Elsevier

The Lancet

Volume 379, Issue 9833, 16–22 June 2012, Pages 2279-2290
The Lancet

Series
Prediabetes: a high-risk state for diabetes development

https://doi.org/10.1016/S0140-6736(12)60283-9Get rights and content

Summary

Prediabetes (intermediate hyperglycaemia) is a high-risk state for diabetes that is defined by glycaemic variables that are higher than normal, but lower than diabetes thresholds. 5–10% of people per year with prediabetes will progress to diabetes, with the same proportion converting back to normoglycaemia. Prevalence of prediabetes is increasing worldwide and experts have projected that more than 470 million people will have prediabetes by 2030. Prediabetes is associated with the simultaneous presence of insulin resistance and β-cell dysfunction—abnormalities that start before glucose changes are detectable. Observational evidence shows associations between prediabetes and early forms of nephropathy, chronic kidney disease, small fibre neuropathy, diabetic retinopathy, and increased risk of macrovascular disease. Multifactorial risk scores using non-invasive measures and blood-based metabolic traits, in addition to glycaemic values, could optimise estimation of diabetes risk. For prediabetic individuals, lifestyle modification is the cornerstone of diabetes prevention, with evidence of a 40–70% relative-risk reduction. Accumulating data also show potential benefits from pharmacotherapy.

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

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

References (121)

  • Diagnosis and classification of diabetes mellitus

    Diabetes Care

    (2011)
  • International Expert Committee report on the role of the A1C assay in the diagnosis of diabetes

    Diabetes Care

    (2009)
  • CM Balion et al.

    Reproducibility of impaired glucose tolerance (IGT) and impaired fasting glucose (IFG) classification: a systematic review

    Clin Chem Lab Med

    (2007)
  • Age- and sex-specific prevalences of diabetes and impaired glucose regulation in 13 European cohorts

    Diabetes Care

    (2003)
  • B Buijsse et al.

    Risk assessment tools for identifying individuals at risk of developing type 2 diabetes

    Epidemiol Rev

    (2011)
  • SV Katikireddi et al.

    Is there a divergence in time trends in the prevalence of impaired glucose tolerance and diabetes? A systematic review in south Asian populations

    Int J Epidemiol

    (2011)
  • National Diabetes Fact Sheet: national estimates and general information on diabetes and prediabetes in the United States, 2011

    (2011)
  • CC Cowie et al.

    Full accounting of diabetes and pre-diabetes in the U.S. population in 1988–1994 and 2005–2006

    Diabetes Care

    (2009)
  • IDF Diabetes Atlas

    (2011)
  • NG Forouhi et al.

    Incidence of type 2 diabetes in England and its association with baseline impaired fasting glucose: the Ely study 1990–2000

    Diabet Med

    (2007)
  • DM Nathan et al.

    Impaired fasting glucose and impaired glucose tolerance: implications for care

    Diabetes Care

    (2007)
  • 10-year follow-up of diabetes incidence and weight loss in the Diabetes Prevention Program Outcomes Study

    Lancet

    (2009)
  • X Zhang et al.

    A1C level and future risk of diabetes: a systematic review

    Diabetes Care

    (2010)
  • C Kim et al.

    Gestational diabetes and the incidence of type 2 diabetes: a systematic review

    Diabetes Care

    (2002)
  • DS Feig et al.

    Risk of development of diabetes mellitus after diagnosis of gestational diabetes

    CMAJ

    (2008)
  • J Lauenborg et al.

    Increasing incidence of diabetes after gestational diabetes: a long-term follow-up in a Danish population

    Diabetes Care

    (2004)
  • Effect of rosiglitazone on the frequency of diabetes in patients with impaired glucose tolerance or impaired fasting glucose: a randomised controlled trial

    Lancet

    (2006)
  • WC Knowler et al.

    Reduction in the incidence of type 2 diabetes with lifestyle intervention or metformin

    N Engl J Med

    (2002)
  • A Ramachandran et al.

