Addressing Key Questions with Statin Therapy

Statins have become an important therapeutic option for managing cardiovascular (CV) risk, yet many questions remain regarding their use. This article addresses some of these questions in the primary care management of patients and highlights the impact of long-term statin therapy on CV end points. Because pitavastatin has recently become available in the United States, more detailed information about this agent is also presented.

Recent Clinical Evidence

Findings from clinical trials continue to add to our understanding of the safety and efficacy of statin therapy; for example, extended follow-up studies from 2 landmark trials show lasting benefit and no evidence of emerging hazards. An analysis of the Heart Protection Study demonstrated that participants randomized to simvastatin 40 mg during the initial 5-year trial had maintained the vascular event reduction of 23% (95% confidence interval [CI], 19-28; P < .0001) at the 6-year follow-up.¹ Similarly, 8 years after the close of the 3-year lipid-lowering arm of the Anglo-Scandinavian Cardiac Outcomes Trial (ASCOT), primary prevention patients originally randomized to atorvastatin had maintained a 14% reduction in all-cause mortality (95% CI, 0.76-0.98; P = .02) and a 15% lower rate of non-CV death (95% CI, 0.73-0.99; P = .03) compared with placebo.² Cancer incidence among those receiving a statin versus those receiving a placebo was similar in both trials. Collectively, these data provide reassurance for the long-term continuation of statin therapy.

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

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 statins^18-21

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

Mechanisms implicating statins in other drug interactions include inhibition of CYP2C9, glucuronidation, and organic anion transporting polypeptide (OATP).³¹ Concomitant treatment with gemfibrozil and a statin produces a significant interaction, as this combination inhibits CYP2C9 and glucuronidation, resulting in marked increases in statin exposure. Similarly, the coadministration of a statin with cyclosporine is clinically relevant. Cyclosporine blocks another key step in statin metabolism, OATP, resulting in elevated concentrations of nearly all statins. The concomitant use of cyclosporine with lovastatin, simvastatin, or pitavastatin is contraindicated, whereas most other agents require dose limitations.^18,23,25,31

Do statins possess a dose-dependent threshold for adverse events?

A general dose-dependent threshold for AEs has been observed with statin therapy. This upper limit is more apparent with certain statins and primarily manifests as myotoxicity or increased hepatic transaminase levels. High-dose simvastatin has shown the most evidence regarding increased myopathy. In the Study of the Effectiveness of Additional Reductions in Cholesterol and Homocysteine (SEARCH) trial, 53 patients (0.9%) in the simvastatin 80-mg group experienced myopathy, including 7 cases (0.1%) of rhabdomyolysis, over a mean of 6.7 years of follow-up.³⁴ By comparison, there were 2 reports of myopathy (0.03%) in the 20-mg group. Similarly, in Phase Z of the A to Z trial, 9 reports (0.4%) of myopathy, including 3 cases of rhabdomyolysis (0.13%), were reported with simvastatin 80 mg over a median of 2 years of follow-up, compared to none with lower doses.³⁵ Lower rates of myopathy and rhabdomyolysis (0.0%-0.3% and 0.0%-0.1%, respectively) were found with atorvastatin 80 mg, fluvastatin 80 mg, and rosuvastatin 40 mg in major trials.³⁶ These data prompted the FDA to publish an advisory on simvastatin dose limitations, including restricting the 80-mg dose.¹⁸ A threshold also has been observed with other statins, as an approximate 3-fold higher incidence of creatine kinase (CK) and hepatic transaminase elevations occur when titrating from moderate to maximal doses.³⁷

Should ethnicity be a factor in selecting a statin?

While no specific recommendations presently exist regarding the selection of statin therapy based on ethnicity, rosuvastatin doses, including the 5-mg starting dose, should be reduced in patients of Asian ancestry because of a 2-fold increase in pharmacokinetic parameters compared to whites.³⁸ Otherwise, the few studies evaluating individual agents among various ethnic groups generally suggest similar effects on pharmacokinetic parameters, lipid changes, and CV outcomes.

One study compared pharmacokinetic parameters of pitavastatin between healthy Caucasian and Japanese men.³⁹ Pitavastatin demonstrated pharmacokinetic bioequivalence between the 2 groups with no clinically relevant differences. A substudy of ASCOT assessed the lipid effects of atorvastatin among whites, blacks, and South Asians.⁴⁰ No significant differences were observed in the reductions in total cholesterol, LDL-C, or triglycerides. Lastly, outcomes were evaluated among different ethnicities in the JUPITER study.⁴¹ Similar reductions in major CV events were noted for whites versus non-whites with Hispanics and blacks experiencing comparable risk reductions.

How should statin-associated myalgia be managed?

