In Japanese patients with elevated cholesterol, type 2 diabetes, and diabetic retinopathy, intensive statin monotherapy wasn’t better than standard statin monotherapy for primary prevention of combined cardiovascular or renal events (the primary endpoint).
The EMPATHY study enrolled “real-world” patients who had a mean LDL-C of 106 mg/dL and diabetic retinopathy but were free of coronary artery disease (CAD).
In a mean follow-up of 3 years, intensive statin therapy to reach an LDL-C < 70 mg/dL versus standard therapy to reach a goal of 100 to 120 mg/dL was not associated with a lower risk of the primary endpoint, a composite of cardiovascular and renal events, Hiroshi Itoh, MD, PhD, from the Department of Endocrinology, Metabolism and Nephrology, Keio University School of Medicine, in Tokyo, Japan, and colleagues report.
However, “in exploratory findings, the secondary endpoints of cerebral events and cerebral infarction were reduced significantly” in patients who received intensive lipid lowering, with no increase in adverse events, findings that need further exploration, say the researchers.
As reported earlier, Itoh had presented the study at the European Society of Cardiology (ESC) 2017 Congress, and it was published online April 6 in Diabetes Care.
In the published article, researchers note that the statin dose for “intensive” therapy in Japan is lower than in the United States and Europe, and “at the last visit in this study, the dose in the intensive group would be considered “moderate to low intensity statin therapy under ACC/AHA guidelines.”
They speculate that “this study failed to find a significant reduction in the primary endpoint because of the smaller than predicted difference in LDL-C between the two treatment groups.”
They had estimated that the mean attained LDL-C levels would be < 70 mg/dL and 110 mg/dL in the intensive versus standard statin therapy groups, respectively, but instead the actual mean LDL-C levels were 77 mg/dL and 104 mg/dL, respectively.
Possibly, “in real-world clinical practice, many Japanese physicians who are not lipid management experts worry about adverse effects such as intracranial hemorrhage from intensive LDL-C lowering and may have been somehow affected by these concerns, even when the protocol stipulated the aggressive target of 70 mg/dL in that study arm,” they suggest.
On the positive side, in addition to the observed benefit of reduced strokes, this study did not show worsening HbA1c levels because of statin therapy (reported in other studies), and there were no between-group differences in cerebral hemorrhages, “potentially eliminating concerns of increased cerebral hemorrhage risk due to intensive statin therapy.”
Stroke Benefit Needs Further Study
In EMPATHY, data were analyzed from more than 5000 patients with hypercholesterolemia and diabetic retinopathy but no CAD who were seen at 323 hospitals and 449 clinics in Japan in 2010 to 2013.
Patients were randomized to receive statin therapy (atorvastatin, rosuvastatin, pitavastatin, pravastatin, fluvastatin, or simvastatin) to reach a target LDL-C < 70 mg/dL (2518 patients) or 100 to 120 mg/dL (2524 patients).
The primary endpoint was the combined incidence of cardiovascular-related deaths or events, including myocardial infarction; unstable angina requiring unscheduled hospitalization or coronary revascularization; cerebral infarction or cerebral revascularization; initiation of chronic dialysis, or doubling or more of serum creatinine; or aortic disease or peripheral arterial disease (including severe ulcers or amputation).
“Today ischemic heart disease, cerebrovascular disease, peripheral vascular disease, and renal impairment are widely understood to be ischemic conditions, and a meta-analysis of randomized controlled and crossover studies has shown that statins inhibit proteinuria and progression of nephropathy,” the researchers write, so for the current study, they “selected a range of primary endpoints based on arteriosclerosis, including renal events.”
The primary composite outcome occurred in 129 patients who had received intensive statin therapy versus 153 patients in the other group, which was not significantly different (hazard ratio [HR], 0.84; P = .15).
However, there were fewer cerebral events in the intensive statin therapy group than in other group, 22 events vs 42 events (HR, 0.52; P = .01).
Both groups had similar rates of adverse events (75%) and serious adverse events (22%).
Thus, according to Itoh and colleagues, “the potential benefit of achieving LDL-C < 70 mg/dL in a treat-to-target strategy in high-risk patients deserves further investigation.”
This study was supported by Shionogi. Itoh reports receiving grants and fees from Shionogi during the study, and outside this published work, he has received grants and fees from Takeda, Nippon Boehringer Ingelheim, Daiichi Sankyo, MSD, Mitsubishi Tanabe, Shionogi, and Taisho Toyama, and grants from Sumitomo Dainippon, Astellas, Kyowa Hakko Kirin, Teijin, Mochida, Ono, Chugai, and Eli Lilly, and fees from Nipro and SBI. Disclosures for the other authors are listed in the article.
Diabetes Care. Published online April 6, 2018. Abstract
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