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DIABETES DIABETES COMPLICATIONSCOMPLICATIONS

By R. Keith Campbell RPh, FASHP, CDEDistinguished Professor of Pharmacy

Wash. State Univ. College of Pharmacy

Clinical Impact of Clinical Impact of DiabetesDiabetes

Major cause of premature death and disability in the United States Leading cause of new cases of blindness in working-aged adults50% of nontraumatic lower extremity amputations 35% of new cases of end-stage renal disease 2–4 fold increase in cardiovascular risk

Harris MI. In Diabetes in America. 2nd ed. 1995.Wingard DL et al. In Diabetes in America. 2nd ed. 1995. Kuller LH. In Diabetes in America. 2nd ed. 1995.

Status of Diabetes Status of Diabetes ManagementManagement

Majority of patients with type 2 diabetes have only fair to poor metabolic control

– fasting serum glucose levels of ≥ 200 mg/dL

– HbA1C levels of 9%-10%

Postprandial blood glucose levels average ~300 mg/dL

< 2% of American adults with diabetes receive optimal quality of care

Beckles GLA et al. Diabetes Care. 1998;21:1432-1438.American Diabetes Association. Diabetes Care. 1998;21(Suppl 1).Colwell JA. Ann Intern Med. 1996;124(1pt2):131-135.Abraira C et al. Diabetes Care. 1992;15:1560-1571.Klein R et al. Am J Epidemiol. 1987;126:415-428.Cowie CC et al. Diabetes in America. 2nd ed.

Diabetes Healthcare System Diabetes Healthcare System ProblemsProblems

Managed Care Places Barriers to Optimal Managed Care Places Barriers to Optimal CareCare

Greater than 90% of patients are seen only by primary care physicians70% of patients receive little or no diabetes educationUp to 70% of patients do not receive annual eye examsLess than half of all patients perform SMBG often enough to improve outcomes

Harris MI et al. Ann Intern Med 1996 Jan 1;124(1 Pt 2):117-22

ADA Standards of CareADA Standards of CarePhysician Visits 2-4 per year

HbA1C Measurement 2-4 per year

Fasting Glucose Measurement/ (SMBG) 4-6 per year/daily

Foot Exams Every Visit

Aspirin Daily

Urine Protein Measurements Yearly

Blood Pressure As needed to achieve goals

Lipid Levels As needed to achieve goals

Dilated Pupil Eye Exam Yearly

Flu and Pneumovax As needed

Causes of Diabetes Causes of Diabetes ComplicationsComplications

Health care delivery problems: lack of implementation of ADA standards of diabetes care; acute healthcare systemCultural, language, access barriersGenetic factorsSustained hyperglycemia resulting in pathophysiological changes and damage to small and large blood vessels

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Harmful Effects of Harmful Effects of HyperglycemiaHyperglycemia

• Increased capillary basement membrane thickening causing microvascular problems

• Impairment of phagocytosis(ability to fight infections)

• Abnormally high levels of minor (glycosylated) proteins: advanced glycosylated end products (AGES) that interfere with the protein’s normal physiology

• Glucose metabolized to sorbitolvia the polyol pathway

• Increased aldose reductase• Faulty lipid metabolism yields

hypercholesterolemia and hypertriglyceridemia

• Increased neonatal morbidity and mortalityOXIDATIVE STRESS with increased levels of Reactive Oxygen Species (ROS) results from 4 major pathways

• Increased blood pressure• Hemorrheologic factors affected

adversely:Increased platelet adhesivenessIncreased serum fibrinogen levelsIncreased blood viscosityDecreased red blood cell flexibilityIncreased coagulation factors like plasminogen activator inhibitor-1

(PAI-1)Increased lipoprotein AIncreased CRP (INFLAMMATION)

• Increased activation of some isoforms of protein kinase C (PKC) causing reduced vascular contractility & oxidative stress with damage to endothelium

Increased sialic acid levels in the bloodIncreased Coronary Artery DiseaseIncreased dental cavities and gum diseaseIncreased weightIncreased incidence of cataracts

Skin disordersDEPRESSION

Increased capillary basement membrane thickening causing microvascular problems

• Impairment of phagocytosis (ability to fight infections)

• Abnormally high levels of minor (glycosylated) proteins: advanced glycosylated end products (AGES) that interfere with the protein’s normal physiology

• Glucose metabolized to sorbitol via the polyolpathway

• Increased aldose reductase• OXIDATIVE STRESS resulting in increased

levels of Reactive Oxygen Species (ROS)

Harmful Effects of Harmful Effects of HyperglycemiaHyperglycemia

The The PolyolPolyol PathwayPathway

Glucose + NADPH Aldose Reductase Sorbitol + NADP

Sorbitol + NAD Sorbitol Dehydrogenase Fructose + NADH

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Harmful Effects of Harmful Effects of Hyperglycemia (cont.)Hyperglycemia (cont.)

