Serum Markers of Oxidative Stress to Assess Mortality Risk in Patients with Type 2 Diabetes

Serum Markers of Oxidative Stress to Assess Mortality Risk in Patients with Type 2 Diabetes

By Aly Becraft, MS and Kevin C Maki, PhD

Hyperglycemia is thought to result in increased reactive oxygen species (ROS) production and weakened antioxidant capacity,1 which can make patients with type 2 diabetes (T2D) susceptible to elevated oxidative stress. Current research relating diabetes complications and oxidative stress is lacking because ROS are difficult to measure directly;2 however, methods that indirectly quantify oxidative stress by measuring derivatives of reactive oxygen metabolites (d-ROMs) as a proxy for ROS production3 and total thiol levels (TTLs) as a proxy for reduction-oxidation (redox) status of blood4 are also available.

Xuan et al. recently published pooled results from two cohort studies in a meta-analysis to investigate the association of these oxidative stress biomarkers with incident major cardiovascular events, total cancer incidence, and cause-specific and all-cause mortality in patients with T2D.5 Diabetes sub-cohorts of the ESTHER and DIANA studies, conducted in Germany, were included. In the ongoing ESTHER cohort, to date, patient follow up visits have been conducted after 2, 5, 8, 11 and 14 years. Follow up in the DIANA study occurred after 4 and 7 years. For this meta-analysis, the 8-year follow-up data from the ESTHER cohort was used as baseline and the 11-year follow-up for repeated biomarker measurements. For the DIANA study, baseline and the 4-year follow-up data were used. Biomarker measurements were conducted on 1029 patients from the ESTHER cohort, of which 720 had repeated measurements. In the DIANA study, measurements of both biomarkers were performed for 1096 baseline study participants, and repeated measurement of d-ROMs was done for 738 participants.

In both cohorts, significantly increased d-ROMs levels were observed in females, current smokers, patients with T2D who had body mass index (BMI) ≥40 kg/m2, those not taking any antidiabetic medication, with insulin therapy, without lipid-lowering medication, with high total cholesterol levels, or with high C-reactive protein (CRP) levels. In addition, significantly lower TTLs in both cohorts were observed in females, alcohol abstainers, and patients with T2DM with BMI ≥40 kg/m2, without any antidiabetic medication, with insulin therapy, with antihypertensive therapy, with anticoagulant medication, with high CRP levels, with estimated glomerular filtration rate (eGFR), or with a history of myocardial infarction, heart failure, or hypertension. Both biomarkers were significantly associated with all-cause mortality in each of the cohorts; however, the associations with cancer mortality and major cardiovascular events were not statistically significant. Adjustment for disease and CRP concentration attenuated observed effect estimates. Subgroup analysis of all-cause mortality demonstrated strong associations with d-ROM levels among males and among patients with T2D with glycated hemoglobin <7%, age <70 years, BMI <30 kg/m2, and a history of coronary heart disease.


The results of this study support the notion that an imbalanced redox system may play a role in increasing premature mortality in patients with T2D. Other evidence supports such a role for oxidative stress,6-8 but it remains to be determined if oxidative stress is also involved in the development of cardiovascular disease and cancer in patients with T2D. Although this study was observational, and thus, the possibility of residual confounding cannot be disregarded, the results demonstrate the potential need for oxidative stress interventions in patients with T2D and illustrate the usefulness of using d-ROMs and TTLs as biomarkers to identify individuals with T2D who may be at increased risk for premature death.




  1. Dincer A, Onal S, Timur S, et al. Differentially displayed proteins as a tool for the development of type 2 diabetes. Ann Clin Biochem. 2009;46:306–310.


  1. Stephens JW, Khanolkar MP, Bain SC. The biological relevance and measurement of plasma markers of oxidative stress in diabetes and cardiovascular disease. Atherosclerosis. 2009;202:321–329.


  1. Kotani K, Sakane N. C-reactive protein and reactive oxygen metabolites in subjects with metabolic syndrome. J Int Med Res. 2012;40:1074–1081.


