Macrovascular Residual Risk Studies

COMMENT

The PROVE IT-TIMI (Pravastatin or Atorvastatin Evaluation and Infection Therapy-Thrombolysis In Myocardial Infarction) 22 trial1 was conducted in patients hospitalized for acute coronary syndrome (ACS) - either acute myocardial infarction (with or without electrocardiographic evidence of ST-segment elevation) or unstable angina. The trial demonstrated that, compared with LDL-C <100 mg/dL (<2.6 mmol/l), LDL-C <70 mg/dL (<1.8 mmol/l) was associated with a significant 28% reduction (p <0.046 for the overall study population) in relative risk of recurrent CHD events after inaugural ACS.

For the PROVE IT-TIMI 22 investigators, the next step was to determine what could be done to further reduce the residual risk of CHD events persisting after optimal statin therapy. As they write, “one potential impediment limiting further reduction in CHD events despite low on-treatment LDL-C is residual elevation in serum triglyceride (TG) levels.” Indeed, major population studies have shown that hypertriglyceridemia is an independent CHD risk factor.2

This post-hoc analysis of the PROVE IT-TIMI 22 trial showed that, compared with LDL-C ≥70 mg/dL and TG ≥150 mg/dL (≥1.7 mmol/l), there were significantly fewer events with LDL-C <70 mg/d and TG <150 mg/dL during the 2-year follow-up (Figure 1 represents unadjusted results).

However, the main result was the 20% reduction in relative risk of CHD associated with low on-treatment TG (<150 mg/dL) after adjustment for LDL-C and other covariates.

The impact of TG levels on risk of recurrent events was also truly impressive in patients who achieved very low levels of LDL-C (<70 mg/dL). Among them, those with TG ≥200 mg/dL had a 50% higher absolute risk of recurrent events compared to those with TG <200 mg/dL (events rate: 20.3% and 13.5%,respectively).

Lowering both LDL-C and TG might markedly reduce the residual CHD risk persisting after optimal statin therapy

There was a 1.6% reduction in CHD risk for each 10-mg/dL decrement in on-treatment TG. Translating this effect in terms of absolute CHD risk reduction, the investigators found that each 10% decrease in TG concentration was associated with a 2.3% lower incidence of recurrent CHD events.

Practical implications: new treatment approaches are needed

One limitation of statin therapy is that it acts mainly through LDL-C reduction but has only limited effects in terms of reduction of TG levels. Therefore, the authors conclude that lowering both LDL-C and TG could reduce the residual CHD risk which remains elevated despite recent diagnostic and therapeutic advancements. Interventions aiming at lowering TG levels include replacement of saturated and trans fats with mono- and polyunsaturated fats, especially omega-3 fatty acids at high doses and niacin or fibrate therapy.

The ongoing ACCORD trial is currently assessing the rates of incident CHD events in patients with type 2 diabetes receiving either a simvastatin-fenofibrate combination or simvastatin alone. Demonstration of a clinical benefit beyond LDL-C lowering would represent a major step in residual CHD risk reduction.