Diabetes, Cognitive Impairment and dementia

1. Diabetes, Cognitive Impairment and dementia Professor Tony Bayer School of Medicine, Cardiff University

2. Diabetes, cognitive impairment and dementia • Epidemiology – impact of diabetes on cognition • Possible pathophysiological mechanisms linking diabetes with cognitive impairment and dementia • Recognising cognitive impairment • Implications for managing diabetes

3. Cognitive function in adults with type 1 diabetes • Meta-analysis of 33 case-control studies of individuals aged 18-50y • Magnitude of cognitive dysfunction is moderate • Most tests examine ability to respond rapidly and cognitive slowing is fundamental deficit – not memory • Differences emerge early, within 2y of diagnosis and children’s brain more susceptible than adults (those with onset age <7y have higher risk than those older • Diabetes Control and Complications Trial Research Group. • Diabetes 1997; 46: 771-86 • McCrimmon RJ et al. Lancet 2012; 379:2291-9

4. Cognitive function in adults with type 1 diabetes New Engl J Med 2007;356:1842-52. CONCLUSIONS No evidence of substantial long-term declines in cognitive function was found in a large group of patients with type 1 diabetes who were carefully followed for an average of 18 years, despite relatively high rates of recurrent severe hypoglycaemia.

5. Cognitive function and decline in type 2 diabetes • Prospective cohort (EVA) study of 961 community dwelling people aged 59-71 (mean 64; 55 with diabetes), with MMSE>26 at baseline • After 4 years, compared to those who had normal glucose or impaired fasting glucose, people with diabetes had lower scores on tests of psychomotor speed, attention and verbal memory Visual attention Verbal memory Facial recognition Attention Psychomotor speed Visual memory Logical reasoning Auditory attention Fontbonne et al. Diab Care 2001; 24: 366-70

6. Cognitive function and decline in type 2 diabetes • Prospective cohort study of 9679 women aged 65-99y (mean 72y; 682 with diabetes) • Women with diabetes had lower baseline scores on 3 tests of cognitive function and experienced an accelerated cognitive decline • Women who had diabetes for >15y had more cognitive impairment at baseline and 57-114% greater risk of major decline than women without diabetes A B Diabetes duration and adjusted odds (95% CI) of A. cognitive impairment at baseline and B. cognitive decline over 4 - 6 years on DSST, Trails B & m-MMSE Gregg et al. Arch Intern Med. 2000;160(2):174-180.

7. Blood glucose and cognitive performance in type 2 diabetes • Cross-sectional study of 2,205 men, aged 55–69y, from Caerphilly, South Wales & adjacent villages; 165 with type 2 diabetes • After adjusting for stroke & vascular risk factors, those with diabetes had cognitive deficits for verbal fluency, NART (crystallised IQ), AH4 (fluid IQ) and CAMCOG. • AH4 score in men with diabetes had a curvilinear relationship with blood glucose; both high and low glucose had worse performance • Gallacher JEJ et al. Eur J Epidemiol 2005; 20: 761-768 (AH4= -66+80 loge glucose-18 loge glucose2; 95% CI -29 to -6, p=0.002)

8. Risk of dementia in Type 2 Diabetes: the Rotterdam Study, 1999 • 6,370 subjects aged 55+, dementia-free at baseline, followed up for an average 2.1.y • Data obtained using a 3-step screening and comprehensive diagnostic work-up and examination of medical files • Mean age of cohort 69y, n = 692 with diabetes • Patients on insulin were at highest risk for dementia (RR of 4.3 95%CI 1.7-10.5) • Population attributable risk of diabetes to incident dementia was 8.8% Ott et al. Neurology 1999; 58: 1937-41

9. Accelerated progression of mild cognitive impairment (MCI) to dementia in people with diabetes • 302 subjects, age >75y, with MCI followed for 9y in the Kungsholmen Project: 155 subjects progressed to dementia. • Multi-adjusted hazard ratio (95% CI) of dementia was 2.87 (1.30-6.34) for baseline diabetes, and 4.96 (2.27-10.84) for pre-diabetes. • In a Kaplan-Meier survival analysis, diabetes and pre-diabetes accelerated the progression from MCI to dementia by 3.18 y. Cumulative hazard for the progression from MCI to dementia by diabetes status in MCI cohort (adjusted for age, sex, and education). Xu W et al. Diabetes, 2010; 59: 2928-35

10. Possible pathophysiological mechanisms linking diabetes with changes in the brain Genetic predisposition DIABETES DEMENTIA Comorbidity Medications Adapted from Biessels GJ et al. Lancet Neurology 2006; 5: 64-74

11. Benefits of timely detection Best Clinical Practice 2012 Potential benefits of timely detection of dementia and/or diabetes

