By Michael H. Crawford, MD
Professor of Medicine, Lucy Stern Chair in Cardiology, University of California, San Francisco
A large trial of moderate doses of rosuvastatin vs. atorvastatin in patients with coronary artery disease has shown that both drugs are equivalent at reducing major adverse cardiovascular and cerebral events, but rosuvastatin is associated with higher rates of new-onset diabetes and cataract surgery.
Lee YJ, Hong SJ, Kang WC, et al. Rosuvastatin versus atorvastatin treatment in adults with coronary artery disease: Secondary analysis of the randomised LODESTAR trial. BMJ 2023;383:e075837.
High-intensity statins are recommended for patients with known coronary artery disease (CAD), but little is known about their comparative efficacy and safety. Thus, these investigators from South Korea conducted the LODESTAR (Low-Density Lipoprotein Cholesterol-targeting Statin Therapy Versus the Intensity-based Statin Therapy in Patients With Coronary Artery Disease) trial.1 A subsection of this trial compared the two high-intensity statins, atorvastatin 40 mg/day and rosuvastatin 20 mg/day, for effectiveness and safety irrespective of low-density lipoprotein (LDL) cholesterol levels. This prospective, randomized, open-label, multicenter trial was conducted at 12 centers in South Korea from 2016 to 2019 and included 4,400 adult patients with stable CAD or acute coronary syndrome (ACS).
In the atorvastatin arm, 2,196 patients were enrolled, and 2,204 patients were enrolled in the rosuvastatin arm. Their mean age was 65 years, 28% were women, and two-thirds had prior percutaneous coronary interventions (PCI). They were followed with complete blood laboratory tests periodically for three years. The primary outcome was major adverse cardiovascular and cerebral events (MACCE): death, myocardial infarction (MI), stroke, or unplanned coronary revascularization. Secondary outcomes included new diabetes, heart failure hospitalization, end-stage renal disease, cataract surgery, and changes in the laboratory tests. Complete clinical follow-up occurred in 99% of the patients at three years. The primary outcome was not significantly different between the rosuvastatin and atorvastatin groups: 8.7% vs. 8.2%, respectively, P = 0.58. Also, none of the components of the primary outcome were significantly different. The mean LDL cholesterol levels were consistently lower in the rosuvastatin group compared to the atorvastatin group (1.7 mmol/L vs. 1.8 mmol/L, P < 0.001). Also, the proportion of participants with LDL cholesterol levels lower than the target of < 1.8 mmol/L was greater in the rosuvastatin group (62.5% vs. 55.2%; P < 0.001). New diabetes occurred more frequently in the rosuvastatin group (7.1% vs. 5.5%, respectively, P = 0.04), as did cataract surgery (2.5% vs. 1.5%, P = 0.02). The authors concluded that rosuvastatin and atorvastatin were comparable for reducing MACCE in adults with CAD, but rosuvastatin was more frequently associated with the onset of diabetes and the occurrence of cataract surgery.
COMMENTARY
When deciding on statin therapy for patients with CAD, potency and potential adverse effects of the various options need to be considered. Only rosuvastatin and atorvastatin, over their range of recommended doses, provide the moderate- to high-intensity LDL cholesterol-lowering recommended for CAD patients. Prior studies of each drug individually have shown clinical benefit in CAD patients. However, rosuvastatin and atorvastatin have been compared for efficacy in only one other study to date.
The SATURN study compared the efficacy of rosuvastatin 40 mg/day to atorvastatin 80 mg/day for reducing coronary artery atheroma volume detected by intravascular ultrasound.2 In SATURN, rosuvastatin reduced LDL cholesterol more than atorvastatin (1.6 mmol/L vs. 1.8 mmol/L, respectively; P < 0.001), but there was no difference in the percent reduction in atheroma volume between the two drugs. However, SATURN had fewer patients than LODESTAR, was of shorter duration (two years), only used maximum doses of the drugs, and did not report clinical outcomes. Also, with higher doses comes the possibility of higher adverse effect rates. Thus, the results of LODESTAR are of interest.
LODESTAR, using moderate doses of the two statins, showed comparable clinical outcomes at the expense of more new-onset diabetes and need for cataract surgery with rosuvastatin. Increased rates of new diabetes have been seen in other statin studies and are believed to be the result of reduced hydroxymethylglutaryl (HMG)-CoA reductase, the target of statin treatment. However, in LODESTAR and other studies, it has not been associated with clinical outcomes. Increased cataract surgery also has been seen in other studies of statins. Cholesterol biosynthesis is critical to maintain the transparency and structure of the eye lens, so this adverse effect is not surprising. Although the observation of increased diabetes and cataracts is concerning, the rates of new diabetes were ≤ 7% and cataract surgery were < 3%.
There are limitations to LODESTAR to consider. It was open-label, but there was a blinded independent committee that adjudicated the results. Also, there were too few events to evaluate the individual components of MACCE. The definition of new diabetes was based on fasting glucose and new diabetes drug prescriptions and did not include hemoglobin (Hgb) A1c levels. However, a post-hoc analysis of Hgb A1c did not change the results. In addition, regular eye examinations were not part of the study, so the incidence of cataract surgery may have been influenced by unmeasured confounders. Finally, the study population was exclusively Asian and may not apply to other groups.
REFERENCES
- Hong SJ, Lee YJ, Lee SJ, et al; LODESTAR Investigators. Treat-to-target or high-intensity statin in patients with coronary artery disease: A randomized clinical trial. JAMA 2023;329:1078-1087.
- Nicholls SJ, Ballantyne CM, Barter PJ, et al. Effect of two intensive statin regimens on progression of coronary disease. N Engl J Med 2011;365:2078-2087.