  1. Marrocco I, Altieri F, Peluso I. Measurement and clinical significance of biomarkers of oxidative stress in humans. Oxid Med Cell Longev. 2017;2017:6501046.


  1. Xuan Y, Gào X, Anusruti A, Holleczek B, Jansen EH, Muhlack DC, Brenner H, Schöttker B. Association of serum markers of oxidative stress with incident major cardiovascular events, cancer incidence and all-Cause mortality in type 2 diabetes patients: pooled results from two cohort studies. Diabetes Care. 2019;Epub ahead of print.


  1. Broedbaek K, Siersma V, Henriksen T, et al. Urinary markers of nucleic acid oxidation and long-term mortality of newly diagnosed type 2 diabetic patients. Diabetes Care. 2011;34:2594– 2596.


  1. Kjaer LK, Oellgaard J, Henriksen T, et al. Indicator of RNA oxidation in urine for the prediction of mortality in patients with type 2 diabetes and microalbuminuria: a post-hoc analysis of the Steno-2 trial. Free Radic Biol Med. 2018;129:247–255.


  1. Kjær LK, Cejvanovic V, Henriksen T, et al. Cardiovascular and all-cause mortality risk associated with urinary excretion of 8-oxoGuo, a biomarker for RNA oxidation, in patients with type 2 diabetes: a prospective cohort study. Diabetes Care. 2017;40:1771–1778.



C-Reactive Protein Levels and Cardiovascular Events after Acute Coronary Syndrome: Results from a Secondary Analysis of the VISTA-16 Trial

C-Reactive Protein Levels and Cardiovascular Events after Acute Coronary Syndrome: Results from a Secondary Analysis of the VISTA-16 Trial

By Aly Becraft, MS; Kevin C Maki, PhD


Each year approximately 29% of heart attack (myocardial infarction) events in the USA occur in people who have previously had a heart attack.1 Even with ideal medical interventions and treatments, there is high risk of subsequent cardiac events and death in people that have suffered an acute coronary syndrome (ACS).2,3 This elevated risk may be lowered if specific biomarkers associated with future adverse cardiac events can be identified and used in long-term management following ACS. Several biomarkers of cardiovascular disease (CVD) are currently being studied, including those related to inflammation, a major contributor to the development of atherothrombosis. Well-studied inflammatory biomarkers include fibrinogen, monocyte chemotactic protein-1, tumor necrosis factor-alpha, C-reactive protein (CRP), and others.4

High-sensitivity CRP (hsCRP) measurement has become a routine and effective method for predicting risk of CVD and is also used as a prognostic marker after ACS.5 Lowered hsCRP levels in patients with chronic CVD treated with anti-inflammatory and statin therapies has been shown to improve treatment outcomes and lower risk of adverse cardiovascular events.3,6 Furthermore, other studies have reported a correlation between CRP levels and the effectiveness of statin treatment7,8 and high-dose statins have been demonstrated to accelerate decreases in hsCRP levels after ACS.9,10 While there is a substantial body of research demonstrating these associations, in order to optimize clinical use, the applications for hsCRP levels in the treatment of CVD are still being investigated.


Mani et al. recently published a secondary analysis of the Vascular Inflammation Suppression to Treat Acute Coronary Syndromes for 16 Weeks (VISTA-16) trial to assess whether longitudinal changes in hsCRP levels were associated with residual risk of cardiovascular events or death following ACS.11 This randomized, double blind, multicenter trial tested treatment of ACS with the secretory phospholipase A2 inhibitor, varespladib, in 5145 patients. Treatment began within 96 hours of an ACS. Only patients with qualifying baseline and longitudinal hsCRP levels measured at weeks 1, 2, 4, 8, and 16 weeks of the trial were used in this secondary analysis (n = 4257). The primary end point of this analysis was the association between hsCRP and a major adverse cardiac event (MACE) defined as the composite of cardiovascular death, non-fatal myocardial infarction, stroke, or hospitalization for unstable angina at 16 weeks. Secondary end points included the associations between hsCRP and individual components of the primary composite end point.11 The trial treatment had no significant effects on hsCRP level.


