Sotagliflozin Reduces HF Events in Patients With Diabetes and CKD Regardless of Albuminuria Status

Apr 02, 2021   |  Michael Szarek, PHD; Deepak L. Bhatt, MD, MPH, MBA, FACC; Philippe Gabriel Steg, MD, FACC

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Quick Takes

  • Sodium-glucose cotransporter 2 (SGLT2) inhibition reduces the risk of total heart failure (HF) events in patients with diabetes and chronic kidney disease (CKD) without requiring a history of stable ischemic heart disease (SIHD) or albuminuria.
  • This therapeutic class can also reduce first major adverse cardiovascular events (MACE) in these patients, but potential benefits on renal events are less certain.

Introduction

Type 2 diabetes increases the risk of CKD, HF, and ischemic events.1-3 As a therapeutic class, SGLT2 inhibitors are an effective treatment for type 2 diabetes.4-6 In addition, outcomes studies have demonstrated SGLT2 inhibition reduces the risk of hospitalization for HF among patients with type 2 diabetes and CKD, with kidney disease characterized by reduced estimated glomerular filtration rate (eGFR)—but still ≥30 mL/min/1.73m2—and either all7 or a subset8 having albuminuria. Furthermore, SGLT2 inhibition has been shown to reduce adverse renal events in this high-risk patient population.7,8

SGLT2 Inhibition in Diabetic Kidney Disease, Regardless of Albuminuria Status

Despite the advances of this therapeutic class in the treatment of type 2 diabetes, until recently it was unknown if SGLT2 inhibition would reduce the risk of cardiovascular events among patients with diabetic kidney disease, regardless of albuminuria status. Recently published results from the SCORED (Effect of Sotagliflozin on Cardiovascular and Renal Events in Patients With Type 2 Diabetes and Moderate Renal Impairment Who Are at Cardiovascular Risk) study of sotagliflozin have provided such data.9 In addition to SGLT2 inhibition, sotagliflozin inhibits gastrointestinal SGLT1, which may result in delayed glucose absorption and reduced postprandial glucose levels.9,10

The SCORED study was a multicenter, double-blind, randomized controlled trial in which 10,584 patients with type 2 diabetes and eGFR of 25-60 mL/min/1.73m2 were assigned to receive sotagliflozin or placebo. Although only a fraction had a history of SIHD (20% with prior myocardial infarction, 22% with prior coronary revascularization), almost 90% had at least 1 major cardiovascular risk factor. Additionally, 31% had a history of HF. Median eGFR of the study population was 44.5 mL/min/1.73m2, including 8% with eGFR <30 mL/min/1.73m2. Importantly, patients were enrolled regardless of the degree of their albuminuria. The overall median albumin-to-creatinine ratio was 74; 35% and 34% of the patients had normoalbuminuria or microalbuminuria, respectively.

Despite follow-up being curtailed due to loss of funding, sotagliflozin reduced the primary endpoint of total cardiovascular deaths, hospitalizations for HF, and urgent visits for HF (5.6 events per 100 patient-years in the sotagliflozin group and 7.5 events per 100 patient-years in the placebo group; hazard ratio [HR] 0.74; 95% confidence interval [CI], 0.63-0.88; p < 0.001). First MACE event (cardiovascular death, non-fatal myocardial infarction, or non-fatal stroke) was also reduced (HR 0.84; 95% CI, 0.72-0.99; p = 0.035), as was total MACE (HR 0.77; 95% CI, 0.65-0.91; p = 0.002). However, due to a relatively low number of events from the abbreviated follow-up, the reduction in a composite renal endpoint (first sustained ≥50% decrease in eGFR, chronic dialysis, renal transplant, or sustained eGFR <15 mL/min/1.73m2) was not significant (HR 0.71; 95% CI, 0.46-1.08; p = 0.11).

