Severe hypoglycemia and risks of vascular events and death
Open accessAbstract
BACKGROUND: Severe hypoglycemia may increase the risk of a poor outcome in patients with type 2 diabetes assigned to an intensive glucose-lowering intervention. We analyzed data from a large study of intensive glucose lowering to explore the relationship between severe hypoglycemia and adverse clinical outcomes. METHODS: We examined the associations between severe hypoglycemia and the risks of macrovascular or microvascular events and death among 11,140 patients with type 2 diabetes, using Cox proportional-hazards models with adjustment for covariates measured at baseline and after randomization. RESULTS: During a median follow-up period of 5 years, 231 patients (2.1%) had at least one severe hypoglycemic episode; 150 had been assigned to intensive glucose control (2.7% of the 5571 patients in that group), and 81 had been assigned to standard glucose control (1.5% of the 5569 patients in that group). The median times from the onset of severe hypoglycemia to the first major macrovascular event, the first major microvascular event, and death were 1.56 years (interquartile range, 0.84 to 2.41), 0.99 years (interquartile range, 0.40 to 2.17), and 1.05 years (interquartile range, 0.34 to 2.41), respectively. During follow-up, severe hypoglycemia was associated with a significant increase in the adjusted risks of major macrovascular events (hazard ratio, 2.88; 95% confidence interval [CI], 2.01 to 4.12), major microvascular events (hazard ratio, 1.81; 95% CI, 1.19 to 2.74), death from a cardiovascular cause (hazard ratio, 2.68; 95% CI, 1.72 to 4.19), and death from any cause (hazard ratio, 2.69; 95% CI, 1.97 to 3.67) (P<0.001 for all comparisons). Similar associations were apparent for a range of nonvascular outcomes, including respiratory, digestive, and skin conditions (P<0.01 for all comparisons). No relationship was found between repeated episodes of severe hypoglycemia and vascular outcomes or death. CONCLUSIONS: Severe hypoglycemia was strongly associated with increased risks of a range of adverse clinical outcomes. It is possible that severe hypoglycemia contributes to adverse outcomes, but these analyses indicate that hypoglycemia is just as likely to be a marker of vulnerability to such events. (Funded by Servier and the National Health and Medical Research Council of Australia; ClinicalTrials.gov number, NCT00145925.).
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The frequency of severe hypoglycemia in the intensive therapy groups of the ACCORD, ADVANCE and VADT trials was 2 to 3 times higher than in standard therapy groups.
“the frequency of severe hypoglycemia in these trials was 2 to 3 times higher in the intensive therapy groups”
From Targets for Glycemic Control (2018) · cites this paper as [31]
Rates of Hypoglycemia over Time (p. 4) reports severe hypoglycemia in 2.7% of ADVANCE’s intensive group versus 1.5% of its standard group—about 1.8 times as frequent. The Discussion (p. 7) also describes a higher rate with intensive treatment in ACCORD, but our copy does not establish a two- to threefold difference across ACCORD, ADVANCE, and VADT. (LLM, conf=0.88)
Experimental — accuracy not yet measuredIn people with type 2 diabetes and established or very high risk for cardiovascular disease, there is a clear association between increased mortality and severe hypoglycemia and symptomatic hypoglycemia.
“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 [63]
The Discussion (p. 6) clearly reports an association between severe hypoglycemia and increased mortality. But the Study Population section (p. 3) includes patients with microvascular disease or just one other cardiovascular risk factor, so it does not establish that all participants had established CVD or were at very high CVD risk. The symptomatic-hypoglycemia part is attributed to citation 64, not this paper. (LLM, conf=0.82)
Experimental — accuracy not yet measuredExposure to severe hypoglycemia is strongly associated with adverse outcomes, including death, in post hoc analyses of trials of strict glycemic control.
“Post hoc analysis of clinical trials examining the effects of strict glycemic control on cardiovascular outcomes showed that exposure to severe hypoglycemia was strongly associated with a range of adverse outcomes, including death (2, 3).”
From Effect of Hypoglycemia on QT Interval in Individuals With and Without Type 2 Diabetes: A Randomized Crossover Trial (2025) · cites this paper as [3]
In ADVANCE, where rates of hypoglycemia were low, a similar pattern of association between severe hypoglycemia and mortality was found.
“In ADVANCE, where rates of hypoglycemia were low, a similar pattern was found (47).”
From Hypoglycemia and Diabetes: A Report of a Workgroup of the American Diabetes Association and The Endocrine Society (2013) · cites this paper as [47]
Higher mortality was reported in participants with 1 or more episodes of severe hypoglycemia in the ACCORD, ADVANCE and VADT trials, irrespective of treatment arms.
“a higher mortality was reported in participants with 1 or more episodes of severe hypoglycemia in the ACCORD (30), ADVANCE (31) and VADT trials (25), irrespective of the different treatment arms in which individual participants were allocated.”
