Context: Diabetes is associated with a several fold increase in the risk of lower extremity amputation. Although a number of epidemiologic studies have reported positive associations between glycaemia and lower extremity amputation, the magnitude of the risk has not been adequately quantified.

Objective: To synthesize the available prospective epidemiologic data on the association between glycaemia as measured by glycosylated haemoglobin and lower extremity amputation in individuals with diabetes.

Data Sources: We searched electronic databases (MED-LINE and EMBASE) and the reference lists of relevant articles.

Study Selection: We considered prospective epidemiologic studies of cohort or nested case-control design that measured glycosylated haemoglobin level and assessed lower extremity amputation as an outcome. Of 2,398 citations identified, we included 14 studies comprising 94,640 subjects and 1,227 cases.

Data Extraction: Data were abstracted using standardized forms or obtained from investigators when published information was insufficient. Data included characteristics of case and control populations, measurement of glycaemia, assay methods, outcome, and covariates.

Results: The overall risk ratio for lower extremity amputation was 1.26 (95% CI, 1.16–1.36) for each percentage point increase in glycosylated hemoglobin level. There was significant heterogeneity across studies (I2: 76%, 67–86%; p< 0.001) not accounted for by recorded study characteristics. Among studies that reported the type of diabetic population, the combined estimate was 1.44 (1.25–1.65) for individuals with type 2 diabetes and 1.18 (95% CI, 1.02–1.38) for type 1 diabetes, but the difference was not statistically significant (p=0.09). We found no significant publication bias.

Conclusions: There a substantial increase in risk of lower extremity amputation associated with every 1% higher HbA1c in individuals with diabetes, highlighting a potential benefit of blood glucose control. In the absence of evidence from clinical trials, this paper supports glucose-lowering as a component of overall care in the patient at high risk of amputation.