Analyzed patients were overweight, had a mean age of 60.3 years and 74% were male.11 Approximately 77% of the patients had hypertension, 51% had hypercholesterolemia and 65% had metabolic syndrome. In addition, 30% of patients had experienced a previous myocardial infarction, 18% had undergone percutaneous coronary intervention, and 36% of patients were using lipid-modifying therapy prior to the trial.


Of the 247 events observed in the VISTA-16 trial, 145 were included in this analysis.11 Baseline hsCRP levels following ACS were associated with higher risk for future MACE and death, as had been shown previously. Longitudinal increases in hsCRP levels were associated with significantly higher incidence of MACE [hazard ratio (HR) per SD 1.16, P < 0.001], myocardial infarction (HR 1.16, P < 0.001), all-cause death (HR 1.25, P < 0.001), and cardiovascular death (HR 1.26, P < 0.001). These relationships were not attenuated in multivariate models that adjusted for several other predictive variables and treatment assignment.  Positive associations between changes in longitudinal hsCRP levels and age (P = 0.03), body mass index (P < 0.001), hypertension (P < 0.001), congestive heart failure (P < 0.001), and active smoking (P = 0.003) were reported. 


Comment: These results suggest that measuring longitudinal changes in hsCRP levels after ACS is useful for assessing residual cardiovascular risk.  Higher baseline hsCRP after ACS and persistent hsCRP elevation were both independently associated with increased risks for MACE and individual MACE components, as well as CVD and total mortality.  Each SD increase in hsCRP during follow-up was associated with an increase of 15% in MACE, 25% in total mortality and 26% in CVD mortality.


The present study adds to previous findings, such as those from the Canakinumab Antiinflammatory Thrombosis Outcome Study,12 which demonstrated similar associations between higher hsCRP levels and adverse cardiovascular outcomes and mortality and further showed that an anti-inflammatory intervention reduced MACE risk. Similarly, results from epidemiological studies have suggested that increases in serial measurement of CRP in relatively healthy populations are associated with adverse cardiovascular outcomes and increased mortality.13,14 Further study is needed to evaluate longer-term outcomes and to assess the efficacy of various treatment modalities to lower MACE and mortality incidence in those identified as having elevated residual risk after ACS due to persistent hsCRP elevation.



