The Pros and Cons of Intensive Statin Therapy: A Review of the Literature

Authors

James J. DiNicolantonio, PharmD1
Asfandyar K. Niazi2
Carl J. Lavie, MD, FACC, FACP, FCCP3
Victor L. Serebruany, MD, PhD4
Evangelos Liberopoulos, MD, FASA, FRSH5
James H. O’Keefe, MD6

1Mid America Heart Institute at Saint Luke’s Hospital, Kansas City, MO; 2Shifa College of Medicine, Islamabad, Pakistan; 3John Ochsner Heart and Vascular Institute, Ochsner Clinical School, University of Queensland School of Medicine, New Orleans, LA, and Pennington Biomedical Research Center, Baton Rouge, LA; 4HeartDrugTM Research Laboratories, Johns Hopkins University, Towson, MD; 5Department of Internal Medicine, University of Ioannina Medical School, Ioannina, Greece; 6Mid America Heart Institute at Saint Luke’s Hospital, University of Missouri–Kansas City, Kansas City, MO

Correspondence: James J. DiNicolantonio, PharmD.
Saint Luke’s Mid America Heart Institute
4401 Wornall Road 600
Kansas City, MO 64111
816-931-1883
Tel: 816-751-8480
E-mail: jjdinicol@gmail.com

Abstract

Statins have been shown to prevent cardiovascular (CV) events and mortality in both the primary and secondary prevention settings. However, the question of whether high-dose (intensive) statin therapy is preferable to low-dose statin therapy remains controversial. This review discusses the positive and negative aspects of intensive statin therapy. In general, intensive statin therapy leads to greater CV risk reduction, greater renal protection, and larger reductions in hospitalizations for patients with coronary heart disease and heart failure. Although recent data from several different analyses suggest that intensive statin therapy modestly increases the risk of new-onset diabetes mellitus (DM) versus moderate-dose statin therapy, there is a greater reduction in CV events that outweighs the small increased risk of DM. Even among those who do develop DM, statin therapy is still highly effective at reducing adverse CV events. The risk of myalgias, myopathies, and other adverse events are generally similar, or mildly increased, with high-dose compared to low-dose statin therapy (with the greatest increase in adverse events seen with simvastatin 80 mg). Moreover, intensive statin therapy in patients with established coronary heart disease is associated with substantial CV benefits, which strongly outweigh the risks.

Keywords:

statin; cerebrovascular disease; cholesterol; cardiovascular disease; myocardial infarction; diabetes

Introduction

Despite the evidence of statin’s benefits in primary and secondary prevention of coronary heart disease (CHD), there is recent controversy as to whether high-dose (intensive) statin therapy should be prescribed in place of the usual low- to moderate-dose statin therapy. The controversy stems from the recent evidence that hints at an increase in the risk of diabetes mellitus (DM) in patients receiving high-dose statin therapy.1–3 However, evidence indicates that a higher dose (more intensive statin therapy) may offer greater cardiovascular (CV) protection. This review summarizes the pros and cons of intensive statin therapy as compared with the usual (low- to moderate-dose) statin therapy.

The Advantages of Intensive Statin Therapy

Epidemiological findings and statin trials indicate that reductions in blood cholesterol and low-density lipoprotein cholesterol (LDL-C) at any level translate into a further reduction in the risk for CHD.4 This would suggest that a more intensive statin therapy may be able to reduce the risk of CV diseases even further than less intensive statin therapy. Higher doses of statins have been shown to be more cardio- and cerebroprotective as compared with the usual doses of statins.4

Effects on the Cardiovascular System

Surrogate Markers

Although a detailed discussion of the impact of statins on surrogate markers (including C-reactive protein), measures of atherosclerosis (including carotid intimal medial thickness), and ultrasound evidence of atherosclerosis is beyond the scope of this review, statins clearly have benefits on all of these surrogate markers, and more so at high or intense doses. 5–7

Cardiovascular End Points

Phase Z of the Aggrastat to Zocor (A to Z) Trial compared the effects of an early intensive statin therapy (40 mg/d of simvastatin for 30 days and then 80 mg/d of simvastatin thereafter) versus a delayed less intensive statin therapy (placebo for 4 months and then 20 mg/d of simvastatin thereafter) in 4497 patients with acute coronary syndrome (ACS).8 Follow-up was for at least 6 months and up to 24 months. In the intensive statin group, LDL-C decreased by 39% in 1 month as compared with the less intensive group, in which patients showed a modest 11% increase during the placebo period and then a 31% decrease from their original LDL-C levels. The primary composite end point of major adverse cardiovascular events (MACE; defined in this study as CV death, nonfatal myocardial infarction [MI], readmission for ACS, and stroke) was numerically, but not statistically significantly, lower in the intensive statin group as compared with the less intensive statin group (14.4% vs 16.7%; hazard ratio (HR), 0.89; 95% confidence interval [CI], 0.76–1.04; P = 0.14). Similarly, CV death (4.1% vs 5.4%; HR, 0.75; 95% CI, 0.57–1.00; P = 0.05) and new-onset heart failure (HF) (3.7% vs 5.0%; HR, 0.72; 95% CI, 0.53–0.98; P = 0.04) were also reduced in the more intensive statin group. However, there were no significant differences in the incidences of MI, readmission for ACS, revascularization, or stroke. This trial showed that a more intensive statin treatment after ACS has positive effects with trends for reducing MACE and HF. It should be noted that the trial did not achieve the prespecified sample size, and that the reduction of the primary outcome measure in the more intensive treatment group was not statistically significant.

