In this prospective cohort study, we discovered the relationship between high HbA1c and PD death. We also found a significantly higher mortality rate in T2D-PD patients with HbA1c ≥ 43.1 mmol/mol compared with those with HbA1c < 43.1 mmol/mol. This difference remained significant after adjusting for age, sex, Townsend deprivation index, and BMI. HbA1c < 43.1 mmol/mol significantly reduced the risk of death in T2D-PD patients, even to the level similar to nonT2D-PD patients. These results suggest that, although 43.1 mmol/mol located in the range of HbA1c for pre-diabetes (38–48 mmol/mol) rather than diabetic diagnosis range,15, 16 the risk of death in T2D-PD patients is significantly elevated with HbA1c ≥ 43.1 mmol/mol. Controlling HbA1c below an optimal level could be a potentially effective and clinically important way to improve the prognosis in patients with T2D-PD.
Interestingly, no significant association was found between blood glucose and PD mortality. The body tightly regulates blood glucose levels as a part of metabolic homeostasis, so blood glucose in normal people is usually maintained within a certain range.17, 18 However, blood glucose level is affected by many factors and fluctuates throughout the day.19–22 The high instability and variability may be the reason for the lack of significant result. Although both can be used as diagnostic indicators of T2D, HbA1c is more stable compared with blood glucose, reflecting the state of glycemic control over a longer period of time.23, 24
In addition, there is no significant association found between T2D and death in PD. This non-significant result may be reasonably explained by antidiabetic medications, a potential confounding factor masking the true association between T2D and PD death, according to previous studies.25–27 Compared to simply describing whether people have T2D or not, HbA1c can more accurately reflect the severity of the disease over this time period, as well as the potential ameliorative effects of antidiabetic medications. Therefore, we ultimately used HbA1c as a core variable in the survival analysis of PD patients, and found that high HbA1c was associated with elevated mortality in T2D-PD patients.
The link between glycemic control and PD has been extensively discussed and studied.8, 28 Notably, α-synuclein aggregation may underlie the observed relationship between HbA1c and PD mortality. Poor glycemic control induces α-synuclein aggregation, promotes apoptosis of dopaminergic neurons,29, 30 and leads to motor deficits. These studies suggest a potential link between HbA1c and PD progression. Our study identified an optimal level in the prediabetic HbA1c range, suggesting that tighter control of HbA1c in T2D-PD patients could be effective in reducing the risk of PD death.
There are several limitations in our study. First, although we included all eligible study individuals in the UKB, the sample size, 2570 participants in this study, still may limit the generalizability of our results. Multicenter studies with larger sample sizes are still needed to further provide more precise estimates of threshold. Second, only Caucasians were included in this study. More studies with different ethnic backgrounds are needed to further validate the results. In addition, we did not study anti-diabetic medications.
Controlling HbA1c below an optimal level could be significantly reduce the risk of death in patients with T2D-PD. It hints that HbA1c would be a potential biomarker for improving life expectancy prognosis of T2D-PD patients. This study will provide theoretical implications for improving the prognosis of PD patients with metabolic diseases.