What are the mechanisms by which Sotagliflozin (Sodium-glucose cotransporter 1 (SGLT1) and Sodium-glucose cotransporter 2 (SGLT2) inhibitor) reduces the risk of Major Adverse Cardiovascular Events (MACE)?

Mechanisms of MACE Reduction with Sotagliflozin

Sotagliflozin reduces MACE through dual SGLT1 and SGLT2 inhibition, which appears to provide unique ischemic cardiovascular benefits beyond the heart failure benefits seen with selective SGLT2 inhibitors, specifically reducing both myocardial infarction and stroke in addition to heart failure events. 1

Dual Mechanism of Action

Sotagliflozin differs fundamentally from selective SGLT2 inhibitors through its combined inhibition of both SGLT1 and SGLT2 transporters 2:

• SGLT2 inhibition in the proximal renal tubule increases urinary glucose excretion, producing diuretic and natriuretic effects, weight loss, and systolic blood pressure reduction 2
• SGLT1 inhibition in the gastrointestinal tract delays intestinal glucose absorption, providing an additional glucose-lowering mechanism not present in selective SGLT2 inhibitors 2

This dual mechanism distinguishes sotagliflozin from highly selective SGLT2 inhibitors like dapagliflozin, empagliflozin, and ertugliflozin 3

Unique Ischemic Cardiovascular Benefits

The most compelling evidence for sotagliflozin's distinct mechanism comes from the SCORED trial analysis, which demonstrated benefits not consistently observed with selective SGLT2 inhibitors 1:

• Total MACE reduction: 4.8 versus 6.3 events per 100 person-years (HR 0.77,95% CI 0.65-0.91) 1
• Myocardial infarction reduction: 1.8 versus 2.7 events per 100 person-years (HR 0.68,95% CI 0.52-0.89) 1
• Stroke reduction: 1.2 versus 1.8 events per 100 person-years (HR 0.66,95% CI 0.48-0.91) 1

This independent reduction in both myocardial infarction and stroke has not been previously observed with selective SGLT2 inhibitors and suggests that combined SGLT1 and SGLT2 inhibition may be the underlying mechanism. 1

Comparison to Selective SGLT2 Inhibitors

Selective SGLT2 inhibitors have demonstrated consistent benefits for heart failure outcomes but not for ischemic events 1:

• SGLT2 inhibitors reduce MACE modestly (RR 0.90,95% CI 0.83-0.98) but do not significantly reduce myocardial infarction (RR 0.97,95% CI 0.85-1.12) 2
• GLP-1 agonists reduce stroke (RR 0.86,95% CI 0.77-0.95) but SGLT2 inhibitors do not (RR 1.12,95% CI 0.93-1.34) 2
• The cardiovascular benefits of selective SGLT2 inhibitors are driven predominantly by reductions in cardiovascular death and heart failure hospitalizations, not ischemic events 2

Proposed Mechanistic Pathways

Hemodynamic Effects

• Sotagliflozin produces diuretic and natriuretic effects through renal SGLT2 inhibition, reducing preload and afterload 2
• Systolic blood pressure reduction of approximately 2.4 mmHg contributes to cardiovascular risk reduction 4
• Volume reduction decreases cardiac workload and may reduce myocardial oxygen demand 2

Metabolic Effects Beyond Glucose Lowering

• The cardiovascular and renal benefits are out of proportion to glucose-lowering effects and persist even when glycemic efficacy is lost at lower eGFR levels 3
• Delayed intestinal glucose absorption via SGLT1 inhibition may provide additional metabolic benefits not present with selective SGLT2 inhibitors 2
• Weight loss and improved insulin sensitivity contribute to overall cardiovascular risk reduction 2

Pleiotropic Renal Effects

• Reduced sodium reabsorption and increased sodium delivery to the distal tubule activate tubuloglomerular feedback, reducing intraglomerular pressure 3
• These hemodynamic changes provide cardiorenal protection independent of glucose lowering 3

Potential Anti-Ischemic Mechanisms

• The unique reduction in myocardial infarction and stroke with sotagliflozin suggests additional anti-atherothrombotic or vascular protective effects beyond those of selective SGLT2 inhibitors 1
• SGLT1 inhibition may contribute to endothelial function improvement or plaque stabilization, though this requires further investigation 1

Clinical Context and Evidence Quality

The SCORED trial enrolled 10,584 patients with type 2 diabetes, chronic kidney disease (eGFR 25-60 mL/min/1.73 m²), and additional cardiovascular risk factors 2. The trial ended early due to loss of funding, requiring prespecified changes to primary endpoints before unblinding 2. Despite this limitation:

• The MACE reduction was consistent across prespecified subgroups stratified by sex, age, geographical region, heart failure status, eGFR, albuminuria, and cardiovascular disease history 1
• Meta-analysis including SCORED and SOLOIST-WHF demonstrated consistent benefits: HF reduction (RR 0.66,95% CI 0.64-0.69), stroke reduction (RR 0.75,95% CI 0.58-0.97), and MACE reduction (RR 0.73,95% CI 0.66-0.81) 4

Common Pitfalls to Avoid

• Do not assume class effect equivalence: Sotagliflozin's dual SGLT1/SGLT2 inhibition produces distinct ischemic benefits not consistently seen with selective SGLT2 inhibitors 1
• Monitor for gastrointestinal effects: SGLT1 inhibition increases diarrhea risk (6.1% versus 3.4% with placebo) due to delayed intestinal glucose absorption 2
• Recognize hypoglycemia risk: Severe hypoglycemia was more common with sotagliflozin (1.5% versus 0.3% with placebo), particularly when combined with insulin or sulfonylureas 2
• Continue despite reduced glycemic efficacy: Like selective SGLT2 inhibitors, cardiovascular benefits persist even when glucose-lowering diminishes at lower eGFR levels 3