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Reversion from prediabetes to normoglycaemia and risk of cardiovascular disease and mortality: the Whitehall II cohort study

Reversion from prediabetes to normoglycaemia and risk of cardiovascular disease and mortality:... Aims/hypothesis Reversion from prediabetes to normoglycaemia is accompanied by an improvement in cardiovascular risk factors, but it is unclear whether this translates into a reduction in risk of cardiovascular disease (CVD) events or death. Hence, we studied the probability of reversion from prediabetes to normoglycaemia and the associated risk of future CVD and death using data from the Whitehall II observational cohort study. Methods Three glycaemic criteria for prediabetes (fasting plasma glucose [FPG] 5.6–6.9 mmol/l, 2 h plasma glucose [2hPG] 7.8–11.0 mmol/l, and HbA 39–47 mmol/mol [5.7–6.4%]) were assessed in 2002–2004 and 2007–2009 for 5193 participants 1c free of known diabetes at enrolment. Among participants with prediabetes in the first examination, we calculated the probability of reversion to normoglycaemia by re-examination according to each glycaemic criterion. Poisson regression analysis was used to estimate and compare incidence rates of a composite endpoint of a CVD event or death in participants with prediabetes who did vs did not revert to normoglycaemia. Analyses were adjusted for age, sex, ethnicity and previous CVD. Results Based on the FPG criterion, 820 participants had prediabetes and 365 (45%) of them had reverted to normoglycaemia in 5 years. The corresponding numbers were 324 and 120 (37%) for the 2hPG criterion and 1709 and 297 (17%) for the HbA 1c criterion. During a median follow-up of 6.7 (interquartile range 6.3–7.2) years, 668 events of non-fatal CVD or death occurred among the 5193 participants. Reverting from 2hPG-defined prediabetes to normoglycaemia vs remaining prediabetic or progressing to diabetes was associated with a halving in event rate (12.7 vs 29.1 per 1000 person-years, p = 0.020). No associ- ation with event rate was observed for reverting from FPG-defined (18.6 vs 18.2 per 1000 person-years, p =0.910) or HbA - 1c defined prediabetes to normoglycaemia (24.5 vs 22.9 per 1000 person-years, p =0.962). Conclusions/interpretation Most people with HbA -defined prediabetes remained prediabetic or progressed to diabetes during 1c 5 years of follow-up. In contrast, reversion to normoglycaemia was frequent among people with FPG- or 2hPG-defined predi- abetes. Only reversion from 2hPG-defined prediabetes to normoglycaemia was associated with a reduction in future risk of CVD and death. Electronic supplementary material The online version of this article (https://doi.org/10.1007/s00125-019-4895-0) contains peer-reviewed but unedited supplementary material, which is available to authorised users. * Dorte Vistisen Department of Medicine, Division of Endocrinology, Metabolism [email protected] and Diabetes, University of Colorado, Anschutz Medical Campus, Aurora, CO, USA * Mika Kivimäki [email protected] Department of Public Health, Aarhus University, Aarhus, Denmark Danish Diabetes Academy, Odense, Denmark Department of Clinical Epidemiology, Steno Diabetes Center Steno Diabetes Center Aarhus, Aarhus, Denmark Copenhagen, Niels Steensens Vej 6, DK-2820 Gentofte, Denmark First Department of Medicine, Faculty of Medicine, Semmelweis University, Budapest, Hungary Department of Epidemiology and Public Health, University College The Research Department for Health and Morbidity in the London, 1–19 Torrington Place, London WC1E 7HB, UK Population, Southern Denmark University, Copenhagen, Denmark 1386 Diabetologia (2019) 62:1385–1390 . . . . . . Keywords 2 h Plasma glucose Cardiovascular disease Fasting plasma glucose HbA Mortality Normoglycaemia 1c Prediabetes Reversion Abbreviations 2 h plasma glucose (2hPG) and HbA were measured. From 1c 2hPG 2 h plasma glucose the 6967 participants at phase 7, we excluded 671 (9.6%) who CVD Cardiovascular disease did not participate at phase 9, 392 (5.6%) with known diabetes FPG Fasting plasma glucose at phase 7, 684 (9.8%) who could not be classified with IEC International Expert Committee normoglycaemia, prediabetes or diabetes at both phases on at least one criterion, and 27 (0.4%) with screen-detected diabetes according to all the three criteria at phase 7, leaving 5193 (74.5%) of the phase 7 participants for analysis (ESM Fig. 1). Introduction For the analyses of FPG and 2hPG, participants had to have Prediabetes increases the risk of cardiovascular disease (CVD) fasted for ≥8 h before the clinical examinations. The University and mortality [1, 2], and reversion from prediabetes to College London Ethics Committee reviewed and approved the normoglycaemia is related to an improvement in a range of study. Written informed consent was obtained from all partici- pants at each study phase. cardiovascular risk factors [3]. However, whether reversion translates into a reduction in risk of CVD or death has yet to Measurements and definitions Participants underwent a stan- be determined. To fill this knowledge gap, the current analysis explored the probability of reversion from prediabetes to dard 75 g OGTT with measurement of FPG and 2hPG using the glucose oxidase method [4]. HbA was measured in normoglycaemia from different definitions of prediabetes 1c and the associated risk of future CVD and death in a longitu- whole blood, drawn into BD Vacutainers (Becton Dickinson, Winnersh, UK), using the validated Tosoh G8 high- dinal follow-up of the well-described Whitehall II observa- tional cohort study. performance ion-exchange liquid chromatography platform (Tosoh