Development of type 2 diabetes mellitus in people with intermediate hyperglycaemia

Bernd Richter; Bianca Hemmingsen; Maria‐Inti Metzendorf; Yemisi Takwoingi

doi:10.1002/14651858.CD012661.pub2

Cochrane Database of Systematic Reviews

Development of type 2 diabetes mellitus in people with intermediate hyperglycaemia

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DOI:

https://doi.org/10.1002/14651858.CD012661.pub2 Copiar DOI

Base de datos:

Cochrane Database of Systematic Reviews

Versión publicada:

29 octubre 2018see what's new

Tipo:

Prognosis

Etapa:

Review

Grupo Editorial Cochrane:

Grupo Cochrane de Trastornos metabólicos y endocrinos

Copyright:

Copyright © 2018 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

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Autores

Bernd Richter

Correspondencia a: Cochrane Metabolic and Endocrine Disorders Group, Institute of General Practice, Medical Faculty of the Heinrich‐Heine‐University Düsseldorf, Düsseldorf, Germany

[email protected]
Bianca Hemmingsen

Cochrane Metabolic and Endocrine Disorders Group, Institute of General Practice, Medical Faculty of the Heinrich‐Heine‐University Düsseldorf, Düsseldorf, Germany
Maria‐Inti Metzendorf

Cochrane Metabolic and Endocrine Disorders Group, Institute of General Practice, Medical Faculty of the Heinrich‐Heine‐University Düsseldorf, Düsseldorf, Germany
Yemisi Takwoingi

Institute of Applied Health Research, University of Birmingham, Birmingham, UK

Contributions of authors

All review authors read and approved the final review draft.

Bernd Richter (BR): protocol and review draft, search strategy development, acquisition of trial reports, trial selection, data extraction of all trials, data analysis, data interpretation and writing of drafts.

Maria‐Inti Metzendorf (MIM): search strategy development, trial selection, check of data extraction, review of drafts.

Bianca Hemmingsen (BH): protocol and review draft, trial selection, data interpretation and review of drafts.

Yemisi Takwoingi (YT): protocol and review draft, data analysis, data interpretation and review of drafts

Sources of support

Internal sources

No sources of support supplied

External sources

World Health Organization, Other.

This review is part of a series of reviews on predictors for the development of type 2 diabetes mellitus in people with intermediate hyperglycaemia and interventions for the prevention or delay of type 2 diabetes mellitus and its associated complications in persons at increased risk for the development of type 2 diabetes mellitus which is funded by the WHO
(Hemmingsen 2016a; Hemmingsen 2016b; Hemmingsen 2016c)

Declarations of interest

BR: the World Health Organization (WHO) funded this review.

MIM: none known.

BH: none known.

YT: none known.

Acknowledgements

The World Health Organization (WHO) funded this review.

We thank Megan Harris for the excellent copy‐editing of our review. We thank Nuala Livingstone, Kerry Dwan, Toby Lasserson, Alex Sutton and especially Carl Moons for their distinguished peer‐reviewing which definitely raised the quality of our review.

Version history

Published

Title

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Authors

Version

2018 Oct 29

Development of type 2 diabetes mellitus in people with intermediate hyperglycaemia

Review

Bernd Richter, Bianca Hemmingsen, Maria‐Inti Metzendorf, Yemisi Takwoingi

https://doi.org/10.1002/14651858.CD012661.pub2

2017 May 12

Intermediate hyperglycaemia as a predictor for the development of type 2 diabetes: prognostic factor exemplar review

Protocol

Bernd Richter, Bianca Hemmingsen, Maria‐Inti Metzendorf, Yemisi Takwoingi

https://doi.org/10.1002/14651858.CD012661

Differences between protocol and review

We changed the title of the protocol from 'Intermediate hyperglycaemia as a predictor for the development of type 2 diabetes: prognostic factor exemplar review' to 'Development of type 2 diabetes mellitus in people with intermediate hyperglycaemia' to fit the objectives of the review. We also modified the objectives from "to assess whether intermediate hyperglycaemia is a predictor for the development of type 2 diabetes mellitus (T2DM)" to objective 1 "to assess the overall prognosis of people with IH for the development of T2DM and to assess how many people with IH revert back to normoglycaemia (regression), and objective 2 "to assess the difference in T2DM incidence in people with IH versus people with normoglycaemia". Both changes reflect the fact that our review addresses two prognostic questions at the same time. First, if people have intermediate hyperglycaemia at baseline, how many individuals develop type 2 diabetes in the future? This research question investigates the cumulative incidence of type 2 diabetes over time and does not depend on a comparison with a group with normoglycaemia at baseline; it is also important to note how many people change back from intermediate hyperglycaemia to normoglycaemia. The second prognostic question is, how does glycaemic status (intermediate hyperglycaemia compared with normoglycaemia) at baseline affect the development of type 2 diabetes? In particular, we were interested in intermediate hyperglycaemia, defined using impaired fasting glucose, impaired glucose tolerance and elevated glycosylated haemoglobin A1c and combinations thereof.

We specified inclusion criteria in more detail to explain the difference between studies evaluating the overall prognosis of people with intermediate hyperglycaemia and studies evaluating intermediate hyperglycaemia versus normoglycaemia as a prognostic factor developing type 2 diabetes mellitus.

Regarding methods, we explained our exclusion criteria in more detail and deleted 'conference abstract' as an exclusion criterion (we moved one formerly excluded study, Misnikova 2011, to 'Studies awaiting classification').

Keywords

MeSH

Medical Subject Headings (MeSH) Keywords

Medical Subject Headings Check Words

Humans;

Figure 1

Study flow diagram

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Figure 2

Risk of bias graph for studies of overall prognosis of people with intermediate hyperglycaemia for developing type 2 diabetes: review authors' judgements about each risk of bias item presented as percentages across all included studies

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Figure 3

'Risk of bias' summary for studies of overall prognosis in people with intermediate hyperglycaemia for developing type 2 diabetes: review authors' judgements about each risk of bias item for each included study (part 1). The summary was split into part 1 (Figure 3) and part 2 (Figure 4) for better legibility

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Figure 4

Risk of bias summary for studies of overall prognosis of people with intermediate hyperglycaemia for developing type 2 diabetes: review authors' judgements about each risk of bias item for each included study (part 2)

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Figure 5

Risk of bias graph for studies of intermediate hyperglycaemia versus normoglycaemia as a prognostic factor for developing type 2 diabetes: review authors' judgements about each risk of bias item presented as percentages across all included studies

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Figure 6

Risk of bias summary for studies of intermediate hyperglycaemia versus normoglycaemia as a prognostic factor for developing type 2 diabetes: review authors' judgements about each risk of bias item for each included study

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Figure 7

Impaired fasting glucose 5.6 mmol/L (IFG_5.6) threshold: association with cumulative type 2 diabetes mellitus (T2DM) incidence over 2–5 years
*Isolated IFG_5.6
CI: confidence interval; M: men; n/N: events/number of participants; W: women

