HbA1c as a screening tool for diabetes mellitus and its use with traditional and novel biochemical parameters to predict cardiovascular risk in a local urban community

Zemlin, Annalise E. (2016-12)

Thesis (PhD)--Stellenbosch University, 2016.

Thesis

ENGLISH SUMMARY: Introduction The global obesity pandemic has reached Africa and the diabetes mellitus (DM) prevalence is increasing in parallel. A high prevalence of DM and risk for cardiovascular disease (CVD) has been described in the South African mixed ancestry population. Recent guidelines advocate using HbA1c as a diagnostic tool for DM and prediabetes, which is more convenient. However, various studies have challenged these cut-offs. There is a paucity of studies validating these cut-offs in Africa. As DM is considered a CVD risk equivalent, emerging markers of CVD and adiposity also need evaluation. The adipokine adiponectin has anti-diabetic, anti-atherogenic and anti-inflammatory properties and levels decrease in obesity. E-selectin, a marker of endothelial cell dysfunction, is associated with subclinical atherosclerosis and hyperglycaemia. Carotid intima-media thickness (CIMT) is a noninvasive measure of subclinical atherosclerosis. The aim of this investigation was to verify recommended HbA1c cut-offs to diagnose DM and prediabetes and to examine the usefulness of emerging markers of subclinical CVD in our population. Methods This investigation consists of four substudies and was performed on participants of the Bellville South Africa Study. In the first, we challenged the recommended HbA1c cut-off of 6.5% to diagnose DM in 946 participants using oral glucose tolerance test (OGTT), fasting blood glucose (FBG), and receiver operator characteristic (ROC) curves. In the second, we derived an optimal HbA1c cut-off to detect prediabetes in 667 participants and validated this in two populations, using OGTT and ROC curves. In the third, we determined high molecular weight (hmw)-adiponectin levels in 101 participants, compared these in participants with and without hyperglycaemia and investigated their relationship with two polymorphisms (rs17300539 and rs266729) reported to affect adiponectin values. In the fourth, we determined E-selectin levels in 307 participants, compared these in participants with and without hyperglycaemia and assessed their effect on CIMT. Results The recommended HbA1c cut-off was not sensitive enough to detect DM. Using FBG, 117 (14%) participants were diagnosed with DM and 50% had an HbA1c of  6.5%; using OGTT 147 (18%) had DM and 46% had an HbA1c of  6.5%. Comparing HbA1c to FBG and OGTT, a cut-off of 6.1% gave a better sensitivity and specificity (area under curve (AUC) 0.85 and 0.82 respectively). Also, the recommended HbA1c cut-off to detect prediabetes was not appropriate and we determined that 5.75% was best. However, the low sensitivity and specificity (64.8% and 60.4% respectively for the derivation and first validation sample and 59.6% and 69.8% for the second validation sample), confirmed that HbA1c alone would miss a significant number of prediabetics. Hmw-adiponectin levels were not affected by glycaemia (median 11.6 g/mL in normoglycaemia vs. 10.5 g/mL in hyperglycaemia; p=0.3060) nor by two common polymorphisms. Using robust correlations, a significant correlation was found between hmw-adiponectin and high density lipoprotein cholesterol (HDL-c) (r=0.45; 95%CI: 0.27-0.59), which was similar in both normo-and hyperglycaemia (p>0.99). This association was attenuated in robust linear regressions adjusted for gender and adiposity. Eselectin levels were significantly higher in hyperglycaemia (median 139.8 g/L vs. 118.8 g/L in normoglycaemia; p=0.0007) but not associated with CIMT. Significant correlations were found between E-selectin and age, markers of glycaemia and inflammation, central obesity and lipid variables. Associations remained significant only with age, hyperglycaemia and C-reactive protein (CRP) in multivariable robust linear regression models. In similar regressions models, age and gender were the main predictors of CIMT, which was not associated with E-selectin. Conclusion The international HbA1c cut-offs recommended to detect DM and prediabetes were not appropriate in our population. Though a cut-off of 6.5% to diagnose DM is a good diagnostic tool with high specificity, the low sensitivity limits its screening use. Similarly, recommended HbA1c values to detect prediabetes may underestimate the true numbers. This emphasizes the importance of local evidence-based values being established. Additionally, hmw-adiponectin was not affected by glycaemia or polymorphisms, but correlated significantly with HDL-c which may explain its beneficial cardiovascular effect. Though Eselectin was influenced by glycaemia, possibly reflecting early endothelial damage, it did not correlate with CIMT, which was determined by age and male gender.

