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Concomitant polyvascular disease, type 2 diabetes sharply raise ischemic risk

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November 9, 2018

Patients with acute coronary syndrome with polyvascular disease and concomitant type 2 diabetes are at heightened long-term risk for ischemic events over 7 years, with the combination of both conditions associated with a particularly malignant atherothrombotic phenotype, according to a secondary analysis of the IMPROVE-IT trial.

In the analysis of IMPROVE-IT, a double-blind, randomized, placebo-controlled trial assessing the effect of ezetimibe added to statin therapy after acute coronary syndrome (ACS), the researchers also found that patients with ACS, polyvascular disease and type 2 diabetes derive consistent, relative benefits — and potentially greater absolute benefits — from ezetimibe therapy vs. patients with just one of these conditions.

“Although we generally think about high-risk patients, such as ACS patients, as a group, clinical characteristics are useful for risk stratification,” Marc P. Bonaca, MD, MPH, associate professor of medicine and director of vascular research at the University of Colorado School of Medicine, told Endocrine Today. “Both diabetes and polyvascular disease are associated with further heightened risk in stable patients and those with ACS. Whether these risks are additive has not been well-described.”

In IMPROVE-IT, researchers analyzed data from 18,144 patients aged at least 50 years who were stabilized after ACS and were randomly assigned to 40 mg daily simvastatin plus either 10 mg daily ezetimibe or matched placebo for a median duration of 6 years. For the post hoc analysis, Bonaca and colleagues analyzed the prespecified trial endpoints by concomitant polyvascular disease at baseline, stratified by concomitant type 2 diabetes.

Within the IMPROVE-IT cohort, 1,005 patients (6%) had peripheral artery disease and 1,071 (6%) had a stroke or transient ischemic attack at baseline. Of those patients, 388 with PAD had type 2 diabetes and 409 with stroke or transient ischemic attack had type 2 diabetes.

After 7 years, the researchers found that patients with polyvascular disease or type 2 diabetes had similar rates of the primary endpoint, defined as cardiovascular death, a major coronary event or stroke (39.8% for polyvascular disease; 39.9% for type 2 diabetes). However, in patients with both polyvascular disease and concomitant type 2 diabetes, the rate of experiencing a primary endpoint event risk rose sharply to 60% (adjusted HR = 1.6; 95% CI, 1.38-1.85).

After adjustment for baseline differences, polyvascular disease and type 2 diabetes were independently associated with a 60% increase in primary endpoint and a 73% increase in the composite of CV death, MI or stroke. Risk for heart failure and the occurrence of any CV hospitalization was increased by 70% and 37%, respectively, in those with polyvascular disease and type 2 diabetes vs. patients without the concomitant conditions, according to researchers.


The researchers found that ezetimibe reduced LDL cholesterol in the cohort by a mean of 14 mg/dL consistently, irrespective of concomitant polyvascular disease and/or type 2 diabetes. RR reduction, they noted, was consistent in patients with and without concomitant polyvascular disease and type 2 diabetes; however, because of the greater absolute risk for these patients, their absolute risk reduction at 7 years was numerically greater vs. those without both conditions, according to the researchers.

“We find in this analysis that, in fact, the risks are additive and ACS patients with diabetes and polyvascular disease have a particularly malignant atherothrombotic risk profile,” Bonaca said. “These high-risk populations derive even greater absolute benefits from preventive therapies, and in the analysis we find a substantial benefit with ezetimibe in these patients.”

Bonaca said the data may be useful for clinicians trying to identify the highest-risk patients who may derive the greatest benefits from preventive therapies.

“Identifying patients with diabetes and polyvascular disease is relatively easy in the clinic and identifies a very high-risk group that derives even greater benefits from preventive therapy,” he said.

In commentary accompanying the study, Subodh Verma, MD, PhD, FRCSC, from the division of cardiac surgery at St. Michael’s Hospital, University of Toronto, and colleagues wrote that the post hoc data should inform clinicians of the malignant CV phenotype that type 2 diabetes plus polyvascular disease confers.

“There is a high prevalence of extracoronary arterial disease in people with diabetes, and physicians should have a heightened awareness of the potential coexistence of cerebrovascular or peripheral artery disease in their patients with diabetes,” Verma and colleagues wrote. “Furthermore, risk reduction therapies — in this case, lipid-lowering drugs — can be very beneficial in this population. The number needed to treat over 7 years to prevent one major vascular event in the subgroup with type 2 diabetes and polyvascular disease was a mere 11.”

The researchers noted in the commentary that, because ezetimibe is now generic, cost-benefit analyses for this subgroup should be favorable. – by Regina Schaffer

For more information:

Marc P. Bonaca , MD , MPH, can be reached at the University of Colorado School of Medicine, 13001 E. 17th Place, Aurora, CO 80045; email:

Disclosures: Merck sponsored the IMPROVE-IT trial through a grant to Brigham and Women’s Hospital. Bonaca reports he has received consultant fees from Amgen, AstraZeneca, Aralez, Bayer, Janssen and Merck. Verma reports he has received support and honoraria from Amgen, AstraZeneca, Boehringer Ingelheim, Janssen, Merck and Novo Nordisk. Please see the study and commentary for the other authors’ relevant financial disclosures.


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