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Figure 8

Impaired fasting glucose 5.6 mmol/L (IFG_5.6) threshold: association with cumulative type 2 diabetes mellitus (T2DM) incidence over 6–12 years
*Isolated IFG_5.6
**'Africa': African Surinamese cohort, 'Asia': Asian Surinamese cohort, 'Australia/Europe/North America': 'ethnic Dutch' cohort.
CI: confidence interval; M: men; n/N: events/number of participants; W: women

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Figure 9

Impaired fasting glucose 6.1 mmol/L (IFG_6.1) threshold: association with cumulative type 2 diabetes mellitus (T2DM) incidence over 2–5 years
*Isolated IFG_6.1
CI: confidence interval; M: men; n/N: events/number of participants; W: women

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Figure 10

Impaired fasting glucose 6.1 mmol/L (IFG_6.1) threshold: association with cumulative type 2 diabetes mellitus (T2DM) incidence over 6–15 years
*Isolated IFG_6.1
CI: confidence interval; n/N: events/number of participants

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Figure 11

Impaired glucose tolerance (IGT): association with cumulative type 2 diabetes mellitus (T2DM) incidence over 1–5 years
*Isolated IGT
CI: confidence interval; n/N: events/number of participants

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Figure 12

Impaired glucose tolerance (IGT): association with cumulative type 2 diabetes mellitus (T2DM) incidence over 6–20 years

*Isolated IGT
CI: confidence interval; M: men; n/N: events/number of participants; W: women

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Figure 13

Combined impaired glucose tolerance (IGT) and impaired fasting glucose (IFG): association with cumulative type 2 diabetes mellitus (T2DM) incidence over 1–12 years
CI: confidence interval; M: men; n/N: events/number of participants; W: women

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Figure 14

Elevated glycosylated haemoglobin A1c (HbA1c) 5.7% threshold: association with cumulative type 2 diabetes mellitus (T2DM) incidence over 4–10 years
CI: confidence interval; n/N: events/number of participants

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Figure 15

Elevated glycosylated haemoglobin A1c (HbA1c) 6.0% threshold: association with cumulative type 2 diabetes mellitus (T2DM) incidence over 3–15 years
CI: confidence interval; n/N: events/number of participants

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Figure 16

Cumulative type 2 diabetes mellitus (T2DM) incidence in children/adolescents over 1–10 years
CI: confidence interval; HbA1c 5.7: glycosylated haemoglobin A1c 5.7% threshold; (i‐)IGT: (isolated) impaired glucose tolerance; n/N: events/number of participants; NO: non‐overweight; OV: overweight

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Figure 17

Regression from intermediate hyperglycaemia to normoglycaemia in adults over 1–5 years
CI: confidence interval; HbA1c_5.7 : glycosylated haemoglobin A1c 5.7%; i‐IFG_5.6/6.1 : (isolated) impaired fasting glucose 5.6/6.1 mmol/L threshold;IGT: impaired glucose tolerance; n/N: events/number of participants

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Figure 18

Regression from intermediate hyperglycaemia to normoglycaemia in adults over 6–11 years
CI: confidence interval; i‐IFG_5.6/6.1 : (isolated) impaired fasting glucose 5.6/6.1 mmol/L threshold; i‐IGT: (isolated) impaired glucose tolerance; n/N: events/number of participants

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Figure 19

Regression from intermediate hyperglycaemia to normoglycaemia in children/adolescents over 1–4 years
CI: confidence interval; IGT: impaired glucose tolerance; n/N: events/number of participants

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Figure 20

IFG: impaired fasting glucose; IRR: incidence rate ratio; n: number of cases; T: person‐time in years

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Figure 21

IFG: impaired fasting glucose; IRR: incidence rate ratio; n: number of cases; T: person‐time in years

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Figure 22

IGT: impaired glucose tolerance; IRR: incidence rate ratio; n: number of cases; T: person‐time in years

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Figure 23

IFG: impaired fasting glucose; IGT: impaired glucose tolerance; IRR: incidence rate ratio; n: number of cases; T: person‐time in years

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Figure 24

IFG: impaired fasting glucose; HbA1c: glycosylated haemoglobin A1c; IRR: incidence rate ratio; n: number of cases; T: person‐time in years

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Figure 25

Overall prognosis of people with intermediate hyperglycaemia (cumulative type 2 diabetes incidence and regression to normoglycaemia) associated with measures of intermediate hyperglycaemia
HbA1c5.7/HbA1c6.0: glycosylated haemoglobin A1c 5.7%/6.0% threshold; IFG5.6/6.1: impaired fasting glucose 5.6/6.1 mmol/L threshold; IGT: impaired glucose tolerance

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Figure 26

Intermediate hyperglycaemia versus normoglycaemia as a prognostic factor for developing type 2 diabetes (associated with different measures and relative risks of intermediate hyperglycaemia)
HbA1c5.7/HbA1c6.0: glycosylated haemoglobin A1c 5.7%/6.0% threshold; IFG5.6/6.1: impaired fasting glucose 5.6/6.1 mmol/L threshold; IGT: impaired glucose tolerance; IRR: incidence rate ratio; OR: odds ratio; HR: hazard ratio

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Analysis 1.1

Comparison 1 Hazard ratio as the effect measure for the development of T2DM, Outcome 1 T2DM incidence (IFG_5.6).

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Analysis 1.2

Comparison 1 Hazard ratio as the effect measure for the development of T2DM, Outcome 2 T2DM incidence (IFG_6.1).

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Analysis 1.3

Comparison 1 Hazard ratio as the effect measure for the development of T2DM, Outcome 3 T2DM incidence (IGT).

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Analysis 1.4

Comparison 1 Hazard ratio as the effect measure for the development of T2DM, Outcome 4 T2DM incidence (IFG + IGT).

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Analysis 1.5

Comparison 1 Hazard ratio as the effect measure for the development of T2DM, Outcome 5 T2DM incidence (HbA1c_5.7).

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Analysis 1.6

Comparison 1 Hazard ratio as the effect measure for the development of T2DM, Outcome 6 T2DM incidence (HbA1c_6.0).

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Analysis 1.7

Comparison 1 Hazard ratio as the effect measure for the development of T2DM, Outcome 7 T2DM incidence (HbA1c + IFG).

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Analysis 2.1

Comparison 2 Odds ratio as the effect measure for the development of T2DM, Outcome 1 T2DM incidence (IFG_5.6).

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Analysis 2.2

Comparison 2 Odds ratio as the effect measure for the development of T2DM, Outcome 2 T2DM incidence (IFG_6.1).

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Analysis 2.3

Comparison 2 Odds ratio as the effect measure for the development of T2DM, Outcome 3 T2DM incidence (IGT).

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Analysis 2.4

Comparison 2 Odds ratio as the effect measure for the development of T2DM, Outcome 4 T2DM incidence (IFG + IGT).

