Objective
Although cardiovascular disease (CVD) is more prevalent in people with type 1 diabetes (T1D), little is known about the progression of CVD, the effectiveness of current medications to combat CVD, or the disease manifestation in T1D. We aim to answer these questions through working with the Wisconsin Diabetes Registry Study (WDRS), a community collaboration that has tracked aging in T1D for the past 30 years with participants coming in for regular blood draws that have been stored, measurements of blood vessel health, surveys about health, and regular clinical checkups.
After 30 years, more than half of the participants of the WDRS have CVD and high blood pressure and have been treated with various medications for CVD. While these CVD treatments have been shown to be effective in the general population, few studies have monitored their effectiveness in T1D. Many of these current CVD treatments function through lowering circulating levels of fat molecules, known as lipids. Lipids are problematic in CVD for two reasons. First, when overly abundant lipids begin to line blood vessels and create blockages. Second, lipids can also serve as signaling molecules that communicate energy demand and energy storage needs to the body. Many lipids communicate these needs through inducing insulin resistance when energy storage is at maximal capacity. The induced insulin resistance leads to worsened blood vessel blockage and decreased heart function. The proposed study will track the effectiveness of CVD treatments in the WDRS by analyzing the stored blood plasma for current markers of CVD and use new technology to measure more than 1000 lipids in the blood. The end goal of this work will be to identify clinical markers of CVD in T1D that can be used for early diagnosis and determine the effectiveness of various CVD drugs in T1D.
Background Rationale
Heart disease is the leading cause of death in the United States. Heart disease also causes lower quality of life often leading to issues with mobility. Fortunately, there are effective treatments for heart diseases, many of which function through lowering circulating levels of fat molecules, known as lipids. Lipids are problematic in heart for two reasons. First, when overly abundant lipids begin to line blood vessels and create blockages. Second, lipids can also serve as signaling molecules that communicate energy demand and energy storage needs to the body. Many lipids communicate these needs through inducing insulin resistance when energy storage is at maximal capacity. The induced insulin resistance leads to worsened blood vessel blockage and decreased heart function. Some of these treatments are used in the general population such as statins which lower cholesterol and blood thinners that improve blood flow through the blood vessels. Other treatments have been shown to be particularly effective in treating heart disease in people with type 2 diabetes such as sodium glucose co-transporter 2 (SGLT2) inhibitors that improve kidney function blocking the re-uptake of glucose and leading to improved heart function. Another effective heart disease treatment in people with type 2 diabetes is glucagon like peptide 1 (GLP1) agonists. GLP1 agonist functions to cause weight loss by slowing the release of food from the stomach leading to a sensation of feeling full. In people with type 2 diabetes GLP1 agonist leads to decreased circulating lipids and improved heart function. Despite these therapies being widely used in the general population and in people with type 2 diabetes, little is known about their effectiveness in people with type 1 diabetes.
People with Type 1 Diabetes (T1D) are three times more likely to die from heart disease than their peers, and this contributes to a 10-15 year lower life expectancy. To increase life expectancy and healthy aging in people with T1D, we aim to identify early markers of heart disease that can lead to early intervention and to determine which heart disease treatments are effective in T1D. The proposed study will track the effectiveness of heart disease treatment in the Wisconsin Diabetes Registry study, a 30 year cohort of people with T1D that have been tracked since T1D diagnosis. This cohort has stored blood plasma that we can use to measure current markers of heart disease and employ new technology to measure more than 1000 lipids in the plasma. We have selected participants in this T1D cohort that are on currently approved heart disease treatments including statins, blood thinners, SGLT2 inhibitors, and GLP1 agonists to determine the effectiveness of these treatments at decreasing heart disease in T1D. The major outcomes of this work will identify lipid markers of heart disease that are shared between people with T1D and their peers as well as determine effective treatments for heart disease in type 1 diabetes.
Description of Project
People with Type 1 Diabetes (T1D) are at a higher risks of heart attack and stroke compared to their peers, contributing to early mortality and decreased health in later life. Despite these disparities in health care, little is known about the progression of heart disease or the effectiveness of treatments in people with T1D. The goal of this application is to examine classic and T1D-specific risk factor profiles for heart disease assessing the effectiveness of current clinical markers such as high blood pressure, cholesterol, and triglyceride levels. We will also add novel measurements including complete blood plasma lipid profiling which allows for the measurement of more than 1000 unique lipids in the plasma. These studies will allow us to observe differences and similarities in people with T1D, to identify those most at risk for heart disease allowing for early intervention and treatment.
Our research team has access to a unique population of people with T1D who have been followed since diagnosis, for more than 30years that are currently on heart disease prevention drugs. These drugs have not been tested for effectiveness in people with T1D. The second goal of this application is to determine the effectiveness of these preventative drugs at improving heart disease outcomes. We will assess the development of heart disease by demonstrate increased coronary artery calcium (CAC) scores linked to heart disease, or increased neck artery wall thickness (carotid intima-media thickness, CIMT) linked to strokes. By adding CAC and CIMT, we will be able to generate more powerful CVD risk prediction models and determine effective therapeutics for the treatment of heart disease in T1D.
