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Follow-up of Glycemic Control and Cardiovascular Outcomes in Type 2 Diabetes
Open accessAbstract
BACKGROUND: The Veterans Affairs Diabetes Trial previously showed that intensive glucose lowering, as compared with standard therapy, did not significantly reduce the rate of major cardiovascular events among 1791 military veterans (median follow-up, 5.6 years). We report the extended follow-up of the study participants. METHODS: After the conclusion of the clinical trial, we followed participants, using central databases to identify procedures, hospitalizations, and deaths (complete cohort, with follow-up data for 92.4% of participants). Most participants agreed to additional data collection by means of annual surveys and periodic chart reviews (survey cohort, with 77.7% follow-up). The primary outcome was the time to the first major cardiovascular event (heart attack, stroke, new or worsening congestive heart failure, amputation for ischemic gangrene, or cardiovascular-related death). Secondary outcomes were cardiovascular mortality and all-cause mortality. RESULTS: The difference in glycated hemoglobin levels between the intensive-therapy group and the standard-therapy group averaged 1.5 percentage points during the trial (median level, 6.9% vs. 8.4%) and declined to 0.2 to 0.3 percentage points by 3 years after the trial ended. Over a median follow-up of 9.8 years, the intensive-therapy group had a significantly lower risk of the primary outcome than did the standard-therapy group (hazard ratio, 0.83; 95% confidence interval [CI], 0.70 to 0.99; P=0.04), with an absolute reduction in risk of 8.6 major cardiovascular events per 1000 person-years, but did not have reduced cardiovascular mortality (hazard ratio, 0.88; 95% CI, 0.64 to 1.20; P=0.42). No reduction in total mortality was evident (hazard ratio in the intensive-therapy group, 1.05; 95% CI, 0.89 to 1.25; P=0.54; median follow-up, 11.8 years). CONCLUSIONS: After nearly 10 years of follow-up, patients with type 2 diabetes who had been randomly assigned to intensive glucose control for 5.6 years had 8.6 fewer major cardiovascular events per 1000 person-years than those assigned to standard therapy, but no improvement was seen in the rate of overall survival. (Funded by the VA Cooperative Studies Program and others; VADT ClinicalTrials.gov number, NCT00032487.).
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“Numerous studies have demonstrated the clinical benefits of early achievement of nearnormal glycemic control in individuals with type 1 diabetes and type 2 diabetes (77-83).”
From Clinical Targets for Continuous Glucose Monitoring Data Interpretation: Recommendations From the International Consensus on Time in Range (2019) · cites this paper as [83]
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“Meta-analyses have clearly shown that tight blood glucose control leads to the suppression of ASCVD incidence795, 796).”
From Japan Atherosclerosis Society (JAS) guidelines for prevention of atherosclerotic cardiovascular diseases 2017 (2018) · cites this paper as [795]
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“Post-trial observational follow-up of the VADT over 10 years has also shown a significant reduction in the primary outcome of major CVD events, with myocardial infarctions and heart failure being the most common outcomes (60).”
From 6. Glycemic Goals, Hypoglycemia, and Hyperglycemic Crises: Standards of Care in Diabetes-2026. (2026) · cites this paper as [60]
Experimental — accuracy not yet measuredThe cited source says what the claim attributes to it.
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“However, during an observational median follow up of 9.8 years, the intensive-therapy group had a significantly lower risk of the primary outcome (MI, stroke, new or worsening congestive heart failure [CHF], amputation for ischemic gangrene, or CV-related death) than did the standard therapy group (HR 0.83, p=0.04), with an absolute reduction in risk of 8.6 major CV events per 1,000 personyears (”
From Targets for Glycemic Control (2018) · cites this paper as [27]
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“Additionally, longer-term epidemiological follow-up of these studies also showed a pattern of CVD benefit (58-60).”
From 6. Glycemic Goals, Hypoglycemia, and Hyperglycemic Crises: Standards of Care in Diabetes-2026. (2026) · cites this paper as [60]
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In the citing paper
“In people with type 2 diabetes and established, or very high risk for, cardiovascular disease (CVD), there is a clear association between an increased mortality and severe hypoglycemia (62,63) and symptomatic hypoglycemia (64).”
From Hypoglycemia (2018) · cites this paper as [62]
Experimental — accuracy not yet measuredIn the citing paper
“However, 10-year follow-up of the VADT cohort (64) did demonstrate a reduction in the risk of cardiovascular events (52.7 [control group] vs. 44.1 [intervention group] events per 1,000 person-years) with no benefit in cardiovascular or overall mortality.”