• Faulty lipid metabolism yields hypercholesterolemia and hypertriglyceridemia

• Increased neonatal morbidity and mortality• Increased blood pressure• Hemorrheologic factors affected adversely:

Increased platelet adhesivenessIncreased serum fibrinogen levelsIncreased blood viscosityDecreased red blood cell flexibilityIncreased coagulation factors like plasminogen

activator inhibitor-1 (PAI-1)Increased lipoprotein AINCREASED CRP (INFLAMMATION)

DyslipidemiasDyslipidemias and Diabetesand Diabetes

Enhanced VLDL SecretionIncreased Small Dense LDL ProductionHypertriglyceridemiaDecreased HDL Secretion

TREATMENT: STATINS (Crestor or Lipitor)

Harmful Effects of Harmful Effects of Hyperglycemia Hyperglycemia (cont.)(cont.)

• Increased activation of some isoforms of protein Kinase C (PKC) causing reduced vascular contractility and oxidative stress

• Increased sialic acid levels in the blood• Increased coronary artery disease• Increased dental cavities and gum disease• Increased weight• Increased incidence of cataracts & glaucoma• Numerous other problems like skin problems, ED,

depression, foot disorders

Major Chronic Major Chronic Complications of DiabetesComplications of DiabetesAccelerated Macrovascular DiseaseRetinopathyNeuropathyNephropathyDermopathyFoot ProblemsNumerous Other

Treating Diabetes Treating Diabetes ComplicationsComplications

Retinopathy: Normalize Blood Glucose, Annual Dilated Pupil Exams, Laser Therapy and Vitrectomy if needed

Nephropathy: Normalize Blood Glucose, ACE Inhibitors

Neuropathy: Normalize Blood Glucose, Capsaicin, Gabapentin, Lyrica, Anti-Depressants (Cymbalta), Preventative foot care

Cardiovascular disease: normalize glucose, statins, ACE-I, aspirin, anti-oxidants

Cardiovascular Risk Factors in Cardiovascular Risk Factors in Patients with DiabetesPatients with Diabetes

GeneticsInsulin

ResistanceHyperinsulinemia

ObesityHypercoagulability

Other (Inflammation)

Glucose Intolerance or

DiabetesDyslipidemia/

Atherosclerosis

Hypertension

LIFESTYLELIFESTYLE

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LIFESTYLELIFESTYLE

ObesitySmokingHypertensionDyslipidemiaInsulin resistance/NIDDM

Major Contributor to:Major Contributor to:

Glucose Glucose Intolerance/DiabetesIntolerance/Diabetes

0%

5%

10%

15%

20%

<8.9% 8.9%-10.7% >10.7%

Stroke

0%

5%

10%

15%

20%

25%

30%

<8.9% 8.9-10.7% >10.7%

Fatal CHD All CHD events

Coronary Events and Stroke are positively Coronary Events and Stroke are positively correlated with HbA1C levelscorrelated with HbA1C levels

7-year incidence of CHD and Stroke by HbA1C Grouping

Lipid Abnormalities

Risk trials such as MRFIT, Framingham, Whitehall and others have shown elevated cholesterol to be a positive predictor of:

– Stroke – PVD-peripheral vascular disease– CHD-coronary heart disease– LEA-lower extremity amputation

The most powerful predictor was decreased HDLTriglycerides are usually elevated in type 2 diabetes and increase the risk at any LDL/HDL combinationCRP is emerging as a major risk factor

AgeAge--adjusted 7adjusted 7--Year Incidence of Year Incidence of CHD Mortality and CHD EventsCHD Mortality and CHD Events

0%5%

10%15%20%25%30%35%

<1.5 1.5-2.6 >2.6

0%

10%

20%

30%

40%

<40 40-50 >50

0%

10%

20%

30%

< 230 230-275 >275

Total Cholesterol

HDL Cholesterol

Triglycerides

Dark color = All CHD Events

Light color = Fatal CHD Events

Chronic Complications: Chronic Complications: HyperlipidemiaHyperlipidemia

Goals of therapyIntensify glycemic controlPrescribe low fat dietInitiating drug therapy

