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 study

Abstract

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 A(1C)) achieved during therapy.

Design: Post hoc epidemiological analysis of a double 2x2 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 A(1C) 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 A(1C) <6.0%) or standard (haemoglobin A(1C) 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 A(1C) 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 A(1C) 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 A(1C) 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.

Conflict of interest statement

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.

Figures

Fig 1 Plot of Kaplan-Meier estimates of the proportion of participants with at least one episode of hypoglycaemia requiring medical assistance

Fig 2 Annual incidence of hypoglycaemia requiring medical assistance by glycaemia treatment group and follow-up year. Percentages are calculated by subtracting estimates from Kaplan-Meier plots

Fig 3 Risk of hypoglycaemia requiring medical assistance by baseline demographic subgroups. The dashed vertical line represents the overall intensive treatment to standard treatment hazard ratio

Fig 4 Risk of hypoglycaemia requiring medical assistance by baseline clinical subgroups. The dashed vertical line represents the overall intensive treatment to standard treatment hazard ratio. *Upper 95% confidence interval of 12.67% truncated at 8.00% for haemoglobin A1C concentration of less than 7.5%

Fig 5 Risk of hypoglycaemia requiring medical assistance by baseline medication subgroups. The dashed vertical line represents the overall intensive treatment to standard treatment hazard ratio

Fig 6 (A) Incidence (95% CI) of HMA by quintiles of baseline haemoglobin A1C concentration. (B) Hazard ratio for baseline haemoglobin A1C concentration relative to a haemoglobin A1C concentration of 7.5% (dotted line). (C) Incidence (95% CI) of hypoglycaemia requiring medical assistance (HMA) by updated average haemoglobin A1C concentration. (D) Hazard ratio for updated average haemoglobin A1C concentration relative to a haemoglobin A1C concentration of 7.5% (dotted line). (E) Incidence (95% CI) of HMA by most recent haemoglobin A1C measurement. (F) Hazard ratio for most recent haemoglobin A1C measurement relative to a haemoglobin A1C concentration of 7.5% (dotted line)*. *The model depicted in (F) contains a significant quadratic term (P=0.04), whereas the models depicted in (B) and (D) were found to be linear on the log scale

Fig 7 (A) Incidence (95% CI) plotted against quintiles of change in haemoglobin A1C concentration between baseline and four months. (B) Hazard ratio for four month change in haemoglobin A1C concentration relative to a 1% unit decline