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

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. 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 meta-regression analyses. 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. 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.