The Pravastatin or Atorvastatin Evaluation and Infection Therapy–Thrombolysis in Myocardial Infarction 22 (PROVE IT-TIMI 22) enrolled 4162 participants with a recent ACS (within the last 10 days) and randomized them to receive either a standard statin therapy (40 mg/d pravastatin) or intensive statin therapy (80 mg/d atorvastatin).9 The LDL-C was reduced to a greater extent in the intensive statin group as compared with the standard statin group (on-treatment LDL-C 62 mg/dL vs 95 mg/dL). At a mean follow-up of 2 years, the primary composite end point of MACE (defined in this study as death from any cause, MI, rehospitalization due to unstable angina, revascularization, and stroke) was lower in the intensive statin group as compared with the standard statin group (22.4% vs 26.3; 16% reduction in MACE with intensive statin therapy: 95% CI, 5–26; P = 0.005) (Figure 1). In the intensive statin group, the risk of death, MI, or urgent revascularization was reduced by 25% (P < 0.001). Additionally, there were significant reductions in the intensive treatment groups for revascularization (14%, P = 0.04), recurrent unstable angina (29%, P = 0.02), and nonsignificant reductions in death from any cause (28%, P = 0.07) and death or MI (18%, P = 0.06). This study demonstrates that in patients with a recent history of ACS, intensive statin therapy is superior to standard statin therapy for reducing the risk of major CV events. There is also the possibility that the intensive statin dose was not the causative factor driving the benefit of atorvastatin over pravastatin. Indeed, the pharmacological differences between atorvastatin and pravastatin may have partly (or entirely) caused these results.

Figure 1. Intensive statin therapy lowers major adverse cardiovascular events (MACE) in acute coronary syndrome patients: the Pravastatin or Atorvastatin Evaluation and Infection Therapy–Thrombolysis in Myocardial Infarction 22 (PROVE IT-TIMI 22) trial.

Figure 1. Intensive statin therapy lowers major adverse cardiovascular events (MACE) in acute coronary syndrome patients: the Pravastatin or Atorvastatin Evaluation and Infection Therapy–Thrombolysis in Myocardial Infarction 22 (PROVE IT-TIMI 22) trial.

The Incremental Decrease in End Points Through Aggressive Lipid Lowering (IDEAL) study compared the effects of high-dose (80 mg/d atorvastatin) versus usual-dose statin therapy (20 mg/d simvastatin) on the incidence of major CHD events in 8888 patients with a history of MI.10 The median follow-up was 4.8 years. Major CHD events, defined as CHD death, confirmed nonfatal MI, or cardiac arrest, were reduced in the atorvastatin group as compared with the simvastatin group (9.3% vs 10.4%; HR, 0.89; 95% CI, 0.78–1.01; P = 0.07). Additionally, nonfatal MI (6.0% vs 7.2%; HR, 0.83; 95% CI, 0.71–0.98; P = 0.02), major CV events (HR, 0.87; 95% CI, 0.77–0.98; P = 0.02), all CHD events (HR, 0.84; 95% CI, 0.76–0.91; P < 0.001), any CV events (HR, 0.84; 95% CI, 0.78–0.91; P < 0.001), peripheral arterial disease (HR, 0.76; 95% CI, 0.61–0.96; P = 0.02), and revascularization (HR, 0.77; 95% CI, 0.69–0.86; P < 0.001) were fewer in the atorvastatin group as compared with the simvastatin group (Figures 2 and 3). However, there was no significant reduction in non-CV death (HR, 0.92; 95% CI, 0.73–1.15; P = 0.47), all-cause mortality (HR, 0.98; 95% CI, 0.85–1.13; P = 0.81), or the individual end points of CHD death or cardiac arrest. The IDEAL study showed that the use of intensive statin therapy (atorvastatin 80 mg/d) leads to a reduction in nonfatal MI and major adverse CV events versus usual dose statin therapy (simvastatin 20 mg/d).

 Figure 2. Cardiovascular benefits of high-dose versus usual-dose statin therapy in patients with a history of MI: the Incremental Decrease in End Points Through Aggressive Lipid Lowering (IDEAL) trial.


Figure 2. Cardiovascular benefits of high-dose versus usual-dose statin therapy in patients with a history of MI: the Incremental Decrease in End Points Through Aggressive Lipid Lowering (IDEAL) trial.

 Figure 3. Cardiovascular benefits of high-dose versus usual-dose statin therapy in patients with a history of MI: the IDEAL trial.


Figure 3. Cardiovascular benefits of high-dose versus usual-dose statin therapy in patients with a history of MI: the IDEAL trial.

