Diabetes Management in Ischemic Stroke Prevention

Diabetes mellitus is a major independent risk factor for ischemic stroke, increasing risk by 2-4 fold. Approximately 20-30% of ischemic stroke patients have diabetes, and an additional 25% have prediabetes or insulin resistance. Beyond glycemic control, specific glucose-lowering agents — particularly GLP-1 receptor agonists and pioglitazone — have demonstrated significant stroke risk reduction in cardiovascular outcome trials. SGLT2 inhibitors, while highly effective for heart failure and renal protection, do not appear to reduce ischemic stroke.

GLP-1 Receptor Agonists: Evidence for Stroke Prevention

Glucagon-like peptide-1 (GLP-1) receptor agonists enhance insulin secretion, suppress glucagon, slow gastric emptying, and promote satiety. Beyond glucose lowering, they have anti-atherosclerotic effects including reduced inflammation, improved endothelial function, and decreased carotid intima-media thickness. Several GLP-1 RAs have demonstrated significant stroke risk reduction in cardiovascular outcome trials.

REWIND (2019): Dulaglutide — Strongest Stroke Signal

The REWIND trial randomized 9,901 patients with T2DM (31% with established CVD) to dulaglutide 1.5 mg weekly or placebo over median 5.4 years:

• MACE: 12.0% vs 13.4% — HR 0.88, p=0.026
• Nonfatal stroke: 2.7% vs 3.5% — HR 0.76, p=0.017 (24% reduction; NNT 125)
• Nonfatal MI: HR 0.96 (NS)
• CV death: HR 0.91 (NS)
• Benefits observed regardless of baseline CVD

REWIND showed the most robust stroke signal among GLP-1 RA trials, with statistically significant 24% reduction in nonfatal stroke.

SUSTAIN-6 (2016): Semaglutide (Injectable)

The SUSTAIN-6 trial randomized 3,297 patients with T2DM and high CV risk to semaglutide (0.5 or 1.0 mg weekly) or placebo over 2 years:

• MACE: 6.6% vs 8.9% — HR 0.74, p=0.02
• Nonfatal stroke: 1.6% vs 2.7% — HR 0.61, p=0.04 (39% reduction)
• Nonfatal MI: HR 0.74 (NS)
• New/worsening nephropathy: HR 0.64, p=0.005
• Note: Retinopathy complications increased (HR 1.76, p=0.02) — likely due to rapid HbA1c reduction

SUSTAIN-6 demonstrated the largest relative stroke reduction (39%), though limited by smaller sample size and shorter follow-up.

LEADER (2016): Liraglutide

The LEADER trial randomized 9,340 patients with T2DM and high CV risk to liraglutide (up to 1.8 mg daily) or placebo over median 3.8 years:

• MACE: 13.0% vs 14.9% — HR 0.87, p=0.01
• Nonfatal stroke: 3.4% vs 3.8% — HR 0.89 (NS)
• CV death: HR 0.78, p=0.007
• All-cause mortality: HR 0.85, p=0.02

LEADER showed trend toward stroke reduction but did not reach significance. The CV benefit was primarily driven by reduction in CV death.

SELECT (2023): Semaglutide in Obesity Without Diabetes

The SELECT trial tested semaglutide 2.4 mg weekly in 17,604 patients with BMI ≥27, established CVD, but no diabetes:

• MACE: 6.5% vs 8.0% — HR 0.80, p<0.001
• Nonfatal stroke: 1.7% vs 1.9% — HR 0.93 (NS)
• Nonfatal MI: HR 0.72, p<0.001
• All-cause mortality: HR 0.81, p=0.005
• Weight loss: 9.4% vs 0.9%

SELECT extends GLP-1 RA benefits to obese patients without diabetes, though stroke-specific benefit was not significant.

SOUL (2025): Oral Semaglutide

The SOUL trial tested oral semaglutide (14 mg daily) in 9,650 patients with T2DM and ASCVD or CKD:

• MACE: 12.0% vs 13.8% — HR 0.86, p=0.006
• Nonfatal stroke: 3.0% vs 3.3% — HR 0.88 (NS)
• Nonfatal MI: HR 0.74
• GI discontinuation: 6.4% vs 2.0%

SOUL confirms CV benefit of oral semaglutide, providing a non-injectable option for patients who prefer oral therapy.

Pioglitazone: Stroke Prevention in Insulin Resistance

Pioglitazone is a thiazolidinedione (TZD) that activates peroxisome proliferator-activated receptor gamma (PPAR-γ), improving insulin sensitivity. The landmark IRIS Trial established its role in stroke prevention for patients with insulin resistance — even without overt diabetes.