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Analysis 2.5

Comparison 2 Odds ratio as the effect measure for the development of T2DM, Outcome 5 T2DM incidence (HbA1c_5.7).

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Analysis 2.6

Comparison 2 Odds ratio as the effect measure for the development of T2DM, Outcome 6 T2DM incidence (HbA1c_6.0).

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Analysis 2.7

Comparison 2 Odds ratio as the effect measure for the development of T2DM, Outcome 7 T2DM incidence (HbA1c_5.7 + IFG_5.6).

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Summary of findings for the main comparison. Summary of findings: overall prognosis of people with intermediate hyperglycaemia for developing T2DM

Outcome: development of T2DM Prognosis of people with intermediate hyperglycaemia
Follow‐up (years)	Cumulative T2DM incidence % (95% CI) [no of studies; no of participants with intermediate hyperglycaemia]						Regression from intermediate hyperglycaemia to normoglycaemia % (95% CI) [no of studies; no of participants with intermediate hyperglycaemia]	Overall certainty of the evidence (GRADE)^a
Follow‐up (years)	IFG_5.6	IFG_6.1	IGT	IFG + IGT	HbA1c_5.7	HbA1c_6.0		Overall certainty of the evidence (GRADE)^a
1	—	—	13 (5–23) [3; 671]	29 (23–36) [1; 207]	—	—	59 (54–64) [2; 375]	⊕⊕⊕⊝ Moderate^b
2	2 (1–2) [1; 1335]	11 (8–14) [2; 549]	16 (9–26) [9; 1998]	—	—	—	46 (36–55) [9; 2852]
3	17 (6–32) [3; 1091]	9 (2–20) [3; 927]	22 (18–27) [3; 417]	34 (28–41) [1; 209]—	—	7 (5–10) [1; 370]	41 (24–69) [7; 1356]
4	17 (13–22) [3; 800]	30 (17–44) [2; 1567]	22 (12–34) [5; 1042]	—	14 (7–23) [3; 5352]	44 (40–48) [2; 627]	33 (26–40) [3; 807]
5	18 (10–27) [7; 3530]	26 (19–33) [11; 3837]	39 (25–53) [12; 3444]	50 (37–63) [5; 478]	25 (18–32) [4; 3524]	38 (26–51) [3; 1462]	34 (27–42) [9; 2603]
6	22 (15–31) [4; 738]	37 (31–43) [5; 279]	29 (25–34) [7; 775]	58 (48–67) [4; 106]	17 (14–20) [1; 675]	—	23 (3–53) [5; 1328]
7	18 (8–30) [5; 980]	15 (0–45) [4; 434]	19 (13–26) [5; 835]	32 (20–45) [4; 753]	21 (16–27) [1; 207]	—	41 (37–45) [4; 679]
8	34 (27–40) [2; 1887]	48 (31–66) [1;29]	43 (37–49) [4; 1021]	52 (47–57) [1; 356]	—	—	39 (33–44) [2; 328]
9	38 (10–70) [3; 1356]	—	53 (45–60) [1; 163]	84 (74–91) [1; 69]	—	—	17 (14–22) [1; 299]
10	23 (14–33) [6; 1542]	29 (17–43) [6; 537]	26 (17–37) [6; 443]	30 (17–44) [2; 49]	31 (29–33) [2; 2854]	—	42 (22–63) [7; 894]
11	—	38 (33–43) [1; 402]	46 (43–49) [1; 1253]	—	—	—	28 (17–39) [2; 736]
12	31 (19–34) [3; 433]	31 (28–33) [1; 1382]	41 (38–43) [2; 1552]	70 (63–76) [2; 207]	—	—	—
15	—	—	—	—	—	29 (19–40) [1; 70]	—
20	—	—	60 (5–68) [1; 114]	—	—	—	—
CI: confidence interval; HbA1c_5.7 : glycosylated haemoglobin A1c, 5.7% threshold; HbA1c_6.0 : glycosylated haemoglobin A1c, 6.0% threshold; IFG_5.6 : impaired fasting glucose, 5.6 mmol/L threshold; IFG_6.1 : impaired fasting glucose, 6.1 mmol/L threshold; IGT: impaired glucose tolerance; T2DM: type 2 diabetes mellitus.
GRADE Working Group grades of evidence High quality: further research is very unlikely to change our confidence in the estimate of effect. Moderate quality: further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate. Low quality: further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate. Very low quality: we are very uncertain about the estimate.
^aWith phase 2 explanatory studies aiming to confirm independent associations between the prognostic factor and the outcome, GRADE starts with 'high quality' (Huguet 2013). We assumed the GRADE factor publication bias was inherent with this type of research (phase 2 design), so we did not use it as a potential downgrading factor ^bDowngraded by one level because of imprecision (wide CIs for most intermediate hyperglycaemia definitions and the association with T2DM incidence and regression from intermediate hyperglycaemia)

Summary of findings for the main comparison. Summary of findings: overall prognosis of people with intermediate hyperglycaemia for developing T2DM

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Summary of findings 2. Summary of findings: risk of intermediate hyperglycaemia (IFG5.6 mmol/L definition) versus normoglycaemia for developing T2DM

Outcome: development of T2DM Prognostic factor: intermediate hyperglycaemia versus normoglycaemia as measured by IFG_5.6
No of studies	No of participants with intermediate hyperglycaemia	Geographic region/special population	Estimated effect (95% CI) [95% prediction interval]	Overall certainty of the evidence (GRADE)^a
HR: 4 IRR: 6 OR: 10	HR: 2385 IRR: 15,661 OR: 6359	Asia/Middle East	HR: 5.07 (3.41–4.86) [1.07–24.02] IRR: 5.23 (3.77–7.25) [1.72–15.89] OR: 2.94 (1.77–4.86) [0.43–19.93]	⊕⊕⊝⊝ Low^b
HR: 3 IRR: 3 OR: 9	HR: 5685 IRR: 6322 OR: 1949	Australia/Europe/North America	HR: 4.15 (1.24–13.9) [N/M] IRR: 4.96 (3.25–7.57) [0.32–77.24] OR: 6.47 (3.81–11.00) [0.99–42.32]
HR: 0 IRR: 0 OR: 1	HR: 0 IRR: 0 OR: 65	Latin America	HR: NA IRR: NA OR: 4.28 (3.21–5.71)
HR: 1 IRR: 1 OR: 1	HR: 947 IRR: 2374 OR: 947	American Indians/Islands	HR: 2.38 (1.85–3.06) IRR: 2.74 (1.88–3.99) OR: 3.12 (2.31–4.21)
HR: 8 IRR: 10 OR: 21	HR: 9017 IRR: 24,357 OR: 9320	Overall	HR: 4.32 (2.61–7.12) [0.75–25.0] IRR: 4.81 (3.67–6.30) [1.95–11.83] OR: 4.15 (2.75–6.28) [0.53–32.4]
CI: confidence interval; HR: hazard ratio;IFG_5.6 : impaired fasting glucose 5.6 mmol/L threshold; IRR: incidence rate ratio; NA: not applicable; N/M: fewer than 3 studies or calculation of the 95% prediction interval did not provide a meaningful estimate; OR: odds ratio; T2DM: type 2 diabetes mellitus.
GRADE Working Group grades of evidence High quality: further research is very unlikely to change our confidence in the estimate of effect. Moderate quality: further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate. Low quality: further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate. Very low quality: we are very uncertain about the estimate.
^aWith phase 2 explanatory studies aiming to confirm independent associations between the prognostic factor and the outcome, GRADE starts with 'high quality' (Huguet 2013). We assumed the GRADE factor publication bias was inherent with this type of research (phase 2 design), so we did not use it as a potential downgrading factor ^bDowngraded by one level because of study limitations (many studies did not adequately adjust for confounders, if at all) and by one level because of imprecision (CIs were wide) and inconsistency (wide 95% prediction intervals sometimes ranging from negative to positive prognostic factor to outcome associations)

