What is the role of sotagliflozin (SGLT2 inhibitor) in managing type 2 diabetes (T2D) patients at high risk of major adverse cardiovascular events (MACE)?

Analysis of Sotagliflozin's Effects on Major Adverse Cardiovascular Events in Type 2 Diabetes

Sotagliflozin demonstrates superior reduction in major adverse cardiovascular events (MACE) compared to selective SGLT2 inhibitors in patients with type 2 diabetes and cardiovascular risk factors, with a 23% relative risk reduction (HR 0.77,95% CI 0.65-0.91) driven by significant reductions in both myocardial infarction and stroke—benefits not consistently observed with other SGLT2 inhibitors. 1

Unique Cardiovascular Benefits of Sotagliflozin

Sotagliflozin's dual SGLT1/SGLT2 inhibition provides distinct ischemic cardiovascular benefits beyond the heart failure benefits seen with selective SGLT2 inhibitors. 2 The prespecified pooled analysis from the Phase 3 program demonstrates:

• Total MACE reduction: 4.8 vs 6.3 events per 100 person-years with sotagliflozin vs placebo (HR 0.77,95% CI 0.65-0.91, p=0.0020) 1
• Myocardial infarction reduction: 1.8 vs 2.7 events per 100 person-years (HR 0.68,95% CI 0.52-0.89, p=0.0041) 1
• Stroke reduction: 1.2 vs 1.8 events per 100 person-years (HR 0.66,95% CI 0.48-0.91, p=0.012) 1

This represents a critical distinction from selective SGLT2 inhibitors, which show modest MACE reduction (RR 0.90,95% CI 0.83-0.98) but do not significantly reduce myocardial infarction or stroke individually. 2

Mechanistic Advantages

The dual inhibition mechanism provides complementary cardiovascular protection through multiple pathways: 2

• SGLT2 inhibition increases urinary glucose excretion, producing diuretic and natriuretic effects that reduce preload and afterload, with systolic blood pressure reduction of approximately 2.4 mmHg 2
• SGLT1 inhibition delays intestinal glucose absorption, providing additional metabolic benefits including improved insulin sensitivity and weight loss 2
• Combined effects reduce cardiac fibrosis and inflammation while improving renal hemodynamics 3

Clinical Context and Patient Population

The pooled analysis enrolled 10,584 patients with type 2 diabetes, chronic kidney disease (eGFR 25-60 mL/min/1.73 m²), and additional cardiovascular risk factors. 1 Key baseline characteristics included:

• 48.6% had established cardiovascular disease 1
• 19.9% had prior myocardial infarction 1
• 8.9% had prior stroke 1
• 22.4% had prior coronary revascularization 1

The cardiovascular benefits remained consistent across all prespecified subgroups stratified by sex, age, geographical region, heart failure status, eGFR, albuminuria, and cardiovascular disease history, with no evidence of heterogeneity. 1

Efficacy Independent of Glycemic Control

Sotagliflozin's cardiovascular benefits occur regardless of baseline HbA1c levels, distinguishing it from glucose-dependent mechanisms: 4

• HbA1c ≤7.5%: HR 0.73 (95% CI 0.57-0.93) 4
• HbA1c 7.6-9.0%: HR 0.77 (95% CI 0.63-0.96) 4
• HbA1c >9.0%: HR 0.65 (95% CI 0.50-0.84) 4
• No interaction by baseline HbA1c (p=0.58) 4

This supports initiating sotagliflozin for cardiovascular protection independent of glycemic targets. 4

Heart Failure Outcomes

Beyond MACE reduction, sotagliflozin demonstrates robust heart failure benefits comparable to selective SGLT2 inhibitors: 5

• Heart failure events: 200 mg sotagliflozin showed superior reduction compared to dapagliflozin (OR 0.79,95% CI 0.66-0.94) and empagliflozin (OR 0.90,95% CI 0.63-1.27) 5
• Composite cardiovascular death/heart failure hospitalization: 33% reduction vs placebo in SOLOIST-WHF (HR 0.67,95% CI 0.52-0.85) 3
• Days alive and out of hospital: 3% increase (91.8 vs 88.9 days per 100 days follow-up), driven primarily by 29% reduction in days dead (RR 0.71,95% CI 0.52-0.99) 6