  1. Mozaffarian D, Benjamin EJ, Go AS, et al. Heart disease and stroke statistics—2015 update: a report from the American Heart Association. Circulation. 2015;131:e29-322
  2. Schwartz GG, Olsson AG, Ezekowitz MD, et al. Myocardial Ischemia Reduction with Aggressive Cholesterol Lowering (MIRACL) Study Investigators. Effects of atorvastatin on early recurrent ischemic events in acute coronary syndromes: the MIRACL study: a randomized controlled trial. JAMA. 2001;285(13):1711-1718.
  3. Cannon CP, Braunwald E, McCabe CH, et al. Pravastatin or Atorvastatin Evaluation and Infection Therapy–Thrombolysis in Myocardial Infarction 22 Investigators. Intensive versus moderate lipid lowering with statins after acute coronary syndromes. N Engl J Med. 2004;350(15):1495-1504.
  4. Dhingra R, Vasan RS. Biomarkers in cardiovascular disease: statistical assessment and section on key novel heart failure biomarkers. Trends Cardiovasc Med. 2017;27(2):123-133.
  5. Ridker PM. Inflammation in atherothrombosis: how to use high-sensitivity C-reactive protein (hsCRP) in clinical practice. Am Heart Hosp J. 2004;2(4 Suppl 1):4-9.
  6. Ridker PM, Everett BM, Thuren T, et al. CANTOS Trial Group. Antiinflammatory therapy with canakinumab for atherosclerotic disease. N Engl J Med. 2017;377(12):1119-1131.
  7. Ridker PM, Rifai N, Clearfield M, et al. Air Force/Texas Coronary Atherosclerosis Prevention Study Investigators. Measurement of C-reactive protein for the targeting of statin therapy in the primary prevention of acute coronary events. N Engl J Med. 2001;344(26):1959-1965.
  8. Ridker PM, Cannon CP, Morrow D, et al. Pravastatin or Atorvastatin Evaluation and Infection Therapy–Thrombolysis in Myocardial Infarction 22 (PROVE IT-TIMI 22) Investigators. C-reactive protein levels and outcomes after statin therapy. N Engl J Med. 2005;352(1):20-28.
  9. Kinlay S, Schwartz GG, Olsson AG, et al. Myocardial Ischemia Reduction with Aggressive Cholesterol Lowering Study Investigators. High-dose atorvastatin enhances the decline ininflammatory markers in patients with acute coronary syndromes in the MIRACL study. Circulation. 2003;108(13):1560-1566.
  1. Macin SM, Perna ER, Farías EF, et al. Atorvastatin has an important acute anti-inflammatory effect in patients with acute coronary syndrome: results of a randomized, double-blind, placebo-controlled study. Am Heart J. 2005;149(3):451-457.
  2. Mani P, Puri R, Schwartz GG, et al. Association of initial and serial C-reactive protein levels with adverse cardiovascular events and death after acute coronary syndrome: a secondary analysis of the VISTA-16 trial. JAMA Cardiol. 2019;Epub ahead of print.
  3. Ridker PM, MacFadyen JG, Everett BM, et al. CANTOS Trial Group. Relationship of C-reactive protein reduction to cardiovascular event reduction following treatment with canakinumab: a secondary analysis from the CANTOS randomised controlled trial. Lancet. 2018;391(10118):319-328.
  4. Currie CJ, Poole CD, Conway P. Evaluation of the association between the first observation and the longitudinal change in C-reactive protein, and all-cause mortality. Heart. 2008;94(4):457-462.
  5. Parrinello CM, Lutsey PL, Ballantyne CM, et al. Six-year change in high-sensitivity C-reactive protein and risk of diabetes, cardiovascular disease, and mortality. Am Heart J. 2015;170(2):380-389.


Photo by Lucas Vasques

Summaries of Late-breaking Science Presentations at the 2018 American Heart Association meeting in Chicago, IL

Summaries of Late-breaking Science Presentations at the 2018 American Heart Association meeting in Chicago, IL

Summaries of Late-breaking Science Presentations at the 2018 American Heart Association meeting in Chicago, IL

 By Heather Nelson Cortes, PhD and Kevin C Maki, PhD

 Dapagliflozin and Cardiovascular Events in the DECLARE-TIMI 58 Trial

The Dapagliflozin Effect on Cardiovascular Events—Thrombolysis in Myocardial Infarction 58 (DECLARE-TIMI 58) Trial was designed to assess the safety and efficacy of dapagliflozin (10 mg/d), a selective sodium-glucose cotransporter (SGLT)-2 inhibitor, in the reduction of cardiovascular events in patients with type 2 diabetes mellitus.  This was a phase 3b, randomized, double-blinded, placebo-controlled trial in 17,160 patients ≥40 y of age with type 2 diabetes and either cardiovascular disease (CVD) or multiple CVD risk factors.  The primary efficacy endpoints were major adverse cardiovascular events (MACE; defined as cardiovascular death, myocardial infarction or ischemic stroke) and a composite of heart failure hospitalization (HHF) or cardiovascular death.  Median follow-up was 4.5 y.  The results for the outcomes including the hazard ratios (HR) and 95% confidence intervals (CI) are shown in the table below.




