Objective
The objectives for this proposal are 1) to determine what dose of acetazolamide maximally lowers glomerular filtration rates within minimal side effects in persons with type 1 diabetes mellitus (T1DM), and 2) to determine if acetazolamide can safely be used to lower glomerular filtration rate with minimal side effects over 10 weeks in persons with T1DM.
Background Rationale
The development of kidney disease is a devastating consequence of type 1 diabetes mellitus (T1DM). The risks of death increase dramatically in persons with T1DM who develop kidney disease, and many go on to require dialysis or kidney transplantation. Recently a new drug class, SGLT-2 inhibitors, have been demonstrated to prevent kidney disease in persons with diabetes. However, these drugs are only approved for use in persons with type 2 diabetes and may be risky in persons with T1DM, as they can cause ketoacidosis. These drugs help prevent kidney disease by lowering pressure in the kidney filter, the glomerulus. Alternative drugs that can lower pressure in the glomerulus but do not cause ketoacidosis would theoretically be of great benefit to persons with T1DM, as they would prevent kidney disease without the risks of ketoacidosis involved with SGLT2-inhibitors.
Acetazolamide is a diuretic that has been in use since 1953 for the treatment of glaucoma, mountain sickness and edema. Preliminary studies in mice, as well as in humans with T1DM demonstrate that acetazolamide can lower glomerular pressure. However, these studies have all been performed for short periods of time (days to weeks). It is unclear if acetazolamide can be safely given to persons with T1DM for longer periods of time. Thus, clinical trials are needed to assess the safety and utility of long term acetazolamide use in persons with T1DM.
Description of Project
The development of kidney disease is a devastating consequence of type 1 diabetes mellitus (T1DM). The risks of death increase dramatically in persons with T1DM who develop kidney disease, and many go on to require dialysis or kidney transplantation. Recently a new drug class, SGLT-2 inhibitors, have been demonstrated to prevent kidney disease in persons with diabetes. However, these drugs are only approved for use in persons with type 2 diabetes and may be risky in persons with T1DM, as they can cause ketoacidosis. These drugs help prevent kidney disease by lowering pressure in the kidney filter, the glomerulus. Alternative drugs that can lower pressure in the glomerulus but do not cause ketoacidosis would theoretically be of great benefit to persons with T1DM, as they would prevent kidney disease without the risks of ketoacidosis involved with SGLT2-inhibitors.
Acetazolamide is a diuretic that has been in use since 1953 for the treatment of glaucoma, mountain sickness and edema. Preliminary studies in mice, as well as in humans with T1DM, demonstrate that acetazolamide can lower glomerular pressure. However, these studies have all been performed for short periods of time (days to weeks). It is unclear if acetazolamide can be safely given to persons with T1DM for longer periods of time. Additionally, the optimal dose of acetazolamide to lower glomerular pressure, with minimal side effects, remains unknown. Thus, we propose a clinical trial of acetazolamide in persons with T1DM. First, we will give 12 study participants two-week courses of three escalating doses of acetazolamide. We will determine which dose optimally lowers glomerular pressure with minimal side effects over 2 weeks. We will then give 25 participants that dose of acetazolamide, or placebo, for 10 weeks. Participants will then switch either from placebo to acetazolamide, or vice versa, depending on which they started with. These data will allow us to assess how well the drug lowers glomerular pressures, as well as the incidence of side effects relative to placebo over 10 weeks in T1DM. These data will lay the critically needed groundwork to design future larger trials of acetazolamide in which we hope to demonstrate acetazolamide can be used to help prevent kidney disease in persons with T1DM in routine clinical practice.
Anticipated Outcome
We anticipate that low doses of acetazolamide, administered over 10 weeks to persons with type 1 diabetes mellitus (T1DM) will effectively lower glomerular pressures and filtration rates, with minimal pill burden or side effects. This would imply that acetazolamide may be safe and effective at preventing the loss of kidney function in persons with T1DM. This work would then serve as a foundation for larger trials studying the effect of acetazolamide on the development of kidney disease over multiple years in persons with T1DM.
Relevance to T1D
Persons with type 1 diabetes mellitus (T1DM) have an increased risk of developing chronic kidney disease and end-stage kidney disease requiring dialysis or a kidney transplant. They are also at increased risk of cardiovascular disease, particularly if they should develop kidney disease. Therapies that lower the risk of kidney disease in persons with T1DM are needed. Recent landmark improvements in therapy to prevent kidney and cardiovascular disease in type 2 diabetes are contraindicated in T1DM. Acetazolamide is an FDA approved medication has the potential to provide similar kidney benefits to persons with T1DM. If this trial is successful, this could represent the first step in major breakthrough in the long-term treatment of T1DM.