Pitavastatin: evidence for its place in treatment of hypercholesterolemia

Abstract

Statins, inhibitors of 3-hydroxy-3-methylglutaryl-coenzyme A reductase, are the most potent pharmacologic agents for lowering total cholesterol (TC) and low-density lipoprotein cholesterol (LDL-C). They have become an accepted standard of care in the treatment of patients with known atherosclerotic cardiovascular disease (secondary prevention) and also those at increased risk of cardiovascular events. There are currently six statin drugs commercially available in the US. Although they are chemically similar and have the same primary mechanisms of action in lowering TC and LDL-C, there are differences in their efficacy or potency, metabolism, drug-drug interactions, and individual tolerability. Considering the numbers of patients who need LDL-C-lowering therapy and questions of individual tolerance and therapeutic response, having a variety of agents to choose from is beneficial for patient care. This paper presents background information on statin treatment and reviews data regarding a new agent, pitavastatin, which has recently been approved for clinical use.

Keywords: HMG CoA reductase inhibitors; class effect; low-density lipoprotein; pitavastatin; statins.

Figure 1

Statins share a number of chemical similarities. They all contain a dihydroxy heptanoic acid HMG-CoA like moiety, which competes for binding to HMG-CoA reductase. The fungal statins all have a naphthalenyl ester base structure. The synthetic statins share a fluorinated phenyl group with a methylethyl side chain and a base structure with five or six-member ring with one or more carbon atoms replaced by nitrogen. All these structural elements participate in binding to HMG-CoA reductase.Copyright © 2009. Adapted with permission from McKenney JM, Ganz P, Wiggins BS, et al. In: Ballantyne CM, editor. Clinical Lipidology A Companion to Braunwald’s Heart Disease. Philadelphia, PA: Saunders Elsevier; 2009.

Figure 2

The rate limiting step in the conversion of Acetyl CoA to cholesterol is 3-hydroxy-3-methylglutaryl-CoA to mevalonate. This reaction is mediated by the enzyme HMG-CoA reductase and HMG-CoA reductase inhibitors, or statins, competitively inhibit this activity.

Figure 3

HMG-CoA reductase inhibitors (statins) reduce TC and LDL-C via a number of mechanisms: Decreased hepatic synthesis of cholesterol, decreased hepatic intracellular cholesterol pool stimulating upregulation of LDL receptor activity, reduced VLDL secretion from hepatocytes leading to decreased remnant lipoproteins and increased tissue uptake of apoB particles from the circulation.

Figure 4

Chemical structure of pitavastatin. Note commonality to other statins in Figure 1.

Figure 5

Metabolic pathway for pitavastatin. Involvement of CYP2C9 is minimal. It is rapidly glucuronized by uridine diphosphate-glucuronyl transferase (UGT) and then converted to a lactone form which is inactive.

Figure 6

Mean percent change in TC, LDL-C, HDL-C and TG from baseline values with daily dose pitavastatin for 12 weeks: Yellow Bar 1 mg, Orange Bar 2 mg, Gray Bar 4 mg.

Figure 7

Data obtained from the post-marketing “LIVES Study” assessed standard lipid parameters in large numbers of patients along with a more in-depth analysis of pitavastatin’s effect on HDL-C over 104 weeks as well as after switching from other statins. In the low-HDL-C group HDL-C increased 14% at 12 weeks and 24.6% at 104 weeks. Significant increases in HDL-C by pitavastatin also occurred after switching from other statins. Note: % change in HDL from no initial pharmacologic treatment (light blue bar) versus any lipid therapy (dark blue bar) and the indicated statins after switching to pitavastatin mean dose <2 mg/day.