In the Treating to New Targets (TNT) trial, 10 001 patients with CHD were randomized to receive either 10 mg/day atorvastatin or 80 mg/day atorvastatin to ascertain if intensive atorvastatin reduces MACE (defined in this study as death from CHD, nonfatal MI, cardiac arrest, or stroke) versus less intense atorvastatin.11 Atorvastatin 80 mg as compared with 10 mg atorvastatin significantly decreased MACE (8.7% vs 10.9%, absolute risk reduction 2.2%, relative risk [RR] reduction 22%; HR, 0.78; 95% CI, 0.69–0.89; P < 0.001). The incidence of overall mortality was similar in both groups. However, there was a higher incidence of increase in liver aminotransferase in participants receiving 80 mg atorvastatin (1.2% vs 0.2%; P < 0.001). Compared with atorvastatin 10 mg, patients on atorvastatin 80 mg also showed a greater reduction in the risk of a major CHD events (HR, 0.80; 95% CI, 0.69–0.92; P = 0.002), any CHD event (HR, 0.79; 95% CI, 0.73–0.86; P < 0.001), cerebrovascular events (HR, 0.77; 95% CI, 0.64–0.93; P = 0.007), HF hospitalization (HR, 0.74; 95% CI, 0.59–0.94; P = 0.01), and any CV event (HR, 0.81; 95% CI, 0.75–0.87; P < 0.001) (Figure 4). However, there were no differences between the groups in terms of all-cause mortality (HR, 1.01; 95% CI, 0.85–1.19; P = 0.92). The TNT trial adds to the body of evidence indicating the superiority of an intensive statin therapy in reducing the incidence of MACE.

 Figure 4. Cardiovascular benefits of atorvastatin (ATV) 80 mg versus atorvastatin 10 mg in patients with coronary heart disease (CHD): the Treating to New Targets (TNT) trial.


Figure 4. Cardiovascular benefits of atorvastatin (ATV) 80 mg versus atorvastatin 10 mg in patients with coronary heart disease (CHD): the Treating to New Targets (TNT) trial.

In a post-hoc analysis of the TNT study the effects of statins in patients with preexisting HF were assessed.12 The results of this analysis showed a significantly lower incidence of hospitalization for HF in the group receiving 80 mg atorvastatin as compared with the group receiving 10 mg atorvastatin (2.4% vs 3.3%; HR, 0.74; 95% CI, 0.59–0.94; P = 0.0116). In patients with a previous history of HF, hospitalization was less common in the 80-mg group as compared with the 10-mg group (10.6% vs 17.3%; HR, 0.59; 95% CI: 0.40–0.88; P = 0.008). However, in patients without a prior history of HF, the incidence of hospitalization was not significantly lower in the 80-mg group as compared with the 10-mg group (1.8% vs 2.0%; HR, 0.87; 95% CI, 0.64–1.16; P = 0.34). It is important to note that this study excluded patients with New York Heart Association class IIIb or IV HF or with a left ventricular ejection fraction < 30%. Thus, the results of this study may not be generalizable to the entire patient population with HF.

The Study of the Effectiveness of Additional Reductions in Cholesterol and Homocysteine (SEARCH) randomized 12 064 patients with a history of MI to receive either 80 mg simvastatin daily or 20 mg simvastatin daily in order to compare the effects on the primary end point of MACE (defined in this study as CHD death, MI, stroke, or arterial revascularization).13 The incidence of MACE was numerically lower in the group receiving the higher dose (24.5% vs 25.7%; 6% proportional reduction: RR 0.94; 95% CI, 0.88–1.01; P = 0.10). Both groups showed similar incidences of hemorrhagic strokes (24 [0.4%] vs 25 [0.4%]) and deaths attributed to CV causes (565 [9.4%] vs 572 [9.5%]) or non-CV causes (399 [6.6%] vs 398 [6.6%]). However, there was a higher incidence of myopathy in patients taking 80 mg as compared with patients taking 20 mg (0.9% vs 0.03%). This study supports the finding that intensive statin therapy consistently shows greater reductions in the incidence of major CV events as compared with less intensive statin therapy. However, this trial led to guidelines suggesting that simvastatin 80 mg should not be utilized in most clinical situations due to a higher incidence of rhabdomyolysis. Additionally, the primary end point of MACE for this study did not show a statistically significant difference between the 2 groups.

The Study Assessing Goals in the Elderly (SAGE) trial randomized 893 ambulatory elderly CHD patients to either atorvastatin 80 mg/day or pravastatin 40 mg/day and followed them for 12 months.14 Despite the fact that the primary end point (absolute change from baseline in total duration of ischemia at month 12) was significantly reduced with both statins (P < 0.001 for each statin at 3 and 12 months) compared with pravastatin, atorvastatin caused a significant reduction in all-cause mortality (HR, 0.33; 95% CI, 0.13–0.83; P = 0.014) and numerically fewer major acute CV events (HR, 0.71; 95% CI, 0.46–1.09; P = 0.114). In summary, compared with moderate pravastatin therapy, intensive atorvastatin therapy led to a significant reduction in all-cause mortality and was associated with a numeric reduction in major acute CV events, with equal effects on ischemia in elderly patients with CHD. The results of this study should be interpreted in light of its small sample size and short follow-up duration.

