5 Lipid-Lowering Studies Pharmacists Should Know About

More than 73 million American adults have high levels of low-density lipoprotein (LDL), also known as “bad cholesterol," according to the CDC.

Of these, the CDC estimates that fewer than half are receiving treatment to lower their levels. Alarmingly, statistics show that people with high total cholesterol have about twice the risk of heart disease as people with ideal levels, while 1 of every 3 deaths in the United States are caused by heart disease, stroke, and other cardiovascular diseases.

Over the years, a number of landmark clinical studies on lipid lowering and cardiovascular health have been published, shaping patients are treated. Here are 5 that every pharmacist should know about:

1. LIPID (1998)¹

By the end of the 1980s a number of studies had shown strong evidence of an association between plasma cholesterol levels and the risk of coronary heart disease (CHD). Trials of cholesterol-lowering therapy had been shown to demonstrate only modest efficacy in lowering cholesterol in people with moderate hypercholesterolemia, with about a 10% reduction in coronary mortality. It was uncertain how cholesterol-lowering therapy affected overall mortality among patients with high cholesterol levels and altered the risk of coronary events in people with lower cholesterol levels.

The LIPID trial was initiated in 1989 to investigate the effects of pravastatin on death from CHD among patients with a history of myocardial infarction or unstable angina and a broad range of initial cholesterol levels. More than 9000 people were recruited for entry into the trial and were randomized to receive either pravastatin 40 mg daily or a placebo over a mean follow-up period of 6.1 years. The patients ranged from aged 31 to 75 and had initial total cholesterol levels ranging from 155 to 271 mg/dL. Both groups received advice on following an appropriate cholesterol-lowering diet. The primary study outcome was mortality from CHD.

Study results showed that death from CHD occurred in 8.3% of the patients in the placebo group compared with 6.4% of those in the pravastatin group, a relative reduction in risk of 24% (p<0.001). Overall mortality, a secondary end point, was 14.1% in the placebo group and 11% in the pravastatin group, a 22% risk reduction (p<0.001). Cardiovascular outcomes were consistently lower among patients assigned to receive pravastatin. The effects of treatment were similar for all predefined subgroups. There were no clinically significant adverse effects (including myopathy) associated with pravastatin treatment.

Conclusion

Pravastatin reduces both mortality from CHD and overall mortality as compared with the placebo.

2. PROVE-IT (2004)²

Following the publication of LIPID and several other cardiovascular studies, it became well established that statins significantly reduce the risk of death and cardiovascular events, yet the optimal level of LDL cholesterol was unclear. In the previous studies, the doses of statins used reduced LDL levels by 25% to 35%. However, some within the medical community had thought that using higher doses of statins would further decrease LDL levels and improvement clinical outcomes.

To test this hypothesis, researchers enrolled 4162 patients who had been hospitalized for an acute coronary syndrome (ACS) within the preceding 10 days and randomized them to receive pravastatin 40 mg daily (standard therapy) or atorvastatin 80 mg daily (intensive therapy). Participants were required to have a total cholesterol level of 240 mg/dL or less at baseline, and all received dietary counseling at several points throughout the trial. The primary outcome was a composite of death from any cause, myocardial infarction, documented unstable angina requiring re-hospitalization, revascularization, and stroke. The study was designed to establish the noninferiority of pravastatin compared with atorvastatin with respect to the time to an end-point event.

After a mean follow-up time of 24 months, the median LDL cholesterol level achieved was 95 mg/dL in the standard-dose pravastatin group and 62 mg/dL in the high-dose atorvastatin group (p<0.001). The rates of the primary end point at 2 years were 26.3% in the pravastatin group and 22.4% in the atorvastatin group, reflecting a 16% reduction in favor of atorvastatin (p=0.005). The benefit of high-dose atorvastatin compared with standard-dose pravastatin emerged as early as 30 days and was consistent over time. The rates of discontinuation of treatment because of an adverse event or patient preference were similar among the 2 groups.

Conclusion

After a recent ACS, high-dose atorvastatin further reduces LDL levels and the rate of cardiovascular events compared with moderate-dose pravastatin.

3. SPARCL (2006)³

Stoke and transient ischemic attack (TIA) are well documented complications of cardiovascular disease. Despite positive data showing efficacy of a variety of secondary preventive therapies, no data existed to show that statin treatment decreases the risk of stroke among patients with a history of stroke or TIA.

The SPARCL trial was designed to determine whether high-dose atorvastatin would reduce the risk of stroke in patients with no known CHD but who had had a stroke or TIA within the previous 6 months. In the trial, 4731 patients were randomly assigned to atorvastatin 80 mg or a placebo. The primary end point was a first nonfatal or fatal stroke.

The mean LDL cholesterol level during the trial was found to be 73 mg/dL among patients receiving atorvastatin and 129 mg/dL among those receiving a placebo. After a median follow-up duration of 4.9 years, a total of 265 patients (11.2%) receiving atorvastatin and 311 patients (13.1%) receiving a placebo had a fatal or nonfatal stroke, representing a 16% risk reduction in favor of atorvastatin (p=0.03). A 45% reduction was noted in the secondary composite end point of major coronary events (p=0.003). However, overall mortality was similar between the 2 groups. The results of a post-hoc analysis showed that the atorvastatin group had a slightly higher number of hemorrhagic strokes compared with placebo group (55 vs 33). Additionally, elevated liver enzyme values were more common in patients taking atorvastatin.

