Comparison of oral glucose tolerance test and HbA1c in detection of disorders of glucose metabolism in patients with acute stroke

Comparison of oral glucose tolerance test and HbA1c in detection of disorders of glucose metabolism in patients with acute stroke | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Original investigation Comparison of oral glucose tolerance test and HbA1c in detection of disorders of glucose metabolism in patients with acute stroke Karl Matz, Jaakko Tuomilehto, Yvonne Teuschl, Alexandra Dachenhausen, and 1 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-50549/v3 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 05 Dec, 2020 Read the published version in Cardiovascular Diabetology → Version 3 posted 4 You are reading this latest preprint version Show more versions Abstract Background: Diabetes is an increasingly important risk factor for ischemic stroke and worsens stroke prognosis. Yet a large proportion of stroke patients who are eventually diabetic are undiagnosed. Therefore, it is important to have sensitive assessment of unrecognized hyperglycaemia in stroke patients. Design: Secondary outcome analysis of a randomized controlled trial focussing on parameters of glucose metabolism and detection of diabetes and prediabetes in patients with acute ischemic stroke (AIS). Methods: A total of 130 consecutively admitted patients with AIS without previously known type 2 diabetes mellitus (T2DM) were screened for diabetes or prediabetes as part of secondary outcome analysis of a randomized controlled trial that tested lifestyle intervention to prevent post-stroke cognitive decline. Patients had the oral glucose tolerance test (OGTT) and glycated hemoglobin (HbA1c) measurements in the second week after stroke onset and after one year. The detection rates of diabetes and prediabetes based on the OGTT or HbA1c values were compared. Results : By any of the applied tests at the second week after stroke onset 62 of 130 patients (48%) had prediabetes or T2DM. Seventy-five patients had results from both tests available, the OGTT and HbA1c; according to the OGTT 40 (53.3%) patients had normal glucose metabolism, 33 (44%) had prediabetes, two (2.7%) T2DM. In 50 (66.7%) patients the HbA1c results were normal, 24 (32%) in the prediabetic and one (1.3%) in the diabetic range. The detection rate for disorders of glucose metabolism was 10% higher (absolute difference; relative difference 29%) with the OGTT compared with HbA1c. After one year the detection rate for prediabetes or T2DM was 7% higher with the OGTT (26% relative difference). The study intervention led to a more favourable evolution of glycemic status after one year. Conclusion: The OGTT is a more sensitive screening tool than HbA1c for the detection of previously unrecognized glycemic disorders in patients with acute stroke with an at least a 25% relative difference in detection rate. Therefore, an OGTT should be performed in all patients with stroke with no history of diabetes. Cardiac & Cardiovascular Systems risk assessment fasting glucose HbA1c oral glucose tolerance test acute stroke type 2 diabetes glucose abnormalities Figures Figure 1 Figure 2 Background Glucose abnormalities, either diabetes type 2 (T2DM) or impaired glucose tolerance (IGT) are common in patients with stroke and impair their prognosis 1, 2, 3, 4, 5 . T2DM and IGT should therefore be included in the risk assessment of stroke patients. We have earlier shown that a high proportion of stroke patients with T2DM and all cases of IGT are undetected prior to the stroke event and would still remain undiscovered if fasting plasma glucose (FPG) alone is determined in the clinical evaluation of stroke patients) 6 . It is a longstanding paradox that the OGTT is used for diabetes diagnosis whereas HbA1c serves as monitoring parameter for antidiabetic treatment. As the recommended 2-hour oral glucose tolerance test (OGTT) may be a time-consuming procedure, an International Expert Committee and the American Diabetes Association (ADA) have recommend the use of HbA1c as a diagnostic test 7 with > 6.5% (48 mmol/mol) as the diagnostic cut-point for T2DM. Also, the World Health Organisation (WHO) Consultation Group has agreed on the use of this HbA1c cut point but stressed that the OGTT should remain as the primary method to diagnose T2DM 8 . With the HbA1c in the guidelines, the OGTT is used less in the routine clinical practice although it is the only way to detect IGT as a postprandial dysregulation of blood glucose. The aim of the present study was to find out how well HbA1c results will compare with the determination of FPG and 2-hour plasma glucose (2hPG) using an OGTT in screening for T2DM and prediabetes in patients with acute non-disabling ischemic stroke during the early post-acute period and after the one-year follow-up. Methods In this study we performed a retrospective analysis of the data regarding glucose metabolism that were collected as part of the protocol in the Austrian Polyintervention Study to Prevent Cognitive Decline after Ischemic Stroke (ASPIS) trial. The study details of ASPIS have been described earlier 9 . In short, the ASPIS trial tested whether a 24-month intensified multidomain intervention, which targeted modifiable risk factors, can prevent post-stroke cognitive decline compared with a control group receiving standard care. A total of 199 patients with acute ischemic stroke during the last three months, aged 40 to 80 years, with a W of 0-2 on admission, and sufficient communication ability were enrolled from five stroke clinics in Austria between 2010 and 2012. Patients were tested for diabetes or prediabetes with HbA1c or an OGTT at baseline in the first or second week after the stroke and at one-year follow-up. Blood samples for FPG and 2hPG were taken in sodium fluoride tubes and analysed immediately with the hexokinase method in a Hitachi Laboratory systems machine. The World Health Organisation (WHO) 1999 criteria for diabetes 10 (either FPG > 7.0 mmol/l or 2hPG ≥ 11.1 mmol/l), impaired fasting glucose (IFG) (FPG 6.1-6.9 mmol/l and 2hPG < 7.8 mmol/l) and IGT (2hPG 7.8-11.0 mmol/l) were used. Those whose FPG and 2hPG were below these levels were considered to have normal plasma glucose. HbA1c was determined from whole blood samples by turbidimetric inhibition immunoassay. HbA1c 48 mmol/mol (6.5%) was considered as the cut-point for diabetes, and a range between 5.7 and 6.4% as prediabetic. Patients with known T2DM did not undergo OGTT and were excluded from this analysis. We further assessed if glucose metabolism improved, stayed stable or worsened between baseline and follow-up. Worsening was defined as progression from normal glucose metabolism to prediabetes or T2DM or from prediabetes toT2DM, improvement as change from T2DM to prediabetes or to normal metabolism or from prediabetes to normal. Statistical analyses Observed agreement between the diagnostic methods were calculated as percentage ratio between overlapping diagnosis and overall numbers of cases with disease. Concordance of methods was calculated as Cohens’ kappa coefficient. Group comparisons between the improving or stable and worsening group were calculated with Chi-square test for categorical variables and with Kruskal-Wallis’ test for numeric variables. The level of significance was set two sided at a=0.05. Statistical analyses were carried out with IBM SPSS Statistics 26.0. Results Of the 199 patients included in the ASPIS trial, 61 (30.7%) had already T2DM according to patients’ history, eight patients without previous diagnosis had no results for HbA1c or the OGTT available to allow classification at baseline, leaving 130 patients for further analysis (see fig.1). The results of the baseline classification were as follows: five patients (3,8%) without a prior diabetes diagnosis were found to have diabetes either by HbA1c or the OGTT results, prediabetes was found in 57 (43.8%) patients, and 68 patients had normal test results (52.3%). Both the OGTT and HbA1c results were available in 75 patients. According to the OGTT 40 (53.3%) patients had normal glucose metabolism, 33 (44%) had prediabetes, two (2.7%) T2DM. According to the HbA1c results 50 (66.7%) were normal, 24 (32%) prediabetic and one T2DM (1.3%), see table 1. The observed agreement in diagnosis of T2DM was 50%, of prediabetes only 42.4%. Cohens’ Kappa coefficient for concordance of HbA1c and the OGTT was 0.205. The detection rate for disorders of glucose metabolism was 16.7% higher (absolute difference; relative difference 28.6%) with the OGTT than with HbA1c. After one year, 28 patients were either study dropouts or had no further tests for glucose metabolism available, leaving 102 subjects for the follow-up analysis: the results of either tests revealed 56 patients as normal (54.9%), 36 as prediabetes (35.3%) and 10 (9.8%) with T2DM (three according to OGTT, one according to HbA1c and six according to updated clinical information). 67 (66%) patients had both tests, OGTT and HBA1c, available for direct comparison: according to OGTT 45 (67.2%) patients had normal glucose metabolism, 19 (28.4%) had prediabetes, and three (4.5%) T2DM. According to HbA1c results 51(76.1%) were normal and 16(23.9%) prediabetic. The observed agreement in classification of normal glucose metabolism was 62.7%, of prediabetes only 20.7%, the detection rate for prediabetes or T2DM was 9.9% (absolute difference; 30% relative difference) higher with OGTT, (see table 1). Cohens’ Kappa coefficient dropped to 0.149. Next we looked how glycemic status changed over time in patients who had tests both at baseline and one-year follow-up: Out of 102 patients 67 (65.7%) remained stable, 16 (15.7%) improved and 19/102 (18.6%) progressed to prediabetes or T2DM. Baseline variables of these three groups are shown in a table in supplemental material. In addition, we compared these groups separately according to their allocation to intervention or control group in the randomized controlled trial: In the intervention group seven (13.7%) of 51 patients showed progression to prediabetes or T2DM, in the control group 12 (23.5%) of 51 patients (p=0.066). 