Summary of findings 2. Summary of findings: risk of intermediate hyperglycaemia (IFG5.6 mmol/L definition) versus normoglycaemia for developing T2DM

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Summary of findings 3. Summary of findings: risk of intermediate hyperglycaemia (IFG6.1 mmol/L definition) versus normoglycaemia for developing T2DM

Outcome: development of T2DM Prognostic factor: intermediate hyperglycaemia as measured by IFG_6.1
No of studies	No of participants with intermediate hyperglycaemia	Geographic region/special population	Estimated effect (95% CI) [95% prediction interval]	Overall certainty of the evidence (GRADE)^a
HR: 5 IRR: 2 OR: 7	HR: 1054 IRR: 1677 OR: 3317	Asia/Middle East	HR: 10.55 (3.61–30.81) [N/M] IRR: 3.62 (1.67–7.83) [N/M] OR: 5.18 (2.32–11.53) [0.29–91.37]	⊕⊕⊝⊝ Low^b
HR: 4 IRR: 4 OR: 7	HR: 1736 IRR: 3438 OR: 1240	Australia/Europe/North America	HR: 3.30 (2.32–4.67) [0.84–12.99] IRR: 8.55 (6.37–11.48) [4.37–16.73] OR: 8.69 (4.95–15.24) [1.20–62.69]
HR: 0 IRR: 0 OR: 1	HR: 0 IRR: 0 OR: 17	Latin America	HR: NA IRR: NA OR: 3.73 (2.18–6.38)
HR: 0 IRR: 0 OR: 0	HR: 0 IRR: 0 OR: 0	American Indians/Islands	HR: NA IRR: NA OR: NA
HR: 9 IRR: 6 OR: 15	HR: 2818 IRR: 5115 OR: 4574	Overall	HR: 5.47 (3.50–8.54) [1.09–27.56] IRR: 6.82 (4.53–10.25) [2.03–22.87] OR: 6.60 (4.18–10.43) [0.93–46.82]
CI: confidence interval; HR: hazard ratio;IFG_6.1 : impaired fasting glucose 6.1 mmol/L threshold; IRR: incidence rate ratio; NA: not applicable; N/M: fewer than 3 studies or calculation of the 95% prediction interval did not provide a meaningful estimate; OR: odds ratio; T2DM: type 2 diabetes mellitus.
GRADE Working Group grades of evidence High quality: further research is very unlikely to change our confidence in the estimate of effect. Moderate quality: further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate. Low quality: further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate. Very low quality: we are very uncertain about the estimate.
^aWith phase 2 explanatory studies aiming to confirm independent associations between the prognostic factor and the outcome, GRADE starts with 'high quality' (Huguet 2013). We assumed the GRADE factor publication bias was inherent with this type of research (phase 2 design), so we did not use it as a potential downgrading factor ^bDowngraded by one level because of study limitations (many studies did not adequately adjust for confounders, if at all) and by one level because of imprecision (CIs were wide) and inconsistency (wide 95% prediction intervals sometimes ranging from negative to positive prognostic factor to outcome associations)

Summary of findings 3. Summary of findings: risk of intermediate hyperglycaemia (IFG6.1 mmol/L definition) versus normoglycaemia for developing T2DM

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Summary of findings 4. Summary of findings: risk of intermediate hyperglycaemia (IGT definition) versus normoglycaemia for developing T2DM

Outcome: development of T2DM Prognostic factor: intermediate hyperglycaemia as measured by IGT
No of studies	No of participants with intermediate hyperglycaemia	Geographic region/special population	Estimated effect (95% CI) [95% prediction interval]	Overall certainty of the evidence (GRADE)^a
HR: 3 IRR: 5 OR: 6	HR: 1780 IRR: 14,809 OR: 1226	Asia/Middle East	HR: 4.48 (2.81–7.15) [N/M] IRR: 3.93 (3.03–5.10) [1.71–9.02] OR: 3.74 (2.83–4.94) [1.70–8.21]	⊕⊕⊝⊝ Low^b
HR: 2 IRR: 5 OR: 11	HR: 2230 IRR: 2572 OR: 1481	Australia/Europe/North America	HR: 2.53 (1.52–4.19) [N/M] IRR: 5.93 (4.11–8.57) [2.38–14.81] OR: 5.20 (3.62–7.45) [1.50–18.09]
HR: 0 IRR: 0 OR: 2	HR: 0 IRR: 0 OR: 381	Latin America	HR: NA IRR: NA OR: 4.94 (3.15–7.76) [N/M]
IRR: 2 OR: 1 HR: 0	IRR: 1087 OR: 51 HR: 0	American Indians/Islands	IRR: 4.46 (3.12–6.38) [N/M] OR: 3.60 (1.40–9.26) HR: NA
HR: 5 IRR: 12 OR: 20	HR: 4010 IRR: 18,468 OR: 3139	Overall	HR: 3.61 (2.31–5.64) [0.69–18.97] IRR: 4.48 (3.59–5.44) [2.60–7.70] OR: 4.61 (3.76–5.64) [2.10–10.13]
CI: confidence interval; HR: hazard ratio;IGT: impaired glucose tolerance; IRR: incidence rate ratio; NA: not applicable; N/M: fewer than 3 studies or calculation of the 95% prediction interval did not provide a meaningful estimate; T2DM: type 2 diabetes mellitus.
GRADE Working Group grades of evidence High quality: further research is very unlikely to change our confidence in the estimate of effect. Moderate quality: further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate. Low quality: further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate. Very low quality: we are very uncertain about the estimate.
^aWith phase 2 explanatory studies aiming to confirm independent associations between the prognostic factor and the outcome, GRADE starts with 'high quality' (Huguet 2013). We assumed the GRADE factor publication bias was inherent with this type of research (phase 2 design), so we did not use it as a potential downgrading factor ^bDowngraded by one level because of study limitations (many studies did not adequately adjust for confounders, if at all) and by one level because of imprecision (CIs were wide) and inconsistency (wide 95% prediction intervals sometimes ranging from negative to positive prognostic factor to outcome associations)

