Association of HbA1c levels with vascular complications and death in patients with type 2 diabetes: evidence of glycaemic thresholds
Open accessAbstract
Aims/hypothesis There is conflicting evidence regarding appropriate glycaemic targets for patients with type 2 diabetes. Here, we investigate the relationship between HbA(1c) and the risks of vascular complications and death in such patients.Methods Eleven thousand one hundred and forty patients were randomised to intensive or standard glucose control in the Action in Diabetes and Vascular disease: Preterax and Diamicron Modified Release Controlled Evaluation (ADVANCE) trial. Glycaemic exposure was assessed as the mean of HbA(1c) measurements during follow-up and prior to the first event. Adjusted risks for each HbA(1c) decile were estimated using Cox models. Possible differences in the association between HbA(1c) and risks at different levels of HbA(1c) were explored using linear spline models.Results There was a non-linear relationship between mean HbA(1c) during follow-up and the risks of macrovascular events, microvascular events and death. Within the range of HbA(1c) studied (5.5-10.5%), there was evidence of 'thresholds', such that below HbA(1c) levels of 7.0% for macrovascular events and death, and 6.5% for microvascular events, there was no significant change in risks (all p > 0.8). Above these thresholds, the risks increased significantly: every 1% higher HbA(1c) level was associated with a 38% higher risk of a macrovascular event, a 40% higher risk of a microvascular event and a 38% higher risk of death (all p < 0.0001).Conclusions/interpretation In patients with type 2 diabetes, HbA(1c) levels were associated with lower risks of macrovascular events and death down to a threshold of 7.0% and microvascular events down to a threshold of 6.5%. There was no evidence of lower risks below these levels but neither was there clear evidence of harm.
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Similar U-shaped curves were observed in a 7-year observational study of people with T1D and a 22-year observational study of more than 20,000 people with T2D.
“Similar U-shaped curves were found in a 7-year observational study of persons with T1D and a 22-year observational study of >20,000 persons with T2D.83,84”
From American Association of Clinical Endocrinology Clinical Practice Guideline: Developing a Diabetes Mellitus Comprehensive Care Plan-2022 Update. (2022) · cites this paper as [84]
The Results (Study population and baseline characteristics; page unavailable) report 11,086 participants, not more than 20,000, and find that risk increased above HbA1c thresholds but had no clear relationship with HbA1c below them—not the claimed U-shaped curve. This paper therefore does not describe the attributed 22-year T2D study; its findings also do not establish the separately mentioned T1D study. (LLM, conf=0.90)
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Experimental — accuracy not yet measuredIn RCTs, targeting lower HbA1c values using glucose-lowering medications has been proven to reduce risks of microvascular diabetes complications (kidney disease, retinopathy, neuropathy) and, in some studies, also macrovascular diabetes complications (cardiovascular events).
“In RCTs, targeting lower HbA1c values using glucose-lowering medications has been proven to reduce risks of microvascular diabetes complications (i.e., kidney disease, retinopathy, neuropathy) and, in some studies, also macrovascular diabetes complications (i.e., cardiovascular events).”
From KDIGO 2022 Clinical Practice Guideline for Diabetes Management in Chronic Kidney Disease (2022) · cites this paper as [193]
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Experimental — accuracy not yet measuredIn T1D or T2D, lower achieved HbA1c levels below 7% versus 8%-9% reduce the risk of overall microvascular complications, including nephropathy and retinopathy, and macrovascular complications in some RCTs.
“In both T1D or T2D, lower achieved levels of HbA1c < 7% ( < 53 mmol/mol) versus 8% -9% (64 -75 mmol/mol) reduce risk of overall microvascular complications, including nephropathy and retinopathy, and macrovascular complications in some RCTs. 189 -193”
From KDIGO 2022 Clinical Practice Guideline for Diabetes Management in Chronic Kidney Disease (2022) · cites this paper as [193]
The Discussion and Conclusions (page not available in our copy) report that, among people with type 2 diabetes, lower achieved HbA1c was associated with lower microvascular risk down to 6.5% and macrovascular risk down to 7%. The Outcomes section includes nephropathy and retinopathy among microvascular events. This post hoc analysis does not establish that lowering HbA1c caused those reductions in an RCT, and it does not study type 1 diabetes or directly test the stated <7% versus 8%–9% comparison. (LLM, conf=0.87)
Experimental — accuracy not yet measuredThe diagnostic HbA1c cut-off for diabetes of 48 mmol/mol (6.5%) was defined by WHO as broadly the level where diabetes-specific microvascular complications start to emerge.
