum Eligible Age: 18 Years
• Maximum Eligible Age: 75 Years
• Eligible Sex: MALE
• Accepts Healthy Volunteers: No

Sponsors

Regeneron Pharmaceuticals

INDUSTRY

Sponsor Role: collaborator

Nantes University Hospital

OTHER

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Bertrand CARIOU

Role: STUDY_CHAIR

Nantes University Hospital

Locations

University Hospital of Nantes

Nantes, , France

Countries

France

Other Identifiers

RC16_0406

Identifier Type: -

Identifier Source: org_study_id