Low levels of high-density lipoprotein cholesterol (HDL-C) and raised triglycerides, affecting millions of patients worldwide, are strongly linked to significantly increased risk of coronary heart disease (CHD) even in patients who achieve or surpass current low density lipoprotein cholesterol (LDL-C) targets.
This has been demonstrated in new analyses of the landmark Prospective Cardiovascular Munster (PROCAM) and the REsiduAl risk Lipids and Standard Therapies (REALIST) surveys, the latter funded and conducted by the Residual Risk Reduction Initiative Foundation or R3i. These data have been presented today at the European Society of Cardiology (ESC) congress.
The final objective of the R3i is to significantly reduce the incidence of both major macrovascular events and microvascular complications (e.g. in patients with type 2 diabetes or affected by the metabolic syndrome) beyond what is already achieved with current treatments.(1),(2)
Earlier studies, largely conducted in patients treated with statins show that lowering LDL-C to currently recognized goals only reduces the relative risk of macrovascular disease by about 23 percent.(3)
"The residual vascular risk driven by the increasing epidemic of obesity, metabolic syndrome and type 2 diabetes is not being adequately treated by clinicians," stated Professor Frank Sacks from Harvard Medical School, Boston, USA and Vice-president of R3i. "While LDL-C is appropriately the current target, we have taken LDL-C reduction to its therapeutic limits without abolishing CVD events. Therefore we urgently need new strategies to address other modifiable risk factors such as atherogenic dyslipidemia."
New insights into lipid-related macrovascular risk
Professor Gerd Assmann, member of the R3i International Steering Committee and President of the Board of the Assmann-Foundation for Prevention, presented a new analysis from PROCAM in which 823 men who survived a myocardial infarction (MI) were matched with an equal number of controls free from MI. This analysis, which was funded by the R3i, demonstrated:
- Low HDL-C and/or elevated triglycerides (TG) was seen in nearly two- thirds of MI patients
- When all risks factors were matched, the odds of experiencing a MI were increased five-fold for men with LDL-C at target (less than or equal to 100mg/dL) presenting a low level of HDL-C ((less than)45 mg/dL) and an elevated level of TG ((greater than)150 mg/dL)
The initial macrovascular findings of REALIST were also presented by Professor Frank Sacks, Vice-President of the R3i. This case-control study conducted in 170 patients hospitalized with CHD in Boston, USA, at goal for LDL-C, matched with 175 controls free from CHD shows that:
- High TG and low HDL-C are strong indicators of residual risk of CHD
- High TG and low HDL-C levels each contribute to the risk of a coronary event in patients with LDL-C levels less than or equal to 130 mg/dL or even less than or equal to 70 mg/dL
- TG and HDL-C appear to act synergistically with the impact of TG increasing when HDL-C is low and the impact of HDL-C increasing when TG levels are high
- When moving from the lowest levels of TG and highest levels of HDL-C to the highest levels of TG and lowest levels of HDL-C, the risk of CHD increases 10-fold
Addressing atherogenic dyslipidemia may reduce the microvascular complications of type 2 diabetes
REALIST is also evaluating the risk of microvascular complications in patients with type 2 diabetes who achieve or approach LDL-C goal. Data collected by Professor Michel Hermans from the Cliniques Universitaires Saint-Luc in Brussels, Belgium, were presented by Professor Paola Fioretto, from the Department of Medical and Surgical Sciences, University of Padua, Italy and showed that:
- Low HDL-C, elevated TG and elevated non-HDL-C levels are more prevalent in patients who developed microvascular complications
- High TG levels are associated with increased risk of incident retinopathy, blindness and diabetic kidney disease
- Low HDL-C levels are associated with incident diabetic kidney disease
Similar to the findings of the macrovascular REALIST survey, the initial microvascular data showed that patients with incident microvascular complications of type 2 diabetes are more likely to present with atherogenic dyslipidemia even when LDL-C is nearly at goal (less than or equal to 130mg/dL).
"Further analysis of microvascular data from this and other centers should confirm the relationship between atherogenic dyslipidemia and microvascular complications of type 2 diabetes," said Professor Fioretto.
Implications of the R3i research program for future treatment
The REALIST research program is being globally extended and data are currently being collected in 27 centers in 12 countries around the world. This will support the major global program of education and advocacy being implemented by the R3i.
The ultimate objective of the R3i Foundation is to identify new indicators of macro- and microvascular residual risk as targets for future treatment strategies.
Residual vascular risk - A public health emergency
"Further reduction of LDL-C by use of the maximum permissible statin dosage is unlikely to be able to substantially lower this residual, largely non-LDL-C mediated risk," says Professor Gerd Assmann from the University of Munster, Germany.
Therefore, while statins are effective, other treatment strategies are urgently needed to address the residual vascular risk which persists in patients despite current standards of care. While the R3i research program will help define appropriate targets for intervention in patients who remain at high residual vascular risk, the ongoing outcomes trials such as ACCORD, AIM-HIGH and HPS2-THRIVE will help determine new treatment strategies to address this risk.