SURPASS-4 Trial: Tirzepatide vs Insulin Glargine in High Cardiovascular Risk Patients

SURPASS-4: Testing Tirzepatide Where It Matters Most

Cardiovascular disease is the leading cause of death in patients with type 2 diabetes. Any new diabetes therapy must demonstrate safety — and ideally benefit — in this high-risk population. The SURPASS-4 trial, published in The Lancet in November 2021 by Del Prato et al., evaluated tirzepatide against insulin glargine in 2,002 patients with type 2 diabetes and established cardiovascular disease or high cardiovascular risk [1].

Study Design

SURPASS-4 was the largest and longest trial in the SURPASS program:

• Duration: 52 weeks primary endpoint, with extension up to 104 weeks for cardiovascular safety assessment
• Population: 2,002 adults with T2D and high cardiovascular risk
• Background therapy: 1-3 oral glucose-lowering agents (metformin, sulfonylureas, SGLT2 inhibitors)
• Comparator: Insulin glargine (Lantus), titrated to fasting glucose 80-100 mg/dL
• Sites: 187 sites across 14 countries

Cardiovascular Risk Criteria (at least one):

• Prior myocardial infarction, stroke, or peripheral arterial disease
• Coronary, carotid, or peripheral artery revascularization
• Unstable angina with ECG changes
• Asymptomatic cardiac ischemia on imaging
• Stage 3+ chronic kidney disease

This was a genuinely high-risk population — approximately 87% had established cardiovascular disease [1].

Glycemic Results

Mean HbA1c Change from Baseline (~8.5%):

• Tirzepatide 5 mg: -2.24%
• Tirzepatide 10 mg: -2.43%
• Tirzepatide 15 mg: -2.58%
• Insulin glargine: -1.44%

HbA1c <7.0%:

• Tirzepatide 15 mg: 87%
• Insulin glargine: 51%

The 2.58% HbA1c reduction with tirzepatide 15 mg was the largest seen in any SURPASS trial, likely reflecting the higher baseline HbA1c in this population. Even optimally titrated insulin glargine could not match tirzepatide's glycemic control [1].

Weight Results

Mean Body Weight Change:

• Tirzepatide 5 mg: -7.1 kg
• Tirzepatide 10 mg: -9.5 kg
• Tirzepatide 15 mg: -11.7 kg
• Insulin glargine: +1.9 kg

Total Weight Difference (15 mg vs. insulin): 13.6 kg (30 lbs)

In a population where cardiovascular risk is directly linked to body weight and metabolic syndrome, this weight difference has potentially life-saving implications [1].

Cardiovascular Safety

The cardiovascular safety data from SURPASS-4 were encouraging:

MACE-4 (Major Adverse Cardiovascular Events):

• Tirzepatide (pooled): HR 0.74 (95% CI: 0.51-1.08)
• This means tirzepatide showed a 26% lower rate of MACE events compared to insulin glargine
• While not statistically significant (the trial was not powered for CV outcomes), the trend was favorable

Individual MACE Components:

• Cardiovascular death: Numerically lower with tirzepatide
• Myocardial infarction: Numerically lower with tirzepatide
• Stroke: Similar between groups
• Hospitalization for unstable angina: Numerically lower with tirzepatide

These results provided sufficient cardiovascular safety reassurance for regulatory approval and suggested potential cardiovascular benefit that warranted further investigation [1].

Kidney Outcomes

A pre-specified post-hoc analysis by Heerspink et al. examined kidney outcomes:

• Tirzepatide reduced albuminuria (urinary albumin-to-creatinine ratio) significantly more than insulin
• The composite kidney endpoint (40% decline in eGFR, kidney failure, or kidney death) showed a favorable trend with tirzepatide
• These findings suggest potential renal protective effects beyond what would be expected from glucose lowering alone [2].

Safety in High-Risk Patients

Hypoglycemia (<54 mg/dL):

• Tirzepatide: 0.4-1.4%
• Insulin glargine: 7.7%

The dramatically lower hypoglycemia rate is particularly important in cardiovascular patients, where hypoglycemia can trigger arrhythmias, myocardial ischemia, and sudden death.

Gastrointestinal Events:

• Nausea: 12-18% (tirzepatide) vs. 2% (insulin)
• Diarrhea: 12-22% vs. 5%
• Generally mild to moderate and transient

Serious Adverse Events:

• Similar rates across groups (approximately 17-20%)
• No new safety signals in this high-risk population [1]

Long-Term Extension Data

The 104-week extension data (published by Guan et al., 2025) showed:

• Sustained glycemic control through 2 years
• Continued weight loss maintenance
• No evidence of tolerance or efficacy waning
• Consistent safety profile over the extended treatment period [3]

Clinical Significance

SURPASS-4 established several critical points:

1. CV safety: Tirzepatide is safe in high-risk cardiovascular patients
2. Potential CV benefit: The favorable MACE trend supports further investigation (SURPASS-CVOT ongoing)
3. Insulin alternative: Even in advanced diabetes requiring insulin, tirzepatide may be a superior option
4. Kidney protection: Potential renal benefits add to the value proposition
5. Hypoglycemia advantage: Dramatically safer than insulin in a population where hypoglycemia is dangerous

References

1. Del Prato S, Kahn SE, Pavo I, et al. "Tirzepatide versus insulin glargine in type 2 diabetes and increased cardiovascular risk (SURPASS-4): a randomised, open-label, parallel-group, multicentre, phase 3 trial." The Lancet. 2021;398(10313):1811-1824. PubMed: 34672967

2. Heerspink HJL, Sattar N, Pavo I, et al. "Effects of tirzepatide versus insulin glargine on kidney outcomes in type 2 diabetes in the SURPASS-4 trial." The Lancet Diabetes & Endocrinology. 2022;10(11):774-785. PubMed: 36152639

3. Guan H, et al. "Long-term efficacy and safety of tirzepatide in participants with type 2 diabetes: 104-week results." Diabetes Care. 2025. PubMed: 40926359