Articles
Intermediate hyperglycaemia to predict progression to type 2 diabetes (ELSA-Brasil): an occupational cohort study in Brazil

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Summary

Background

The burden of diabetes is increasing worldwide and diabetes can be prevented with intervention in people with impaired glucose tolerance (IGT). Intermediate hyperglycaemia defined without an oral glucose tolerance test as impaired fasting glucose (IFG) and high HbA1c are also used to characterise risk. We aimed to assess the prognostic properties of five definitions of intermediate hyperglycaemia (also known as prediabetes) on the basis of their ability to predict who will progress to diabetes.

Methods

The Brazilian Longitudinal Study of Adult Health (ELSA-Brasil) is an occupational cohort study of active or retired civil servants, aged 35–74 years, recruited from public universities and research institutes in six state capital cities in Brazil. We excluded participants who provided insufficient information to ascertain diabetes status, those without information on relevant covariates, and those with diabetes. We classified type 2 diabetes on the basis of self-report, medication use, measures of fasting plasma glucose (FPG), 2 h plasma glucose, and HbA1c. We used five laboratory definitions of intermediate hyperglycaemia: IGT (2 h plasma glucose ≥7·8 mmol/L [≥140 mg/dL]); IFG based on American Diabetes Association (ADA) criteria (FPG ≥5·5 mmol/L [≥100 mg/dL]); IFG based on WHO criteria (FPG ≥6·1 mmol/L [≥110 mg/dL]); HbA1c based on ADA criteria (HbA1c ≥39 mmol/mol [5·7%]); and HbA1c based on International Expert Committee criteria, IEC-HbA1c, (HbA1c ≥42 mmol/mol [6·0%]). We estimated risk of each definition using Cox regression and overall predictability (area under the receiver operating characteristic curve [AUC]) using logistic regression.

Findings

We recruited 15 105 participants from Aug 18, 2008, to Dec 20, 2010, and followed up for a mean of 3·7 (SD 0·63) years. Diabetes incidence rate was 2·0 per 100 person-years (95% CI 1·8–2·1). Among the 11 199 eligible participants, 6563 (59%) presented with some form of intermediate hyperglycaemia. ADA-IFG (4870/11 199 [43·5%), IEC-HbA1c (1005 [9·0%]), and ADA-HbA1c (2299 [20·5%]) poorly predicted diabetes (3·5–3·6 per 100 person-years). WHO-IFG (1140 [10·2%]) and IGT (2245 [20·0%]) predicted greater conversion (7·5 per 100 person-years and 5·8 per 100 person-years, respectively). All definitions presented either low sensitivity or specificity. Combinations of tests improved prognostic properties, with the combination of IGT or WHO-IFG showing the best, but still insufficient, predictability (sensitivity 67·7%, 95% CI 64·5–70·1; specificity 77·9%, 77·1–78·7). The AUC for the three underlying glycaemic tests was 65·0% (95% CI 63·0–66·9) for HbA1c, 74·6% (72·7–76·4) for FPG, and 77·1% (75·4–78·8) for 2 h plasma glucose, whereas the AUC for a score composed of clinical information was 71·6% (69·8–73·3). When this score was combined with results of an oral glucose tolerance test, the AUC reached 82·4% (80·9–83·9).

Interpretation

IFG based on WHO criteria and IGT predict diabetes progression better than do the other three definitions of intermediate hyperglycaemia, but their sensitivity is low. IFG based on ADA criteria has better sensitivity than the others, but classifies almost half of adults as having intermediate hyperglycaemia and poorly predicts diabetes. Combining glycaemic results with clinical information improves prognostic properties of those at risk.

Funding

The Brazilian Ministry of Health (Science and Technology Department), the Brazilian Ministry of Science, Technology and Innovation (Financiadora de Estudos e Projetos and Conselho Nacional de Desenvolvimento Científico e Tecnológico), and the Coordenação de Aperfeiçoamento de Pessoal de Nível Superior–Brasil (CAPES).

Introduction

The burden of chronic non-communicable diseases constitutes one of the major challenges to health and development in the 21st century. The prevalence of diabetes has risen over the past four decades, and is likely to continue to do so in most countries.1 In 2017, type 2 diabetes was the eighth leading cause of disability-adjusted life-years (DALYs) lost worldwide and high fasting plasma glucose (FPG) was the fifth leading risk factor in terms of the burden of disease caused. In Brazil, type 2 diabetes was the sixth leading cause of DALYs lost and high FPG the fifth leading risk factor.2

Research in context

Evidence before this study

We searched PubMed for systematic reviews and meta-analyses published between Nov 9, 2008, and Nov 8, 2018, using the terms “prediabetic state”, “intermediate hyperglycemia”, “diabetes incidence“, “disease progression”, “prognostic”, or “sensitivity and specificity”. The three principal systematic reviews that we found provide evidence that having intermediate hyperglycaemia, frequently called prediabetes, predicts progression to diabetes. However, the rate of progression varies remarkably across multiple definitions of intermediate hyperglycaemia and across studies. For impaired glucose tolerance and impaired fasting glucose, as defined by WHO, rates are higher than are those for other definitions, particularly for impaired fasting glucose as defined by the American Diabetes Association (ADA-IFG). Few studies have assessed recommended definitions using concomitant measures of all three glycaemic tests: fasting plasma glucose measurement, oral glucose tolerance test (OGTT), and HbA1c measurement. Furthermore, evidence so far on progression is primarily based on studies from high-income countries in North America, Europe, Asia, and the Middle East, and rarely from Latin America.