12 patients (23.5%) in the intervention group improved their glucose metabolism compared to only four (7.8%) in the control group (see figure 2). Discussion Summary The main finding of this study was that in patients which subacute minor stroke the OGTT detects up to 25 to 29% more patients with prediabetes or T2DM than HbA1c regardless if performed early after the event or at one-year follow-up. The odds that prediabetes was detected by the OGTT was 2.6 higher compared to HbA1c measurement alone. As in several previous studies 9, 11, 12 disorders of glucose metabolism were highly prevalent (more than 60%) in patients with AIS. Overall, the concordance between the OGTT and HbA1c results was low, which has also been found by several other studies 13, 14 . During the one-year observation the classification of glucose disorders in stroke patients in the trial was not invariable, although about two thirds of the patients did not change their original category. A multifactorial lifestyle-oriented intervention resulted in a non-significant statistical trend for a higher percentage of patients who improved in their glucose metabolism in the intervention group than the control group receiving a standard care. With improvements in lifestyle 15 , or treatment with metformin 16 , acarbose 17 , pioglitazone 18 or liraglutide 19 the risk of the conversion from prediabetes to frank T2DM can be reduced. Detection of diabetes and prediabetes is also of importance for secondary prevention of ischemic stroke, for example pioglitazone 20 reduces the risk of stroke recurrence in stroke patients with prediabetes or T2DM. Diagnostic advantage of OGTT American Diabetes Association has recommended HbA1c as the tool for diagnosing T2DM and defined a cut-off level 48 mmol/mol to indicate diabetes 7 . Since long-term hyperglycaemia is necessary to raise HbA1c to this level (when other causes of HbA1c elevation are excluded), HbA1c above this cut point obviously has a high specificity. Due to this high specificity, also WHO has agreed that HbA1c 48 mmol/mol (6.5%) or above can be used to diagnose diabetes, but WHO still gives preference to the determination of glucose and use of the OGTT due to the superior sensitivity 8 . The sensitivity of HbA1c alone is low leaving many people with T2DM and all people with IGT undetected. However, screening for prediabetes is especially important in patients with already treated other vascular risk factors 21 . Therefore, the WHO report emphasizes that HbA1c value below 48 mmol/mol does not exclude diabetes diagnosed using glucose tests, and that there is insufficient evidence to make any formal recommendation on the interpretation of HbA1c levels below 48 mmol/mol. Our results in acute stroke patients provides a very strong support to this statement. Prognostic advantage of OGTT There is also evidence that the parameters of the OGTT correlate better with outcomes of vascular disease than HbA1c. A German study among 1015 patients admitted for coronary angiography found T2DM in 149 patients by an OGTT, but only 42 by HbA1c 22 and the severity of coronary heart disease (CHD) correlated with 2hPG in the OGTT. This is in keeping with the data from previous studies that have shown that 2hPG is the best predictor of the three glycaemic parameters for incident cardiovascular events 23 , total mortality 24 or intima-media thickness of carotid arteries 25 . Postprandial glycemic peaks seem also lead to maladaptive with vascular remodeling 26 . Several studies in the general population have confirmed that 2hPG is a predictor of cardiovascular outcome independent of FPG and HbA1c 27, 28, 29 . In the EUROSPIRE-IV survey 30 2h-PG in contrast to HbA1c was an independent predictor of subsequent new cardiovascular events in a large cohort of patients with CHD. Both HbA1c and 2h-PG were independent predictors of incident new T2DM during follow-up. Furthermore, in a Chinese study newly diagnosed T2DM was independently associated with one-year mortality, functional outcome and stroke recurrence 31 . In our previous observational study we also showed that undiagnosed T2DM may worsen the prognosis in stroke patients. 6 Strengths The strength of our study is that we ascertained consecutively patients admitted that were assessed and reassessed within the settings of a randomized controlled trial. Secondly, we performed a follow-up up investigation after 12 months and therefore our results do not rely only on measurements during the acute stroke period. Limitations Weak points of our study are the low number of patients investigated as this was a regionally conducted multi-centre trial and the considerable number of dropouts. Despites this weakness in quantity our results are robust over time from baseline to follow up and confirmatory with other studies. Furthermore, it can be stated that part of the hyperglycemic states that were classified as diabetes and prediabetes at baseline can be interpreted as acute hyperglycemic stress responses 32 especially in severe strokes and that the OGTT is more sensitive to these acute fluctuations of blood glucose levels. However, we still observed the difference between OGTT and HbA1c after one year when stress induced hyperglycemia was no longer existing, and the influence of stroke severity was probably low as mostly minor strokes were included into the trial. Recently a study 33 found that several parameters referring to the metabolic syndrome fairly predicted persistent IGT in patients with acute minor stroke. In addition, we found a trend for a lower rate of progression of disorders of glucose metabolism among those who underwent multimodal interventions for risk factor control compared with the control group. An improved detection of prediabetes and early T2DM using an OGTT could help to focus and tailor preventive interventions to improve or maintain cardiovascular and metabolic health. Conclusion In the clinical evaluation of patients with acute stroke the assessment of the glycemic status is important in order to assign adequate preventive management to correct metabolic abnormalities that may influence the prognosis. The OGTT is a more sensitive method than HbA1c to detect and monitor disorders of glucose metabolism in patients with an ischemic stroke. The OGTT should be carried out in all stroke patients who have not been found to be diabetic before the stroke event. Abbreviations ADA - American Diabetes Association, AIS - acute ischemic stroke, ASPIS - Austrian Polyintervention Study to Prevent Cognitive Decline after Ischemic Stroke, FPG - fasting plasma glucose, HbA1c - glycated hemoglobin, IFG - impaired fasting glucose, IGT - impaired glucose tolerance, NIHSS - National Institutes of Health Stroke Scale, mRS - modified Rankin Scale, OGTT - oral glucose tolerance test, T2DM -type 2 diabetes mellitus, 2hPG - 2-hour plasma glucose, WHO - World Health Organization. Declarations Ethics approval and consent to participate This study was conducted according to the Helsinki Declaration. All study participants gave written informed consent for the study. The trial was approved by the regional Ethics’ committee of Lower Austria. Consent for publication All authors declared their consent to publication of this work. Availability of data and materials: not applicable. Competing interests The authors declare to have no competing interest with the topic of this publication. Funding The Austrian Polyintervention Study to Prevent Cognitive Decline after Ischemic Stroke trial was supported by a Grant from the NÖ Forschungs- und Bildungsges.m.b.H (former Life Science Krems GmbH), Austria with the Grant Agreement Number LS09-002. Clinical Trial Registration—URL: http://clinicaltrials.gov. Unique identifier: NCT01109836. Authors’ contribution Karl Matz designed and conducted the study and wrote the manuscript; Jaakko Tuomilehto designed the study and wrote the manuscript. Yvonne Teuschl performed the statistical analysis and reviewed the manuscript; Paulina Kurzmann performed additional statistical analyses; Alexandra Dachenhausen reviewed the manuscript; Michael Brainin designed the study, consulted the preparation and conduction of the study and reviewed the manuscript. Acknowledgements We thank all colleagues, nurses and laboratory technicians involved in investigating patients, obtaining and analysing blood samples. References 1 Norhammar A, Tenerz A, Nilsson G, et al.: Glucose metabolism in patients with acute myocardial infarction and no previous diagnosis of diabetes mellitus: a prospective study. Lancet 2002; 359 (9324): 2140- 2144. 2 Bartnik M, Rydén L, Ferrari R, et al.: 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):1880-1890. 3 Hu DY, Pan CY, Yu JM: The relationship between coronary artery disease and abnormal glucose regulation in China: the China Heart Survey. Eur Heart J 2006; 27 (21): 2573-2579. 4 Tamita K, Katayama M, Takagi T, et al.: Impact of newly diagnosed abnormal glucose tolerance on long-term prognosis in patients with acute myocardial infarction. Circ J 2007; 71(6): 834-841. 5 Bartnik M, Malmberg K, Norhammar A, et al.: Newly detected abnormal glucose tolerance: an important predictor of long-term outcome after myocardial infarction. Eur Heart J 2004; 25: 1990-1997. 6 Matz K, Keresztes K, Tatschl C, et al.: Disorders of glucose metabolism in acute stroke patients: an underrecognized problem. Diabetes care 2006; 29(4): 792 - 797. 7 American Diabetes Association. Diagnosis and classification of diabetes mellitus. Diabetes Care 2010; 33 Suppl 1: S62-69. 8 WHO Consultation. Use of glycated haemoglobin (HbA1c) in the diagnosis of diabetes mellitus. Abbreviated Report of a WHO Consultation. World Health Organization. Geneva 2011 9 Matz K, Teuschl Y, Firlinger B, et al.: ASPIS Study Group. Multidomain lifestyle interventions for the prevention of cognitive cecline after ischemic stroke: a randomized trial. Stroke 2015; 46: 2874-2880. 10 World Health Organization: Definition, iagnosis and Classification of Diabetes Mellitus and its Complications: Report of a WHO Consultation. Part 1: Diagnosis and Classification of Diabetes Mellitus. Geneva, World Health Org., 1999. 11 Jia Q, Zheng H, Zhao X, et al.; Investigators for the Survey on Abnormal Glucose Regulation in Patients With Acute Stroke Across China (ACROSS-China). Abnormal glucose regulation in patients with acute stroke across China: prevalence and baseline patient characteristics. Stroke 2012; 43: 650-657. 12 Vancheri F, Curcio M, Burgio A, et al.: Impaired glucose metabolism in patients with acute stroke and no previous diagnosis of diabetes mellitus. QJM. 2005; 98(12): 871-878. 13 Wu S, Shi Y, Pan Y, Li J, et al.: Glycated hemoglobin independently or in combination with fasting plasma glucose versus oral glucose tolerance test to detect abnormal glycometabolism in acute ischemic stroke: a Chinese cross-sectional study. BMC Neurol 2014, 12; 14: 177. 14 Zhang X, Shi Q, Zheng H, et al.: Prevalence of abnormal glucose regulation according to different diagnostic driteria in ischaemic Ssroke without a history of diabetes. Biomed Res Int 2018, 8358724 15 Tuomilehto J, Lindström J, Eriksson JG, et al.; Finnish Diabetes Prevention Study Group. Prevention of type 2 diabetes mellitus by changes in lifestyle among subjects with impaired glucose tolerance. N Engl J Med 2001; 344(18): 1343-1350. 16 Knowler WC, Barrett-Connor E, Fowler SE, et al. ; Diabetes Prevention Program Research Group. Reduction in the incidence of type 2 diabetes with lifestyle intervention or metformin. N Engl J Med 2002; 346(6): 393-403. 17 Chiasson JL, Josse RG, Gomis R, et al. ; STOP-NIDDM Trial Research Group. Acarbose for prevention of type 2 diabetes mellitus: the STOP-NIDDM randomised trial. Lancet 2002; 359(9323): 2072-2077. 