Relation of Lipoprotein(a) Levels to Incident Type 2 Diabetes and Modification by Alirocumab Treatment

Abstract

Objective: In observational data, lower levels of lipoprotein(a) have been associated with greater prevalence of type 2 diabetes. Whether pharmacologic lowering of lipoprotein(a) influences incident type 2 diabetes is unknown. We determined the relationship of lipoprotein(a) concentration with incident type 2 diabetes and effects of treatment with alirocumab, a PCSK9 inhibitor.

Research design and methods: In the ODYSSEY OUTCOMES trial alirocumab was compared with placebo in patients with acute coronary syndrome. Incident diabetes was determined from laboratory, medication, and adverse event data.

Results: Among 13,480 patients without diabetes at baseline, 1,324 developed type 2 diabetes 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 1.04 (95% CI 1.02-1.06, P < 0.001) for incident type 2 diabetes. Alirocumab reduced lipoprotein(a) by a median 23.2% with greater absolute reductions from higher baseline levels and no overall effect on incident type 2 diabetes (hazard ratio 0.95, 95% CI 0.85-1.05). At low baseline lipoprotein(a) levels, alirocumab tended to reduce incident type 2 diabetes, while at high baseline lipoprotein(a) alirocumab tended to increase incident type 2 diabetes compared with 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 hazard ratio 1.07 (95% CI 1.03-1.12; P = 0.0002) for incident type 2 diabetes.

Conclusions: In patients with acute coronary syndrome, baseline lipoprotein(a) concentration associated inversely with incident type 2 diabetes. Alirocumab had neutral overall effect on incident type 2 diabetes. However, treatment-related reductions in lipoprotein(a), more pronounced from high baseline levels, were associated with increased risk of incident type 2 diabetes. Whether these findings pertain to other therapies that reduce lipoprotein(a) is undetermined.

Trial registration: ClinicalTrials.gov NCT01663402.

Figure 1

Spline analysis of probability of incident type 2 diabetes by baseline lipoprotein(a) [Lp(a)] and treatment group. The probability of incident type 2 diabetes during follow-up is shown as a function of baseline lipoprotein(a) for each treatment group, estimated from a logistic regression model with a logit link function, the logarithm of follow-up time as an offset variable, and adjustment for race, current smoking, and baseline BMI and triglyceride level. Spline effect is a piecewise cubic curve with degree = 3 with knots at quartiles of baseline lipoprotein(a). Spline effect P = 0.0002 for placebo group, P = 0.82 for alirocumab group. The interaction P value of treatment and baseline lipoprotein(a) on incident type 2 diabetes (P_interaction) was 0.003 unadjusted and 0.006 adjusted for the baseline characteristics indicated above.

Figure 2

Incidence rate for type 2 diabetes by baseline lipoprotein(a) [Lp(a)] quartile and treatment with placebo or alirocumab. Left panel: incidence rates for type 2 diabetes by treatment group and quartile of baseline lipoprotein(a) for patients without diabetes at baseline (total n = 13,480). Baseline lipoprotein(a) quartile ranges are: quartile 1, <6.9 mg/dL; quartile 2, 6.9 to <21.9 mg/dL; quartile 3, 21.9 to <61.1 mg/dL; and quartile 4, ≥61.1 mg/dL. In the placebo group, increasing quartile of baseline lipoprotein(a) was associated with decreasing incidence rate for type 2 diabetes (P_trend = 0.0003). Right panel: Forest plot depicting treatment hazard ratio (HR) (95% CI) for incident type 2 diabetes by quartile of baseline lipoprotein(a). The point estimate for the treatment hazard ratio increased monotonically from baseline lipoprotein(a) quartile 1 to quartile 4 (P_trend = 0.025).