Brain Health And HbA1c In Prediabetes

Data analysis suggests that patients with prediabetes have a similar risk for declines in brain function to patients diagnosed with diabetes.

Hyperglycemic states have been associated with poor cognitive function, dementia, and brain alterations. However, no studies have been conducted to evaluate the impact of prediabetes on neurological function. A study conducted in the United Kingdom (UK) sought to assess the association between various glycemic states and their effect on Alzheimer’s disease risk, vascular dementia risk, baseline cognitive function, cognitive decline, hippocampal volume, and white matter hyperintensity volume.  

The study was pulled from the UK Biobank and included 449,973 patients from 40 – 69 years of age during 2006 – 2010. Patients were divided into five categories: 22,187 with known diabetes, 3,279 with undiagnosed diabetes (A1C > 6.5%),15,229 with prediabetes (A1C 6.0 -6.5%), 198,969 with normoglycemic glucose levels (A1C 5.4 – 6.0%), and 210,309 with low-normal glucose (A1C < 5.4%). Demographics, educational status, smoking status, body mass index (BMI), baseline cardiovascular disease (CVD), and antihypertensive and statin medication use were also analyzed. Statistical analysis was conducted utilizing Cox proportional hazards models to examine the relationship between glucose levels and brain health. More patients with diabetes were ex-smokers, and those with known diabetes had a higher probability of concurrent statin and antihypertensive medication use.   

Patients with undiagnosed and known diabetes had a 2% slower reaction time, while patients with prediabetes had a 1% slower reaction time, on a symbol matching test. Paradoxically, patients with known diabetes made 3% fewer errors on a visual memory test than patients with normal glucose levels. However, memory protection may be seen with glycemic control in patients on antihyperglycemic therapy. Results showed that patients with low-normal A1Cs had lower WMH volume and greater hippocampal volume than patients with normal glucose levels. In contrast, prediabetes, undiagnosed, and known diabetes were associated with higher WMH volume and lower hippocampal volume. Known diabetes was also associated with excess all-cause dementia and Alzheimer’s disease risk (HR 1.91, 95% CI 1.66 – 2.21 and HR 1.84, 95% CI 1.44 – 2.36, respectively). Patients with prediabetes and diabetes had an elevated risk of dementia (HR 1.75, 95% CI 1.19 – 2.59 and HR 3.73, 95% CI 2.90 – 4.80, respectively, while low-normal HbA1c was not linked to vascular dementia. Health-related adjustments amplified the connection between glycemia and vascular dementia, with a 54% risk increase in the prediabetes group and a three-fold risk increase in the known diabetes group. This increase was primarily attributed to the use of antihypertensive medication. For the outcome of cognitive decline, prediabetes and diabetes were associated with a 42% and 39% respective increase in cognitive decline. Further analysis revealed that patients with a higher BMI were less prone to experience cognitive decline in both groups (OR 0.97, 95% CI 0.95 – 0.99).  

This study showed that prediabetes is associated with a decline in neurological health, although this decrease may be attributed to antihypertensive medication use. Whereas past studies hypothesized that patients with prediabetes are at risk of brain health decline, this study confirmed that the risk is comparable to that of diagnosed diabetes. This conclusion encourages prompt identification and prevention in these individuals to prevent the onset or progression of neurological decline. Further studies are needed to evaluate the risk of certain cardiovascular medications on brain health, as antihypertensive medication use was associated with worse effects on brain health. Another astonishing finding was that patients with low-normal HbA1c levels had lower WMH volume and greater hippocampal volume than patients with normal glycemic levels. Furthermore, it is unknown whether HbA1C levels below 5.4% offer neurological protection, although it may be attributed to the younger age and healthier patient population of this subgroup in the study.  

Practice Pearls 

• Patients with prediabetes and diabetes are at an increased risk of cognitive decline and dementia. 
• Antihypertensive therapy was associated with an increased risk of vascular dementia in patients with diabetes and prediabetes. This may prompt the association that hypertension drives neurological decline.   
• Further studies can be done to determine the impact of low-normal A1c levels on neurological health compared to normal glycemic levels.   

Reference for “Brain Health And HbA1c In Prediabetes”:
Garfield V, Farmaki A, Eastwood S V., et al. Brain health across the entire glycaemic spectrum: the UK Biobank. Diabetes, Obes Metab. 2021.  

Macrina Ghali, PharmD Candidate 2021, Florida A&M University, College of Pharmacy and Pharmaceutical Sciences