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Macro- and Microvascular Residual Risk Studies

11 January 2010
Testing the limits of statin therapy: In the ASPEN study, atorvastatin 10 mg/day did not reduce major cardiovascular events in patients with diabetes (without additional risk factors) ASPEN
Efficacy and safety of atorvastatin in the prevention of cardiovascular end points in subjects with type 2 diabetes: the Atorvastatin Study for Prevention of Coronary Heart Disease Endpoints in non-insulin-dependent diabetes mellitus (ASPEN). Diabetes Care 2006;29:1478-85.
Knopp RH, d’Emden M, Smilde JG, Pocock SJ
Objective: To assess the effect of 10 mg atorvastatin versus placebo on CVD prevention in subjects with type 2 diabetes (with and without prior myocardial infarction or interventional procedure) and LDL cholesterol (LDL-C) levels below contemporary guideline targets
Inclusion criteria:
  • Type 2 diabetes diagnosed ≥3 years before screening
LDL-C ≤160 mg/dL (4.1 mmol/l) or ≤140 mg/dL (3.6 mmol/l) if subjects had myocardial infarction or an interventional procedure >3 months before screening
Exclusion criteria:
  • HbA1c >10%
  • BP >160/100 mmHg
  • BMI >35 kg/m2
  Triglycerides >600 mg/dL
Study population:
2,410 subjects with type 2 diabetes aged 40–75 years.
Primary endpoint:
Time to first occurrence of a major CHD event (composite endpoint)
Secondary endpoint:
Time to first occurrence of individual components of the primary composite endpoint; all-cause mortality.
Study design:
Randomized, double-blind, parallel group study of primary and secondary prevention
Method: Subjects followed for a median of 4 years. Primary efficacy analyzed using a Cox proportional hazards model (ITT analysis)
Main results:

Non-significant reduction of primary endpoint in the atorvastatin group

  1. Overall study population: HR 0.90 [95% CI 0.73 –1.12]
  2. Primary prevention: HR 0.97 [95% CI 0.74 –1.28]
Secondary prevention: HR 0.82 [95% CI 0.59 –1.15]
Author's conclusion: ASPEN results did not confirm the benefit of therapy but do not detract from the imperative that the majority of diabetic patients deserve LDL-C lowering to currently recommended targets


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.

  Atorvastatin   Placebo   Unadjusted hazard P
n (%) Rate* n (%) Rate* ratio  
Metabolic syndrome (n=3926) 47 2.4% 7.6 61 3.1% 9.9 0.77 0.52 1.12 0.1675
No metabolic syndrome (n=6379) 53 1.7% 5.1 93 2.9% 9.1 0.56 0.40 0.79 0.0007

*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.

These data suggest that, instead of a “statin for all” single-strategy, lipid-related cardiovascular prevention should target all risk factors present in individuals with diabetes, including those not receiving proper consideration or hierarchical priority in current recommendations and guidelines.

Together with statin therapy in patients with elevated LDL-C and/or high cardiovascular risk, glycemic control, blood pressure control, lifestyle changes, smoking cessation, and antiplatelet therapy are key measures to be adapted to individual diabetic patients. However, even with this up-to-date approach, patients with diabetes remain exposed to an important residual risk of cardiovascular events and microvascular complications. Targeting atherogenic dyslipidemia also appears to be a most promising strategy to reduce micro- and macrovascular residual risk.

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


1. Colhoun HM, et al., on behalf of the CARDS investigators. Primary prevention of cardiovascular disease with atorvastatin in type 2 diabetes in the Collaborative Atorvastatin Diabetes Study (CARDS): multicentre randomised placebo-controlled trial. Lancet 2004;364:685-96.

2. Sever PS, et al., for the Ascot Investigators. Prevention of coronary and stroke events with atorvastatin in hypertensive patient who have average or lower-than-average cholesterol concentrations, in the Anglo-Scandinavian Cardiac Outcomes Trial—Lipid Lowering Arm (ASCOT-LLA): a multicentre randomised controlled trial. Lancet 2003;361:1149-58

Key words Diabetes – Normal LDL-C levels – Macrovascular events – Statin therapy