Bioscience, Tessenderlo, Belgium). Prediabetes was defined as FPG 5.6–6.9 mmol/l, 2hPG 7.8– 11.0 mmol/l and/or HbA 39–47 mmol/mol (5.7–6.4%) ac- Methods 1c cording to criteria from the ADA [5]. For each of the three criteria, normoglycaemia and diabetes were defined as values Study population The Whitehall II study is an occupational below and above the cut-off points for prediabetes, respectively. cohort of 10,308 British civil servants who have been followed Diabetes could also be diagnosed by a doctor outside the study. up with clinical examinations every 5 years since 1985 [4]. The The primary outcome was a composite endpoint of a CVD current analysis utilised data from phase 7 (2002–2004) and event or death between 2007–2009 (phase 9) and the end of phase 9 (2007–2009), when fasting plasma glucose (FPG), Diabetologia (2019) 62:1385–1390 1387 follow-up (30 June 2015). Adjudicated CVD events included FPG criterion Among 820 participants with FPG-defined pre- fatal and non-fatal myocardial infarction and stroke [2]. All- diabetes at baseline, 365 (45%) reverted to normoglycaemia cause mortality was obtained from the NHS Central Registry, and 111 (14%) progressed to diabetes at the 5 year re-exami- which provided information on the cause and date of death. nation. From the 5 year re-examination, median (interquartile range) follow-up time was 6.7 (6.3–7.2) years, during which Statistical analysis All analyses were conducted separately for 96 (12%) developed CVD or died. Reverting from prediabetes the three glycaemic criteria, in accordance with the guidelines to normoglycaemia was not associated with a difference in from ADA [5] and the International Expert Committee (IEC) rate of developing CVD or dying vs remaining prediabetic [6], which suggest that the different criteria to define predia- or progressing to diabetes (18.6 vs 18.2 per 1000 person- betes and diabetes should not be combined. For each criterion, years, p =0.962) (Fig. 1a, ESM Table 1). participants with screen-detected diabetes at baseline by the given glycaemic criterion were excluded. 2hPG criterion Among 324 participants with 2hPG-defined Among individuals with prediabetes at phase 7, we calcu- prediabetes at baseline, 120 (37%) reverted to normoglycaemia lated the probability of reversion to normoglycaemia at the and73(23%) progressedtodiabetesafter 5years.Follow-up phase 9 re-examination approximately 5 years later. Poisson time for CVD and death was 6.7 (6.4–7.2) years, during which regression analysis with log(person time) as offset was used to 47 (15%) developed CVD or died. Reverting from prediabetes estimate and compare incidence rates of future CVD or death to normoglycaemia was associated with a halving of the event in individuals with prediabetes who did or did not revert to rate vs remaining prediabetic/progressing to diabetes (12.7 vs normoglycaemia. The follow-up period of each participant 29.1 per 1000 person-years, p = 0.020), and was largely un- was split into 1 year age bands to account for the non- changed after adjustment for age, sex, ethnicity and previous constant effect of age over time on CVD risk and mortality. CVD (Fig. 1a,ESM Table 1). Analyses were adjusted for age, sex, ethnicity and previous Among the 324 participants with prediabetes at baseline, CVD. A complete case approach was used. 220 also had prediabetes according to the FPG and/or HbA 1c All participants with 2hPG available also had measure- criteria. At the 5 year re-examination, 21 (10%) of these had ments of FPG and HbA (but not vice versa). Among partic- reverted to normoglycaemia according to the FPG and/or 1c ipants with 2hPG-defined prediabetes and elevated FPG and/ HbA criteria but not according to the 2hPG criterion. 1c or HbA , we compared event rates between participants who However, improvement in FPG or HbA without improve- 1c 1c did or did not revert to normoglycaemia on FPG and/or ment in 2hPG was not associated with a lower event rate (32.1 HbA , without normalising 2hPG (ESM Fig.1). vs 28.8 per 1000 person-years, respectively, p =0.835). 1c We further estimated the associations of changes in FPG, 2hPG or HbA from phase 7 to phase 9 with risk of future HbA criterion Among 1709 participants with HbA -defined 1c 1c 1c CVD or death, excluding participants with known diabetes at prediabetes at baseline, 297 (17%) reverted to normoglycaemia phase 9 because they were likely to be receiving treatment. and233 (14%)progressedtodiabetesafter 5 years.Follow-up Statistical analyses were performed in R, version 3.4.1 (R time for an event was 6.7 (6.3–7.2) years, during which 258 Foundation for Statistical Computing, Vienna, Austria). (15%) developed CVD or died. Reverting from prediabetes to normoglycaemia was not associated with a difference in rate of developing CVD or dying vs remaining prediabetic/progressing Results to diabetes (24.5 vs 22.9 per 1000 person-years, p =0.962) (Fig. 1a,ESM Table 1). The study population was predominantly men (73%) and of The analysis of absolute changes in FPG, 2hPG or HbA 1c white ethnicity (93%), 769 (15%) had pre-existing CVD, and from phase 7 to phase 9 confirmed the results (Fig. 1b,ESM the average age was 60 years (range 50–73 years) at the first Table 2). clinical examination (phase 7). During a median follow-up of 6.7 (interquartile range 6.3–7.2) years, 668 events of non-fatal CVD or death occurred among the 5193 participants. Discussion Comparing normoglycaemia vs prediabetes by each glycaemic criterion (Table 1), more men than women had In this cohort study, reversion from 2hPG-defined prediabetes prediabetes defined by FPG whereas no sex difference was to normoglycaemia was associated with an approximately observed for prediabetes defined by 2hPG or HbA . 