(n = 8582)


(n = 8578)

HR (95% CI)



Rate/1000 patient-y






0.93 (0.84 to 1.03)





0.83 (0.73 to 0.95)





0.73 (0.61 to 0.88)

Cardiovascular death



0.98 (0.82 to 1.17)

All-cause mortality



0.93 (0.82 to 1.04)

Renal composite1



0.76 (0.67 to 0.87)

1Renal outcome was described as a 40% decrease in estimated glomerular filtration rate to <60 mL/min/1.73 m2, end-stage renal disease or death from renal or cardiovascular cause.


Conclusion:  Compared to placebo, dapagliflozin was safe and reduced the composite of cardiovascular death or HHF, but did not significantly reduce the incidence of MACE.


Wiviott SD, Raz I, Bonaca MP, et al. Dapagliflozin and cardiovascular outcomes in type 2 diabetes. N Engl J Med. 2018; Epub ahead of print.



Ezetimibe and Cerebro- and Cardiovascular Events in the EWTOPIA Trial
The role of lipid-lowering therapy in elderly (≥75 y of age) Japanese men and women with elevated low-density lipoprotein cholesterol (LDL-C) levels, but no history of coronary artery disease had not been well studied previously.  The Ezetimibe Lipid Lowering Trial on Prevention of Atherosclerosis in 75 or Older (EWTOPIA 75) investigation was a prospective, multi-center, open-label, blinded endpoint, randomized controlled trial conducted between 2009-2016 in Japanese men and women whose LDL-C level was ≥140 mg/dL and who had one or more cardiovascular risk factors (diabetes, hypertension, smoking, low high-density lipoprotein cholesterol, high triglycerides, previous history of cerebral infarction or peripheral artery disease). 

The primary endpoint was MACE, defined as a composite of sudden cardiac death, myocardial infarction, coronary revascularization, and/or stroke.  Secondary outcomes included cardiac events, cerebrovascular events, and all-cause mortality.  Eligible patients were randomized to either an ezetimibe group (10 mg/d plus dietary counseling; n = 1716) or a control group (dietary counseling alone; n = 1695).  LDL-C levels were reduced significantly more among patients taking ezetimibe (from 161 to 120 mg/dL) compared to subjects in the control group (from 162 to 131 mg/dL) (p < 0.001 for interaction).  The results for the outcomes are shown in the table below.



HR (95% CI)



0.66 (0.50 to 0.86)


Cardiac events

0.60 (0.37 to 0.98)


Cerebrovascular events

0.78 (0.55 to 1.11)


All-cause mortality

1.09 (0.89 to 1.34)


Conclusions:  In an elderly (≥75 y) Japanese population, ezetimibe (10 mg/d) plus dietary counseling compared to dietary counseling alone for primary prevention (elevated LDL-C, no history of CVD), was shown to help prevent cerebro- and cardiovascular events. 


Kumbhani DJ.  Ezetimibe in prevention of cerebro- and cardiovascular events in middle- to high-risk, elderly (75 years old or over) patients with elevated LDL-cholesterol – EWTOPIA 75.

Ouchi Y. Ezetimibe in prevention of cerebro- and cardiovascular events in middle-to high-risk, elderly (75 years old or over) patients with elevated LDL-cholesterol: a multicenter, randomized, controlled, open-label trial. Presented at AHA 2018. November 10, 2018. Chicago, IL.



The Cardiovascular Inflammation Reduction Trial (CIRT): Low Dose Methotrexate for the Prevention of Atherosclerotic Events
CIRT was a randomized, double-blind trial of low-dose methotrexate (LD-MTX; target dose 15-20 mg/week) or placebo in patients with a prior myocardial infarction or multi-vessel coronary disease who also had either type 2 diabetes or metabolic syndrome.  It was designed to investigate whether inhibiting inflammation with LD-MTX might provide a similar cardiovascular benefit to that shown previously by treatment with canakinumab, an anti-inflammatory agent.  At the outset of CIRT, the primary endpoint was a composite of nonfatal myocardial infarction, nonfatal stroke or cardiovascular death.  Towards the end of the trial, but before the trial was unblinded, hospitalization for unstable angina that led to urgent revascularization was added to the composite primary endpoint.