This is in contrast to the CREDENCE (Canagliflozin and Renal Events in Diabetes With Established Nephropathy Clinical Evaluation) study in patients with diabetes and albuminuric kidney disease. In the CREDENCE study, in addition to reducing first MACE events (HR 0.80; 95% CI, 0.67-0.95; p = 0.01), the SGLT2 inhibitor canagliflozin significantly reduced the primary composite renal endpoint (HR 0.70; 95% CI, 0.59-0.82; p < 0.001).7 It is notable, however, that the renal endpoint event rates in the placebo groups in both studies were quite similar (0.7 and 0.6 events per 100 patient-years in the SCORED and CREDENCE studies, respectively), and the estimated treatment HR were nearly identical. Adverse events that were more common with sotagliflozin than with placebo were diarrhea (8.5% vs. 6.0%; p < 0.001), diabetic ketoacidosis (0.6% vs. 0.3%; p = 0.02), genital mycotic infections (2.4% vs. 0.9%; p < 0.001), and volume depletion (5.3% vs. 4.0%; p = 0.003).

In post hoc analyses of the SCORED study involving subgroups determined by albuminuria status, patients with normoalbuminuria did not appear to clearly benefit from sotagliflozin treatment on the primary endpoint (HR 1.05; 95% CI, 0.76-1.46), first MACE event (HR 0.99; 95% CI, 0.72-1.36), or total MACE events (HR 0.90; 95% CI, 0.64-1.26). In contrast, patients with microalbuminuria did appear to benefit from sotagliflozin on the primary endpoint (HR 0.74; 95% CI, 0.57-0.97) but less so on first MACE event (HR 0.98; 95% CI, 0.75-1.28) or total MACE events (HR 0.87; 95% CI, 0.66-1.16).

Conclusion

In the SCORED study, a setting where enrolled patients with diabetes and CKD were not required to have a history of SIHD, HF, or albuminuria, SGLT2 inhibition reduced the risk of total HF events, as well as first MACE events and total MACE events, with a non-significant reduction in a composite renal endpoint. Studies of longer duration are required to determine the potential incremental nephroprotective benefits of SGLT2/1 inhibitors in high-risk patient populations.

References

  1. Rawshani A, Rawshani A, Franzén S, et al. Mortality and Cardiovascular Disease in Type 1 and Type 2 Diabetes. N Engl J Med 2017;376:1407-18.
  2. Thomas MC, Cooper ME, Zimmet P. Changing epidemiology of type 2 diabetes mellitus and associated chronic kidney disease. Nat Rev Nephrol 2016;12:73-81.
  3. Thomas MC. Type 2 Diabetes and Heart Failure: Challenges and Solutions. Curr Cardiol Rev 2016;12:249-55.
  4. Bhatt DL, Verma S, Braunwald E. The DAPA-HF Trial: A Momentous Victory in the War against Heart Failure. Cell Metab 2019;30:847-9.
  5. Verma S, Bhatt DL. More CREDENCE for SGLT2 Inhibition. Circulation 2019;140:1448-50.
  6. Connelly KA, Bhatt DL, Verma S. Can We DECLARE a Victory against Cardio-Renal Disease in Diabetes? Cell Metab 2018;28:813-5.
  7. Perkovic V, Jardine MJ, Neal B, et al. Canagliflozin and Renal Outcomes in Type 2 Diabetes and Nephropathy. N Engl J Med 2019;380:2295-306.
  8. Neal B, Perkovic V, Mahaffey KW, et al. Canagliflozin and Cardiovascular and Renal Events in Type 2 Diabetes. N Engl J Med 2017;377:644-57.
  9. Bhatt DL, Szarek M, Pitt B, et al. Sotagliflozin in Patients with Diabetes and Chronic Kidney Disease. N Engl J Med 2021;384:129-39.
  10. Bhatt DL, Szarek M, Steg PG, et al. Sotagliflozin in Patients with Diabetes and Recent Worsening Heart Failure. N Engl J Med 2021;384:117-28.

Clinical Topics: Dyslipidemia, Heart Failure and Cardiomyopathies, Stable Ischemic Heart Disease, Lipid Metabolism, Acute Heart Failure, Chronic Angina

Keywords: Angina, Stable, Diabetes Mellitus, Type 2, Heart Failure, Sodium-Glucose Transporter 2, Diabetic Nephropathies, Glomerular Filtration Rate, Cardiovascular Diseases, Risk Factors, Glycosides, Sodium-Glucose Transporter 1, Renal Insufficiency, Chronic, Hospitalization, Myocardial Ischemia


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