    The Indian Diabetes Prevention Programme shows that lifestyle modification and metformin prevent type 2 diabetes in Asian Indian subjects with impaired glucose tolerance (IDPP-1)

    Diabetologia

    (2006)
  • JS Torgerson et al.

    XENical in the prevention of diabetes in obese subjects (XENDOS) study: a randomized study of orlistat as an adjunct to lifestyle changes for the prevention of type 2 diabetes in obese patients

    Diabetes Care

    (2004)
  • J Tuomilehto et al.

    Prevention of type 2 diabetes mellitus by changes in lifestyle among subjects with impaired glucose tolerance

    N Engl J Med

    (2001)
  • RA DeFronzo et al.

    Pioglitazone for diabetes prevention in impaired glucose tolerance

    N Engl J Med

    (2011)
  • D Noble et al.

    Risk models and scores for type 2 diabetes: systematic review

    BMJ

    (2011)
  • A Tirosh et al.

    Normal fasting plasma glucose levels and type 2 diabetes in young men

    N Engl J Med

    (2005)
  • W Rathmann et al.

    Prediction models for incident type 2 diabetes mellitusin the older population: KORA S4/F4 cohort study

    Diabet Med

    (2010)
  • PW Wilson et al.

    Prediction of incident diabetes mellitus in middle-aged adults: the Framingham Offspring Study

    Arch Intern Med

    (2007)
  • M Carstensen et al.

    Accelerated increase in serum interleukin-1 receptor antagonist starts 6 years before diagnosis of type 2 diabetes: Whitehall II prospective cohort study

    Diabetes

    (2010)
  • N Sattar et al.

    Serial metabolic measurements and conversion to type 2 diabetes in the west of Scotland coronary prevention study: specific elevations in alanine aminotransferase and triglycerides suggest hepatic fat accumulation as a potential contributing factor

    Diabetes

    (2007)
  • MA Abdul-Ghani et al.

    Contributions of beta-cell dysfunction and insulin resistance to the pathogenesis of impaired glucose tolerance and impaired fasting glucose

    Diabetes Care

    (2006)
  • RA DeFronzo

    Banting Lecture. From the triumvirate to the ominous octet: a new paradigm for the treatment of type 2 diabetes mellitus

    Diabetes

    (2009)
  • E Ferrannini et al.

    Mode of onset of type 2 diabetes from normal or impaired glucose tolerance

    Diabetes

    (2004)
  • CC Mason et al.

    Progression to type 2 diabetes characterized by moderate then rapid glucose increases

    Diabetes

    (2007)
  • A Gastaldelli et al.

    Beta-cell dysfunction and glucose intolerance: results from the San Antonio metabolism (SAM) study

    Diabetologia

    (2004)
  • GC Weir et al.

    Five stages of evolving beta-cell dysfunction during progression to diabetes

    Diabetes

    (2004)
  • KS Polonsky et al.

    Quantitative study of insulin secretion and clearance in normal and obese subjects

    J Clin Invest

    (1988)
  • RA DeFronzo et al.

    Preservation of beta-cell function: the key to diabetes prevention

    J Clin Endocrinol Metab

    (2011)
  • M Pendergrass et al.

    Muscle glucose transport and phosphorylation in type 2 diabetic, obese nondiabetic, and genetically predisposed individuals

    Am J Physiol Endocrinol Metab

    (2007)
  • SE Kahn

    The relative contributions of insulin resistance and beta-cell dysfunction to the pathophysiology of type 2 diabetes

    Diabetologia

    (2003)
  • E Ferrannini et al.

    Insulin resistance, insulin response, and obesity as indicators of metabolic risk

    J Clin Endocrinol Metab

    (2007)
  • AE Butler et al.

    Beta-cell deficit and increased beta-cell apoptosis in humans with type 2 diabetes

    Diabetes

    (2003)
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