HDL Cholesterol as a Residual Risk Factor for Vascular Events and All-Cause Mortality in Patients With Type 2 Diabetes

Sharif S, van der Graaf Y, Nathoe HM, et al, on behalf of the SMART Study Group
Diabetes Care. 2016; published online ahead of print

Background

Current cardiovascular (CV) prevention guidelines mainly focus on LDL-C treatment with statin therapy in patients with type 2 diabetes mellitus (T2DM), although the dyslipidaemia associated with T2DM is mainly characterised by high triglycerides, low HDL-C, and elevated small-dense LDL-C particles [1-3].
After effective LDL-C lowering in patients with T2DM, a significant residual risk for CV events remains, and it is hypothesised that this residual risk can be decreased, if plasma HDL-C levels are elevated [4-6]. However, whether HDL-C levels are an independent risk factor for CV disease even after efficacious LDL-C lowering, remains a matter of discussion [7,8].
This study evaluated whether low HDL-C levels remain a residual risk factor for CV disease and mortality in patients with T2DM when attaining low LDL-C treatment goals or when LDL-C is treated with intensive lipid-lowering therapy. For this purpose, data of 1829 T2DM patients with clinically manifest vascular disease or with known important risk factors of the prospective SMART (Second Manifestations of ARTerial disease) cohort study [8] were used. A total of 335 new CV events and 385 deaths occurred during a median follow-up of 7.0 years (IQR: 3.9–10.4).

Main results

• In all patients with T2DM, the risk of MI decreased by 7% per 0.1 mmol/L increase in HDL-C (adjusted HR: 0.93; 95% CI: 0.87–1.00), but there was no clear association with any other CV end point. No association was found between plasma HDL-C and all-cause mortality (HR: 0.99; 95% CI: 0.96–1.03).
• In patients with LDL-C levels <2.0 mmol/L, higher HDL-C was related to higher risk of all-cause mortality (HR: 1.14; 95% CI: 1.07–1.22). A 0.1 mmol/L higher HDL-C was related to a higher risk of vascular mortality (HR: 1.12; 95% CI 1.03–1.22). Higher HDL-C was related to a higher risk for CV events (HR: 1.10; 95% CI: 1.02–1.18).
• In patients with LDL-C levels between 2.0 and 2.5 mmol/L, higher HDL-C was related to a lower risk  of CV events (HR: 0.85; 95% CI: 0.75–0.95).  
• No evidence was seen for effect modification of the relation between HDL-c and CV events or mortality by lipid-lowering therapy or the intensity thereof.
• In patients on intensive lipid-lowering therapy, a 0.1 mmol/L increase in HDL-C was associated with a 17% higher risk for MI (HR: 1.17; 95% CI: 1.00–1.37), while a 15% lower risk for MI (HR: 0.85; 95% CI: 0.74–0.99) in patients on usual dose lipid-lowering therapy.

Conclusion

In high-risk T2DM patients, the relationship between HDL-C levels and CV event risk is dependent on LDL-C levels. When LDL-C levels <2.0 mmol/L, higher HDL-C was associated with a higher risk for CV events and all-cause mortality. On the other hand, in high-risk T2DM patients with LDL-C between 2.0 and 2.5 mmol/L, higher HDL-C was related to a decreased risk of CV events.

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