Low HDL-cholesterol and high triglycerides linked to increased risk of CHD

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.

"The R3i has a huge task ahead to get people recognizing the threat of residual vascular risk and acting to better manage it," said Professor Jean-Charles Fruchart of the University of Lille, France and President of the R3i. "We have to look beyond using statins as a silver bullet to reduce LDL-cholesterol. The mindset that reducing one component to prevent heart disease is wrong and needs to change."

Epidemiological study methods

The PROCAM analysis used a case-control approach in which 823 men who had survived a MI were matched with an equal number of controls. Patients, who were matched for age, smoking status, type 2 diabetes status, blood pressure and LDL-C to an equal number of MI-free controls from the PROCAM cohort of 50,000 participants, a unique prospective investigation of coronary artery disease (CAD) and stroke risk factors in Germany.

The macrovascular REALIST survey was designed to determine, in patients at goal for LDL-C (less than or equal to 130 mg/dL whether treated or untreated for elevated LDL-C) with a first or subsequent coronary event, whether low HDL-C and/or elevated TG levels are associated with a significant risk of coronary event after adjustment for other risk factors. Adult male or female patients admitted to coronary care units (CCUs) or explored in cardiac catheter laboratories were matched with controls hospitalized for other reasons.

The microvascular REALIST survey was designed to determine whether low HDL-C and/or elevated TG levels are associated with a significant residual risk of microvascular complications. Data will be adjusted for other risk factors such as age, gender, diabetes duration, HbA1C, LDL-C levels, blood pressure, BMI and smoking status in patients with type 2 diabetes nearly at goal for LDL-C and presenting with incident microvascular complication (retinopathy, maculopathy or nephropathy). Diabetic neuropathy is an exploratory disease due to difficulties in establishing it with certainty in retrospective analysis. The REALIST surveys are currently being conducted in Belgium, Croatia, France, Italy, Japan, Philippines, Poland, Saudi Arabia, Spain, Thailand, Turkey and the U.S.

In the past three decades in the U.S., while the prevalence of abnormal levels of LDL-C has decreased, the prevalence of combined abnormal TG (greater than or equal to 150 mg/dL) and HDL-C ((less than)40 mg/dL) has doubled and the prevalence of elevated TG (greater than or equal to 150 mg/dL) has increased five-fold.(5) Elevated TG ((greater than)150 mg/dL) is also common, affecting about 50 percent of adults with prior CVD.(6)

Atherogenic dyslipidemia contributes to the increased risk of macrovascular events such as myocardial infarction and stroke, and may be implicated in microvascular complications such as diabetic eye, kidney and lower limb disease.(7)

- Among patients achieving LDL-C (less than)70 mg/dL with a statin, CVD risk is almost 60 percent greater for patients with TG (greater than) 200 mg/dL(8)

- In patients achieving LDL-C (less than)70 mg/dL with a statin, CV risk was higher in patients with a low HDL-C (HDL-C (less than)37
mg/dL vs. those with a HDL-C (greater than)55 mg/dL)(9)