50% lower risk of a CVD event or death compared with re- 1c Participants with 2hPG- or HbA -, but not FPG-defined pre- maining with prediabetes or progressing to diabetes. Despite 1c diabetes were older (p < 0.001) and more likely to be of non- prediabetes being a known risk factor for CVD, we found that white ethnicity (p ≤ 0.044) compared with their reversion from FPG- or HbA -defined prediabetes to 1c normoglycaemic counterparts. normoglycaemia was not associated with a lower risk of 1388 Diabetologia (2019) 62:1385–1390 Table 1 Characteristics of study participants at the first clinical examination (phase 7) by glycaemic criterion Characteristic FPG criterion 2hPG criterion HbA criterion 1c Normoglycaemia Prediabetes Normoglycaemia Prediabetes Normoglycaemia Prediabetes n 2130 820 2154 324 3337 1709 Men (%) 70.0 (68.1, 72.0) 83.9 (81.2, 86.4) 75.7 (73.8, 77.5) 76.2 (71.2, 80.8) 72.6 (71.0, 74.1) 73.6 (71.5, 75.7) White ethnicity (%) 92.5 (91.3, 93.6) 93.2 (91.2, 94.8) 93.1 (91.9, 94.1) 89.8 (86.0, 92.9) 96.3 (95.6, 96.9) 89.4 (87.9, 90.8) Age (years) 60.2 ± 5.8 60.6 ± 5.8 59.6 ± 5.6 62.0 ± 6.1 60.2 ± 5.7 61.6 ± 5.9 BMI (kg/m ) 24.0 ± 3.1 24.9 ± 3.2 24.0 ± 3.1 24.9 ± 3.1 23.9 ± 3.0 24.6 ± 3.3 Total cholesterol (mmol/l) 5.7 ± 1.0 5.8 ± 1.0 5.7 ± 1.0 5.7 ± 1.0 5.7 ± 1.0 5.8 ± 1.0 HDL-cholesterol (mmol/l) 1.6 ± 0.5 1.5 ± 0.4 1.6 ± 0.4 1.5 ± 0.4 1.6 ± 0.5 1.5 ± 0.4 LDL-cholesterol (mmol/l) 3.5 ± 0.9 3.6 ± 0.9 3.6 ± 0.9 3.6 ± 0.9 3.5 ± 0.9 3.6 ± 0.9 Triacylglycerols (mmol/l) 1.1 (0.8–1.5) 1.2 (0.9–1.7) 1.1 (0.8–1.5) 1.3 (0.9–1.85) 1.1 (0.8–1.5) 1.2 (0.9–1.8) Systolic BP (mmHg) 126.0 ± 16.3 131.2 ± 16.4 125.6 ± 15.7 130.6 ± 16.7 126.3 ± 16.1 129.0 ± 16.3 Diastolic BP (mmHg) 73.6 ± 10.3 76.5 ± 10.1 73.7 ± 10.3 75.0 ± 10.2 73.8 ± 10.4 74.9 ± 10.2 FPG (mmol/l) 5.0 ± 0.3 5.9 ± 0.3 5.3 ± 0.5 5.6 ± 0.7 5.2 ± 0.5 5.5 ± 0.6 2hPG (mmol/l) 5.9 ± 1.5 6.9 ± 2.0 5.7 ± 1.1 8.9 ± 0.9 5.9 ± 1.5 6.6 ± 1.9 HbA (mmol/mol) 33.0 ± 4.0 35.0 ± 5 33.0 ± 4 36.0 ± 5 35.0 ± 3.0 42.0 ± 2.0 1c HbA (%) 5.2 ± 0.4 5.4 ± 0.4 5.2 ± 0.4 5.4 ± 0.4 5.4 ± 0.3 6.0 ± 0.2 1c Previous CVD (%) 12.4 (11.1, 13.9) 17.1 (14.6, 19.8) 12.5 (11.2, 14) 18.5 (14.4, 23.2) 11.4 (10.4, 12.6) 18.0 (16.2, 19.9) Family history of DM (%) 9.3 (8.1, 10.6) 12.3 (10.1, 14.8) 9.1 (7.9, 10.4) 10.0 (6.9, 13.8) 8.4 (7.4, 9.4) 12.2 (10.7, 13.9) Current smoker (%) 8.0 (6.9, 9.2) 7.9 (6.2, 10.0) 7.7 (6.6, 8.9) 4.6 (2.6, 7.5) 6.0 (5.2, 6.9) 9.2 (7.9, 10.7) Alcohol intake (units/week) 8.0 (2.0–16.0) 12.0 (5.0–21.0) 10.0 (4.0–18.0) 9.0 (3.0–17.0) 10.0 (4.0–18.0) 8.0 (2.0–16.0) Antihypertensive treatment (%) 19.5 (17.9, 21.3) 28.2 (25.1, 31.4) 18.4 (16.8, 20.1) 33.3 (28.2, 38.8) 17.9 (16.6, 19.3) 26.6 (24.5, 28.8) Lipid-lowering treatment (%) 7.8 (6.7, 9.0) 13.4 (11.2, 15.9) 7.5 (6.4, 8.7) 15.4 (11.7, 19.8) 6.9 (6.0, 7.8) 13.4 (11.8, 15.1) Data are means±SD, medians (25–75% percentiles; IQR) or proportions (95% CI) HbA : normoglycaemia: <39 mmol/mol (5.7%), prediabetes 39–47 mmol/mol (5.7–6.4%), Fasting plasma glucose: normoglycaemia: <5.6 mmol/l, 1c prediabetes 5.6–6.9 mmol/l, 2hPG: normoglycaemia: <7.8 mmol/l, prediabetes 7.8–11.0 mmol/l DM, diabetes mellitus CVD or death. Outside pregnancy, the OGTT has largely been Our results support previous findings from the Diabetes eliminated for diagnosing diabetes, particularly with the recent Prevention Program (DPP), where individuals with 2hPG- widespread standardisation of the HbA assay. However, our defined prediabetes who reverted to normoglycaemia experi- 1c findings suggest that identification of people with elevated enced a concomitant reduction in their cardiovascular risk 2hPG should be considered for CVD risk stratification either profile [9]. Previous observations from a general Dutch pop- by re-introducing the OGTT for diagnosing prediabetes and ulation also suggested that 2hPG levels are more strongly diabetes or by other methods [7, 8]. associated with all-cause and cardiovascular mortality than Fig. 1 Rate ratios (RRs) of an event (CVD or death) for reverting from prediabetes to normoglycaemia vs not reverting (a) or for decreasing 1 SD in glycaemic measure over 5 years from phase 7 to phase 9 (b). Grey: unadjusted RR; light blue: adjusting for age and sex; dark blue: further adjusting for previous CVD. The RR for 1 SD decrease (b) is further adjusted for baseline glycaemia in all the analyses. The x-axisisona natural logarithmic scale Diabetologia (2019) 62:1385–1390 1389 FPG or HbA levels in the non-diabetic range [10]. These 20 years [15]. In contrast, the lack of accepted guidelines 1c results may reflect underlying pathophysiological differences for people with prediabetes has made the prevalence of in, for example, insulin resistance, which is more pronounced diabetes-related complications now virtually identical for in elevated 2hPG than in elevated FPG and HbA [11]. people with prediabetes vs those with diabetes [16]. The 1c We found reversion to normoglycaemia from HbA - current findings highlight the reduced risk for CVD and 1c defined prediabetes to be less likely than from FPG- death associated with reversion from 2hPG-defined or 2hPG-defined prediabetes. While our results on prediabetes, specifically, to normoglycaemia. These find- reversion rates for FPG- and 2hPG-defined prediabetes ings have important implications for additional cardio- are consistent with previous findings [12], evidence on vascular risk stratification and intervention in a land- the ability to revert from HbA -defined prediabetes to scape that has become increasingly controversial [17]. 