A meta-analysis was conducted on individual participant data of 39 612 participants from 5 randomized controlled trials (RCTs) with a median follow-up of 5.1 years to compare the effects of more versus less intensive statin therapy.4 The results of this meta-analysis showed that as compared with less intensive statin therapy, more intensive statin therapy led to a weighted mean further reduction in LDL-C of 0.51 mmol/L at 1 year and a significant 15% reduction (95% CI, 11–18; P < 0.0001) in MACE. In addition, there were significant reductions in the individual end points of CHD death or nonfatal MI (13%; 95% CI, 7–19; P < 0.0001), coronary revascularization (19%; 95% CI, 15–24; P < 0.0001), and ischemic stroke (16%; 95% CI, 5–26; P = 0.005). This meta-analysis also compared the effects of statin therapy versus control. The combined results of both analyses showed that each 1.0 mmol/L reduction in the LDL-C led to a significant reduction in the incidences of MACE (RR, 0.78; 95% CI, 0.76–0.80; P < 0.0001), all-cause mortality (10%; RR, 0.90; 95% CI, 0.87–0.93; P < 0.0001), deaths due to CHD (RR, 0.80; 99% CI, 0.74–0.87; P < 0.0001) and deaths due to other CV causes (RR, 0.89; 99% CI, 0.81–0.98; P = 0.002). Conversely, LDL-C reduction did not have a significant effect on the incidence of deaths due to stroke (RR, 0.96; 95% CI, 0.84–1.09; P = 0.5), other CV causes (RR, 0.98; 99% CI, 0.81–1.18; P = 0.8), cancer or other non-CV causes (RR, 0.97; 95% CI, 0.92–1.03; P = 0.3), or on the incidence of cancer (RR, 1.00; 95% CI, 0.96–1.04; P = 0.9). This meta-analysis demonstrated that irrespective of the baseline LDL-C levels, a further decrease in the LDL-C levels led to a continued benefit in terms of reduced incidence of CHD events.

Another meta-analysis provides evidence of not only protective effects on the heart but also on the brain with the use of high-dose statin therapy versus standard-dose statin therapy.15 Indeed, intensive statin therapy in 27 548 patients enrolled in 4 large trials led to a significant reduction in coronary death or MI (odds reduction, 16%; P < 0.00001), coronary death or any CV event (P < 0.00001), and a trend toward a reduction in CV mortality (odds reduction, 12%; P = 0.054). Moreover, stroke was significantly reduced (odds reduction, 18%; P = 0.012) with intensive statin therapy.

A meta-analysis was conducted to determine whether the use of statins before cardiac surgery had an impact on clinical outcomes.16 This analysis was based on 91 491 patients undergoing cardiac surgery from a total of 54 trials. The use of statins preoperatively significantly reduced the incidence of all-cause mortality (absolute risk reduction, 0.9%; odds reduction, 31%; odds ratio (OR), 0.69; 95% CI, 0.59–0.81; P < 0.0001). Statins also reduced the incidence of postoperative atrial fibrillation (OR, 0.71; 95% CI, 0.61–0.82; P < 0.01), new-onset atrial fibrillation (OR, 0.68; 95% CI, 0.54–0.85; P < 0.01), stroke (OR, 0.83; 95% CI, 0.74–0.93; P < 0.01), intensive care unit stay (weighted mean difference (WMD), –0.14; 95% CI, –0.23 to –0.03; P < 0.01), and in-hospital stay (WMD, –0.57; 95% CI, –0.76 to –0.38; P < 0.01). This meta-analysis thus provides evidence that preoperative statin use leads to better patient outcomes and improved survival rates in patients undergoing cardiac surgery. This meta-analysis, however, included both RCTs and observational studies, which may have reduced the reliability of the results and thus should be interpreted with caution.

Effects on the Brain

A prospective, nonrandomized observational study of 448 patients with ischemic stroke was performed to ascertain the effect of statin therapy as well as dose on clinical outcomes,17 which suggested that statins improve early and late mortality as well as functional outcome compared with patients not treated with statins, and this effect was dose-dependent; that is, a higher, more intensive statin therapy may lead to better outcomes if given before or after ischemic stroke occurrence.

Similar results were seen in the Stroke Prevention by Aggressive Reduction in Cholesterol Levels (SPARCL) trial,18 which randomized 4731 patients who had experienced a stroke or transient ischemic attack (TIA) within 1 to 6 months of study entry to receive either 80 mg/day of atorvastatin or placebo, and looked at first fatal or nonfatal stroke as the primary end point. This study found that the participants on atorvastatin had a lower risk of fatal or nonfatal stroke (11.2% vs 13.15; 5-year absolute risk reduction, 2.2%; adjusted HR, 0.84; 95% CI, 0.71–0.99; P = 0.03). Similarly, the group on atorvastatin also had a significant 5-year absolute reduction in the risk of MACE (3.5%; HR, 0.80; 95% CI, 0.69–0.92; P = 0.002). In the post-hoc analyses, the adjusted hazard ratios for each type of stroke (ischemic, hemorrhagic, or unclassified) were evaluated. Patients in the atorvastatin group had a lower risk of ischemic and unclassified stroke (HR, 0.78; 95% CI, 0.66–0.94 for ischemic stroke; HR, 0.55; 95% CI, 0.21–1.40 for unclassified stroke). However, patients receiving atorvastatin also had a higher risk of hemorrhagic stroke (HR, 1.66; 95% CI, 1.08–2.55), an effect not noted in the aggregate of the high-dose atorvastatin studies.

The results of this study demonstrated that in patients with a history of stroke or TIA, high-dose statin therapy leads to a reduction in the incidence of ischemic stroke and MACE at the cost of an increased risk in hemorrhagic stroke. It is important to note that the reduction in ischemic and unclassified strokes far outnumbered the hemorrhagic strokes caused, as there was a significant reduction in overall strokes with atorvastatin versus placebo (265/2365 vs 311/2366; RR, 0.85; 95% CI, 0.73–0.99).18 Despite the fact that SPARCL did not compare high- versus low-dose statin therapy, the benefit as well as the harm cannot be directly applied to low-dose statin therapy.

