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High rate of abnormal glucose tolerance in Brazilian individuals undergoing coronary angiography

Abstract

Introduction

Undiagnosed hyperglycemia is common in high cardiovascular risk individuals, especially in those with coronary artery disease (CAD). There is no consensus about the optimal method for the screening of hyperglycemia in this population.

Subjects and methods

Five hundred and fourteen Brazilian individuals undergoing coronary angiography, without previously known diabetes mellitus (DM), had their glycemic status evaluated by both fasting plasma glucose (FPG) and HbA1c, being classified in normal (N), prediabetes (PD), and DM according to American Diabetes Association criteria. Concordance between both methods was assessed by Cohen’s κ. Accuracy of FPG and HbA1c to diagnose CAD was evaluated as proof-of-concept.

Results

Among individuals screened by FPG, 41.2% had PD and 6% had DM. Among those screened by HbA1c, 52.7% had PD and 12.7% had DM. Concordance for a positive screening of PD occurred in 125 individuals (κ = 0.084). Eighteen individuals had a concordant positive screening of DM (κ = 0.310). As a predictor of CAD, accuracy of FPG was 0.554 (p = 0.009) and of HbA1c 0.557 (p = 0.006).

Conclusion

a high frequency of hyperglycemia, between 47 and 65%, was found in individuals submitted to coronary angiography without previously known glucose disturbances, using FPG and HbA1c as screening methods respectively.HbA1c detected significantly more individuals with both PD and DM than FPG. Concordance between both methods is low. The question of which is the gold-standard method to diagnose hyperglycemia in this population is still open.

Cardiovascular disease; hyperglycemia; coronary angiography


INTRODUCTION

Coronary artery disease (CAD) is frequently associated with glucose disturbances. Undiagnosed hyperglycemia is common in acute coronary syndromes (ACS) (1Ye Y, Xie H, Zhao X, Zhang S. The oral glucose tolerance test for the diagnosis of diabetes mellitus in patients during acute coronary syndrome hospitalization: a meta-analysis of diagnostic test accuracy. Cardiovasc Diabetol. 2012;27;11:155.). Hemoglobin A1c (HbA1c) is a suitable option to screen for previous diabetes mellitus (DM) in this population since it bears some advantages such as showing less biological variability and not requiring fasting samples (2American Diabetes Association: Standards of medical care in diabetes – 2013. Diabetes Care. 2013;36(Suppl 1):S11-66.,3Vergès B, Avignon A, Bonnet F, Catargi B, Cattan S, Cosson E, et al.; Diabetes and Cardiovascular Disease study group of the Société Francophone du Diabète (SFD), in collaboration with the Société Française de Cardiologie (SFC). Consensus statement on the care of the hyperglycaemic/diabetic patient during and in the immediate follow-up of acute coronary syndrome. Diabetes Metab. 2012;38(2):113-27.). Although DM can remain asymptomatic for many years prior to diagnosis, acute hyperglycemia can ensue in clinical conditions such as ACS (4Kollias A, Diamanti-Kandarakis E. Oral glucose tolerance test in patients with undiagnosed diabetes and coronary artery disease: when should it be performed? Diabetologia. 2012;55(4):1221-2.). This can lead to potential differences in the occurrence of glucose disturbances when individuals are studied electively or during these episodes, raising the question of a gold-standard method for diagnosing hyperglycemia. Some but not all studies have used the oral glucose tolerance test (OGTT) as such method, as comparator for either fasting plasma glucose (FPG) or HbA1c (5Doerr R, Hoffmann U, Otter W, Heinemann L, Hunger-Battefeld W, Kulzer B, et al. Oral glucose tolerance test and HbA1c for diagnosis of diabetes in patients undergoing coronary angiography: [corrected] the Silent Diabetes Study. Diabetologia. 2011;54(11):2923-30.,6Sattar N, Preiss D. HbA1c in type 2 diabetes diagnostic criteria: addressing the right questions to move the field forwards. Diabetologia. 2012;55(6):1564-7.).

In this study we aim to assess the frequency of DM and prediabetes (PD) in patients electively undergoing coronary angiography, using both FPG and HbA1c as classification criteria.

SUBJECTS AND METHODS

A total of 823 patients who electively underwent coronary angiography at the Federal University of São Paulo (Unifesp) were enrolled in the present study, according to previously described criteria (7Bittencourt C, Piveta VM, Oliveira CS, Crispim F, Meira D, Saddi-Rosa P, et al. Association of classical risk factors and coronary artery disease in type 2 diabetic patients submitted to coronary angiography. Diabetol Metab Syndr. 2014;6(1):46.). The study was approved by the ethics committee of Unifesp. After the exclusion of 309 individuals with previously known DM (38% of our sample), 514 patients had their glycemic status assessed by FPG and HbA1c (HPLC). They were classified by both criteria according to American Diabetes Association guidelines in normal, PD, and DM (2American Diabetes Association: Standards of medical care in diabetes – 2013. Diabetes Care. 2013;36(Suppl 1):S11-66.). Individuals with impaired fasting glucose (IFG) were classified as PD for the sake of simplicity, since a unified nomenclature could be used for both diagnostic tools. CAD was defined as any stenosis > 50% in at least one major coronary vessel or branch. Cohen’s kappa (κ) was use to assess concordance between FPG and HbA1c. The accuracy of both to predict CAD was assessed as area under ROC curve (ROC-AUC) and 95% confidence intervals (CI).