The two areas of innovation of this work are the T1D population and the new technology applied to track heart disease progression. The T1D population is a group of community collaborators with T1D that have diligently worked with medical providers to provide blood plasma every three years for 30 years and the past blood plasma samples have been stored. These stored blood plasma samples allow us to measure heart disease risk factors in people with T1D before they develop blood vessel calcification. The second point of innovation is the complete lipid profiles which are made possible by new technology. These lipid profiles will allow us to test the effectiveness of current markers such as triglycerides while determining if there are new lipids that could better predict heart disease. These studies will allow us to develop early risk factor markers and to determine the effectiveness of current heart disease treatments. These are the first critical steps toward improving quality and length of life in those with T1D as they age in good health.
Anticipated Outcome
The outcome of the proposed studies will be to identify risk factors and effective treatment for heart disease in people with type 1 diabetes (T1D). A large body of research has shown that heart disease is more prevalent in people with either T1D or Type 2 Diabetes. These findings have led to the development of therapeutic drugs that better treat heart disease progression in people with Type 2 Diabetes including the use of sodium glucose co-transporter 2 (SGLT2) inhibitors that improve kidney function by blocking the re-uptake of glucose, and glucagon like peptide 1 (GLP1) agonists that cause weight loss by decreasing appetite. Despite these targeted interventions for people with Type 2 Diabetes, little work has been done to determine the effectiveness of therapeutic drugs in heart diseases prevention in people with T1D.
The proposed work collaborates with a T1D population cohort that has been monitored for 30 years. This T1D cohort has vascular health assessment, yearly measurements of traditional markers of heart disease, and stored blood plasma samples. Of the more than 500 people with T1D who participate in this study, more than half currently have vascular calcification indicative of heart disease and are treated by approved drugs including statins, blood thinners, SGLT2 inhibitors, and GLP1 agonists. We will perform another measurement of blood vessel calcification to determine heart disease progression since starting the therapeutic drug treatment and draw blood for plasma measurement of traditional markers of heart disease including cholesterol and triglycerides. We will also use this blood plasma to perform measurements with new technology to look at all of the blood plasma lipids including 1000 unique lipids. Along with the blood that will be drawn in the 2022-2023 cohort, we will measure markers in stored samples from 5 year, 10 years, 15 years, and 20 years of monitoring. Measuring these banked samples will allow us to determine plasma lipids that predict the development of disease. We will use computation modeling to determine the effectiveness of traditional heart disease markers and compare them to new markers.
The outcome of these studies will be effective risk factors and the development of a diagnostic decision tree that will guide clinicians in T1D specific progression of heart disease and its effective treatment with heart disease drugs. We will publish these studies in top medical journals such as JCI, Lancet, or Diabetes Care to ensure they are widely available and present this work at top conferences in the field including the American Diabetes Association National Conference. We will use the results of this study to apply for further national funding to support T1D research and life expectnancy. Finally, the data from this T1D cohort will be part of the Wisconsin Diabetes Research Center Translational Research Core data base. The data will be used to allow for further discoveries that will lead to improved quality of life and longer life expectancy for people with T1D.
Relevance to T1D
For more than 100 years the major focus of type 1 diabetes (T1D) research has been on increasing survival from the initial diagnosis of T1D including developing new technology to improve the administration of insulin and improving glucose monitoring. The advances in research have led to a longer life expectancy, but there is still a 10-15 year decrease in life expectancy for people with T1D compared to their peers. A part of this decrease in life expectancy is the development of secondary disease such as heart disease, which is three times more prevalent in people with T1D compared to their peers. Besides decreasing life expectancy, heart disease lowers quality of life in people with T1D by decreasing mobility, leading to more frequent doctor’s appointments, and is associated with a decline in cognitive function with aging. The work in this proposal will improve quality of life and life expectancy in people with T1D by identifying early diagnostic markers of heart disease and effective treatments strategies.
Heart disease is best treated with early intervention and therapeutic treatment. Early diagnosis is typically found through use of disease progression markers including cholesterol, triglycerides, and high blood pressure. The establishment of these markers was done in all male population studies using people from Western European Descent. It has been more recently appreciated that these markers under-diagnose heart disease in women and in diverse populations. The effectiveness of these markers at predicting heart disease in people with T1D is unknown. We aim to determine how effective these markers are and to use novel technology to identify markers that can lead to earlier diagnosis of heart disease risk in people with T1D. The work in this proposal will collaborate with a 30-year study that has collected and stored blood plasma samples from people with T1D. This cohort has also had regular checkups including assessment of artery health and heart disease risk. We will take the stored blood plasma samples from this cohort to measure traditional markers of heart disease development, and to perform global lipid measurements that allow for the quantification of more than 1000 unique lipids in the plasma. These measurements will allow us to determine risk factors for heart disease development in people with T1D.
Heart disease is currently treated and prevented with several drugs to lower lipids and thin blood. Although these drugs are well tested in the general population and in people with Type 2 Diabetes, little is known about the effectiveness of these treatments in people with T1D. More than half of the people in the 30-year T1D cohort are currently on drugs to treat heart disease development and lower blood lipid levels. We have selected samples from people with T1D that are on several heart disease drugs to test the effectiveness of these drugs at treating heart disease in T1D. We will use computational modeling to determine the effectiveness of these treatments by determining the progression of blood vessel blockage and blood lipid levels in people with T1D. Through identifying early risk factors that can diagnose heart disease before it develops, and determining the effectiveness of heart disease treatment, the work in this proposal will improve quantity and quality of life for people with T1D.