Sotagliflozin to Slow Kidney Function Decline in Persons With Type 1 Diabetes and Diabetic Kidney Disease

Effectiveness and Safety of Sotagliflozin in Slowing Kidney Function Decline in Persons With Type 1 Diabetes and Moderate to Severe Diabetic Kidney Disease

Powerful new drugs that can prevent or delay end stage kidney disease (ESKD) - so called sodium-glucose cotransporter-2 inhibitors (SGLT2i) - are now available for patients with type 2 diabetes. Whether these drugs have similar effects in patients with type 1 diabetes (T1D) remains unknown because of the few studies in this population, due to concerns about the 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 SGLT2i sotagliflozin (SOTA) to very low levels. In the present study, a similar DKA prevention program will be used to carry-out a 3-year trial to test the kidney benefit of SOTA in 150 persons with T1D and moderate to advanced DKD. 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 a similarly looking inactive tablet (placebo) every day for 3 years followed by 2-months without treatment. Neither the participants nor the study staff will know whether a person was assigned to taking 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 in those treated with this drug as compared to those who took the inactive tablet. 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. If successful, this study will provide efficacy and safety data that could be used to seek FDA approval of SOTA for the prevention of kidney function decline in patients with T1D and DKD.

Despite improvements in glycemia management and the use of renin-angiotensin system blockade (RASB), the overall incidence of ESKD incidence in the US T1D population is not decreasing. For patients with type 2 diabetes (T2D), powerful new drugs that can prevent or delay ESKD, sodium-glucose cotransporter-2 inhibitors (SGLT2i), are now available. Whether similar results can be achieved 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) associated with SGLT2i therapy in T1D. One of the few T1D studies conducted to date (inTandem, a sotagliflozin [SOTA] trial), showed that implementation of an enhanced DKA risk monitoring and mitigation strategy can reduce DKA incidence to <1%/year in subjects on 200 mg/day of this dual SGLT1 and SGLT2 inhibitor. The goals of the present study are to evaluate the renal effectiveness of SGLT2i in T1D and to better understand the benefit/risk ratio of SOTA 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. The study, carried out by the Preventing Early Renal Loss (PERL) and the Canadian Institute of Health Research (CIHR)-funded SUGARNSALT (S&S) consortia, is a multi-center, double-blind, placebo-controlled, parallel-group randomized clinical trial in 150 patients with T1D and moderate to advanced diabetic kidney disease (estimated glomerular filtration rate [eGFR] 20-60 ml/min/1.73 m2 and ACR>200 mg/g). After a 2-month run-in period, during which diabetes care is standardized and education on monitoring and minimizing DKA implemented, eligible study subjects are randomized in a 1:1 ratio to receive placebo or once daily 200 mg SOTA for 3 years followed by a 2-month wash-out period. The eGFR at the end of the wash-out adjusted by its baseline value will be used as the primary outcome on which SOTA efficacy on DKD progression will be evaluated. An intensive DKA risk mitigation plan will be implemented based on the inTandem enhanced protocol as well as on the STICH (Stop SGLT2i, Insulin administration, Carbohydrate intake, Hydration) and STOP-DKA protocols. Cornerstones of this plan will be enhanced participant education, close follow-up with study staff, continuous glucose monitoring, and systematic ketone body (beta-hydroxybutyrate [BHB]) self-monitoring. If successful, the present study will provide efficacy and safety data that could be used to seek FDA and Health Canada approval of SOTA for a T1D DKD indication. Based on the available data in T1D, it can be conservatively postulated that SOTA may reduce eGFR loss by 2 ml/min/1.73 m2 per year. Depending on the baseline eGFR, this would translate to a 5-10 year delay of ESKD. The reduction in morbidity and mortality resulting from the prevention or delay of ESKD due to the use of SOTA would have a major impact on the lives of T1D patients with significant DKD as well as on society at large, substantially reducing the human and financial costs associated with this condition.