1c normoglycaemia is scarce [12]. A Japanese study Acknowledgements We thank all participating women and men in the reported a reversion rate of 32% in a study population Whitehall II study, as well as all Whitehall II research scientists, study and that was, on average, 10 years younger than the partici- data managers and clinical and administrative staff who make the study pants of the Whitehall II study [12]. There is less day-to- possible. Some of the data were presented as an abstract at the 15th day variation in HbA , and levels in the non-diabetic International Congress of Behavioral Medicine in 2018. 1c range may largely be explained by non-glycaemic Data availability Whitehall II data, protocols and other metadata are factors, such as age and ethnicity [13], and may therefore available to the scientific community. Please refer to the Whitehall II data not be modifiable to the same degree as FPG and 2hPG sharing policy at https://www.ucl.ac.uk/whitehallII/data-sharing. levels. We have chosen not to combine different definitions Funding The UK Medical Research Council (K013351, R024227), British Heart Foundation (RG/13/2/30098), and the US National of prediabetes and assess the impact of overall reverting Institutes of Health (R01HL36310, R01AG013196) have supported to normoglycaemia. Combining definitions is not in collection of data in the Whitehall II study. accordance with ADA and IEC and will greatly inflate AH and DRW are supported by the Danish Diabetes Academy, which the prevalence of prediabetes [14]. Furthermore, the is funded by an unrestricted grant from the Novo Nordisk Foundation. Support was further provided by the Steno Diabetes Center Aarhus corresponding state of normoglycaemia needs to be (SDCA) which is partially funded by an unrestricted donation from the defined as normal values on all three criteria, which Novo Nordisk Foundation. KF is supported by a grant from the Novo may not be relevant in clinical practice. Alternatively, Nordisk Foundation. MK is supported by the Medical Research Council specific states of prediabetes and normoglycaemia will (K013351, R024227, S011676), NordForsk, the Academy of Finland (311492) and Helsinki Institute of Life Sciences. The funders of the study have to be applied, resultinginnumeroustransition had no role in study design, data collection, analysis, interpretation or possibilities for which this study is not powered to writing of the report. examine (ESM Fig. 2 and 3). Results from the current analysis are strengthened by Duality of interest KF is funded by the Novo Nordisk Foundation. LP reports personal fees from Novo Nordisk, Merck Astra Zeneca, the longitudinal, well-described, large population size Boeringer-Ingelheim, Orexigen, Sanofi and Janssen. MK reports research and the validated ascertainment of CVD events. grants from the UK Medical Research Council (K013351, R024227, Nevertheless, reversion cannot be ascribed to interven- S011676), NordForsk, Academy of Finland and Helsinki Institute of tion effects, since the cohort is strictly observational, and Life Science during the conduct of the study. MEJ has received research grants from AstraZeneca, AMGEN AB, Sanofi Aventis and Boehringer- all conclusions remain associative and not necessarily Ingelheim (Investigator-initiated research). The other authors declare no causative. There is still controversy between different competing interests. diabetes organisations with respect to whether HbA 1c or FPG should be used to define prediabetes. Our results Contribution statement DVand KF contributed to the study concept and design, planned the statistical analyses and drafted the manuscript. DV did not show a reduced risk of CVD or death when conducted the statistical analysis. All authors contributed to the interpre- people with either HbA - or FPG-defined prediabetes 1c tation of data. EB, MK, AT and DW contributed to the acquisition of data. were able to revert to normoglycemia, based on the All authors revised the manuscript critically and approved the final ver- respective criterion. On the other hand, we found reversion sion of the manuscript. DV and KF are guarantors of the contents of the article and, as such, had full access to all the data in the study and take from 2hPG-defined prediabetes to be associated with a responsibility for the integrity of the data and the accuracy of the data halving of the risk of CVD and death. Although the different analysis. diagnostic criteria for prediabetes are likely to remain, the current results would contend that only reversion from Open Access This article is distributed under the terms of the Creative 2hPG-defined prediabetes to normoglycaemia is sensitive Commons Attribution 4.0 International License (http:// enough to detect cardiovascular benefit. creativecommons.org/licenses/by/4.0/), which permits unrestricted use, Guidelines for people with diabetes are increasingly distribution, and reproduction in any medium, provided you give appro- priate credit to the original author(s) and the source, provide a link to the comprehensive [5], and accordingly, the incidence of Creative Commons license, and indicate if changes were made. complications has dramatically decreased over the past 1390 Diabetologia (2019) 62:1385–1390 from the Diabetes Prevention Program Outcomes Study. 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Front Endocrinol 9(82). https://doi.org/10.3389/fendo.2018.00082 Publisher’snote Springer Nature remains neutral with regard to jurisdic- 9. Perreault L, Temprosa M, Mather KJ, Horton E, Kitabchi A, Larkin tional claims in published maps and institutional affiliations. M et al (2014) Regression from prediabetes to normal glucose reg- ulation is associated with reduction in cardiovascular risk: results http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Diabetologia Springer Journals

