Objective
The goals of this research are first, to find out if montelukast slows the progression of kidney disease in people with type 1 diabetes, and second, to determine what effects montelukast may have on kidney and vascular inflammation, as well as whether these changes explain the benefits observed with montelukast. The overarching hypothesis of this proposal is that montelukast lowers kidney and vascular inflammation and thereby improves the function of the kidneys and the circulatory system in type 1 diabetes.
Background Rationale
Diabetic kidney disease is the leading cause of kidney failure in the developed world. Current diabetes treatments, such as control of high blood sugar, blood pressure and cholesterol have so far been unable to slow or prevent the development and progression of diabetic kidney disease. Results from drug trials in diabetic kidney disease have provided modest results, due to limited understanding of the processes that start and drive diabetic kidney disease. Thus, identifying new and safe treatments for kidney disease in type 1 diabetes is a priority.
Animal research suggests that diabetes is associated with increased inflammation. Indeed, inflammation is thought to be a key contributor to diabetic kidney disease and cardiovascular disease in type 1 diabetes. In particular, leukotrienes, inflammatory chemicals the body releases in response to allergic reactions, have been implicated in the development of kidney and heart disease.
Stress from diabetes can lead the kidneys to work harder; this extra work requires more energy and oxygen. However, our research shows that type 1 diabetes is also associated with processes which impair the cells’ ability to generate and use fuel adequately, including inability to use insulin to break down sugar effectively (insulin resistance), and inefficiency of the energy “powerhouses” of the cells (mitochondrial dysfunction). Treatments that block leukotrienes may lower the chances of experiencing worsening of kidney and heart disease in type 1 diabetes.
In support of this hypothesis, we have shown that montelukast, a medication that blocks leukotrienes, prevents the development of kidney disease and diabetic eye disease in mice. Currently, there are no human studies examining the benefits of montelukast on kidney and heart disease in people with T1D. Therefore, we are proposing a clinical trial to examine whether montelukast therapy will improve kidney and blood vessel function in people with T1D to potentially identify a new, safe, inexpensive, and effective treatment for diabetic kidney disease and cardiovascular disease in T1D.
Description of Project
Kidney disease is a common problem among people with type 1 diabetes and can lead to disability, dialysis, and early death. In fact, the life expectancy of a child diagnosed with type 1 diabetes at age 10 is shortened by 17 years, a prognosis unchanged over the past four decades despite advances in blood sugar, cholesterol, and blood pressure control. A potential explanation is the narrow focus on correcting the clinical presentation and risk factors of type 1 diabetes, such as blood sugar, blood pressure and cholesterol, rather than understanding and targeting the inflammatory processes that may drive diabetic kidney disease.
Inflammation plays a key role in the development of kidney disease in type 1 diabetes and targeting leukotrienes, inflammatory chemicals the body releases in response to allergic reactions, may represent a promising therapy to slow the progression of diabetic kidney disease. The current proposal will investigate whether montelukast, a leukotriene blocker, lowers increased levels of protein in the urine (an early marker of diabetic kidney disease), and improves kidney and cardiovascular function in people with type 1 diabetes and kidney disease. All 50 participants who take part in the study will have a series of tests of their kidneys and blood vessels at the start of the study. After this, everyone in the study will be given a study drug to take daily for 6 months. For half the people in the study this will be the leukotriene blocker montelukast and for the other half it will be a pill that looks just like it but has no medicine in it (placebo). Which type of pill the person receives will be determined by chance. At the end of the study, we will repeat the series of kidney and circulatory system tests.
Anticipated Outcome
We anticipate that treatment with montelukast will reduce the amount of protein in the urine and will improve kidney function in people with T1D. We also expect that treatment with montelukast will improve blood vessel function in people with T1D. Results from this study will be used to design a larger, national trial examining the effect of montelukast on clinical outcomes in people with T1D.
Relevance to T1D
Diabetic kidney disease is a common cause of heart disease and early death in type 1 diabetes. In fact, almost 40% of people with type 1 diabetes will develop diabetic kidney disease. Large studies in Europe and the United States have established that people with type 1 diabetes and diabetic kidney disease have almost 4-fold higher rates of death than the general population. The same studies have also shown that people with type 1 diabetes but without diabetic kidney disease have no higher rates of death than the general population. Despite advances in blood sugar monitoring, insulin therapy, and technology, some people with type 1 diabetes still develop diabetic kidney disease. It is therefore important to find new ways to protect against kidney disease.
The development of new treatments to halt or prevent diabetic kidney disease in type 1 diabetes has been slow and disappointing. This trend can be at least partially explained by a limited understanding of the processes that initiate and drive diabetic kidney disease. We believe inflammation may contribute to development of kidney and heart disease. The purposes of this study are to find out if montelukast, a tolerable, safe, and inexpensive leukotriene blocker, can stop progression of kidney and heart disease in people with type 1 diabetes.