Contribution of intestinal triglyceride-rich lipoproteins to residual atherosclerotic cardiovascular disease risk in individuals with type 2 diabetes on statin therapy

Abstract

Aims/hypothesis: This study explored the hypothesis that significant abnormalities in the metabolism of intestinally derived lipoproteins are present in individuals with type 2 diabetes on statin therapy. These abnormalities may contribute to residual CVD risk.

Methods: To investigate the kinetics of ApoB-48- and ApoB-100-containing lipoproteins, we performed a secondary analysis of 11 overweight/obese individuals with type 2 diabetes who were treated with lifestyle counselling and on a stable dose of metformin who were from an earlier clinical study, and compared these with 11 control participants frequency-matched for age, BMI and sex. Participants in both groups were on a similar statin regimen during the study. Stable isotope tracers were used to determine the kinetics of the following in response to a standard fat-rich meal: (1) apolipoprotein (Apo)B-48 in chylomicrons and VLDL; (2) ApoB-100 in VLDL, intermediate-density lipoprotein (IDL) and LDL; and (3) triglyceride (TG) in VLDL.

Results: The fasting lipid profile did not differ significantly between the two groups. Compared with control participants, in individuals with type 2 diabetes, chylomicron TG and ApoB-48 levels exhibited an approximately twofold higher response to the fat-rich meal, and a twofold higher increment was observed in ApoB-48 particles in the VLDL₁ and VLDL₂ density ranges (all p < 0.05). Again comparing control participants with individuals with type 2 diabetes, in the latter, total ApoB-48 production was 25% higher (556 ± 57 vs 446 ± 57 mg/day; p < 0.001), conversion (fractional transfer rate) of chylomicrons to VLDL was around 40% lower (35 ± 25 vs 82 ± 58 pools/day; p=0.034) and direct clearance of chylomicrons was 5.6-fold higher (5.6 ± 2.2 vs 1.0 ± 1.8 pools/day; p < 0.001). During the postprandial period, ApoB-48 particles accounted for a higher proportion of total VLDL in individuals with type 2 diabetes (44%) compared with control participants (25%), and these ApoB-48 VLDL particles exhibited a fivefold longer residence time in the circulation (p < 0.01). No between-group differences were seen in the kinetics of ApoB-100 and TG in VLDL, or in LDL ApoB-100 production, pool size and clearance rate. As compared with control participants, the IDL ApoB-100 pool in individuals with type 2 diabetes was higher due to increased conversion from VLDL₂.

Conclusions/interpretation: Abnormalities in the metabolism of intestinally derived ApoB-48-containing lipoproteins in individuals with type 2 diabetes on statins may help to explain the residual risk of CVD and may be suitable targets for interventions.

Trial registration: ClinicalTrials.gov NCT02948777.

Keywords: Apolipoprotein B-100; Apolipoprotein B-48; Chylomicrons; Liver; Metabolism; Postprandial; Stable isotope; VLDL.

Fig. 1

Response to standard fat-rich meal in control individuals and individuals with type 2 diabetes on statins. The metabolic protocol began at the 0 h timepoint with the injection of [D₃]leucine and [D₅]glycerol tracers. At the 2 h timepoint, participants consumed a standard fat-rich meal within 15 min. Blood samples were taken immediately before the meal and at frequent intervals thereafter for 8 h (ending at the 10 h timepoint) to quantify the postprandial response in (a) plasma TG, (b) chylomicron (CM) TG. In addition, the ApoB-48 concentration in the (c) CM, and (d) VLDL₁ and (e) VLDL₂ density intervals was also assessed at the same timepoints. The content of ApoB-100 in (f) VLDL₁ and (g) VLDL₂ was determined at 0 h, 6 h and 10 h. Responses in the control individuals and individuals with type 2 diabetes were compared using repeated measures ANOVA and by determining the AUC (see AUC data in Table 2)

Fig. 2

Summary of ApoB-48 and ApoB-100 kinetics in control individuals and individuals with type 2 diabetes on statins. Key kinetic rate constants are shown for the metabolism of (a) ApoB-48 and (b) ApoB-100. Production rates are given in mg/day and conversion (fractional transfer rates) or clearance rates in pools/day. The ApoB-48 pool size for chylomicrons, VLDL₁ and VLDL₂ (a) was determined as the time-averaged concentration of ApoB-48 (summed concentrations divided by number of timepoints) across the postprandial (PostP) period (2–10 h, as shown in Fig. 1c–e). Total ApoB-48 production rates into all density intervals are given in blue boxes in schematic (a), for both the basal state (fasting) and for the PostP period. Basal production, blue text; PostP production, red text. In (b), pool sizes (in mg) were determined for VLDL₁, VLDL₂, IDL and LDL from the average measured plasma concentration of these ApoB-100 lipoproteins. B48, ApoB-48; B100, ApoB-100. *p < 0.05, **p < 0.01 and ***p < 0.001 vs control, calculated using the Mann–Whitney U test