From 6. Glycemic Targets: Standards of Care in Diabetes—2023 (2023) · cites this paper as [64]
In the citing paper
“However, 10-year follow-up of the VADT cohort (64) did demonstrate a reduction in the risk of cardiovascular events (52.7 [control group] vs. 44.1 [intervention group] events per 1,000 person-years) with no benefit in cardiovascular or overall mortality.”
From 6. Glycemic Targets: Standards of Care in Diabetes—2023 (2023) · cites this paper as [64]
In the citing paper
“However, 10-year follow-up of the VADT cohort (64) did demonstrate a reduction in the risk of cardiovascular events (52.7 [control group] vs. 44.1 [intervention group] events per 1,000 person-years) with no benefit in cardiovascular or overall mortality.”
From 6. Glycemic Targets: Standards of Care in Diabetes—2023 (2023) · cites this paper as [64]
In the citing paper
“In all three trials, severe hypoglycemia was significantly more likely in participants who were randomly assigned to the intensive glycemic control arm.”
From 6. Glycemic Targets: Standards of Care in Diabetes—2023 (2023) · cites this paper as [64]
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“Despite longer-term studies establishing a positive legacy effect of tight glycemic control on CV outcomes [15, 92], an increase in CV mortality was reported in high-risk individuals (those with additional CV risk factors) assigned to intensive glucose control in the ACCORD trial [90, 93].”
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Long non-coding RNA MEG3 mediates high glucose-induced endothelial cell dysfunction.
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“More recent randomized controlled studies–such as ACCORD [178], Action in Diabetes and Vascular Disease: Preterax and Diamicron - Modified Release Controlled Evaluation (ADVANCE) [179] and Veterans Administration Diabetes Trial (VADT) [180]–did not show any benefit of intensive glycaemic control on CV mortality.”
MethodPrediabetes is not a risk factor for subclinical coronary atherosclerosis
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“These observations in people with both T1D and T2D and the sophisticated statistical analyses of the DCCT/EDIC cohort are clinically important.”
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Cardiovascular inflammation is reduced with methotrexate in diabetes
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“Although earlier landmark type 2 diabetes trials cohesively concluded that intensive glucose lowering reduces microvascular complications [8, 9], there has been less concordance on the impact of tight glycemic control on macrovascular risk.”
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Metadata
- Authors
- Hayward, R. A., Reaven, P. D., Wiitala, W. L., Bahn, G. D., Reda, D. J., Ge, L., McCarren, M., Duckworth, W. C., & Emanuele, N. V.
- Affiliations
- Edward Hines, Jr. VA Hospital (US)
- Phoenix VA Health Care System (US)
- VA Ann Arbor Healthcare System (US)
- Veterans Health Administration (US)
- Venue
- New England Journal of Medicine
- Publisher
- Massachusetts Medical Society
- Published
- 2015-06-04
- Volume
- 372
- Issue
- 23
- Pages
- 2197-2206
- ISSN
- 0028-4793 (ISSN-L)
- 1533-4406
- OpenAlex
- W2153552938
- Cited by
- 668
- References
- 27
- Citations by year
- 2026: 14 · 2025: 23 · 2024: 30 · 2023: 47 · 2022: 28 · 2021: 53 · 2020: 60 · 2019: 77 · 2018: 73 · 2017: 105 · 2016: 113 · 2015: 44
- FWCI
- 97.07
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- New England Journal of Medicine (publishedVersion)
- PubMed (publishedVersion)
- Funders
- U.S. Department of Veterans Affairs (98‐004)
- Amgen
- AstraZeneca
- Health Services Research and Development
- Novo Nordisk
- National Institutes of Health (98-004)
- National Heart, Lung, and Blood Institute (R01HL067690, R01HL094775)
- National Institute of Diabetes and Digestive and Kidney Diseases (P30DK092926)
- 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
- type 2 diabetes, tight glycemic control, glycemic control, HbA1c, major cardiovascular events, cardiovascular mortality, all-cause mortality, military veterans, long-term follow-up, cardiovascular risk reduction, congestive heart failure, amputation, stroke, myocardial infarction, ischemic gangrene
- MeSH terms
- Aged, Blood Glucose, Cardiovascular Diseases, Diabetes Mellitus, Type 2, Female, Follow-Up Studies, Glycated Hemoglobin, Humans, Hypoglycemic Agents, Male, Middle Aged, Risk, Survival Analysis
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