Risk LDLCholesterol

HDLCholesterol Triglycerides

Higher > 130 <35 > 400

Borderline 100-129 35-45 200-399

Lower <100 >45 <200

ObesityObesityIn the recent NHANES III Survey

– 33% of Caucasian women, 47% of Mexican American women, and 49% of African American women were overweight

The risk of the development of type 2 diabetes increased 1.4 fold for every 17% increase in body weightObesity increases the risk for developing hypertension by 6 fold over lean individualsWeight Reduction:

– reverses many cases of secondary sulfonylurea failure, improves insulin sensitivity

– In men: pant size of > 42 inches is a major indicator of IR

– In Women: > 35 inches

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HypertensionHypertension

The single most important prognostic factor for cardiovascular risk in patients both with diabetes and those without.

Virtually all patients with diabetes who have proteinuria also have hypertension.

New guidelines suggest that BPs we thought were “OK” were probably harmful, especially for persons with diabetes.

AgeAge--adjusted Cardiovascular adjusted Cardiovascular Mortality rates by Systolic BPMortality rates by Systolic BP

0

50

100

150

200

250

<120 120-139 140-159 160-179 180-199 >200

Without Diabetes With Diabetes

Rate per10,000

person-yr

Multiple Risk Factor Intervention Trial, Diabetes Care 1993:16

Chronic Complications: Chronic Complications: HypertensionHypertension

Normalize blood pressure Use of antihypertensive drugs

Patient education regarding exercise and the use of sodium and alcoholWeight management counseling

1301308080

The Effect of Diabetes on The Effect of Diabetes on Blood Coagulation FactorsBlood Coagulation Factors

Increased Fibrinogen– Also independently increased by smoking and age

Increased Factor VII

Increased vonWillebrand Factor (8)

Increased levels of Tissue Plasminogen Activator Inhibitor (PAI-1)

CRP (Inflammation)

Some Statistics on SmokingSome Statistics on Smoking

* versus non smokers without IDDM* versus non smokers without IDDM+ versus non smokers with IDDM+ versus non smokers with IDDM

on any given visit

SmokingOklahoma Oklahoma ‘‘8989

On average, 25% of persons with diabetes smoke

Smoking cessation programs vary from 3% to 22% long term effectiveness

Increases the risk of nephropathy over

2.5X

Only 25% of physicians counsel their patients to quit smoking on any given visit

Smoking increases the risk for deterioration of retinopathy 3 foSmoking increases the risk for deterioration of retinopathy 3 foldld

Direct medical costs related to smoking for those over 35 were $694 per person of which nearly 70% went to Hospital Care

Odds of being hospitalized Odds of being hospitalized within the last 12 monthswithin the last 12 months

CONTROLCONTROLNonNon--smokerssmokers 1.01.0Smokers Smokers 1.31.3IDDMIDDMNonNon--smokers*smokers* 1.91.9Smokers*Smokers* 6.06.0IDDMIDDMNonNon--smokerssmokers 1.01.0Smokers+Smokers+ 3.13.1

Why is Diabetic Eye Disease Why is Diabetic Eye Disease Newsworthy?Newsworthy?

More than 150 million people worldwide have diabetesMost people with diabetes will develop some form of eye complicationsDiabetes is the leading cause of blindness among working-age adults in industrialized countriesWith regular screening and earlier diagnosis, these numbers can be reduced

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Risk of Complications in Type 1 Diabetes

Renal failure 15-20 xGangrene 20 xBlindness 15-20 xCHD 2-6 xCoronary death 2-3 xStroke 2-3 x

Effect of Diabetes on Cardiovascular Disease Effect of Diabetes on Cardiovascular Disease (CVD) Death Rates(CVD) Death Rates

Stamler J, Vaccaro O, Neaton JD, et al. Diabetes Care. 1993;16:440.