Reversion from prediabetes to normoglycaemia and risk of cardiovascular disease and mortality: the Whitehall II cohort study

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Springer Journals
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Copyright © 2019 by The Author(s)
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Medicine & Public Health; Internal Medicine; Metabolic Diseases; Human Physiology
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0012-186X
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1432-0428
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10.1007/s00125-019-4895-0
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Abstract

Aims/hypothesis Reversion from prediabetes to normoglycaemia is accompanied by an improvement in cardiovascular risk factors, but it is unclear whether this translates into a reduction in risk of cardiovascular disease (CVD) events or death. Hence, we studied the probability of reversion from prediabetes to normoglycaemia and the associated risk of future CVD and death using data from the Whitehall II observational cohort study. Methods Three glycaemic criteria for prediabetes (fasting plasma glucose [FPG] 5.6–6.9 mmol/l, 2 h plasma glucose [2hPG] 7.8–11.0 mmol/l, and HbA 39–47 mmol/mol [5.7–6.4%]) were assessed in 2002–2004 and 2007–2009 for 5193 participants 1c free of known diabetes at enrolment. Among participants with prediabetes in the first examination, we calculated the probability of reversion to normoglycaemia by re-examination according to each glycaemic criterion. Poisson regression analysis was used to estimate and compare incidence rates of a composite endpoint of a CVD event or death in participants with prediabetes who did vs did not revert to normoglycaemia. Analyses were adjusted for age, sex, ethnicity and previous CVD. Results Based on the FPG criterion, 820 participants had prediabetes and 365 (45%) of them had reverted to normoglycaemia in 5 years. The corresponding numbers were 324 and 120 (37%) for the 2hPG criterion and 1709 and 297 (17%) for the HbA 1c criterion. During a median follow-up of 6.7 (interquartile range 6.3–7.2) years, 668 events of non-fatal CVD or death occurred among the 5193 participants. Reverting from 2hPG-defined prediabetes to normoglycaemia vs remaining prediabetic or progressing to diabetes was associated with a halving in event rate (12.7 vs 29.1 per 1000 person-years, p = 0.020). No associ- ation with event rate was observed for reverting from FPG-defined (18.6 vs 18.2 per 1000 person-years, p =0.910) or HbA - 1c defined prediabetes to normoglycaemia (24.5 vs 22.9 per 1000 person-years, p =0.962). Conclusions/interpretation Most people with HbA -defined prediabetes remained prediabetic or progressed to diabetes during 1c 5 years of follow-up. In contrast, reversion to normoglycaemia was frequent among people with FPG- or 2hPG-defined predi- abetes. Only reversion from 2hPG-defined prediabetes to normoglycaemia was associated with a reduction in future risk of CVD and death. Electronic supplementary material The online version of this article (https://doi.org/10.1007/s00125-019-4895-0) contains peer-reviewed but unedited supplementary material, which is available to authorised users. * Dorte Vistisen Department of Medicine, Division of Endocrinology, Metabolism [email protected] and Diabetes, University of Colorado, Anschutz Medical Campus, Aurora, CO, USA * Mika Kivimäki [email protected] Department of Public Health, Aarhus University, Aarhus, Denmark Danish Diabetes Academy, Odense, Denmark Department of Clinical Epidemiology, Steno Diabetes Center Steno Diabetes Center Aarhus, Aarhus, Denmark Copenhagen, Niels Steensens Vej 6, DK-2820 Gentofte, Denmark First Department of Medicine, Faculty of Medicine, Semmelweis University, Budapest, Hungary Department of Epidemiology and Public Health, University College The Research Department for Health and Morbidity in the London, 1–19 Torrington Place, London WC1E 7HB, UK Population, Southern Denmark University, Copenhagen, Denmark 1386 Diabetologia (2019) 62:1385–1390 . . . . . . Keywords 2 h Plasma glucose Cardiovascular disease Fasting plasma glucose HbA Mortality Normoglycaemia 1c Prediabetes Reversion Abbreviations 2 h plasma glucose (2hPG) and HbA were measured. From 1c 2hPG 2 h plasma glucose the 6967 participants at phase 7, we excluded 671 (9.6%) who CVD Cardiovascular disease did not participate at phase 9, 392 (5.6%) with known diabetes FPG Fasting plasma glucose at phase 7, 684 (9.8%) who could not be classified with IEC International Expert Committee normoglycaemia, prediabetes or diabetes at both phases on at least one criterion, and 27 (0.4%) with screen-detected diabetes according to all the three criteria at phase 7, leaving 5193 (74.5%) of the phase 7 participants for analysis (ESM Fig. 1). Introduction For the analyses of FPG and 2hPG, participants had to have Prediabetes increases the risk of cardiovascular disease (CVD) fasted for ≥8 h before the clinical examinations. The University and mortality [1, 2], and reversion from prediabetes to College London Ethics Committee reviewed and approved the normoglycaemia is related to an improvement in a range of study. Written informed consent was obtained from all partici- pants at each study phase. cardiovascular risk factors [3]. However, whether reversion translates into a reduction in risk of CVD or death has yet to Measurements and definitions Participants underwent a stan- be determined. To fill this knowledge gap, the current analysis explored the probability of reversion from prediabetes to dard 75 g OGTT with measurement of FPG and 2hPG