DPP-4 inhibitor and the Brain

Surat Tanprawate, MD, MSc(Lond.), FRCP(T)1, 2 1Division of Neurology, Department of Medicine

2The Northern Neuroscience Centre Chiang Mai University

NNC CMUThe Northern Neuroscience Centre

Chiang Mai University

NNC CMUThe Northern Neuroscience Centre

Chiang Mai University

Issue of DM and the Brain Neurological complication of Diabetes and

guideline recommendation

Real life practice

New insight and future trends

Neurological of Diabetes and Guideline recommendation

What guideline guides us?

DM complicatio

nRisk

Trials of glycemic control to prevent

strokeResult from

the trialRecommendation from ASA stroke guideline (2014)

First stroke

- DM double risk of stroke

- DM may be responsible for >8% of first ischemic stroke

- 20% of DM pt. will die of stroke

- DM is RR for the first stroke -> 1.5-3.7

UKPDS (diet restriction vs intensive therapy)

ACCORD (intensive Rx HbA1c

NNC CMUThe Northern Neuroscience Centre

Chiang Mai University

DDP-4 inhibitor, glycemic control and stroke prevention

No major study available

NNC CMUThe Northern Neuroscience Centre

Chiang Mai University

Diabetic neuropathy Diabetic neuropathies are heterogenous with diverse clinical

manifestation (focal vs diffuse) : Most common forms: DPN, and autonomic neuropathy

Risk Trials of glycemic control to prevent DPNResult from the

trial Recommendation

DPN4% to 10% by 5 years

50% by 25 years

DCCT/EDIC research trial - in DM type 1

ACCORD trial: Intensive blood glucose control and vascular outcome

Cochrane Rev

Glycemic control was shown to effectively prevent DPN and CAN in type I DM

Glycemic control may modestly slow progression in type 2 DM

Tight glycemic control implement early in the course of DM, has been shown to effectively prevent or delay development of DPN and CAN in DM type 1, but evidence is not strong in DM type 2

Martin CL, et al Diabetes Care 2014;37:3138Patel A, et al. N Engl J Med 2008;358:25602572 Callaghan BC et al. Cochrane Database Syst Rev 2012;6

NNC CMUThe Northern Neuroscience Centre

Chiang Mai University

Diabetic neuropathy, glycemic control with DPP-4 inhibitor

Real life practiceWhat we concern?

NNC CMUThe Northern Neuroscience Centre

Chiang Mai University

The studies on hypoglycaemic event related to cognitive impairment

Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications Study Research Group; Jacobson AM, Musen G, Ryan CM, et al. Long-term effect of diabetes and its treatment on cognitive function. N Engl J Med. 2007;356:1842-1852.

Punthakee Z, et al.ACCORD Group of Investigators: ACCORD-MIND Investigators. Poor cognitive function and risk of severe hypoglycemia in type 2 diabetes: post hoc epidemiologic analysis of the ACCORD trial. Diabetes Care. 2012;35(4):787-93.

Aung PP, et al. Edinburgh Type2 Diabetes Study Investigators. Severe hypoglycaemia and late-life cognitive ability in older people with Type 2 diabetes: the Edinburgh Type 2 Diabetes Study. Diabet Med. 2012;29:328-336.

Whitmer RA et al. Hypoglycemic episodes and risk of dementia in older patients with type 2 diabetes mellitus. JAMA. 2009;301:1565-1572.

NNC CMUThe Northern Neuroscience Centre

Chiang Mai University

Association between hypoglycaemia and dementia in biracial cohort of older adult with DMYaffe K. et al. JAMA Intern Med. 2013 July 22; 173(14)

783 older adult with DM, 12 years F/U period, severe hypoglycaemic episode with cognitive assessment record

61 participants (7.8%) had a reported hypoglycemic event

148 (18.9%) developed dementia

Those who experienced a hypoglycemic event had a 2-fold increased risk for developing dementia

NNC CMUThe Northern Neuroscience Centre

Chiang Mai University

Hyperglycemia and glycemic fluctuations

Oxidative stress Advanced glycation end-products

Endothelial dysfunction Cerebral hyperosmolarity

Microangiopathy Macroangiopathy

HT and Dyslipidemia

Cognitive disorders

DementiaInflammation

GeneticsAge

Insulin resistanceInsulin can regulate

phosphorylation of tau protein and clearance of

amyloid protein

Hypoglycemia

Buysschaert M et al. Medecine Maladies Mtaboliques 2015;9:47-52

Cognitive impairment in Diabetes

New insight and Future trends

Diabetes & Dementia: how sweet we are?

Craft, S. (2007). Curr Alzheimer Res 4, 147-52.

IDE, Insulin degrading enzyme FFA, Free fatty acid

peripheral hyperinsulinemia decrease insulin transport into the CNS

Long term increase can transport into the brain

Slaked I et al. British Journal of Pharmacology (2012) 166 15861599

GLP-1 : an emerging opportunity to treat neurodegenerative disease

17

Hiranya Pintana, Nattayaporn Apaijai, Nipon Chattipakorn and Siriporn C Chattipakorn from Chiang Mai University Journal of Endocrinology 218.1 (2013): 1-11.

DPP-4 Inhibitors improve cognition and brain mitochondrial function of insulin resistant in Rat

J Diabetes Investig 2015