IRIS Trial (2016): Pioglitazone After Stroke/TIA

The IRIS (Insulin Resistance Intervention after Stroke) trial randomized 3,876 patients with recent ischemic stroke or TIA, insulin resistance (HOMA-IR >3.0), but no diabetes, to pioglitazone 45 mg or placebo over median 4.8 years:

• Primary endpoint (stroke or MI): 9.0% vs 11.8% — HR 0.76, p=0.007 (24% reduction; NNT 36)
• Ischemic stroke: Reduced by 28% (2.8% absolute risk reduction over 5 years)
• Progression to diabetes: 3.8% vs 7.7% — HR 0.48, p<0.001 (52% reduction)
• Weight gain: +2.6 kg with pioglitazone
• Bone fractures: 5.1% vs 3.2% (HR 1.6) — mainly in women
• Heart failure: No significant increase in this population

IRIS demonstrated that targeting insulin resistance — not just hyperglycemia — can prevent recurrent stroke. The benefits were consistent across subgroups including those with prediabetes (HbA1c 5.7-6.4%).

SGLT2 Inhibitors: Limited Stroke Benefit

Sodium-glucose cotransporter 2 (SGLT2) inhibitors have revolutionized management of heart failure and diabetic kidney disease. However, despite reducing MACE in several trials, they do not significantly reduce ischemic stroke.

Meta-Analysis of SGLT2 Inhibitor Trials

A meta-analysis of 5 major trials (EMPA-REG, CANVAS, DECLARE-TIMI 58, CREDENCE, VERTIS CV; N=46,969) found:

• Total stroke: RR 0.95 (95% CI 0.79-1.13) — No significant effect
• Ischemic stroke: RR 0.99 (95% CI 0.88-1.11) — No significant effect
• Hemorrhagic stroke: RR 0.49 (95% CI 0.30-0.82) — 50% reduction (limited events)
• MACE: Reduced primarily through CV death and HF hospitalization

The CV benefit of SGLT2 inhibitors appears to be mediated through hemodynamic/diuretic effects (HF reduction, renal protection) rather than anti-atherosclerotic mechanisms. This explains why MI and ischemic stroke are not reduced.

Glycemic Targets

Intensive glycemic control reduces microvascular complications but has not consistently reduced macrovascular events including stroke. The ACCORD, ADVANCE, and VADT trials showed no significant stroke reduction with intensive glucose control, and ACCORD showed increased mortality.

Current recommendations:

• HbA1c <7% for most adults with diabetes
• HbA1c <6.5% may be appropriate for selected patients (short duration, long life expectancy, no significant CVD) if achievable without hypoglycemia
• HbA1c <8% for patients with limited life expectancy, advanced complications, extensive comorbidities, or history of severe hypoglycemia
• Avoid hypoglycemia: Associated with increased CV events and possibly stroke

Medications and Stroke Prevention: Summary Table

* Statistically significant. NS = not significant. HR = hazard ratio for stroke endpoint.

Practical Algorithm

Trial Comparison Table

* Statistically significant. QW = weekly; QD = daily.

References

1. Gerstein HC, et al. Dulaglutide and cardiovascular outcomes in type 2 diabetes (REWIND). Lancet. 2019;394:121-130.
2. Marso SP, et al. Semaglutide and cardiovascular outcomes in patients with type 2 diabetes (SUSTAIN-6). N Engl J Med. 2016;375:1834-1844.
3. Marso SP, et al. Liraglutide and cardiovascular outcomes in type 2 diabetes (LEADER). N Engl J Med. 2016;375:311-322.
4. Lincoff AM, et al. Semaglutide and cardiovascular outcomes in obesity without diabetes (SELECT). N Engl J Med. 2023;389:2221-2232.
5. Husain M, et al. Oral semaglutide and cardiovascular outcomes in type 2 diabetes (SOUL). N Engl J Med. 2025 (in press).
6. Gerstein HC, et al. Cardiovascular and renal outcomes with efpeglenatide in type 2 diabetes (AMPLITUDE-O). N Engl J Med. 2021;385:896-907.
7. Kernan WN, et al. Pioglitazone after ischemic stroke or transient ischemic attack (IRIS). N Engl J Med. 2016;374:1321-1331.
8. Zinman B, et al. Empagliflozin, cardiovascular outcomes, and mortality in type 2 diabetes (EMPA-REG OUTCOME). N Engl J Med. 2015;373:2117-2128.
9. Neal B, et al. Canagliflozin and cardiovascular and renal events in type 2 diabetes (CANVAS). N Engl J Med. 2017;377:644-657.
10. Zhou Z, et al. Effects of SGLT2 inhibitors on stroke and its subtypes: a systematic review and meta-analysis. Sci Rep. 2021;11:15748.
11. American Diabetes Association. Standards of Care in Diabetes—2024. Diabetes Care. 2024;47(Suppl 1):S1-S291.