using the glucose oxidase method [4]. HbA was measured in normoglycaemia from different definitions of prediabetes 1c and the associated risk of future CVD and death in a longitu- whole blood, drawn into BD Vacutainers (Becton Dickinson, Winnersh, UK), using the validated Tosoh G8 high- dinal follow-up of the well-described Whitehall II observa- tional cohort study. performance ion-exchange liquid chromatography platform (Tosoh Bioscience, Tessenderlo, Belgium). Prediabetes was defined as FPG 5.6–6.9 mmol/l, 2hPG 7.8– 11.0 mmol/l and/or HbA 39–47 mmol/mol (5.7–6.4%) ac- Methods 1c cording to criteria from the ADA [5]. For each of the three criteria, normoglycaemia and diabetes were defined as values Study population The Whitehall II study is an occupational below and above the cut-off points for prediabetes, respectively. cohort of 10,308 British civil servants who have been followed Diabetes could also be diagnosed by a doctor outside the study. up with clinical examinations every 5 years since 1985 [4]. The The primary outcome was a composite endpoint of a CVD current analysis utilised data from phase 7 (2002–2004) and event or death between 2007–2009 (phase 9) and the end of phase 9 (2007–2009), when fasting plasma glucose (FPG), Diabetologia (2019) 62:1385–1390 1387 follow-up (30 June 2015). Adjudicated CVD events included FPG criterion Among 820 participants with FPG-defined pre- fatal and non-fatal myocardial infarction and stroke [2]. All- diabetes at baseline, 365 (45%) reverted to normoglycaemia cause mortality was obtained from the NHS Central Registry, and 111 (14%) progressed to diabetes at the 5 year re-exami- which provided information on the cause and date of death. nation. From the 5 year re-examination, median (interquartile range) follow-up time was 6.7 (6.3–7.2) years, during which Statistical analysis All analyses were conducted separately for 96 (12%) developed CVD or died. Reverting from prediabetes the three glycaemic criteria, in accordance with the guidelines to normoglycaemia was not associated with a difference in from ADA [5] and the International Expert Committee (IEC) rate of developing CVD or dying vs remaining prediabetic [6], which suggest that the different criteria to define predia- or progressing to diabetes (18.6 vs 18.2 per 1000 person- betes and diabetes should not be combined. For each criterion, years, p =0.962) (Fig. 1a, ESM Table 1). participants with screen-detected diabetes at baseline by the given glycaemic criterion were excluded. 2hPG criterion Among 324 participants with 2hPG-defined Among individuals with prediabetes at phase 7, we calcu- prediabetes at baseline, 120 (37%) reverted to normoglycaemia lated the probability of reversion to normoglycaemia at the and73(23%) progressedtodiabetesafter 5years.Follow-up phase 9 re-examination approximately 5 years later. Poisson time for CVD and death was 6.7 (6.4–7.2) years, during which regression analysis with log(person time) as offset was used to 47 (15%) developed CVD or died. Reverting from prediabetes estimate and compare incidence rates of future CVD or death to normoglycaemia was associated with a halving of the event in individuals with prediabetes who did or did not revert to rate vs remaining prediabetic/progressing to diabetes (12.7 vs normoglycaemia. The follow-up period of each participant 29.1 per 1000 person-years, p = 0.020), and was largely un- was split into 1 year age bands to account for the non- changed after adjustment for age, sex, ethnicity and previous constant effect of age over time on CVD risk and mortality. CVD (Fig. 1a,ESM Table 1). Analyses were adjusted for age, sex, ethnicity and previous Among the 324 participants with prediabetes at baseline, CVD. A complete case approach was used. 220 also had prediabetes according to the FPG and/or HbA 1c All participants with 2hPG available also had measure- criteria. At the 5 year re-examination, 21 (10%) of these had ments of FPG and HbA (but not vice versa). Among partic- reverted to normoglycaemia according to the FPG and/or 1c ipants with 2hPG-defined prediabetes and elevated FPG and/ HbA criteria but not according to the 2hPG criterion. 1c or HbA , we compared event rates between participants who However, improvement in FPG or HbA without improve- 1c 1c did or did not revert to normoglycaemia on FPG and/or ment in 2hPG was not associated with a lower event rate (32.1 HbA , without normalising 2hPG (ESM Fig.1). vs 28.8 per 1000 person-years, respectively, p =0.835). 1c We further estimated the associations of changes in FPG, 2hPG or HbA from phase 7 to phase 9 with risk of future HbA criterion Among 1709 participants with HbA -defined 1c 1c 1c CVD or death, excluding participants with known diabetes at prediabetes at baseline, 297 (17%) reverted to normoglycaemia phase 9 because they were likely to be receiving treatment. and233 (14%)progressedtodiabetesafter 5 years.Follow-up Statistical analyses were performed in R, version 3.4.1 (R time for an event was 6.7 (6.3–7.2) years, during which 258 Foundation for Statistical Computing, Vienna, Austria). (15%) developed CVD or died. Reverting from prediabetes to normoglycaemia was not associated with a difference in rate of developing CVD or dying vs remaining prediabetic/progressing Results to diabetes (24.5 vs 22.9 per 1000 person-years, p =0.962) (Fig. 1a,ESM Table 1). The study population was predominantly men (73%) and of The analysis of absolute changes in FPG, 2hPG or HbA 1c white ethnicity (93%), 769 (15%) had pre-existing CVD, and from phase 7 to phase 9 confirmed the results (Fig. 1b,ESM the average age was 60 years (range 50–73 years) at the first Table 2). clinical examination (phase 7). During a median follow-up of 6.7 (interquartile range 6.3–7.2) years, 668 events of non-fatal CVD or death occurred among the 5193 participants. Discussion Comparing normoglycaemia vs prediabetes by each glycaemic criterion (Table 1), more men than women had In this cohort study, reversion from 2hPG-defined prediabetes prediabetes defined by FPG whereas no sex difference was to normoglycaemia was associated with an approximately observed for prediabetes defined by 2hPG or HbA . 