“The diagnostic HbA1c cut-off for diabetes of 48 mmol/mol (6.5%) was defined by WHO as broadly the level where diabetes-specific microvascular complications start to emerge [90, 91].”
Observational studies have shown a U-shaped relationship between HbA1c and clinical outcome, suggesting that lower HbA1c is not always better.
“Also, observational studies have shown a U-shaped relationship between HbA1c and clinical outcome, suggesting that lower HbA1c is not always better.135,136”
From 2023 ESC guidelines for the management of cardiovascular disease in patients with diabetes. (2023) · cites this paper as [136]
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Cites
Robust Locally Weighted Regression and Smoothing Scatterplots
Cleveland, W. S. (1979) · Journal of the American Statistical Association · doi:10.1080/01621459.1979.10481038 · Cited by 11,594 · see citing works
Stratton, I. M. (2000) · BMJ · doi:10.1136/bmj.321.7258.405 · Cited by 9,059 · see citing works
Effects of Intensive Glucose Lowering in Type 2 Diabetes
(2008) · New England Journal of Medicine · doi:10.1056/nejmoa0802743 · Cited by 7,888 · see citing works
Intensive blood glucose control and vascular outcomes in patients with type 2 diabetes
(2008) · New England Journal of Medicine · doi:10.1056/nejmoa0802987 · Cited by 7,397 · see citing works
The Emerging Risk Factors Collaboration (2010) · The Lancet · doi:10.1016/s0140-6736(10)60484-9 · Cited by 5,125 · see citing works
Glucose control and vascular complications in veterans with type 2 diabetes
Duckworth, W., Abraira, C., Moritz, T., Reda, D., Emanuele, N., Reaven, P. D., Zieve, F. J., Marks, J., Davis, S. N., Hayward, R., et al. (2009) · New England Journal of Medicine · doi:10.1056/nejmoa0808431 · Cited by 4,762 · see citing works
Robust Locally Weighted Regression and Smoothing Scatterplots
Cleveland, W. S. (1979) · Journal of the American Statistical Association · doi:10.2307/2286407 · Cited by 2,063 · see citing works
Coutinho, M., Gerstein, H. C., Wang, Y., & Yusuf, S. (1999) · Diabetes Care · doi:10.2337/diacare.22.2.233 · Cited by 1,685 · see citing works
Meta-analysis: glycosylated hemoglobin and cardiovascular disease in diabetes mellitus
Selvin, E., Marinopoulos, S., Berkenblit, G., Rami, T., Brancati, F. L., Powe, N. R., & Golden, S. H. (2004) · Annals of Internal Medicine · doi:10.7326/0003-4819-141-6-200409210-00007 · Cited by 1,657 · see citing works
Glycated hemoglobin, diabetes, and cardiovascular risk in nondiabetic adults
Selvin, E., Steffes, M. W., Zhu, H., Matsushita, K., Wagenknecht, L., Pankow, J., Coresh, J., & Brancati, F. L. (2010) · New England Journal of Medicine · doi:10.1056/nejmoa0908359 · Cited by 1,544 · see citing works
Intensive glucose control and macrovascular outcomes in type 2 diabetes
Turnbull, F. M., Abraira, C., Anderson, R. J., Byington, R. P., Chalmers, J. P., Duckworth, W. C., Evans, G. W., Gerstein, H. C., Holman, R. R., Moritz, T. E., et al. (2009) · Diabetologia · doi:10.1007/s00125-009-1470-0 · Cited by 1,189 · see citing works
Self-citationKhaw, K.-T., Wareham, N., Bingham, S., Luben, R., Welch, A., & Day, N. (2004) · Annals of Internal Medicine · doi:10.7326/0003-4819-141-6-200409210-00006 · Cited by 974 · see citing works
Survival as a function of HbA1c in people with type 2 diabetes: a retrospective cohort study
Currie, C. J., Peters, J. R., Tynan, A., Evans, M., Heine, R. J., Bracco, O. L., Zagar, T., & Poole, C. D. (2010) · The Lancet · doi:10.1016/s0140-6736(09)61969-3 · Cited by 874 · see citing works
Paget's Disease of the Mandible
Patel, M., & Bhalla, A. K. (2008) · New England Journal of Medicine · doi:10.1056/nejmicm066227 · Cited by 610 · see citing works
Easton, D. F., Peto, J., & Babiker, A. G. (1991) · Statistics in Medicine · doi:10.1002/sim.4780100703 · Cited by 434 · see citing works
