Effect of vitamin E supplementation on HDL function by haptoglobin genotype in type 1 diabetes: results from the HapE randomized crossover pilot trial

Abstract

Aims: Haptoglobin (Hp) genotype 2-2 increases cardiovascular diabetes complications. In type 2 diabetes, α-tocopherol was shown to lower cardiovascular risk in Hp 2-2, potentially through HDL function improvements. Similar type 1 diabetes data are lacking. We conducted a randomized crossover pilot of α-tocopherol supplementation on HDL function [i.e., cholesterol efflux (CE) and HDL-associated lipid peroxides (LP)] and lipoprotein subfractions in type 1 diabetes.

Methods: Hp genotype was assessed in members of two Allegheny County, PA, type 1 diabetes registries and the CACTI cohort; 30 were randomly selected within Hp genotype, and 28 Hp 1-1, 31 Hp 2-1 and 30 Hp 2-2 were allocated to daily α-tocopherol or placebo for 8 weeks with a 4-week washout.

Results: Baseline CE decreased with the number of Hp 2 alleles (p-trend = 0.003). There were no differences in LP or lipoprotein subfractions. In intention-to-treat analysis stratified by Hp, α-tocopherol increased CE in Hp 2-2 (β = 0.79, p = 0.03) and LP in Hp 1 allele carriers (β Hp 1-1 = 0.18, p = 0.05; β Hp 2-1 = 0.21, p = 0.07); reduced HDL particle size (β = -0.07, p = 0.03) in Hp 1-1 carriers; increased LDL particle concentration in Hp 1-1; and decreased it in Hp 2-2 carriers. However, no significant interactions were observed by Hp.

Conclusions: In this type 1 diabetes study, HDL function worsened with the number of Hp 2 alleles. α-Tocopherol improved HDL function in Hp 2-2 carriers and appeared to adversely affect lipid peroxides and lipoprotein subfractions among Hp 1 allele carriers. As no significant interactions were observed, findings require replication in larger studies.

Keywords: Double-blinded placebo-controlled randomized trial; HDL function; Haptoglobin genotype; NMR lipoprotein subfractions; Type 1 diabetes; Vitamin E.

Figure 1

Flow diagram of the HapE cross-over trial

Figure 2. Effect of vitamin E treatment (mean, standard error), adjusting for period and using random effects for participant ID nested within treatment sequence

Figure 2A. Treatment effect on cholesterol efflux (p-value_treatment = 0.72 for Hp 1-1, p-value_treatment = 0.81 for Hp 2-1 and p-value_treatment = 0.03 for Hp 2-2) Figure 2B. Treatment effect on HDL-associated lipid peroxides (p-value_treatment = 0.05 for Hp 1-1, p-value_treatment = 0.07 for Hp 2-1 and p-value_treatment = 0.60 for Hp 2-2) Figure 2C. Treatment effect on HDL size (p-value treatment = 0.03 for Hp 1-1, p-value treatment = 0.37 for Hp 2-1 and p-value treatment = 0.40 for Hp 2-2) Figure 2D. Treatment effect on total LDL particle concentration (p-value treatment = 0.10 for Hp 1-1, p-value treatment = 0.24 for Hp 2-1 and p-value treatment = 0.12 for Hp 2-2)

Figure 2. Effect of vitamin E treatment (mean, standard error), adjusting for period and using random effects for participant ID nested within treatment sequence

Figure 2A. Treatment effect on cholesterol efflux (p-value_treatment = 0.72 for Hp 1-1, p-value_treatment = 0.81 for Hp 2-1 and p-value_treatment = 0.03 for Hp 2-2) Figure 2B. Treatment effect on HDL-associated lipid peroxides (p-value_treatment = 0.05 for Hp 1-1, p-value_treatment = 0.07 for Hp 2-1 and p-value_treatment = 0.60 for Hp 2-2) Figure 2C. Treatment effect on HDL size (p-value treatment = 0.03 for Hp 1-1, p-value treatment = 0.37 for Hp 2-1 and p-value treatment = 0.40 for Hp 2-2) Figure 2D. Treatment effect on total LDL particle concentration (p-value treatment = 0.10 for Hp 1-1, p-value treatment = 0.24 for Hp 2-1 and p-value treatment = 0.12 for Hp 2-2)

Figure 2. Effect of vitamin E treatment (mean, standard error), adjusting for period and using random effects for participant ID nested within treatment sequence

Figure 2A. Treatment effect on cholesterol efflux (p-value_treatment = 0.72 for Hp 1-1, p-value_treatment = 0.81 for Hp 2-1 and p-value_treatment = 0.03 for Hp 2-2) Figure 2B. Treatment effect on HDL-associated lipid peroxides (p-value_treatment = 0.05 for Hp 1-1, p-value_treatment = 0.07 for Hp 2-1 and p-value_treatment = 0.60 for Hp 2-2) Figure 2C. Treatment effect on HDL size (p-value treatment = 0.03 for Hp 1-1, p-value treatment = 0.37 for Hp 2-1 and p-value treatment = 0.40 for Hp 2-2) Figure 2D. Treatment effect on total LDL particle concentration (p-value treatment = 0.10 for Hp 1-1, p-value treatment = 0.24 for Hp 2-1 and p-value treatment = 0.12 for Hp 2-2)

Figure 2. Effect of vitamin E treatment (mean, standard error), adjusting for period and using random effects for participant ID nested within treatment sequence

Figure 2A. Treatment effect on cholesterol efflux (p-value_treatment = 0.72 for Hp 1-1, p-value_treatment = 0.81 for Hp 2-1 and p-value_treatment = 0.03 for Hp 2-2) Figure 2B. Treatment effect on HDL-associated lipid peroxides (p-value_treatment = 0.05 for Hp 1-1, p-value_treatment = 0.07 for Hp 2-1 and p-value_treatment = 0.60 for Hp 2-2) Figure 2C. Treatment effect on HDL size (p-value treatment = 0.03 for Hp 1-1, p-value treatment = 0.37 for Hp 2-1 and p-value treatment = 0.40 for Hp 2-2) Figure 2D. Treatment effect on total LDL particle concentration (p-value treatment = 0.10 for Hp 1-1, p-value treatment = 0.24 for Hp 2-1 and p-value treatment = 0.12 for Hp 2-2)