Study of the Inflammatory Activity in Diabetic Patients With Stable Angina Treated With Simvastatin and Ezetimibe

Condition(s) targeted: Diabetes; Stable Angina

Intervention: simvastatin or ezetimibe/simvastatin, 6 weeks (Drug)

Phase: N/A

Status: Recruiting

Sponsored by: University of Sao Paulo

Official(s) and/or principal investigator(s):
CARLOS V SERRANO, PHD, Principal Investigator, Affiliation: Heart Institute (InCor) HCFMUSP

Overall contact:
Carlos V Serrano, phd, Phone: 55-11-30695058, Ext: 55-11, Email: carlos.serrano@incor.usp.br

This study is designed to test the hypothesis that the association of ezetimibe to simvastatin will enhance the anti-inflammatory properties observed with simvastatin alone in high-risk cardiovascular patients such as diabetic patients with stable coronary syndromes. Inflammation will be denoted by measuring the following markers: C-reactive protein (CRP), interleukin (IL)-6, IL-1, monocyte chemoattractant protein (MCP)-1, soluble intercellular adhesion molecule (sICAM)-1 and oxidized LDL-C (oxLDL). Progenitor endothelial cells are also determined.

Diabetic patients with known, stable coronary artery disease and LDL-C levels between 90-160 mg/dl will be randomized to two lipid-lowering regimens: simvastatin 80 mg or ezetimibe/simvastatin 10/20 mg, for six weeks. Blood samples are collected before and after lipid-lowering treatment for determination of inflammatory markers. Throughout the study, all participants are encouraged to follow diet, perform physical activity and to take other medications.

Official title: Study of the Inflammatory Activity in Diabetic Patients With Stable Angina Treated With Simvastatin and Ezetimibe

Study design: Treatment, Randomized, Open Label, Active Control, Single Group Assignment, Efficacy Study

Primary outcome: Inflammation will be denoted by measuring the following markers: CRP, interleukins, MCP-1, sICAM-1 and oxLDL. Progenitor endothelial cells are also determined.

Detailed description: Background Cardiovascular disease (CVD) is a major cause of morbidity and mortality among patients with diabetes. It is estimated that cardiovascular complications are responsible for as many as 75% of deaths among people with type 2 diabetes. Individuals with diabetes carry a 2- to 4-fold increased risk of CVD, including coronary heart disease (CHD), stroke, and peripheral vascular disease when compared with nondiabetic individuals. Recent studies show that individuals with diabetes have an absolute risk of major coronary events similar to that of nondiabetic individuals with established CHD. , In the National Cholesterol Education Panel Adult Treatment Panel III (NCEP ATP III) guidelines, diabetes is considered a CHD equivalent; therefore, the lipid targets for individuals with diabetes are the same as those for individuals with established CHD. The primary target is an LDL-C of less than 100 mg/dL. In a more recent published update, the ATP III panel lowered the cut point for pharmacologic intervention, based in part on the HPS results, from greater than 130 mg/dL to greater than 100 mg/dL and in addition provided an optional lower target of 70 mg/dL for very high-risk subjects, such as those with diabetes and heart disease. Along with these modifications, ATP III also proposed that if a statin is to be used, a dose that achieves at least 30% to 40% LDL-C lowering should be chosen.

These recommendations recently have found support in the results of the Treatment To New Targets Study, which compared the effects of greater LDL-C lowering with atorvastatin 80 mg to atorvastatin 10 mg (mean on-treatment LDL-C 77 mg/dL versus 101 mg/dL, respectively) in 10,003 subjects with CVD, 15% of whom had diabetes. This study also suggested that further benefit may be achieved by lowering LDL-C values to a mean of ~70 mg/dL in the average subject with stable CHD, not just those with high risk.

An insufficient LDL-C reduction with statins often is treated with ezetimibe, an intestinal cholesterol absorption inhibitor, in combination with statin. It is not known whether this combination therapy has the same pleiotropic effects as a statin monotherapy.

Reducing the level of LDL-C with statins induces important pleiotropic effects such as decreasing monocyte-endotelial cell adhesion interactions . Moreover, the reduction of LDL-C levels may be beneficial for restoring endothelial function which, in turn, may have important implications for diminishing the incidence of adverse coronary events. Pravastatin has shown to be very efficient in lowering LDL-C plasmatic levels and repairing endothelial function , , .

Aims This study is designed to test the hypothesis that the association of ezetimibe to simvastatin will enhance the anti-inflammatory properties observed with simvastatin alone in high-risk cardiovascular patients such as diabetic patients with stable coronary syndromes. Inflammation will be denoted by measuring the following markers: C-reactive protein (CRP), interleukin (IL)-6, IL-1, monocyte chemoattractant protein (MCP)-1, soluble intercellular adhesion molecule (sICAM)-1 and oxidized LDL-C (oxLDL). Progenitor endothelial cells are also determined.

Study Design Diabetic patients with known, stable coronary artery disease and LDL-C levels between 90-160 mg/dl will be randomized to two lipid-lowering regimens: simvastatin 80 mg or ezetimibe/simvastatin 10/20 mg, for six weeks. Blood samples are collected before and after lipid-lowering treatment for determination of inflammatory markers. Throughout the study, all participants are encouraged to follow diet, perform physical activity and to take other medications.

The number of participants required to test our hypothesis is based on prior studies reporting the relation between inflammatory marker generation and hypercholesterolemia in a patient population. These indicate that 80 patients with stable angina are needed to detect a 20% increase in adhesion molecule expression, based on a power of 0. 80 and an alpha of 0. 05.

Determination of anti-inflammatory protection Peripheral blood samples are collected according to protocol: Afterwards, samples were processed immediately for the experiments below.

- CRP .

- sICAM-1 expression.

- IL-1 and IL-6.

- MCP-1.

- LDL oxidized

- Progenitor endothelial cells.

Minimum age: 45 Years. Maximum age: 80 Years. Gender(s): Both.

Criteria:

Inclusion Criteria:

- Diabetic patients

- Stable angina

- LDL cholesterol 70-160 mg/dl

Exclusion Criteria:

- Renal failure

- Age>80

- Simvastatin current treatment>20mg

- Hepatic disease

Carlos V Serrano, phd, Phone: 55-11-30695058, Ext: 55-11, Email: carlos.serrano@incor.usp.br

Heart Institute (InCor) HCFMUSP, Sao Paulo 05403-000, Brazil; Recruiting
Carlos V Serrano, phd, Phone: 55-11-30695058, Ext: 11-55, Email: carlos.serrano@incor.usp.br
CARLOS V SERRANO, PHD, Principal Investigator

Starting date: January 2006
Ending date: May 2007
Last updated: May 15, 2007