Relation of Lipoprotein(a) Levels to Incident Type 2 Diabetes and Modification by Alirocumab Treatment
Observational data associate greater prevalence of type 2 diabetes (T2D) with lower lipoprotein(a) levels. Whether pharmacologic lowering of lipoprotein(a) influences incident T2D is unknown. We determined the relationship of lipoprotein(a) concentration to incident T2D and effects of treatment with alirocumab, a PCSK9 inhibitor.
RESEARCH DESIGN AND METHODS
The ODYSSEY OUTCOMES trial compared alirocumab with placebo in patients with acute coronary syndrome (ACS). Incident diabetes was determined from laboratory, medication, and adverse event data.
Among 13,480 patients without diabetes at baseline, 1324 developed T2D over a median 2.7 years. Median baseline lipoprotein(a) was 21.9 mg/dL. With placebo, 10 mg/dL lower baseline lipoprotein(a) was associated with hazard ratio (HR) 1.04 (95% CI 1.02-1.06, P<0.001) for incident T2D. Alirocumab reduced lipoprotein(a) by a median 23.2% with greater absolute reductions from higher baseline levels and no overall effect on incident T2D (HR 0.95, 95% CI 0.85–1.05). At low baseline lipoprotein(a) levels alirocumab tended to reduce incident T2D, while at high baseline lipoprotein(a) alirocumab tended to increase incident T2D compared to placebo (treatment-baseline lipoprotein(a) interaction P=0.006). In the alirocumab group, a 10 mg/dL decrease in lipoprotein(a) from baseline was associated with HR 1.07 (95% CI 1.03−1.12; P=0.0002) for incident T2D.
In patients with ACS, baseline lipoprotein(a) concentration associated inversely with incident T2D. Alirocumab had neutral overall effect on incident T2D. However, treatment-related reductions in lipoprotein(a), more pronounced from high baseline levels, were associated with increased risk of incident T2D. Whether these findings pertain to other therapies that reduce lipoprotein(a) is undetermined.