Added value of this study

This study, done in Brazil, a middle-income country in Latin America, assessed all five recommended definitions of intermediate hyperglycaemia in terms of their capacity to predict diabetes. On the basis of data from ELSA-Brasil, a contemporary cohort study of adults living in six capital cities, with measurements of fasting plasma glucose, OGTTs, and HbA1c measurements at baseline and follow-up, we found generally high rates of progression to diabetes for all definitions of intermediate hyperglycaemia, consistent with previous studies. However, the definitions' prognostic properties were questionable: all recommended definitions had either low sensitivity or low specificity in the prediction of diabetes. Combining definitions did not resolve this problem. The high percentage of classifying intermediate hyperglycaemia coupled with a low specificity in predicting progression to diabetes of the ADA-IFG definition brings into doubt its use as a diagnostic category per se. Simple clinical and sociodemographic information combined with glycaemic values in the form of a clinical score improved diagnostic properties, with scores including OGTT values reaching good predictability.

Implications of all the available evidence

The high prevalence of intermediate hyperglycaemia and its documented rate of progression to diabetes highlights the ongoing diabetes epidemic in Brazil, which shows no signs of abating. Our findings question recommended definitions of intermediate hyperglycaemia when used alone in screening high-risk individuals for diabetes prevention, owing to the definitions' poor diagnostic properties. Further, targeting high-risk individuals for diabetes prevention might benefit from the incorporation of risk scores using readily available clinical information. The high prevalence of intermediate hyperglycaemia, which is similar to that found in many high-income countries, challenges the ability to identify and treat all high-risk individuals in a population, highlighting the need to complement screen-and-treat strategies with population-based approaches to diabetes prevention.

Hyperglycaemia below the threshold for diabetes, which we refer to as intermediate hyperglycaemia, can predict increased risk for developing diabetes. Diabetes prevention or delay is effective when targeting patients with impaired glucose tolerance (IGT). However, the need for doing an oral glucose tolerance test (OGTT) to screen them has limited the application of such strategies in this population because drinking a sweet solution in a laboratory can be nauseating and staying there for more than 2 h can be inconvenient.3 Other definitions of intermediate hyperglycaemia that are not based on an OGTT have been proposed that are based on FPG or HbA1c. Systematic reviews including studies predominantly from high-income countries found higher progression rates for those with IGT and impaired fasting glucose (IFG), as defined by WHO, than for those with IFG defined by the American Diabetes Association (ADA) and with increased HbA1c, as defined by the International Expert Committee (IEC).4, 5, 6 Furthermore, intermediate hyperglycaemia definitions based on different tests (measures of glucose or HbA1c) and thresholds show a variety of phenotypes, with important implications for the characterisation of the disease's burden, natural history, prognosis, screening, and implementation and monitoring of interventions.7

Little is known regarding the characterisation of diabetes progression in low-income and middle-income countries, where the burden of diabetes is highest. Thus, we aimed to provide estimates of diabetes incidence in the Longitudinal Study of Adult Health (ELSA–Brasil), a large, contemporary cohort study of Brazilian adults, ascertaining diabetes with self-reported information, measures of FPG and HbA1c, and OGTTs. Specifically, we assessed prognostic properties of five definitions of intermediate hyperglycaemia on the basis of their ability to predict who will progress to type 2 diabetes.

Section snippets

Study design and participants

ELSA–Brasil is a prospective, occupational, cohort study to investigate diabetes, cardiovascular disease, and other chronic conditions over time. The cohort was recruited between Aug 18, 2008, and Dec 20, 2010, in six capital cities of different regions of Brazil. We enrolled 15 105 active or retired civil servants of public universities or research institutions, aged 35–74 years. A comprehensive set of questionnaires, clinical measurements, and laboratory tests were carried out at baseline

Results

At visit 1, we excluded 150 participants who provided insufficient information to ascertain diabetes status, 418 without information on relevant covariates (ie, age, sex, self-identified skin colour or race, educational level, weight, and height), and 2505 with diabetes. 12 032 participants were at risk to develop diabetes over follow-up (figure 1). Of these, 769 did not attend the scheduled visit 2, and 64 provided insufficient information to ascertain diabetes status or relevant covariates at

Discussion

Of 11 199 participants without diabetes at baseline in the ELSA-Brasil, a contemporary, occupational cohort of people aged 35–74 years, living in a middle-income country that has a huge burden of diabetes, 59% presented one form or another of the five currently recommended definitions of intermediate hyperglycaemia. Agreement between these definitions was poor. Risk of conversion to diabetes after an average of 3·7 years of follow-up varied importantly across definitions, the highest rates

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