We searched PubMed for work published up to and including January, 2012, with the terms “prediabetes”, “impaired glucose tolerance”, or “impaired fasting glucose”. For the epidemiology section, we also searched with the terms “incidence” or “prevalence”; for the complications section, “nephropathy”, “albuminuria”, “microalbuminuria”, “chronic kidney disease”, “neuropathy”, “autonomic”, “heart rate variability”, “orthostatic”, “idiopathic neuropathy”, “erectile dysfunction”, or “Valsalva”; for
SeriesPrediabetes: a high-risk state for diabetes development
Introduction
Prediabetes, typically defined as blood glucose concentrations higher than normal, but lower than diabetes thresholds, is a high-risk state for diabetes development. Diagnostic criteria for prediabetes have changed over time and vary depending on the institution of origin (table 1).
According to WHO, people are at high risk of developing diabetes if they have one of two distinct states: impaired fasting glucose (IFG), defined as a fasting plasma glucose (FPG) concentration of ≥6·1 and <7·0 mmol/L, without impaired glucose tolerance (IGT); and IGT, defined as an FPG concentration of <7·0 mmol/L and a 2 h postload plasma glucose concentration of ≥7·8 and <11·1 mmol/L, measured during a 75 g oral glucose tolerance test (OGTT).1 The American Diabetes Association (ADA) applies the same thresholds for IGT, but uses a lower cutoff value for IFG (FPG 5·6–6·9 mmol/L), and has introduced glycated haemoglobin A1c (HbA1c) 5·7–6·4% as a new category for high diabetes risk.2
The term prediabetes has been criticised because many people with prediabetes do not progress to diabetes, and it might imply that no intervention is necessary because no disease is present. Furthermore, diabetes risk does not necessarily differ between people with prediabetes and those with a combination of other diabetes risk factors. Indeed, WHO use the term intermediate hyperglycaemia and an International Expert Committee convened by the ADA prefers the “high-risk state of developing diabetes” to prediabetes.1, 3 For brevity, we use the term prediabetes in this Series paper to refer to IFG, IGT, and high-risk HbA1c concentrations.
Reproducibility of thresholds used to define prediabetes (around 50%) is lower than that for diabetes diagnostic criteria (>70%),4 and each of the alternative definitions (based on IFG, IGT, or HbA1c) produce overlapping groups with distinct and shared abnormalities. People with IFG can have different pathophysiological abnormalities from those with IGT—eg, in white people, overlap in abnormalities between those with IFG and those with IGT can be as low as 25%5—and those with both IFG and IGT tend to have more advanced disturbance of glycaemic homoeostasis.5
Individual risk factors for diabetes (eg, history of gestational diabetes or a first-degree relative with diabetes) or a combination of risk factors (eg, metabolic syndrome) can also be used to define populations at risk for diabetes, but their predictive value is poorer than that of a prediabetes classification. Additionally, risk scores for incident diabetes based on a combination of non-invasive or blood-based risk factors are under development to identify individuals at high risk of developing diabetes.6 In this Series paper we provide an updated review of the evidence of vascular complications and underlying pathophysiology of prediabetes, and discuss the clinical implications.