The American Diabetes Association guidelines recognize sotagliflozin's efficacy in patients recently hospitalized for worsening heart failure, with benefits observed regardless of ejection fraction. 3

Safety Profile and Adverse Events

Critical safety considerations distinguish sotagliflozin from selective SGLT2 inhibitors: 3

• Diarrhea: More common with sotagliflozin (6.1% vs 3.4% placebo), likely related to SGLT1 inhibition in the gastrointestinal tract 3, 5
• Severe hypoglycemia: Increased risk (1.5% vs 0.3% placebo), particularly when combined with insulin or sulfonylureas 3
• Diabetic ketoacidosis: No increased risk compared to other SGLT inhibitors 5
• Urinary tract infections: No increased risk 5

When initiating sotagliflozin with background insulin or sulfonylureas, reduce these agents by approximately 20% to prevent hypoglycemia. 7

Comparative Effectiveness

Network meta-analysis comparing sotagliflozin to selective SGLT2 inhibitors reveals: 5

• MACE prevention: 200 mg sotagliflozin superior to dapagliflozin (OR 0.76,95% CI 0.66-0.87) 5
• Cardiovascular death: Empagliflozin superior to sotagliflozin (OR 1.46,95% CI 1.04-2.05) 5
• Blood pressure reduction: Sotagliflozin inferior to empagliflozin (MD 1.30 mmHg, 95% CI 0.03-2.56) and dapagliflozin (MD 2.25 mmHg, 95% CI 0.35-4.14) 5

Clinical Application Algorithm

For patients with type 2 diabetes and high cardiovascular risk, prioritize sotagliflozin when: 3, 2

1. Established atherosclerotic cardiovascular disease with prior myocardial infarction or stroke requiring specific ischemic event reduction 1
2. Chronic kidney disease (eGFR 25-60 mL/min/1.73 m²) with cardiovascular risk factors 3
3. Recent heart failure hospitalization requiring rapid cardiovascular protection 3
4. Multiple cardiovascular risk factors despite well-controlled HbA1c 4

Exercise caution with sotagliflozin in patients: 3

• On high-dose insulin or sulfonylureas (reduce doses by 20% at initiation) 7
• With history of recurrent gastrointestinal issues (monitor for diarrhea) 3
• With eGFR <30 mL/min/1.73 m² (excluded from trials) 3

Critical Pitfalls to Avoid

Do not assume class effect equivalence between sotagliflozin and selective SGLT2 inhibitors. 2 While all SGLT2 inhibitors reduce heart failure hospitalizations, sotagliflozin's dual SGLT1/SGLT2 inhibition produces distinct reductions in myocardial infarction and stroke not consistently observed with empagliflozin, canagliflozin, or dapagliflozin. 2, 1

Do not withhold sotagliflozin based solely on HbA1c levels. 4 The cardiovascular benefits persist across the entire HbA1c spectrum, indicating mechanisms independent of glucose lowering. 4

Do not overlook the increased hypoglycemia risk when combining with insulin or sulfonylureas. 3 Proactive dose reduction of these agents is essential to prevent severe hypoglycemic events. 7

Strength of Evidence

The pooled analysis represents high-quality evidence from the SCORED and SOLOIST-WHF trials, though both ended early due to loss of funding, resulting in prespecified changes to primary endpoints. 1 Despite early termination, the consistent MACE reduction across all prespecified subgroups and the magnitude of effect on individual ischemic endpoints (myocardial infarction and stroke) provide robust evidence for sotagliflozin's unique cardiovascular benefits. 1

The American Diabetes Association and American College of Cardiology guidelines now recognize SGLT2 inhibitors as a class for cardiovascular risk reduction, though they do not preferentially recommend one agent over another. 7 However, the distinct ischemic benefits of sotagliflozin warrant consideration for patients requiring specific reduction in myocardial infarction and stroke risk. 2, 1