Effects on the Kidneys

The TNT trial was conducted on 10 001 patients with CHD, with and without chronic kidney disease (CKD), with all the participants randomized to atorvastatin 10 mg/day for 8 weeks and then randomized to receive either 80 mg/day atorvastatin or 10 mg/day atorvastatin.19 Participants in the 80-mg group with CKD showed a 35% lower RR of MACE as compared with the participants in the 10-mg group (13.9% vs 20.9%; HR, 0.65; 95% CI, 0.43–0.98; P = 0.04). Similarly, in patients with normal glomerular filtration rate (GFR), the participants in the 80-mg group had a 10% lower RR of developing MACE when compared with the participants in the 10-mg group (12.8% vs 14.1%; HR, 0.90; 95% CI, 0.63–1.29; P = 0.56). In addition to the CV benefits, the intensive statin therapy group also displayed signs of beneficial effects on the kidneys. The increase in GFR was significantly greater in the 80-mg group as compared with the 10-mg group (2.6 ± 0.5 mL/min per 1.73 m2 vs 0.5 ± 0.4 mL/min per 1.73 m2; P = 0.001). Additionally, patients with DM and CKD at baseline also received a significant 35% relative reduction in the risk of having a first MACE (HR, 0.65; 95% CI, 0.43–0.98; P = 0.04). An important finding of the TNT trial is that the positive effects of an intensive statin therapy were more robust in participants with CKD or DM as compared to those without.

Additionally, the Atorvastatin for Reduction of Myocardial Damage during Angioplasty–Contrast-Induced Nephropathy (ARMYDA CIN) trial was conducted on 241 patients undergoing percutaneous coronary intervention, to assess whether a short high-dose atorvastatin treatment could lead to a reduced incidence of contrast-induced nephropathy,20 which suggested that short-term treatment with a high-dose statin prevents contrast-induced nephropathy, shortens hospital stay, and improves renal function.

The Disadvantages of Intensive Statin Therapy

Nephrotoxicity

A recent retrospective observational analysis of administrative databases using 9 population-based cohort studies (totaling 2 067 639 patients) found that in patients with non-CKD, current users of high-potency statins were 34% more likely to be hospitalized with acute kidney injury (AKI) within 120 days after starting treatment (fixed effect rate ratio, 1.34; 95% CI, 1.25–1.43).21 Patients with CKD did not have a significant increase in AKI with high-potency statins (RR, 1.10; 95% CI, 0.99–1.23). The authors concluded that high-potency statins are associated with an increased rate of AKI compared with low-potency statins. However, several criticisms about these data were reported: (1) retrospective data cannot prove causation; (2) the results likely reflect reverse causation (ie, patients taking high-potency statins are at a higher risk for AKI; (3) all hidden confounders could not be adjusted for; and (4) RCTs indicate that atorvastatin has the largest amount of data showing positive effects on renal function, atorvastatin compared with other statins (and especially when compared with rosuvastatin) provides greater beneficial effects on the kidneys, and high-dose atorvastatin is more renoprotective than low-dose atorvastatin.22 Other considerations are that the results of an increased risk of AKI with high-potency statins are not relevant with a number need to harm (NNH) of 1700 over 120 days to produce 1 extra case of AKI. As the NNH is very high and there was no related increase in morbidity and mortality, the increase in AKI with high-potency statins does not seem to be clinical relevant.

Atorvastatin was shown to have more beneficial effects on the kidneys as compared to rosuvastatin in the Prospective Evaluation of Proteinuria and Renal Function in Diabetic Patients with Progressive Renal Disease (PLANET I) and Prospective Evaluation of Proteinuria and Renal Function in Nondiabetic Patients with Progressive Renal Disease (PLANET II) trials.23 These 2 trials compared the effects of high-dose atorvastatin (80 mg/d) with high-dose rosuvastatin (10 or 40 mg/d) in patients with hypercholesterolemia and moderate proteinuria. The PLANET I trial enrolled 325 participants with type 1 or type 2 diabetes, whereas the PLANET II trial involved 220 patients without diabetes. The primary outcome of these trials was a difference in the urinary protein/creatinine ratio from the start to the end of the study.

The PLANET I trial found less decline in estimated GFR with atorvastatin (–1 to –2 mL/min) compared with rosuvastatin 10 mg (–4 mL/min) and rosuvastatin 40 (–8 mL/min). Moreover, rosuvastatin 40 mg/day as compared with atorvastatin 80 mg/day significantly increased the rate of acute renal failure by approximately 4-fold (4.1% vs 0.9%, respectively; P < 0.05), increased the rate at which serum creatinine levels doubled (4.9% vs 0.0%, respectively; P < 0.01), and increased serum creatinine level doubling or the rate of acute renal failure (7.3% vs 0.09%, respectively; P < 0.01). The PLANET II trial found that proteinuria was reduced by approximately 20% with high-dose atorvastatin therapy, whereas rosuvastatin 10 mg/day and 40 mg/day had no effect on the proteinuria. Additionally, rosuvastatin 40 mg/day caused a significant reduction in GFR, which was not seen with atorvastatin or low-dose rosuvastatin. Thus, high-dose rosuvastatin may be particularly detrimental to kidney function in these select patients. Despite the fact that these trials cannot determine if atorvastatin is particularly beneficial on renal function or if rosuvastatin is particularly harmful, there is a clear difference on renal function between these 2 potent statins.