Available, N. A. N. (2001) · Diabetologia · doi:10.1007/s001250100612 · Cited by 180 · see citing works
for the ADVANCE Collaborative Group, Kengne, A. P., Patel, A. A., Colagiuri, S., Heller, S. R., Hamet, P., Marre, M., Pan, C., Zoungas, S., Grobbee, D. E., et al. (2010) · Diabetologia · doi:10.1007/s00125-010-1681-4 · Cited by 132 · see citing works
Self-citationInterim monitoring of clinical trials based on long-term binary endpoints
Marschner, I. C., & Becker, S. L. (2001) · Statistics in Medicine · doi:10.1002/1097-0258(20010130)20:2 · Cited by 36 · see citing works
Dale, A. C., Midthjell, K., Nilsen, T. I. L., Wiseth, R., & Vatten, L. J. (2009) · European Heart Journal · doi:10.1093/eurheartj/ehp039 · Cited by 34 · see citing works
(NDR), O. B. O. T. N. D. R., Guðbjörnsdóttir, S., Eliasson, B., Eeg‐Olofsson, K., Zethelius, B., & Cederholm, J. (2011) · Diabetologia · doi:10.1007/s00125-011-2218-1 · Cited by 23 · see citing works
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Research works printed but not linked: 1
- [19]19. Kengne AP, Patel A, Colagiuri S et al (2010) The Framingham and UKPDS risk equations do not reliably estimate the probability of cardiovascular events in a large ethnically diverse sample of patients with diabetes: the ADVANCE Study. Diabetologia 53 (5):821-831
Cited by
Sorted by citations
2023 ESC guidelines for the management of cardiovascular disease in patients with diabetes.
Marx, N., Federici, M., Schütt, K., Müller-Wieland, D., Ajjan, R. A., Antunes, M. J., Christodorescu, R. M., Crawford, C., Di Angelantonio, E., Eliasson, B., et al. (2023) · European Heart Journal · doi:10.1093/eurheartj/ehad192 · Cited by 1,642 · see citing works
KDIGO 2020 Clinical practice guideline for diabetes management in chronic kidney disease
de Boer, I. H., Caramori, M. L., Chan, J. C. N., Heerspink, H. J. L., Hurst, C., Khunti, K., Liew, A., Michos, E. D., Navaneethan, S. D., Olowu, W. A., et al. (2020) · Kidney International · doi:10.1016/j.kint.2020.06.019 · Cited by 1,399 · see citing works
Self-citationKDIGO 2022 Clinical Practice Guideline for Diabetes Management in Chronic Kidney Disease
Rossing, P., Caramori, M. L., Chan, J. C. N., Heerspink, H. J. L., Hurst, C., Khunti, K., Liew, A., Michos, E. D., Navaneethan, S. D., Olowu, W. A., et al. (2022) · Kidney International · doi:10.1016/j.kint.2022.06.008 · Cited by 1,373 · see citing works
Self-citationZoungas, S., Arima, H., Gerstein, H. C., Holman, R. R., Woodward, M., Reaven, P., Hayward, R. A., Craven, T., Coleman, R. L., & Chalmers, J. (2017) · The Lancet Diabetes & Endocrinology · doi:10.1016/s2213-8587(17)30104-3 · Cited by 529 · see citing works
Self-citationBlonde, L., Umpierrez, G. E., Reddy, S. S., McGill, J. B., Berga, S. L., Bush, M., Chandrasekaran, S., DeFronzo, R. A., Einhorn, D., Galindo, R. J., et al. (2022) · Endocrine Practice · doi:10.1016/j.eprac.2022.08.002 · Cited by 507 · see citing works
Nouwen, A., Adriaanse, M. C., van Dam, K., Iversen, M. M., Viechtbauer, W., Peyrot, M., Caramlau, I., Kokoszka, A., Kanc, K., de Groot, M., et al. (2019) · Diabetic Medicine · doi:10.1111/dme.14054 · Cited by 301 · see citing works
Churuangsuk, C., Hall, J., Reynolds, A., Griffin, S. J., Combet, E., & Lean, M. E. J. (2022) · Diabetologia · doi:10.1007/s00125-021-05577-2 · Cited by 204 · see citing works
Revisiting the links between glycaemia, diabetes and cardiovascular disease
Sattar, N. (2013) · Diabetologia · doi:10.1007/s00125-012-2817-5 · Cited by 163 · see citing works
Glycemia reduction in type 2 diabetes–microvascular and cardiovascular outcomes
The GRADE Study Research Group (2022) · New England Journal of Medicine · doi:10.1056/nejmoa2200436 · Cited by 159 · see citing works
Mamo, Y., Bekele, F., Nigussie, T., & Zewudie, A. (2019) · BMC Endocrine Disorders · doi:10.1186/s12902-019-0421-0 · Cited by 147 · see citing works
