The effects of baseline characteristics, glycaemia treatment approach, and glycated haemoglobin concentration on the risk of severe hypoglycaemia: post hoc epidemiological analysis of the ACCORD studyBMJ 2010; 340 doi: https://doi.org/10.1136/bmj.b5444 (Published 08 January 2010) Cite this as: BMJ 2010;340:b5444
- Michael E Miller, professor of biostatistics1,
- Denise E Bonds, medical officer2,
- Hertzel C Gerstein, professor of medicine and clinical epidemiology & biostatistics3,
- Elizabeth R Seaquist, professor of medicine4,
- Richard M Bergenstal, executive director5,
- Jorge Calles-Escandon, associate professor of medicine6,
- R Dale Childress, clinical assistant professor of medicine7,
- Timothy E Craven, senior biostatistician1,
- Robert M Cuddihy, medical director5,
- George Dailey, head of diabetes research8,
- Mark N Feinglos, professor of medicine9,
- Farmarz Ismail-Beigi, professor of medicine10,
- Joe F Largay, clinical instructor of medicine11,
- Patrick J O’Connor, senior clinical investigator12,
- Terri Paul, associate professor of medicine13,
- Peter J Savage, senior adviser for clinical diabetes studies 14,
- Ulrich K Schubart, professor of medicine15,
- Ajay Sood, assistant professor of medicine10,
- Saul Genuth, professor of medicine10,
- for the ACCORD Investigators
- 1Division of Public Health Sciences, Wake Forest University School of Medicine, Winston-Salem, NC 27157-1063, USA
- 2National Heart Lung and Blood Institute, National Institute of Health, Bethesda, MD 20892, USA
- 3McMaster University and Hamilton Health Sciences, Population Health Research Institute, Hamilton, Ontario L8L 2X2, Canada
- 4Department of Medicine, University of Minnesota, Minneapolis, MN 55455, USA
- 5International Diabetes Center at Park Nicollet, Minneapolis, MN 55416-2699, USA
- 6Section of Endocrinology and Metabolism, Department of Internal Medicine, Wake Forest University School of Medicine, Winston-Salem, NC 27157, USA
- 7Memphis Veterans Affairs Medical Center, Memphis, TN 38104, USA
- 8Whittier Institute for Diabetes, La Jolla, CA 92037, USA
- 9Division of Endocrinology, Metabolism, and Nutrition, Duke University Medical Center, Durham, NC 27710, USA
- 10Case Western Reserve University, Cleveland, OH 44106, USA
- 11Department of Medicine, Division of Endocrinology, University of North Carolina, Chapel Hill, NC 27514, USA
- 12HealthPartners Research Foundation, Minneapolis, MN 55440-1524, USA
- 13Department of Medicine, Schulich School of Medicine and Dentistry, University of Western Ontario, London, Ontario N6A 5C1, Canada
- 14National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD 20892, USA
- 15Albert Einstein College of Medicine, Jacobi Medical Center, Bronx, NY 10461, USA
- Correspondence to: M E Miller
- Accepted 16 November 2009
Objectives To investigate potential determinants of severe hypoglycaemia, including baseline characteristics, in the Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial and the association of severe hypoglycaemia with levels of glycated haemoglobin (haemoglobin A1C) achieved during therapy.
Design Post hoc epidemiological analysis of a double 2×2 factorial, randomised, controlled trial.
Setting Diabetes clinics, research clinics, and primary care clinics.
Participants 10 209 of the 10 251 participants enrolled in the ACCORD study with type 2 diabetes, a haemoglobin A1C concentration of 7.5% or more during screening, and aged 40-79 years with established cardiovascular disease or 55-79 years with evidence of significant atherosclerosis, albuminuria, left ventricular hypertrophy, or two or more additional risk factors for cardiovascular disease (dyslipidaemia, hypertension, current smoker, or obese).
Interventions Intensive (haemoglobin A1C <6.0%) or standard (haemoglobin A1C 7.0-7.9%) glucose control.
Main outcome measures Severe hypoglycaemia was defined as episodes of “low blood glucose” requiring the assistance of another person and documentation of either a plasma glucose less than 2.8 mmol/l (<50 mg/dl) or symptoms that promptly resolved with oral carbohydrate, intravenous glucose, or glucagon.
Results The annual incidence of hypoglycaemia was 3.14% in the intensive treatment group and 1.03% in the standard glycaemia group. We found significantly increased risks for hypoglycaemia among women (P=0.0300), African-Americans (P<0.0001 compared with non-Hispanic whites), those with less than a high school education (P<0.0500 compared with college graduates), aged participants (P<0.0001 per 1 year increase), and those who used insulin at trial entry (P<0.0001). For every 1% unit decline in the haemoglobin A1C concentration from baseline to 4 month visit, there was a 28% (95% CI 19% to 37%) and 14% (4% to 23%) reduced risk of hypoglycaemia requiring medical assistance in the standard and intensive groups, respectively. In both treatment groups, the risk of hypoglycaemia requiring medical assistance increased with each 1% unit increment in the average updated haemoglobin A1C concentration (standard arm: hazard ratio 1.76, 95% CI 1.50 to 2.06; intensive arm: hazard ratio 1.15, 95% CI 1.02 to 1.21).
