Association between glycated haemoglobin and the risk of lower extremity amputation in patients with diabetes mellitus—review and meta-analysis

Abstract

Aims/hypothesis Diabetes increases the risk of lower extremity amputation (LEA). Although epidemiological studies report positive associations between glycaemia and LEA, the magnitude of the risk is not adequately quantified and clinical trials to date have not provided conclusive evidence about glucose lowering and LEA risk. We synthesised the available prospective epidemiological data on the association between glycaemia measured by HbA 1c and the risk of LEA in individuals with diabetes. Methods We searched electronic databases and reference lists of relevant articles. We considered prospective epidemiological studies that had measured HbA 1c level and assessed LEA as an outcome among diabetic individuals without acute foot ulcerations or previous history of amputation. Of 2,548 citations identified, we included 14 studies comprising 94,640 participants and 1,227 LEA cases. We abstracted data using standardised forms and obtained data from investigators when required. Data included characteristics of study populations, HbA 1c assay methods, outcome and covariates. Study-specific relative risk estimates were pooled using random-effects model meta-analysis; heterogeneity was explored with metaregression analyses. Results The overall RR for LEA was 1.26 (95% CI 1.16-1.36) for each percentage point increase in HbA 1c . There was considerable heterogeneity across studies (I 2 76%, 67-86%; p<0.001), which was not accounted for by recorded study characteristics. The estimated RR was 1.44 (95% CI 1.25-1.65) for type 2 diabetes and 1.18 (95% CI 1.02-1.38) for type 1 diabetes; however, the difference was not statistically significant (p=0.09). We found no strong evidence for publication bias. Conclusions/interpretation There is a substantial increase in risk of LEA associated with glycaemia in individuals with diabetes. In the absence of conclusive evidence from trials, this paper provides further epidemiological support for glucose-lowering as a strategy to reduce amputation in a population without acute foot ulceration or former amputation; it also provides disease modellers with estimates to assess the overall burden of hyperglycaemia.

Diabetic foot ulceration and amputation

“…Chronic hyperglycemia and insulin use, which could be considered a marker for glycemic control, have been shown to be independent risk factors for LEA in persons with DM (Adler et al, 1999;Davis et al, 2006;Adler et al, 2010). Elevated HbA1c is associated with risk of LEA such that for every 1% increase in HbA1c there is an associated 26% to 36% increased risk of LEA (Adler et al, 2010).…”

Stratification of foot risk predicts the incidence of new foot disease, but do we yet know that the adoption of routine screening reduces it?

“…Other factors may be important, too, including visual impairment (with risk of foot trauma), renal dialysis (not referred to in this paper but known to be a powerful risk factor [3]) and HbA 1c . The role of the last of these may relate to its association with the development, or progression, of other complications of diabetes [4].…”

The importance of HbA1C and erythrocyte sedimentation rate as prognostic factors in predicting the outcome of diabetic foot ulcer disease

“…Each one percentage point increase in HbA1C was associated with a 26% increase in risk of LEA. 18 Kaplan-Meier survival analysis showed that amputation was independently associated with higher HbA1C values, and the hazard ratio for amputation associated with an HbA1C value of greater than 7.5% was 1.20. 19 Our data showed that the increase in incidence of LEA if far greater than 26% for every 1% increase of HbA1C.…”

“…12 Another study by Adler et al showed high HbA1C levels are a known risk factor for LEA. 13 In India, it is estimated that approximately 40,000 legs are being amputated every year, of which 75% are neuropathic with secondary infection, which are potentially preventable. It was found that approximately all foot ulcer patients have HbA1C level uncontrolled with 86% of them having HbA1C level of 8.86%.…”