The association between symptomatic, severe hypoglycaemia and mortality in type 2 diabetes: retrospective epidemiological analysis of the ACCORD studyBMJ 2010; 340 doi: https://doi.org/10.1136/bmj.b4909 (Published 08 January 2010) Cite this as: BMJ 2010;340:b4909
- Denise E Bonds, medical officer1,
- Michael E Miller, professor of biostatistics2,
- Richard M Bergenstal, executive director3,
- John B Buse, professor of medicine4,
- Robert P Byington, professor of epidemiology and prevention2,
- Jeff A Cutler, research consultant1,
- R James Dudl, diabetes clinical lead5,
- Faramarz Ismail-Beigi, professor of medicine6,
- Angela R Kimel, research associate2,
- Byron Hoogwerf, clinical research physician78,
- Karen R Horowitz, associate professor of medicine6,
- Peter J Savage, senior advisor for clinical diabetes studies9,
- Elizabeth R Seaquist, professor of medicine10,
- Debra L Simmons, associate professor of medicine1112,
- William I Sivitz, professor of medicine13,
- Joann M Speril-Hillen, senior clinical investigator14,
- Mary Ellen Sweeney, associate professor of medicine1516
- 1National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD 20892, USA
- 2Division of Public Health Sciences, Wake Forest University Health Sciences, Winston-Salem, NC 27157-1063, USA
- 3International Diabetes Center at Park Nicollet, Minneapolis, MN 55416-2699, USA
- 4University of North Carolina School of Medicine, Chapel Hill, NC 27514, USA
- 5Care Management Institute, Kaiser Permanente, Oakland, CA 94612, USA
- 6Case Western Reserve University, Cleveland, OH 44106, USA
- 7Department of Endocrinology, Diabetes, and Metabolism, Cleveland Clinic, Cleveland, OH 44195, USA
- 8Lilly USA, Lilly Corporate Center, Indianapolis, IN 46285, USA
- 9National Institute of Diabetes and Digestive and Kidney Disease, National Institutes of Health, Bethesda, MD 20892, USA
- 10Department of Medicine, University of Minnesota, Minneapolis, MN 55455, USA
- 11University of Arkansas for Medical Sciences, Little Rock, AR 72205, USA
- 12John L McClellan Memorial Veterans Hospital, Central Arkansas Veterans Healthcare System, Little Rock, AR 72205, USA
- 13Department of Internal Medicine, University of Iowa Health Care, Iowa City, IA 52242, USA
- 14HealthPartners Research Foundation, Minneapolis, MN 55440-1524, USA
- 15Emory University School of Medicine, Atlanta, GA 30322, USA
- 16Atlanta Veterans Administration Medical Center, Atlanta, GA 30033, USA
- Correspondence to: DE Bonds
- Accepted 30 September 2009
Objective To determine whether there is a link between hypoglycaemia and mortality among participants in the Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial.
Design Retrospective epidemiological analysis of data from the ACCORD trial.
Setting Diabetes clinics, research clinics, and primary care clinics.
Participants Patients were eligible for the ACCORD study if they had type 2 diabetes, a glycated haemoglobin (haemoglobin A1C) concentration of 7.5% or more during screening, and were aged 40-79 years with established cardiovascular disease or 55-79 years with evidence of subclinical disease or two additional cardiovascular risk factors.
Intervention Intensive (haemoglobin A1C <6.0%) or standard (haemoglobin A1C 7.0-7.9%) glucose control.
Outcome measures Symptomatic, severe hypoglycaemia, manifest as either blood glucose concentration of less than 2.8 mmol/l (<50 mg/dl) or symptoms that resolved with treatment and that required either the assistance of another person or medical assistance, and all cause and cause specific mortality, including a specific assessment for involvement of hypoglycaemia.
Results 10 194 of the 10 251 participants enrolled in the ACCORD study who had at least one assessment for hypoglycaemia during regular follow-up for vital status were included in this analysis. Unadjusted annual mortality among patients in the intensive glucose control arm was 2.8% in those who had one or more episodes of hypoglycaemia requiring any assistance compared with 1.2% for those with no episodes (53 deaths per 1924 person years and 201 deaths per 16 315 person years, respectively; adjusted hazard ratio (HR) 1.41, 95% CI 1.03 to 1.93). A similar pattern was seen among participants in the standard glucose control arm (3.7% (21 deaths per 564 person years) v 1.0% (176 deaths per 17 297 person years); adjusted HR 2.30, 95% CI 1.46 to 3.65). On the other hand, among participants with at least one hypoglycaemic episode requiring any assistance, a non-significantly lower risk of death was seen in those in the intensive arm compared with those in the standard arm (adjusted HR 0.74, 95% 0.46 to 1.23). A significantly lower risk was observed in the intensive arm compared with the standard arm in participants who had experienced at least one hypoglycaemic episode requiring medical assistance (adjusted HR 0.55, 95% CI 0.31 to 0.99). Of the 451 deaths that occurred in ACCORD up to the time when the intensive treatment arm was closed, one death was adjudicated as definitely related to hypoglycaemia.