Age

Age

-- Adj

uste

d C

VD

Dea

th R

ate

Adj

uste

d C

VD

Dea

th R

ate

Per

10,

000

Per

son

Per

10,

000

Per

son --

Yea

rsY

ears

40

60

80

100

120

140

0

20

None One Only Two Only All Three

Nondiabetic patients

Diabetic patients

Progression of Nephropathy in Diabetes

Plasma creatinine

Glomerular filtration rate

Microalbuminuria Microalbuminuria -- ProteinuriaProteinuria

Kidney failure

B

B

B

B

B B B

J

J

J

J JJ

J

H H HH

HH

H

1- 5- 10- 15- 20- 25- 30+0

20

40

60

80

100

%

Duration of diabetes

B Any J Background H Proliferative

Prevalence of Retinopathy by Duration of Diabetes

Diabetologia 1994

% affected% affected

Diabetes AMD Glaucoma Progressive Myopia Misc.0

10

20

30

40

50

Epidemiology of impaired vision in the elderlyEpidemiology of impaired vision in the elderly

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Complications Complications Pathogenesis Pathogenesis Hyperglycemia

Aldose-Reductase De-novo DAG ->ß2 PKC

AGE formation

Diabetic complications

The Human EyeThe Human Eye

Cornea

Lens

Retina

Optic nerve

NaturalNatural History of Diabetic RetinopathyHistory of Diabetic Retinopathy

Pre-clinical DR

Mild non proliferative DR

Moderate, non-proliferative DR

MaculopathySevere, non-proliferative

DR (pre-proliferative)

Proliferative DR

Advanced diabetic eye disease

60%60%

25%25%

10%10%

<5%<5%

NaturalNatural History of Diabetic RetinopathyHistory of Diabetic Retinopathy

Pre-clinical DR

Mild non proliferative DR

Moderate, non-proliferative DR

MaculopathySevere, non-proliferative

DR (pre-proliferative)

Proliferative DR

Advanced diabetic eye disease

Normaleyesight

Some problems

BLINDNESS!

PrePre--clinical Diabetic Retinopathyclinical Diabetic Retinopathy

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Moderate NPDR: Moderate NPDR: Red Lesions and Hard ExudatesRed Lesions and Hard Exudates MaculopathyMaculopathy

PDR: New Vessels ElsewherePDR: New Vessels Elsewhere PDR: Vitreous HaemorrhagePDR: Vitreous Haemorrhage

ADED: Retinal DetachmentADED: Retinal DetachmentTreatment of DR:Treatment of DR:

• Photocoagulation (laser therapy):– Panretinal (proliferative)– Focal and/or grid (maculopathy)– Vitrectomy

• Medical:– Metabolic control– Blood pressure control

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What should a person with What should a person with diabetes do to prevent diabetes do to prevent

blindness?blindness?Keep blood glucose values as close as possible to non-diabetic levels [below 6.1 mmol/l (110 mm/dl) and below 7.8 mmol/l (140 mm/dl) after meals]

Keep blood pressure below 130/80 mmHg

HAVE HIS/HER EYES CHECKED ONCE A YEAR for diabetic retinopathy

Diabetic Diabetic MicrovMicrovascularascular DDysfunctionysfunctionHyperglycaemia

PKC-β activation

Microvascular dysfunction

Leakage

Macular oedema

Visual loss

Capillary nonperfusion

VEGF/VPF production

PKC-β2 activation

Proliferative retinopathy

Capillary Capillary NonperfusionNonperfusion

As a result of vascular damage, some capillaries become occluded (nonperfused). As a result others dilate and become leaky

Capillary nonperfusion is the result of diabetes-induced abnormalities of both the vessel wall and the circulating blood

Protein Protein KinaseKinase CC--BetaBeta

Elevated blood sugar (hyperglycaemia) results in activation of PKC-ß

PKC-ß has been linked to hyperglycaemia-induced microvascular dysfunction

This dysfunction results in the development of DR/DME and other complications

VEGF/VPF ProductionVEGF/VPF Production

Retina damaged by capillary nonperfusioninduces production of growth factors such as VEGF (vascular endothelial growth factor)

VEGF mediates a significant portion of retinal neovascularization (new blood vessels) and excessive vascular permeability (VP) characteristic of PDR

VEGF

Combines with receptor

Translocation of PKC-β2from cytosolic to membranous position

Vascular proliferation

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VEGF vs. VEGF vs. ContrControlol

VEGF Control

VEGF and PKCVEGF and PKC--ßßInhibitionInhibition

VEGF VEGF+PKCßi

VEGF and PKCVEGF and PKC--ßß

PKC activation is critical step in hypoxic and hyperglycemic stimulation of VEGF expression