Hemorrhagic Stroke

The SPARCL trial, as described previously, suggested a small increase in the risk of hemorrhagic stroke in patients started on atorvastatin 80 mg/day within 1 to 6 months of experiencing a stroke or TIA.18 Despite the small increase in hemorrhagic stroke, atorvastatin caused a significant reduction in overall strokes (11.2% vs 13.1%; 5-year absolute risk reduction, 2.2%; adjusted HR, 0.84; 95% CI, 0.71–0.99; P = 0.03) and major CV events (stroke plus any major CHD event) (3.5%; HR, 0.80; 95% CI, 0.69–0.92; P = 0.002). Even though there was an increase in hemorrhagic strokes (HR, 1.66; 95% CI, 1.08–2.55), the incidence of ischemic and unclassified stroke decreased (HR, 0.78; 95% CI, 0.66–0.94 for ischemic stroke; HR, 0.55; 95% CI, 0.21–1.40 for unclassified stroke) with statin therapy as compared with placebo. Whether or not this increase in the risk of hemorrhagic stroke is dose dependent (or statin dependent) is not clear. However, when patients with hemorrhagic stroke as an entry criterion were excluded, there was still an increased risk of hemorrhagic stroke (RR, 1.64; 95% CI, 1.12–2.40) despite a significant reduction in ischemic stroke (RR, 0.80; 95% CI, 0.69–0.92).21 In summary, atorvastatin led to a reduction in overall stroke, ischemic stroke, and major CV events at the cost of an increased risk of hemorrhagic stroke. Thus, there was an overall net benefit of high-dose statin in these patients.

A meta-analysis was conducted to confirm whether statins increase the risk of hemorrhagic strokes in patients with a history of cerebrovascular diseases.24 The researchers identified 4 studies (Cholesterol And Recurrent Events [CARE] trial, Long-Term Intervention with Pravastatin in Ischaemic Disease [LIPID] trial, the Heart Protection Study [HPS], and SPARCL) of 8832 patients with a history of cerebrovascular diseases. Statin users had a lower RR for overall stroke (RR, 0.88; 95% CI, 0.78–0.99) and ischemic stroke (RR, 0.80; 95% CI, 0.70–0.92) but a higher RR for hemorrhagic stroke (RR, 1.73; 95% CI, 1.19–2.50). The incidence of MACE was also reduced in statin users as compared with nonusers (pooled RR, 0.83; 95% CI, 0.76–0.90). Additionally, in the HPS trial, which did not include patients with hemorrhagic stroke, a subgroup analysis in patients with a history of ischemic cerebrovascular disease found a similar increased risk of hemorrhagic stroke. This adds to the evidence from the SPARCL sensitivity analysis, showing an increased risk of hemorrhagic stroke in patients solely having ischemic stroke as an entry criterion. Thus, it unlikely that the increased risk in hemorrhagic stroke with statin therapy is solely caused by a recurrence in hemorrhagic stroke in those who have already experiencing such an event.

In summary, statins decrease the risk of developing ischemic strokes; however, the net benefit is slightly diminished because of an associated increase in the incidence of hemorrhagic stroke, but only in patients who have experienced a stroke/TIA. Although it is uncertain if a lower potency statin regimen would be associated with a decreased incidence of hemorrhagic stroke, considering that the incidence of ischemic stroke was approximately 10 times greater than that of hemorrhagic stroke, and that MACE was also reduced, the overall effect of statin therapy in patients with a history of stroke/TIA seems to be positive.

Diabetes Mellitus

A cohort analysis was conducted to assess whether statin therapy in nondiabetics led to an increased incidence of DM.1 The 8412 subjects included in the cohort included men and women over the ages of 45 and 55 years, respectively. Statin users were matched with controls based on sex, age, atherosclerotic comorbidities, and year of entry into the study, and the study participants were followed for 7.2 years. The incidence of DM was significantly greater in statin users as compared with the control group (2.4% vs 2.1%; HR, 1.15; 95% CI, 1.08–1.22; P < 0.001). However, patient outcomes were more favorable in statin users. Adverse CV events including MI (HR, 0.82; 95% CI, 0.68–0.98), ischemic stroke (HR, 0.94; 95% CI, 0.86–1.03), MACE (HR, 0.91; 95% CI, 0.84–0.99) and in-hospital mortality (HR, 0.61; 95% CI, 0.55–0.67) were decreased in statin users as compared with nonusers. Overall, the risk-benefit analyses found that statin treatment was beneficial in high-risk patients (HR, 0.89; 95% CI, 0.83–0.95) and for secondary prevention (HR, 0.89; 95% CI, 0.83–0.96). This suggests that the CV benefits of statins outweigh the risk of developing DM. Indeed, drug-induced or statin-induced DM does not seem to be equivalent to diet-induced/lifestyle-induced DM as far as CV risk is concerned. Even though statins may have led to a small increase in the incidence of DM, there was still a reduction in MACE (HR, 0.75; 95% CI, 0.59–0.97). Additionally, in-hospital deaths were similar in statin-related high-risk diabetics (HR, 1.11; 95% CI, 0.83–1.49) and in the secondary prevention population (HR, 1.08; 95% CI, 0.79–1.47) as compared with nondiabetic controls. The small increase in DM with statin use does not seem to be of clinical relevance.