50% lower risk of a CVD event or death compared with re- 1c Participants with 2hPG- or HbA -, but not FPG-defined pre- maining with prediabetes or progressing to diabetes. Despite 1c diabetes were older (p < 0.001) and more likely to be of non- prediabetes being a known risk factor for CVD, we found that white ethnicity (p ≤ 0.044) compared with their reversion from FPG- or HbA -defined prediabetes to 1c normoglycaemic counterparts. normoglycaemia was not associated with a lower risk of 1388 Diabetologia (2019) 62:1385–1390 Table 1 Characteristics of study participants at the first clinical examination (phase 7) by glycaemic criterion Characteristic FPG criterion 2hPG criterion HbA criterion 1c Normoglycaemia Prediabetes Normoglycaemia Prediabetes Normoglycaemia Prediabetes n 2130 820 2154 324 3337 1709 Men (%) 70.0 (68.1, 72.0) 83.9 (81.2, 86.4) 75.7 (73.8, 77.5) 76.2 (71.2, 80.8) 72.6 (71.0, 74.1) 73.6 (71.5, 75.7) White ethnicity (%) 92.5 (91.3, 93.6) 93.2 (91.2, 94.8) 93.1 (91.9, 94.1) 89.8 (86.0, 92.9) 96.3 (95.6, 96.9) 89.4 (87.9, 90.8) Age (years) 60.2 ± 5.8 60.6 ± 5.8 59.6 ± 5.6 62.0 ± 6.1 60.2 ± 5.7 61.6 ± 5.9 BMI (kg/m ) 24.0 ± 3.1 24.9 ± 3.2 24.0 ± 3.1 24.9 ± 3.1 23.9 ± 3.0 24.6 ± 3.3 Total cholesterol (mmol/l) 5.7 ± 1.0 5.8 ± 1.0 5.7 ± 1.0 5.7 ± 1.0 5.7 ± 1.0 5.8 ± 1.0 HDL-cholesterol (mmol/l) 1.6 ± 0.5 1.5 ± 0.4 1.6 ± 0.4 1.5 ± 0.4 1.6 ± 0.5 1.5 ± 0.4 LDL-cholesterol (mmol/l) 3.5 ± 0.9 3.6 ± 0.9 3.6 ± 0.9 3.6 ± 0.9 3.5 ± 0.9 3.6 ± 0.9 Triacylglycerols (mmol/l) 1.1 (0.8–1.5) 1.2 (0.9–1.7) 1.1 (0.8–1.5) 1.3 (0.9–1.85) 1.1 (0.8–1.5) 1.2 (0.9–1.8) Systolic BP (mmHg) 126.0 ± 16.3 131.2 ± 16.4 125.6 ± 15.7 130.6 ± 16.7 126.3 ± 16.1 129.0 ± 16.3 Diastolic BP (mmHg) 73.6 ± 10.3 76.5 ± 10.1 73.7 ± 10.3 75.0 ± 10.2 73.8 ± 10.4 74.9 ± 10.2 FPG (mmol/l) 5.0 ± 0.3 5.9 ± 0.3 5.3 ± 0.5 5.6 ± 0.7 5.2 ± 0.5 5.5 ± 0.6 2hPG (mmol/l) 5.9 ± 1.5 6.9 ± 2.0 5.7 ± 1.1 8.9 ± 0.9 5.9 ± 1.5 6.6 ± 1.9 HbA (mmol/mol) 33.0 ± 4.0 35.0 ± 5 33.0 ± 4 36.0 ± 5 35.0 ± 3.0 42.0 ± 2.0 1c HbA (%) 5.2 ± 0.4 5.4 ± 0.4 5.2 ± 0.4 5.4 ± 0.4 5.4 ± 0.3 6.0 ± 0.2 1c Previous CVD (%) 12.4 (11.1, 13.9) 17.1 (14.6, 19.8) 12.5 (11.2, 14) 18.5 (14.4, 23.2) 11.4 (10.4, 12.6) 18.0 (16.2, 19.9) Family history of DM (%) 9.3 (8.1, 10.6) 12.3 (10.1, 14.8) 9.1 (7.9, 10.4) 10.0 (6.9, 13.8) 8.4 (7.4, 9.4) 12.2 (10.7, 13.9) Current smoker (%) 8.0 (6.9, 9.2) 7.9 (6.2, 10.0) 7.7 (6.6, 8.9) 4.6 (2.6, 7.5) 6.0 (5.2, 6.9) 9.2 (7.9, 10.7) Alcohol intake (units/week) 8.0 (2.0–16.0) 12.0 (5.0–21.0) 10.0 (4.0–18.0) 9.0 (3.0–17.0) 10.0 (4.0–18.0) 8.0 (2.0–16.0) Antihypertensive treatment (%) 19.5 (17.9, 21.3) 28.2 (25.1, 31.4) 18.4 (16.8, 20.1) 33.3 (28.2, 38.8) 17.9 (16.6, 19.3) 26.6 (24.5, 28.8) Lipid-lowering treatment (%) 7.8 (6.7, 9.0) 13.4 (11.2, 15.9) 7.5 (6.4, 8.7) 15.4 (11.7, 19.8) 6.9 (6.0, 7.8) 13.4 (11.8, 15.1) Data are means±SD, medians (25–75% percentiles; IQR) or proportions (95% CI) HbA : normoglycaemia: <39 mmol/mol (5.7%), prediabetes 39–47 mmol/mol (5.7–6.4%), Fasting plasma glucose: normoglycaemia: <5.6 mmol/l, 1c prediabetes 5.6–6.9 mmol/l, 2hPG: normoglycaemia: <7.8 mmol/l, prediabetes 7.8–11.0 mmol/l DM, diabetes mellitus CVD or death. Outside pregnancy, the OGTT has largely been Our results support previous findings from the Diabetes eliminated for diagnosing diabetes, particularly with the recent Prevention Program (DPP), where individuals with 2hPG- widespread standardisation of the HbA assay. However, our defined prediabetes who reverted to normoglycaemia experi- 1c findings suggest that identification of people with elevated enced a concomitant reduction in their cardiovascular risk 2hPG should be considered for CVD risk stratification either profile [9]. Previous observations from a general Dutch pop- by re-introducing the OGTT for diagnosing prediabetes and ulation also suggested that 2hPG levels are more strongly diabetes or by other methods [7, 8]. associated with all-cause and cardiovascular mortality than Fig. 1 Rate ratios (RRs) of an event (CVD or death) for reverting from prediabetes to normoglycaemia vs not reverting (a) or for decreasing 1 SD in glycaemic measure over 5 years from phase 7 to phase 9 (b). Grey: unadjusted RR; light blue: adjusting for age and sex; dark blue: further adjusting for previous CVD. The RR for 1 SD decrease (b) is further adjusted for baseline glycaemia in all the analyses. The x-axisisona natural logarithmic scale Diabetologia (2019) 62:1385–1390 1389 FPG or HbA levels in the non-diabetic range [10]. These 20 years [15]. In contrast, the lack of accepted guidelines 1c results may reflect underlying pathophysiological differences for people with prediabetes has made the prevalence of in, for example, insulin resistance, which is more pronounced diabetes-related complications now virtually identical for in elevated 2hPG than in elevated FPG and HbA [11]. people with prediabetes vs those with diabetes [16]. The 1c We found reversion to normoglycaemia from HbA - current findings highlight the reduced risk for CVD and 1c defined prediabetes to be less likely than from FPG- death associated with reversion from 2hPG-defined or 2hPG-defined prediabetes. While our results on prediabetes, specifically, to normoglycaemia. These find- reversion rates for FPG- and 2hPG-defined prediabetes ings have important implications for additional cardio- are consistent with previous findings [12], evidence on vascular risk stratification and intervention in a land- the ability to revert from HbA -defined prediabetes to scape that has become increasingly controversial [17]. 