Independent association of atherogenic dyslipidaemia with all‐cause mortality in individuals with type 2 diabetes and modifying effect of gender: a prospective cohort study
Authors: Orsi Emanuela , Penno Giuseppe , Solini Anna , Bonora Enzo , Fondelli Cecilia , Trevisan Roberto , Vedovato Monica , Cavalot Franco , Morano Susanna , Baroni Marco G. , Nicolucci Antonio , Pugliese Giuseppe ,   for the Renal Insufficiency And Cardiovascular Events (RIACE) Study Group, Pugliese Giuseppe , Penno Giuseppe , Solini Anna , Bonora Enzo , Orsi Emanuela , Trevisan Roberto , Laviola Luigi , Nicolucci Antonio 
Published: January 2021

Abstract
Background
Atherogenic dyslipidaemia has been implicated in the residual risk for cardiovascular morbidity and mortality, which remains despite attainment of LDL cholesterol goals especially in individuals with type 2 diabetes. However, its relationship with all-cause death has not been sufficiently explored. This analysis evaluated the independent association of increased triglycerides and triglyceride:HDL cholesterol ratio (TG:HDL) and decreased HDL cholesterol with total mortality and the possible modifying effect of gender in a large cohort of patients with type 2 diabetes.

Methods
This observational, prospective study enrolled 15,773 patients in 19 Diabetes Clinics throughout Italy in the years 2006–2008. Triglycerides and total and HDL cholesterol were measured by colorimetric enzymatic methods. Vital status was retrieved on 31 October 2015 for 15,656 patients (99.3%). Participants were stratified by quartiles of triglycerides, HDL cholesterol, and TG:HDL.

Results
There were 3,602 deaths over a follow-up 7.42 ± 2.05 years (31.0 × 1000 person-years). In the unadjusted analyses, the highest TG:HDL (but not triglyceride) and the lowest HDL cholesterol quartile were associated with increased death rate and mortality risk. When sequentially adjusting for confounders, including total, LDL, or non-HDL cholesterol and lipid-lowering treatment, mortality risk was significantly higher in the highest triglyceride (hazard ratio 1.167 [95% confidence interval 1.055–1.291], p = 0.003) and TG:HDL (1.192 [1.082–1.314], p < 0.0001) and the lowest HDL cholesterol (1.232 [1.117–1.360], p < 0.0001) quartile, though the association of triglycerides and HDL cholesterol disappeared after further adjustment for each other. Interaction with gender was significant only for HDL cholesterol (p = 0.0009). The relationship with death was stronger for triglycerides in males and HDL cholesterol in females, with these associations remaining significant even after adjustment for HDL cholesterol (1.161 [1.019–1.324], p = 0.025, for the highest vs the lowest triglyceride quartile) and triglycerides (1.366 [1.176–1.587], p < 0.0001, for the lowest vs the highest HDL cholesterol quartile).

Conclusions
In patients with type 2 diabetes, higher triglycerides and TG:HDL and lower HDL cholesterol were independently associated with increased all-cause mortality, with a modifying effect of gender for triglycerides and HDL cholesterol. These data suggest that atherogenic dyslipidaemia, especially TG:HDL, may serve as predictor of all-cause death in these individuals.
Trial registration ClinicalTrials.gov, NCT00715481, 15 July, 2008