Conclusion Symptomatic, severe hypoglycaemia was associated with an increased risk of death within each study arm. However, among participants who experienced at least one episode of hypoglycaemia, the risk of death was lower in such participants in the intensive arm than in the standard arm. Symptomatic, severe hypoglycaemia does not appear to account for the difference in mortality between the two study arms up to the time when the ACCORD intensive glycaemia arm was discontinued.
Trial registration NCT00000620.
Contributors: DEB contributed to the ongoing monitoring and conduct of the trial, participated in the interpretation of the results, and wrote the majority of the first draft. MEM contributed to the development of the protocol and the design, performed analyses for the study, participated in study interpretation, and wrote portions of the first draft. RMB contributed to the design and conduct of the trial and review, study interpretation, and editing of the manuscript. JBB participated in the design and conduct of the trial, conceptualising the analyses, and editing the manuscript. RPB contributed to the development of the trial protocol and to trial design, performed some analyses for the paper, participated in its interpretation, and contributed to the writing. JAC participated in the design and oversaw the trial, the conceptualisation of this paper, and many revisions of the content and presentation. RJD reviewed the manuscript and contributed segments where his knowledge provided information important to the accuracy of the work. FIB suggested new analyses and helped in the interpretation of the data and editing of the manuscript. ARK oversaw the regulatory aspect of the study, including all ethics approvals, managed the hypoglycaemia adjudication process, and contributed edits to two drafts of this paper. BH contributed to data collection, development of hypoglycaemia definitions and adjudication, conceptualising the analyses, review and editing of the manuscript, and approved the final version of the manuscript. KRH participated in the adjudication of hypoglycaemia, mortality, and cardiovascular outcomes, participated in data interpretation, contributed to data collection, and managed participants in the trial. PJS was involved in the design of the ACCORD clinical trial and the development of the hypoglycaemia monitoring and the treatment/prevention programme, participated in a clinical chart review to supplement the data on hypoglycaemic events, and assisted in the development of the analysis plan for assessing the impact of hypoglycaemia in ACCORD. In addition, PJS was involved in the planning and writing of the manuscript. ERS contributed to the development of the protocol, participated in study interpretation, and participated in writing the manuscript. DLS contributed to the development and implementation of the trial protocol, management of patients, and review of the paper. WIS reviewed and helped edit the paper, and carried out the research (that is, he managed study participants). JMSH participated in protocol development, design, and implementation and reviewed and edited the manuscript. MES contributed to the development and implementation of the trial protocol, management of patients, and review of the paper. All authors approved the final draft. DEB is the guarantor.
Funding: This study was supported by grants from the National Heart, Lung, and Blood Institute (N01-HC-95178, N01-HC-95179, N01-HC-95180, N01-HC-95181, N01-HC-95182, N01-HC-95183, N01-HC-95184, IAA-Y1-HC-9035, and IAA-Y1-HC-1010); by other components of the National Institutes of Health, including the National Institute of Diabetes and Digestive and Kidney Diseases, the National Institute on Aging, and the National Eye Institute; by the Centers for Disease Control and Prevention; and by General Clinical Research Centers. The following companies provided study medications, equipment, or supplies: Abbott Laboratories, Amylin Pharmaceuticals, AstraZeneca, Bayer HealthCare, Closer Healthcare, GlaxoSmithKline, King Pharmaceuticals, Merck, Novartis, Novo Nordisk, Omron Healthcare, Sanofi-Aventis, and Schering-Plough.
Competing interests: RMB receives research grant support and/or is a member of a scientific advisory board for the following companies: Amylin Pharmaceuticals, Abbott Diabetes Care, Bayer, Eli Lilly, Intuity Medical, LifeScan, Mannkind, Medtronic-Minimed, National Institutes of Health, Novo Nordisk, ResMed, Roche, Sanofi-Aventis, Valeritas, and UnitedHealth Group. All the above activities are performed under contract with the non-profit Park Nicollet Institute and the International Diabetes Center, Minneapolis, MN, USA. RMB receives no personal compensation for any of these activities. He also inherited Merck stock. JBB is a shareholder of Insulet. Under contracts with his employer, JBB has been an investigator, consultant, or speaker for Amylin Pharmaceuticals, Bayhill Therapeutics, Becton, Dickinson and Company Research Laboratories, Bristol-Myers Squibb, Dexcom, Eli Lilly, GlaxoSmithKline, Intekrin, Intuity Medical, Johnson & Johnson, MannKind, Medtronic, Merck, MicroIslet, Novartis, Novo Nordisk, Osiris, Pfizer, Roche, Sanofi-Aventis, Transition Therapeutics, and Wyeth. BH is a full-time employee of Lilly USA (Endocrine), Indianapolis, IN, USA. ERS has been reimbursed by Pfizer for participating in the review of applications for visiting professorships and has been a paid consultant for Merck. WIS receives research funds from GlaxoSmithKline and has been reimbursed by Merck as a consultant at a Global Experts Forum. The remaining authors declare no competing interests.
Ethical approval: The proposal for this research was approved by the Wake Forest University Health Sciences Institutional Review Board and the review boards of all participating universities.
Data Sharing: No additional data are available at this time.
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