Fenofibrate decreased amputation risk in type 2 diabetes

Patients with type 2 diabetes had a 36% lower risk for first-time amputations — particularly below the ankle —when assigned to long-term treatment with fenofibrate compared with patients assigned to placebo, according to data from the FIELD study.

“We have identified that fenofibrate is the first pharmacological agent to substantially reduce the risk of a diabetic amputation, irrespective of lipid profile, blood pressure or glycemic control,” Kushwin Rajamani, MBBCh, of the National Health and Medical Research Council Clinical Trials Centre, University of Sydney, told Endocrine Today.

FIELD researchers randomly assigned 9,795 patients with type 2 diabetes aged 50 to 75 to once-daily micronized fenofibrate 200 mg (n=4,895) or matched placebo (n=4,900). Follow-up was a median of five years.

Data on nontraumatic amputations were classified as minor or major by two clinicians masked to treatment allocation. Minor amputations were defined as those below the ankle and major amputations were defined as those above the ankle.

Lower-limb amputations caused by diabetes were reported in 115 patients; 47 had more than one amputation. Although the risk for a first nontraumatic amputation was lower in the fenofibrate group compared with the placebo group (HR=0.64; 95% CI, 0.44-0.94), the risk for major amputations did not differ significantly between groups.

The researchers calculated a number needed to treat of 197 to prevent at least one amputation over five years with fenofibrate; the number needed to treat was much lower (25) for individuals with previous foot ulcer and albuminura.

Patients who had amputations performed during the study period were more likely to be men, smokers, have a longer median duration of diabetes, previous cardiovascular disease, microvascular disease and a previous nontraumatic amputation or skin ulcer compared with patients who had other CV events or patients who had neither event (P<.001). Another characteristic associated with amputations was height — researchers reported a 1.6-fold increase in risk for every 10-cm increase in height.

In addition, patients with amputations had more prescriptions of angiotensin-converting enzyme inhibitors at baseline and were more likely to be assigned to insulin compared with the other two aforementioned groups. Mean lipid concentrations differed by no more than 0.2 mmol/L.

The mechanism of action remains unclear, according to the researchers, but lipids may play a role; mean lipid concentrations differed by no more than 0.2 mmol/L.

Use of fenofibrate could help reduce the substantial mortality, morbidity and economic burden associated with diabetes-related amputation, the researchers concluded.

“Our results support the use of fenofibrate in addition to current standards of diabetes care — good glycemic control and use of ACE inhibitors/angiotensin II receptor blockers — to significantly reduce the risk of an amputation,” Rajamani said. “This observed benefit is particularly important for patients with above average amputation risk, such as those with previous foot ulceration and albuminuria.” – by Jennifer Southall

Rajamani K. Lancet. 2009;373:1780-1788.

The authors report a low overall incidence of amputation but, small numbers of events notwithstanding, show a reduced risk for amputation in patients receiving fenofibrate. Unfortunately, the data do not allow determination of whether any lipid-lowering intervention would do as well. Therefore, I don’t see this latest installment of the FIELD study having much impact on practice patterns, as aggressive lipid-lowering therapy is already standard of care for patients with diabetes. Lacking comparative data showing that fibric acid derivatives are superior to statins, most will continue to prescribe statins due to their more favorable adverse event profiles.

– Robert D. Blank, MD, PhD

Endocrine Today Editorial Board member

The majority of amputations in the diabetic population are due to a combination of neuropathy, peripheral vascular disease and infection. Most often the sequence of events is neuropathy leading to ulceration followed by infection and ischemia. Since neuropathy has recently been shown to be associated with hypertriglyceridemia, it may be that neuropathy rather than peripheral vascular disease was improved with fenofibrate.

– David S.H. Bell, MD

Endocrine Today Editorial Board member