It is uncertain whether conditions characterized by increased circulating triglyceride concentrations are causal in coronary heart disease. Although epidemiological associations have suggested a positive correlation between triglyceride levels and coronary risk, these associations disappear after controlling for HDL and LDL cholesterol.
In this study the authors assessed a promoter polymorphism (rs662799) of the apolipoprotein A5 (APOA5) gene that is known to lead to triglyceride-rich VLDL, The promoter polymorphism was studied in relation to triglyceride concentrations, several other cardiac risk factors, and the risk of coronary heart disease. In addition, the authors compared disease risk for patients with genetically-raised triglyceride concentration (20,842 patient with coronary heart disease, 35206 controls) with that recorded for equivalent differences in circulating triglyceride concentration in prospective studies (302430 participants with no history of cardiovascular disease; 12785 incident cases of coronary heart disease). Lastly, to provide mechanistic insights, the rs662799 polymorphism was also analysed in 1795 people without a history of cardiovascular disease who had information about lipoprotein concentration and diameter obtained by nuclear magnetic resonance spectroscopy.
The rs662799 polymorphism was not significantly associated with non-lipid risk factors or LDL cholesterol, and was only modestly associated with lower HDL cholesterol, lower apolipoprotein AI, and higher apolipoprotein B (figure). However, for each C allele inherited, mean triglyceride concentration was 0.25mmol/L higher. Rs662799 was significantly associated with higher VLDL particle concentration, and smaller HDL size, factors that could mediate the effects of triglyceride.
A polymorphism of the APOA5 gene that is strongly associated with triglyceride levels is associated with a significantly higher risk of coronary heart disease. The data suggest a causal association between triglyceride-mediated pathways and coronary heart disease.
• Triglyceride Coronary Disease Genetics Consortium and Emerging Risk Factors Collaboration, Sarwar N, Sandhu MS, Ricketts SL, Butterworth AS, Di Angelantonio E, et al. Triglyceride-Mediated pathways and coronary disease: Collaborative analysis of 101 studies. Lancet 2010, May 8;375(9726):1634-9.
NAVIGATOR shows need for new direction
Type 2 diabetes is one of the primary risk factors for cardiovascular disease and individuals with impaired glucose tolerance are at increased risk for both diabetes and cardiovascular disease. Interventions that reduce risk in these individuals may therefore have large future benefits on a societal level, preventing both morbidity and mortality. Several trials have already shown that both lifestyle interventions such as weight loss and increased physical activity as well as some drugs such as metformin and rosiglitazone can reduce the risk of developing diabetes, but it is unclear whether these interventions reduce the risk of developing cardiovascular complications.
To examine this issue the authors conducted the NAVIGATOR (Nateglinide And Valsartan in Impaired Glucose Tolerance Outcomes Research) trial, a multinational, randomised, placebo-controlled study, which recruited 9306 individuals with impaired glucose tolerance and either established cardiovascular disease or cardiovascular risk factors and randomised them in a 2 by 2 factorial design to receive a combination of nateglinide, valsartan and placebo, in addition to a lifestyle modification program. Nateglinide is an insulin secretagogue which was used to try and reduce post-prandial glucose levels, while valsartan was employed after observational data from other studies of ACE inhibitors and ARBs suggested these drugs may reduce the incidence of diabetes. The three co-primary outcomes were the development of diabetes, an extended composite that included death from CV causes, non-fatal MI and hospitalisation for heart failure and a core composite outcome that excluded unstable angina and revascularisation from the extended composite.
In back-to-back publications, the authors of these studies present the five year follow-up of these trials: Nateglinide had no statistically significant effect on the cumulative incidence of diabetes (36% and 34% respectively, HR 1.07, p=0.05) and no effect on either the extended or the core cardiovascular outcome measures either. Valsartan fared little better and while it did have a statistically significant effect on the incidence of diabetes (HR 0.86, p<0.001), its effect was small (an absolute risk reduction of only 3.7%) and again, there was no evidence of any benefit in either of the cardiovascular co-primary outcomes.
Nateglinide, a novel therapeutic agent, did not prevent diabetes in patients with impaired glucose tolerance. The angiotensin receptor blocker valsartan did, however, have a significant – if small – effect on the incidence of diabetes in a similar cohort.
• NAVIGATOR Study Group Effect of nateglinide on the incidence of diabetes and cardiovascular events. N Engl J Med. 2010 Apr 22;362(16):1463-76.
• NAVIGATOR Study Group Effect of valsartan on the incidence of diabetes and cardiovascular events. N Engl J Med. 2010 Apr 22;362(16):1477-90.