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Macrovascular Residual Risk THROUGH LANDMARK STUDY

2 October 2008
Substantial residual risk of fatal and non-fatal events after 5 years of statin therapy in diabetes: meta-analysis of 14 trials

Efficacy of cholesterol-lowering therapy in 18686 people with diabetes in 14 randomised trials of statins. Lancet 2008;371:117-25

Cholesterol Treatment Trialists
Summary
Comments & References
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STUDY SUMMARY
Objective To evaluate the outcomes of previous trials on statin therapy in people with diabetes.
Study population
18,686 patients with diabetes (1,466 with type 1 and 17,220 with type 2; 6,956 with a history of vascular disease and
11,730 without) and 71,370 without diabetes who were administered statins in 14 randomized trials.
Main endpoint Major vascular events as a combined endpoint including major coronary events, coronary revascularization, and stroke.
Study design Meta-analysis of randomized trials.
Methods
Weighted estimates on clinical outcomes per 1.0 mmol/L (39 mg/dl) reduction in LDL-cholesterol (LDL-C)
Main results Proportional reduction per mmol/L reduction in LDL-cholesterol during mean follow-up of 4.3 years in people with diabetes:
  • 9% in all-cause mortality (p=0.02; non-significant*) (vs. 13% in non-diabetic, p<0.0001)
  • 12% in CHD mortality (p=0.03; non-significant*), similar to those without diabetes,
  • Significant 21% reduction in all major vascular events (P<0·0001) (similar to those without diabetes).
  • Proportional effects of statin therapy were similar whether prior history of vascular disease or not.
Author's conclusion

Statin therapy should be considered for all people with diabetes who are at sufficiently high risk of vascular events.

*The multiple comparisons were expressed with 99% confidence intervals (CIs), which means that the p value had to be inferior to 0.01 to be considered as statistically significant.

COMMENT

The first meta-analysis of 90,056 people from 14 randomized trials of statin therapy (the Cholesterol Treatment Trialists’ [CTT] Collaboration)1 showed that lowering LDL-C by 1 mmol/L
(39 mg/dl) reduced the risk of major vascular events (defined as the composite outcome of myocardial infarction or coronary death, stroke, or coronary revascularization) by about one fifth. The population consisted of a wide range of high-risk individuals, with differing baseline lipid profiles and other presenting characteristics. At least 20% of study participants had diabetes, and to independently establish the effects of statins in this group, a further sub-analysis was performed.
As the list of 14 trials was closed in 2004, two important studies in type 2 diabetes, ASPEN and 4D, both showing negative results and both involving atorvastatin, could not be included in this analysis. Based on their published summaries, their inclusion would not have changed the overall results according to the authors. A third negative trial, CORONA (rosuvastatin) in people with heart failure of whom 30% had diabetes was also not included.
The primary meta-analyses were the effects on clinical outcomes in each trial weighted by the absolute LDL-C difference in that trial at the end of the first year of follow-up. Results were reported as the effects per 1·0 mmol/L reduction in LDL-C.

Non-significant reductions in all-cause and CHD mortality
During a mean follow-up of 4.3 years there was a non-significant 9% reduction in all-cause mortality (p=0.02) in people with diabetes compared to a significant 13% reduction in those without diabetes (p<0.0001).
There was also a non-significant 12% reduction in CHD mortality (p=0.03) compared to a significant 22% reduction in patients without diabetes.
The reduction in non-CHD vascular death and non-vascular death (3 and 5%, respectively with or without diabetes) was also not significant either for patients with or without diabetes.

The only statistically significant result obtained on mortality in the diabetes subgroup was a 13% relative reduction in all-vascular mortality (p=0.008).

Among participants with diabetes, there was however a significant 21% reduction (p<0.0001) in the incidence of major vascular events per mmol/L LDL-C reduction, which was similar to the 21% reduction per mmol/L LDL-C cholesterol reduction in those without diabetes (p<0.0001). This corresponded to:

  • a 22% reduction in major coronary events (p<0.0001),
  • a 25% reduction in coronary revascularization ( p<0.0001)
  • a 21% reduction in stroke (p=0.0002).

The effect on each outcome was similar in participants irrespective of whether or not they had diabetes.

Statins leave unaddressed a huge residual risk of fatal and non-fatal events
Statin use was associated in this meta-analysis of diabetic patients with a benefit (roughly 20% reduction) in major vascular events (similar to that observed in patients without diabetes) and whatever the subgroup analyzed. However, statins did not significantly reduce either total or CHD mortality in patients with diabetes.
The reductions of CHD death, non-CHD vascular death, non-vascular death or all cause mortality associated with statin therapy and LDL-C reduction were not statistically significant for 99% CIs in patients with diabetes.The absolute reduction for any cause of death (i.e. CHD, CVD and all cause mortality) was lower than 1% in people with diabetes and consistently lower than in people without diabetes.

The 9% reduction of all cause mortality obtained in diabetes is nearly 50% smaller than that observed in non-diabetic subjects (13%), leaving a residual risk in diabetic subjects on statin treatment 50% higher than in those without diabetes.

The data from this large meta-analysis of 14 well-designed randomized statin trials should prompt clinicians to be aware of the substantial residual risk of fatal and non-fatal vascular events that persists in people with diabetes and LDL-C lowered by statins for about 5 years.

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Figure 1:Proportional effects on cause-specific mortality per mmol/L reduction in LDL cholesterol in participants presenting
with or without diabetes. Diamonds or squares to the left of the solid line indicate benefit with treatment,
but this is significant (i.e., p<0.05 and p<0.01, respectively) only if the diamond or horizontal line does not overlap the solid line.

References
  1. Cholesterol Treatment Trialists’ (CTT) Collaboration. Am J Cardiol 1995;75:1130–34
Key words LDL-cholesterol reduction – Diabetes - Reduction of major cardiovascular events