Effect of Serum LDL Cholesterol Concentration on Pancreatic Insulin Secretion

NCT04314167 — Not applicable, Terminated, 9 participants, University Hospital Tuebingen

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Registry	NCT04314167
Status	Terminated - poor recruitment
Phase	Not applicable
Study type	Interventional; na, single group, masking: none, basic science
Enrollment	9 (Actual)
Sponsor	University Hospital Tuebingen (Other)
Conditions	Hypercholesterolemia, Insulin Resistance, Insulin Secretion
Interventions	Lowering cholesterol concentrations by PCSK-9 inhibitor (Drug)
Dates	start 2020-07-28, primary completion 2024-03-01, completion 2024-03-01, first posted 2020-03-19, last updated 2024-05-16
Locations	1 site in Germany

-Summary

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.

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+Arms and interventions

Arm	Type	Interventions	Description
LDL lowering therapy	Experimental	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.

Lowering cholesterol concentrations by PCSK-9 inhibitor (Drug): Patients will receive the PCSK9-inhibitor Evolocumab as part of routine clinical management within the indication of this drug.

+Outcome measures

Primary outcomes

Change in insulin secretion. [before and after 12 weeks of treatment with a PCSK9-inhibitor.]: 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).

Secondary outcomes

Change in insulin sensitivity. [before and after 12 weeks of treatment with a PCSK9-inhibitor.]: 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).
Change in insulin clearance. [before and after 12 weeks of treatment with a PCSK9-inhibitor.]: 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).
Change in glucose tolerance. [before and after 12 weeks of treatment with a PCSK9-inhibitor.]: Effect of lowering LDL cholesterol levels on glucose tolerance assessed by 75g oral glucose tolerance test

+Eligibility

Sex: All, ages: 18 Years to 75 Years

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

+Locations (1)

Facility	City	Country	Status
University of Tuebingen, Department of Internal Medicine IV	Tübingen	Germany

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