18 Kernan WN, Viscoli CM, Furie KL, et al. ; IRIS Trial Investigators. Pioglitazone after ischemic stroke or transient ischemic attack. N Engl J Med 2016; 374(14): 1321-1331. 19 le Roux CW, Astrup A, Fujioka K, et al. ; SCALE Obesity Prediabetes NN8022-1839 Study Group. 3 years of liraglutide versus placebo for type 2 diabetes risk reduction and weight management in individuals with prediabetes: a randomised, double-blind trial. Lancet 2017; 389(10077): 1399-1409. 20 Lee M, Saver JL, Liao HW, Lin CH,et al.:. Pioglitazone for Secondary Stroke Prevention: A Systematic Review and Meta-Analysis. Stroke 2017; 48: 388-393. 21 Shahim B, Gyberg V, De Bacquer D, et al.: Undetected dysglycaemia common in primary care patients treated for hypertension and/or dyslipidaemia: on the need for a screening strategy in clinical practice. A report from EUROASPIRE IV a registry from the EuroObservational Research Programme of the European Society of Cardiology. Cardiovasc Diabetol 2018; 24; 17: 21. 22 Dorr R, Stumpf J, Spitzer SG, et al.: [Prevalence of undetected diabetes mellitus in invasive and interventional cardiology. Silent diabetes in the catheterization laboratory]. Herz 2012; 37(3): 244-250. 23 Qiao Q, Pyorala K, Pyorala M, et al.: Two-hour glucose is a better risk predictor for incident coronary heart disease and cardiovascular mortality than fasting glucose. European heart journal 2002; 23 (16): 1267-1275. 24 DECODE Study Group, the European Diabetes Epidemiology Group. Glucose tolerance and cardiovascular mortality: comparison of fasting and 2-hour diagnostic criteria. Archives of internal medicine 2001; 161(3): 397-405. 25 Temelkova-Kurktschiev TS, Koehler C, et al.: Postchallenge plasma glucose and glycemic spikes are more strongly associated with atherosclerosis than fasting glucose or HbA1c level. Diabetes Care 2000; 23(12): 1830-1834. 26 Foreman YD, Brouwers MCGJ, et al.: The oral glucose tolerance test-derived incremental glucose peak is associated with greater arterial stiffness and maladaptive arterial remodeling: The Maastricht Study. Cardiovasc Diabetol 2019; 14;18 :152. 27 DECODE Study Group, European Diabetes Epidemiology Group.Is the current definition for diabetes relevant to mortality risk from all causes and cardiovascular and noncardiovascular diseases? Diabetes care 2003; 26(3): 688-696. 28 Qiao Q, Dekker JM, de Vegt F, et al.: Two prospective studies found that elevated 2-hr glucose predicted male mortality independent of fasting glucose and HbA1c. Journal of clinical epidemiology 2004; 57(6): 590-596. 29 Meigs JB, Nathan DM, D’Agostino RB Sr et al.; Framingham Offspring Study. Fasting and postchallenge glycemia and cardiovascular disease risk: the Framingham Offspring Study. Diabetes Care 2002;25: 1845–1850 30 Shahim B, De Bacquer D, De Backer G, et al.: The prognostic value of fasting plasma glucose, two-hour postload glucose, and HbA1c in patients with coronary artery disease: A report from EUROASPIRE IV: A Survey from the European Society of Cardiology. Diabetes Care 2017; 40(9): 1233-1240. 31 Jing J, Pan Y, Zhao X, et al. Prognosis of ischemic stroke with newly diagnosed diabetes mellitus according to hemoglobin A1c criteria in Chinese population. Stroke 2016; 47: 2038-2044. 32 Capes SE, Hunt D, Malmberg K, et al.: Stress hyperglycemia and prognosis of stroke in nondiabetic and diabetic patients: a systematic overview. Stroke 2001; 32: 2426–2432. 33 Osei E, den Hertog HM, Fonville S, et al.: Prediction of persistent impaired glucose tolerance in patients with minor ischemic stroke or transient ischemic attack. J Stroke Cerebrovasc Dis 2020; 29(6): 104815. Table Baseline HbA1c Normal Prediabetes Diabetes OGTT Normal 30 10 0 Prediabetes 19 14 0 Diabetes 1 0 1 12 Months HbA1c Normal Prediabetes Diabetes OGTT Normal 37 8 0 Prediabetes 13 6 0 Diabetes 1 2 0 Table 1 Cross table of resulting classifications by OGTT and HbA1c in patients who had both tests at baseline (n=75) and 12 months follow up (n=67) Supplementary Files Supplementaltable.docx Cite Share Download PDF Status: Published Journal Publication published 05 Dec, 2020 Read the published version in Cardiovascular Diabetology → Version 3 posted Editorial decision: Accept 17 Nov, 2020 Editor assigned by journal 15 Nov, 2020 Submission checks completed at journal 15 Nov, 2020 Editor invited by journal 15 Nov, 2020 You are reading this latest preprint version Show more versions Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-50549","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Original investigation","associatedPublications":[],"authors":[{"id":4850679,"identity":"f4d2f330-ef14-4faf-9fb5-1b278e9ed82e","order_by":0,"name":"Karl Matz","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAABCklEQVRIiWNgGAWjYBACCQYGxgNgFnuDAVSMsYGQFoYDYJrnAJoWHoJaJBIMUKVwaZFsP/vgAGOOXZ38zMcbHxfUHGYwuN3cwPCjhkHeHocWaZ50gwOM25IlGGenFRvPOAbUcudgA2PPMQbDHhxa5BjSGIBamCWYpXPMpHnYDtdvuJHYwMDbwMCIUwv/M5CWegk2yTNALf+AtgC1MP5tYLDHpUVaAmzLYQkeCR4zad42iBZmoC2JuLRIzgDakrjtuOQMHqBfePvSGSSBWg7LHJNI7jmAXYvE+TTGBx+3VfPLtx/e+JjnmzUD3430hw/f1NjYtjfgsAYEEtAFDkAibBSMglEwCkYBuQAALoNUS0/kSqsAAAAASUVORK5CYII=","orcid":"https://orcid.org/0000-0002-2851-9897","institution":"Danube University Krems","correspondingAuthor":true,"submittingAuthor":false,"prefix":"","firstName":"Karl","middleName":"","lastName":"Matz","suffix":""},{"id":4850680,"identity":"0a5162f6-86bc-4afc-a627-2adcbef65761","order_by":1,"name":"Jaakko Tuomilehto","email":"","orcid":"","institution":"Department of public health, University of Helsinki","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Jaakko","middleName":"","lastName":"Tuomilehto","suffix":""},{"id":4850681,"identity":"22b684f5-0f64-416f-a7c4-33352e2c4a01","order_by":2,"name":"Yvonne Teuschl","email":"","orcid":"","institution":"Danube University Krems","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Yvonne","middleName":"","lastName":"Teuschl","suffix":""},{"id":4850682,"identity":"47e0e93f-6c39-4061-a650-cd2500cf54a6","order_by":3,"name":"Alexandra Dachenhausen","email":"","orcid":"","institution":"Danube University Krems","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Alexandra","middleName":"","lastName":"Dachenhausen","suffix":""},{"id":4850683,"identity":"3d254a8d-44fa-4061-81d6-58aee90eb5d1","order_by":4,"name":"Michael Brainin","email":"","orcid":"","institution":"Danube University Krems","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Michael","middleName":"","lastName":"Brainin","suffix":""}],"badges":[],"createdAt":"2020-07-29 10:29:35","currentVersionCode":3,"declarations":"","doi":"10.21203/rs.3.rs-50549/v3","doiUrl":"https://doi.org/10.21203/rs.3.rs-50549/v3","draftVersion":[],"editorialEvents":[{"content":"https://doi.org/10.1186/s12933-020-01182-6","type":"published","date":"2020-12-05T15:01:21+00:00"}],"editorialNote":"","failedWorkflow":false,"files":[{"id":3665537,"identity":"34959cdd-ce3e-44a3-b443-8c93b4c38654","added_by":"auto","created_at":"2020-11-18 15:28:10","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":332278,"visible":true,"origin":"","legend":"CONSORT flow diagram of classification for disorders of glucose metabolism during the ASPIS randomized controlled trial","description":"","filename":"1.png","url":"https://assets-eu.researchsquare.com/files/rs-50549/v3/2a8ba9dffcfae8a32d7f6548.png"},{"id":3665539,"identity":"8668819b-4698-4a0e-b5be-8094f2c4ca00","added_by":"auto","created_at":"2020-11-18 15:28:10","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":326206,"visible":true,"origin":"","legend":"Percentage of progressive diabetic metabolic disorder (DMD), stable or improved glucose metabolism (GM) between baseline and one year follow up in the multifactorial intervention group of the ASPIS trial and in controls. Both, OGTT and HbA1c were used for diagnosis, patients were classified to PD or T2DM if either the OGTT or HbA1c criteria were fulfilled. Progressive DMD was defined as progression from normal GM to PD or T2DM or from PD to T2DM, improved GM as change of GM in the opposite direction. ","description":"","filename":"2.png","url":"https://assets-eu.researchsquare.com/files/rs-50549/v3/a1b9de8e48da73dd06c8ef9d.png"},{"id":13615660,"identity":"c3dabd3e-b955-494f-a35c-df9b96df9f9e","added_by":"auto","created_at":"2021-09-17 06:46:26","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":676496,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-50549/v3/44747506-8b81-4f82-bdf1-708cf8a54c25.pdf"},{"id":3665538,"identity":"21160dca-7fbd-4e4e-8fa8-56c22015fe49","added_by":"auto","created_at":"2020-11-18 15:28:10","extension":"docx","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":16134,"visible":true,"origin":"","legend":"","description":"","filename":"Supplementaltable.docx","url":"https://assets-eu.researchsquare.com/files/rs-50549/v3/d36e0fe542f23b3caa1c6d64.docx"}],"financialInterests":"","formattedTitle":"Comparison of oral glucose tolerance test and HbA1c in detection of disorders of glucose metabolism in patients with acute stroke","fulltext":[{"header":"Background","content":"\u003cp\u003eGlucose abnormalities, either diabetes type 2 (T2DM) or impaired glucose tolerance (IGT) are common in patients with stroke and impair their prognosis\u003csup\u003e1, 2, 3, 4, 5\u003c/sup\u003e. T2DM and IGT should therefore be included in the risk assessment of stroke patients. We have earlier shown that a high proportion of stroke patients with T2DM and all cases of IGT are undetected prior to the stroke event and would still remain undiscovered if fasting plasma glucose (FPG) alone is determined in the clinical evaluation of stroke patients)\u003csup\u003e6\u003c/sup\u003e.\u003c/p\u003e\n\u003cp\u003eIt is a longstanding paradox that the OGTT is used for diabetes diagnosis whereas HbA1c serves as monitoring parameter for antidiabetic treatment. As the recommended 2-hour oral glucose tolerance test (OGTT) may be a time-consuming procedure, an International Expert Committee and the American Diabetes Association (ADA) have recommend the use of HbA1c as a diagnostic test\u003csup\u003e7\u003c/sup\u003e with \u003cu\u003e\u0026gt;\u003c/u\u003e 6.5% (48 mmol/mol) as the diagnostic cut-point for T2DM. Also, the World Health Organisation (WHO) Consultation Group has agreed on the use of this HbA1c cut point but stressed that the OGTT should remain as the primary method to diagnose T2DM\u003csup\u003e8\u003c/sup\u003e. With the HbA1c in the guidelines, the OGTT is used less in the routine clinical practice although it is the only way to detect IGT as a postprandial dysregulation of blood glucose.\u003c/p\u003e\n\u003cp\u003eThe aim of the present study was to find out how well HbA1c results will compare with the determination of FPG and 2-hour plasma glucose (2hPG) using an OGTT in screening for T2DM and prediabetes in patients with acute non-disabling ischemic stroke during the early post-acute period and after the one-year follow-up.