Approximately 11% of patients receiving moderate- to high-dose statin therapy experience muscle symptoms.⁴² This common AE can greatly affect therapy by reducing quality of life and adherence and limiting treatment outcomes. A step-wise approach can be implemented to minimize the risk of myotoxicity.

The first step is to avoid critical drug interactions that increase statin exposure. The statins most susceptible to interactions are those metabolized by CYP3A4—simvastatin, lovastatin, and atorvastatin. Medications commonly used that inhibit CYP3A4 include macrolide antibiotics and azole antifungals.⁴²

Second, establishing a firm diagnosis of statin- associated myalgia is critical. This is often challenging given that many comorbid conditions (eg, arthritis) are associated with muscle symptoms. Ruling out other possible contributors, such as thyroid dysfunction, electrolyte abnormalities, and recent muscle injury, also should be considered. Temporary discontinuation of the statin to determine if symptoms improve is suggested. Monitoring the CK level is prudent in symptomatic patients to gauge potential myotoxicity and determine if therapy should be discontinued. The National Lipid Association recommends stopping statin therapy when signs and symptoms of rhabdomyolysis are present, including CK >10,000 IU/L or >10 times the upper limit of normal with elevated serum creatinine or requiring intravenous hydration.⁴²

Other steps include switching to a different statin, reducing the statin dose, or using intermittent dosing (eg, every other day or twice weekly) with an extended half-life statin (eg, atorvastatin or rosuvastatin).⁴² Lastly, a bile acid resin or the cholesterol absorption inhibitor ezetimibe can be used. These classes produce only moderate reductions in LDL-C (~20%) but are unlikely to cause muscle symptoms.

Continue to complete the online evaluation and receive your certification of completion.

Statins have become an important therapeutic option for managing cardiovascular (CV) risk, yet many questions remain regarding their use. This article addresses some of these questions in the primary care management of patients and highlights the impact of long-term statin therapy on CV end points. Because pitavastatin has recently become available in the United States, more detailed information about this agent is also presented.

Recent Clinical Evidence

Findings from clinical trials continue to add to our understanding of the safety and efficacy of statin therapy; for example, extended follow-up studies from 2 landmark trials show lasting benefit and no evidence of emerging hazards. An analysis of the Heart Protection Study demonstrated that participants randomized to simvastatin 40 mg during the initial 5-year trial had maintained the vascular event reduction of 23% (95% confidence interval [CI], 19-28; P < .0001) at the 6-year follow-up.¹ Similarly, 8 years after the close of the 3-year lipid-lowering arm of the Anglo-Scandinavian Cardiac Outcomes Trial (ASCOT), primary prevention patients originally randomized to atorvastatin had maintained a 14% reduction in all-cause mortality (95% CI, 0.76-0.98; P = .02) and a 15% lower rate of non-CV death (95% CI, 0.73-0.99; P = .03) compared with placebo.² Cancer incidence among those receiving a statin versus those receiving a placebo was similar in both trials. Collectively, these data provide reassurance for the long-term continuation of statin therapy.

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

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 statins^18-21

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

Mechanisms implicating statins in other drug interactions include inhibition of CYP2C9, glucuronidation, and organic anion transporting polypeptide (OATP).³¹ Concomitant treatment with gemfibrozil and a statin produces a significant interaction, as this combination inhibits CYP2C9 and glucuronidation, resulting in marked increases in statin exposure. Similarly, the coadministration of a statin with cyclosporine is clinically relevant. Cyclosporine blocks another key step in statin metabolism, OATP, resulting in elevated concentrations of nearly all statins. The concomitant use of cyclosporine with lovastatin, simvastatin, or pitavastatin is contraindicated, whereas most other agents require dose limitations.^18,23,25,31

Do statins possess a dose-dependent threshold for adverse events?

A general dose-dependent threshold for AEs has been observed with statin therapy. This upper limit is more apparent with certain statins and primarily manifests as myotoxicity or increased hepatic transaminase levels. High-dose simvastatin has shown the most evidence regarding increased myopathy. In the Study of the Effectiveness of Additional Reductions in Cholesterol and Homocysteine (SEARCH) trial, 53 patients (0.9%) in the simvastatin 80-mg group experienced myopathy, including 7 cases (0.1%) of rhabdomyolysis, over a mean of 6.7 years of follow-up.³⁴ By comparison, there were 2 reports of myopathy (0.03%) in the 20-mg group. Similarly, in Phase Z of the A to Z trial, 9 reports (0.4%) of myopathy, including 3 cases of rhabdomyolysis (0.13%), were reported with simvastatin 80 mg over a median of 2 years of follow-up, compared to none with lower doses.³⁵ Lower rates of myopathy and rhabdomyolysis (0.0%-0.3% and 0.0%-0.1%, respectively) were found with atorvastatin 80 mg, fluvastatin 80 mg, and rosuvastatin 40 mg in major trials.³⁶ These data prompted the FDA to publish an advisory on simvastatin dose limitations, including restricting the 80-mg dose.¹⁸ A threshold also has been observed with other statins, as an approximate 3-fold higher incidence of creatine kinase (CK) and hepatic transaminase elevations occur when titrating from moderate to maximal doses.³⁷

Should ethnicity be a factor in selecting a statin?

