What is the context for use of sotagliflozin and what are its additional benefits over empagliflozin (Empa) in patients with type 1 or type 2 diabetes?

Sotagliflozin: Context for Use and Comparison to Empagliflozin

FDA-Approved Indication and Context

Sotagliflozin is FDA-approved specifically for reducing cardiovascular death, heart failure hospitalization, and urgent heart failure visits in patients with heart failure OR type 2 diabetes with CKD plus additional cardiovascular risk factors—NOT for glycemic management of diabetes. 1

The key distinction is that sotagliflozin is a dual SGLT1/SGLT2 inhibitor, blocking both renal glucose reabsorption (SGLT2) and intestinal glucose absorption (SGLT1), whereas empagliflozin is a selective SGLT2 inhibitor. 1, 2

Clinical Context for Sotagliflozin Use

Heart Failure Population

• SOLOIST-WHF trial: Enrolled patients hospitalized for worsening heart failure (requiring IV diuretics, elevated natriuretic peptides), started sotagliflozin either before or within 3 days of discharge. 1
• Reduced total cardiovascular deaths and heart failure hospitalizations/urgent visits by 33% (HR 0.67 [95% CI 0.52–0.85]) over 9 months. 1
• Worked across the ejection fraction spectrum, though only 21% had EF >50%, limiting HFpEF-specific conclusions. 1

Type 2 Diabetes with CKD Population

• SCORED trial: Enrolled 10,584 patients with type 2 diabetes, CKD, and additional cardiovascular risk factors. 1
• Reduced total cardiovascular deaths, heart failure hospitalizations, and urgent visits (5.6 vs 7.5 events per 100 patient-years). 1
• Reduced heart failure hospitalizations and urgent visits specifically (3.5% vs 5.1%). 1
• Did NOT significantly reduce cardiovascular death or all-cause mortality alone. 1

Additional Benefits Over Empagliflozin

Theoretical Advantages (Dual SGLT1/2 Inhibition)

• Delayed intestinal glucose absorption via SGLT1 inhibition reduces postprandial glucose excursions beyond what SGLT2 inhibition alone achieves. 1, 2, 3
• May provide appetite suppression through gut-mediated mechanisms not seen with selective SGLT2 inhibitors. 3

Evidence-Based Reality Check

There are NO head-to-head trials comparing sotagliflozin to empagliflozin, so direct superiority claims cannot be made. The cardiovascular benefits appear similar in magnitude:

• Empagliflozin reduced cardiovascular death/heart failure hospitalization by 21% in EMPEROR-Reduced (HR 0.79). 1
• Sotagliflozin reduced similar composite outcomes by 33% in SOLOIST-WHF (HR 0.67), though this was a shorter, underpowered trial. 1

Critical Safety Differences

Sotagliflozin carries significantly higher risks than empagliflozin:

• Diarrhea: 6.1% vs 3.4% with placebo (due to SGLT1 inhibition in the gut). 1
• Severe hypoglycemia: 1.5% vs 0.3% with placebo (likely from delayed carbohydrate absorption). 1
• Diabetic ketoacidosis: Eight-fold increased risk in type 1 diabetes trials. 4

Practical Algorithm for Choosing Between Sotagliflozin and Empagliflozin

Choose Empagliflozin (First-Line) When:

• Patient has heart failure (any ejection fraction) with or without diabetes—empagliflozin has robust Class I guideline recommendations. 5
• Patient has type 2 diabetes with established cardiovascular disease or CKD—empagliflozin has proven mortality benefit. 5
• Patient is at risk for gastrointestinal side effects or hypoglycemia. 1

Consider Sotagliflozin When:

• Patient has recent heart failure hospitalization (within 3 days) and needs immediate initiation—this was the SOLOIST-WHF population. 1
• Patient has type 2 diabetes with CKD and high cardiovascular risk but cannot tolerate other SGLT2 inhibitors (though evidence for this is weak). 1
• Patient requires additional postprandial glucose control beyond what SGLT2 inhibition provides (theoretical benefit, not proven clinically superior). 2, 3

Avoid Sotagliflozin When:

• Type 1 diabetes: Not FDA-approved for glycemic management, and the American College of Cardiology recommends avoiding SGLT inhibitors in T1DM with heart failure due to DKA risk. 4
• Patient has history of recurrent diarrhea or gastrointestinal disorders. 1
• Patient is prone to hypoglycemia or has erratic carbohydrate intake. 1

Critical Caveats

Funding and Trial Limitations

Both SCORED and SOLOIST-WHF ended early due to lack of funding, requiring post-hoc changes to primary endpoints before unblinding, which weakens the evidence quality. 1

No Mortality Benefit

Unlike empagliflozin in EMPEROR-Reduced, sotagliflozin did not significantly reduce cardiovascular death or all-cause mortality in either major trial. 1

Guideline Positioning

The 2024 ADA guidelines recommend SGLT2 inhibitors with proven benefit for heart failure—empagliflozin and dapagliflozin have stronger evidence bases and are mentioned more prominently than sotagliflozin. 1, 5

Cost and Availability

Sotagliflozin is newer and likely more expensive than generic empagliflozin, with no proven superiority to justify the cost difference in most clinical scenarios. 5