Addressing Key Questions with Statin Therapy

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Medical Education Library

Addressing Key Questions with Statin Therapy

June 2012 · Vol. 61, No. 06 Suppl: S34-S39

References

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Results from a meta-analysis involving 34,272 participants without coronary heart disease from 14 randomized controlled trials (16 trial arms) comparing statins to placebo demonstrated significant reductions in all major events with statins, including a reduction of 16% in all-cause mortality (95% CI, 0.73-0.96), 30% in combined fatal and nonfatal CV disease end points (95% CI, 0.61-0.79), and 34% in revascularization rates (95% CI, 0.53-0.83).³ The meta-analysis found no evidence of significant harm caused by a statin or negative effects on patient quality of life.

Pitavastatin

Pitavastatin was approved in the United States in 2009, although it has been available in Japan since 2003. Pitava-statin is a synthetic lipophilic statin with an 11-hour half-life. Following oral ingestion, it enters the enterohepatic circulation without the formation of active metabolites. Pitavastatin is principally metabolized by the cytochrome-P450 (CYP) 2C9 isoenzyme and avoids the major CYP3A4 pathway; thus CYP-mediated drug interactions are greatly reduced.⁴

Several 12-week dose comparative studies with pitavastatin have been conducted. The first study randomized subjects (N = 857) to 1 of 4 groups: pitavastatin 2 or 4 mg/d or simvastatin 20 or 40 mg/d.⁵ Pitavastatin 2 mg demonstrated significantly greater reductions in low- density lipoprotein cholesterol (LDL-C; 39% vs 35%; P = .014) and greater reductions in non–high-density lipoprotein cholesterol (non–HDL-C) than did simvastatin 20 mg/d. Pitavastatin 4 mg/d and simvastatin 40 mg/d each reduced LDL-C by about 44%. Pitavastatin 4 mg/d has also been compared to atorvastatin 20 mg/d in 418 subjects.⁶ After 12 weeks, pitavastatin 4 mg/d and atorvastatin 20 mg/d produced similar reductions in LDL-C (~42%). No differences between groups were noted for other parameters, including HDL-C and non–HDL-C.

Long-term extension studies have evaluated the safety and efficacy of pitavastatin. Patients randomized to pitava-statin, atorvastatin, or simvastatin for 12 weeks received open-label pitavastatin 4 mg/d for up to 52 weeks (N = 1353).⁷ Notable findings included maintenance of LDL-C reductions from the end of the 12-week trial to 52 weeks with all 3 treatments. HDL-C levels continued to increase during follow up, rising 14.3% from baseline. Another long-term study compared pitavastatin 4 mg/d and atorvastatin 20 or 40 mg/d (N = 212).⁶ Both statins produced similar reductions in LDL-C and improvements in other major lipoproteins; however, atorvastatin significantly increased fasting blood glucose from baseline (7.2%; P < .05), whereas pitavastatin showed a nonsignificant increase of 2.1%.

The Japanese LIVALO Effectiveness and Safety (LIVES) Study (N = 20,000) evaluated the effects of pitavastatin 1 to 4 mg daily in clinical practice.⁸ Among patients with abnormal baseline values, treatment with pitavastatin was associated with a 29% reduction in LDL-C and a 23% reduction in triglycerides after 2 years. There was a 5.9% overall increase in HDL-C and a 24.6% increase among those with baseline HDL-C values <40 mg/dL. Pitavastatin was also associated with an improvement in glycosylated hemoglobin (A1C) values among those with diabetes mellitus (DM). Concomitant antidiabetic therapy was continued during the study. These findings suggest that pitavastatin does not worsen glycemic parameters. A 5-year extension of the LIVES study (N = 6582) demonstrated that long-term treatment with pitavastatin maintained the LDL-C reductions observed in the 2-year trial.⁸ Furthermore, HDL-C levels continued to climb, with an overall 29% increase among those with baseline values < 40 mg/dL. Patients who achieved both LDL-C and HDL-C targets experienced the greatest reductions in CV and cerebrovascular risk.

Finally, the Japan Assessment of Pitavastatin and Ator-vastatin in Acute Coronary Syndrome (JAPAN-ACS) study was a prospective, open-label trial that investigated the effects of pitavastatin 4 mg/d and atorvastatin 20 mg/d on coronary plaque volume (PV) among patients with acute coronary syndrome (N = 252) undergoing intravascular ultrasound.⁹ After 8 to 12 months of treatment, the mean change in PV was – 16.9 ± 13.9% and – 18.1 ± 14.2% in the pitavastatin and atorvastatin groups, respectively. Each statin produced significant but equivalent regression of PV.

Other key findings from additional pitavastatin clinical trials are found in TABLE 1 .^10-17

table 1

Key findings from pitavastatin clinical trials

Statins	Population	Findings/Comments
Dose Comparative Studies
Pitavastatin 4 mg vs Simvastatin 40 mg¹⁵	Dyslipidemic adults with ≥2 CV risk factors (N = 355)	Each statin: LDL-C ↓ by 44% at 12 weeks >80% reached LDL-C goal
Pitavastatin 2 mg, 4 mg¹⁷	Dyslipidemic adults age ≥65 years (N = 545)	LDL-C ↓ by 43%, HDL-C ↑ by 9.6% at 60 weeks Only 17% required uptitration to 4 mg 89%-94% achieved LDL-C goals
Pitavastatin 4 mg vs Simvastatin 40-80 mg¹⁶	Dyslipidemic adults with ≥ 2 CV risk factors (N=178)	Each statin: LDL-C ↓ by ~42% at 44 weeks Discontinuation (5.8% vs 10.5%), myalgia (4.1% vs 12.3%) for pitavastatin vs simvastatin, respectively
Other Clinical Trials
Pitavastatin 2 mg vs Atorvastatin 10 mg vs Rosuvastatin 2.5 mg¹⁰	Dyslipidemic adults with CV risk factors (N=302)	All agents: LDL-C ↓ by 40%-45% at 16 weeks Atorvastatin and rosuvastatin: A1C ↑
Pitavastatin 2 mg vs Rosuvastatin 2.5 mg¹¹	Dyslipidemic adults with type 2 DM (N = 90)	Both agents: Inflammation ↓, lipids improved, no adverse effects on glycemic control Rosuvastatin: Greater LDL-C ↓, hsCRP vs pitavastatin
Pitavastatin 2.3 mg vs Atorvastatin 11.3 mg vs Pravastatin 10.3 mg vs No statin¹³	Previous PCI (N = 743)	Each statin: Major coronary events ↓ LDL-C and HDL-C: Predicted coronary events Pitavastatin and atorvastatin: Greater LDL-C ↓ vs pravastatin Only pitavastatin: Significant HDL-C ↑ vs no statin
Pitavastatin 2 mg vs Atorvastatin 10 mg¹²	ACS patients who underwent emergency PCI and IVUS (N = 160)	Fibrofatty composition, PV: Significant ↓ with pitavastatin
Pitavastatin 2 mg¹⁴	Adults with acute MI (N = 1039)	71% achieved LDL-C goal at 12 months Pitavastatin: Favorable effects on biomarkers maintained at 12 months
A1C, glycosylated hemoglobin; ACS, acute coronary syndrome; CV, cardiovascular; DM, diabetes mellitus; HDL-C, high-density lipoprotein cholesterol; hsCRP, high-sensitivity C-reactive protein; IVUS, intravascular ultrasound; LDL-C, low-density lipoprotein cholesterol; MI, myocardial infarction; PCI, percutaneous coronary intervention; PV, plaque volume.