J Clin Endocrinol Metab. 2014 Mar;99(3):800-7.

Glycemic control and all-cause mortality risk in type 1 diabetes patients: the EURODIAB Prospective Complications Study

Schoenaker DA1, Simon D, Chaturvedi N, Fuller JH, Soedamah-Muthu SS; EURODIAB Prospective Complications Study Group.
  • 1School of Population Health (D.A.J.M.S.), University of Queensland, Brisbane, 4006 Queensland, Australia; Department of Diabetes, la Pitié Hospital and University Pierre et Marie Curie, 75013 Paris, France; INSERM CESP (D.S.), U-1018, 94805 Villejuif, France; National Heart and Lung Institute (N.C.), Imperial College London, London W2 1PG, United Kingdom; Department of Epidemiology and Public Health (J.H.F.), University College London, London WC1E 6BT, United Kingdom; and Division of Human Nutrition (S.S.S.-M.), Wageningen University, 6700 EV Wageningen, The Netherlands.

 

Abstract

CONTEXT: Glycemic targets and the benefit of intensive glucose control are currently under debate because intensive glycemic control has been suggested to have negative effects on mortality risk in type 2 diabetes patients.

OBJECTIVE: We examined the association between glycated hemoglobin (HbA1c) and all-cause mortality in patients with type 1 diabetes mellitus.

DESIGN, SETTING, AND PATIENTS: A clinic-based prospective cohort study was performed in 2764 European patients with type 1 diabetes aged 15-60 years enrolled in the EURODIAB Prospective Complications Study.

OUTCOME MEASURE: Possible nonlinearity of the association between HbA1c and all-cause mortality was examined using multivariable restricted cubic spline regression using three (at HbA1c 5.6%, 8.1%, and 11.8%) and five knots (additionally at HbA1c 7.1% and 9.5%). Mortality data were collected approximately 7 years after baseline examination.

RESULTS: HbA1c was related to all-cause mortality in a nonlinear manner after adjustment for age and sex. All-cause mortality risk was increased at both low (5.6%) and high (11.8%) HbA1c compared with the reference (median HbA1c: 8.1%) following a U-shaped association [P overall effect = .008 and .04, P nonlinearity = .03 and .11 (three and five knots, respectively)].

CONCLUSIONS: Results from our study in type 1 diabetes patients suggest that target HbA1c below a certain threshold may not be appropriate in this population. We recognize that these low HbA1c levels may be related to anemia, renal insufficiency, infection, or other factors not available in our database. If our data are confirmed, the potential mechanisms underlying this increased mortality risk among those with low HbA1c will need further study.

PMID: 24423327

 

SUPPLEMENT:

Treatment of type 1 diabetes patients aims to keep glucose levels, indicated by glycated hemoglobine (HbA1c), within a normal range to prevent complications. Professional organisations advice HbA1c levels of less than 6.5% or 7.0% (1, 2). In order to meet these guidelines, health care providers often intensify therapy. Individualized guidelines may be applied based on a patient’s age, complications and comorbidities, life expectancy, and personal preferences.

In studies among type 2 diabetes patients, safety concerns have been raised over intensive glucose control treatment. Lower glucose levels were found to have a negative effect on mortality risk in these patients. These findings may have important implications for treatment goals of type 2 diabetes patients, but it remains unclear whether this also applies to type 1 diabetes patients.

Type 1 and type 2 diabetes differ regarding risk factors for complications, and the earlier disease onset of type 1 diabetes increases the lifetime risk for complications more compared with type 2 diabetes. Findings on the effect of intensive glucose control can therefore not be automatically translated to type 1 diabetes.

The aim of our study was to explore the association between glucose levels and the risk of mortality from any cause in patients with type 1 diabetes.
Our observations study included 2,764 European type 1 diabetes patients who participated in the EURODIAB Prospective Complications Study between 1989 and 1991. All participants were aged 15-60 years and follow-up for seven years.

As expected, risk of death increased with higher glucose levels. Moreover, results from our study showed for the first time in type 1 diabetes patients that there was increased all-cause mortality risk also at low glucose levels. The lowest risk of death appeared to be in the low 7% range (Figure 1).
Why might risk of death be increased at low glucose levels in both type 1 and type 2 diabetes patients? The cause of the relationship between low glucose levels and increased all-cause mortality risk remains unclear. The mechanism for this relationship might relate to higher rates of hypoglycaemic episodes, or could be related to anaemia, renal insufficiency, or infections.

Even though we were not able to disentangle the underlying mechanisms of the relationship between low glucose levels and increased all-cause mortality risk, our results are relevant to the discussion about the potential risk of aiming for intensive glycemic control in patients with diabetes. Our observations indicate that we should be cautious in aiming to meet strict glucose control guidelines in all type 1 diabetes patients. Glucose levels below a certain threshold may not be appropriate for all patients.

 

References

1. American Diabetes Association. Standards of medical care in diabetes – 2014. Diabetes Care. 2014; 37: S14-S80.
2. Handelsman Y, Mechanick JI, Blonde L, et al. American Association of Clinical Endocrinologists medical guidelines for clinical practice for developing a diabetes mellitus comprehensive care plan. Endocr Pract. 2011; 17(suppl 2): 1-53.

Contact

Danielle Schoenaker, MSc
University of Queensland – School of Public Health
Herston Road
Herston, QLD, 4006, Brisbane, Australia
d.schoenaker@uq.edu.au
Figure-1Figure 1. Association between HbA1c and all-cause mortality risk in type 1 diabetes patients in the EURODIAB Prospective Complications Study. The Journal of Clinical Endocrinology & Metabolism, 2014. 99(3): 800-807

 

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