Impact Of Lipidlowering On Cardiovascular Endpoints

Cardiovascular disease (CVD) is a major cause of morbidity and mortality in patients with diabetes, and their risk is similar to that of non-diabetics with prior myocardial infarction (MI) (24). Improved glycemic control alone seems not to be sufficient to improve the CVD risk profile of patients with diabetes. In this regard, in the UKPDS, more intensive hypoglycemic therapy was associated with a 25% risk reduction in microvascular end points compared with conventional therapy (p=0.01), whereas risk reductions in fatal or nonfatal MI did not reach significance (fatal MI, 6% risk reduction, p=0.94; nonfatal MI, 21% risk reduction, p= 0.06) (25).

Following is a brief review the available evidence of cardiovascular benefit of lipid-lowering therapy in patients with diabetes.

Statin Treatment for Patients With Diabetes

There are sufficient numbers of patients with diabetes in the major secondary prevention trials with statins to allow meaningful subgroup analyses. In the Scandinavian Simvastatin Survival Study (4S) (26) an initial analysis described the impact of simvastatin (20-40 mg/day) on 202 patients with diabetes out of a total of 4444 patients with established CHD and raised cholesterol concentrations (212-309 mg/dL, 5.5-8.0 mmol/L). In the diabetic subgroup, simvastatin produced similar effects on serum lipid and lipoprotein concentrations over the course of the trial as in non-diabetics, with reductions in total and LDL cholesterol of 24% and 34%, respectively, an 8% increase in HDL and a 9% reduction in triglyceride. It should be pointed out that the entry criteria for 4S stipulated total serum triglycerides 220 mg/dL (< 2.5 mmol/L). These changes were associated with a significant reduction in major coronary events - relative risk (RR) reduction 0.45 (p=0.002). The reduction in the primary end-point of 4S - all-cause mortality - was not significant, given the small numbers, but did approach significance. RR reduction was 0.57 (p=0.087). A further analysis of 4S data using the new diagnostic criterion for diabetes from the American Diabetes Association, i.e. a fasting plasma venous glucose of > 126 mg/dL (7mmol/L) revealed 483 patients with diabetes (27). In this larger group, the RR reduction for major coronary events was 0.58 (p=0.001), with a highly significant reduction in revascularisations. Total and coronary mortality were also reduced, but these reductions did not reach statistical significance due to the small sample sizes. In 678 patients with impaired fasting glucose (110-125mg/dL, 6.0-6.9 mmol/L) there was a significant reduction in coronary events (RR=0.62; p=0.003) and total mortality (RR=0.57; p=0.02). These results have been analysed with regard to cost-effectiveness and resource utilisation, and have been found to be highly cost-effective (28).

Subgroup analysis of 586 patients with diabetes included in the Cholesterol and Recurrent Events (CARE) trial provided additional evidence of the benefit of statin therapy (29). Pravastatin 40 mg/day was associated with a RR reduction in major coronary events of 25% (p=0.05). Further evidence of the benefit of pravastatin therapy in patients with diabetes comes from the subgroup analysis of 782 patients with diabetes in the long-term intervention with pravastatin in ischemic disease (LIPID) trial (5).

Furthermore, patients with diabetes have been shown to have CHD risk reductions similar to those of non-diabetics, as shown in many primary and secondary CHD trials (Table 1).

For example the heart protection study (HPS) randomized 20,536 patients at risk of occlusive arterial disease to either simvastatin 40 mg/day or placebo (30). This patient population included a subgroup of 5963 patients with known diabetes (31). At the end of the 5-year treatment period, patients in the overall population treated with statin experienced a 24% reduction in major vascular events (i.e. CHD death, nonfatal MI, stroke and revascularization) compared with patients given placebo. The risk reduction was similar in the subgroup with diabetes (22%). Additional data from HPS demonstrated the impact of low HDL cholesterol on CVD risk in patients with diabetes. In the diabetic subgroup, a greater risk for vascular events was observed in placebo-treated patients with low baseline HDL cholesterol levels (31.1%) than in placebo-treated patients with high baseline LDL cholesterol levels (27.9%), suggesting that strategies targeting low levels of HDL cholesterol may result in benefit in addition to those that target high LDL cholesterol concentrations.

TABLE 1 Coronary Heart Disease (CHD) Prevention Trials with Statins in Subgroup Analyses of Patients with Diabetes Mellitus



Patients with diabetes (n)

Overall CHD risk reduction (%)

CHD risk reduction in patients with diabetes (%)

P value

Primary prevention

Diabetes Sustenance

Diabetes Sustenance

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