• Evolocumab (REPATHA) is a monoclonal antibody targeting PCSK9, leading to increased recycling of LDL receptors and significant reductions in LDL cholesterol levels.
• Its use in patients already on statins offers incremental LDL-C lowering, making it particularly useful in high-risk populations like T1D, where residual cardiovascular risk remains high despite standard therapy. 

At the American Diabetes Association (ADA) annual conference held in Chicago, emerging data spotlighted the elevated cardiovascular risk faced by individuals with T1D. Amgen presented an abstract titled “Cardiovascular Efficacy of Evolocumab in Persons with T1D: Insights from the FOURIER Trial,” highlighting the potential benefit of intensive LDL-C lowering in this high-risk population.

Executive Summary

Evolocumab, a PCSK9 inhibitor, has already demonstrated cardiovascular benefits in patients with Atherosclerotic Cardiovascular Disease (ASCVD). The FOURIER trial extends this evidence to individuals with Type 1 Diabetes Mellitus (T1DM), a group with notably elevated cardiovascular risk. The trial suggests that intensive LDL-C lowering with evolocumab, added to optimized statin therapy, offers substantial clinical benefits, especially in the high-risk T1DM subgroup. 

Trial Design

The FOURIER trial (NCT01764633) investigated whether adding evolocumab to statin therapy improves cardiovascular outcomes in patients with ASCVD, including subgroups with no diabetes, T2DM, and T1DM. The primary endpoint was a composite of cardiovascular death, myocardial infarction, stroke, hospitalization for unstable angina, or coronary revascularization.

Results

• Over a 2.5-year follow-up, Kaplan–Meier event rates for the primary endpoint in the placebo group showed a clear risk gradient: 11.0% in participants without diabetes, 15.2% in those with T2DM, and 20.4% in those with T1DM, indicating progressively higher cardiovascular risk across groups.
• In participants without diabetes, evolocumab reduced the risk of primary events with a Hazard Ratio (HR) of 0.87 (95% CI: 0.79–0.96) and an Absolute Risk Reduction (ARR) of 1.27%.
• Among those with T2DM, the HR was 0.84 (95% CI: 0.75–0.93) with an ARR of 2.53%.
• In the T1DM group, evolocumab achieved the greatest relative benefit with an HR of 0.66 (95% CI: 0.32–1.38) and the highest ARR of 7.31%.
• For the key secondary endpoint—cardiovascular death, myocardial infarction, or stroke—the T1DM group experienced the largest relative risk reduction at 42% (HR 0.58, 95% CI: 0.26–1.32) and an absolute risk reduction of 9.05%.
• Despite the strong signals of benefit in the T1DM population, the interpretation is limited by the small sample size, leading to wider confidence intervals.

Conclusion

The cardiovascular burden in T1DM patients remains substantially high, and conventional statin therapy may not fully mitigate this risk. The FOURIER trial indicates that adding evolocumab offers meaningful additional protection, with the highest absolute benefit observed in T1DM despite their small representation.

Future Outlook

While the data are promising, larger, T1DM-specific trials are needed to validate these observations with adequate statistical power. Meanwhile, clinicians may consider evolocumab for high-risk T1DM patients with ASCVD who remain above LDL-C goals on statins alone. The evolving role of PCSK9 inhibitors in diabetes-associated ASCVD risk management holds considerable promise.