Eligible patients were randomly assigned to either LD-MTX (n = 2391) or placebo (n = 2395), and all patients also received 1 mg folate/day.  The trial was stopped after a median follow-up of 2.3 years (maximum 5.1 years) because it had crossed a pre-specified boundary for futility for both the original and final endpoints, and due to the lack of evidence for a reduction in C-reactive protein (CRP) with LD-MTX.  Median changes in inflammatory markers from enrollment to eight months in the LD-MTX and placebo groups, respectively, were 0.09 and 0.05 mg/L for CRP, -0.24 and -0.31 pg/mL for interleukin (IL)-1ß and 0.30 and 0.04 pg/mL for IL-6 (all p >0.05).  Results for the cardiovascular endpoints are shown below.




(n = 2391)


(n = 2395)

HR (95% CI)



Rate/100 patient-y



Original MACE



1.01 (0.82 to 1.25)


Final MACE



0.96 (0.79 to 1.16)


Conclusions:  In patients with prior myocardial infarction or multivessel CVD with either type 2 diabetes or metabolic syndrome, LD-MTX did not reduce inflammatory markers or cardiovascular events when compared to placebo.


Ridker PM, Everett BM, Pradhan A, et al. Low-dose methotrexate for the prevention of atherosclerotic events. N Engl J Med. 2018; Epub ahead of print.

Photo by Aaron Bean

An Independent Summary of Low-Density Lipoprotein Cholesterol Lowering With Evolocumab and Outcomes in Patients with Peripheral Artery Disease: Insights from the FOURIER Trial

An Independent Summary of Low-Density Lipoprotein Cholesterol Lowering With Evolocumab and Outcomes in Patients with Peripheral Artery Disease: Insights from the FOURIER Trial (Further Cardiovascular Outcomes Research with PCSK9 Inhibition in Subjects with Elevated Risk).1

An Independent Summary of Low-Density Lipoprotein Cholesterol Lowering With Evolocumab and Outcomes in Patients with Peripheral Artery Disease: Insights from the FOURIER Trial (Further Cardiovascular Outcomes Research with PCSK9 Inhibition in Subjects with Elevated Risk).1

By Kristen N Smith, PhD, RD, LD; Kevin C Maki, PhD

Background: Peripheral artery disease (PAD) is considered an indicator of a malignant vascular phenotype with event occurrences greater than other stable populations with atherosclerosis.2,3 Patients who have symptomatic PAD have a greater risk of major adverse cardiovascular events (MACE)4 and they also experience significant morbidity from major adverse limb events (MALE).5,6



Event Includes

Major adverse cardiovascular events (MACE)

Myocardial infarction (MI), stroke and cardiovascular death

Major adverse limb events (MALE)

Acute limb ischemia, urgent peripheral revascularization and major amputation


Methods of lowering lipid levels have been shown to help reduce MACE in stable patients with coronary heart disease or atherosclerosis risk factors, but there have been few well-developed, well-powered prospective randomized trials of low-density lipoprotein (LDL-C) reduction in patients with PAD.7 In particular, these prior studies have not examined relationships between the ability of LDL-C reductions to consequently reduce the risk of MALE.5,8-10  There is a shortage of information regarding the impact of reducing LDL-C on event risk in patients with PAD without prior MI or stroke.7,11,12

 In the FOURIER (Further Cardiovascular Outcomes Research with PCSK9 Inhibition in Subjects with Elevated Risk) trial, researchers gathered data on the use of evolocumab (a monoclonal antibody that inhibits proprotein convertase subtilisin kexin type 9 [PCSK9] and lowers LDL-C levels) compared with placebo in statin-treated patients with atherosclerotic disease in the coronary, cerebrovascular or peripheral artery bed. The FOURIER trial allowed the testing of the following hypotheses:1

  1. Patients with PAD would be at greater risk of MACE relative to patients with coronary or cerebrovascular disease without PAD;
  2. Consistent relative risk reductions in MACE with evolocumab would translate to larger absolute risk reductions in patients with PAD relative to those without;
  3. LDL-C reduction with evolocumab would significantly reduce MALE with benefits extending to very low levels of LDL-C.