Section snippets
Epidemiology and temporal trends
Glycaemic concentrations are rapidly rising in people living in developed and developing countries.7 Pooled data from 2·7 million adults participating in health surveys and epidemiological studies suggest that age-standardised mean FPG was 5·5 mmol/L in men and 5·4 mmol/L in women in 2008, a rise of 0·1 mmol/L since 1980. People living in Oceania had the highest mean FPG of any region (6·1 mmol/L for men and women), but mean FPG was also high in those from some other regions (south and central
Progression from prediabetes to diabetes
Around 5–10% of people with prediabetes become diabetic every year, although the conversion rate varies with population characteristics and prediabetes definitions.12, 13 In a meta-analysis of prospective studies published between 1979 and 2004, annualised incidence rates of progression to diabetes in patients with isolated IGT (4–6%) or isolated IFG (6–9%) were lower than in those with both IFG and IGT (15–19%).14 In subsequent major studies, progression estimates have been similar—annualised
Reversion to normoglycaemia
Several trials have reported reductions in the risk of diabetes development in prediabetic individuals after lifestyle and drug-based interventions.15, 24, 25, 26, 27, 28 Prediabetes can convert back to normoglycaemia. In a population-based observational study of the natural history of diabetes in England, 55–80% of participants with IFG at baseline had normal FPG at 10 year follow-up.12 Other studies have reported lower conversion rates29—eg, 19% in controls in the DPP outcomes study.15
Risk prediction
As with prediabetic status, diabetes risk models provide methods for identification of individuals at risk of diabetes on the basis of indices available to family doctors. However, no diabetes prediction model has been universally accepted, and given that ethnic origin is strongly related to diabetes risk, recalibration of prediction algorithms might be necessary when models are applied to different populations.30 Table 2 presents a selection of diabetes risk models used in Australia, Europe,
Trajectories of glycaemic changes in prediabetes
In healthy people, blood glucose is strictly regulated. FPG is maintained at 3·9–5·6 mmol/L,37 and postmeal increases rarely exceed 3 mmol/L.38 During development of type 2 diabetes, homoeostasis of fasting and postload glucose becomes abnormal.39
As proven by studies with repeat measures of glucose concentrations, insulin sensitivity, and insulin secretion, development of diabetes from normal glucose tolerance is a continuous process.35, 36, 40, 41 We described trajectories of fasting and
Nephropathy and kidney disease in prediabetes
People with prediabetes can have concomitant damage to end organs such as eyes, kidneys, blood vessels, and heart, which is traditionally thought to be a complication of diabetes. Here, we briefly review evidence for complications that are particularly relevant to prediabetes: nephropathies and chronic kidney disease; neuropathies; diabetic retinopathy; and macrovascular diseases.
Prediabetes has been linked to increased risk of early forms of nephropathy and chronic kidney disease, defined by
Neuropathies in prediabetes
The strongest supportive evidence is for the association between prediabetes and autonomic neuropathy in particular, although the method used to measure autonomic neuropathy seems to be crucial. Prediabetes is associated with decreased heart-rate variability61 (a marker of parasympathetic function),62, 63, 64, 65 decreased postural changes in heart rate,62 increased prevalence of erectile dysfunction in men,66 and a worse profile in tests of sympathetic and parasympathetic function.67 No
Diabetic retinopathy
Prediabetes might be associated with an increased risk of diabetic retinopathy, although findings vary depending on how diabetic retinopathy is detected.51, 79, 80, 81, 82, 83 In a study of more than 5000 Pima Indians, retinopathy ascertained by direct ophthalmoscopy was associated with prediabetic status.51 Measures of retinal vascular changes, such as lower arteriole-to-venule ratio and increased retinal arteriole or venular calibre, have also been related to prediabetes or increased risk of
Macrovascular disease
Prediabetes is linked with increased risks of major manifestations of vascular disease, but whether raised disease risks depend on development of clinical diabetes is unclear.84, 85 Cross-sectional studies provide evidence in favour of vascular risk effects of mild or moderate hyperglycaemia because an excess prevalence of coronary disease is reported in people with fasting or postload hyperglycaemia lower than the diabetic threshold.86, 87 Compared with coronary disease, less certainty exists
Lifestyle intervention
Prediabetes should be treated to prevent progression to diabetes, mitigate some of the potential results of progression to diabetes, and prevent the potential effects of prediabetes itself. Most studies in this research specialty have focused on diabetes incidence in prediabetic individuals, and support the notion that lifestyle change should be the cornerstone for diabetes prevention.
The primary aim of lifestyle interventions is to prevent or delay development of type 2 diabetes and its
Clinical and public health implications
By defining people as prediabetic (also known as intermediate hyperglycaemia or high risk for diabetes), a heterogeneous patient population is identified, characterised by the simultaneous presence of insulin resistance and β-cell dysfunction. Multifactorial diabetes risk scores are promising approaches to further improve identification of individuals at high risk of diabetes development, although whether risk scores will help prevent diabetes more than the classic definition of prediabetes is
Search strategy and selection criteria
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