12. Mini–Cog : a quick screen for significant cognitive impairment in people with diabetes Mini-Cog Step 1: ask patient to repeat 3 unrelated words – apple, table, penny – and remember them Step 2: ask patient to draw a clock face – so draw a large circle, put in the numbers so it looks like a clock and then set time to 5 to 3. (Score clock as normal if patient sets the correct time and all numbers in roughly correct positions) Step 3: ask patient to recall the 3 words from Step 1. (Score 1 point for each recalled word) Scoring: • In a GP study of older people with type 2 diabetes, Mini-Cog had sensitivity of 86%, specificity of 91%, positive predictive value of 54% and negative predictive value of 98% for dementia. • Not influenced by education, culture or language; performance comparable to MMSE. • Sinclair AJ et al. Diab Res ClinPract 2013

13. Impact of glycaemic control on cognition • ACCORD-MIND - Memory in Diabetes Sub-study of the Action to Control Cardiovascular Risk in Diabetes (ACCORD) Trial • 2977 patients aged 55-80 (mean 62y) with type 2 diabetes, treated with standard care or intensive glycaemic control. • 20% of patients found to have undetected cognitive impairment at baseline • No difference in DSST score (or any other cognitive tests) at 40 mths. • Greater mean total brain volume on MRI on intensive than standard treatment (p=0.0007) Launer et al. Lancet Neurol 2011;10:969-77 • Baseline cognitive function (DSST score) significantly associated with risk of severe hypoglycemia (p<0.0001) • Punthakee et al. • Diab Care 2012; • 35:787-793

14. Longitudinal cohort study (1980– 2007) of 16,667 patients with type 2 diabetes (mean age 65y): at least one episode of severe hypoglycaemia in 1465 (8.8%) Dementia risk adjusted for age, sex, race, BMI, education, comorbidities, diabetes duration, 7-year mean HbA1c, and duration of insulin use Hypoglycaemic episodes and risk of dementia in older patients with type 2 diabetes

15. Individualising HbA1c Goals • Review glycaemic targets if: • Significant cognitive impairment • Hypoglycaemia unawareness • History of falls • Evidence of advanced/poorly controlled cardiovascular and/or microvascular complications • Life expectancy <3 years • End of life/palliative care Usual HbA1c targets if dementia HbA1c 8.1–9% (65–75 mmol/mol) Based on Triplitt C. Consult Pharm. 2010;25(Suppl B):19–27; Sinclair AJ, Diabetes Metab. 2011;37(Suppl 3):S27–38.

16. Adverse effect of dementia diagnosis on management of diabetes • Retrospective cohort study of 288,805 Medicare beneficiaries with diabetes; 44,717 (15%) with comorbid dementia Thorpe et al. JAGS 2012; 60: 644-51

17. Early stage Dementia In a dementia care setting In a diabetes care setting • STEP 1: Awareness and screening for dementia • Screen for cognitive impairment dementia if risk factors present or patient/carer concern- MMSE or Mini-cog. • Assess for acute confusional state and treat (could be related to diabetes and/or infection/pain). • Assessment of cognition/capacity to understand and retain information. • STEP 1: Symptom awareness and active screening: • Proactive screening (at diagnosis of dementia and annually). • STEP 2: Symptom alleviation & complication screen: • Consult with diabetes team or GP to start diabetes treatment to alleviate physical symptoms. • Aim to for fasting BG 7-9 range (HbA1c 7-8%, 53-64 mmol/mol) • Screen for complications (eyes, feet, kidney , CVD) – repeat bi-annually. • Eliminate diabetes symptoms and or con-current infection that may exacerbate confusional state. • STEP 2: Manage cognitive deficit • Ensure self-management deficits are addressed in context of cognitive impairment in partnership with carers. • Eliminate diabetes symptoms and or con-current infection that may exacerbate confusional state. • STEP 3: Risk minimisation: • Prevent complications that will reduce QoL (eye and feet). • Reduce falls and hypoglycaemia risk –medicines review (consult diabetes team or GP). • Prevent hyperglycaemic symptoms • Promote good nutrition • STEP 3: Minimise therapy risk • Avoid overly intensive management use therapies that reduce risk of hypoglycaemia. • Focus education and support on carers as well as patient. • Aim to achieve fasting BG 6-9 range (A1c 7 -8%, 53-64 mmol/mol) • STEP 4: Palliation and therapy minimisation (advanced dementia): • Reduce diabetes therapy to minimum – focus on preventing acute symptoms. • STEP 4: Palliation and therapy minimisation (advanced dementia): • Reduce diabetes therapy to min to prevent acute symptoms. • Involve/patient carers in discussion Advanced Dementia Achieving best clinical practice (2013)

18. A diagnosis of diabetes in a person with dementia indicates … • a need to reconsider aims of care and glucose targets • an indicator to review adherence to diabetes treatment and assess nutritional status • a reminder to undertake a cardiovascular risk assessment • a prompt to review hypoglycaemia risk