In this meta-analysis of 16 prospective cohort studies comprising more than 890,000 individuals, we found that the presence of prediabetes at baseline was significantly associated with increased risks of cancer in the general population, particularly for liver cancer and stomach or colorectal cancer. The risks were increased when a lower FPG value of 5.6–6.9 mmol/l was used, according to the current ADA definition of IFG, as well as in participants with IGT. The results were consistent across cancer endpoints, age, study characteristics, follow-up duration and ethnicity.

The lower threshold ADA definition of IFG released in 2003 resulted in a twofold to fivefold increase in the prevalence of IFG in most populations [5]. The lower cut-off point has been controversial [29] and has not been adopted by other guidelines, which have retained the threshold of 6.1–6.9 mmol/l [3]. One of the most important arguments against using the lower threshold is that it greatly increases the prevalence of IFG, but without enough data to support the clinical prognostic implications [30]. In this study, there was sufficient power to show that prediabetes defined as IFG 5.6–6.9 mmol/l, IFG 6.1–6.9 mmol/l, IGT or combined IFG 6.1–6.9 mmol/l and/or IGT was associated with increased risks of cancer. The results were consistent across specific endpoints, ethnicities and durations of follow-up, and after adjustment for potential confounders. More importantly, the risks of cancer were very similar with different definitions of prediabetes. These findings support the lower threshold definition IFG proposed by the ADA, and highlight the clinical value of the early management of hyperglycaemia to prevent cancer.

Several mechanisms may be involved in the association between prediabetes and cancer risk. First, chronic hyperglycaemia and its related conditions, such as chronic oxidative stress and the accumulation of advanced glycation end-products, may act as carcinogenic factors [31]. It has been reported that diabetes is associated with an increased production of reactive oxygen species and greater oxidative damage to DNA [32, 33]. Recently, it has also been reported that the overall frequency of DNA damage and cytotoxicity correlates with the level of HbA 1c in people with prediabetes [34].

Second, insulin resistance is a core defect responsible for the development of diabetes, and is established in individuals with prediabetes [35]. The compensatory hyperinsulinaemia and increased level of bioavailable IGF 1 related to insulin resistance may promote the proliferation of cancer cells and may also relate to worsened cancer outcomes [13].

Third, genetic ‘interferences’ may also play an important role in the development of cancer in prediabetic individuals. A recent study has suggested that nuclear receptor coactivator 5 is a haploinsufficient tumour suppressor, and that a deficiency of nuclear receptor coactivator 5 increases susceptibility to both glucose intolerance and hepatocellular carcinoma, partially by increasing IL-6 expression [36]. In contrast, epidemiological studies have suggested that men with diabetes are less likely to develop prostate cancer than non-diabetic men [37], possibly because of a genetic mechanism linked to the HNF1β gene (also known as TCF2), which predisposes to diabetes but may protect men from prostate cancer [38]. It is interesting that in our study, prediabetes was most strongly associated with liver cancer, but not associated with prostate, kidney or bladder cancer. Although these results are unlikely to completely explain the epidemiological association between prediabetes and site-specific cancer, they provide a new insight into a possible direct causal link.

These findings have important clinical and public health implications. In the US population aged ≥18 years, the age-adjusted prevalence of prediabetes increased from 29.2% in 1999–2002 to 36.2% in 2007–2010 [39]. Considering the high prevalence of prediabetes, as well as the robust and significant association between prediabetes and cancer demonstrated in our study, successful intervention in this large population could have a major public health impact. The ADA suggest that lifestyle intervention is the mainstay of treatment for prediabetes in the general population, and metformin is recommended for delaying progression to overt diabetes if individuals present with other related risk factors, such as a BMI ≥35 kg/m2, dyslipidaemia, hypertension, a family history of diabetes or an HbA 1c >6% (42 mmol/mol) [40]. It should be noted that metformin is now considered as having some ‘protective’ anticancer properties. Notably, metformin mediates an approximately 30% reduction in the lifetime risk of cancer in diabetic patients [41]. However, whether this is true in prediabetic individuals is not yet known. Long-term, large-scale studies of high-risk individuals, especially those with IGT or a combination of IGT and IFG, are urgently needed to explore the effects of metformin interventions on the risk of cancer in people with prediabetes.

The main strengths of this meta-analysis are its very large sample size, with more than 890,000 participants. Furthermore, we only included prospective cohort studies that reported adjusted RRs. Prediabetes is associated with obesity and overweight [1], which are also acknowledged as risk factors for cancer. In the sensitivity analyses, we found that, in studies that adjusted for BMI, prediabetes remained associated with an increased risk of cancer.

This meta-analysis has some limitations. First, individuals with prediabetes are more likely to progress to diabetes than those with normoglycaemia, but most of the studies included did not adjust for subsequent blood glucose levels or interventions. Nevertheless, our study indicates that, on the basis of a snapshot blood glucose measurement, prediabetes is associated with an increased risk of cancer. Second, the ADA recently recommended an HbA 1c of 5.7–6.4% (39–46 mmol/mol) as another diagnostic marker for prediabetes [42]. We did not include this criterion in our study because few of the retrieved articles reported it. Future prospective cohort studies that include testing of HbA 1c may provide more information on the association between prediabetes and cancer. Third, the adjusted confounders in the studies included were inconsistent. The heterogeneity in adjustment is a potential source of bias in our study. The number of studies included in subgroup analyses and the site-specific cancer analyses was limited, and there was significant heterogeneity in some of the subgroups. Finally, although we found that, after controlling for BMI, the presence of prediabetes remained associated with an increased risk of cancer, residual confounding by body fat distribution (instead of overall fatness reflected by BMI) still, however, remains.

In conclusion, this meta-analysis revealed that prediabetes was associated with an increased risk of cancer. The risk increased in people with an FPG as low as 5.6 mmol/l. These results reaffirm the importance of screening for prediabetes using the ADA criteria, with a view to cancer prevention. This information is important to health professionals and those engaged in the prevention of cancer.