Summary of findings 4. Summary of findings: risk of intermediate hyperglycaemia (IGT definition) versus normoglycaemia for developing T2DM

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Summary of findings 5. Summary of findings: risk of intermediate hyperglycaemia (combined IFG and IGT definition) versus normoglycaemia for developing T2DM

Outcome: development of T2DM Prognostic factor: intermediate hyperglycaemia as measured by combined IFG and IGT
No of studies	No of participants with intermediate hyperglycaemia	Geographic region/special population	Estimated effect (95% CI) [95% prediction interval]	Overall certainty of the evidence (GRADE)^a
HR: 3 IRR: 4 OR: 3	HR: 461 IRR: 3166 OR: 498	Asia/Middle East	HR: 10.20 (5.45–19.09) [N/M] IRR: 11.20 (5.59–22.43) [N/M] OR: 6.99 (3.09–15.83) [N/M]	⊕⊕⊝⊝ Low^b
HR: 1 IRR: 4 OR: 6	HR: 221 IRR: 699 OR: 154	Australia/Europe/North America	HR: 3.80 (2.30–6.28) [N/M] IRR: 13.92 (9.99–19.40) [6.71–28.85] OR: 20.95 (12.40–35.40) [4.93–89.05]
HR: 0 IRR: 0 OR: 0	HR: 0 IRR: 0 OR: 0	Latin America	HR: NA IRR: NA OR: NA
HR: 1 IRR: 1 OR: 0	HR: 356 IRR: 605 OR: 0	American Indians/Islands	HR: 4.06 (3.05–5.40) IRR: 5.18 (3.42–7.83) OR: NA
HR: 5 IRR: 9 OR: 9	HR: 1038 IRR: 4470 OR: 652	Overall	HR: 6.90 (4.15–11.45) [1.06–44.95] IRR: 10.94 (7.22–16.58) [2.58–46.46] OR: 13.14 (7.41–23.30) [1.84–93.66]
CI: confidence interval; HR: hazard ratio;IFG: impaired fasting glucose; IGT: impaired glucose tolerance; IRR: incidence rate ratio; NA: not applicable; N/M: fewer than 3 studies or calculation of the 95% prediction interval did not provide a meaningful estimate; OR: odds ratio; T2DM: type 2 diabetes mellitus.
GRADE Working Group grades of evidence High quality: further research is very unlikely to change our confidence in the estimate of effect. Moderate quality: further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate. Low quality: further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate. Very low quality: we are very uncertain about the estimate.
^aWith phase 2 explanatory studies aiming to confirm independent associations between the prognostic factor and the outcome, GRADE starts with 'high quality' (Huguet 2013). We assumed the GRADE factor publication bias was inherent with this type of research (phase 2 design), so we did not use it as a potential downgrading factor ^bDowngraded by one level because of study limitations (many studies did not adequately adjust for confounders, if at all) and by one level because of imprecision (CIs were wide) and inconsistency (wide 95% prediction intervals)

Summary of findings 5. Summary of findings: risk of intermediate hyperglycaemia (combined IFG and IGT definition) versus normoglycaemia for developing T2DM

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Summary of findings 6. Summary of findings: risk of intermediate hyperglycaemia (HbA1c5.7 definition) versus normoglycaemia for developing T2DM

Outcome: development of T2DM Prognostic factor: intermediate hyperglycaemia as measured by HbA1c_5.7
No of studies	No of participants with intermediate hyperglycaemia	Geographic region/special population	Estimated effect (95% CI) [95% prediction interval]	Overall certainty of the evidence (GRADE)^a
HR: 3 IRR: 1 OR: 1	HR: 3196 IRR: 1965 OR: 675	Asia/Middle East	HR: 7.21 (5.14–10.11) [0.81–64.52] IRR: 6.62 (4.18–10.49) [N/M] OR: 4.54 (2.65–7.78) [N/M]	⊕⊕⊝⊝ Low^b
HR: 1 IRR: 0 OR: 2	HR: 2027 IRR: 0 OR: 231	Australia/Europe/North America	HR: 2.71 (2.48–2.96) [N/M] IRR: NA OR: 4.38 (1.36–14.15) [N/M]
HR: 0 IRR: 0 OR: 0	HR: 0 IRR: 0 OR: 0	Latin America	HR: NA IRR: NA OR: NA
HR: 0 IRR: 0 OR: 0	HR: 0 IRR: 0 OR: 0	American Indians/Islands	HR: NA IRR: NA OR: NA
HR: 4 IRR: 1 OR: 3	HR: 5223 IRR: 1965 OR: 906	Overall	HR: 5.55 (2.77–11.12) [0.23–141.18] IRR: 6.62 (4.18–10.49) [N/M] OR: 4.43 (2.20–8.88) [N/M]
CI: confidence interval; HbA1c_5.7 : glycosylated haemoglobin A1c 5.7% threshold; HR: hazard ratio;IRR: incidence rate ratio; NA: not applicable; N/M: fewer than 3 studies or calculation of the 95% prediction interval did not provide a meaningful estimate; OR: odds ratio; T2DM: type 2 diabetes mellitus.
GRADE Working Group grades of evidence High quality: further research is very unlikely to change our confidence in the estimate of effect. Moderate quality: further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate. Low quality: further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate. Very low quality: we are very uncertain about the estimate.
^aWith phase 2 explanatory studies aiming to confirm independent associations between the prognostic factor and the outcome, GRADE starts with 'high quality' (Huguet 2013). We assumed the GRADE factor publication bias was inherent with this type of research (phase 2 design), so we did not use it as a potential downgrading factor ^bDowngraded by one level because of study limitations (many studies did not adequately adjust for confounders, if at all) and by one level because of imprecision (CIs were wide) and inconsistency (95% prediction intervals sometimes ranging from negative to positive prognostic factor to outcome associations)

Summary of findings 6. Summary of findings: risk of intermediate hyperglycaemia (HbA1c5.7 definition) versus normoglycaemia for developing T2DM

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Summary of findings 7. Summary of findings: risk of intermediate hyperglycaemia (HbA1c6.0 definition) versus normoglycaemia for developing T2DM

