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Changing Evidence for Treating Diabetic Microvascular Complications (DMC):

Awareness for Future PracticeJames R Gavin III, MD, PhD

Clinical Professor of Medicine and Senior Health Advisor

Emory University School of MedicineExecutive Vice President of Clinical Affairs

Healing Our Village, Inc.Atlanta, Georgia

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Presentation Outline• Overview: Hyperglycemia-activated

metabolic pathways• Clinical evidence for pathogenetic

treatments– Antioxidants– Aldose reductase inhibitors (ARIs)– Advanced glycation endproduct (AGE)

inhibitors– PKC β inhibitors

• Roundtable discussion

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Some Cells Are More Susceptible to Hyperglycemia-induced Damage

• Cells in tissues affected by DMC cannot reduce glucose transport to compensate for high plasma glucose– Tissues: retina, kidney, nerves

– Cell types: endothelial cells, mesangial cells

• High intracellular glucose results

Brownlee M. Diabetes. 2005;54:1615-1625.

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Metabolic Pathways Leading to DMC

Polyolpathway

Diabetic nephropathy

Diabetic retinopathy

Diabetic neuropathy

Diabetes

Ulcers/amputations

Hyperglycemia

Superoxideoverproduction

PKC βactivation

Vision loss

Renal disease

Diabetes-induced microvascular damage

GlycationDiacylglycerol

©2005 International Medical Press.

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Pathogenesis-based Treatments Interrupt Metabolic Pathways to DMC

Glycation

Superoxideoverproduction

Polyolpathway

PKC βactivation

Antioxidants

Aldose ReductaseInhibitors (ARIs)

Advanced GlycationEndproduct (AGE)

Inhibitors

PKC β Inhibitors

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Clinical Evidence Regarding Pathogenesis-based Treatments

• Antioxidants*

• Aldose reductase inhibitors (ARIs)*

• AGE inhibitors*

• PKC β inhibitors*

*Not US FDA approved for the treatment of DMC.

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Antioxidants

• Vitamin E• Alpha lipoic acid (ALA)

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Vitamin E: Diabetic Neuropathy• Manzella et al, 2001

– Autonomic nervous system function– 50 patients with type 2 diabetes– 600 mg/day or placebo for 4 months– Results

• Improved metabolic indices (fasting insulin, A1C)• Improved heart rate variability indices

• Tütüncü et al, 1998– Nerve conduction– 21 patients with type 2 diabetes– 900 mg/day or placebo for 6 months– Results

• Improved nerve conduction velocity • No changes in glycemic indices

Manzella D, et al. Am J Clin Nutr. 2001;73:1052-1057.Tütüncü N, et al. Diabetes Care. 1998;21:1915-1918.

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Vitamin E: Diabetic Retinopathy

• Retinal blood flow (RBF) and creatinine clearance• 36 type 1 diabetes patients + 9 nondiabetic

controls• 1800 IU/day• 8-month crossover study• Results

– No effect on A1C– Significant increase in RBF to level seen in normal

patients– Normalized baseline creatinine clearance

Bursell SE, et al. Diabetes Care. 1999;22:1245-1251.

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Vitamin E: Diabetic Nephropathy• Heart Outcomes Prevention Evaluation

(HOPE) Study– 4.5 years– 400 IU/day or placebo– Includes MICRO-HOPE substudy

• 3,654 type 2 diabetes patients – Cardiovascular (CV) disease or coronary risk factor– 55+ years of age

• Results– No effect on composite cardiovascular outcome– No effect on nephropathy, new microalbuminuria,

dialysisLonn E, et al. Diabetes Care. 2002;25:1919-1927.

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ALA: Diabetic Peripheral NeuropathyMeta-analysis

• ALADIN I, ALADIN III, SYDNEY, NATHAN II trials• ALA (n = 716) and placebo (n = 542)• Predominantly type 2 diabetes patients• 600 mg/day iv, 3 weeks• Primary analysis: Total Symptom Score (TSS)• Results

– Relative difference in favor of ALA for TSS– More responders in ALA than placebo group (P <0.05)– Pain, burning, numbness, pin-prick and touch

pressure sensation, and ankle reflexes improved– Adverse events did not differ

Ziegler D, et al. Diabet Med. 2004;21:114-121.