\u003c/p\u003e"},{"header":"Methods","content":"\u003cp\u003eIn this study we performed a retrospective analysis of the data regarding glucose metabolism that were collected as part of the protocol in the Austrian Polyintervention Study to Prevent Cognitive Decline after Ischemic Stroke (ASPIS) trial. The study details of ASPIS have been described earlier\u003csup\u003e9\u003c/sup\u003e. In short, the ASPIS trial tested whether a 24-month intensified multidomain intervention, which targeted modifiable risk factors, can prevent post-stroke cognitive decline compared with a control group receiving standard care. A total of \u0026nbsp;199 patients with acute ischemic stroke during the last three months, aged 40 to 80 years, with a W of 0-2 on admission, and sufficient communication ability were enrolled from five stroke clinics in Austria between 2010 and 2012.\u003c/p\u003e\n\u003cp\u003ePatients were tested for diabetes or prediabetes with HbA1c or an OGTT at baseline in the first or second week after the stroke and at one-year follow-up. Blood samples for FPG and 2hPG were taken in sodium fluoride tubes and analysed immediately with the hexokinase method in a Hitachi Laboratory systems machine. The World Health Organisation (WHO) 1999 criteria for diabetes\u003csup\u003e10\u003c/sup\u003e (either FPG \u003cu\u003e\u0026gt;\u003c/u\u003e 7.0 mmol/l or 2hPG \u003cu\u003e\u0026ge;\u003c/u\u003e11.1 mmol/l), impaired fasting glucose (IFG) (FPG 6.1-6.9 mmol/l and 2hPG \u0026lt; 7.8 mmol/l) and IGT (2hPG 7.8-11.0 mmol/l) were used. Those whose FPG and 2hPG were below these levels were considered to have normal plasma glucose. HbA1c was determined from whole blood samples by turbidimetric inhibition immunoassay. HbA1c 48 mmol/mol (6.5%) was considered as the cut-point for diabetes, and a range between 5.7 and 6.4% as prediabetic. Patients with known T2DM did not undergo OGTT and were excluded from this analysis.\u003c/p\u003e\n\u003cp\u003eWe further assessed if glucose metabolism improved, stayed stable or worsened between baseline and follow-up. Worsening was defined as progression from normal glucose metabolism to prediabetes or T2DM or from prediabetes toT2DM, improvement as change from T2DM to prediabetes or to normal metabolism or from prediabetes to normal.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eStatistical analyses\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eObserved agreement between the diagnostic methods were calculated as percentage ratio between overlapping diagnosis and overall numbers of cases with disease. Concordance of methods was calculated as Cohens\u0026rsquo; kappa coefficient.\u003c/p\u003e\n\u003cp\u003eGroup comparisons between the improving or stable and worsening group were calculated with Chi-square test for categorical variables and with Kruskal-Wallis\u0026rsquo; test for numeric variables. The level of significance was set two sided at a=0.05. Statistical analyses were carried out with IBM SPSS Statistics 26.0.\u003c/p\u003e"},{"header":"Results","content":"\u003cp\u003eOf the 199 patients included in the ASPIS trial, 61 (30.7%) had already T2DM according to patients\u0026rsquo; history, eight patients without previous diagnosis had no results for HbA1c or the OGTT available to allow classification at baseline, leaving 130 patients for further analysis (see fig.1). The results of the baseline classification were as follows: five patients (3,8%) without a prior diabetes diagnosis were found to have diabetes either by HbA1c or the OGTT results, prediabetes was found in 57 (43.8%) patients, and 68 patients had normal test results (52.3%).\u003c/p\u003e\n\u003cp\u003eBoth the OGTT and HbA1c results were available in 75 patients. According to the OGTT 40 (53.3%) patients had normal glucose metabolism, 33 (44%) had prediabetes, two (2.7%) T2DM. According to the HbA1c results 50 (66.7%) were normal, 24 (32%) prediabetic and one T2DM (1.3%), see table 1. The observed agreement in diagnosis of T2DM was 50%, of prediabetes only 42.4%. Cohens\u0026rsquo; Kappa coefficient for concordance of HbA1c and the OGTT was 0.205. The detection rate for disorders of glucose metabolism was 16.7% higher (absolute difference; relative difference 28.6%) with the OGTT than with HbA1c.\u003c/p\u003e\n\u003cp\u003eAfter one year, \u0026nbsp;28 patients were either study dropouts or had no further tests for glucose metabolism available, leaving 102 subjects for the follow-up analysis: the results of either tests revealed 56 patients as normal (54.9%), 36 as prediabetes (35.3%) and 10 (9.8%) with T2DM (three according to OGTT, one according to HbA1c and six according to updated clinical information).\u003c/p\u003e\n\u003cp\u003e67 (66%) patients had both tests, OGTT and HBA1c, available for direct comparison: according to OGTT 45 (67.2%) patients had normal glucose metabolism, 19 (28.4%) had prediabetes, and three (4.5%) T2DM. According to HbA1c results 51(76.1%) were normal and 16(23.9%) prediabetic. The observed agreement in classification of normal glucose metabolism was 62.7%, of prediabetes only 20.7%, the detection rate for prediabetes or T2DM was 9.9% (absolute difference; 30% relative difference) higher with OGTT, (see table 1). Cohens\u0026rsquo; Kappa coefficient dropped to 0.149.\u003c/p\u003e\n\u003cp\u003eNext we looked how glycemic status changed over time in patients who had tests both at baseline and one-year follow-up: Out of 102 patients 67 (65.7%) remained stable, 16 (15.7%) improved and 19/102 (18.6%) progressed to prediabetes or T2DM. Baseline variables of these three groups are shown in a table in supplemental material. In addition, we compared these groups separately according to their allocation to intervention or control group in the randomized controlled trial: In the intervention group seven (13.7%) of 51 patients showed progression to prediabetes or T2DM, in the control group 12 (23.5%) of 51 patients (p=0.066). 12 patients (23.5%) in the intervention group improved their glucose metabolism compared to only four (7.8%) in the control group (see figure 2).\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003e\u003cstrong\u003e\u003cem\u003eSummary\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe main finding of this study was that in patients which subacute minor stroke the OGTT detects up to 25 to 29% more patients with prediabetes or T2DM than HbA1c regardless if performed early after the event or at one-year follow-up. The odds that prediabetes was detected by the OGTT was 2.6 higher compared to HbA1c measurement alone. As in several previous studies\u003csup\u003e9, 11, 12\u003c/sup\u003e disorders of glucose metabolism were highly prevalent (more than 60%) in patients with AIS. Overall, the concordance between the OGTT and HbA1c results was low, which has also been found by several other studies\u003csup\u003e13, 14\u003c/sup\u003e.\u003c/p\u003e\n\u003cp\u003eDuring the one-year observation the classification of glucose disorders in stroke patients in the trial was not invariable, although about two thirds of the patients did not change their original category. A multifactorial lifestyle-oriented intervention resulted in a non-significant statistical trend for a higher percentage of patients who improved in their glucose metabolism in the intervention group than the control group receiving a standard care. With improvements in lifestyle\u003csup\u003e15\u003c/sup\u003e, or treatment with metformin\u003csup\u003e16\u003c/sup\u003e, acarbose\u003csup\u003e17\u003c/sup\u003e, pioglitazone\u003csup\u003e18\u003c/sup\u003e or liraglutide\u003csup\u003e19\u003c/sup\u003e the risk of the conversion from prediabetes to frank T2DM can be reduced. Detection of diabetes and prediabetes is also of importance for secondary prevention of ischemic stroke, for example pioglitazone\u003csup\u003e20\u003c/sup\u003e reduces the risk of stroke recurrence in stroke patients with prediabetes or T2DM.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u003cem\u003eDiagnostic advantage of OGTT\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAmerican Diabetes Association has recommended HbA1c as the tool for diagnosing T2DM and defined a cut-off level 48 mmol/mol to indicate diabetes\u003csup\u003e7\u003c/sup\u003e. Since long-term hyperglycaemia is necessary to raise HbA1c to this level (when other causes of HbA1c elevation are excluded), HbA1c above this cut point obviously has a high specificity. Due to this high specificity, also WHO has agreed that HbA1c 48 mmol/mol (6.5%) or above can be used to diagnose diabetes, but WHO still gives preference to the determination of glucose and use of the OGTT due to the superior sensitivity\u003csup\u003e8\u003c/sup\u003e. The sensitivity of HbA1c alone is low leaving many people with T2DM and all people with IGT undetected. However, screening for prediabetes is especially important in patients with already treated other vascular risk factors\u003csup\u003e21\u003c/sup\u003e. Therefore, the WHO report emphasizes that HbA1c value below 48 mmol/mol does not exclude diabetes diagnosed using glucose tests, and that there is insufficient evidence to make any formal recommendation on the interpretation of HbA1c levels below 48 mmol/mol. Our results in acute stroke patients provides a very strong support to this statement.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u003cem\u003ePrognostic advantage of OGTT\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThere is also evidence that the parameters of the OGTT correlate better with outcomes of vascular disease than HbA1c. A German study among 1015 patients admitted for coronary angiography found T2DM in 149 patients by an OGTT, but only 42 by HbA1c\u003csup\u003e22\u003c/sup\u003e and the severity of coronary heart disease (CHD) correlated with 2hPG in the OGTT. This is in keeping with the data from previous studies that have shown that 2hPG is the best predictor of the three glycaemic parameters for incident cardiovascular events\u003csup\u003e23\u003c/sup\u003e, total mortality\u003csup\u003e24\u003c/sup\u003e or intima-media thickness of carotid arteries\u003csup\u003e25\u003c/sup\u003e. Postprandial glycemic peaks seem also lead to maladaptive with vascular remodeling\u003csup\u003e26\u003c/sup\u003e. Several studies in the general population have confirmed that 2hPG is a predictor of cardiovascular outcome independent of FPG and HbA1c \u003csup\u003e27, 28, 29\u003c/sup\u003e. In the EUROSPIRE-IV survey\u003csup\u003e30\u003c/sup\u003e 2h-PG in contrast to HbA1c was an independent predictor of subsequent new cardiovascular events in a large cohort of patients with CHD. Both HbA1c and 2h-PG were independent predictors of incident new T2DM during follow-up. Furthermore, in a Chinese study newly diagnosed T2DM was independently associated with one-year mortality, functional outcome and stroke recurrence\u003csup\u003e31\u003c/sup\u003e. In our previous observational study we also showed that undiagnosed T2DM may worsen the prognosis in stroke patients.