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rom Medscape Education Clinical Briefs

Diabetic Foot Ulceration and Cardiovascular Disease CME

News Author: Miriam E. Tucker
CME Author: Desiree Lie, MD, MSED


CME Released: 10/25/2012; Valid for credit through 10/25/2013



According to the authors, risk for cardiovascular disease (CVD) and all-cause mortality is twice as high in patients with diabetes compared with patients without diabetes, and observational studies have suggested an even higher mortality among patients with diabetes who have foot ulcers. Diabetic foot ulceration (DFU) also correlates with a higher risk for CVD among patients with diabetes.

This is a systematic review and meta-analysis of studies reporting on DFU in patients with diabetes to assess the risk for DFU associated with mortality in those patients.


Diabetic foot ulceration was associated with a nearly 2-fold increased risk for all-cause mortality above that of diabetes alone, according to a meta-analysis of 8 studies.

The risks for both CVD and all-cause mortality among people with diabetes mellitus are approximately double those of people without diabetes, the researchers explain. This new systematic review and meta-analysis, published online August 14 and in the November issue of Diabetologia, examines the influence of DFU on that already-elevated risk.

"We provide the largest scale evidence to date that patients with DFU have a higher risk of all-cause mortality compared with patients with diabetes but without a history of foot ulceration," write Jack R.W. Brownrigg, BSc, from St. George's Vascular Institute, London, United Kingdom, and colleagues.

In addition, the researchers say, the findings suggest that increased all-cause mortality risk among patients with DFU is not just the result of excess CVD.

The authors analyzed 8 studies published between 1996 and 2011 that reported on a total 17,830 patients with 81,116 patient-years of follow-up. Half of the studies were done in the United States, 2 were done in Europe, 1 in Australasia, and 1 in South-East Asia. Patients with both type 1 and type 2 diabetes were included in all but 1 study, in which all patients had type 2 diabetes.

The 3095 patients with DFU had a significantly longer duration of diabetes, at 12.72 years, compared with the 14,735 patients without DFU (7.19 years; P < .005). The prevalence of coronary artery disease was significantly higher among those with DFU (31.4% vs 14.7%), as was that of both hypertension (57.6% vs 35.7%) and hypercholesterolemia (47.6% vs 11.1%), with all P values < .001.

During follow-up, there were a total 3619 deaths from any cause. The DFU population had a 1.89 pooled relative risk (95% confidence interval [CI], 1.60 – 2.23) for all-cause mortality compared with the patients with diabetes without DFU. Unadjusted rates of all-cause mortality were 99.9 per 1000 person-years for the DFU population vs 41.6/1000 person-years in the diabetes-only group.

Further analysis of a total 3138 patients in 4 studies for whom information on cardiovascular mortality was available showed that rates of fatal myocardial infarction and fatal stroke were also higher among those with DFU, with relative risks of 2.22 (95% CI, 1.09 – 4.53) and 1.41 (95% CI, 0.61 – 3.24), respectively.

However, the overall proportion of deaths resulting from cardiovascular causes was almost the same in the DFU and non-DFU groups: 43.6% of the 117 DFU patients and 44.2% of the 952 diabetes-only patients. "These findings imply that the excess CVD risk observed in DFU patients only partly accounts for the increased mortality rate," the investigators write.

The excess mortality in patients with DFU may also relate to their more advanced stage of diabetes, with greater overall disease burden and noncardiovascular complications of foot ulceration such as sepsis, the authors suggest.

"Our data support the hypothesis that, in order to attenuate the excess mortality associated with DFU, strategies focusing on both more aggressive modification of CVD risk factors and ulcer prevention might be required."

This study was not funded by any external sources. The authors have disclosed no relevant financial relationships.

Diabetologia. 2012;55:2906-2912. Abstract



  • Included were studies with at least 1 year of follow-up with outcomes on fatal CVD (fatal myocardial infarction and stroke) in individuals with diabetes mellitus who also had DFU.
  • Excluded were studies that only included patients with lower-limb arterial occlusive disease.
  • The electronic databases of PubMed, Embase, and the Cochrane Library were searched form inception to 2011.
  • Information on study size, patient characteristics including CVD risk factors, and absolute number of events were abstracted by 2 independent researchers.
  • 8 studies published between 2006 and 2011 reporting on 17,830 patients and 81,116 person-years of follow-up were included in the analysis.
  • 4 studies were based in the United States, 2 in Europe, 1 in Australasia, and 1 in South East Asia.
  • Patients were primarily from clinic populations.
  • All studies reported on patients with type 1 and type 2 diabetes, except a single study that reported only on patients with type 2 diabetes.
  • 6 studies were prospective cohort studies, and 1 was a retrospective cohort study.
  • Average follow-up ranged from 2 to 10 years, the number of participants in each study ranged from 16 to 2100 patients, mean age ranged from 58 to 73 years, and duration of diabetes was between 6 and 16 years.
  • In the studies, between 11.1% and 30.1% of the participants were current smokers, 30.1% to 87.5% had hypertension, and between 36% and 98% were men.
  • The DFU group had a longer duration of diabetes (12.72 vs 7.19 years) compared with the group without DFU.
  • The prevalence of heart disease, stroke, hypertension, and hypercholesterolemia was significantly higher in the DFU group.
  • There were 3619 deaths from any cause over the course of 81,116 person-years of follow-up.
  • DFU was associated with increased risk for all-cause mortality (pooled risk ratio, 1.89) compared with no DFU.
  • "Crude event rates for all-cause mortality were 99.9 per 1,000 person-years in the DFU population and 41.6 in the diabetes-only population," according to the authors.
  • There were no differences in RR for studies lasting 3 years or less vs those more than 3 years in duration.
  • For death from CVD, there were 113 deaths from cerebrovascular accidents (CVA) or stroke and 359 deaths from myocardial infarction over the course of 28,189 person-years of follow-up in 4 studies.
  • The risk ratios for fatal myocardial infarction and CVA were 2.22 and 1.41, respectively, for those with DFU compared with those without DFU.
  • CVD accounted for 43.6% of deaths in patients with DFU and 44.2% of those without DFU.
  • There was no evidence of heterogeneity for these outcomes.
  • Crude events rates per 1000 were 16.8 and 11.8 for fatal myocardial infarction and CVA, respectively, and 4.6 and 3.8 for fatal CVAs for DFU and non-DFU patients, respectively.
  • The authors conclude that patients with DFU have a higher risk for all-cause mortality compared with patients with diabetes without DFU.
  • However, they note that DFU and non-DFU patients had similar risk for CVA and myocardial infarction, and suggest that the excess risk for mortality associated with DFU was not fully accounted for by CVD risk but may reflect more advanced ulcer disease and noncardiovascular complications.
  • Thus, they recommended that strategies to reduce mortality in patients with diabetes address both CVD risk factors and ulcer prevention.




  • The presence of DFU is associated with higher all-cause mortality in patients with type 1 or 2 diabetes.
  • The risk for higher mortality associated with DFU is not fully explained by increased cardiovascular mortality alone among patients with diabetes.



PV Mayer

Dr. Perry Mayer is the Medical Director of The Mayer Institute (TMI), a center of excellence in the treatment of the diabetic foot. He received his undergraduate degree from Queen’s University, Kingston and medical degree from the Royal College of Surgeons in Ireland.

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