Effect of Serum LDL Cholesterol Concentration on Pancreatic Insulin Secretion

Dyslipidemia is characterized by low levels of HDLs, hypertriglyceridemia as well as an increases proportion of small dense LDLs. Changes in lipoprotein particles and its concentrations, especially increased levels of pro-atherogenic LDL particles play an important role in the development of cardiovascular diseases. It is well established that statin/PCSK9-inhibitor treatment is very effective in lowering LDL cholesterol levels and therefore in preventing cardiovascular events. Besides the beneficial effects on cardiovascular system, these therapies are unfortunately linked to increased risk for type 2 diabetes.

However underlying mechanisms for the association between LDL cholesterol levels and the risk for type 2 diabetes remains largely unknown.Type 2 diabetes is especially characterized by insulin resistance and impaired insulin secretion from pancreatic beta-cells. Insulin resistance alone is insufficient to cause type 2 diabetes, as long as the ß-cell is able to compensate for the increased demand for insulin. Once this compensatory mechanism reaches its physiological limits, individuals progress to type 2 diabetes. Accordingly we aimed to investigate the associations between LDL cholesterol concentrations and the key issue in the pathogenesis of type 2 diabetes, insulin secretion before and after lowering cholesterol concentration by treatment with Evolocumab for 12 weeks in patients with medical indication for a treatment with a PCSK9-inhibitor. Therefore, patients will either undergo a hyperglycemic clamp or a oral glucose tolerance test in randomized manner.

Study Overview

• Status: Recruiting
• Conditions: Insulin Resistance; Hypercholesterolemia; Insulin Secretion
• Intervention / Treatment: Drug: Lowering cholesterol concentrations by PCSK-9 inhibitor

• Study Type: Interventional
• Enrollment (Anticipated): 40
• Phase: Not Applicable

Contacts and Locations

• Study Contact: Name: Andreas Fritsche, Prof.; Phone Number: 0049 (0)7071-29 80590; Email: andreas.fritsche@med.uni-tuebingen.de

Study Locations

• Germany
  • Tuebingen, Germany, 72076
    • Recruiting
    • University of Tuebingen, Department of Internal Medicine IV
    • Contact: Andreas Fritsche, Prof; Phone Number: +49 7071 29 80590; Email: andreas.fritsche@med.uni-tuebingen.de

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 75 years (ADULT, OLDER_ADULT)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Understand and voluntarily sign an informed consent document prior to any study related assessments/procedures
• Medical indication for the treatment with a PCSK9-inhibitor
• HbA1c < 6,5%

Exclusion Criteria:

• Diabetes mellitus
• Pregnant women or breastfeeding
• Hb < 11.5 g/dl (males) or Hb < 10.5 g/dl (females)
• treatment with any medication that effects on blood glucose concentrations, e.g. antidiabetic drugs or steroids
• Any pancreatic disease

Study Plan

How is the study designed?

Design Details

• Primary Purpose: BASIC_SCIENCE
• Allocation: NA
• Interventional Model: SINGLE_GROUP
• Masking: NONE

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
EXPERIMENTAL: LDL lowering therapy; Patients will receive the PCSK9-inhibitor Evolocumab as part of routine clinical management within the indication of this drug.	Drug: Lowering cholesterol concentrations by PCSK-9 inhibitor; Patients will receive the PCSK9-inhibitor Evolocumab as part of routine clinical management within the indication of this drug.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in insulin secretion.	Effect of lowering LDL cholesterol levels on insulins secretion.This will be quantified in half of the patients by a hyperglycemic clamp and in the other half by a 75 g oral glucose tolerance test (randomized assignment).	before and after 12 weeks of treatment with a PCSK9-inhibitor.

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in insulin sensitivity.	Effect of lowering LDL cholesterol levels on insulin sensitivity. This will be quantified in half of the patients by a hyperglycemic clamp and in the other half by a 75 g oral glucose tolerance test (randomized assignment).	before and after 12 weeks of treatment with a PCSK9-inhibitor.
Change in insulin clearance.	Effect of of lowering LDL cholesterol levels on insulin clearance.This will be quantified in half of the patients by a hyperglycemic clamp and in the other half by a 75 g oral glucose tolerance test (randomized assignment).	before and after 12 weeks of treatment with a PCSK9-inhibitor.
Change in glucose tolerance.	Effect of lowering LDL cholesterol levels on glucose tolerance assessed by 75g oral glucose tolerance test	before and after 12 weeks of treatment with a PCSK9-inhibitor.

Collaborators and Investigators

• Sponsor: University Hospital Tuebingen

Study record dates

Study Major Dates

• Study Start (ACTUAL): July 28, 2020
• Primary Completion (ANTICIPATED): March 15, 2023
• Study Completion (ANTICIPATED): June 15, 2023

Study Registration Dates

• First Submitted: March 10, 2020
• First Submitted That Met QC Criteria: March 18, 2020
• First Posted (ACTUAL): March 19, 2020

Study Record Updates

• Last Update Posted (ACTUAL): August 25, 2022
• Last Update Submitted That Met QC Criteria: August 24, 2022
• Last Verified: August 1, 2022

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Glucose Metabolism Disorders; Metabolic Diseases; Hyperinsulinism; Lipid Metabolism Disorders; Hyperlipidemias; Dyslipidemias; Insulin Resistance; Hypercholesterolemia
• Other Study ID Numbers: 045/2020BO2

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No