This secondary analysis of the FOURIER study provided additional information on patients not only with cardiovascular risk factors, but also specifically of those meeting the criteria for PAD. 

 Methods: The FOURIER study was a randomized, double-blind, placebo-controlled, multinational clinical trial (1242 sites in 49 countries) investigating evolocumab versus placebo in 27,564 subjects with atherosclerotic disease. These subjects were followed for a median of 2.2 years.

 Inclusion Criteria:

  • Subjects were 40 to 85 years of age;
  • Clinically evident atherosclerotic cardiovascular disease (history of MI, non-hemorrhagic stroke or symptomatic PAD)
  • Fasting LDL-C of 70 mg/dL or greater OR non-high-density-lipoprotein cholesterol of 100 mg/dL or higher while on an optimized regimen of lipid-lowering medication (“preferably a high-intensity statin but must have been at least atorvastatin at a dose of 20 mg daily or its equivalent, with or without ezetimibe”).

 For the subset of patients with PAD, qualifications were met if the subjects had intermittent lower extremity claudication and an ankle brachial index <0.85, or a history of peripheral artery revascularization procedure or a history of amputation attributable to atherosclerotic disease.

Study endpoints are outlined in the following table: 

Primary End Points

Secondary End Points

Additional End Points of Interest

Major cardiovascular events, the composite of:


§  Cardiovascular death

§  MI

§  Stroke

§  Hospitalization for unstable angina

§  Coronary revascularization

The composite of:


§  Cardiovascular death

§  MI

§  Stroke




§  Acute limb ischemia

§  Major amputation

§  Urgent peripheral revascularization for ischemia



Patients in this study were randomly assigned in a 1:1 ratio to receive either subcutaneous injections of evolocumab (either 140 mg every 2 weeks or 420 mg every month, according to patient preference) or matching placebo.

Results: Of the 27,564 subjects participating in the FOURIER study, 3642 patients (13.2%) had PAD. Within this subset, 1505 (41%) met the criteria for PAD but had no prior MI or stroke.  Use of evolocumab significantly reduced the primary end point (outlined above) in patients with PAD (hazard ratio [HR] 0.79; 95% confidence interval [CI] 0.66-0.94; p=0.0098) and in patients without PAD (HR 0.86; 95% CI 0.80-0.93; p=0.0003; pinteraction=0.40). Results of the secondary end point (outlined above) mirrored the primary end point. The HR for patients with PAD was 0.73 (95% CI 0.59-0.91; p=0.0040) and was 0.81 (95% CI 0.73-0.90; p<0.0001) for those without PAD (pinteraction=0.41). Since patients with PAD experience elevated risk, they also had larger absolute risk reductions for the primary end point (3.5% with PAD, 1.6% without PAD) and the secondary end point (3.5% for patients with PAD, 1.4% for those without PAD).

Treatment with evolocumab was also associated with reduced risk of MALE in all patients (HR 0.58; 95% CI, 0.38-0.88; p=0.0093) and these effects were consistent regardless of PAD status. The researchers noted a consistent relationship between lower (achieved) LDL-C and reduced risk of limb events (p=0.026 for the beta coefficient) that extended to values <10 mg/dL.

There were no differences in the incidence of adverse events or serious adverse events with evolocumab relative to placebo. Rates of treatment discontinuation were also similar between groups (1.3% evolocumab versus 1.5% placebo, p=0.57).

Comment: The FOURIER study provided evidence showing that patients with PAD were at greater risk of both MACE and MALE compared to patients with prior MI or stroke and no PAD, and captured the effects of the use of evolocumab as an adjunct to statin. Ultimately, the use of evolocumab assisted in reducing the risk of MACE (greater reductions in the subjects with PAD) and the concomitant LDL-C reductions associated with evolocumab treatment also decreased risk of MALE.