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ALA: Diabetic NeuropathyTSS Results

Favors α-lipoic acid; P <0.05

Meta-analysis

NATHAN II

SYDNEY

ALADIN III

ALADIN I

∆% -40 -20 0 20 40 60 80

Change in TSS relative to placebo at 3 weeks vs baseline

Ziegler D, et al. Diabet Med. 2004;21:114-121.

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ALA: Diabetic Nephropathy

• Exploratory study– Prospective, open, nonrandomized– 18 months

• 84 patients with type 1 or type 2 diabetes– Control (n = 49)– ALA 600 mg/day (n = 35)

• Results– Urinary albumin concentration (UAC) increased from

baseline in control group (P <0.05)– UAC did not change in ALA group

Morcos M, et al. Diabetes Res Clin Pract. 2001;52:175-183.

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Aldose Reductase Inhibitors (ARIs)

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ARIs: Diabetic Peripheral Neuropathy (DPN)

Agent Results Status

Alrestatin Minor benefits (S) Withdrawn (toxicity)

Tolrestat Minor benefits (S, EP) Withdrawn (toxicity)

Ponalrestat No efficacy Withdrawn

Zenarestat Minor benefits (EP, M) Withdrawn (toxicity)

Epalrestat Minor benefits (S, EP) Marketed in Japan

Sorbinil Benefits (S, EP, M) Withdrawn (toxicity)

Fidarestat* Minor benefits (S, EP) Under investigation

EP = electrophysiology; M = motor; S = symptoms*Study described in the module, “New Evidence for the Treatment of Painful DPN.”

Boulton AJM, et al. Diabetes Care. 2004;27:1458-1486.

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ARIs: Diabetic Retinopathy

Agent Dose Result

Epalrestat1 300 mg/day Improvement

Ponalrestat2 600 mg/day No clinically significant effect

Tolrestat3 200 mg/day Little effect

Sorbinil4 250 mg/day Little effect

1Steele JW, et al. Drugs Aging. 1993;3:532-555.2Arauz-Pacheco C, et al. J Diabetes Complications. 1992;6:131-137.

3Van Gerven JM, et al. Doc Ophthalmol. 1994;87:355-365.4Sorbinil Retinopathy Trial Research Group. Arch Ophthalmol. 1990;108:1234-1244.

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ARIs: Diabetic Nephropathy

Agent Dose Result

Epalrestat1 150 mg/day Maintained UAE*

Ponalrestat2 600 mg/day No effect

Tolrestat3 200 mg/day Decreased UAE and GFR†

Sorbinil No published clinical trial data

*Urinary albumin excretion.†Glomerular filtration rate.

1Iso K, et al. J Diabetes Complications. 2001;15:241-244.2Ranganathan S, et al. Diabetes Metab. 1993;19:257-261.

3Passariello N, et al. Diabetes Care. 1993;16:789-795.

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Advanced Glycation Endproducts(AGE) Receptor Blockers

• A class of toxic, complex products resulting from glycooxidation or possibly lipid oxidation

• Overproduced in diabetes

• Associated with tissue damage and endothelial dysfunction

• Highly significant correlation has been shown between AGE deposits and severity of diabetic complications

Wautier JL, Guillausseau PJ. Diabetes Metab (Paris). 2001;27:535-542.

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AGE Inhibitors

• Aminoguanidine (pimagedine)

• Benfotiamine (lipid soluble thiamine derivative)

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Aminoguanidine: Diabetic NephropathyStudy Design and Patient Characteristics• Study design

– Randomized, double-masked, placebo-controlled– 2-4 years– N = 690– Placebo, 150 mg BID, 300 mg BID– 1O endpoint: serum creatinine doubling– 2O endpoints: proteinuria, kidney function, retinopathy

evaluations• Patient characteristics

– Type 1 diabetes– 22-50 years old– Retinopathy and nephropathy present– Exclusions: unstable diabetes, nondiabetic nephropathy, abnormal

liver function, antinuclear antibody titer ≥1:80, active peptic ulcer, severe autonomic neuropathy, clinical coronary artery disease

Bolton WK, et al. Am J Nephrol. 2004;24:32-40.

