No evidence of an increased mortality risk associated with low levels of glycated haemoglobin in a non-diabetic UK population

There is debate about increased mortality risk associated with low levels of glycaemia. To address this issue, we examined the shape of the risk relationship between glycated haemoglobin and mortality in a UK population. In 17,196 men and women aged 39-82 years participating in the European Prospective Investigation into Cancer and Nutrition (EPIC) Study in Norfolk without known diabetes or cardiovascular disease, we estimated HRs for total and cause-specific mortality comparing categories of glycated haemoglobin (< 4.5%, 4.5% to < 5.0%, 5.0% to < 5.5% [reference], 5.5% to < 6.0%, 6.0% to < 6.5%, and a parts per thousand yen6.5%) using Cox regression. During a mean (+/- SD) follow-up of 11.2 (+/- 2.1) years 1,953 participants died. The HR for all-cause mortality increased with categories of increasing glycated haemoglobin in adjusted analyses (HR 0.94 [95% CI 0.72-1.22], 0.99 [0.86-1.13], 1.00 [0.92-1.08], 1.10 [1.02-1.19], 1.29 [1.14-1.46] and 1.45 [1.16-1.80]). Spline regression suggested no increased risk at the low end of the distribution. Indeed, the HR for all-cause mortality was virtually constant in the low range and only started to rise when the level was approximately 5.5%. There were similar associations of glycated haemoglobin with cause-specific mortality, with the strongest association being seen for cardiovascular mortality. Our findings in a large non-diabetic population do not support the concern about increased mortality risk with low glycated haemoglobin. Differences in population characteristics might explain contrary results of earlier studies and need further exploration.