Objective
The goals of this clinical trial are:
1. To determine whether treatment with the SGLT2 inhibitor sotagliflozin (SOTA) can slow loss of kidney function in persons with T1D and moderate to advanced diabetic kidney disease. After a 2-month period, during which diabetes care will be standardized and education on monitoring and minimizing DKA risk is implemented, 150 persons with T1D and diabetic kidney disease will be randomly assigned (50/50) to take one table of SOTA (200 mg) or a similarly looking inactive tablet (placebo) daily for 3 years followed by 2-months without treatment (drug washout). Neither the participants nor the study staff will know whether a person has been assigned to taking SOTA or the inactive tablet. Kidney function at the end of drug washout will be compared between the two treatment groups to see whether SOTA prevented kidney function loss in those treated with this drug as compared to those who took the inactive tablet.
2. To institute and evaluate the efficacy of an advanced DKA prevention program for the safe use of SOTA in persons with T1D and moderate to advanced DKD. The DKA prevention program will include participant education, close follow-up with study staff, continuous glucose monitoring, and systematic ketone body self-monitoring with a meter provided by the study. The effectiveness of this program will be evaluated by comparing levels of ketone bodies and number of DKA events between persons treated with SOTA and those taking the inactive tablet in the study described under #1.
Background Rationale
Diabetic kidney disease (DKD) is the long-term complication of type 1 diabetes (T1D) imposing the highest social and economic burden. After 40 years of diabetes, about 1 in 3 patients with T1D has increased amounts of proteins in their urine and has started to lose kidney filtering function. These findings indicate high risk of progression to end-stage kidney disease (ESKD) meaning that dialysis or a kidney transplant are needed for survival. The improvements in glucose and blood pressure control during the past 20 years have been successful in postponing the onset of ESRD to later in life but have not affected the overall frequency of this severe complication, which has in fact been steadily increasing over this time period. Thus, DKD remains one of the most important causes of major illness and premature death among people with T1D. For patients with T2D, powerful new drugs that can prevent or delay ESKD, sodium-glucose cotransporter-2 inhibitors (SGLT2i), are now available. Whether these drugs have similar effects in T1D remains unknown because of the paucity of studies in this population, due to concerns about the 2- to 3-fold increase in risk of diabetic ketoacidosis (DKA), a serious, potentially fatal acute complication of diabetes due to the accumulation of substances called ketone bodies observed with SGLT2i therapy in T1D. One of the few T1D studies conducted to date showed that implementing an enhanced DKA prevention plan can reduce the risk of DKA associated with the SGLT21 sotagliflozin (SOTA) to acceptably low levels. Nonetheless, the potential increase in DKA risk with SGLT2i use has discouraged most pharmaceutical companies from studies in T1D patients. Fortunately, Lexicon Therapeutics, (the manufacturer of SOTA), has committed to providing this drug and placebo to evaluate the renal effectiveness of SGLT2i in T1D and to better understand their benefit/risk ratio in T1D persons with moderate to advanced diabetic kidney disease (DKD), two goals that are warranted and critical given the high risk of death and ESKD in this population. For this study, we will leverage the expertise in clinical research of diabetes and its complications available at 15 academic sites in the US and Canada that are part of the PERL and SUGARNSALT consortia. We will focus on persons with T1D and moderate to advanced diabetic kidney disease since these are at very high risk of ESKD and are therefore most in need of therapies protecting the kidney. Preliminary data also suggest that persons with moderate to advanced DKD may be at lower risk of DKA and this study will provide the opportunity to see whether this is true.
