Transcript EDIC: Long Term Benefit of Intensive Treatment

Complications in Type 1 Diabetes:
Nephropathy
Peter A. Gottlieb, MD
Barbara Davis Center
University of Colorado Health Sciences Center
Denver, CO
Why do complications occur?
• Insulin hypothesis
• Glucose hypothesis
• DCCT and many other studies support
glucose hypothesis
EDIC: Long Term Benefit of
Intensive Treatment
-The Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions
and Complications Research Group. N Engl J Med 2000;342:381-9.
EDIC: Long Term Benefit of
Intensive Treatment
-The Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions
and Complications Research Group. N Engl J Med 2000;342:381-9.
EDIC: Long Term Benefit of
Intensive Treatment
- The Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions
and Complications Research Group. N Engl J Med 2000;342:381-9.
• Transient hyperglycemia
leads to oxidative stress
which increases
complications
• Testing of this hypothesis
is needed to determine if
this is indeed true
Diabetic Nephropathy:
Pathogenesis
• Increased intraglomerular
pressure
• Mesangial cell expansion
• Reactive Oxygen Species (ROS)
• Endothelial cell dysfunction
• Increased Glomerular Basement
Membrane Thickness and
Interstitial Fibrosis
DETAIL Study: Head to Head
Comparison of ACE vs. ARB in
Type 2 DN
• 5 yr, prospective, multicenter,
randomized study in T2DM with HTN
and early DN
• 120 subjects onTelmisartan 40-80
mg/day vs. 130 subjects on Enalapril
10-20 mg/day
• Primary endpoint: Change in GFR
• Secondary endpoints: Change in
albuminuria, BP, CR, other CV
outcome measures
DETAIL:
Baseline Characteristics
DETAIL: Equivalent Protection from
ACE and ARB in Change GFR
DETAIL: Key Points
• Use of ACE or ARB slows down
loss of GFR in T2DM with
nephropathy
• Confirms previous shorter term
studies
• Additional protection seen for
CV complications
ACE and ARB Lower Proteinuria
better than ACE alone in T2DM
• Small 24 week study with 26 pts
demonstrated that combination therapy of
Losartan with Enalapril reduced proteinura
greater than increased dose of Enalapril
alone
• Blood pressure was similarly lowered in
both groups
• CRP levels were lowered in combined
treatment group, unchanged in ACE alone
• Other parameters measured were not
significantly different between groups
Igarashi, et al, Endocrine Journal, 2006, epub
Prevention and Treatment of
Diabetic Nephropathy in T1DM
• Periodic screening for
microalbuminuria – timed overnight
samples beginning at 5 years from
diagnosis
• Treatment of either microalbuminuria
or HTN (to 120/80 or age-matched
target) with ACE or ARB
• Use ACE or ARB, ACE with ARB and
Diuretics, then consider other
therapies based on clinical
considerations
How do complications occur?
• Activation of Polyol Pathway
• Accumulation of Advanced
Glycosylation End Products
• Protein Kinase C Pathway
• Flux Through the Hexosamine
Pathway
• Oxygen Radicals and Enhanced
Oxidative Stress
• Altered Expression of Growth Factors
and Vasoactive Mediators
Aldose Reductase and
Polyol Pathway
- Brownlee, M. Nature 2001 414:13 813-820.
AGE Pathway
- Brownlee, M. Nature 2001 414:13 813-820.
How can we intervene?
• Polyol Pathway – Sorbinil, Zenarestat
• Advanced Glycosylation End Products
– Aminoguanidine, sR RAGE
• Protein Kinase C Pathway – Selective
PKC inhibitors such as LY333531
• Flux through Hexamine – ?
• Oxidative Stress – Vitamin C, Vitamin
E, a lipoic acid
• Altered Expression of Growth Factors
– VEGF inhibitors
Effect of a-lipoic acid on
experiemental diabetic retinopathy
Lin, et al, Diabetologia, 2006, 49:1089-1096
Do they work?
•
•
•
•
•
Sorbinil, Zenarestat - Toxicity, Ineffective
Aminoguanidine, sR RAGE - ?
PKC inhibitors - LY333531 - Maybe
Flux through Hexamine – ?
Oxidative Stress – Vitamin C, Vitamin E, a
lipoic acid – Small effect?
• Altered Expression of Growth Factors –
VEGF inhibitors - Unknown
Why have our best efforts not
succeeded?
• Toxicity
• Drug Development – Efficacy
• Need to target multiple pathways at
once
• Or something else?
Unified Theory of
Complications
- Brownlee, M. Nature 2001 414:13 813-820.
Inhibition of GAPDH Affects
Multiple Complication Pathways
- Du X, et al. J. Clin. Invest. 112:1049–1057 (2003).
New Therapeutic Approaches
• Glyceraldehyde-3-phosphate and fructose6-phosphate are major substrates for
complication pathways
• Benfotiamine, is a derivative of the B
vitamin thiamine
• Activates the thiamine dependent pentose
phosphate enzyme transketolase which
converts these compounds away from
these pathways
• Affecting this pathway changes substrate
availability for polyol, hexosamine,
diacylglycerol (PKC), AGE pathway and NFkB signaling
MMF and ACE synergize to
Reverse Experimental DN
Wu, et al. Inflamm res. 2006. 192-199
MMF and ACE synergize to
Reverse Experimental DN
TGFb
ED1
MCP-1
Wu, et al. Inflamm res. 2006. 192-199
Unified Theory of
Complications
Benfotiamine
PARP inhibitors
- Brownlee, M. Nature 2001 414:13 813-820.
New Therapeutic Approaches
• Molecules which can affect
GAPDH activity
• Superoxide Dismutase
• Poly(ADPribose)polymerase
(PARP) inhibitors, PJ34
Summary
• Tight control of blood sugars is the best
means to prevent and reverse
complications of diabetes
• Reducing glycemic variability may also
contribute to the development of
complications and can be achieved with
CGMS
• Therapies such as PKC inhibitors which
attack single pathways may be of benefit
• New therapeutic approaches which can
target multiple pathways simultaneously
may offer the best chance to prevent
complications
Thank you