Statin therapy does not eliminate cardiovascular risk due to low high density lipoprotein cholesterol in diabetes patients

HDL Forum Editor Dr Anthony Wierzbicki discusses findings from a new meta-analysis from the Cholesterol Treatment Trialists’ (CTT) Collaborators, published in The Lancet, January 11, 2008. Diabetes patients with a low level of high density lipoprotein (HDL) cholesterol remain at increased cardiovascular risk, despite statin therapy.

Efficacy of cholesterol-lowering therapy in 18 686 people with diabetes in 14 randomised trials of statins: a meta-analysis. Lancet 2008;371:117-25.

Statins are widely used in people with diabetes. The aim of this meta-analysis was to evaluate whether statins confer more or less benefit in people with diabetes than in those without diabetes. While the majority of studies have shown clinical benefits with statin therapy in patients with diabetes, some recent trials have failed to show any clear benefit. In the ASPEN trial (Atorvastatin Study for Prevention of Coronary Heart Disease Endpoints in Non-Insulin-Dependent Diabetes Mellitus)1 there was a non-significant 10% reduction in the primary composite endpoint (cardiovascular death, non-fatal myocardial infarction [MI], non-fatal stroke, recanalisation, coronary artery bypass surgery, resuscitated cardiac arrest, and worsening or unstable angina requiring hospitalization). Similarly in the German Diabetes and Dialysis Study (4D) in patients with diabetes and nephropathy who were undergoing dialysis, atorvastatin therapy reduced low-density lipoprotein (LDL) cholesterol levels by 42% but failed to significantly reduce cardiovascular events (reduction by 8%).2

The CTT Collaborators also investigated whether statins are beneficial in diabetes people with elevated triglycerides, low HDL cholesterol, or both. Both of these lipid abnormalities are commonly seen in diabetes patients, and are commonly referred to diabetic dyslipidaemia.

The meta-analysis included data from 18,686 people with diabetes and a further 71,370 people without diabetes from 14 randomised trials. During a mean follow-up of 4.3 years there were 3,247 major vascular events in people with diabetes. The CTT Collaborators showed that there was a significant relative reduction in vascular mortality (by 13%, p=0.008) and vascular events (by 21%, p<0.0001) per mmol/L reduction in low-density lipoprotein (LDL) cholesterol (table 1). These findings were similar in people without diabetes. Additionally, the relative risk reduction was similar irrespective of previous history of vascular disease, age or sex. These results confirm the value of statin therapy in diabetes patients. The CTT Collaborators concluded: 'Most people with diabetes should now be considered for statin therapy, unless their risk is low (as in children), or statin therapy has been shown to be unsuitable for them (as in pregnancy).'

Table 1. Effect of statin therapy in people with and without diabetes


Endpoint
Event rate
  
 StatinControlRelative risk reduction (CI)aP-value
Vascular mortality    
Diabetes6.4%7.2%13% (0-24%)p<0.008
No diabetes4.2%5.3%18% (12-24%) P<0.0001
Vascular events    
Diabetes15.6%19.2%21% (14-28%)p<0.0001
No diabetes13.7%17.4%21% (18-24%)P<0.0001

However, it is also evident from data presented in this paper that people with diabetes remain at higher residual risk for vascular events, than those without diabetes, despite statin therapy. Subgroup analysis showed that event rates for major vascular events were higher in people with diabetes and low HDL cholesterol or elevated triglycerides than in those with values at current targets. Statistical tests for trends were however not statistically significant (table 2).

Table 2. Effect of low HDL cholesterol or elevated triglycerides on vascular events in statin-treated people with diabetes


Endpoint
Event rate
 
 StatinControlRelative risk reduction (CI)a
Vascular mortality   
≤0.9 mmol/L 22.8%26.3%18% (5-29%)
>0.9 to ≤1.1 mmol/L16%20.3%25% (11-37%)
>1.1 mmol/L4.2%11.5%14.4%
Vascular events   
≤1.4 mmol/L13.6%17%26% (13-38%)
1.4 to ≤2.0 mmol/L14.7%18.2%18% (5-30%)
2.0 mmol/L4.2%18%17% (6-27%)

Among statin-treated patients, vascular event rates in people with low HDL cholesterol (≤0.9 mmol/L or ≤35 mg/dL) were 50% higher than in those with above target values (>1.1. mmol/L) (22.8% vs. 11.5%). Additionally, statin-treated patients with low HDL cholesterol levels had a 37% higher vascular event rate than control patients with above target HDL cholesterol values (22.8% vs. 14.4%).

These results suggest that statin fails to eliminate the residual risk due to low HDL cholesterol and/or elevated triglycerides which are a common feature of diabetic dyslipidaemia.

While statin therapy is clearly effective in reducing vascular risk in diabetes patients, these insights argue for the need for additional therapy aimed at raising low HDL cholesterol and lowering elevated triglycerides to reduce residual vascular risk.

References

1. Knopp RH, d’Emden M, Smilde JG et al. Efficacy and safety of atorvastatin in the prevention of cardiovascular endpoints 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.

2. Wanner C, Krane V, Marz W for the German Diabetes and Dialysis Study Investigators. Atorvastatin in patients with type 2 diabetes mellitus undergoing hemodialysis. N Engl J Med 2005; 353: 238-48.

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