Objective
The goals of this research are first, to find out if dapagliflozin slows the progression of early kidney disease
in young people with type 1 diabetes, and second, to determine what effects dapagliflozin may have on
oxygen levels in the kidneys and the genes involved in energy metabolism, as well as whether these changes
explain the benefits observed with dapagliflozin. The overarching hypothesis of this proposal is that
dapagliflozin lowers the workload and improves the fuel generation of the kidneys and thereby stops the
development of diabetic kidney disease in young people with type 1 diabetes. The specific goals of the
proposal include:
1. Determine the effect of dapagliflozin compared with placebo on kidney oxygenation in adolescents with
type 1 diabetes.
2. Examine how genes involved in determining the kidney cells’ ability to generate and use fuel change with
dapagliflozin treatment in adolescents with type 1 diabetes.
Background Rationale
Diabetic kidney disease is the leading cause of kidney failure in the Western 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 diabetic kidney disease, and a lack of interventions during the early stages of the disease, when therapy
or medication is most likely to be beneficial.
Animal research suggests that diabetes causes 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).
Taken together, the energy demand of the kidneys exceeds the cells’ ability to create and use fuel. We believe
this mismatch between requirement and availability of energy drives injury to the kidneys, as well as other
complications in type 1 diabetes. This proposal seeks to determine whether a new diabetes drug, a sodiumglucose
cotransporter-2 (SGLT2) inhibitor, can correct the imbalance in energy metabolism that contributes
to the development of early diabetic kidney disease in young people with type 1 diabetes.
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 changes in energy metabolism that may drive diabetic kidney disease.
The kidneys require a lot of oxygen and energy to constantly filter the entire blood volume and rely on several
different sources of fuel to meet these needs. In patients with type 1 diabetes, the kidneys must work harder,
due to demands of filtering elevated amounts of sugar in the blood, increased salt retention and more urine
production. To support this extra work, the kidneys require additional energy and oxygen. However, type 1
diabetes is characterized by insulin resistance (inability of cells to respond normally to insulin), as well as
impaired mitochondrial function (the energy “powerhouses” of the cells), both of which limit the kidneys’
ability to efficiently break down sugar and other fuel sources to use as energy.
This study is a clinical trial to see if a new diabetes drug, a sodium-glucose cotransporter-2 (SGLT2) inhibitor
called dapagliflozin, will delay the development of early kidney disease in adolescents with type 1 diabetes.
We believe dapagliflozin will protect the kidneys against disease by lowering their high energy needs due to
the effects of type 1 diabetes, and improve their ability to generate energy, thereby raising their oxygen
levels. All 100 participants who takes part in the study will have a series of tests of their kidneys at the start
of the study including advanced MRI to measure oxygen content in the kidneys. A subset of participants will
also undergo a kidney biopsy which involves removing a small piece of kidney tissue with a needle under
local anesthetic. After this, everyone in the study will be given a study drug to take daily for 16 weeks. For
half the people in the study this will be the new drug dapagliflozin 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 tests and MRI, and the subset who had
a kidney biopsy will have a repeat biopsy after which we will stop the study drug. An important hurdle to safe
use of drugs like dapagliflozin in type 1 diabetes is the poorly understood mechanism of kidney protection.
Therefore, our proposed study is critical to better understand the role of dapagliflozin in preventing diabetic
kidney disease in type 1 diabetes.
Anticipated Outcome
In the proposed study, we will evaluate the effects of a new diabetes drug, dapagliflozin, on early diabetic
kidney disease in adolescents with type 1 diabetes. We anticipate finding higher oxygen content in the
kidneys after dapagliflozin treatment, and that this effect is explained by a lower kidney workload and
improved fuel generation. In addition, we expect to discover patterns of genes activated by dapagliflozin that
may explain how this drug protects the kidneys from disease. Before this type of medicine can be used
safely in clinical practice to prevent or reverse early kidney disease, we need to understand how it works in
type 1 diabetes.
Relevance to T1D
Diabetic kidney disease is a common cause of heart disease and early mortality 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 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, as well as a lack of medical therapies during early stages of the
disease, when benefit from treatment is most likely to be achieved. We believe an imbalance between energy
demand and delivery in type 1 diabetes may contribute to early development of kidney disease. The purposes
of this study are to find out if dapagliflozin, a new promising diabetes drug, can stop progression of early
kidney disease in young people with type 1 diabetes, and if dapagliflozin can resolve the mismatch in energy
metabolism thought to drive the development of early kidney disease.