RESULTS

A high prevalence of PD was seen in this sample using both FPG (41%) and HbA1c (53%). DM was found in 6% and 13% using FPG and HbA1c, respectively (Figure 1). Diagnosis of PD was concordant in 125 individuals using both FPG and HbA1c. Agreement was very poor, with κ = 0.084, despite being statistically significant. Only 18 individuals had concordant DM diagnoses by both methods, but agreement was moderate with κ = 0.310 (Table 1). Accuracy of FPG in predicting CAD was 0.554 (0.514-0.593), p = 0.009. For HbA1c, ROC-AUC was 0.557 (0.517-0.597), p = 0.006. Due to the poor accuracy values, no cut-point evaluation was attempted.

Figure 1
Relative frequencies of normal glucose tolerance, PD, and DM according to the diagnostic method employed (values in parentheses are absolute numbers of individuals in each category).

Table 1
Concordance of PD and DM diagnosis made by both fasting plasma FPG and HbA1c

DISCUSSION

In this study a high frequency of glucose disturbances was seen in Brazilian individuals electively undergoing coronary angiography. We have compared FPG and HbA1c as methods to stratify glycemic status. HbA1c detected more individuals with both PD and DM than FPG. Accuracy of both methods to predict CAD, evaluated as a proof of concept, was very low.

In the Euro Heart Survey, the majority of 2,107 patients with ACS had altered glucose tolerance (AGT), more diagnosed with OGTT (~60%) than FPG (~20%) (8Bartnik M, Rydén L, Ferrari R, Malmberg K, Pyörälä K, Simoons M, et al.; Euro Heart Survey Investigators. The prevalence of abnormal glucose regulation in patients with coronary artery disease across Europe. The Euro Heart Survey on diabetes and the heart. Eur Heart J. 2004;25(21):1880-90.). Similar prevalence of AGT (65%) was seen in a Chinese study of both elective patients and those with ACS. Approximately 85% of the cases would be undiagnosed without the OGTT. Interestingly, values were roughly compatible with the current classification (9Hu DY, Pan CY, Yu JM; China Heart Survey Group. The relationship between coronary artery disease and abnormal glucose regulation in China: the China Heart Survey. Eur Heart J. 2006;27(21):2573-9.), although there was no analysis of HbA1c as a diagnostic criteria in either case. In another study, among 401 individuals studied with CT angiography, 26% with newly diagnosed DM were found. Individuals with significant stenosis had higher FPG, post load glucose, and HbA1c than individuals without or with non-significant stenosis (1010 Xu Y, Bi Y, Li M, Wang T, Sun K, Xu M, et al. Significant coronary stenosis in asymptomatic Chinese with different glycemic status. Diabetes Care. 2013;36(6):1687-94.). Doerr and cols. analyzed the accuracy of HbA1c above 6.5% to diagnose DM in 1015 individuals undergoing coronary angiography, finding low sensitivity (~18%), but good specificity (~97%). In this study, according to HbA1c levels, 38% had PD and 4% DM. A potential source of bias in this study was the adoption of the OGTT as the gold-standard for the diagnosis of DM. Besides, OGTTs were performed after the coronary angiography, therefore stress induced by the procedure could raise the frequency of false positive results in the OGTT, influencing the accuracy of HbA1c by disagreeing with it (5Doerr R, Hoffmann U, Otter W, Heinemann L, Hunger-Battefeld W, Kulzer B, et al. Oral glucose tolerance test and HbA1c for diagnosis of diabetes in patients undergoing coronary angiography: [corrected] the Silent Diabetes Study. Diabetologia. 2011;54(11):2923-30.). The influence of timing of OGTT has been hypothesized to compromise reproducibility of the results (4Kollias A, Diamanti-Kandarakis E. Oral glucose tolerance test in patients with undiagnosed diabetes and coronary artery disease: when should it be performed? Diabetologia. 2012;55(4):1221-2.). In an Italian study of 780 individuals without previous DM, 53.9% had PD, with FPG, 2-h post challenge glucose, and HbA1c diagnosing respectively 28.1%, 31.7%, and 31.5% of individuals. There was poor agreement between FPG and HbA1c (κ = 0.332), and between 2-h post challenge glucose and HbA1c (κ = 0.299) (1111 Marini MA, Succurro E, Castaldo E, Cufone S, Arturi F, Sciacqua A, et al. Cardiometabolic risk profiles and carotid atherosclerosis in individuals with prediabetes identified by fasting glucose, postchallenge glucose, and hemoglobin A1c criteria. Diabetes Care. 2012;35(5):1144-9.). Kowalska and cols. assessed 363 men without previous DM referred to coronary angiography (no ACS), finding 36% with PD and 16% with DM, then concluding that most unrecognized glucose disturbances can be explained by FPG alone (1212 Kowalska I, Prokop J, Bachórzewska-Gajewska H, Telejko B, Kinalskal I, et al. Disturbances of glucose metabolism in men referred for coronary arteriography. Postload glycemia as predictor for coronary atherosclerosis. Diabetes Care. 2001;24(5):897-901.). In 400 Chinese adults admitted for coronary angiography, accuracy of HbA1c was similar to FPG in individuals without CAD, but lower in CAD patients in the identification of DM (~21%) utilizing OGTT as the gold-standard (1313 Wang JS, Lee IT, Lee WJ, Lin SY, Fu CP, Ting CT, et al. Performance of HbA1c and fasting plasma glucose in screening for diabetes in patients undergoing coronary angiography. Diabetes Care. 2013;36(5):1138-40.). The differences observed among various studies could be attributable not only to the different diagnostic tests employed, but also to ethnic and demographic differences among studied populations.