\u003csup\u003e6\u003c/sup\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u003cem\u003eStrengths\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe strength of our study is that we ascertained consecutively patients admitted that were assessed and reassessed within the settings of a randomized controlled trial. Secondly, we performed a follow-up up investigation after 12 months and therefore our results do not rely only on measurements during the acute stroke period.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u003cem\u003eLimitations\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eWeak points of our study are the low number of patients investigated as this was a regionally conducted multi-centre trial and the considerable number of dropouts. Despites this weakness in quantity our results are robust over time from baseline to follow up and confirmatory with other studies. Furthermore, it can be stated that part of the hyperglycemic states that were classified as diabetes and prediabetes at baseline can be interpreted as acute hyperglycemic stress responses\u003csup\u003e32\u003c/sup\u003e especially in severe strokes and that the OGTT is more sensitive to these acute fluctuations of blood glucose levels. However, we still observed the difference between OGTT and HbA1c after one year when stress induced hyperglycemia was no longer existing, and the influence of stroke severity was probably low as mostly minor strokes were included into the trial. Recently a study\u003csup\u003e33\u003c/sup\u003e found that several parameters referring to the metabolic syndrome fairly predicted persistent IGT in patients with acute minor stroke.\u003c/p\u003e\n\u003cp\u003eIn addition, we found a trend for a lower rate of progression of disorders of glucose metabolism among those who underwent multimodal interventions for risk factor control compared with the control group. An improved detection of prediabetes and early T2DM using an OGTT could help to focus and tailor preventive interventions to improve or maintain cardiovascular and metabolic health.\u003c/p\u003e"},{"header":"Conclusion","content":"\u003cp\u003eIn the clinical evaluation of patients with acute stroke the assessment of the glycemic status is important in order to assign adequate preventive management to correct metabolic abnormalities that may influence the prognosis. The OGTT is a more sensitive method than HbA1c to detect and monitor disorders of glucose metabolism in patients with an ischemic stroke. \u0026nbsp;The OGTT should be carried out in all stroke patients who have not been found to be diabetic before the stroke event.\u003c/p\u003e"},{"header":"Abbreviations","content":"\u003cp\u003eADA - American Diabetes Association, AIS - acute ischemic stroke, ASPIS - Austrian Polyintervention Study to Prevent Cognitive Decline after Ischemic Stroke, FPG - fasting plasma glucose, HbA1c - glycated hemoglobin, IFG - impaired fasting glucose, IGT - impaired glucose tolerance, NIHSS - National Institutes of Health Stroke Scale, mRS - modified Rankin Scale, OGTT - oral glucose tolerance test, T2DM -type 2 diabetes mellitus, 2hPG - 2-hour plasma glucose, WHO - World Health Organization.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cu\u003eEthics approval and consent to participate\u003c/u\u003e\u003cu\u003e\u003cbr /\u003e\u003c/u\u003eThis study was conducted according to the Helsinki Declaration. All study participants gave written informed consent for the study. The trial was approved by the regional Ethics\u0026rsquo; committee of Lower Austria.\u003c/p\u003e\n\u003cp\u003e\u003cu\u003eConsent for publication\u003c/u\u003e\u003c/p\u003e\n\u003cp\u003eAll authors declared their consent to publication of this work.\u003c/p\u003e\n\u003cp\u003e\u003cu\u003eAvailability of data and materials:\u003c/u\u003e\u003c/p\u003e\n\u003cp\u003enot applicable.\u003c/p\u003e\n\u003cp\u003e\u003cu\u003eCompeting interests\u003c/u\u003e\u003c/p\u003e\n\u003cp\u003eThe authors declare to have no competing interest with the topic of this publication.\u003c/p\u003e\n\u003cp\u003e\u003cu\u003eFunding\u003c/u\u003e\u003c/p\u003e\n\u003cp\u003eThe Austrian Polyintervention Study to Prevent Cognitive Decline after Ischemic Stroke trial was supported by a Grant from the N\u0026Ouml; Forschungs- und Bildungsges.m.b.H (former Life Science Krems GmbH), Austria with the Grant Agreement Number LS09-002.\u003c/p\u003e\n\u003cp\u003eClinical Trial Registration\u0026mdash;URL: http://clinicaltrials.gov. Unique identifier: NCT01109836.\u003c/p\u003e\n\u003cp\u003e\u003cu\u003eAuthors\u0026rsquo; contribution\u003c/u\u003e\u003c/p\u003e\n\u003cp\u003eKarl Matz designed and conducted the study and wrote the manuscript; Jaakko Tuomilehto designed the study and wrote the manuscript. Yvonne Teuschl performed the statistical analysis and reviewed the manuscript; Paulina Kurzmann performed additional statistical analyses; Alexandra Dachenhausen reviewed the manuscript; Michael Brainin designed the study, consulted the preparation and conduction of the study and reviewed the manuscript.\u003c/p\u003e\n\u003cp\u003e\u003cu\u003eAcknowledgements\u003c/u\u003e\u003c/p\u003e\n\u003cp\u003eWe thank all colleagues, nurses and laboratory technicians involved in investigating patients, obtaining and analysing blood samples.\u003c/p\u003e"},{"header":"References","content":"\u003cp\u003e1 Norhammar A, Tenerz A, Nilsson G, et al.: Glucose metabolism in patients with acute myocardial infarction and no previous diagnosis of diabetes mellitus: a prospective study. Lancet 2002; 359 (9324): 2140- 2144.\u003c/p\u003e\n\u003cp\u003e2 Bartnik M, Ryd\u0026eacute;n L, Ferrari R, et al.: 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):1880-1890.\u003c/p\u003e\n\u003cp\u003e3 Hu DY, Pan CY, Yu JM: The relationship between coronary artery disease and abnormal glucose regulation in China: the China Heart Survey. Eur Heart J 2006; 27 (21): 2573-2579.\u003c/p\u003e\n\u003cp\u003e4 Tamita K, Katayama M, Takagi T, et al.: Impact of newly diagnosed abnormal glucose tolerance on long-term prognosis in patients with acute myocardial infarction. Circ J 2007; 71(6): 834-841.\u003c/p\u003e\n\u003cp\u003e5 Bartnik M, Malmberg K, Norhammar A, et al.: Newly detected abnormal glucose tolerance: an important predictor of long-term outcome after myocardial infarction. Eur Heart J 2004; 25: 1990-1997.\u003c/p\u003e\n\u003cp\u003e6 Matz K, Keresztes K, Tatschl C, et al.: Disorders of glucose metabolism in acute stroke patients: an underrecognized problem. Diabetes care 2006; 29(4): 792 - 797.\u003c/p\u003e\n\u003cp\u003e7 American Diabetes Association. Diagnosis and classification of diabetes mellitus. Diabetes Care 2010; 33 Suppl 1: S62-69.\u003c/p\u003e\n\u003cp\u003e8 WHO Consultation. Use of glycated haemoglobin (HbA1c) in the diagnosis of diabetes mellitus. Abbreviated Report of a WHO Consultation. World Health Organization. Geneva 2011\u003c/p\u003e\n\u003cp\u003e9 Matz K, Teuschl Y, Firlinger B, et al.: ASPIS Study Group. Multidomain lifestyle interventions for the prevention of cognitive cecline after ischemic stroke: a randomized trial. Stroke 2015; 46: 2874-2880.\u003c/p\u003e\n\u003cp\u003e10 World Health Organization: Definition, iagnosis and Classification of Diabetes Mellitus and its Complications: Report of a WHO Consultation. Part 1: Diagnosis and Classification of Diabetes Mellitus. Geneva, World Health Org., 1999.\u003c/p\u003e\n\u003cp\u003e11 Jia Q, Zheng H, Zhao X, et al.; Investigators for the Survey on Abnormal Glucose Regulation in Patients With Acute Stroke Across China (ACROSS-China). Abnormal glucose regulation in patients with acute stroke across China: prevalence and baseline patient characteristics. Stroke 2012; 43: 650-657.\u003c/p\u003e\n\u003cp\u003e12 Vancheri F, Curcio M, Burgio A, et al.: Impaired glucose metabolism in patients with acute stroke and no previous diagnosis of diabetes mellitus.\u0026nbsp;QJM. 2005; 98(12): 871-878.\u003c/p\u003e\n\u003cp\u003e13 Wu S, Shi Y, Pan Y, Li J, et al.: Glycated hemoglobin independently or in combination with fasting plasma glucose versus oral glucose tolerance test to detect abnormal glycometabolism in acute ischemic stroke: a Chinese cross-sectional study. BMC Neurol 2014, 12; 14: 177.\u003c/p\u003e\n\u003cp\u003e14 Zhang X, Shi Q, Zheng H, et al.: Prevalence of abnormal glucose regulation according to different diagnostic driteria in ischaemic Ssroke without a history of diabetes. Biomed Res Int 2018, 8358724\u003c/p\u003e\n\u003cp\u003e15 Tuomilehto J, Lindstr\u0026ouml;m J, Eriksson JG, et al.; Finnish Diabetes Prevention Study Group. Prevention of type 2 diabetes mellitus by changes in lifestyle among subjects with impaired glucose tolerance. N Engl J Med 2001; 344(18): 1343-1350.\u003c/p\u003e\n\u003cp\u003e16 Knowler WC, Barrett-Connor E, Fowler SE, et al. ; Diabetes Prevention Program Research Group. Reduction in the incidence of type 2 diabetes with lifestyle intervention or metformin. N Engl J Med 2002; 346(6): 393-403.\u003c/p\u003e\n\u003cp\u003e17 Chiasson JL, Josse RG, Gomis R, et al. ; STOP-NIDDM Trial Research Group. Acarbose for prevention of type 2 diabetes mellitus: the STOP-NIDDM randomised trial. Lancet 2002; 359(9323): 2072-2077.\u003c/p\u003e\n\u003cp\u003e18 Kernan WN, Viscoli CM, Furie KL, et al. ; IRIS Trial Investigators. Pioglitazone after ischemic stroke or transient ischemic attack. N Engl J Med 2016; 374(14): 1321-1331.\u003c/p\u003e\n\u003cp\u003e19 le Roux CW, Astrup A, Fujioka K, et al. ; SCALE Obesity Prediabetes NN8022-1839 Study Group. 3 years of liraglutide versus placebo for type 2 diabetes risk reduction and weight management in individuals with prediabetes: a randomised, double-blind trial. Lancet 2017; 389(10077): 1399-1409.\u003c/p\u003e\n\u003cp\u003e20 Lee M, Saver JL, Liao HW, Lin CH,et al.:. Pioglitazone for Secondary Stroke Prevention: A Systematic Review and Meta-Analysis. Stroke 2017; 48: 388-393.\u003c/p\u003e\n\u003cp\u003e21 Shahim B, Gyberg V, De Bacquer D, et al.: Undetected dysglycaemia common in primary care patients treated for hypertension and/or dyslipidaemia: on the need for a screening strategy in clinical practice. A report from EUROASPIRE IV a registry from the EuroObservational Research Programme of the European Society of Cardiology. Cardiovasc Diabetol 2018; 24; 17: 21.\u003c/p\u003e\n\u003cp\u003e22 Dorr R, Stumpf J, Spitzer SG, et al.: [Prevalence of undetected diabetes mellitus in invasive and interventional cardiology. Silent diabetes in the catheterization laboratory]. Herz 2012; 37(3): 244-250.\u003c/p\u003e\n\u003cp\u003e23 Qiao Q, Pyorala K, Pyorala M, et al.: Two-hour glucose is a better risk predictor for incident coronary heart disease and cardiovascular mortality than fasting glucose. European heart journal 2002; 23 (16): 1267-1275.