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Prediabetes linked to multiple health problems

24th March 2022

A review in a recent issue of Diabetologia suggests there is more to prediabetes than just an increased risk of developing type 2 diabetes. Impaired glucose metabolism in prediabetes is also associated with an increased risk of cardiovascular disease, cancer and dementia, meaning it should perhaps be taken more seriously. Dr Susan Aldridge reports.

Prediabetes is characterised by impaired glucose metabolism that doesn’t fulfil the diagnostic criteria for type 2 diabetes. Definitions vary. So, for instance, the American Diabetes Association (ADA) defines it as impaired fasting glucose (IFG; fasting plasma glucose between 5.6 and 6.9 mmol/l), impaired glucose tolerance (IGT; two-hour glucose 7.8 to 11.0 mmol/l during a 75 g oral glucose tolerance test [OGTT]), or HbA1cin the range 39 to 47 mmol/l.

According to the International Diabetes Federation (IDF) the prevalence of IGT in the adult population was estimated to be 7.5% in 2019 and is set to increase to 8.6% by 2045. And a recent study found a prevalence of prediabetes as high as 35.7% in China. Prediabetes, as the name suggests, has a high risk of progressing to type 2 diabetes. Metabolic abnormalities are already present which could, in themselves, increase the risk of multiple comorbidities and chronic complications that are traditionally seen as being related to diabetes. For instance, there is evidence that prediabetes is linked with a higher risk of cardiovascular outcomes and chronic kidney disease, and maybe also cognitive disorders and cancer. A recent UK study found that around half of people with type 2 diabetes already had either a macrovascular or microvascular complication by the time of their diagnosis.

However, prediabetes can be treated by lifestyle intervention, including weight loss, to delay or even prevent the onset of type 2 diabetes. Tackling prediabetes might also prevent other health complications in the longer term – but we need to know more about what these complications actually are and more about the clinical significance of prediabetes beyond increased type 2 diabetes risk. Which is why researchers at the German Diabetes Centre in Düsseldorf have carried out an umbrella review of all the available evidence on the association between prediabetes and the incidence of comorbidities and diabetes-related complications.

The review surveys the literature up to mid-2021, covering systematic reviews with meta-analyses from prospective studies, with prediabetes being defined according to the ADA, World Health Organisation and IDF criteria. The evidence was also graded from high to low. In all, 16 articles containing a total of 95 meta-analyses were studied, of which 13 focused on adults from general populations and four on specific patient groups, including those with pre-existing cardiovascular disease or who had percutaneous coronary intervention, and those with a history of stroke or transient ischaemic attack.

The health impact of prediabetes

The review found that prediabetes is associated with a higher risk of all-cause mortality and new cardiovascular events, coronary heart disease, stroke, heart failure and atrial fibrillation. There is also a higher risk of chronic kidney disease, all cancers, all liver cancer, hepatocellular carcinoma and breast cancer, and all-cause dementia. The risk was higher for those with previous cardiovascular problems. And the size of the effect depended upon how prediabetes was defined. It was higher for IGT-defined prediabetes and weaker for HbA1cdefined prediabetes compared with IFG-defined prediabetes.

Prediabetes defined by IFG or IGT, but not defined by HbA1cwas associated with an 8% to 25% risk of all-cause mortality. As a comparison, the risk for all-cause mortality is 60% to 100% higher in people with diabetes than in those without the condition, according to recent studies. The effect size in prediabetes was higher where this was defined by IGT than by IFT. This is an important clinical observation, pointing to the utility of the OGTT for identifying high-risk individuals.

Prediabetes defined by all three methods was linked with risk of cardiovascular mortality and multiple cardiovascular outcomes. The excess risk is around one-third of the cardiovascular risk associated with diabetes itself. 

For microvascular complications, there was one meta-analysis that showed that prediabetes is associated with a 10 to 25% higher risk of chronic kidney disease (CKD). In comparison, diabetes itself is associated with a three-fold higher risk of CKD. There was no relevant evidence, however, on diabetic retinopathy and related conditions. However, the researchers point out that evidence is now accumulating on a link between peripheral and cardiac autonomic neuropathy and prediabetes.

Depending on how it is defined, prediabetes is associated with an 11% to 25% increased total cancer incidence. For diabetes, total cancer incidence and mortality is 10 to 40% higher than it is among those without diabetes. The link between prediabetes and cancer was higher for all liver cancer and hepatocellular carcinoma than for other cancers.

When it came to mental health, prediabetes was linked to an 18 to 47% increased risk of all-cause dementia. In diabetes, this excess risk is estimated to be 60 to 130%, depending on the type of dementia and the age of the individual. However, the researchers did not find any link between prediabetes and cognitive impairment or depressive symptoms, although both are increased in diabetes itself. It is perhaps surprising to find that prediabetes is associated with dementia, but not with cognitive impairment. This might be because the meta-analyses were based on only a small number of studies and further research might clarify the association.

This was the first systematic overview of evidence on the association between prediabetes and so-called diabetes-related complications. It identifies some gaps in our knowledge, particularly where some of the evidence was of low quality. Some of the participants may have gone on to develop type 2 diabetes, which may have accounted, at least in part, for any subsequent health problems.

This review reveals a wide range of health issues associated with prediabetes, including cardiovascular problems, cancer and dementia. The risks were lower than those experienced by those who actually have type 2 diabetes, but higher than those with neither prediabetes nor type 2 diabetes. This suggests a dose-response relationship between impaired glucose tolerance and these health problems.

The researchers conclude that given the high global prevalence of prediabetes and this evidence on its association with multiple comorbidities, research in this area should be intensified. More attention should also be given to meeting the challenge of prediabetes by lifestyle intervention – so people can avoid not just type 2 diabetes, but many other health problems in the future.

Read this paper at:

Schlesinger S, Neuenschwander M, Babaresko J. Land A, Maalmi H, Rathmann W, Roden M, Herder C. Prediabetes and risk of mortality, diabetes-related complications and comorbidities: umbrella review of meta-analyses of prospective studies. Diabetologia (2022) 65:275–285.

Any opinions expressed in this article are the responsibility of the EASD e-Learning Programme Director, Dr Eleanor D Kennedy.

For more on the topics covered in this article, enrol on the following EASD e-Learning courses:

Watch out for our module about multimorbidity, Diabetes in an ageing society, written and presented by Professor Cees Tack, which launches in September 2022.