Another observational study conducted on this topic enrolled 161 808 postmenopausal patients between the ages of 50 and 79 years.25 The use of statin therapy among patients was recorded at enrollment and 3 years later. These patients were classified as either statin users or statin nonusers and then followed to monitor the development of diabetes. Overall, there were 10 242 cases of new-onset diabetes reported during the study period. The use of statin at enrollment in this study was associated with a risk of development of diabetes (HR, 1.71; 95% CI, 1.61–1.83). After adjusting for potential confounders, the results remained significant (HR, 1.48; 95% CI, 1.38–1.59). These results applied for all statins. However, the question remains: Does increasing statin dose increase the risk of diabetes?

A recent meta-analysis of RCTs was performed to investigate whether intensive-dose statin therapy was associated with an increased risk of new-onset DM compared with moderate-dose statin therapy2; 5 trials totaling 32 752 patients without DM at baseline were analyzed. Compared with moderate-dose statin therapy, intensive-dose statin therapy was associated with a small (12%) increase in the risk of DM (OR, 1.12; 95% CI, 1.04–1.22; 2.0 additional cases in the intensive-dose statin group per 1000 patient-years). However, this slight increased risk of DM was heavily outweighed by the 16% reduction (6.5 fewer cases of CV events vs moderate-dose statin therapy per 1000 patient years) in CV events. It was calculated that the NNH per year was 498 for new-onset DM, whereas the NNT per year for intensive-dose statin therapy was 155 to prevent 1 CV event. Thus, in patients without DM, for every case of DM caused, 3.2 CV events are prevented per year with intensive-dose statin therapy, a positive benefit-to-risk ratio.

Is there a difference among statins regarding the risk of diabetes? A meta-analysis to determine if statins increase the risk of DM was performed and included 13 trials, with 91 140 patients, with a mean follow-up of 4 years.3 The results of this analysis showed that there was only a small increase in risk (9%) of developing DM with chronic statin use (OR, 1.09; 95% CI, 1.02–1.17). The NNH was 255 patients (95% CI, 150–852); that is, 255 patients would need to be treated with a statin for 4 years for 1 extra case of DM to occur (12.23 vs 11.25 cases per 1000 patient-years with statin therapy and control therapy, respectively). Breaking down the risk of DM by individual statin therapy indicated that only rosuvastatin was associated with a statistically significant increase in DM (OR, 1.18; 95% CI, 1.04–1.33). This was not seen with atorvastatin (OR, 1.14; 95% CI, 0.89–1.46), simvastatin (OR, 1.11; 95% CI, 0.97–1.26), pravastatin (OR, 1.03; 95% CI, 0.90–1.19), or lovastatin (OR, 0.98; 95% CI, 0.70–1.38). It is noteworthy that the association of the development of diabetes with atorvastatin was calculated on the basis of a single study, which makes the results less reliable. Considering the fact that the confidence interval was extremely wide and the NNH was quite high, the small increase in the incidence of DM with statin use does not outweigh the CV benefit, especially in individuals at moderate or high CV risk or existing CV disease. However, the increased incidence DM (albeit small) does warrant increased attention to glucose levels for patients on statins, and emphasis on concomitant therapeutic lifestyle changes.

Adverse Muscular Events

A meta-analysis was conducted to assess the incidence of muscle-related adverse events and discontinuation rates in statin users.26 The researchers identified 86 000 participants from 119 studies. The discontinuation rates for all statins, except for cerivastatin, were lower (OR, 0.88; 95% CI, 0.84–0.93; largest effect with pravastatin: OR, 0.79; 95% CI, 0.74–0.84), whereas the discontinuation rates for cerivastatin were higher (1.45; 95% CI, 0.98–2.16) than for placebo. Additionally, the potent statins (atorvastatin and rosuvastatin) had a lower risk of discontinuation compared with certain lower potency statins (simvastatin and lovastatin) (OR, 0.93; 95% CI, 0.75–1.14; and OR, 0.68; 95% CI, 0.26–1.77; vs OR, 1.00; 95% CI, 0.89–1.11 and OR, 1.10; 95% CI, 0.98–1.24, respectively). The incidence of rhabdomyolysis was not significantly higher in the statin group (OR, 1.59; 95% CI, 0.54–4.70). The incidence of myositis was significantly higher in patients on statins even after excluding cerivastatin (OR, 2.56; 95% CI, 1.12–5.58 including cerivastatin; 3.36; 95% CI, 0.59–19.3 excluding cerivastatin). Elevation of creatinine kinase level was not significantly raised in statins excluding cerivastatin (1.11; 95% CI, 0.78–1.59) but was significant increased with cerivastatin (2.93; 95% CI, 1.08–7.92).

