Key Questions
The following are common questions asked by family physicians when considering statin therapy to treat patients with dyslipidemia.
What are the key lipoprotein differences among available statins?
Nearly all statins are able to provide the minimal 30% to 40% LDL-C reduction as suggested by the National Cholesterol Education Program Adult Treatment Panel III for high-risk patients ( TABLE 2 ).18-22 If greater reductions are required, higher doses of more potent agents, such as atorvastatin and rosuvastatin, may be needed.
Statins also provide moderate increases in HDL-C, with subtle differences observed among the agents. Atorvastatin and fluvastatin usually provide the smallest increases in HDL-C (up to ~6%), whereas simvastatin, pitavastatin, and rosuvastatin produce more robust increases (~5% to 10%).20,21,23 The effect of statins on non–HDL-C is similar to their effect on LDL-C.22 Non–HDL-C is a secondary target of therapy in patients with triglyceride levels ≥200 mg/dL. Non–HDL-C includes all atherogenic particles (ie, LDL-C and triglyceride-rich lipoproteins) and is calculated as the difference between total cholesterol and HDL-C. The non–HDL-C goal is 30 mg/dL higher than the LDL-C goal. Clinical investigation continues to demonstrate that non–HDL-C is a valuable predictor of CV risk. An analysis of statin-treated patients indicated that compared with LDL-C and apolipoprotein B, non–HDL-C has a greater strength of association for risk of future CV events.24
table 2
Range of Low-Density Lipoprotein Cholesterol (LDL-C)–lowering among statins18-21
| LDL-C Range (↓) | Atorvastatin | Fluvastatin | Lovastatin | Pitavastatin | Pravastatin | Rosuvastatin | Simvastatin |
|---|---|---|---|---|---|---|---|
| 20%-25% | — | 20 mg | — | — | — | — | — |
| 25%-30% | — | 40 mg | — | — | 10 mg | — | — |
| 30%-35% | — | 80 mg | 20 mg | 1 mg | 20 mg | — | 10 mg |
| 35%-40% | 10 mg | — | 40 mg | 2 mg | 40 mg | — | 20 mg |
| 40%-45% | 20 mg | — | 80 mg | 4 mg | 80 mg | 5 mg | 40 mg |
| 45%-50% | 40 mg | — | — | — | — | 10 mg | — |
| 50%-60% | 80 mg | — | — | — | — | 20 mg | — |
| >60% | — | — | — | — | — | 40 mg | — |
Is diabetes really a consequence of statin therapy? If so, do differences exist among the statins?
The US Food and Drug Administration (FDA) recently added warnings to all statin labeling indicating that statins can raise blood glucose and A1C levels.25 These effects appear to be modest and dose dependent. This concern initially emerged in the Justification for the Use of statins in Prevention: an Intervention Trial Evaluating Rosuva-statin (JUPITER) study when statin users experienced a 25% higher incidence of new onset DM compared to those receiving placebo.26 The short-term effects of various atorvastatin doses on glycemic indices further support these findings.27 Compared to placebo, all atorvastatin doses significantly increased A1C and fasting plasma insulin levels after 8 weeks (all, P < .01). Additionally, a meta-analysis of 5 major statin trials involving 32,752 patients demonstrated that patients receiving intensive-dose statin therapy had a 12% higher risk of developing DM than patients receiving moderate-dose statin therapy.28
The association between statin therapy and DM is considered a class effect; differences among the statins are controversial. In an analysis of 13 major randomized controlled trials, pravastatin produced a nonsignificant 3% increase in new onset DM, whereas rosuvastatin was associated with an 18% increase.28 A 16-week, head-to-head comparison showed that pitavastatin had no effect on A1C, while modest increases were seen with low-dose atorvastatin and rosuvastatin.10 In another study, atorvastatin but not pitavastatin produced significant (P < .03) increases in glycoalbumin and A1C (P < .01), whereas fasting glucose and insulin levels tended to decrease with pitavastatin.29 However, findings from the meta-analysis showed that the individual studies lacked sufficient specific data to detect heterogeneity between statins.30
Overall, statins are associated with modest increases in glycemic indices and new onset DM. This association appears to be greater with high-dose therapy; however, additional trials are needed to fully understand possible differences among statins.
Which drug interactions are clinically important?
As statin pharmacokinetic data have accumulated, critical drug interactions have become more apparent. The major concern is increased statin exposure secondary to limited metabolism, resulting in more dose-dependent AEs, such as muscle injury. CYP3A4 isoenzyme involvement is common in clinically significant interactions. Lovastatin, simvastatin, and to a lesser extent, atorvastatin are all substrates for CYP3A4.31 The FDA recently updated labeling for simvastatin and lovastatin to provide information on contraindications and dose limitations with concomitant agents [www.fda.gov/Drugs/DrugSafety/ucm293877.htm].18,25
Statins have differing effects on warfarin metabolism, with most agents increasing the international normalized ratio (INR). Conversely, atorvastatin and pitavastatin have shown no significant effect on prothrombin time when added to chronic warfarin therapy.23,32 Despite this, appropriate INR monitoring is suggested when any statin is added to warfarin treatment.
Another recent FDA advisory focusing on human immunodeficiency virus and hepatitis C virus protease inhibitors further emphasizes the importance of statin interactions.33 The advisory provides specific dose limitations and contraindications for 7 statins. Similar to other potent CYP3A4 inhibitors, protease inhibitors can increase lovastatin and simvastatin levels by 13- to 20-fold. No information is available for fluvastatin, while no dose limitations are needed for pitavastatin or pravastatin.33