Outcome: development of T2DM Prognostic factor: intermediate hyperglycaemia as measured by HbA1c_6.0
No of studies	No of participants with intermediate hyperglycaemia	Geographic region/special population	Estimated effect (95% CI) [95% prediction interval]	Overall certainty of the evidence (GRADE)^a
HR: 2 IRR: 0 OR: 1	HR: 1040 IRR: 0 OR: 370	Australia/Europe/North America	HR: 5.09 (1.69–15.37) [N/M] IRR: NA OR: 15.60 (6.90–35.27) [N/M]	⊕⊕⊝⊝ Low^b
HR: 4 IRR: 0 OR: 1	HR: 3492 IRR: 0 OR: 1103	Asia/Middle East	HR: 13.12 (4.10–41.96) [N/M] IRR: NA OR: 23.20 (18.70–28.78) [N/M]
HR: 0 IRR: 0 OR: 0	HR: 0 IRR: 0 OR: 0	Latin America	HR: NA IRR: NA OR: NA
IRR: 0 OR: 1 HR: 0	IRR: 0 OR: 121 HR: 0	American Indians/Islands	IRR: NA OR: 5.89 (4.23–8.20) [N/M] HR: NA
HR: 6 IRR: 0 OR: 3	HR: 4532 IRR: 0 OR: 1594	Overall	HR: 10.10 (3.59–28.43) [N/M] IRR: NA OR: 12.79 [4.56–35.85] [N/M]
CI: confidence interval; HbA1c_6.0 : glycosylated haemoglobin A1c 6.0% threshold; HR: hazard ratio;IRR: incidence rate ratio; NA: not applicable; N/M: fewer than 3 studies or calculation of the 95% prediction interval did not provide a meaningful estimate; OR: odds ratio; T2DM: type 2 diabetes mellitus.
GRADE Working Group grades of evidence High quality: further research is very unlikely to change our confidence in the estimate of effect. Moderate quality: further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate. Low quality: further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate. Very low quality: we are very uncertain about the estimate.
^aWith phase 2 explanatory studies aiming to confirm independent associations between the prognostic factor and the outcome, GRADE starts with 'high quality' (Huguet 2013). We assumed the GRADE factor publication bias was inherent with this type of research (phase 2 design), so we did not use it as a potential downgrading factor ^bDowngraded by one level because of study limitations (many studies did not adequately adjust for confounders, if at all) and by one level because of imprecision (most CIs were wide)

Summary of findings 7. Summary of findings: risk of intermediate hyperglycaemia (HbA1c6.0 definition) versus normoglycaemia for developing T2DM

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Table 1. Overview: overall prognosis of people with intermediate hyperglycaemia and regression from intermediate hyperglycaemia to normoglycaemia

Follow‐up time (years)

% (95% CI) cumulative T2DM incidence
[no of studies; no of participants with IH]

% (95% CI) regression from IH to normoglycaemia
[no of studies; no of participants with IH]

IFG_5.6

IFG_6.1

IGT

IFG + IGT

HbA1c_5.7

HbA1c_6.0

1

—

13 (5–23)

[3; 671]

29 (23–36)

[1; 207]

—

59 (54–64)

[2; 375]

2

2 (1–2)

[1; 1335]

11 (8–14)

[2; 549]

16 (9–26)

[9; 1998]

—

46 (36–55)

[9; 2852]

3

17 (6–32)

[3; 1091]

9 (2–20)

[3; 927]

22 (18–27)

[3; 417]

34 (28–41)

[1; 209]

—

7 (5–10)

[1; 370]

41 (24–59)

[7; 1356]

4

17 (13–22)

[3; 800]

30 (17–44)

[2; 1567]

22 (12–34)

[5; 1042]

—

14 (7–23)

[3; 5352]

44 (40–48)

[2; 627]

33 (26–40)

[3; 807]

5

18 (10–27)

[7; 3530]

26 (19–33)

[11; 3837]

39 (25–53)

[12; 3444]

50 (37–63)

[5; 478]

25 (18–32)

[4; 3524]

38 (26–51)

[3; 1462]

34 (27–42)

[9; 2603]

6

22 (15–31)

[4; 738]

37 (31–43)

[5; 279]

29 (25–34)

[7; 775]

58 (48–67)

[4; 106]

17 (14–20)

[1; 675]

—

23 (3–53)

[5; 1328]

7

18 (8–30)

[5; 980]

15 (0–45)

[4; 434]

19 (13–26)

[5; 835]

32 (20–45)

[4; 753]

21 (16–27)

[1; 207]

—

41 (37–45)

[4; 679]

8

34 (27–40)

[2; 1887]

48 (31–66)

[1;29]

43 (37–49)

[4; 1021]

52 (47–57)

[1; 356]

—

39 (33–44)

[2; 328]

9

38 (10–70)

[3; 1356]

—

53 (45–60)

[1; 163]

84 (74–91)

[1; 69]

—

17 (14–22)

[1; 299]

10

23 (14–33)

[6; 1542]

29 (17–43)

[6; 537]

26 (17–37)

[6; 443]

30 (17–44)

[2; 49]

31 (29–33)

[2; 2854]

—

42 (22–63)

[7; 894]

11

—

38 (33–43)

[1; 402]

46 (43–49)

[1; 1253]

—

28 (17–39)

[2; 736]

12

31 (19–34)

[3; 433]

31 (28–33)

[1; 1382]

41 (38–43)

[2; 1552]

70 (63–76)

[2; 207]

—

15

—

29 (19–40)

[1; 70]

—

20

—

60 (5–68)

[1; 114]

—

CI: confidence interval; HbA1c: glycosylated haemoglobin A1c; HbA1c_5.7/6.0 (threshold 5.7% or 6.0%); IFG_5.6/6.1 : impaired fasting glucose (threshold 5.6 mmol/L or 6.1 mmol/L); IGT: impaired glucose tolerance; IFG + IGT: both IFG and IGT; IH: intermediate hyperglycaemia; T2DM: type 2 diabetes mellitus

Table 1. Overview: overall prognosis of people with intermediate hyperglycaemia and regression from intermediate hyperglycaemia to normoglycaemia

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Table 2. Overview: intermediate hyperglycaemia versus normoglycaemia as a prognostic factor for the development of type 2 diabetes