Myalgia was not seen in statins when cerivastatin was excluded (1.09; 95% CI, 0.97–1.23) but was significantly increased with cerivastatin (1.74; 95% CI, 0.51–5.91). This meta-analysis showed that even though there was a high incidence of myositis in patients on statins, excluding cerivastatin, there was no significant increased risk of rhabdomyolysis, raised creatinine kinase, or myalgia. In addition, the discontinuation rates for all statins, except cerivastatin, were lower than for placebo and not higher but in fact relatively lower with the more potent statins versus the less potent statins. However, there is ample evidence indicating that high-dose simvastatin (80 mg/d) has the most drug–drug interactions as well as the greatest risk among the statins for myopathy/rhabdomyolysis.27 Additionally, hepatic dysfunction along with drug and nutritional interactions may increase the exposure of many statins (especially simvastatin and lovastatin; to a lesser extent rosuvastatin, fluvastatin, and atorvastatin; and rarely pravastatin) and can actually result in increased efficacy along with toxicity.

Cancer

The PROspective Study of Pravastatin in the Elderly at Risk of vascular disease (PROSPER) trial randomized 5804 older patients (ages between 70 and 82 years) at risk for CV disease to receive either pravastatin or placebo and followed them for an average of 3.2 years.28 The primary end point was a composite of CHD death, nonfatal MI, and fatal or nonfatal stroke. As compared with the placebo group, the pravastatin group had a 34% lower LDL-C concentration and a significantly lower incidence of the primary end point (HR, 0.85; 95% CI, 0.74–0.97; P = 0.014). Additionally, there was a reduced incidence of mortality due to CHD (24%; P = 0.043) and a reduction in the risk of nonfatal MI (HR, 0.81; 95% CI, 0.69–0.94; P = 0.006) in the pravastatin group. However, the incidence of cancer was higher in the pravastatin group as compared with placebo (25% higher in the pravastatin group; HR, 1.25; 95% CI, 1.04–1.51; P = 0.020). The finding of a higher incidence of cancer in the group treated with pravastatin as compared with that treated with placebo may be a cause for concern with long-term pravastatin use and should be investigated in an RCT to see if this was just a spurious finding.

A meta-analysis conducted specifically to assess whether pravastatin increases the incidence of cancer in elderly patients enrolled 12 trials with a total of 42 902 patients.29 The results of this meta-analysis did not show any statistically significant association between the use of pravastatin and the incidence of cancer (fixed-effects model: RR, 1.06; 95% CI, 0.99–1.13; random-effects model: RR, 1.06; 95% CI, 0.97–1.14), although there was a trend toward an increased incidence of cancer. However, the meta-regression analysis showed that, with increasing age, pravastatin therapy was significantly associated with an increasing risk of cancer (P = 0.006). There is a lack of conclusive evidence regarding whether statins may be associated with cancer in an elderly population, and because of its enormous public health implication this area should be investigated further. If statins are in fact associated with cancer, it is also unclear whether a higher dose of statins may lead to an increased risk of cancer. Currently, however, there is no evidence that higher dose statins are associated with an increased risk of cancer versus lower dose statins. It is possible that the reduction of cardiovascular risk means that we are seeing more cancers in people who would otherwise have died of cardiovascular disease.

In the 5 trials of more versus less intensive statin therapy, reduction of LDL-C to a mean of about 2 mmol/L had no significant effect on the incidence of cancer at all sites combined (RR, 1.02 per 1.0 mmol/L LDL-C reduction; 95% CI, 0.89–1.18; P = 0.8) or at any particular site. Similarly, there was no significant effect in the 21 trials of statin versus control and, taking all 26 trials together, there was no evidence of an excess of cancer at all sites combined (RR, 1.00 per 1.0 mmol/L LDL-C reduction; 95% CI, 0.96–1.04; P = 0.9) or at any particular site.4 There was also no indication that reduction of LDL-C in individuals with lower baseline concentrations increased cancer incidence (indeed, if anything, the opposite pattern was observed; trend P = 0.1). Additionally, a meta-analysis of individual data from 175 000 patients in 27 randomized trials with a median follow-up of 5 years indicated that statin therapy had no effect on the incidence of cancer or cancer mortality or any type of cancer.30

Conclusion

Intensive statin therapy leads to considerable positive health outcomes (reduction in MACE, improved renal function, and a greater reduction in HF hospitalizations in CHD patients with HF) over less intensive statin therapy. The risk of a higher incidence of adverse events with increasing doses of statins has not been proven, but there does seem to be a slightly increased risk of DM with more intensive statin therapy (12%), which is outweighed by a larger reduction in CV events (16%). Lastly, it is uncertain if intensive statin therapy leads to a higher risk of hemorrhagic stroke in patients who have experienced a stroke/TIA compared with a lower intensity statin regimen. In general, the CV risk reduction benefits from an intensive statin therapy seem to overshadow any potential small increased risk in adverse events, especially for patients at high risk of CV events, such as those with known CHD.

Conflict of Interest Statement

Carl J. Lavie, MD, FACC, FACP, FCCP, served as a speaker and consultant for Abbott (now Abbvie), AstraZeneca (nonstatin), and Pfizer. Evangelos Liberopoulos, MD, FASA, FRSH, served as a speaker and consultant for AstraZeneca, Pfizer, Abbott (now Abbvie), and MSD. James H. O’Keefe, MD, served as a speaker and consultant for AstraZeneca and Pfizer. James J. DiNicolantonio, PharmD, Asfandyar K. Niazi, and Victor L. Serebruany, MD, PhD, have no conflicts of interest to declare.

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