Abstract
Aims/hypothesis 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. Methods 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 ≥6.5%) using Cox regression. Results 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. Conclusions/interpretation 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.
Generated Summary
The study, a prospective cohort study in the UK, investigated the relationship between glycated haemoglobin (HbA1c) levels and mortality in a non-diabetic population. The research examined 17,196 men and women aged 39-82 years from the European Prospective Investigation into Cancer and Nutrition (EPIC) Study in Norfolk, without known diabetes or cardiovascular disease. The researchers estimated hazard ratios (HRs) for total and cause-specific mortality, comparing different categories of HbA1c using Cox regression analysis. The aim was to address the debate surrounding the increased mortality risk associated with low levels of glycaemia by assessing the shape of the risk relationship between HbA1c and mortality. The study utilized a mean follow-up period of 11.2 years, with participants categorized into six HbA1c levels. The analysis included both continuous and categorical assessments of HbA1c’s association with mortality.
Key Findings & Statistics
- During a mean 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]).
- Baseline characteristics of the study population showed a mean age of 59.2 years and a mean glycated haemoglobin level of 5.3%.
- 3,742 (22%) individuals had glycated haemoglobin levels below 5%.
- Cardiovascular risk factors increased with increasing glycated haemoglobin levels.
- Variables of liver damage (ALT and AST) increased with increasing glycated haemoglobin levels.
- No significant interaction was found between sex and glycated haemoglobin for any of the outcomes (p>0.15).
- The risk for all-cause death increased throughout the whole range of glycated haemoglobin concentration.
- Piecewise-linear and restricted-cubic spline regression suggested that the HR for all-cause mortality (relative to a level of 5.3%) is virtually constant for the low range of glycated haemoglobin and starts to increase at approximately 5.5%.
- There was no statistically significant departure from linearity (p=0.65).
- The estimated HRs for death from all causes according to the baseline category of glycated haemoglobin adjusted for age and sex showed a continuous increase in the risk of all-cause mortality with categories of increasing glycated haemoglobin (Fig. 1a).
- For cardiovascular mortality, the HRs (95% CIs) for each glycated haemoglobin category were: <5.0% – 1.00, 5.0 to <5.5% – 1.00 (0.85-1.17), 5.5 to <6.0% – 1.30 (1.13-1.48), 6.0 to <6.5% – 1.21 (1.05-1.38), and ≥6.5% – 1.61 (1.09-2.36).
- For cancer-related mortality, the HRs (95% CIs) for each glycated haemoglobin category were: <5.0% – 1.00, 5.0 to <5.5% – 1.00 (0.89-1.12), 5.5 to <6.0% – 1.13 (1.01-1.25), 6.0 to <6.5% – 1.39 (1.17-1.66), and ≥6.5% – 1.36 (0.96-1.91).
Other Important Findings
- 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%.
- Similar associations of glycated haemoglobin were observed with cause-specific mortality, with the strongest association being for cardiovascular mortality.
- Piecewise-linear and restricted-cubic spline regression suggested that the HR for all-cause mortality (relative to a level of 5.3%) is virtually constant for the low range of glycated haemoglobin and starts to increase at approximately 5.5%.
- The association of glycated haemoglobin was largest for cardiovascular mortality, although the association with cancer-related mortality showed a similar trend.
Limitations Noted in the Document
- The study population was predominantly white European, which limits the generalizability of the findings to other ethnic groups.
- The analysis was based on a single measurement of glycated haemoglobin at baseline, which could lead to underestimation of the true association due to error from random variability.
- The study did not have sufficient events to exclude an increased risk of mortality from specific cancer subtypes in individuals with low glycated haemoglobin.
Conclusion
The study’s findings do not support the concern about increased mortality risk associated with low glycated haemoglobin in a non-diabetic UK population. The HR for all-cause mortality increased with increasing glycated haemoglobin, with the risk starting to rise around a level of 5.5%. The associations for cardiovascular and cancer-related mortality showed similar patterns. The shape of the risk relationship between glycaemia and health outcomes has implications for intervention targets, suggesting a possible ‘basement’ level to the graded relation between glycaemia and health risk. This basement range, found in this study, corresponds to the ‘normal’ range of glycated haemoglobin in the general population. The study’s results suggest that there may be no relevant mortality benefit from further lowering of glycated haemoglobin. Differences in population characteristics might explain the discrepant results across study populations, and further research is needed to explore determinants of low glycated haemoglobin which are concurrently associated with increased mortality.