While no specific recommendations presently exist regarding the selection of statin therapy based on ethnicity, rosuvastatin doses, including the 5-mg starting dose, should be reduced in patients of Asian ancestry because of a 2-fold increase in pharmacokinetic parameters compared to whites.³⁸ Otherwise, the few studies evaluating individual agents among various ethnic groups generally suggest similar effects on pharmacokinetic parameters, lipid changes, and CV outcomes.

One study compared pharmacokinetic parameters of pitavastatin between healthy Caucasian and Japanese men.³⁹ Pitavastatin demonstrated pharmacokinetic bioequivalence between the 2 groups with no clinically relevant differences. A substudy of ASCOT assessed the lipid effects of atorvastatin among whites, blacks, and South Asians.⁴⁰ No significant differences were observed in the reductions in total cholesterol, LDL-C, or triglycerides. Lastly, outcomes were evaluated among different ethnicities in the JUPITER study.⁴¹ Similar reductions in major CV events were noted for whites versus non-whites with Hispanics and blacks experiencing comparable risk reductions.

How should statin-associated myalgia be managed?

Approximately 11% of patients receiving moderate- to high-dose statin therapy experience muscle symptoms.⁴² This common AE can greatly affect therapy by reducing quality of life and adherence and limiting treatment outcomes. A step-wise approach can be implemented to minimize the risk of myotoxicity.

The first step is to avoid critical drug interactions that increase statin exposure. The statins most susceptible to interactions are those metabolized by CYP3A4—simvastatin, lovastatin, and atorvastatin. Medications commonly used that inhibit CYP3A4 include macrolide antibiotics and azole antifungals.⁴²

Second, establishing a firm diagnosis of statin- associated myalgia is critical. This is often challenging given that many comorbid conditions (eg, arthritis) are associated with muscle symptoms. Ruling out other possible contributors, such as thyroid dysfunction, electrolyte abnormalities, and recent muscle injury, also should be considered. Temporary discontinuation of the statin to determine if symptoms improve is suggested. Monitoring the CK level is prudent in symptomatic patients to gauge potential myotoxicity and determine if therapy should be discontinued. The National Lipid Association recommends stopping statin therapy when signs and symptoms of rhabdomyolysis are present, including CK >10,000 IU/L or >10 times the upper limit of normal with elevated serum creatinine or requiring intravenous hydration.⁴²

Other steps include switching to a different statin, reducing the statin dose, or using intermittent dosing (eg, every other day or twice weekly) with an extended half-life statin (eg, atorvastatin or rosuvastatin).⁴² Lastly, a bile acid resin or the cholesterol absorption inhibitor ezetimibe can be used. These classes produce only moderate reductions in LDL-C (~20%) but are unlikely to cause muscle symptoms.

Continue to complete the online evaluation and receive your certification of completion.

Statins have become an important therapeutic option for managing cardiovascular (CV) risk, yet many questions remain regarding their use. This article addresses some of these questions in the primary care management of patients and highlights the impact of long-term statin therapy on CV end points. Because pitavastatin has recently become available in the United States, more detailed information about this agent is also presented.

Recent Clinical Evidence

Findings from clinical trials continue to add to our understanding of the safety and efficacy of statin therapy; for example, extended follow-up studies from 2 landmark trials show lasting benefit and no evidence of emerging hazards. An analysis of the Heart Protection Study demonstrated that participants randomized to simvastatin 40 mg during the initial 5-year trial had maintained the vascular event reduction of 23% (95% confidence interval [CI], 19-28; P < .0001) at the 6-year follow-up.¹ Similarly, 8 years after the close of the 3-year lipid-lowering arm of the Anglo-Scandinavian Cardiac Outcomes Trial (ASCOT), primary prevention patients originally randomized to atorvastatin had maintained a 14% reduction in all-cause mortality (95% CI, 0.76-0.98; P = .02) and a 15% lower rate of non-CV death (95% CI, 0.73-0.99; P = .03) compared with placebo.² Cancer incidence among those receiving a statin versus those receiving a placebo was similar in both trials. Collectively, these data provide reassurance for the long-term continuation of statin therapy.