\u003c/p\u003e\n\u003cp\u003e24 DECODE Study Group, the European Diabetes Epidemiology Group. Glucose tolerance and cardiovascular mortality: comparison of fasting and 2-hour diagnostic criteria. Archives of internal medicine 2001; 161(3): 397-405.\u003c/p\u003e\n\u003cp\u003e25 Temelkova-Kurktschiev TS, Koehler C, et al.: Postchallenge plasma glucose and glycemic spikes are more strongly associated with atherosclerosis than fasting glucose or HbA1c level. Diabetes Care 2000; 23(12): 1830-1834.\u003c/p\u003e\n\u003cp\u003e26 Foreman YD, Brouwers MCGJ, et al.: The oral glucose tolerance test-derived incremental glucose peak is associated with greater arterial stiffness and maladaptive arterial remodeling: The Maastricht Study. Cardiovasc Diabetol 2019; 14;18 :152.\u003c/p\u003e\n\u003cp\u003e27 DECODE Study Group, European Diabetes Epidemiology Group.Is the current definition for diabetes relevant to mortality risk from all causes and cardiovascular and noncardiovascular diseases? Diabetes care 2003; 26(3): 688-696.\u003c/p\u003e\n\u003cp\u003e28 Qiao Q, Dekker JM, de Vegt F, et al.: Two prospective studies found that elevated 2-hr glucose predicted male mortality independent of fasting glucose and HbA1c. Journal of clinical epidemiology 2004; 57(6): 590-596.\u003c/p\u003e\n\u003cp\u003e29 Meigs JB, Nathan DM, D\u0026rsquo;Agostino RB Sr et al.; Framingham Offspring Study. Fasting and postchallenge glycemia and cardiovascular disease risk: the Framingham Offspring Study. Diabetes Care 2002;25: 1845\u0026ndash;1850\u003c/p\u003e\n\u003cp\u003e30 Shahim B, De Bacquer D, De Backer G, et al.: The prognostic value of fasting plasma glucose, two-hour postload glucose, and HbA1c\u0026nbsp;in patients with coronary artery disease: A report from EUROASPIRE IV: A Survey from the European Society of Cardiology.\u0026nbsp;Diabetes Care 2017; 40(9): 1233-1240.\u003c/p\u003e\n\u003cp\u003e31 Jing J, Pan Y, Zhao X, et al. Prognosis of ischemic stroke with newly diagnosed diabetes mellitus according to hemoglobin A1c criteria in Chinese population. Stroke 2016; 47: 2038-2044.\u003c/p\u003e\n\u003cp\u003e32 Capes SE, Hunt D, Malmberg K, et al.: Stress hyperglycemia and prognosis of stroke in nondiabetic and diabetic patients: a systematic overview.\u0026nbsp;Stroke\u0026nbsp;2001; 32: 2426\u0026ndash;2432.\u003c/p\u003e\n\u003cp\u003e33 Osei E, den Hertog HM, Fonville S, et al.: Prediction of persistent impaired glucose tolerance in patients with minor ischemic stroke or transient ischemic attack.\u0026nbsp;J Stroke Cerebrovasc Dis 2020; 29(6): 104815.\u003c/p\u003e"},{"header":"Table","content":"\u003ctable border=\"1\" cellpadding=\"0\" cellspacing=\"0\" style=\"border-collapse: collapse;border: none;\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"2\" rowspan=\"2\" style=\"width: 134.85pt;border: 1pt solid windowtext;padding: 0in 5.4pt;height: 22.7pt;\" width=\"30.82191780821918%\"\u003e\n \u003cp style='margin: 0in;line-height: normal;font-size:16px;font-family: \"Times New Roman\", serif;'\u003e\u003cem\u003e\u003cspan style=\"font-family: Verdana, Geneva, sans-serif; font-size: 11px; color: rgb(0, 0, 0);\"\u003eBaseline\u003c/span\u003e\u003c/em\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"3\" style=\"width: 303.15pt;border-top-width: 1pt;border-right-width: 1pt;border-bottom-width: 1pt;border-style: solid solid solid none;border-top-color: windowtext;border-right-color: windowtext;border-bottom-color: windowtext;background-color: rgb(242, 242, 242);padding: 0in 5.4pt;height: 22.7pt;background-position: initial initial;background-repeat: initial initial;\" width=\"69.17808219178082%\"\u003e\n \u003cp style='margin: 0in;line-height: normal;font-size:16px;font-family: \"Times New Roman\", serif;text-align: center;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-family: Verdana, Geneva, sans-serif;\"\u003e\u003cspan style=\"font-size: 11px;\"\u003e\u003cstrong\u003eHbA1c\u003c/strong\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 97.6pt;border-style: none solid solid none;border-bottom-width: 1pt;border-bottom-color: windowtext;border-right-width: 1pt;border-right-color: windowtext;padding: 0in 5.4pt;height: 22.7pt;\" width=\"32.17821782178218%\"\u003e\n \u003cp style='margin: 0in;line-height: normal;font-size:16px;font-family: \"Times New Roman\", serif;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-family: Verdana, Geneva, sans-serif;\"\u003e\u003cspan style=\"font-size: 11px;\"\u003eNormal\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 106.35pt;border-style: none solid solid none;border-bottom-width: 1pt;border-bottom-color: windowtext;border-right-width: 1pt;border-right-color: windowtext;padding: 0in 5.4pt;height: 22.7pt;\" width=\"35.148514851485146%\"\u003e\n \u003cp style='margin: 0in;line-height: normal;font-size:16px;font-family: \"Times New Roman\", serif;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-family: Verdana, Geneva, sans-serif;\"\u003e\u003cspan style=\"font-size: 11px;\"\u003ePrediabetes\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 99.2pt;border-style: none solid solid none;border-bottom-width: 1pt;border-bottom-color: windowtext;border-right-width: 1pt;border-right-color: windowtext;padding: 0in 5.4pt;height: 22.7pt;\" width=\"32.67326732673267%\"\u003e\n \u003cp style='margin: 0in;line-height: normal;font-size:16px;font-family: \"Times New Roman\", serif;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-family: Verdana, Geneva, sans-serif;\"\u003e\u003cspan style=\"font-size: 11px;\"\u003eDiabetes\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd rowspan=\"3\" style=\"width: 53.1pt;border-right-width: 1pt;border-bottom-width: 1pt;border-left-width: 1pt;border-style: none solid solid;border-right-color: windowtext;border-bottom-color: windowtext;border-left-color: windowtext;background-color: rgb(242, 242, 242);padding: 0in 5.4pt;height: 22.7pt;background-position: initial initial;background-repeat: initial initial;\" width=\"12.157534246575343%\"\u003e\n \u003cp style='margin: 0in;line-height: normal;font-size:16px;font-family: \"Times New Roman\", serif;text-align: center;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-family: Verdana, Geneva, sans-serif;\"\u003e\u003cspan style=\"font-size: 11px;\"\u003e\u003cstrong\u003eOGTT\u003c/strong\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 81.75pt;border-style: none solid solid none;border-bottom-width: 1pt;border-bottom-color: windowtext;border-right-width: 1pt;border-right-color: windowtext;padding: 0in 5.4pt;height: 22.7pt;\" width=\"18.664383561643834%\"\u003e\n \u003cp style='margin: 0in;line-height: normal;font-size:16px;font-family: \"Times New Roman\", serif;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-family: Verdana, Geneva, sans-serif;\"\u003e\u003cspan style=\"font-size: 11px;\"\u003eNormal\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 97.6pt;border-style: none solid solid none;border-bottom-width: 1pt;border-bottom-color: windowtext;border-right-width: 1pt;border-right-color: windowtext;padding: 0in 5.4pt;height: 22.7pt;\" width=\"22.26027397260274%\"\u003e\n \u003cp style='margin: 0in;line-height: normal;font-size:16px;font-family: \"Times New Roman\", serif;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-family: Verdana, Geneva, sans-serif;\"\u003e\u003cspan style=\"font-size: 11px;\"\u003e30\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 106.35pt;border-style: none solid solid none;border-bottom-width: 1pt;border-bottom-color: windowtext;border-right-width: 1pt;border-right-color: windowtext;padding: 0in 5.4pt;height: 22.7pt;\" width=\"24.315068493150687%\"\u003e\n \u003cp style='margin: 0in;line-height: normal;font-size:16px;font-family: \"Times New Roman\", serif;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-family: Verdana, Geneva, sans-serif;\"\u003e\u003cspan style=\"font-size: 11px;\"\u003e10\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 99.2pt;border-style: none solid solid none;border-bottom-width: 1pt;border-bottom-color: windowtext;border-right-width: 1pt;border-right-color: windowtext;padding: 0in 5.4pt;height: 22.7pt;\" width=\"22.602739726027398%\"\u003e\n \u003cp style='margin: 0in;line-height: normal;font-size:16px;font-family: \"Times New Roman\", serif;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-family: Verdana, Geneva, sans-serif;\"\u003e\u003cspan style=\"font-size: 11px;\"\u003e0\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 81.75pt;border-style: none solid solid none;border-bottom-width: 1pt;border-bottom-color: windowtext;border-right-width: 1pt;border-right-color: windowtext;padding: 0in 5.4pt;height: 22.7pt;\" width=\"21.24756335282651%\"\u003e\n \u003cp style='margin: 0in;line-height: normal;font-size:16px;font-family: \"Times New Roman\", serif;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-family: Verdana, Geneva, sans-serif;\"\u003e\u003cspan style=\"font-size: 11px;\"\u003ePrediabetes\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 97.6pt;border-style: none solid solid none;border-bottom-width: 1pt;border-bottom-color: windowtext;border-right-width: 1pt;border-right-color: windowtext;padding: 0in 5.4pt;height: 22.7pt;\" width=\"25.341130604288498%\"\u003e\n \u003cp style='margin: 0in;line-height: normal;font-size:16px;font-family: \"Times New Roman\", serif;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-family: Verdana, Geneva, sans-serif;\"\u003e\u003cspan style=\"font-size: 11px;\"\u003e19\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 106.35pt;border-style: none solid solid none;border-bottom-width: 1pt;border-bottom-color: windowtext;border-right-width: 1pt;border-right-color: windowtext;padding: 0in 5.4pt;height: 22.7pt;\" width=\"27.680311890838208%\"\u003e\n \u003cp style='margin: 0in;line-height: normal;font-size:16px;font-family: \"Times New Roman\", serif;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-family: Verdana, Geneva, sans-serif;\"\u003e\u003cspan style=\"font-size: 11px;\"\u003e14\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 99.2pt;border-style: none solid solid none;border-bottom-width: 1pt;border-bottom-color: windowtext;border-right-width: 1pt;border-right-color: windowtext;padding: 0in 5.4pt;height: 22.7pt;\" width=\"25.730994152046783%\"\u003e\n \u003cp style='margin: 0in;line-height: normal;font-size:16px;font-family: \"Times New Roman\", serif;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-family: Verdana, Geneva, sans-serif;\"\u003e\u003cspan style=\"font-size: 11px;\"\u003e0\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 81.75pt;border-style: none solid solid none;border-bottom-width: 1pt;border-bottom-color: windowtext;border-right-width: 1pt;border-right-color: windowtext;padding: 0in 5.4pt;height: 22.7pt;\" width=\"21.24756335282651%\"\u003e\n \u003cp style='margin: 0in;line-height: normal;font-size:16px;font-family: \"Times New