Medication adherence and glycemic control among newly diagnosed diabetes patients
Lin, L.-K., Sun, Y., Heng, B. H., Chew, D. E. K., & Chong, P.-N. (2017) · BMJ Open Diabetes Research & Care · doi:10.1136/bmjdrc-2017-000429 · Cited by 123 · see citing works
Borror, A., Zieff, G., Battaglini, C., & Stoner, L. (2018) · Sports Medicine · doi:10.1007/s40279-018-0864-x · Cited by 106 · see citing works
Hussein, H., Zaccardi, F., Khunti, K., Davies, M. J., Patsko, E., Dhalwani, N. N., Kloecker, D. E., Ioannidou, E., & Gray, L. J. (2020) · Diabetes, Obesity and Metabolism · doi:10.1111/dom.14008 · Cited by 82 · see citing works
Ikeda, F., Doi, Y., Ninomiya, T., Hirakawa, Y., Mukai, N., Hata, J., Shikata, K., Yoshida, D., Matsumoto, T., Kitazono, T., et al. (2013) · Cardiovascular Diabetology · doi:10.1186/1475-2840-12-164 · Cited by 67 · see citing works
Self-citationDarakjian, L., Deodhar, M., Turgeon, J., & Michaud, V. (2021) · International Journal of Molecular Sciences · doi:10.3390/ijms22094967 · Cited by 53 · see citing works
Schoenaker, D. A. J. M., Simon, D., Chaturvedi, N., Fuller, J. H., Soedamah-Muthu, S. S., & the EURODIAB Prospective Complications Study Group (2014) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jc.2013-2824 · Cited by 43 · see citing works
Carlson, A. L., Huyett, L. M., Jantz, J., Chang, A., Vienneau, T., & Ly, T. T. (2021) · Diabetes Research and Clinical Practice · doi:10.1016/j.diabres.2021.108735 · Cited by 20 · see citing works
- Authors
- for the ADVANCE Collaborative Group, Zoungas, S., Chalmers, J., Ninomiya, T., Li, Q., Cooper, M. E., Colagiuri, S., Fulcher, G., de Galan, B. E., Harrap, S., Hamet, P., Heller, S., MacMahon, S., Marre, M., Poulter, N., Travert, F., Patel, A., Neal, B., & Woodward, M.
- Affiliations
- The George Institute for Global Health (AU)
- Baker Heart and Diabetes Institute (AU)
- The University of Sydney (AU)
- Royal North Shore Hospital (AU)
- The Royal Melbourne Hospital (AU)
- Centre Hospitalier de l’Université de Montréal (CA)
- Assistance Publique – Hôpitaux de Paris (FR)
- Johns Hopkins University (US)
- Corresponding author
- Zoungas, S.
- ORCID
- Venue
- Diabetologia
- Published
- 2011-12-21
- Volume
- 55
- Issue
- 3
- Pages
- 636-643
- ISSN
- 0012-186X (ISSN-L)
- 1432-0428
- OpenAlex
- W2147521434
- Cited by
- 358
- References
- 20
- Citations by year
- 2026: 13 · 2025: 21 · 2024: 24 · 2023: 21 · 2022: 31 · 2021: 25 · 2020: 26 · 2019: 23 · 2018: 21 · 2017: 25 · 2016: 27 · 2015: 30 · 2014: 25 · 2013: 26 · 2012: 19
- FWCI
- 18.27
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Diabetologia (publishedVersion)
- PubMed (publishedVersion)
- Radboud Repository (Radboud University) (submittedVersion)
- Funders
- High Blood Pressure Research Council of Australia
- Ministerio de Economía y Competitividad
- Servier
- Medical Research Council
- National Health and Medical Research Council (211086, 358395, 571281, IDs 358395)
- Topics
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Diabetes Treatment and Management
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Diabetes Management and Research
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Diabetes, Cardiovascular Risks, and Lipoproteins
- Keywords
- HbA1c, type 2 diabetes, glycemic targets, macrovascular complications, microvascular complications, mortality, tight glycemic control, ADVANCE trial, nonlinear dose-response relationship
- MeSH terms
- Aged, Aged, 80 and over, Antihypertensive Agents, Blood Glucose, Diabetes Mellitus, Type 2, Diabetic Angiopathies, Drug Therapy, Combination, Female, Follow-Up Studies, Glycated Hemoglobin, Humans, Hyperglycemia, Hypertension, Hypoglycemic Agents, Male, Middle Aged, Risk Factors, Cohort Studies, Proportional Hazards Models, Microvessels
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