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

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 statins^18-21

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

Mechanisms implicating statins in other drug interactions include inhibition of CYP2C9, glucuronidation, and organic anion transporting polypeptide (OATP).³¹ Concomitant treatment with gemfibrozil and a statin produces a significant interaction, as this combination inhibits CYP2C9 and glucuronidation, resulting in marked increases in statin exposure. Similarly, the coadministration of a statin with cyclosporine is clinically relevant. Cyclosporine blocks another key step in statin metabolism, OATP, resulting in elevated concentrations of nearly all statins. The concomitant use of cyclosporine with lovastatin, simvastatin, or pitavastatin is contraindicated, whereas most other agents require dose limitations.^18,23,25,31

Do statins possess a dose-dependent threshold for adverse events?

A general dose-dependent threshold for AEs has been observed with statin therapy. This upper limit is more apparent with certain statins and primarily manifests as myotoxicity or increased hepatic transaminase levels. High-dose simvastatin has shown the most evidence regarding increased myopathy. In the Study of the Effectiveness of Additional Reductions in Cholesterol and Homocysteine (SEARCH) trial, 53 patients (0.9%) in the simvastatin 80-mg group experienced myopathy, including 7 cases (0.1%) of rhabdomyolysis, over a mean of 6.7 years of follow-up.³⁴ By comparison, there were 2 reports of myopathy (0.03%) in the 20-mg group. Similarly, in Phase Z of the A to Z trial, 9 reports (0.4%) of myopathy, including 3 cases of rhabdomyolysis (0.13%), were reported with simvastatin 80 mg over a median of 2 years of follow-up, compared to none with lower doses.³⁵ Lower rates of myopathy and rhabdomyolysis (0.0%-0.3% and 0.0%-0.1%, respectively) were found with atorvastatin 80 mg, fluvastatin 80 mg, and rosuvastatin 40 mg in major trials.³⁶ These data prompted the FDA to publish an advisory on simvastatin dose limitations, including restricting the 80-mg dose.¹⁸ A threshold also has been observed with other statins, as an approximate 3-fold higher incidence of creatine kinase (CK) and hepatic transaminase elevations occur when titrating from moderate to maximal doses.³⁷

Should ethnicity be a factor in selecting a statin?

While no specific recommendations presently exist regarding the selection of statin therapy based on ethnicity, rosuvastatin doses, including the 5-mg starting dose, should be reduced in patients of Asian ancestry because of a 2-fold increase in pharmacokinetic parameters compared to whites.³⁸ Otherwise, the few studies evaluating individual agents among various ethnic groups generally suggest similar effects on pharmacokinetic parameters, lipid changes, and CV outcomes.

One study compared pharmacokinetic parameters of pitavastatin between healthy Caucasian and Japanese men.³⁹ Pitavastatin demonstrated pharmacokinetic bioequivalence between the 2 groups with no clinically relevant differences. A substudy of ASCOT assessed the lipid effects of atorvastatin among whites, blacks, and South Asians.⁴⁰ No significant differences were observed in the reductions in total cholesterol, LDL-C, or triglycerides. Lastly, outcomes were evaluated among different ethnicities in the JUPITER study.⁴¹ Similar reductions in major CV events were noted for whites versus non-whites with Hispanics and blacks experiencing comparable risk reductions.

How should statin-associated myalgia be managed?

Approximately 11% of patients receiving moderate- to high-dose statin therapy experience muscle symptoms.⁴² This common AE can greatly affect therapy by reducing quality of life and adherence and limiting treatment outcomes. A step-wise approach can be implemented to minimize the risk of myotoxicity.

The first step is to avoid critical drug interactions that increase statin exposure. The statins most susceptible to interactions are those metabolized by CYP3A4—simvastatin, lovastatin, and atorvastatin. Medications commonly used that inhibit CYP3A4 include macrolide antibiotics and azole antifungals.⁴²

Second, establishing a firm diagnosis of statin- associated myalgia is critical. This is often challenging given that many comorbid conditions (eg, arthritis) are associated with muscle symptoms. Ruling out other possible contributors, such as thyroid dysfunction, electrolyte abnormalities, and recent muscle injury, also should be considered. Temporary discontinuation of the statin to determine if symptoms improve is suggested. Monitoring the CK level is prudent in symptomatic patients to gauge potential myotoxicity and determine if therapy should be discontinued. The National Lipid Association recommends stopping statin therapy when signs and symptoms of rhabdomyolysis are present, including CK >10,000 IU/L or >10 times the upper limit of normal with elevated serum creatinine or requiring intravenous hydration.⁴²

Other steps include switching to a different statin, reducing the statin dose, or using intermittent dosing (eg, every other day or twice weekly) with an extended half-life statin (eg, atorvastatin or rosuvastatin).⁴² Lastly, a bile acid resin or the cholesterol absorption inhibitor ezetimibe can be used. These classes produce only moderate reductions in LDL-C (~20%) but are unlikely to cause muscle symptoms.

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