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Diabetes Distilled: Association between prediabetes and risk of all-cause mortality and cardiovascular disease. Updated meta-analysis

This updated and very large, high-quality meta-analysis explored the relationship between prediabetes and the risk of all-cause mortality and incident cardiovascular disease (CVD) in the general population as well as in those with a history of atherosclerotic CVD. Compared to those with normal glucose regulation, individuals with prediabetes were demonstrated to have a higher risk of all-cause mortality and CVD, both in the general population and in those with a history of atherosclerotic CVD. These findings have significant implications for the future screening and management of prediabetes in primary and secondary prevention of CVD.

Prediabetes is very common; a recent cross-sectional study suggested that more than a third of adults in England had prediabetes and that the prevalence had tripled over the preceding 8 years (Mainous et al, 2014). However, as this was a cross-sectional study, it was not possible to identify how many of these individuals progressed to type 2 diabetes.

The label of prediabetes has been hotly debated over the years, with critics citing inconsistent evidence that prediabetes is associated with an increased risk of cardiovascular disease (CVD) and mortality in the general population, unlike type 2 diabetes. Furthermore, there is a lack of high-quality evidence exploring the impact of prediabetes in those with established CVD (i.e. in the context of secondary prevention).

Further muddying the waters are varying definitions for those with abnormal glucose regulation but not meeting the criteria for type 2 diabetes. A previous UK expert position statement recommended an HbA1c range of 42–47 mmol/mol (6.0–6.5) to define those with prediabetes (John et al, 2012). Impaired glucose tolerance (IGT; 2-hour plasma glucose post-75-g oral glucose load 7.8–11 mmol/L) and impaired fasting glycaemia (IFG; fasting blood glucose 6.1–6.9 mmol/L) have previously been widely used in primary care, whereas the NHS Diabetes Prevention Programme has adopted non-diabetic hyperglycaemia as its preferred terminology and uses an HbA1c range of 42–47 mmol/mol to define this. Indeed, the authors of the above cross-sectional study used American Diabetes Association criteria to define prediabetes (different again: HbA1c 39–46 mmol/mol). This clearly will have impacted the observed prevalence in this study. International consensus is urgently required.

The present very large (>10 million participants) and well-conducted meta-analysis sought to explore the impact of prediabetes on prognosis in those with and without atherosclerotic CVD. Additionally, the authors investigated whether different definitions of prediabetes affected prognosis in these groups of individuals.

In the general population, prediabetes carried an increased risk of all-cause mortality (relative risk 1.13; 95% confidence interval [CI] 1.10–1.17) and composite CVD (relative risk 1.15; 95% CI 1.11–1.18). Different definitions of prediabetes did appear to significantly impact the risk of all outcomes except coronary heart disease. Specifically, IGT carried a higher risk of all-cause mortality and CVD than IFG. Additionally, fasting plasma glucose concentrations >5.6 mmol/L were associated with increased mortality. This increased risk was mainly driven by fasting plasma glucose concentrations in the range of 6.1–6.9 mmol/L. This heterogeneity in outcomes has important implications on the selection of high-risk individuals for future diabetes prevention studies.

In those with atherosclerotic CVD, prediabetes carried an increased risk of all-cause mortality (relative risk 1.36; 95% CI 1.21–1.54) and composite CVD (relative risk 1.37; 95% CI 1.23–1.53). Different definitions of prediabetes did not appear to significantly impact any outcomes, in contrast to the general population. This overall increased risk suggests that appropriate management of prediabetes should be an additional pillar of key therapeutic strategies for the secondary prevention of CVD, such as antiplatelet use.

One of the main limitations of this study is that it remains unclear whether the increased risk of mortality and CVD observed is due to prediabetes itself or the progression of prediabetes to overt type 2 diabetes during follow-up. Past studies such as the Finnish Diabetes Prevention Study suggest the predictive properties of IGT for cardiovascular risk are not explained by the development of overt diabetes during follow-up (Qiao et al, 2003).

In summary, prediabetes is associated with an increased risk of all-cause mortality and CVD in the general population and in those with atherosclerotic CVD. This has significant implications for the screening and management of prediabetes in the primary and secondary prevention of CVD. Finally, given the high prevalence of prediabetes, interventions such as the NHS Diabetes Prevention Programme are pivotal to maintain the cardiometabolic health of the nation.

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John WG; UK Department of Health Advisory Committee on Diabetes (2012) Use of HbA1c in the diagnosis of diabetes mellitus in the UK. The implementation of World Health Organization guidance 2011. Diabet Med 29: 1350–7

Mainous AG, Tanner RJ, Baker R et al (2014) Prevalence of prediabetes in England from 2003 to 2011: population-based, cross-sectional study. BMJ Open 4: e005002

Qiao Q, Jousilahti P, Eriksson J, Tuomilehto J (2003) Predictive properties of impaired glucose tolerance for cardiovascular risk are not explained by the development of overt diabetes during follow-up. Diabetes Care 26: 2910–4

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