From Targets for Glycemic Control (2018) · cites this paper as [31]
An association of level 3 hypoglycemia with mortality was also found in the ADVANCE trial and in clinical practice.
“An association of level 3 hypoglycemia with mortality was also found in the ADVANCE trial and in clinical practice (77,78).”
From 6. Glycemic Goals, Hypoglycemia, and Hyperglycemic Crises: Standards of Care in Diabetes-2026. (2026) · cites this paper as [77]
U500 regular insulin may improve glycemia in persons with severe insulin resistance (e.g., requiring more than 200 total units of insulin per day).
“U500 regular insulin (contains 500 units/mL of regular insulin) may improve glycemia in the therapy of persons with DM who have severe insulin resistance (eg, require >200 total units of insulin/day).1102–1105”
From American Association of Clinical Endocrinology Clinical Practice Guideline: Developing a Diabetes Mellitus Comprehensive Care Plan-2022 Update. (2022) · cites this paper as [1105]
The Study Population section (p. 3) describes an intensive glucose-lowering regimen using modified-release gliclazide and other drugs as required. Searches for U500 insulin and the >200-units-per-day criterion found no passage in our copy addressing whether U500 improves glycemia in people with severe insulin resistance. (LLM, conf=0.76)
Experimental — accuracy not yet measuredMultiple studies have shown a strong relationship between hypoglycemia, whether severe or not severe, and cardiovascular events and mortality.
“multiple studies have shown a strong relationship between hypoglycemia (severe or not severe) and cardiovascular events and mortality”
From Clinical management of stable coronary artery disease in patients with type 2 diabetes mellitus: a scientific statement from the American Heart Association (2020) · cites this paper as [197]
All three trials clearly demonstrated that an episode of severe hypoglycemia was associated with an increased risk of subsequent mortality.
“All three trials clearly demonstrated that an episode of severe hypoglycemia was associated with an increased risk of subsequent mortality.”
From Hypoglycemia and Diabetes: A Report of a Workgroup of the American Diabetes Association and The Endocrine Society (2013) · cites this paper as [47]
In ADVANCE, where rates of hypoglycemia were low, a similar pattern was found.
“In ADVANCE, where rates of hypoglycemia were low, a similar pattern was found (47).”
From Hypoglycemia and Diabetes: A Report of a Workgroup of the American Diabetes Association and The Endocrine Society (2013) · cites this paper as [47]
An association of level 3 hypoglycemia with mortality was found in the ADVANCE trial.
“An association of level 3 hypoglycemia with mortality was also found in the ADVANCE trial (90).”
From 6. Glycemic Targets: <i>Standards of Care in Diabetes—2023</i> (2023) · cites this paper as [90]
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- Authors
- Zoungas, S., Patel, A., Chalmers, J., de Galan, B. E., Li, Q., Billot, L., Woodward, M., Ninomiya, T., Neal, B., MacMahon, S., Grobbee, D. E., Kengne, A. P., Marre, M., & Heller, S.
- Affiliations
- The University of Sydney (AU)
- University Medical Center Utrecht (NL)
- Hôpital Bichat-Claude-Bernard (FR)
- National Health Service (GB)
- ORCID
- Venue
- New England Journal of Medicine
- Publisher
- Massachusetts Medical Society
- Published
- 2010-10-07
- Volume
- 363
- Issue
- 15
- Pages
- 1410-1418
- ISSN
- 0028-4793 (ISSN-L)
- 1533-4406
- OpenAlex
- W2097995302
- Semantic Scholar
- b73e51368b0f6c3d0c425e6670188db927bc8b09
- Cited by
- 1,471
- References
- 31
- Citations by year
- 2026: 33 · 2025: 49 · 2024: 64 · 2023: 60 · 2022: 66 · 2021: 103 · 2020: 119 · 2019: 99 · 2018: 113 · 2017: 103 · 2016: 107 · 2015: 147 · 2014: 106 · 2013: 98 · 2012: 103
- FWCI
- 71.78
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- New England Journal of Medicine (publishedVersion)
- PubMed (publishedVersion)
- Radboud Repository (Radboud University) (submittedVersion)
- Radboud Repository (Radboud University) (submittedVersion, other-oa)
- Topics
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Diabetes Management and Research
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Diabetes Treatment and Management
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Diabetes, Cardiovascular Risks, and Lipoproteins
- Keywords
- severe hypoglycemia, type 2 diabetes, tight glycemic control, macrovascular events, cardiovascular mortality, all-cause mortality, adverse clinical outcomes, diabetes complications, UKPDS
- MeSH terms
- Blood Glucose, Cardiovascular Diseases, Diabetes Mellitus, Type 2, Female, Follow-Up Studies, Gliclazide, Humans, Hypoglycemia, Hypoglycemic Agents, Male, Middle Aged, Risk Factors, Vascular Diseases, Proportional Hazards Models, Microvessels
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