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Terminal trajectory of HbA1c for 10 years supports the HbA1c paradox: a longitudinal study using Health and
Zeyi Zhang1, Longshan Yang2, Heng Cao1
1Department of Surgical Intensive Care Unit, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, China.
Insights
High and low hemoglobin A1c (HbA1c) levels show complex associations with mortality risk in older adults. The study suggests reverse causation, where declining HbA1c may indicate impending death, not necessarily cause it.
Area of Science:
- Gerontology
- Endocrinology
- Epidemiology
Background:
- Glycemic control, measured by hemoglobin A1c (HbA1c), is crucial for managing diabetes and predicting health outcomes.
- Understanding the relationship between HbA1c and mortality in elderly populations is essential for clinical practice and public health strategies.
Purpose of the Study:
- To investigate the dynamic associations between HbA1c levels and all-cause mortality in individuals aged 50 years and older.
- To analyze the terminal trajectory of HbA1c in the years preceding death to elucidate potential underlying mechanisms.
Main Methods:
- A longitudinal study utilizing data from the Health and Retirement Study (HRS) involving 10,408 participants aged ≥50 years.
- Cox regression with restricted cubic splines assessed HbA1c associations with mortality over time, while linear mixed-effect models analyzed terminal HbA1c trajectories using a backward time scale.
Main Results:
- Mortality risk associated with the highest HbA1c quartile diminished with shorter follow-up periods.
- Conversely, the lowest HbA1c quartile showed increased mortality risk over shorter follow-ups.
- Both decedents with and without diabetes exhibited an accelerating decline in HbA1c 5-6 years before death.
Conclusions:
- The association between HbA1c and mortality is time-varying and linked to a terminal decline in HbA1c.
- Both high and low HbA1c levels may have distinct clinical implications for mortality risk.
- Reverse causation, where a pre-terminal decline in HbA1c reflects an early manifestation of death, may explain the observed 'HbA1c paradox'.
Objectives:
We aimed to assess the potential time-varying associations between HbA1c and mortality, as well as the terminal trajectory of HbA1c in the elderly to reveal the underlying mechanisms.
Design:
The design is a longitudinal study using data from the Health and Retirement Study.
Setting And Participants:
Data were from the Health and Retirement Study. A total of 10,408 participants aged ≥50 years with available HbA1c measurements at baseline (2006/2008) were included.
Methods:
Longitudinal HbA1c measured at 2010/2012 and 2014/2016 were collected. HbA1c values measured three times for their associations with all-cause mortality were assessed using Cox regression and restricted cubic splines. HbA1c terminal trajectories over 10 years before death were analyzed using linear mixed-effect models with a backward time scale.
Results:
Women constitute 59.6% of the participants with a mean age of 69 years, with 3,070 decedents during the follow-up (8.9 years). The mortality rate during follow-up was 29.5%. Increased mortality risk became insignificant for the highest quartile of HbA1c compared to the third quartile (aHR 1.148, 1.302, and 1.069 for a follow-up of 8.9, 6.5, and 3.2 years, respectively) with a shorter follow-up, while it became higher for the lowest quartile of HbA1c (aHR 0.986, 1.068, and 1.439 for a follow-up of 8.9, 6.5, and 3.2 years, respectively). Accordingly, for both decedents with and without diabetes, an initial increase in HbA1c was followed by an accelerating terminal decline starting 5-6 years before death.
Conclusions And Implications:
The time-varying association between HbA1c and mortality mapped to the terminal trajectory in HbA1c. High and low HbA1c may have different clinical relationships with mortality. The HbA1c paradox may be partially explained by reverse causation, namely, early manifestation of death.
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