Ratio (95% CI) 95% prediction interval^a,b [no of studies; no of participants with IH/no of participants with normoglycaemia]
Hazard ratio
Region	IFG_5.6 cohort	IFG_6.1 cohort	IGT cohort	IFG + IGT cohort	HbA1c_5.7 cohort	HbA1c_6.0 cohort	HbA1c_5.7 + IFG_5.6 cohort
Asia/Middle East	5.07 (3.41‐7.53) 1.07–24.02 [4; 2385/12,837]	10.55 (3.61–30.81) NA^b [5; 1054/9756]	4.48 (2.81–7.15) NA^b [3; 1780/6695]	10.20 (5.45–19.09) NA^b [3; 461/6695]	7.21 (5.14–10.11) 0.81–64.52 [3; 3196/13,609]	13.12 (4.10–41.96) NA^b [4; 3492/19,242]	32.50 (23.00–45.92)^c NA^a [1; 410/4149]
Australia/Europe/North America	4.15 (1.24–13.87) NA^b [3; 5685/12,837]	3.30 (2.32–4.67) 0.84–12.99 [4; 1736/8835]	2.53 (1.52–4.19) NA^a [2; 2230/5871]	3.80 (2.30–6.28) NA^a [1; 221/1429]	2.71 (2.48–2.96) NA^a [1: 2027/6215]	5.09 (1.69–15.37) NA^a [2; 1040/6925]	—
Latin America	—	2.06 (1.76–2.41) NA^b [1; 28/66]	—	—	—	—	—
American Indians/Islands	2.38 (1.85–3.06) NA^a [1; 947/595]	—	—	4.06 (3.05–5.40) NA^a [1; 356/595]	—	—	—
Overall	4.32 (2.61–7.12) 0.75–25.01 [8; 9017/25,850]	5.47 (3.50–8.54) 1.09–27.56 [9; 2818/18,591]	3.61 (2.31–5.64) 0.69–18.97 [5; 4010/12,566]	6.90 (4.15–11.45) 1.06–44.95 [5; 1038/8719]	5.55 (2.77–11.12) 0.23–141.18 [4; 5223/19,824]	10.10 (3.59–28.43) NA^b [6; 4532/26,167]	32.50 (23.00–45.92) NA^a [1; 410/4149]
Incidence rate ratio
Region	IFG_5.6 cohort	IFG_6.1 cohort	IGT cohort	IFG + IGT cohort	HbA1c_5.7 cohort	HbA1c_6.0 cohort	HbA1c_5.7 + IFG_5.6 cohort
Asia/Middle East	5.23 (3.77–7.25) 1.72–15.89 [6; 15,661/145,597]	3.62 (1.67–7.83) NA^a [2; 1677/36,334]	3.93 (3.03–5.10) 1.71–9.02 [5; 14,809/73,128]	11.20 (5.59–22.43) NA^b [4; 3166/69,463]	6.62 (4.18–10.49) NA^a [1; 1965/19961]	—	40.72 (29.30–56.61) NA^a [1; 1641/19,961]
Australia/Europe/North America	4.96 (3.25–7.57) 0.32–77.24 [3; 6322/8062]	8.55 (6.37–11.48) 4.37–16.73 [4; 3438/20,246]	5.93 (4.11–8.57) 2.38–14.81 [5; 2572/22,329]	13.92 (9.99–19.40) 6.71–28.85 [4; 699/18,966]	—	—	—
Latin America	—	—	—	—	—	—	—
American Indians/Islands	2.74 (1.88–3.99) NA^a [1; 2374/1613]	—	4.46 (3.12–6.38) NA^a [2; 1087/2952]	5.18 (3.42–7.83) NA^a [1; 605/1613]	—	—	—
Overall	4.81 (3.67–6.30) 1.95–11.83 [10; 24,357/155,272]	6.82 (4.53–10.25) 2.03–22.87 [6; 5115/56,580]	4.48 (3.69–5.44) 2.60–7.70 [12; 18,468/98,409]	10.94 (7.22–16.58) 2.58–46.46 [9; 4470/90,072]	6.62 (4.18–10.5) NA^a [1; 1965/19961]	—	40.72 (29.30–56.61) NA^a [1; 1641/19,961]
Odds ratio
	IFG_5.6 cohort	IFG_6.1 cohort	IGT cohort	IFG + IGT cohort	HbA1c_5.7 cohort	HbA1c_6.0 cohort	HbA1c_5.7 + IFG_5.6 cohort
Asia/Middle East	2.94 (1.77–4.86) 0.43–19.93 [10; 6359/28,218]	5.18 (2.32–11.53) 0.29–91.37 [7; 3317/25,604]	3.74 (2.83–4.94) 1.70–8.21 [6; 1226/7417]	6.99 (3.09–15.83) NA^b [3; 498/3704]	4.54 (2.65–7.78) NA^a [1; 675/462]	23.20 (18.70–28.78) NA^a [1; 1103/10,763]	46.70 (33.60–64.91) NA^a [1; 1951/10,761]
Australia/Europe/North America	6.47 (3.81–11.00) 0.99–42.32 [9; 1949/7920]	8.69 (4.95–15.24) 1.20–62.69 [7; 1240/5094]	5.20 (3.62–7.45) 1.50–18.09 [11; 1481/7684]	20.95 (12.40–35.40) 4.93–89.05 [6; 154/5300]	4.38 (1.36–14.15) NA^a [2; 231/2100]	15.60 (6.90–35.27) NA^a [1; 370/5365]	26.20 (16.30–41.11) NA^a [1; 169/1125]
Latin America	4.28 (3.21–5.71) NA^a [1; 65/1594]	3.73 (2.18–6.38) NA^a [1; 17/1594]	4.94 (3.15–7.76) NA^a [2; 381/3097]	—	—	—	—
American Indians/Islands	3.12 (2.31–4.21) NA^a [1; 947/595]	—	3.60 (1.40–9.26) NA^a [1; 51/215]	—	—	5.89 (4.23–8.20) NA^a [1; 121/595]	—
Overall	4.15 (2.75–6.28) 0.54–32.00 [21; 9320/38,327]	6.60 (4.18–10.43) 0.93–46.82 [15; 4574/32,292]	4.61 (3.76–5.64) 2.10–10.13 [20; 3139/18,413]	13.14 (7.41–23.30) 1.84–93.66 [9; 652/9004]	4.43 (2.20–8.88) NA^b [3; 906/2562]	12.8 [4.56–35.9] NA^b [3; 1594/16,723]	35.91 (20.43–63.12) NA^a [2; 2120/11,886]
CI: confidence interval; HbA1c: glycosylated haemoglobin A1c; HbA1c_5.7/6.0 (threshold 5.7% or 6.0%); HbA1c_5.7 + IFG_5.6 : both HbA1c_5.7 and IFG_5.6; IFG_5.6/6.1 : impaired fasting glucose (threshold 5.6 mmol/L or 6.1 mmol/L); IGT: impaired glucose tolerance; IFG + IGT: both IFG and IGT; IH: intermediate hyperglycaemia; NA: not applicable; T2DM: type 2 diabetes mellitus; NR: not reported ^aWith fewer than 3 studies a prediction interval could not be calculated ^bCalculation of the 95% prediction interval did not provide a meaningful estimate ^cCombination of HbA1c_6.0 plus IFG_5.6 at baseline showed a hazard ratio for T2DM development of 53.7 (95% CI 38.4–75.1)

Table 2. Overview: intermediate hyperglycaemia versus normoglycaemia as a prognostic factor for the development of type 2 diabetes

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Comparison 1. Hazard ratio as the effect measure for the development of T2DM

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 T2DM incidence (IFG_5.6) Show forest plot	8	34867	Hazard Ratio (Random, 95% CI)	4.32 [2.61, 7.12]

1.1 Asia/Middle East	4	14803	Hazard Ratio (Random, 95% CI)	5.07 [3.41, 7.53]
1.2 Australia/Europe/North America	3	18522	Hazard Ratio (Random, 95% CI)	4.15 [1.24, 13.87]
1.3 American Indians/Islands	1	1542	Hazard Ratio (Random, 95% CI)	2.38 [1.85, 3.06]
2 T2DM incidence (IFG_6.1) Show forest plot	10	21475	Hazard Ratio (Random, 95% CI)	5.47 [3.50, 8.54]

