Emanuela Orsi1, Giuseppe Penno2, Anna Solini3, Enzo Bonora4, Cecilia Fondelli5, Roberto Trevisan6, Monica Vedovato7, Franco Cavalot8, Susanna Morano9, Marco G Baroni10, Antonio Nicolucci11, Giuseppe Pugliese12. 1. Diabetes Unit, IRCCS "Cà Granda - Ospedale Maggiore Policlinico" Foundation, Milan, Italy. 2. Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy. 3. Department of Surgical, Medical, Molecular and Critical Area Pathology, University of Pisa, Pisa, Italy. 4. Division of Endocrinology, Diabetes and Metabolism, University and Hospital Trust of Verona, Verona, Italy. 5. Diabetes Unit, University of Siena, Siena, Italy. 6. Endocrinology and Diabetes Unit, Azienda Ospedaliera Papa Giovanni XXIII, Bergamo, Italy. 7. Department of Clinical and Experimental Medicine, University of Padua, Padua, Italy. 8. Department of Clinical and Biological Sciences, University of Turin, Orbassano, Italy. 9. Department of Experimental Medicine, "La Sapienza" University, Rome, Italy. 10. Department of Clinical Medicine, Public Health, and Life and Environment Sciences, University of L'Aquila, L'Aquila, Italy. 11. Centre for Outcomes Research and Clinical Epidemiology (CORESEARCH), Pescara, Italy. 12. Department of Clinical and Molecular Medicine, "La Sapienza" University, Via di Grottarossa, 1035-1039, 00189, Rome, Italy. giuseppe.pugliese@uniroma1.it.
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.
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.
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