Reducing Amputation Risk in Diabetes With Peripheral Artery Disease

Findings reported in the Journal of Clinical Endocrinology and Metabolism linked statin therapy with reduced risk for lower limb amputation, in-hospital cardiovascular death, and all-cause mortality in patients with diabetes and peripheral artery disease (PAD).¹

Associated with an increased prevalence of PAD — a marker of systemic atherosclerosis² — diabetes is also linked with an elevated risk for critical ischemia and contralateral leg disease.^3,4 “When not managed properly, PAD may lead to amputation resulting in disability, hospitalization, and death,” Po-Hsun Huang, MD, PhD, of the Division of Cardiology at Taipei Veterans General Hospital in Taiwan, and colleagues wrote. 

Previous results demonstrated benefits of statins on both functional reserve and cardiovascular events in patients with PAD, and guidelines by the American College of Cardiology/American Heart Association and the European Society of Cardiology recommend statin therapy for such individuals.^5-8 However, there is limited research investigating whether or not statins reduce the risk of amputation.

“[D]eath is a potential competing risk for amputation. Because many [patients with diabetes] with PAD may die before the initial amputation, this issue has not been fully clarified,” Dr Huang and colleagues noted.

In the present study, the researchers conducted an observational cohort study, analyzing information from a nationwide diabetes database to determine the association between statin use and the rate of lower extremity amputation in high-risk patients with PAD. They examined sociodemographic data and a wide range of clinical variables, including comorbidities and concomitant use of other drugs.

In both treatment groups, the regimen had been initiated in the 90 days following PAD diagnosis. Lower extremity amputation was the main outcome, and in-hospital cardiovascular death and all-cause mortality were the secondary outcomes. Patients receiving a combination of the 2 medications were excluded from the study.

A total of 69,332 adult patients with diabetes and PAD (mean age, 62.6±13 years; 49% men) were divided into 3 groups: 11,409 patients were prescribed statins, 4430 were prescribed non-statin lipid-lowering agents, and 53,493 patients did not take either drug. Hypertension was the most commonly observed comorbid condition, affecting 73.6% of patients. Other comorbidities included coronary artery disease (44.9%), cerebrovascular disease (30.8%), heart failure (14.6%), chronic kidney disease (19%), atrial fibrillation (3.5%), and cancer (11%). Comorbidities were more common in the statin group.

Over a mean follow-up of 5.7 years, statin users demonstrated a reduced risk for amputation (adjusted hazard ratio [aHR] 0.75; 95% CI, 0.62-0.90), in-hospital cardiovascular death (aHR 0.78; 95% CI, 0.69-0.87), and all-cause mortality (aHR 0.73; 95% CI, 0.69-0.77), compared with patients never treated with lipid-lowering agents. Propensity-score matching analysis further supported these results, showing a decreased risk for amputation (HR 0.77; 95% CI, 0.61-0.97) and cardiovascular death (HR 0.78; 95% CI, 0.68-0.89).

The group taking non-statin lipid-lowering agents did not show a significant decrease in amputation risk (aHR 0.95; 95% CI, 0.73-1.23), although they did have a reduced risk for cardiovascular death and mortality.

“These findings suggest that statin therapy not only reduces the risk of adverse cardiovascular events, but also has favorable[ly] effects of limb prognosis in [patients with diabetes] with PAD,” the researchers concluded.

Study Limitations

• The primary limitation noted is unmeasured confounding factors “inherent in the use of administrative data.” Bias attributed to these unmeasured confounding factors cannot be ruled out completely.

• The researchers lacked data on blood glucose or hemoglobin A1c levels, instead matching cohorts based on use of glucose-lowering medication.

• Lifestyle information — including smoking status, alcohol consumption, and obesity — was not included in the database.

• Currently, no step-by-step guidelines for indications of amputation exist.

References

1. Hsu CY, Chen YT, Su YW, Chang CC, Huang PH, Lin SJ. Statin therapy reduces future risk of lower limb amputation in patient with diabetes and peripheral artery disease [published online April 7, 2017]. J Clin Endocrinol Metab.  doi:10.1210/jc.2016-3717
2. Marso SP, Hiatt WR. Peripheral arterial disease in patients with diabetes. J Am Coll Cardiol. 2006;47(5):921-929. doi:10.1016/j.jacc.2005.09.065
3. Virkkunen J, Heikkinen M, Lepantalo M, Metsanoja R, Salenius JP; for the Finnvasc Study Group. Diabetes as an independent risk factor for early postoperative complications in critical limb ischemia. J Vasc Surg. 2004;40(4):761-767. doi:10.1016/j.jvs.2004.07.040
4. Faglia E, Clerici G, Mantero M, et al. Incidence of critical limb ischemia and amputation outcome in contralateral limb in diabetic patients hospitalized for unilateral critical limb ischemia during 1999-2003 and followed-up until 2005. Diabetes Res Clin Pract. 2007;77(3):445-450. doi:10.1016/j.diabres.2007.01.010
5. Feringa HH, Karagiannis SE, van Waning VH, et al. The effect of intensified lipid-lowering therapy on long-term prognosis in patients with peripheral arterial disease. J Vasc Surg. 2007;45(5):936-943. doi:10.1016/j.jvs.2007.01.024
6. Westin GG, Armstrong EJ, Bang H, et al. Association between statin medications and mortality, major adverse cardiovascular event, and amputation-free survival rates in patients with critical limb ischemia. J Am Coll Cardiol. 2014;63(7):682-690. doi:10.1016/j.jacc.2013.09.073
7. Anderson JL, Halperin JL, Albert NM, et al. Management of patients with peripheral artery disease (compilation of 2005 and 2011 ACCF/AHA guideline recommendations): a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. Circulation. 2013;127(3):1425-1443. doi:10.1161/CIR.0b013e31828b82aa
8. Tendera M, Aboyans V, Bartelink ML, et al; for the European Stroke Organization and the ESC Committee for Practice Guidelines. ESC Guidelines on the diagnosis and treatment of peripheral artery diseases: Document covering atherosclerotic disease of extracranial carotid and vertebral, mesenteric, renal, upper and lower extremity arteries: the Task Force on the Diagnosis and Treatment of Peripheral Artery Diseases of the European Society of Cardiology (ESC). Eur Heart J. 2011;32(22):2851-2906. doi:10.1093/eurheartj/ehr211