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• Results– 1O endpoint – serum creatinine doubling

• No overall treatment effect• Benefit in subgroup with baseline protein excretion >2 g/24 h

(P = 0.02) – 2O endpoints

• Slowed estimated GFR (eGFR) decline (P = 0.05)• Significant reduction in proteinuria (P ≤0.001)• Fewer patients with retinopathy progression (P = 0.03)

• Adverse events– Autoantibody production– Glomerulonephritis– Transient flu-like syndrome– Liver enzyme elevations– Anemia

Aminoguanidine: Diabetic NephropathyResults and Adverse Events

Bolton WK, et al. Am J Nephrol. 2004;24:32-440.

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Benfotiamine: DPN (BEDIP* Study) Study Design and Patient Characteristics• Study design

– Randomized, placebo-controlled, double-blind, pilot study– 3 weeks– 2 x 50 mg benfotiamine 4 x daily (400 mg/d) vs placebo– N = 40– Endpoints: neuropathy score, vibration detection threshold (VDT),

physician and patient assessment• Patient characteristics

– Type 1 or type 2 diabetes– 18-70 years old– Symptomatic DPN, no longer than 2 years duration– No prolonged DPN treatment– No vitamin supplements within 4 weeks of study start

*BEDIP = BEnfotiamine in the treatment of DIabetic Polyneuropathy.Haupt E, et al. J Clin Pharmacol. 2005;43:71-77.

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Benfotiamine: BEDIP StudyResults

Examinations

Active drugPlacebo

E1 E2 E3 E4 E5 E6 E7

0.250

-0.25-0.5

-0.75-1

-1.25-1.5Sc

ore

–(D

iffer

ence

)

• Improved neuropathy score relative to placebo group (P = 0.0287)• No change in VDT• Decreased pain and perceived improvement• No observable side effects

Mean change (±SEM) in neuropathy score at consecutive examinations

Haupt E, et al. J Clin Pharmacol. 2005;43:71-77.

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Common Pathophysiology Among DMC Via Protein Kinase C β Activation

©2005. International Medical Press

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PKC β Inhibitors

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PKC β Inhibition: Ruboxistaurin*• Retinopathy

– The PKC-DRS Study Group. Diabetes. 2005;54:2188-2197.

– Strøm C, et al. Invest Ophthalmol Vis Sci. 2005;46:3855-3858.

• Neuropathy– Vinik AI, et al. Clin Ther. 2005;27:1164-1180.

• Nephropathy– Tuttle K, et al. Diabetes Care. 2005;28:2686-2690.

*Currently the only selective PKC β inhibitor with published data from DMC clinical trials.

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PKC β Inhibition: Diabetic RetinopathyStudy Design and Patient Characteristics

• Study design– Multicenter, double-masked, randomized, placebo-controlled– N = 252– Placebo vs ruboxistaurin (6, 16, or 32 mg/day)– 36-46 months– Primary endpoint: retinopathy progression– Secondary endpoint: moderate visual loss (MVL)

• Patient characteristics– Type 1 or type 2 diabetes– 20-84 years old– Moderate to very severe nonproliferative diabetic retinopathy (NPDR)– Visual acuity (Snellen) of 20/125 or better – Exclusions: history of panretinal photocoagulation or glaucoma, significant

heart disease in previous 6 mos, significant hepatic disease, SBP ≥180 mm Hg or DBP ≥105 mm Hg, major surgery in previous 3 mos

The PKC-DRS Study Group. Diabetes. 2005;54:2188-2197.

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Ruboxistaurin Delays MVL in Patients With Nonproliferative Diabetic Retinopathy (NPDR)

Prob

abili

ty o

f MVL

(%) 50

40

30

20

10

0

Months0 6 12 18 24 30 36 42

Placebo8 mg16 mg32 mg

Log Rank P values:Overall: 0.06932 mg vs placebo: 0.038

The PKC-DRS Study Group. Diabetes. 2005;54:2188-2197.

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Ruboxistaurin: Diabetic RetinopathyOther Results

• No significant adverse effects

• No effect on retinopathy progression

• Reduction in sustained MVL in patients with DME at baseline – 32 mg/day

– P = 0.017

The PKC-DRS Study Group. Diabetes. 2005;54:2188-2197.

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PKC β Inhibition: Vascular Leakage in DME* Summary

• Study design– Placebo vs ruboxistaurin (4, 16, or 32 mg/d)– 18 months– Primary endpoint: retinal vascular leakage– Secondary endpoints: A1C level, resting BP

• Reduced retinal vascular leakage– Only at 4 mg/day (P = 0.032)– Only in patients with baseline permeability ≥5.8 nm/s

• Small number of eyes– N = 41 (55 eyes)– Conclusions are not strong– Nonlinear dose response

• No significant changes in BP or A1C*Diabetic macular edema.

