Low LDL Target Resulted in No Clinical Gain in Non-CAD Diabetes: EMPATHY

Marlene Busko

September 27, 2017

BARCELONA, SPAIN — Cardiovascular risk did not drop significantly over 3 years with intensive statin therapy, compared with a standard statin regimen, in a randomized trial that entered only dyslipidemic patients with diabetic retinopathy but no history of coronary disease[1].

In the Japan-based EMPATHY trial with >5000 patients, reduction in risk of a wide-ranging cardiovascular primary end point was 16% (P=0.15) for statin therapy to an LDL-C target of <70 mg/dL, compared with a target range >100 but <120 mg/dL.

On the other hand, the risk of cerebral infarction, a secondary end point, fell by nearly half (P=0.02) in the group with the lower LDL-C target, Dr Hiroshi Itoh (Keio University School of Medicine, Tokyo, Japan) reported at the European Society of Cardiology (ESC) 2017 Congress.

And in a post hoc analysis limited to patients in either study arm who, on average, actually achieved their LDL-C targets, risk of the primary end point fell by 52% (P=0.007).

Thus, "achieving LDL-cholesterol below 70 mg/dL in a treat-to-target strategy in high-risk patients with hypercholesterolemia and diabetic retinopathy may have benefit" and deserves further investigation, Itoh said during a press briefing.

"We consider that this study can provide the first evidence focusing on patients with diabetic retinopathy and the first evidence using a treat-to-target strategy," he said.

The cohort that achieved their targets made up about 40% of all patients in EMPATHY, Ito told theheart.org | Medscape Cardiology.

In the standard-therapy group, he said, possibly "it was quite difficult to control their cholesterol in this narrow range" between 100 and 120 mg/dL. And in the intensive-therapy group, he speculated, the cost of statins (which the patients paid for themselves) or media reports of adverse events on high-intensity statins that appeared during the course of the trial may have deterred patients from adhering to them.

At the media briefing, moderator Prof Hector Bueno (Spanish National Center for Cardiovascular Research, Madrid) wanted to know more about the statin doses.

Itoh clarified that clinicians could prescribe any statin, at any dose, and noted that there are differences in approved doses in Japan vs other countries. The doses in the standard-therapy group remained the same, but doses for some statins in the intensive-therapy group doubled, he said.

EMPATHY, designed in 2010, compared statin therapy to an LDL-C target of <70 mg/dL (intensive therapy), based on 2008 ACC/ADA guidelines[2], vs treating an LDL-C target of >100 and <120 mg/dL (standard therapy) based on 2007 Japan Atherosclerosis Society (JAS) guidelines[3] for primary CVD prevention patients with diabetic retinopathy.

It randomized 5042 patients with hypercholesterolemia, type 2 diabetes, and diabetic retinopathy who had no history of CAD or stroke to receive intensive (2518 patients) or standard (2524) statin therapy. Their mean age was 63 and mean BMI was 26; 48% were male. Their mean LDL-cholesterol was 106 mg/dL.

The patients had a history of diabetes averaging 13 years and a mean HbA1c of 7.8%. Half had nephropathy and 31% had neuropathy. At baseline, about half were taking a statin.

The patients were treated for 2 to 5 years (mean 3 years). The primary end point encompassed "cardiovascular diseases or death due to CV diseases," including cardiac, cerebral, renal, and vascular events, Ito noted during the presentation.

Specifically included in the end point were MI, unstable angina prompting hospitalization, PCI or CABG, ischemic stroke or cerebral revascularization, initiation of chronic dialysis, creatinine increase by at least two times, or a range of peripheral vascular events including aortic dissection, severe lower-limb ischemia, or revascularization[4].

The primary outcome occurred in fewer patients in the intensive-therapy group than in the standard-therapy group, but the difference wasn't significant (HR 0.84, 95% CI 0.67–1.07; P=0.15).

LDL-C at 36 months was 104.1 mg/dL in the standard-therapy group vs 76.5 mg/dL in the intensive-therapy group, for a difference of 27.7 mg/dL (P<0.001), smaller than the expected difference of 40 mg/dL, Ito said. So the group performed a post hoc analysis in the study's patients who met their prespecified targets.

On average, patients who met the intensive-therapy target were almost half as likely to have a CV event as patients in the standard-therapy group (HR 0.48, 95% CI 0.28–0.82; P=0.007). This relationship remained similar in patients who reached the lower LDL-cholesterol target only at the last visit.

The risks of cardiac events, renal events, and vascular events were not on their own significantly reduced for patients in the intensive-therapy arm. But they showed significant reductions in cerebral events (HR 0.52, 95% CI 0.31–0.88; P=0.01), including stroke (HR 0.64, 95% CI 0.40–1.01; P=0.05) and specifically cerebral infarction (HR 0.54, 95% CI 0.32–0.90, P=0.02).

Itoh said the reduction in cerebral events, but not cardiac events, may be related to the higher proportion of stroke to cardiac events in Japan than in Europe and the US.

Patients in the intensive-therapy group were more likely than other patients to have adverse drug events (10.1% vs 6.7%, P<0.001), but most of these events were mild, he said.

Thus, the research suggests the "potential importance" of achieving an LDL-cholesterol target below 70 mg/dL in high-risk patients with advanced diabetes," Itoh reiterated, which warrants further study.

The study was funded by Shionogi. Itoh has research contracts at Takeda Pharmaceutical, Nippon Boehringer Ingelheim, Daiichi Sankyo, MSD, Mitsubishi Tanabe Pharma, Shionogi, Taisho Toyama, Sumitomo Dainippon Pharma, Astellas, Kyowa Hakko Kirin, Teijin Pharma, Mochida Pharmaceutical, Ono Pharmaceutical, Chugai Pharmaceutical, and Eli Lilly Japan and consulting fees from Nipro Corporation and SBI Pharmaceuticals.

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