Conclusion

In patients with recent stroke or TIA, high-dose atorvastatin reduces the risk of recurrent stroke and cardiovascular events, despite a small increase in the incidence of hemorrhagic stroke.

4. JUPITER (2008)⁴

By 2008, treatment guidelines universally recommended statin therapy for patients with established vascular disease, diabetes, and overt hyperlipidemia. However, half of all myocardial infarctions and strokes were occurring in presumably healthy men and women with normal levels of LDL cholesterol. As a result, researchers looked to assess the impact of high-sensitivity C-reactive protein (HS-CRP), an inflammatory biomarker that independently predicts future vascular events, regardless of LDL cholesterol level, and whether individuals with high HS-CRP levels and normal cholesterol would benefit from statin therapy.

JUPITER was conducted as a randomized, double-blind, placebo-controlled trial, conducted at 1315 sites in 26 countries. Researchers randomly assigned 17,802 apparently healthy men and women with LDL cholesterol levels of less than 130 mg/dL and HS-CRP levels of 2.0 mg/L or higher to rosuvastatin 20 mg daily or a placebo. The primary outcome was the occurrence of a first major cardiovascular event.

The trial was stopped early after a median follow-up of 1.9 years, following a pre-specified efficacy evaluation. Rosuvastatin was shown to reduce LDL cholesterol levels by 50% and HS-CRP levels by 37%. The rates of the primary end point were 0.77 and 1.36 per 100 person-years of follow-up in the rosuvastatin and placebo groups, respectively (46% reduction; p<0.00001). Rosuvastatin was also associated with significant reductions in the rates of the individual components of the primary end point. Consistent effects were observed in all subgroups that were evaluated. There were no differences in myopathy or cancer between the groups, though those receiving rosuvastatin had a higher incidence of physician-reported diabetes.

With its publication, JUPITER became the first clinical trial to indicate that statin therapy may provide benefit to patients with low-to-normal LDL levels and no known cardiovascular disease.

Conclusion

Among patients with normal LDL levels but elevated HS-CRP, rosuvastatin reduces the incidence of cardiovascular events.

5. IMPROVE-IT (2015)⁵

Although statins have been well-established to lower LDL levels and the risk of cardiovascular events, researchers have continued to explore the benefit of additional lipid-modifying therapies. Zetia (ezetimibe) is a cholesterol absorption inhibitor, which when added to statins, reduces LDL cholesterol by 23% to 24%, on average. Whether the addition of ezetimibe to statin therapy also leads to a benefit in clinical outcomes was not known.

To assess long-term outcomes with ezetimibe, researchers conducted a double-blind, randomized trial involving 18,144 patients who had been hospitalized for an ACS within the preceding 10 days and had LDL cholesterol levels of 50 to 100 mg/dL if they were receiving lipid-lowering therapy or 50 to 125 mg/dL if they were not receiving lipid-lowering therapy. Patients were randomly assigned in a 1:1 ratio to receive simvastatin 40 mg plus ezetimibe 10 mg daily or simvastatin 40 mg plus a placebo. The primary end point was a composite of cardiovascular death, nonfatal myocardial infarction, unstable angina requiring re-hospitalization, coronary revascularization, or nonfatal stroke. The median follow-up was 6 years.

Study results showed that ezetimibe resulted in incremental lowering of LDL cholesterol levels when added to statin therapy (average LDL level of 53.7 mg/dL in the combination group, versus 69.5 mg/dL in the simvastatin monotherapy group; p<0.001). The event rate for the primary end point at 7 years was 32.7% in the combination group, compared with 34.7% in the simvastatin-monotherapy group, representing a 6.4% risk reduction (p=0.016). The benefit appeared to emerge after 1 year of treatment. Rates of pre-specified adverse effects and cancer were similar in the 2 groups.

Conclusion

After a recent ACS, the addition of ezetimibe to moderate-intensity statin therapy is associated with a reduction in cardiovascular mortality when compared to statin therapy alone.

Studies that merit an honorable mention are 4S (1994), CARE (1996), MIRACL (2001), A to Z (2004), TNT (2005), IDEAL (2005), SEARCH (2010), ODYSSEY LONG TERM (2015), and FOURIER (2017).

References

• LIPID study group. Prevention of cardiovascular events and death with pravastatin in patients with coronary heart disease and a broad range of initial cholesterol levels. N Engl J Med. 1998;339(19):1349-1357. doi:10.1056/nejm199811053391902.
• Cannon CP, Braunwald E, McCabe CH, et al. Intensive versus moderate lipid lowering with statins after acute coronary syndromes. N Engl J Med. 2004;Apr 8;350(15):1495-504.
• Amarenco P, Bogousslavsky J, Callahan A, et al. High-dose atorvastatin after stroke or transient ischemic attack. N Engl J Med. 2006;355(6):549-559.
• Ridker PM, Danielson E, Fonseca FA, et al. Rosuvastatin to prevent vascular events in men and women with elevated C-reactive protein. N Engl J Med. 2008;359(21):2195-207. doi: 10.1056/NEJMoa0807646.
• Cannon CP, Blazing MA, Giugliano RP, et al. Ezetimibe added to statin therapy after acute coronary syndromes. N Engl J Med. 2015;372(25):2387-97. doi: 10.1056/NEJMoa1410489.