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The Northern Neuroscience Centre

Chiang Mai University

NNC CMU
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

The Northern Neuroscience Centre


Chiang Mai University

NNC CMU
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

Risk

complicatio
n
-

First
stroke

Recurrent
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

Trials of glycemic
control to prevent
stroke

Result from
the trial

Recommendation
from ASA stroke
guideline (2014)

UKPDS (diet restriction vs


intensive therapy)
ACCORD (intensive Rx
HbA1c<6% vs standard
HbA1c7-7.9%)
ADVANCE (
Veterans Affairs Diabetes Trial
(standard care vs reduce
HbA1c by 1.5%)

No effect on
reducing stroke
on therapeutic
group

Glycemic control has


no evidence to reduce
incident of stroke

No major study

Using the exiting


guideline from ADA
recommendation for
glycemic control and
cardiovascular risk
factor management

No major trials for secondary


prevention of stroke: The
DM was associated
treatment based on trials in non
with a 60% increase
stroke or mixed population
risk for recurrence
Insulin Resistance Intervention
stroke (RR,
After Stroke Trial (IRIS) 1.59;95% CI
ongoing trial
1.07-2.37)
ACT NOW trial- pioglitazone
and measures IMT

The Northern Neuroscience Centre


Chiang Mai University

NNC CMU
DDP-4 inhibitor, glycemic control and
stroke prevention

No major study available

The Northern Neuroscience Centre


Chiang Mai University

NNC CMU
Diabetic neuropathy

Diabetic neuropathies are heterogenous with diverse clinical


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

Risk

DPN

4% to 10% by 5
years
50% by 25 years

Trials of glycemic
Result from the
control to prevent DPN
trial

Recommendation

Glycemic control was


DCCT/EDIC research trial - in shown to effectively
Tight glycemic control
prevent DPN and CAN implement early in the
DM type 1
in type I DM
course of DM, has been
ACCORD trial: Intensive blood
shown to effectively prevent
glucose control and vascular Glycemic control may or delay development of
modestly slow
outcome
DPN and CAN in DM type 1,
progression in type 2
but evidence is not strong in
DM
Cochrane Rev
DM type 2
Martin CL, et al Diabetes Care 2014;37:3138
Patel A, et al. N Engl J Med 2008;358:25602572
Callaghan BC et al. Cochrane Database Syst Rev 2012;6

The Northern Neuroscience Centre


Chiang Mai University

NNC CMU
Diabetic neuropathy, glycemic control
with DPP-4 inhibitor

Real life practice


What we concern?

The Northern Neuroscience Centre


Chiang Mai University

NNC CMU
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.

The Northern Neuroscience Centre


Chiang Mai University

NNC CMU
Association between
hypoglycaemia and
dementia in biracial cohort
of older adult with DM
Yaffe 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

The Northern Neuroscience Centre


Chiang Mai University

Cognitive impairment in Diabetes

Microangiopathy

Hypoglycemia

NNC CMU

Hyperglycemia and glycemic


fluctuations
Oxidative stress
Advanced glycation end-products
Endothelial dysfunction
Cerebral hyperosmolarity

Cognitive disorders

HT and Dyslipidemia

Macroangiopathy

Inflammation

Dementia
Insulin resistance
Insulin can regulate
phosphorylation of tau
protein and clearance of
amyloid protein

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

New insight and


Future trends
Diabetes & Dementia: how sweet we are?

IDE, Insulin degrading enzyme


FFA, Free fatty acid

peripheral hyperinsulinemia
decrease insulin transport into the
CNS

Long term
increase can
transport into
the brain

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

GLP-1 : an emerging opportunity to treat


neurodegenerative disease

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

DPP-4 Inhibitors improve cognition and brain mitochondrial function of


insulin resistant in Rat

Hiranya Pintana, Nattayaporn Apaijai, Nipon Chattipakorn and Siriporn C Chattipakorn from
Chiang Mai University Journal of Endocrinology 218.1 (2013): 1-11.
17

J Diabetes Investig 2015