Macro- and Microvascular Residual Risk Studies

COMMENT

ASPEN investigated the possible cardiovascular benefits of atorvastatin 10 mg/day in a mixed population of diabetic patients in primary and secondary prevention. After the demonstration in major clinical trials of significant reductions in cardiovascular morbidity and mortality in diabetic patients with elevated LDL-C levels and/or other cardiovascular risk factors, ASPEN’s investigators explored the possibility of reducing major cardiovascular events in diabetic patients with LDL-C close to recommended levels at that time (mean: 133 mg/dL at study entry) and virtually no other modifiable risk factor. Positive results would have had important implications, probably leading to the recommendation that all diabetic patients should receive a statin, irrespective of their current LDL-C and cardiovascular risk levels.

No significant reduction in primary endpoint
Unfortunately, despite a significant 29% reduction in LDL-C (p <0.001) in patients receiving atorvastatin compared with placebo, ASPEN failed to demonstrate any significant clinical benefit after 4-year treatment. Reduction of major CHD events was not significant in the whole study population, neither in the primary and secondary prevention subsets. In addition, all-cause mortality was similar between treatment groups during the 4-year treatment phase, with even a trend to a slightly higher mortality in the total cohort (5.8% atorvastatin and 5.7% placebo) and the primary prevention subgroup (4.6 and 4.3%). A reverse tendency was observed in the secondary prevention subgroup (10.3 and 10.7%).
This in sharp contrast with the Collaborative Atorvastatin Diabetes Study (CARDS) trial1, a primary prevention trial reporting significant benefits of the same treatment (atorvastatin 10 mg daily) in diabetic patients with even lower concentrations of LDL-C at baseline (mean: 118 mg/dL). In CARDS, atorvastatin 10 mg daily reduced by 37% (p=0.001) a composite endpoint of major cardiovascular events (myocardial infarction, unstable angina, acute CHD death, resuscitated cardiac arrest, coronary revascularization procedures, or stroke).

Unlike statin trials reporting clinical benefits, ASPEN selected low-risk patients
The CARDS population and the ASPEN primary prevention cohort were not superposable. CARDS inclusion criteria required that participants had at least one complication of diabetes or concomitant risk factor, including retinopathy, albuminuria, current smoking, and hypertension. Therefore, the trial was conducted in a selected population with advanced diabetes-related microvascular and/or high cardiovascular risk.
On the contrary, ASPEN inclusion and exclusion criteria systematically selected lower-risk patients, with LDL-C levels close to normal and good control of glycemia (HbA1c = 7.5-7.6%) and blood pressure (133/76 mmHg). Control of both glycemia and blood pressure has been shown to effectively reduce cardiovascular risk in type 2 diabetic patients. In addition, there were only 12-13% current smokers in ASPEN, as opposed to 22-23% in CARDS.
Thus, ASPEN results are in line with data from other statin trials showing that the absolute benefit of statins relates to the absolute pre-trial risk of the patient.
As stated by ASPEN’s investigators, triglycerides and HDL-C abnormalities are further contributors to CVD risk in diabetes beyond LDL-C.

Statins less effective in patients with atherogenic dyslipidemia
In this respect, another worth-mentioning statin trial is the ASCOT-LLA study,2 in which atorvastatin 10 mg daily given for 3.3 years reduced by 36% the rate of non-fatal myocardial infarction and fatal CHD in a population of hypertensive patients. Subgroup analyses clearly showed that treatment was only effective in people without metabolic syndrome (Table 1), a condition often associated with low HDL-C levels and elevated triglycerides.

*per 1000 patients-years

Table 1. In the ASCOT-LLA study, atorvastatin failed to prevent cardiovascular events in individuals with metabolic syndrome, while being highly efficient in people without this condition. The likely candidate explanation is that LDL-C lowering therapy does not adequately impact the cardiovascular risk associated with atherogenic dyslipidemia.

Figure 1. ASPEN primary end point. Cumulative hazard ratios in the overall study population.