Results
The study population was predominantly men (73%) and of white ethnicity (93%), 769 (15%) had pre-existing CVD, and the average age was 60 years (range 50–73 years) at the first 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. Comparing normoglycaemia vs prediabetes by each glycaemic criterion (Table
1), more men than women had prediabetes defined by FPG whereas no sex difference was observed for prediabetes defined by 2hPG or HbA
1c. Participants with 2hPG- or HbA
1c-, but not FPG-defined prediabetes were older (
p < 0.001) and more likely to be of non-white ethnicity (
p ≤ 0.044) compared with their normoglycaemic counterparts.
Table 1
Characteristics of study participants at the first clinical examination (phase 7) by glycaemic criterion
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/m2) | 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 |
HbA1c (mmol/mol) | 33.0 ± 4.0 | 35.0 ± 5 | 33.0 ± 4 | 36.0 ± 5 | 35.0 ± 3.0 | 42.0 ± 2.0 |
HbA1c (%) | 5.2 ± 0.4 | 5.4 ± 0.4 | 5.2 ± 0.4 | 5.4 ± 0.4 | 5.4 ± 0.3 | 6.0 ± 0.2 |
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) |
Discussion
In this cohort study, reversion from 2hPG-defined prediabetes to normoglycaemia was associated with an approximately 50% lower risk of a CVD event or death compared with remaining with prediabetes or progressing to diabetes. Despite prediabetes being a known risk factor for CVD, we found that reversion from FPG- or HbA
1c-defined prediabetes to normoglycaemia was not associated with a lower risk of CVD or death. Outside pregnancy, the OGTT has largely been eliminated for diagnosing diabetes, particularly with the recent widespread standardisation of the HbA
1c assay. However, our findings suggest that identification of people with elevated 2hPG should be considered for CVD risk stratification either by re-introducing the OGTT for diagnosing prediabetes and diabetes or by other methods [
7,
8].
Our results support previous findings from the Diabetes Prevention Program (DPP), where individuals with 2hPG-defined prediabetes who reverted to normoglycaemia experienced a concomitant reduction in their cardiovascular risk profile [
9]. Previous observations from a general Dutch population also suggested that 2hPG levels are more strongly associated with all-cause and cardiovascular mortality than FPG or HbA
1c levels in the non-diabetic range [
10]. These results may reflect underlying pathophysiological differences in, for example, insulin resistance, which is more pronounced in elevated 2hPG than in elevated FPG and HbA
1c [
11].
We found reversion to normoglycaemia from HbA
1c-defined prediabetes to be less likely than from FPG- or 2hPG-defined prediabetes. While our results on reversion rates for FPG- and 2hPG-defined prediabetes are consistent with previous findings [
12], evidence on the ability to revert from HbA
1c-defined prediabetes to normoglycaemia is scarce [
12]. A Japanese study reported a reversion rate of 32% in a study population that was, on average, 10 years younger than the participants of the Whitehall II study [
12]. There is less day-to-day variation in HbA
1c, and levels in the non-diabetic range may largely be explained by non-glycaemic factors, such as age and ethnicity [
13], and may therefore not be modifiable to the same degree as FPG and 2hPG levels.
We have chosen not to combine different definitions of prediabetes and assess the impact of overall reverting to normoglycaemia. Combining definitions is not in accordance with ADA and IEC and will greatly inflate the prevalence of prediabetes [
14]. Furthermore, the corresponding state of normoglycaemia needs to be defined as normal values on all three criteria, which may not be relevant in clinical practice. Alternatively, specific states of prediabetes and normoglycaemia will have to be applied, resulting in numerous transition possibilities for which this study is not powered to examine (ESM Fig.
2 and
3).
Results from the current analysis are strengthened by the longitudinal, well-described, large population size and the validated ascertainment of CVD events. Nevertheless, reversion cannot be ascribed to intervention effects, since the cohort is strictly observational, and all conclusions remain associative and not necessarily causative. There is still controversy between different diabetes organisations with respect to whether HbA1c or FPG should be used to define prediabetes. Our results did not show a reduced risk of CVD or death when people with either HbA1c- or FPG-defined prediabetes were able to revert to normoglycemia, based on the respective criterion. On the other hand, we found reversion from 2hPG-defined prediabetes to be associated with a halving of the risk of CVD and death. Although the different diagnostic criteria for prediabetes are likely to remain, the current results would contend that only reversion from 2hPG-defined prediabetes to normoglycaemia is sensitive enough to detect cardiovascular benefit.
Guidelines for people with diabetes are increasingly comprehensive [
5], and accordingly, the incidence of complications has dramatically decreased over the past 20 years [
15]. In contrast, the lack of accepted guidelines for people with prediabetes has made the prevalence of diabetes-related complications now virtually identical for people with prediabetes vs those with diabetes [
16]. The current findings highlight the reduced risk for CVD and death associated with reversion from 2hPG-defined prediabetes, specifically, to normoglycaemia. These findings have important implications for additional cardiovascular risk stratification and intervention in a landscape that has become increasingly controversial [
17].
Duality of interest
KF is funded by the Novo Nordisk Foundation. LP reports personal fees from Novo Nordisk, Merck Astra Zeneca, Boeringer-Ingelheim, Orexigen, Sanofi and Janssen. MK reports research grants from the UK Medical Research Council (K013351, R024227, S011676), NordForsk, Academy of Finland and Helsinki Institute of Life Science during the conduct of the study. MEJ has received research grants from AstraZeneca, AMGEN AB, Sanofi Aventis and Boehringer-Ingelheim (Investigator-initiated research). The other authors declare no competing interests.
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