2.1 Asia/Middle East	5	10810	Hazard Ratio (Random, 95% CI)	10.55 [3.61, 30.81]
2.2 Australia/Europe/North America	4	10571	Hazard Ratio (Random, 95% CI)	3.30 [2.32, 4.67]
2.3 Latin America	1	94	Hazard Ratio (Random, 95% CI)	2.06 [1.76, 2.41]
3 T2DM incidence (IGT) Show forest plot	5	16576	Hazard Ratio (Random, 95% CI)	3.61 [2.31, 5.64]

3.1 Asia/Middle East	3	8475	Hazard Ratio (Random, 95% CI)	4.48 [2.81, 7.15]
3.2 Australia/Europe/North America	2	8101	Hazard Ratio (Random, 95% CI)	2.53 [1.52, 4.19]
4 T2DM incidence (IFG + IGT) Show forest plot	5	9757	Hazard Ratio (Random, 95% CI)	6.90 [4.15, 11.45]

4.1 Asia/Middle East	3	7156	Hazard Ratio (Random, 95% CI)	10.20 [5.45, 19.09]
4.2 Australia/Europe/North America	1	1650	Hazard Ratio (Random, 95% CI)	3.80 [2.30, 6.28]
4.3 American Indians/Islands	1	951	Hazard Ratio (Random, 95% CI)	4.06 [3.05, 5.40]
5 T2DM incidence (HbA1c_5.7) Show forest plot	4	25047	Hazard Ratio (Random, 95% CI)	5.55 [2.77, 11.12]

5.1 Asia	3	16805	Hazard Ratio (Random, 95% CI)	7.21 [5.14, 10.11]
5.2 Australia/Europe/North America	1	8242	Hazard Ratio (Random, 95% CI)	2.71 [2.48, 2.96]
6 T2DM incidence (HbA1c_6.0) Show forest plot	6	30699	Hazard Ratio (Random, 95% CI)	10.10 [3.59, 28.43]

6.1 Asia/Middle East	4	22734	Hazard Ratio (Random, 95% CI)	13.12 [4.10, 41.96]
6.2 Australia/Europe/North America	2	7965	Hazard Ratio (Random, 95% CI)	5.09 [1.69, 15.37]
7 T2DM incidence (HbA1c + IFG) Show forest plot	1		Hazard Ratio (Fixed, 95% CI)	Subtotals only

7.1 HbA1c5.7 + IFG5.6	1	4559	Hazard Ratio (Fixed, 95% CI)	32.50 [23.00, 45.92]
7.2 HbA1c5.7 + IFG6.1	1	5357	Hazard Ratio (Fixed, 95% CI)	37.90 [28.10, 51.12]
7.3 HbA1c6.0 + IFG5.6	1	4628	Hazard Ratio (Fixed, 95% CI)	53.70 [38.40, 75.09]
7.4 HbA1c6.0 + IFG6.1	1	5802	Hazard Ratio (Fixed, 95% CI)	52.30 [37.80, 72.37]

Comparison 1. Hazard ratio as the effect measure for the development of T2DM

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Comparison 2. Odds ratio as the effect measure for the development of T2DM

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 T2DM incidence (IFG_5.6) Show forest plot	21	47647	Odds Ratio (Random, 95% CI)	4.15 [2.75, 6.28]

1.1 Asia/Middle East	10	34577	Odds Ratio (Random, 95% CI)	2.94 [1.77, 4.86]
1.2 Australia/Europe/North America	9	9869	Odds Ratio (Random, 95% CI)	6.47 [3.81, 11.00]
1.3 Latin America	1	1659	Odds Ratio (Random, 95% CI)	4.28 [3.21, 5.71]
1.4 American Indians/Islands	1	1542	Odds Ratio (Random, 95% CI)	3.12 [2.31, 4.21]
2 T2DM incidence (IFG_6.1) Show forest plot	15	36866	Odds Ratio (Random, 95% CI)	6.60 [4.18, 10.43]

2.1 Asia/Middle East	7	28921	Odds Ratio (Random, 95% CI)	5.18 [2.32, 11.53]
2.2 Australia/Europe/North America	7	6334	Odds Ratio (Random, 95% CI)	8.69 [4.95, 15.24]
2.3 Latin America	1	1611	Odds Ratio (Random, 95% CI)	3.73 [2.18, 6.38]
3 T2DM incidence (IGT) Show forest plot	20	21552	Odds Ratio (Random, 95% CI)	4.61 [3.76, 5.64]

3.1 Asia/Middle East	6	8643	Odds Ratio (Random, 95% CI)	3.74 [2.83, 4.94]
3.2 Australia/Europe/North America	11	9165	Odds Ratio (Random, 95% CI)	5.20 [3.62, 7.45]
3.3 Latin America	2	3478	Odds Ratio (Random, 95% CI)	4.94 [3.15, 7.76]
3.4 American Indians/Islands	1	266	Odds Ratio (Random, 95% CI)	3.60 [1.40, 9.26]
4 T2DM incidence (IFG + IGT) Show forest plot	9	9656	Odds Ratio (Random, 95% CI)	13.14 [7.41, 23.30]

4.1 Asia/Middle East	3	4202	Odds Ratio (Random, 95% CI)	6.99 [3.09, 15.83]
4.2 Australia/Europe/North America	6	5454	Odds Ratio (Random, 95% CI)	20.95 [12.40, 35.40]
5 T2DM incidence (HbA1c_5.7) Show forest plot	3	3468	Odds Ratio (Random, 95% CI)	4.43 [2.20, 8.88]

5.1 Asia/Middle East	1	1137	Odds Ratio (Random, 95% CI)	4.54 [2.65, 7.78]
5.2 Europe/North America	2	2331	Odds Ratio (Random, 95% CI)	4.38 [1.36, 14.15]
6 T2DM incidence (HbA1c_6.0) Show forest plot	3	18317	Odds Ratio (Random, 95% CI)	12.79 [4.56, 35.85]

6.1 Asia/Middle East	1	11866	Odds Ratio (Random, 95% CI)	23.20 [18.70, 28.78]
6.2 Australia/Europe/North America	1	5735	Odds Ratio (Random, 95% CI)	15.60 [6.90, 35.27]
6.3 American Indians/Islands	1	716	Odds Ratio (Random, 95% CI)	5.89 [4.23, 8.20]
7 T2DM incidence (HbA1c_5.7 + IFG_5.6) Show forest plot	2	14006	Odds Ratio (Random, 95% CI)	35.91 [20.43, 63.12]

7.1 Australia/Europe/North America	1	1294	Odds Ratio (Random, 95% CI)	26.20 [16.30, 42.11]
7.2 Asia/Middle East	1	12712	Odds Ratio (Random, 95% CI)	46.70 [33.60, 64.91]

Comparison 2. Odds ratio as the effect measure for the development of T2DM

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