How to reach LDL targets quickly in patients with diabetes or metabolic syndrome

Methods

Patient population

We extracted the study population from prespecified pooling of data from ACTFAST 1 and 2,^14,15 which were 12-week, multicenter, prospective, open-label trials that used the same protocol. A full description of inclusion and exclusion criteria for ACTFAST has been published elsewhere.^14,15

Briefly, subjects were either statin-free or statin-treated at baseline, had CHD or a CHD equivalent, had an LDL-C level between 100 and 220 mg/dL (2.6-5.7 mmol/L) and triglycerides =600 mg/dL (6.8 mmol/L), and were willing to follow a recommended diet.

We excluded patients if they had used other lipid-lowering therapy in the prior 2 months (except for statins in the statin-treated study arm) or if they were receiving >40 mg/d of any statin. Patients taking atorvastatin at screening were excluded because the study's goal was to assess the benefits of switching over to a flexible starting dose of atorvastatin. We defined diabetes and MetSyn according to the American Diabetes Association criteria¹⁶ and the NCEP 2001 criteria,¹ respectively.

Doses reflected LDL-C baseline-target gap and prior statin use

If patients were statin free at baseline, we assigned them to 6 weeks of treatment with atorvastatin, at 10, 20, 40, or 80 mg/d, according to their baseline LDL-C level ( FIGURE 1 ). For patients who had been taking a statin at screening, starting doses of atorvastatin for each LDL-C increment were doubled.

If patients did not reach LDL-C targets at the end of 6 weeks, we titrated their regimen to the next higher dose for an additional 6 weeks. Patients initially allocated to receive atorvastatin at 80 mg who did not reach LDL-C targets continued at that dose, and we added a more intense therapeutic lifestyle intervention (NCEP II step 2 diet).¹

We obtained blood samples at baseline screening, week 6, and week 12, to measure 12-hour fasting serum lipid profiles and to make routine safety assessments (hematology and chemistry). Patients received dietary counseling at all visits.

The ACTFAST protocol and amendments were approved by appropriately constituted central or local institutional review boards, and all patients gave written informed consent.

FIGURE 1
How treatment doses were determined

Statin-free patients received a specified dose of atorvastatin according to their baseline low-density lipoprotein cholesterol (LDL-C) level. Patients who had been treated with another statin at screening received atorvastatin at a dose double that given to statin-free patients with equivalent LDL-C levels, for a maximum dose of 80 mg.

Primary efficacy outcome: LDL-C levels of <100 mg/dL

The primary efficacy outcome was the proportion of patients with either diabetes or MetSyn achieving NCEP Adult Treatment Panel-III target LDL-C levels of <100 mg/dL (<2.6 mmol/L) after 12 weeks of treatment.¹ Secondary efficacy parameters were described in ACTFAST 1.¹⁴

We analyzed data according to intention-to-treat (ITT), using the last observation carried forward (LOCF) for missing data. The ITT population consisted of all patients who took at least 1 dose of study medication, and had at least 1 subsequent assessment.

Results

Between January 2003 and February 2004, 3634 subjects were screened for ACTFAST 1 and 2, and 2717 patients were enrolled from 12 countries (Canada, Greece, Hungary, Ireland, Italy, Poland, Portugal, Russia, Slovakia, Spain, Switzerland, and the United Kingdom). Ethnicity was recorded for about 80% of patients; more than 90% were Caucasian.

Diabetes

The ITT population included 1024 patients with diabetes, of whom 97% had type 2 diabetes and 73% were statin-free ( TABLE 1 ). Baseline laboratory parameters are available online, in TABLE W1 .

After 12 weeks of treatment, 81% (95% confidence interval [CI], 77.8%-83.5%) of statin-free and 60% (95% CI, 53.9%-65.4%) of statin-treated patients with diabetes achieved LDLC target of <100 mg/dL ( FIGURE 2 ). In contrast, among patients without diabetes (n=1693), 77% (95% CI, 73.9%-79.3%) of statin-free and 59% (95% CI, 55.4%-62.5%) of statin-treated patients achieved target.

For diabetes patients, mean percent reductions in total cholesterol, TC/HDL-C, LDL-C, triglycerides, non-HDL-C and apolipoprotein B (apo B) were significant vs baseline for all doses in both statin-free and statin-treated subjects ( TABLE 2 ). Significant increases in HDL-C were seen only with the 10- and 80-mg doses in statin-free patients.