This brings us to the debate whether HbA1c and FPG identify the same individuals is a relevant question. Any methods that evaluate blood glucose are in fact simplified ways to understand much more complex phenomena in the pathophysiology of DM, therefore a gold-standard for diagnosis DM and related disturbances may be regarded as virtually non-existent (6Sattar N, Preiss D. HbA1c in type 2 diabetes diagnostic criteria: addressing the right questions to move the field forwards. Diabetologia. 2012;55(6):1564-7.). Besides, limitations of HbA1c in the diagnosis of PD could further increase the complexity of this debate. While the ADA recommends the utilization of this method for the diagnosis of PD, other recommendations such as those from the World Health Organization state that there is insufficient evidence to interpret HbA1c values below 6.5% with diagnostic purpose (1414 World Health Organization. Use of glycated haemoglobin in the diagnosis of diabetes mellitus: abbreviated report of a WHO consultation. Geneva: World Health Organization; 2011.).

Another possible approach would be utilizing glucose measurements to estimate the risk of endpoints. We have assessed the accuracy of FPG and HbA1c to predict CAD. Since there are already well-established diagnostic tools for CAD, this was evaluated as a proof-of-concept. Accuracy was low for both methods, leaving the question of which gold-standard test should be used as a comparator to be further investigated.

Some limitations of our study must be addressed. Firstly, glycemic status was not confirmed by a second laboratory measurements with either method. Therefore, patients cannot be regarded as having a diagnosis of PD or DM, but only a positive screening for those conditions. Secondly, PD is represented only by individuals with IFG. Impaired glucose tolerance (IGT) has not a strong agreement with IFG, since they represent different pathophysiological aspects of incipient glucose disturbance and may be associated with different cardiovascular risk profiles (1515 Piveta VM, Bittencourt CS, Oliveira CS, Saddi-Rosa P, Meira DM, Giuffrida FM, et al. Individuals with prediabetes identified by HbA1c undergoing coronary angiography have worse cardiometabolic profile than those identified by fasting glucose. Diabetol Metab Syndr. 2014;6:138.,1616 Oliveira CS, Vieira JG, Ghiringhello MT, Hauache OM, Oliveira CH, Khawali C, et al. Diagnosis of hyperglycemia in a cohort of Brazilian subjects: fasting plasma glucose- and oral glucose tolerance test-based glycemic status are associated with different profiles of insulin sensitivity and insulin secretion. Diabetes Care. 2007;30(8):2135-7.). The absence of OGTTs in our investigation could lower the agreement ratio between blood glucose and HbA1c. Nevertheless, we think this group is adequate to represent a group of intermediate cardiovascular risk in between normal and DM.

In conclusion, PD and DM are highly prevalent in individuals without previously known glucose disturbances undergoing elective coronary angiography, being found in 47 to 65% of individuals, using FPG and HbA1c as screening methods respectively. Concordance between both methods is low, but the question of which is the best tool for identifying individuals at risk of both DM and CAD is still open.

Individual contributions: Valdecira M. Piveta researched data and wrote the manuscript; Fernando M. A. Giuffrida wrote the manuscript, performed statistical analyses, and supervised the project; Celia S. Bittencourt, Carolina S. V. Oliveira, Pedro Saddi-Rosa, and Deyse M. Meira researched data and wrote the manuscript; André F. Reis wrote the manuscript, researched data, supervised the project, and is the guarantor of the study. All authors have read and approved the final version.

