Can Sotagliflozin Prevent Cardiovascular Ailments for Patients with Diabetes and Chronic Kidney Disease
Cardiovascular diseases, including stroke, are major healthcare issues affecting humans worldwide. Between 2010 and 2030, the estimated total medical costs might escalate to from $273–$818 billion in the United States alone. Modifiable risk factors for stroke include hypertension, diabetes, smoking and lipid management. Diabetes is a well-established risk factor for stroke. It can cause pathologic changes in blood vessels, kidney damage, and can lead to stroke if the cerebral vasculature is affected directly. Additionally, mortality is higher and poststroke outcomes are poorer in patients with stroke with uncontrolled glucose levels.
Sotagliflozin is a sodium-glucose cotransporter (SGLT) 2 inhibitor indicated for the treatment of diabetes mellitus, which also exhibits activity in the gastrointestinal tract via SGLT1 inhibition. Although approved for use by the European Commission, sotagliflozin was denied FDA approval in 2019 over concerns about diabetes ketoacidosis. Interestingly, results from the SOLOIST-WHF trial found sotagliflozin reduced deaths and hospitalizations in patients with type 2 diabetes and acute decompensated heart failure. This drug could be useful in preventing cardiovascular ailments in patients with chronic kidney diseases and diabetes, and these effects have not been fully described. In this study, called SCORED, researchers conducted a trial for patients with type 2 diabetes mellitus, chronic kidney disease, and risks for cardiovascular disease which were assigned a 1:1 ratio to receive sotagliflozin or placebo.
Study Design
The study conducted was a phase 3, randomized, double-blind placebo-controlled trial to compare the effects of sotagliflozin with placebo in patients with chronic kidney disease, type 2 diabetes, and other cardiovascular risks. All the patients in the study received standard-of-care treatment.
The final trials were completed in March 2020 prior to the study losing its funding from sponsors. This led to a revision of end-points and revised protocols. The first original sponsor was Sanofi, then it was transferred to Lexicon Pharmaceuticals in January 2020.
The committees in charge consisted of academic physicians and representatives from sponsors who developed the statistical analysis plan and protocol for the trial and interpretation of results. The sponsors also provided the sotagliflozin and placebo. The statistical analysis was then performed by an independent academic statistician (second author) with protocols approved by the institutional review board, ethics committee, and relevant health authority for each trial.
The authors verified the accuracy and completeness of the data. They reported all adverse events and followed the approved protocol and statistical analysis plan. Also, an independent board managed the trial. They managed the confidentiality issues between the author and sponsors. The sponsor was given the right to review and comment on the manuscript. The authors were also not restricted from publishing the result of the trial.
Subjects of the Study
The trials were given to individuals 18 years or older with type 2 diabetes mellitus with a glycated hemoglobin level of 7% or higher, or chronic kidney disease, and additional cardiovascular risk factors.
The risk factors consisted of at least one major cardiovascular risk in 18 years of age or older and at least 2 minor cardiovascular risks in 55 years age or older. Written consents were obtained for all patients.
Statistical Analysis
The original objective of the trial is to establish the noninferiority of sotagliflozin to placebo and the superiority of sotagliflozin over placebo with respect to the first occurrence of death from cardiovascular causes of heart failure.
The researchers estimated that for 10,500 random patients, 1189 events would be needed to test with respect to the first occurrence of major adverse cardiovascular event on the basis of the upper boundary of a two-sided 95% confidence interval for the hazard ratio being less than 1.3, and 844 events would be needed to test for superiority with respect to the first occurrence of death from cardiovascular causes or hospitalization for heart failure. All analyses were conducted using the intention-to-treat principle. To allow for analysis of total events, competing-risk marginal models were used according to heart-failure criteria and geographic region, with deaths not included in given end-point treated as competing for terminal events, were applied to create hazard ratios with Wald 95% confidence intervals and P values.
Study Results
There were 19,188 patients screened in total. 10,584 were enrolled and were halved into two groups of 5292. The first half took the sotagliflozin, the second was assigned with a placebo. Their cases were observed for 16 months.
The median age for all patients was 69 years. Females were 44.9% and were 82.7% white. Vital status was available for 99.4% of the patients. A total of 142 or 1.3% of patients couldn’t complete their final trial visits which meant they had unknown end-of-trial vital status. The median duration of exposure to sotagliflozin was 14.2 months and the median duration of exposure to placebo was 14.3 months.
The rate of primary end-point events was 5.6 events per 100 patient-year in the sotagliflozin group. It was 7.5 events per 100 patient-year in the placebo group. The rate of deaths in the cardiovascular cause per 100 patient-years was 2.2 with sotagliflozin and 2.4 with placebo.
For the original coprimary endpoint of the first occurrence of death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke, the hazard ratio was 0.84 (95% CI, 0.72 to 0.99); for the original coprimary endpoint of the first occurrence of death from cardiovascular causes or hospitalization for heart failure, the hazard ratio was 0.77 (95% CI, 0.66 to 0.91). The researchers also found that diarrhea, genital mycotic infections, diabetic ketoacidosis were more common in the sotagliflozin than in the placebo group.
In the trials of patients with type 2 diabetes mellitus, chronic kidney disease, and other additional cardiovascular risks, the SGLT inhibitor sotagliflozin resulted in a lower risk of the composite primary endpoint of the total number of deaths from cardiovascular causes of heart failure.
The data of deaths from cardiovascular causes and renal endpoints did not have a significant difference between the trial groups. Side effects of sotagliflozin included diarrhea, volume depletion, diabetic ketoacidosis, and genital mycotic infection.
While previous studies required patients to have a urinary albumin-to-creatinine ratio of at least 200 or 300, the study’s trial did not require this. They also didn’t require a history of heart failure. And despite the low eGFR in the total population, kidney injury did not differ much between the sotagliflozin and placebo group.
The potential mechanism of SGLT2 inhibition includes improved oxygen supply, weight loss, enhanced myocardial energetics, adaptive cellular reprogramming, and renal and systemic natriuretic effects. Whether there are additional cardiovascular benefits from the SGLT1 inhibition, remains to be determined.
Limitations of the Study
Limitations of the study include premature cessation due to loss of funding which resulted in the uncompleted duration of follow-up. Because of this, the primary endpoint was changed to preserve statistical power.
The alteration to heart failure-related endpoint was done during the time when there was evidence that SGLT2 inhibitors were proved to reduce heart failure. Sotagliflozin with SGLT1/2 activity has not been studied for this situation. Sotagliflozin is an SGLT2 inhibitor that also has gastrointestinal SGLT1 inhibition. SGLT2 inhibition is found to increase urinary glucose excretion, while SGLT1 inhibition delays glucose absorption and reduces postprandial glucose.
The researchers conducted the trial to determine if sotagliflozin was non-inferior to placebo in reducing ischemic events or if it was superior in reducing heart failure events. Based on the current data about SGLT2 inhibitors, the researchers aimed to examine whether sotagliflozin would reduce the number of deaths from cardiovascular causes.
Conclusion
In patients with chronic kidney disease and diabetes (with/without albuminuria), sotagliflozin resulted in a lower risk of composite deaths from heart failure and cardiovascular causes.
The study showed that sodium-glucose cotransporter 2 (SGLT2) inhibitors are effective in treating type 2 diabetes and lowering the risk of hospitalization for heart failure among patients with or without a history of heart failure. Based on the trial results, the researchers encourage the use of SGLT2 inhibition for patients with chronic kidney disease and diabetes.
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