Conclusions A greater drop in haemoglobin A1C concentration from baseline to the 4 month visit was not associated with an increased risk for hypoglycaemia. Patients with poorer glycaemic control had a greater risk of hypoglycaemia, irrespective of treatment group. Identification of baseline subgroups with increased risk for severe hypoglycaemia can provide guidance to clinicians attempting to modify patient therapy on the basis of individual risk.
Trial registration ClinicalTrials.gov number NCT00000620.
Contributors: MEM contributed to the development of the protocol and the design, performed analyses for the study, participated in data interpretation, and wrote the majority of the first draft. DEB, HCG, and ERS contributed to the development of the protocol and to the design, participated in data interpretation, and wrote portions of the first draft. RMB contributed to the development of the protocol, participated in data interpretation, and edited the manuscript. JCE participated in data interpretation and editing of the manuscript results and discussion sections. RDC managed study participants and participated in data interpretation and editing of the manuscript. TEC contributed to development of study manuals, performed analyses for the study, and undertook data analysis and writing and review of the first draft. RMC participated in the study’s implementation, managed study patients, and took part in interpretation and editing of the manuscript. GD participated in data collection, interpretation of analyses, and editing of the manuscript. MNF contributed to development of the paper and wrote a portion of the first draft. FIB contributed to development of the paper, interpretation of the results, and editing of the manuscript. JFL contributed to development of the operations manual and participated in development of the methods section and editing of the manuscript. PJO participated in the study design, conceptualisation of the paper, and editing of the manuscript. TP participated in data interpretation and editing of the manuscript. PJS participated in protocol development, trial operations, and planning and writing of portions of the first draft. UKS contributed to the presentation and interpretation of the analyses and writing portions of the first draft. AS contributed to execution of the study, participated in the interpretation of the data, and helped in the editing of the manuscript. SG participated in protocol development, internal monitoring of hypoglycaemia rates during the study, and interpretation and writing a portion of the first draft. All authors approved the final draft. MEM is the guarantor.
Funding: The authors were supported by contracts 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 Pharmaceutical, AstraZeneca, Bayer HealthCare, Closer Healthcare, GlaxoSmithKline, King Pharmaceuticals, Merck, Novartis, Novo Nordisk, Omron Healthcare, Sanofi-Aventis, and Schering-Plough.
Competing interests: MEM has received honorariums for consulting from Hoffman-LaRoche. HCG has received research grants and honorariums for consulting and speaking from the following companies that manufacture glucose lowering medications: Sanofi-Aventis, GlaxoSmithKline, and Merck. He has also received honorariums for consulting and/or speaking from NovoNordisk, Lilly, Roche, BristolMyersSquibb, and AstraZeneca. HCG holds the Population Health Institute chair in diabetes research sponsored by Aventis. ERS has served as a consultant for Merck and has reviewed applications for the Pfizer Visiting Professorship Program. RMB and RMC have served as principal investigator or coinvestigator for industry sponsored clinical trials research. All honorariums, speaking fees, consulting fees, and research and educational support are paid directly to the non-profit International Diabetes Center, of which RMB and RMC are salaried employees. JCE is a member of Merck and Sanofi-Aventis speaker’s bureau and holds a clinical grant funded by Merck. RDC has received honorariums for consulting and speaking from the following companies that manufacture glucose lowering medications: Sanofi-Aventis, GlaxoSmithKline, and Merck. He has also received honorariums for consulting and/or speaking from Pfizer and has served as a consultant for NovoNordisk. GD has served as an investigator, speaker, and occasional consultant for Sanofi-Aventis and Merck, and as an investigator for NovoNordisk, Eli Lilly/Amylin, Mannkind, Pfizer, Boeringer Ingelheim, Novartis, GlaxoSmithKline, and BristolMyersSquibb. JFL has received honorariums from the American Academy of Physician Assistants, Amylin, AstraZeneca, NovoNordisk, and Smith’s Medical, has been a consultant for AstraZeneca, and has received grants or research support from the following companies: Amylin; Hoffman-LaRoche; Medtronic; NovoNordisk; Novartis; Osiris; Pfizer; National Institutes for Heath/National Heart, Lung, and Blood Institute; Tranistion Therapeutics; and Tolerx. AS has received consulting honorariums from Pfizer, Novartis, and Medtronic, speaking fees from Pfizer, and was a principal investigator of a clinical trial sponsored by Sanofi-Aventis. SG has been a consultant for Merck and Sanofi-Aventis, and owns stock in Johnson and Johnson and in Novartis (<$5000 each). The remaining authors have no competing interests.
Ethical approval: This study was approved by the Wake Forest University Health Sciences institutional review board and the review boards of all participating institutions. Written, informed consent was provided by all participants.
Data sharing: No additional data available at this time.
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