REFERENCES

  • 1
    Ye Y, Xie H, Zhao X, Zhang S. The oral glucose tolerance test for the diagnosis of diabetes mellitus in patients during acute coronary syndrome hospitalization: a meta-analysis of diagnostic test accuracy. Cardiovasc Diabetol. 2012;27;11:155.
  • 2
    American Diabetes Association: Standards of medical care in diabetes – 2013. Diabetes Care. 2013;36(Suppl 1):S11-66.
  • 3
    Vergès B, Avignon A, Bonnet F, Catargi B, Cattan S, Cosson E, et al.; Diabetes and Cardiovascular Disease study group of the Société Francophone du Diabète (SFD), in collaboration with the Société Française de Cardiologie (SFC). Consensus statement on the care of the hyperglycaemic/diabetic patient during and in the immediate follow-up of acute coronary syndrome. Diabetes Metab. 2012;38(2):113-27.
  • 4
    Kollias A, Diamanti-Kandarakis E. Oral glucose tolerance test in patients with undiagnosed diabetes and coronary artery disease: when should it be performed? Diabetologia. 2012;55(4):1221-2.
  • 5
    Doerr R, Hoffmann U, Otter W, Heinemann L, Hunger-Battefeld W, Kulzer B, et al. Oral glucose tolerance test and HbA1c for diagnosis of diabetes in patients undergoing coronary angiography: [corrected] the Silent Diabetes Study. Diabetologia. 2011;54(11):2923-30.
  • 6
    Sattar N, Preiss D. HbA1c in type 2 diabetes diagnostic criteria: addressing the right questions to move the field forwards. Diabetologia. 2012;55(6):1564-7.
  • 7
    Bittencourt C, Piveta VM, Oliveira CS, Crispim F, Meira D, Saddi-Rosa P, et al. Association of classical risk factors and coronary artery disease in type 2 diabetic patients submitted to coronary angiography. Diabetol Metab Syndr. 2014;6(1):46.
  • 8
    Bartnik M, Rydén L, Ferrari R, Malmberg K, Pyörälä K, Simoons M, et al.; Euro Heart Survey Investigators. The prevalence of abnormal glucose regulation in patients with coronary artery disease across Europe. The Euro Heart Survey on diabetes and the heart. Eur Heart J. 2004;25(21):1880-90.
  • 9
    Hu DY, Pan CY, Yu JM; China Heart Survey Group. The relationship between coronary artery disease and abnormal glucose regulation in China: the China Heart Survey. Eur Heart J. 2006;27(21):2573-9.
  • 10
    Xu Y, Bi Y, Li M, Wang T, Sun K, Xu M, et al. Significant coronary stenosis in asymptomatic Chinese with different glycemic status. Diabetes Care. 2013;36(6):1687-94.
  • 11
    Marini MA, Succurro E, Castaldo E, Cufone S, Arturi F, Sciacqua A, et al. Cardiometabolic risk profiles and carotid atherosclerosis in individuals with prediabetes identified by fasting glucose, postchallenge glucose, and hemoglobin A1c criteria. Diabetes Care. 2012;35(5):1144-9.
  • 12
    Kowalska I, Prokop J, Bachórzewska-Gajewska H, Telejko B, Kinalskal I, et al. Disturbances of glucose metabolism in men referred for coronary arteriography. Postload glycemia as predictor for coronary atherosclerosis. Diabetes Care. 2001;24(5):897-901.
  • 13
    Wang JS, Lee IT, Lee WJ, Lin SY, Fu CP, Ting CT, et al. Performance of HbA1c and fasting plasma glucose in screening for diabetes in patients undergoing coronary angiography. Diabetes Care. 2013;36(5):1138-40.
  • 14
    World Health Organization. Use of glycated haemoglobin in the diagnosis of diabetes mellitus: abbreviated report of a WHO consultation. Geneva: World Health Organization; 2011.
  • 15
    Piveta VM, Bittencourt CS, Oliveira CS, Saddi-Rosa P, Meira DM, Giuffrida FM, et al. Individuals with prediabetes identified by HbA1c undergoing coronary angiography have worse cardiometabolic profile than those identified by fasting glucose. Diabetol Metab Syndr. 2014;6:138.
  • 16
    Oliveira CS, Vieira JG, Ghiringhello MT, Hauache OM, Oliveira CH, Khawali C, et al. Diagnosis of hyperglycemia in a cohort of Brazilian subjects: fasting plasma glucose- and oral glucose tolerance test-based glycemic status are associated with different profiles of insulin sensitivity and insulin secretion. Diabetes Care. 2007;30(8):2135-7.

Publication Dates

  • Publication in this collection
    Aug 2015

History

  • Received
    2 Mar 2015
  • Accepted
    21 Mar 2015
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