Roman\", serif;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-family: Verdana, Geneva, sans-serif;\"\u003e\u003cspan style=\"font-size: 11px;\"\u003eDiabetes\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 97.6pt;border-style: none solid solid none;border-bottom-width: 1pt;border-bottom-color: windowtext;border-right-width: 1pt;border-right-color: windowtext;padding: 0in 5.4pt;height: 22.7pt;\" width=\"25.341130604288498%\"\u003e\n \u003cp style='margin: 0in;line-height: normal;font-size:16px;font-family: \"Times New Roman\", serif;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-family: Verdana, Geneva, sans-serif;\"\u003e\u003cspan style=\"font-size: 11px;\"\u003e1\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 106.35pt;border-style: none solid solid none;border-bottom-width: 1pt;border-bottom-color: windowtext;border-right-width: 1pt;border-right-color: windowtext;padding: 0in 5.4pt;height: 22.7pt;\" width=\"27.680311890838208%\"\u003e\n \u003cp style='margin: 0in;line-height: normal;font-size:16px;font-family: \"Times New Roman\", serif;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-family: Verdana, Geneva, sans-serif;\"\u003e\u003cspan style=\"font-size: 11px;\"\u003e0\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 99.2pt;border-style: none solid solid none;border-bottom-width: 1pt;border-bottom-color: windowtext;border-right-width: 1pt;border-right-color: windowtext;padding: 0in 5.4pt;height: 22.7pt;\" width=\"25.730994152046783%\"\u003e\n \u003cp style='margin: 0in;line-height: normal;font-size:16px;font-family: \"Times New Roman\", serif;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-family: Verdana, Geneva, sans-serif;\"\u003e\u003cspan style=\"font-size: 11px;\"\u003e1\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"2\" rowspan=\"2\" style=\"width: 134.85pt;border-right-width: 1pt;border-bottom-width: 1pt;border-left-width: 1pt;border-style: none solid solid;border-right-color: windowtext;border-bottom-color: windowtext;border-left-color: windowtext;padding: 0in 5.4pt;height: 22.7pt;\" width=\"30.82191780821918%\"\u003e\n \u003cp style='margin: 0in;line-height: normal;font-size:16px;font-family: \"Times New Roman\", serif;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-family: Verdana, Geneva, sans-serif;\"\u003e\u003cspan style=\"font-size: 11px;\"\u003e\u003cem\u003e12 Months\u003c/em\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"3\" style=\"width: 303.15pt;border-style: none solid solid none;border-bottom-width: 1pt;border-bottom-color: windowtext;border-right-width: 1pt;border-right-color: windowtext;background-color: rgb(242, 242, 242);padding: 0in 5.4pt;height: 22.7pt;background-position: initial initial;background-repeat: initial initial;\" width=\"69.17808219178082%\"\u003e\n \u003cp style='margin: 0in;line-height: normal;font-size:16px;font-family: \"Times New Roman\", serif;text-align: center;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-family: Verdana, Geneva, sans-serif;\"\u003e\u003cspan style=\"font-size: 11px;\"\u003e\u003cstrong\u003eHbA1c\u003c/strong\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 97.6pt;border-style: none solid solid none;border-bottom-width: 1pt;border-bottom-color: windowtext;border-right-width: 1pt;border-right-color: windowtext;padding: 0in 5.4pt;height: 22.7pt;\" width=\"32.17821782178218%\"\u003e\n \u003cp style='margin: 0in;line-height: normal;font-size:16px;font-family: \"Times New Roman\", serif;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-family: Verdana, Geneva, sans-serif;\"\u003e\u003cspan style=\"font-size: 11px;\"\u003eNormal\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 106.35pt;border-style: none solid solid none;border-bottom-width: 1pt;border-bottom-color: windowtext;border-right-width: 1pt;border-right-color: windowtext;padding: 0in 5.4pt;height: 22.7pt;\" width=\"35.148514851485146%\"\u003e\n \u003cp style='margin: 0in;line-height: normal;font-size:16px;font-family: \"Times New Roman\", serif;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-family: Verdana, Geneva, sans-serif;\"\u003e\u003cspan style=\"font-size: 11px;\"\u003ePrediabetes\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 99.2pt;border-style: none solid solid none;border-bottom-width: 1pt;border-bottom-color: windowtext;border-right-width: 1pt;border-right-color: windowtext;padding: 0in 5.4pt;height: 22.7pt;\" width=\"32.67326732673267%\"\u003e\n \u003cp style='margin: 0in;line-height: normal;font-size:16px;font-family: \"Times New Roman\", serif;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-family: Verdana, Geneva, sans-serif;\"\u003e\u003cspan style=\"font-size: 11px;\"\u003eDiabetes\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd rowspan=\"3\" style=\"width: 53.1pt;border-right-width: 1pt;border-bottom-width: 1pt;border-left-width: 1pt;border-style: none solid solid;border-right-color: windowtext;border-bottom-color: windowtext;border-left-color: windowtext;background-color: rgb(242, 242, 242);padding: 0in 5.4pt;height: 22.7pt;background-position: initial initial;background-repeat: initial initial;\" width=\"12.157534246575343%\"\u003e\n \u003cp style='margin: 0in;line-height: normal;font-size:16px;font-family: \"Times New Roman\", serif;text-align: center;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-family: Verdana, Geneva, sans-serif;\"\u003e\u003cspan style=\"font-size: 11px;\"\u003e\u003cstrong\u003eOGTT\u003c/strong\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 81.75pt;border-style: none solid solid none;border-bottom-width: 1pt;border-bottom-color: windowtext;border-right-width: 1pt;border-right-color: windowtext;padding: 0in 5.4pt;height: 22.7pt;\" width=\"18.664383561643834%\"\u003e\n \u003cp style='margin: 0in;line-height: normal;font-size:16px;font-family: \"Times New Roman\", serif;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-family: Verdana, Geneva, sans-serif;\"\u003e\u003cspan style=\"font-size: 11px;\"\u003eNormal\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 97.6pt;border-style: none solid solid none;border-bottom-width: 1pt;border-bottom-color: windowtext;border-right-width: 1pt;border-right-color: windowtext;padding: 0in 5.4pt;height: 22.7pt;\" width=\"22.26027397260274%\"\u003e\n \u003cp style='margin: 0in;line-height: normal;font-size:16px;font-family: \"Times New Roman\", serif;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-family: Verdana, Geneva, sans-serif;\"\u003e\u003cspan style=\"font-size: 11px;\"\u003e37\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 106.35pt;border-style: none solid solid none;border-bottom-width: 1pt;border-bottom-color: windowtext;border-right-width: 1pt;border-right-color: windowtext;padding: 0in 5.4pt;height: 22.7pt;\" width=\"24.315068493150687%\"\u003e\n \u003cp style='margin: 0in;line-height: normal;font-size:16px;font-family: \"Times New Roman\", serif;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-family: Verdana, Geneva, sans-serif;\"\u003e\u003cspan style=\"font-size: 11px;\"\u003e8\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 99.2pt;border-style: none solid solid none;border-bottom-width: 1pt;border-bottom-color: windowtext;border-right-width: 1pt;border-right-color: windowtext;padding: 0in 5.4pt;height: 22.7pt;\" width=\"22.602739726027398%\"\u003e\n \u003cp style='margin: 0in;line-height: normal;font-size:16px;font-family: \"Times New Roman\", serif;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-family: Verdana, Geneva, sans-serif;\"\u003e\u003cspan style=\"font-size: 11px;\"\u003e0\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 81.75pt;border-style: none solid solid none;border-bottom-width: 1pt;border-bottom-color: windowtext;border-right-width: 1pt;border-right-color: windowtext;padding: 0in 5.4pt;height: 22.7pt;\" width=\"21.24756335282651%\"\u003e\n \u003cp style='margin: 0in;line-height: normal;font-size:16px;font-family: \"Times New Roman\", serif;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-family: Verdana, Geneva, sans-serif;\"\u003e\u003cspan style=\"font-size: 11px;\"\u003ePrediabetes\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 97.6pt;border-style: none solid solid none;border-bottom-width: 1pt;border-bottom-color: windowtext;border-right-width: 1pt;border-right-color: windowtext;padding: 0in 5.4pt;height: 22.7pt;\" width=\"25.341130604288498%\"\u003e\n \u003cp style='margin: 0in;line-height: normal;font-size:16px;font-family: \"Times New Roman\", serif;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-family: Verdana, Geneva, sans-serif;\"\u003e\u003cspan style=\"font-size: 11px;\"\u003e13\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 106.35pt;border-style: none solid solid none;border-bottom-width: 1pt;border-bottom-color: windowtext;border-right-width: 1pt;border-right-color: windowtext;padding: 0in 5.4pt;height: 22.7pt;\" width=\"27.680311890838208%\"\u003e\n \u003cp style='margin: 0in;line-height: normal;font-size:16px;font-family: \"Times New Roman\", serif;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-family: Verdana, Geneva, sans-serif;\"\u003e\u003cspan style=\"font-size: 11px;\"\u003e6\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 99.2pt;border-style: none solid solid none;border-bottom-width: 1pt;border-bottom-color: windowtext;border-right-width: 1pt;border-right-color: windowtext;padding: 0in 5.4pt;height: 22.7pt;\" width=\"25.730994152046783%\"\u003e\n \u003cp style='margin: 0in;line-height: normal;font-size:16px;font-family: \"Times New Roman\", serif;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-family: Verdana, Geneva, sans-serif;\"\u003e\u003cspan style=\"font-size: 11px;\"\u003e0\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 81.75pt;border-style: none solid solid none;border-bottom-width: 1pt;border-bottom-color: windowtext;border-right-width: 1pt;border-right-color: windowtext;padding: 0in 5.4pt;height: 22.7pt;\" width=\"21.24756335282651%\"\u003e\n \u003cp style='margin: 0in;line-height: normal;font-size:16px;font-family: \"Times New Roman\", serif;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-family: Verdana, Geneva, sans-serif;\"\u003e\u003cspan style=\"font-size: 11px;\"\u003eDiabetes\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 97.6pt;border-style: none solid solid none;border-bottom-width: 1pt;border-bottom-color: windowtext;border-right-width: 1pt;border-right-color: windowtext;padding: 0in 5.4pt;height: 22.7pt;\" width=\"25.341130604288498%\"\u003e\n \u003cp style='margin: 0in;line-height: normal;font-size:16px;font-family: \"Times New Roman\", serif;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-family: Verdana, Geneva, sans-serif;\"\u003e\u003cspan style=\"font-size: 11px;\"\u003e1\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 106.35pt;border-style: none solid solid none;border-bottom-width: 1pt;border-bottom-color: windowtext;border-right-width: 1pt;border-right-color: windowtext;padding: 0in 5.4pt;height: 22.7pt;\" width=\"27.680311890838208%\"\u003e\n \u003cp style='margin: 0in;line-height: normal;font-size:16px;font-family: \"Times New Roman\", serif;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-family: Verdana, Geneva, sans-serif;\"\u003e\u003cspan style=\"font-size: 11px;\"\u003e2\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 99.2pt;border-style: none solid solid none;border-bottom-width: 1pt;border-bottom-color: windowtext;border-right-width: 1pt;border-right-color: windowtext;padding: 0in 5.4pt;height: 22.7pt;\" width=\"25.730994152046783%\"\u003e\n \u003cp style='margin: 0in;line-height: normal;font-size:16px;font-family: \"Times New Roman\", serif;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-family: Verdana, Geneva, sans-serif;\"\u003e\u003cspan style=\"font-size: 11px;\"\u003e0\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp style='margin: 0in 0in 6pt 65.2pt;line-height: normal;font-size:13px;font-family: \"Times New Roman\", serif;text-indent: -65.75pt;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-family: Verdana, Geneva, sans-serif;\"\u003e\u003cspan style=\"font-size: 11px;\"\u003e\u003cstrong\u003eTable 1 \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;\u003c/strong\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003cspan style=\"font-family: Verdana, Geneva, sans-serif; font-size: 11px; color: rgb(0, 0, 0);\"\u003eCross table of resulting classifications by OGTT and HbA1c in patients who had both tests at baseline (n=75) and 12 months follow up (n=67)\u003c/span\u003e\u003c/p\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"cardiovascular-diabetology","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"cvdb","sideBox":"Learn more about [Cardiovascular Diabetology](http://cardiab.biomedcentral.com/)","snPcode":"12933","submissionUrl":"https://submission.nature.com/new-submission/12933/3","title":"Cardiovascular Diabetology","twitterHandle":"@BioMedCentral","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"BMC/SO AJ","inReviewEnabled":true,"inReviewRevisionsEnabled":true},"keywords":"risk assessment, fasting glucose, HbA1c, oral glucose tolerance test, acute stroke, type 2 diabetes, glucose abnormalities","lastPublishedDoi":"10.21203/rs.3.rs-50549/v3","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-50549/v3","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cem\u003eBackground:\u003c/em\u003e Diabetes is an increasingly important risk factor for ischemic stroke and worsens stroke prognosis. \u0026nbsp;Yet a large proportion of stroke patients who are eventually diabetic are undiagnosed. Therefore, it is important to have sensitive assessment of unrecognized hyperglycaemia in stroke patients.\u003c/p\u003e\u003cp\u003e\u003cem\u003eDesign:\u003c/em\u003e Secondary outcome analysis of a randomized controlled trial focussing on parameters of glucose metabolism and detection of diabetes and prediabetes in patients with acute ischemic stroke (AIS).\u003c/p\u003e\u003cp\u003e\u003cem\u003eMethods:\u003c/em\u003e \u0026nbsp;A total of 130 consecutively admitted patients with AIS without previously known type 2 diabetes mellitus (T2DM) were screened for diabetes or prediabetes as part of secondary outcome analysis of a randomized controlled trial that tested lifestyle intervention to prevent post-stroke cognitive decline. Patients had the oral glucose tolerance test (OGTT) and glycated hemoglobin (HbA1c) measurements in the second week after stroke onset and after one year.\u0026nbsp;The detection rates of diabetes and prediabetes based on the OGTT or HbA1c values were compared.\u003c/p\u003e\u003cp\u003e\u003cem\u003eResults\u003c/em\u003e: By any of the applied tests at the second week after stroke onset 62 of 130 patients (48%) had prediabetes or T2DM. Seventy-five patients had results from both tests available, the OGTT and HbA1c; according to the OGTT 40 (53.3%) patients had normal glucose metabolism, 33 (44%) had prediabetes, two (2.7%) T2DM. In 50 (66.7%) patients the HbA1c results were normal, 24 (32%) in the prediabetic and one (1.3%) in the diabetic range. The detection rate for disorders of glucose metabolism was 10% higher (absolute difference; relative difference 29%) with the OGTT compared with HbA1c. After one year the detection rate for prediabetes or T2DM was 7% higher with the OGTT (26% relative difference).\u003c/p\u003e\u003cp\u003eThe study intervention led to a more favourable evolution of glycemic status after one year.\u003c/p\u003e\u003cp\u003e\u003cem\u003eConclusion: \u003c/em\u003eThe OGTT is a more sensitive screening tool than HbA1c for the detection of previously unrecognized glycemic disorders in patients with acute stroke with an at least a 25% relative difference in detection rate. Therefore, an OGTT should be performed in all patients with stroke with no history of diabetes.\u003c/p\u003e","manuscriptTitle":"Comparison of oral glucose tolerance test and HbA1c in detection of disorders of glucose metabolism in patients with acute stroke","msid":"","msnumber":"","nonDraftVersions":[{"code":3,"date":"2020-11-18 15:28:09","doi":"10.21203/rs.3.rs-50549/v3","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Accept","date":"2020-11-18T00:00:00+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2020-11-16T00:00:00+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2020-11-15T23:00:00+00:00","index":"","fulltext":""},{"type":"editorInvited","content":"","date":"2020-11-15T23:00:00+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"cardiovascular-diabetology","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"cvdb","sideBox":"Learn more about [Cardiovascular Diabetology](http://cardiab.biomedcentral.com/)","snPcode":"12933","submissionUrl":"https://submission.nature.com/new-submission/12933/3","title":"Cardiovascular Diabetology","twitterHandle":"@BioMedCentral","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"BMC/SO AJ","inReviewEnabled":true,"inReviewRevisionsEnabled":true}},{"code":2,"date":"2020-11-05 19:07:52","doi":"10.21203/rs.3.rs-50549/v2","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Minor Revision","date":"2020-11-08T00:00:00+00:00","index":"","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2020-11-04T00:00:00+00:00","index":1,"fulltext":"Recommendation: Reviewer's comments unavailable due to the journal's policy.\n"},{"type":"editorInvitedReview","content":"","date":"2020-11-04T00:00:00+00:00","index":2,"fulltext":"Recommendation: Reviewer's comments unavailable due to the journal's policy.\n"},{"type":"reviewerAgreed","content":"","date":"2020-10-29T00:00:00+00:00","index":3,"fulltext":""},{"type":"reviewerAgreed","content":"","date":"2020-10-28T01:00:00+00:00","index":2,"fulltext":""},{"type":"reviewersInvited","content":"","date":"2020-10-28T00:00:00+00:00","index":"","fulltext":""},{"type":"reviewerAgreed","content":"","date":"2020-10-28T00:00:00+00:00","index":1,"fulltext":""},{"type":"editorAssigned","content":"","date":"2020-10-27T00:00:00+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2020-10-26T23:00:00+00:00","index":"","fulltext":""},{"type":"editorInvited","content":"","date":"2020-10-26T23:00:00+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"cardiovascular-diabetology","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"cvdb","sideBox":"Learn more about [Cardiovascular Diabetology](http://cardiab.biomedcentral.com/)","snPcode":"12933","submissionUrl":"https://submission.nature.com/new-submission/12933/3","title":"Cardiovascular Diabetology","twitterHandle":"@BioMedCentral","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"BMC/SO AJ","inReviewEnabled":true,"inReviewRevisionsEnabled":true}},{"code":1,"date":"2020-08-03 17:10:43","doi":"10.21203/rs.3.rs-50549/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"reviewerAgreed","content":"","date":"2020-09-03T12:00:00+00:00","index":4,"fulltext":""},{"type":"editorInvitedReview","content":"","date":"2020-09-03T12:00:00+00:00","index":3,"fulltext":"Recommendation: Reviewer's comments unavailable due to the journal's policy.\n"},{"type":"editorInvitedReview","content":"","date":"2020-09-03T12:00:00+00:00","index":4,"fulltext":"Recommendation: Reviewer's comments unavailable due to the journal's policy.\n"},{"type":"decision","content":"Major Revision","date":"2020-09-03T12:00:00+00:00","index":"","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2020-08-17T12:00:00+00:00","index":2,"fulltext":"Recommendation: Reviewer's comments unavailable due to the journal's policy.\n"},{"type":"reviewerAgreed","content":"","date":"2020-08-16T12:00:00+00:00","index":2,"fulltext":""},{"type":"reviewerAgreed","content":"","date":"2020-08-16T12:00:00+00:00","index":3,"fulltext":""},{"type":"editorInvitedReview","content":"","date":"2020-08-14T12:00:00+00:00","index":1,"fulltext":"Recommendation: Reviewer's comments unavailable due to the journal's policy.\n"},{"type":"reviewersInvited","content":"","date":"2020-08-13T12:00:00+00:00","index":"","fulltext":""},{"type":"reviewerAgreed","content":"","date":"2020-08-13T12:00:00+00:00","index":1,"fulltext":""},{"type":"editorAssigned","content":"","date":"2020-08-12T12:00:00+00:00","index":"","fulltext":""},{"type":"editorInvited","content":"","date":"2020-08-11T12:00:00+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2020-07-30T12:00:00+00:00","index":"","fulltext":""},{"type":"submitted","content":"","date":"2020-07-28T12:00:00+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"cardiovascular-diabetology","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"cvdb","sideBox":"Learn more about [Cardiovascular Diabetology](http://cardiab.biomedcentral.com/)","snPcode":"12933","submissionUrl":"https://submission.nature.com/new-submission/12933/3","title":"Cardiovascular Diabetology","twitterHandle":"@BioMedCentral","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"BMC/SO AJ","inReviewEnabled":true,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"d72fd3b7-84db-451e-ae38-51e8e8ec20e3","owner":[],"postedDate":"November 18th, 2020","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[{"id":991924,"name":"Cardiac \u0026 Cardiovascular Systems"}],"tags":[],"updatedAt":"2020-12-06T15:02:46+00:00","versionOfRecord":{"articleIdentity":"rs-50549","link":"https://doi.org/10.1186/s12933-020-01182-6","journal":{"identity":"cardiovascular-diabetology","isVorOnly":false,"title":"Cardiovascular Diabetology"},"publishedOn":"2020-12-05 15:01:21","publishedOnDateReadable":"December 5th, 2020"},"versionCreatedAt":"2020-11-18 15:28:09","video":"","vorDoi":"10.1186/s12933-020-01182-6","vorDoiUrl":"https://doi.org/10.1186/s12933-020-01182-6","workflowStages":[]},"version":"v3","identity":"rs-50549","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-50549","identity":"rs-50549","version":["v3"]},"buildId":"WrCJVZZCHTDjtuVLN7oU0","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}