Inclusion Criteria:

• Type1 diabetes (T1D) continuously treated with insulin within one year from diagnosis.
• Duration of T1D ≥ 8 years;
• eGFR based on serum creatinine and cystatin c (2021 serum creatinine-cystatin C CKD-EPI equation) between 20 and 60 ml/min/1.73 m2 at screening (with the option of a second eGFR measurement within 4 weeks from the first one if the eGFR was in the range of >60 to ≤65 or ≥16 to <20 ml/min/1.73 m2);
• a. First morning void urinary albumin creatinine ratio (UACR) ≥200 mg/g at Screening or on repeat measurement within 4 weeks from the first one, or b. First morning void urinary UACR ≥100 mg/g at Screening or on repeat measurement within 4 weeks and at least one uACR >=30 in the previous 2 years while treated with RASB at a stable dose;
• HbA1c at screening <10% (with the option of a second HbA1c measurement within 4 weeks from the first one if the HbA1c was ≤10.2%);
• Receiving standard of care, including renin angiotensin system blockers (RASB) at a clinically appropriate dose, unless contraindicated or not tolerated.
• Willing and able to comply with schedule of events and protocol requirements, including written informed consent, and willing to wear a continuous glucose monitoring (CGM) device for the entire duration of the study.
• a. Blood pressure ≤155/95 mmHg at screening, or b. BP ≤155/95 mmHg at the end of the run-in period, or c. consistent BP ≤155/95 mmHg on home monitoring during the run-in period, as determined by study site investigator, despite BP values >155/95 mmHg in clinic.

Exclusion Criteria:

• Type 2 diabetes or monogenic forms of diabetes or diabetes secondary to pancreatic disease;
• Use of automated insulin delivery devices that are not approved by health regulatory agencies, or used in ways that do not align with manufacturer recommendations;
• Use of any SGLT inhibitor in the previous 2 months;
• Use of dual medication RASB therapy (spironolactone, eplerenone, finerenone are allowed in combination with RASB therapy);
• Use of GLP-1 receptor agonists and other non-insulin glucose-lowering agents if not on stable dose for > 2 months at screening (patients can be rescreened after being on stable dose for > 2 months);
• Use of anti tumor necrosis factor (TNF) alpha biologic medications at screening;
• Known allergies, hypersensitivity, or intolerance to SOTA;
• History of ≥3 severe hypoglycemic events (requiring third-party assistance for correction) within 3 months of screening;
• History of diabetic ketoacidosis (DKA) or non-ketotic hyperosmolar state within 3 months of screening OR >1 episode of DKA or non-ketotic hyperosmolar state within 12 months of screening;
• Blood beta-hydroxybutyrate (BHB) >0.6 mmol/L for >2 hours on >2 occasions during the Run-in period;
• Inadequate beta hydroxybutyrate (BHB) testing (<50% of the prescribed measurements) during Run-in;
• History of primary renal glycosuria;
• History of biopsy-proven non-diabetic chronic kidney disease (CKD);
• History of kidney transplant or currently on chronic dialysis;
• Current or past history of decompensated cirrhosis (defined as variceal bleeding, ascites or hepatic encephalopathy), and/or known diagnosis of cirrhosis based on liver biopsy, imaging, or elastography, and/or aspartate aminotransferase (AST) or alanine transaminase (ALT) at screening >2 times upper limit of normal, and/or total bilirubin at screening >1.3 times upper limit of normal).
• History of severe acquired immune deficiency syndrome or human immunodeficiency virus (HIV) infection or severely immunocompromised status;
• Cancer treatment (excluding non-melanoma skin cancer treated by excision, carcinoma in situ of the cervix or uterus, ductal breast cancer in situ, resected non-metastatic breast or prostate cancer) within one year of screening.
• Illicit drug abuse within 6 months of screening;
• Heavy alcohol use (for men, 5 drinks or more on any day or 15 drinks or more per week; for women, 4 drinks or more on any day or 8 drinks or more per week);
• Participation in another interventional clinical research study within 30 days of screening;
• Breastfeeding, pregnancy, or unwillingness to be on contraception during the trial;
• Presence of a clinically significant medical history, physical examination, or laboratory finding that may interfere with any aspect of study conduct or interpretation of results;
• Any condition that may render the patient unable to comply with study requirements and/or complete the study.