Strøm C, et al. Invest Ophthalmol Vis Sci. 2005;46:3855-3858.

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PKC β Inhibition: DPN Study Design and Patient Characteristics

• Study design– Phase 2 trial with post-hoc analyses of symptomatic patients– Placebo vs ruboxistaurin (32 or 64 mg/d)– N = 205– 1 year– Primary endpoint: vibration detection threshold (VDT)– Secondary endpoints: Neuropathy Total Symptom Score-6 (NTSS-6),

neurologic examination, nerve electrophysiology, Neuropathy Impairment Score (NIS), Clinical Global Impressions (CGI), safety

• Patient characteristics– Type 1 or type 2 diabetes with DPN– 45.6 ± 8.41 years old– Exclusions: advanced neuropathy, likely need to initiate insulin therapy,

neurologic disease, neuropathy due to causes other than diabetes, exposureto agents associated with neuropathy

Vinik AI, et al. Clin Ther. 2005;27:1164-1180.

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PKC β Inhibition: DPN Results

• Main analysis: no treatment differences for VDT, NIS, or NTSS-6

• Post-hoc analyses of patients with less severe DPN– NTSS-6 scores improved significantly

• 64 mg/d • P ≤0.015

– VDT improved significantly• 32 and 64 mg/d doses• P <0.03

• Adverse effects– Diarrhea: significantly higher in ruboxistaurin vs placebo– Vomiting, pneumonia, dehydration, diabetic ketoacidosis

Vinik AI, et al. Clin Ther. 2005;27:1164-1180.

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PKC β Inhibition: DPNResults–Change in NTSS-6 Score

Improvement80

60

40

20

0% o

f Pat

ient

s 59.1A

0

65.4

RBX 32 mg(n = 22)

7.7

62.5*

4.2†

40.0

20.0

RBX 64 mg(n = 26)

RBX Combined

(n = 48)

Placebo(n = 35)

Worsening

B 100

80

60

40

20

0

% o

f Pat

ient

s 75.0

0

84.6

7.7

80.0‡

4.0

36.0

20.0

RBX 32 mg(n = 12)

RBX 64 mg(n = 13)

RBX Combined

(n = 25)

Placebo(n = 25)

Patients with symptomatic (A) and less severe symptomatic (B) DPN. Relative to placebo: *P = 0.049, †P = 0.032, ‡P = 0.004.

Vinik AI, et al. Clin Ther. 2005;27:1164-1180.

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PKC β Inhibition: Diabetic NephropathyStudy Design and Patient Characteristics

• Study design– Randomized, double blind, placebo-controlled, multicenter, pilot study– 1 year– N = 123– Placebo and 32 mg/day ruboxistaurin– ACEIs and ARBs* continued during trial– Primary endpoint: albumin-to-creatinine ratio (ACR) change– Secondary endpoints: estimated GFR (eGFR), adverse events

• Patient characteristics– Type 2 diabetes and nephropathy– ACR 200-2000 mg/g despite ACEI/ARB use – Exclusions: kidney transplant, high serum creatinine, mean arterial

BP >110 mm Hg, A1C >11%, congestive heart failure, abnormal liver function, cancer, use of strong cytochrome P450 3A4 inhibitors, recent initiation of lipid-lowering therapy

*ACEI = angiotensin convering-enzyme inhibitor; ARB = angiotensin receptor blocker.Tuttle K, et al. Diabetes Care. 2005;28:2686-2690.

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PKC β Inhibition: Diabetic Nephropathy Results

• ACR ↓24% from baseline in ruboxistauringroup– P = 0.02– No significant difference in placebo group

• eGFR did not change in ruboxistaurin group– P = 0.185– Significant decrease in placebo group

• Not powered to assess differences between groups

Tuttle K, et al. Diabetes Care. 2005;28 :2686-2690.

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Summary• Agents are in development to inhibit

hyperglycemia-activated pathogenetic pathways that contribute to DMC– Antioxidants– ARIs– AGE inhibitors– PKC β inhibitors

• The amount and strength of clinical evidence supporting the use of each class varies

• Benefits may be most apparent in particular patient subsets

• Stronger evidence and consensus on benefit may be needed before results can be translated to clinical use