The Collaborative Atorvastatin Diabetes Study

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A Primary Prevention Trial, Collaborative Atorvastatin Diabetes Study (CARDS), exclusively in patients with type 2 diabetes who had one additional risk factor was recently published [28]. A total of 2838 patients, age range 40-75 years, were randomized to 10 mg atorvastatin versus placebo and followed over a mean period of 3.9 years. In this trial, the mean LDL-cholesterol level was 118 mg/dL, which was reduced by 40% in the drug treated group. The combined primary end-points of acute CHD events, coronary re-vascularization or stroke were reduced by 37% (P = 0.001), whereas stroke events were reduced by 48%, and total mortality by 27% (P = 0.059). The risk reductions were independent of baseline lipid levels and in post-hoc analyses 743 patients with baseline LDL < 100 mg/dL had a 26% reduction in major cardiovascular events, which is consistent with the results in the HPS [25].

Fig. 1. Effects of simvastatin on first major vascular event in patients who do or do not have diabetes according to presenting features and baseline blood lipid concentrations. CI, confidence interval. The numbers in columns two and three represent the number of individuals with a given characteristic/total number in that group (% of total with the given characteristic). The last column represents the proportional reduction in risk (and CIs); the size of the rectangular box varies according to the relative number of subjects. (Adaptedfrom Collins R, Armitage J, Parish S, Sleigh P, Peto R. MRC/BHF Heart Protection Study of cholesterol-lowering with simvastatin in 5963 people with diabetes: a randomised placebo-controlled trial. Lancet 2003;361(9374):2005-16; with permission.)

Fig. 1. Effects of simvastatin on first major vascular event in patients who do or do not have diabetes according to presenting features and baseline blood lipid concentrations. CI, confidence interval. The numbers in columns two and three represent the number of individuals with a given characteristic/total number in that group (% of total with the given characteristic). The last column represents the proportional reduction in risk (and CIs); the size of the rectangular box varies according to the relative number of subjects. (Adaptedfrom Collins R, Armitage J, Parish S, Sleigh P, Peto R. MRC/BHF Heart Protection Study of cholesterol-lowering with simvastatin in 5963 people with diabetes: a randomised placebo-controlled trial. Lancet 2003;361(9374):2005-16; with permission.)

Intensive versus moderate lipid intervention in acute coronary syndromes

Two Large Lipid-Intervention Trials in patients with acute coronary syndromes were recently completed. PROVE-IT (Pravastatin or Atorvastatin Evaluation and Infection Therapy) Trial compared high dose (80 mg) atorvastatin with moderate dose pravastatin (40 mg) in 4162 patients presenting within 10 days of the acute coronary event. The median LDL reduction to 62 mg/dL and 95 mg/dL respectively, resulted in a 16% reduction in the composite primary endpoint (P = 0.005) over 24 months [29]. A similar, but non-significant, trend was seen in 734 (18%) of patients with diabetes. There were no major adverse effects except a small but significant difference in the number of patients (3.3% versus 1.1%) with ALT >3 fold above the upper limit of normal. In contrast, in the A to Z trial, 4497 patients presenting with acute coronary syndromes were randomized within 4 days to an early intensive treatment arm with simvastatin 40 mg/d for one month followed by 80 mg/d, and a delayed conservative strategy of placebo for 4 months, followed by 20 mg/d simvastatin [30]. 1059 (24%) of patients had diabetes. There were no significant differences in composite primary end-points in initial 4 months but from 4 thru 24 months, there was a 25% reduction in the simvastatin only group (P = 0.02). The differences in outcome between PROVE-IT and the A to Z trial could be due to several possible reasons, including a delayed initiation of intensive treatment and other factors such as less differential in LDL-cholesterol levels, less than expected number of events, and 33% rate of study-drug discontinuation in the A to Z Trial. However, it is noteworthy that, in contrast to the PROVE-IT Trial with 80 mg atorvastatin, there were 9 patients in the 80 mg simvastatin group in the A to Z trial with evidence of myopathy (CK > 10 x upper limit of normal) and 3 of these patients had rhabdomyolysis. These findings underscore the need for greater vigilance for adverse effects and safety issues in patients on high dose statins.

The Post Coronary Bypass Graft Trial was an angiographic regression trial that compared aggressive cholesterol lowering with moderate cholesterol lowering. After a mean follow-up of 4.3 years, the angiographic end points were comparable in the subgroup that had diabetes (n = 116) and the nondiabetic cohort (n = 1235) [31].

Thus, the overall efficacy of statins seems to be dependent largely on baseline risk of vascular disease, duration of treatment, and perhaps, the LDL level that is achieved. The ideal level of LDL is unknown; additional trials with specific targets are needed. A recent meta-analysis of 58 randomized trials of cholesterol lowering concluded that an approximate decrease in LDL cholesterol of 40 mg/dL resulted in a 33% decrease in CHD events by 5 years; additional benefits may accrue with a greater decrease in LDL cholesterol over the long term [32]. The average LDL reductions and outcomes seemed to be similar in the diabetic subgroups.

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