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Cited by 137Diabetes Management and ResearchDiabetes Treatment and ManagementHyperglycemia and glycemic control in critically ill and hospitalized patients

Death during intensive glycemic therapy of diabetes: mechanisms and implications

Open access
Cryer, Philip E.·2011·The American Journal of Medicine
DOI 10.1016/j.amjmed.2011.08.008PMC PMC3464092
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Abstract

Despite its documented microvascular1–3 and potential macrovascular4,5 benefits in both type 1 and type 2 diabetes mellitus, intensive glycemic therapy was not found to produce macrovascular benefits, let alone survival benefits, in three recent randomized clinical trials: Action to Control Cardiovascular Risk in Diabetes (ACCORD),6 Action in Diabetes and Vascular Disease: Preterax and Diamicron Modified Release Controlled Evaluation (ADVANCE),7 and Veterans Affairs Diabetes Trial (VADT).8 Similarly, it was not found to produce a survival benefit in hyperglycemic intensive care unit patients.9–11 Indeed, intensive glycemic therapy resulted in increased mortality in one large trial involving patients with type 2 diabetes6 and in another large trial involving critically ill individuals (Normoglycemia in Intensive Care—Survival Using Glucose Algorithm Regulation (NICE-SUGAR)).9 Regardless of the specific causative mechanisms, the latter findings are of concern. It appears that some aspect of intensive therapy increased the risk of death.

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  • The main cause of hypoglycemia is intensification of antihyperglycemic therapy, almost always with sulfonylureas or insulin, aimed at lower A1C targets, as shown by intensive therapy trials.

    “The primary cause of hypoglycemia is intensification of antihyperglycemic therapy (almost always using SUs [or to a lesser extent glinides] and/or insulin) aimed at achieving lower A1C targets, as demonstrated by intensive therapy trials.1202,1203”

    From American Association of Clinical Endocrinology Clinical Practice Guideline: Developing a Diabetes Mellitus Comprehensive Care Plan-2022 Update. (2022) · cites this paper as [1203]

    In the paper’s discussion of glycemic goals (page unavailable), Cryer links hypoglycemia risk to sulfonylureas, glinides, and insulin, and describes ACCORD’s lower A1C goal and planned drug intensification. The paper does not establish that intensification is the primary cause of hypoglycemia; it describes iatrogenic hypoglycemia as arising from an interplay of therapeutic hyperinsulinemia and compromised defenses. (LLM, conf=0.82)

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  • HAAF is maladaptive because defective glucose counterregulation and hypoglycemia unawareness substantially increase the risk of severe hypoglycemia with its morbidity and potential mortality.

    “On the other hand, HAAF is clearly maladaptive since defective glucose counterregulation and hypoglycemia unawareness substantially increase the risk of severe hypoglycemia with its morbidity and potential mortality (26).”

    From Hypoglycemia and Diabetes: A Report of a Workgroup of the American Diabetes Association and The Endocrine Society (2013) · cites this paper as [26]

    The main text (page unavailable) identifies defective glucose counterregulation and hypoglycemia unawareness as components of HAAF and says metabolic HAAF increases the risk of iatrogenic hypoglycemia. It also says hypoglycemia causes recurrent morbidity and can be fatal. The cited passages do not establish the claim’s more specific assertion that HAAF substantially increases the risk of *severe* hypoglycemia. (LLM, conf=0.78)

    Experimental — accuracy not yet measured

  • Hypoglycemia puts patients with diabetes at risk for injury and death.

    “Hypoglycemia puts patients at risk for injury and death.”

    From Hypoglycemia and Diabetes: A Report of a Workgroup of the American Diabetes Association and The Endocrine Society (2013) · cites this paper as [26]

  • Most episodes of fatal hypoglycemia are probably the result of mechanisms other than profound and prolonged hypoglycemia, such as ventricular arrhythmias.

    “Although profound and prolonged hypoglycemia can cause brain death, most episodes of fatal hypoglycemia are probably the result of other mechanisms, such as ventricular arrhythmias (26).”

    From Hypoglycemia and Diabetes: A Report of a Workgroup of the American Diabetes Association and The Endocrine Society (2013) · cites this paper as [26]

  • Profound and prolonged hypoglycemia can cause brain death.

    “Although profound and prolonged hypoglycemia can cause brain death, most episodes of fatal hypoglycemia are probably the result of other mechanisms, such as ventricular arrhythmias (26).”

    From Hypoglycemia and Diabetes: A Report of a Workgroup of the American Diabetes Association and The Endocrine Society (2013) · cites this paper as [26]

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Authors
Cryer, P. E.
Affiliations
Washington University in St. Louis (US)
Corresponding author
Cryer, Philip E.
Venue
The American Journal of Medicine
Publisher
Elsevier BV
Published
2011-11
Volume
124
Issue
11
Pages
993-996
ISSN
0002-9343 (ISSN-L)
DOI
10.1016/j.amjmed.2011.08.008
PMC
PMC3464092
OpenAlex
W2044277864
Semantic Scholar
bcc2ac94423ef826cfcd974b1f808d52497258e4
Cited by
137
References
68
Citations by year
2025: 5 · 2024: 7 · 2023: 7 · 2022: 8 · 2021: 8 · 2020: 9 · 2019: 15 · 2018: 8 · 2017: 10 · 2016: 10 · 2015: 10 · 2014: 12 · 2013: 18 · 2012: 10
FWCI
10.48
Type
journal article
Language
en
Open access
Licence
Locations
  • The American Journal of Medicine (publishedVersion)
  • PubMed (publishedVersion)
  • PubMed Central (acceptedVersion)
Funders
  • American Diabetes Association
  • Bristol-Myers Squibb
  • AstraZeneca
  • MannKind Corporation
  • Novo Nordisk
  • National Institutes of Health (5p60dk020579-35, DK20579, P60-DK-20579, RR‐00036)
  • National Institute of Diabetes and Digestive and Kidney Diseases (R37DK027085, P60-DK20579, R37-DK27085, T32 DK07120, P60-DK-020579, T32DK007120)
  • National Center for Research Resources (UL1-RR-24992, M01-RR00036, UL1RR024992, M01RR000036)
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 › Hyperglycemia and glycemic control in critically ill and hospitalized patients
Keywords
diabetes mortality, type 1 diabetes, type 2 diabetes, cardiovascular risk, tight glycemic control, cardiovascular complications
MeSH terms
Female, Humans, Hypoglycemia, Hypoglycemic Agents, Male, Hospital Mortality

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