The FOURIER study provided clinical outcomes in a broad population with polyvascular disease and within those with isolated PAD (no history of MI or stroke). The results illustrated the benefits of the use of evolocumab added as an adjunct to a statin treatment in both groups, with minimal adverse events. Based on the results of this study, the combined usage of evolocumab plus statin treatment provided significant reductions in cardiovascular disease-related outcomes and warrants additional attention as a method of improving health outcomes in patients with PAD.


  1. Bonaca MP, Nault P, Giugliano RP, et al. Low-Density Lipoprotein Cholesterol Lowering With Evolocumab and Outcomes in Patients With Peripheral Artery Disease: Insights From the FOURIER Trial (Further Cardiovascular Outcomes Research With PCSK9 Inhibition in Subjects With Elevated Risk). Circulation. 2017.
  2. Criqui MH, Aboyans V. Epidemiology of peripheral artery disease. Circulation research. 2015;116(9):1509-1526.
  3. Bonaca MP, Bhatt DL, Storey RF, et al. Ticagrelor for Prevention of Ischemic Events After Myocardial Infarction in Patients With Peripheral Artery Disease. Journal of the American College of Cardiology. 2016;67(23):2719-2728.
  4. Aboyans V, Ricco JB, Bartelink MEL, et al. 2017 ESC Guidelines on the Diagnosis and Treatment of Peripheral Arterial Diseases, in collaboration with the European Society for Vascular Surgery (ESVS): Document covering atherosclerotic disease of extracranial carotid and vertebral, mesenteric, renal, upper and lower extremity arteriesEndorsed by: the European Stroke Organization (ESO)The Task Force for the Diagnosis and Treatment of Peripheral Arterial Diseases of the European Society of Cardiology (ESC) and of the European Society for Vascular Surgery (ESVS). European heart journal. 2017.
  5. Kumbhani DJ, Steg PG, Cannon CP, et al. Statin therapy and long-term adverse limb outcomes in patients with peripheral artery disease: insights from the REACH registry. European heart journal. 2014;35(41):2864-2872.
  6. Jones WS, Baumgartner I, Hiatt WR, et al. Ticagrelor Compared With Clopidogrel in Patients With Prior Lower Extremity Revascularization for Peripheral Artery Disease. Circulation. 2017;135(3):241-250.
  7. Aung PP, Maxwell HG, Jepson RG, Price JF, Leng GC. Lipid-lowering for peripheral arterial disease of the lower limb. The Cochrane database of systematic reviews. 2007(4):CD000123.
  8. Aronow WS, Nayak D, Woodworth S, Ahn C. Effect of simvastatin versus placebo on treadmill exercise time until the onset of intermittent claudication in older patients with peripheral arterial disease at six months and at one year after treatment. The American journal of cardiology. 2003;92(6):711-712.
  9. Mohler ER, 3rd, Hiatt WR, Creager MA. Cholesterol reduction with atorvastatin improves walking distance in patients with peripheral arterial disease. Circulation. 2003;108(12):1481-1486.
  10. Spring S, Simon R, van der Loo B, et al. High-dose atorvastatin in peripheral arterial disease (PAD): effect on endothelial function, intima-media-thickness and local progression of PAD. An open randomized controlled pilot trial. Thrombosis and haemostasis. 2008;99(1):182-189.
  11. Bonaca MP, Scirica BM, Creager MA, et al. Vorapaxar in patients with peripheral artery disease: results from TRA2{degrees}P-TIMI 50. Circulation. 2013;127(14):1522-1529, 1529e1521-1526.
  12. Hiatt WR, Fowkes FG, Heizer G, et al. Ticagrelor versus Clopidogrel in Symptomatic Peripheral Artery Disease. The New England journal of medicine. 2017;376(1):32-40.


test tubes