HbA1c variability linked to cognitive decline in non-diabetic older adults

In people with type 2 diabetes, glycaemic variability – measured as HbA_1c changes over time – has been shown to predict cardiovascular events, mortality and the progression of other diabetes-related complications (Wan et al, 2016; Forbes et al, 2018; Echouffo-Tcheugui et al, 2019). Some of the harmful effects of this variability can also been seen in individuals with type 1 diabetes (Waden et al, 2009), including children (Nazim et al, 2014). There is a substantial body of evidence linking diabetes to an increased risk of dementia that is both vascular and neurogenerative in origin (Ninomiya, 2014; Sinclair et al, 2014). Indeed, variability in HbA_1c has also been linked to cognitive decline in those with diabetes (Lee et al, 2019). However, what is not clear is whether HbA_1c variability (a marker of prevailing glucose) is associated with an increased risk of dementia in a non-diabetic general population of adults. 

In an attempt to answer this question, Yu et al (2020) performed a pooled analysis of two large population cohorts – the Health and Retirement Study (HRS) and the English Longitudinal Study of Ageing (ELSA) Study – which comprised diverse populations (age ≥50 years), see our Digest here. Both studies performed repeated measurements of HbA_1c and cognitive assessments at set time intervals. The studies enrolled more than 6,000 subjects (HRS: 20% had diabetes; ELSA 6% had diabetes) with a mean age of 63 years. The results reported reflected a median follow-up of over 10 years. In summary, the highest levels of HbA_1c variability were associated with both accelerated cognitive decline and memory function when compared with the lowest quartile of HbA_1c. In individuals without diabetes, each one standard deviation increment in HbA_1c coefficient of variation was associated with significantly higher rates of decline in memory and executive function in the fully adjusted model. The findings were independent of the mean HbA_1c levels, and these associations were not observed in individuals with diabetes.

These are interesting and important observations and suggest clinicians should give greater consideration to HbA_1cmeasurement as a potential predictor of risk for future cognitive decline and development of dementia in patients with no history of diabetes. While observational studies of this nature do not provide an explanation for the lack of this association with diabetes, they may reflect other factors such treatment differences or the duration of diabetes. It is wise not to overinterpret the results in view of the long intervals between HbA_1c measurements (4 years), the potential differences in the studies’ participants (HRS was performed in North America and ELSA in the UK), and the lack of information about how this glycaemic variability is associated with the actual incidence of various types of dementia, such as Alzheimer’s disease.
 
Click the links below to access the latest Diabetes Digests related to older people:

• Association between HbA_1c variation and cognitive decline in older people
• Guidance on managing type 1 diabetes in older people
• Older people with diabetes and low vitamin D at higher risk of peripheral neuropathy
• Polypharmacy increases mortality and MI in elderly with diabetes

Echouffo-Tcheugui JB, Zhao S, Brock G et al (2019) Visit-to-visit glycemic variability and risks of cardiovascular events and all-cause mortality: the ALLHAT study. Diabetes Care 42: 486–93
Forbes A, Murrells T, Mulnier H, Sinclair AJ (2018) Mean HbA_1c, HbA_1c variability, and mortality in people with diabetes aged 70 years and older: a retrospective cohort study. Lancet Diabetes Endocrinol 6: 476–86
Lee ATC, Richards M, Chan WC et al (2019) Higher dementia incidence in older adults with type 2 diabetes and large reduction in HbA1c. Age Ageing 48: 838–44
Nazim J, Fendler W, Starzyk J (2014) Metabolic control and its variability are major risk factors for microalbuminuria in children with type 1 diabetes. Endokrynol Pol 65: 83–9
Ninomiya T (2014) Diabetes mellitus and dementia. Curr Diab Rep 14: 487
Waden J, Forsblom C, Thorn LM et al (2009) A1C variability predicts incident cardiovascular events, microalbuminuria, and overt diabetic nephropathy in patients with type 1 diabetes. Diabetes 58: 2649–55
Sinclair AJ, Hillson R, Bayer AJ; National Expert Working Group (2014) Diabetes and dementia in older people: a Best Clinical Practice Statement by a multidisciplinary National Expert Working Group. Diabet Med 31: 1024–31 
Wan EY, Fung CS, Fong DY, Lam CL (2016) Association of variability in hemoglobin A1c with cardiovascular diseases and mortality in Chinese patients with type 2 diabetes mellitus – a retrospective population-based cohort study. J Diabetes Complicat 30: 1240–7
Yu ZB, Zhu Y, Li D et al (2020) Association between visit-to-visit variability of HbA_1c and cognitive decline: a pooled analysis of two prospective population-based cohorts. Diabetologia 63: 85–94