1c normoglycaemia is scarce [12]. A Japanese study Acknowledgements We thank all participating women and men in the reported a reversion rate of 32% in a study population Whitehall II study, as well as all Whitehall II research scientists, study and that was, on average, 10 years younger than the partici- data managers and clinical and administrative staff who make the study pants of the Whitehall II study [12]. There is less day-to- possible. Some of the data were presented as an abstract at the 15th day variation in HbA , and levels in the non-diabetic International Congress of Behavioral Medicine in 2018. 1c range may largely be explained by non-glycaemic Data availability Whitehall II data, protocols and other metadata are factors, such as age and ethnicity [13], and may therefore available to the scientific community. Please refer to the Whitehall II data not be modifiable to the same degree as FPG and 2hPG sharing policy at https://www.ucl.ac.uk/whitehallII/data-sharing. levels. We have chosen not to combine different definitions Funding The UK Medical Research Council (K013351, R024227), British Heart Foundation (RG/13/2/30098), and the US National of prediabetes and assess the impact of overall reverting Institutes of Health (R01HL36310, R01AG013196) have supported to normoglycaemia. Combining definitions is not in collection of data in the Whitehall II study. accordance with ADA and IEC and will greatly inflate AH and DRW are supported by the Danish Diabetes Academy, which the prevalence of prediabetes [14]. Furthermore, the is funded by an unrestricted grant from the Novo Nordisk Foundation. Support was further provided by the Steno Diabetes Center Aarhus corresponding state of normoglycaemia needs to be (SDCA) which is partially funded by an unrestricted donation from the defined as normal values on all three criteria, which Novo Nordisk Foundation. KF is supported by a grant from the Novo may not be relevant in clinical practice. Alternatively, Nordisk Foundation. MK is supported by the Medical Research Council specific states of prediabetes and normoglycaemia will (K013351, R024227, S011676), NordForsk, the Academy of Finland (311492) and Helsinki Institute of Life Sciences. The funders of the study have to be applied, resultinginnumeroustransition had no role in study design, data collection, analysis, interpretation or possibilities for which this study is not powered to writing of the report. examine (ESM Fig. 2 and 3). Results from the current analysis are strengthened by Duality of interest KF is funded by the Novo Nordisk Foundation. LP reports personal fees from Novo Nordisk, Merck Astra Zeneca, the longitudinal, well-described, large population size Boeringer-Ingelheim, Orexigen, Sanofi and Janssen. MK reports research and the validated ascertainment of CVD events. grants from the UK Medical Research Council (K013351, R024227, Nevertheless, reversion cannot be ascribed to interven- S011676), NordForsk, Academy of Finland and Helsinki Institute of tion effects, since the cohort is strictly observational, and Life Science during the conduct of the study. MEJ has received research grants from AstraZeneca, AMGEN AB, Sanofi Aventis and Boehringer- all conclusions remain associative and not necessarily Ingelheim (Investigator-initiated research). The other authors declare no causative. There is still controversy between different competing interests. diabetes organisations with respect to whether HbA 1c or FPG should be used to define prediabetes. Our results Contribution statement DVand KF contributed to the study concept and design, planned the statistical analyses and drafted the manuscript. DV did not show a reduced risk of CVD or death when conducted the statistical analysis. All authors contributed to the interpre- people with either HbA - or FPG-defined prediabetes 1c tation of data. EB, MK, AT and DW contributed to the acquisition of data. were able to revert to normoglycemia, based on the All authors revised the manuscript critically and approved the final ver- respective criterion. On the other hand, we found reversion sion of the manuscript. DV and KF are guarantors of the contents of the article and, as such, had full access to all the data in the study and take from 2hPG-defined prediabetes to be associated with a responsibility for the integrity of the data and the accuracy of the data halving of the risk of CVD and death. Although the different analysis. diagnostic criteria for prediabetes are likely to remain, the current results would contend that only reversion from Open Access This article is distributed under the terms of the Creative 2hPG-defined prediabetes to normoglycaemia is sensitive Commons Attribution 4.0 International License (http:// enough to detect cardiovascular benefit. creativecommons.org/licenses/by/4.0/), which permits unrestricted use, Guidelines for people with diabetes are increasingly distribution, and reproduction in any medium, provided you give appro- priate credit to the original author(s) and the source, provide a link to the comprehensive [5], and accordingly, the incidence of Creative Commons license, and indicate if changes were made. complications has dramatically decreased over the past 1390 Diabetologia (2019) 62:1385–1390 from the Diabetes Prevention Program Outcomes Study. 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