Description of Project
Diabetic kidney disease (DKD) remains the leading cause of end-stage kidney disease, rising in frequency in parallel with the epidemic of diabetes worldwide. The estimated lifetime risk of kidney disease in persons with type 1 diabetes (T1D) has been reported to be as high as 50%, although risk may be lower in excellent care environments. In addition to being at risk of end stage kidney disease (ESKD), which requires a kidney transplant or dialysis for survival, persons with T1D and DKD are at a markedly increased risk of cardiovascular complications and premature mortality. For patients with T2D, powerful new drugs that can prevent or delay ESKD, sodium-glucose cotransporter-2 inhibitors (SGLT2i), are now available. Whether these drugs have similar effects in T1D remains unknown because of the paucity of studies in this population, due to concerns about the 2- to 3-fold increase in risk of diabetic ketoacidosis (DKA, a serious, potentially fatal acute complication of diabetes due to the accumulation of substances called ketone bodies) observed with SGLT2i therapy in T1D. One of the few T1D studies conducted to date showed that implementing an enhanced DKA prevention plan can reduce the risk of DKA associated with the SGLT21 sotagliflozin (SOTA) to acceptably low levels. Herein we propose to use a similar DKA prevention program to carry-out a 3-year trial to test the kidney benefit of the SOTA in 150 persons with T1D and moderate to advanced DKD. A secondary trial aim is to evaluate the effectiveness of this DKA prevention program in limiting the increased DKA risk in persons with T1D and serious DKD treated with SGLT2i. After a 2-month period, during which diabetes care will be standardized and education on monitoring and minimizing DKA implemented, eligible study subjects will be randomly assigned (50/50) to take one tablet of SOTA (200 mg) or an identical appearing inactive tablet (placebo) daily for 3 years followed by 2-months without treatment. Neither the participants nor the study staff will know whether a person was assigned to SOTA or the inactive tablet. Kidney function at the end of the study will be compared between the two treatment groups to see whether SOTA prevented kidney function loss when compared to those on placebo. The DKA prevention program will include participant education, close follow-up with study staff, continuous glucose monitoring, and systematic ketone body self-monitoring with a special meter provided by the study. If successful, this study will provide efficacy and safety data that could be used to seek FDA and Health Canada approval of SOTA for the prevention of kidney function decline in patients with T1D and DKD. Based on preliminary data in T1D, one can conservatively postulate that SOTA may on average delay ESKD by 5 to 10 years and, in some persons, it may prevent it altogether. The reduction in suffering and mortality resulting from these beneficial effects would have a major impact on the lives of patients with T1D and serious DKD as well as on society at large, significantly reducing the human and financial costs associated with this condition.
Anticipated Outcome
SOTA is approved in Europe (but not in the US) as a therapy for persons with T1D. Through this clinical trial, we will gather data on the efficacy and safety of SOTA that could be used to seek FDA and Canada Health approval of this drug to prevent of kidney function decline in patients with T1D and DKD. While our study is focused on patients with DKD, the results of this study may prompt future studies to see whether this drug can also prevent kidney function decline in patients with T1D and milder DKD. In people with T2D or without diabetes, SGLT2i drugs such as SOTA also have major beneficial effects on cardiovascular health that are in part independent of the benefits on kidney function. The number of participants in our study will be too small to test whether SOTA can prevent cardiovascular events such as heart attacks, heart failure, or death due to heart disease in person with T1D. However, positive results from our study may prompt larger studies aimed at studying this additional beneficial effect of SOTA.
Relevance to T1D
The two interventions currently available to prevent diabetic kidney disease or slow its progression to end-stage kidney disease (ESKD), i.e., intensive glycemic control and lowering blood pressure by means of renin-angiotensin system blockers (RASB) and other antihypertensive drugs, have not succeeded in lowering the risk of these complications in the T1D population. In fact, the incidence of new cases of T1D-related ESKD in the US, albeit at a somewhat older age, has continued to increase since these interventions were introduced in the early 90’s. Thus, there is a critical need for new therapies. Through this study, we will determine whether an SGLT2 inhibitor drug sotagliflozin (SOTA), in the class of drugs known to prevent kidney function decline in people with T2D or without diabetes, has a similar beneficial effect in persons with T1D. Based on preliminary data in T1D, one can conservatively postulate that SOTA may on average delay ESKD by 5 to 10 years and, in some persons, it may prevent it altogether. If successful in demonstrating these beneficial effects, the resulting reduction in suffering and death would have a major impact on the lives of patients with T1D and DKD as well as on society at large, significantly reducing the human suffering and financial costs associated with this condition.