AFRIKAANSE OPSOMMING: Inleiding Die globale obesiteits pandemie is ook in Afrika aanwesig, en daarmee saam is daar „n styging in die prevalensie van diabetes mellitus (DM). Daar is bevind dat die Suid Afrikaanse gemengde afkoms populasie „n hoë prevalensie van DM asook „n verhoogde risiko van kardiovaskulere siekte (KVS) het. Huidige riglyne beveel aan dat HbA1c gebruik word as „n diagnostiese toets vir DM en prediabetes, wat baie geriefliker is. Maar studies in verskillende populasiegroepe bevraagteken hierdie afsnypunte. Daar is „n gebrek aan validasie studies van hierdie afsnypunte vanuit Afrika. Aangesien DM beskou word as „n KVS risiko ekwivalent, behoort nuwe merkers van KVS en obesiteit in ons populasie ge-evalueer te word. Die adipokine adiponektien het anti-diabetiese, anti-aterogene en anti-inflammatoriese kenmerke en vlakke daal in obesiteit. E-selektien, „n merker van endoteelsel disfunksie, is geassosieer met subkliniese aterosklerose en hiperglisemie. Meting van die karotis intima-media dikte (KIMD) is „n nie-indringende metode om subkliniese aterosklerose te bepaal. Die doel van hierdie studie is om die afsnypunte van HbA1c om DM en prediabetes te diagnoseer te verifieer en om die nut van nuwer merkers van subkliniese KVS in ons populasie te evalueer. Metodes Hierdie ondersoek bestaan uit vier substudies en is uitgevoer op deelnemers van die Bellville- South Africa Projek. In die eerste studie, bevraagteken ons die HbA1c afsnypunt van 6.5% om DM te diagnoseer in 946 deelnemers deur middel van die orale glukose toleransie toets (OGTT) of „n vastende bloedglukose (VBG) te bepaal, en het die optimale HbA1c afsnypunt te bepaal met behulp van “receiver operator characteristic (ROC)” kurwes. In die tweede, het ons die optimale HbA1c afsnypunt om prediabetes te diagnoseer in 667 deelnemers bepaal, en hierdie waarde bevestig in twee daaropvolgende studiegroepe met die hulp van OGTT en ROC kurwes. In die derde, het ons hoë molekulere gewig (hmg)-adiponektien vlakke bepaal in 101 deelnemers, dit vergelyk dié met en sonder hiperglisemie en te ondersoek of hierdie vlakke beïnvloed word deur twee polimorfismes (rs17300539 en rs266729) wat beskryf is om adiponektien vlakke te beïnvloed. In die vierde het ons E-selektien vlakke op 307 deelnemers bepaal, die vlakke vergelyk in dié met en sonder hiperglisemie, en gekorreleer met KIMD. Resultate Die aanbevole HbA1c afsnypunt om DM te diagnoseer is nie sensitief genoeg is in ons bevolking nie. Deur net VBG te gebruik, is 117 (14%) met DM gediagnoseer en slegs 50% het „n HbA1c waarde van  6.5% gehad. Deur middel van OGTT is 147 (18%) met DM gediagnoseer en 46% het „n HbA1c waarde van  6.5% gehad. Deur HbA1c met VBG en OGTT te vergelyk, is daar bepaal dat „n afsnypunt van 6.1% „n beter sensitiwiteit en spesifisiteit gee (Area onder Kurwe (AOK) 0.85 en 0.82 respektiewelik). Ons het verder bevind dat die aanbevole HbA1c afsnypunt om prediabetes te diagnoseer nie toepaslik is nie en dat „n afsnypunt van 5.75% beter is. Maar die lae sensitiwiteit en spesifisiteit (64.8% en 60.4% onderskeidelik vir die afleiding en eerste bevestigings groep en 59.6% en 69.8% onderskeidelik vir die tweede bevestigingsgroep) het bewys dat HbA1c alleen „n beduidende hoeveelheid mense met prediabetes sou mis. Hmg-adiponektien vlakke was nie geaffekteer deur glisemie nie (mediaan 11.6 g/mL in normoglisemie en 10.5 g/mL in hiperglisemie; p=0.3060) en is ook nie geaffekteer deur twee algemene polimorfismes nie. Deur middel van robuuste korrelasies is „n beduidende korrelasie gevind tussen hmg-adiponektien en hoëdigtheidslipoproteïen cholesterol (HDL-c) (r=0.45; 95%CI: 0.27-0.59), wat soortgelyk was in die normo- en hiperglisemiese deelnemers (p>0.99). Hierdie assosiasie is betekenisvol verswak in robuuste liniêre regressive berekeninge wat gekorrigeer het vir geslag en obesiteit. E-selektien vlakke was betekenisvol hoër in hiperglisemie (mediaan 139.8 g/L teenoor 118.8 g/L in normoglisemie; p=0.0007) maar was nie geassosieerd met KIMD nie. Betekenisvolle korrelasies is gevind tusen E-selektien en ouderdom, merkers van glisemie en inflammasie, sentrale obesiteit en lipiedwaardes. Met meerveranderlike robuuste liniêre regressie modelle, het hierdie verhoudings betekenisvol gebly slegs met ouderdom, hiperglisemie en C-reaktiewe proteien (CRP). In soortgelyke regressie modelle, was ouderdom en geslag die hoof voorspellers van KIMD, wat nie geassossieer was met Eselektienvlakke nie. Gevolgtrekking Die internasionale aanbevole HbA1c afsnypunte om DM en prediabetes te diagnoseer is nie toepaslik in ons bevolking nie. Alhoewel die afsnypunt van 6.5% om DM te diagnoseer „n goeie diagnostiese metode is met „n hoë spesifisiteit, beperk die lae sensitiwiteit die siftings gebruik hiervan. Die aanbevole HbA1c afsnypunt om prediabetes te diagnoseer mag die toestand in ons bevolking onderdiagnoseer. Dit beklemtoon die belangrikheid dat uitkomsgebaseerde afsnypunte vir Afrikabevolkings bepaal en bevestig moet word. Daarbenewens is gevind dat hmg-adiponektien nie geaffekteer is deur glisemie of polimorfismes nie, maar dat dit betekenisvol korreleer met HDL-c wat die voordelige kardiovaskulere effekte van hierdie merker mag verduidelik. Alhoewel die endoteeldisfunksie merker E-selektien beïnvloed was deur hiperglisemie, moontlik as gevolg van vroeë endoteelskade, het dit nie gekorreleer met KIMD nie. Laasgenoemde is wel beïnvloed deur ouderdom en manlike geslag.

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