The incidence of elevations in aspartate aminotransferase (AST) or alanine aminotransferase (ALT) >3 times and creatine kinase (CK) >10 times the upper limit of normal were 1.1% and 0.1%, respectively, for patients with diabetes, and 0.9% and 0.08% for those with MetSyn, which did not differ from those of patients without diabetes (1.2% and 0%, respectively) or MetSyn (1.3% and 0%, respectively).
TABLE W1
Baseline lipid values for patients with diabetes or metabolic syndrome (mean ± SD)
| DIABETES | STATIN-FREE (N=744) | STATIN-TREATED (N=280) | ALL (N=1024) |
|---|---|---|---|
| Total cholesterol, mg/dL | 225.8±32.7* | 210.8±29.9 | 221.7±32.6 |
| LDL-C, mg/dL | 149.4±26.8* | 133.8±24.3 | 145.1±27.0 |
| HDL-C, mg/dL | 50.0±12.5 | 50.2±12.0 | 50.1±12.4 |
| TC/HDL-C | 4.7±1.1* | 4.4±1.0 | 4.6±1.1 |
| Triglycerides, mg/dL | 173.8±85.1 | 179.4±80.4 | 175.3±83.8 |
| Apo B, g/L | 1.1±0.2 | 1.1±0.2 | 1.1±0.2 |
| HbA1C, % | 7.2±1.2 | 7.4±1.3 | 7.3±1.2 |
| FPG, mmol/L | 8.2±2.9 | 8.2±2.6 | 8.2±2.8 |
| METABOLIC SYNDROME | STATIN-FREE (N=839) | STATIN-TREATED (N=412) | ALL (N=1251) |
| Total cholesterol, mg/dL | 229.3±34.1* | 215.7±32.7 | 224.9±34.2 |
| LDL-C, mg/dL | 152.3±27.8* | 137.8±26.6 | 147.5±28.3 |
| HDL-C, mg/dL | 45.3±11.0 | 46.1±10.4 | 45.5±10.8 |
| TC/HDL-C | 5.3±1.3* | 4.9±1.1 | 5.2±1.2 |
| Triglycerides, mg/dL | 206.4±88.7 | 211.2±83.7 | 208.0±87.1 |
| Apo B, g/L | 1.2±0.2 | 1.1±0.2 | 1.2±0.2 |
| HbA1C, % | 6.7±1.2 | 6.6±1.2 | 6.7±1.2 |
| FPG, mmol/L | 7.4±2.5 | 7.1±2.3 | 7.3±2.4 |
| LDL-C, low-density lipoprotein cholesterol; HDL-C, high-density lipoprotein cholesterol; TC/HDL-C, total cholesterol/HDL-C ratio; Apo B, apolipoprotein B; HbA1C, hemoglobin A1C; FPG, fasting plasma glucose; SD, standard deviation. | |||
| *P<.05 statin-free vs statin-treated. | |||
Discussion
Despite their increased cardiovascular risk, patients with diabetes and MetSyn often do not reach lipid targets.17 In patients with diabetes, lowering LDL-C levels reduces the risk of a cardiovascular event by 25% to 50%.18-23 Atorvastatin has demonstrated its efficacy for the primary prevention of cardiovascular events among patients with diabetes.22,23
MetSyn also increases the risk of cardiovascular events and mortality.10-13 Atorvastatin has been used effectively to achieve LDL-C goals in hypercholesterolemic patients with MetSyn.24,25
Higher starting doses of statins are generally beneficial. This substudy of ACTFAST demonstrates that by initiating therapy at doses selected according to baseline LDL-C levels, 81% of statin-free and 60% of statin-treated subjects with diabetes and 78% of statin-free and 57% of statin-treated subjects with MetSyn achieved a target LDL-C of <100 mg/dL within 6 to 12 weeks. Among statin-treated patients, atorvastatin provided additional reduction in lipid parameters over what was achieved with the statin they had been using at baseline.
Other studies have also suggested that patients at high risk for cardiovascular events, such as those with diabetes or MetSyn, may benefit from starting therapy at a higher dose of atorvastatin.14,15,26,27 In the New Atorvastatin Starting Doses: A Comparison (NASDAC) study, patients were randomized to receive various starting doses of atorvastatin, regardless of their baseline LDL-C value.26 The proportion of patients with CHD or a CHD-equivalent (of whom 150 had diabetes) who achieved LDL-C target (<100 mg/dL) with 10, 20, 40, and 80 mg/d was 47%, 66%, 81% and 80%, respectively, demonstrating that a higher starting dose is required to achieve target.
However, lower doses may work depending on LDL-C levels. In contrast to NASDAC, statin-free patients with diabetes or MetSyn in ACTFAST showed better results on 10- and 20-mg doses, because baseline LDL-C was taken into account. The Atorvastatin Goal Achievement Across Risk Levels (ATGOAL) study used a design similar to ACTFAST, assigning patients with dyslipidemia to starting doses of atorvastatin for 8 weeks, at 10, 20, 40, or 80 mg, based on their CHD risk category and the magnitude of LDL-C reduction necessary to reach lipid targets.27 Of the 1298 patients, 705 were at high CHD risk (43.8% with diabetes), and 81.1% of these high-risk patients achieved an LDL-C <100 mg/dL.
No safety issues arose when initiating atorvastatin at higher doses in patients with diabetes or MetSyn. The incidence of clinically elevated AST, ALT, or CK levels in ACTFAST was low and comparable to that reported in meta-analyses (0.96%).28,29
Benefits of our dosing algorithm seem clear. Aggressive treatment with atorvastatin across the dose range improves LDL-C target achievement compared with usual care,30,31 and current NCEP-III recommendations support the use of a higher initial dose in patients requiring large LDL-C reductions.1 Atorva-statin is approved in many countries at starting doses ranging from 10 to 40 mg, with a titration to 80 mg, if needed, to achieve LDL-C target. ACTFAST suggests that, in patients with diabetes or MetSyn, initiation of atorvastatin at a dose appropriate for the required level of LDL-C reduction would facilitate achievement of LDL-C targets.
One meta-analysis of trials demonstrated that a 10-mg/dL reduction in LDL-C could result in a 5.4% reduction in major vascular events and a 3.1% reduction in all-cause mortality over 5 years.32 In our study, patients with diabetes or MetSyn experienced reductions in LDL-C of approximately 57 mg/dL, which, if maintained over 5 years, could be expected to translate into reductions of 30% in major vascular events and 17% in mortality. Therefore, a regimen that allows a larger number of high-risk patients to achieve substantial reductions in LDL-C levels quickly could significantly improve cardiovascular outcomes.