PKC-ß activation is required for VEGF to induce its proliferativeand permeability effects

PKCPKC--ßß InhibitionInhibition

Selective inhibition of PKC-ß has been shown to block hyperglycemia-induced expression of VEGF at multiple points along the pathway

Results in ameliorating effect on diabetes-induced vascular complications

Effect of PKCEffect of PKC--ßß inhibition inhibition on on NeovascularizationNeovascularization

2

3

4

1

3.1

1.9

P = 0.04Neovascularization

Score

Placebo PKC-ßInhibitor

Danis P, et al. IOVS 1998; 39:171-179

LY 333531 LY 333531 RuboxistaurinRuboxistaurin

Investigational compound in Phase III trials being developed as a pharmaceutical treatment for DR/DMESelective inhibitor of PKC-ß designed to measure reduction in progression of PPDR to PDRBeing studied to treat underlying cause of DR/DME (hyperglycaemia-induced microvascular dysfunction) rather than treating symptoms

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The natural history of diabetic retinopathy is well known,

BUTBUT at present the only treatment available for sight-threatening

retinopathy is with the laser, an invasive form of treatment

Hypertension and Hypertension and DiabetesDiabetes

Hypertension Increases Risk of

Nephropathy

Hypertension Increases Risk of

Retinopathy

Diabetics Have More Hypertension

Hypertensives Have More Diabetes

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DIABETES & DEPRESSIONDIABETES & DEPRESSION

The incidence of moderate depression in diabetes patients approaches 40 % of patients.The stress of living with diabetes and a chronic condition accounts for some of the increased incidence.Many diabetes patients are not evaluated nor treated for depression.

Diabetes NeuropathiesDiabetes Neuropathies

• Focal neuropathy• Distal symmetrical polyneuropathy• Autonomic neuropathy

Visceral (Autonomic) Visceral (Autonomic) NeuropathiesNeuropathies

Impaired CV reflexesGastroparesisDiarrhea or constipationNeurogenic bladderSexual dysfunctionNeurotrophic arthropathyNeurotrophic ulcer

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Chronic Complications:Chronic Complications:Autonomic NeuropathiesAutonomic Neuropathies

Orthrostatic hypotensionReduced hypoglycemic awarenessBladder dysfunctionGastroparesis / ConstipationDiarrheaFecal incontinenceSexual dysfunction

Erectile DysfunctionErectile DysfunctionPathophysiologyPathophysiology

Organic

Psychogenic

Mixed

AgingHypertension Diabetes mellitus Benign Prostatic HypertrophyCardiovascular diseaseSmokingDepressionAlcoholismRegional trauma or surgeryChronic neurologic diseaseEndocrinopathyDrugs

Adapted from Morgentaler. Lancet. 1999;354:1713-1718.

ED Is VascularED Is VascularDiabetes

Hypertension Oxidative stress

Endothelial cell injury

Vasoconstriction

Erectile dysfunction

OutcomesOutcomes

Dyslipidemia

Tobacco

Thrombosis

Atherosclerosis

PrecursorsPrecursorsPhysiology of ErectionPhysiology of Erection

Miller TA. Am Fam Physician. 2000;61:95-104,109-110.

TadalafilTadalafil: Mechanism of Action: Mechanism of Action

Sadovsky R et al. Int J Clin Pract. 2001;55:115-128.

Cialis (tadalafil) & other

(PDE5 inhibitors)

Sexual stimulation

Nitric oxide released

Guanylate cyclase

cGMP formation

Decreased cytosolic Ca2+

Penile smooth muscle relaxation

Penile erection

PDE5 isoenzymeX

Female IssuesFemale Issues

Communication/relationship issuesDesire/decreased ability to have an orgasmPost-menopausal changes/lubricationConfronting a partner’s ability to now get an erectionVaginal yeast infections in women with diabetes

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Advantages of Advantages of TadalafilTadalafil

Not impacted by food or drink36 hour duration of activity results in many benefits to both partners: reduces pressure, greater spontaneityNo flushing, no increased heart rate, no effect on sperm, no blue haze, more specific inhibitor just in the penisCan be used with Flomax up to .4 mg/day

Foot Problems:Foot Problems:Warning Signs and Warning Signs and

SystemsSystemsLoss of peripheral pulsesLoss of distal foot and toe sensation– Semmes /

Weinstein 10 gram monofilament testing

Diabetic GangreneDiabetic Gangrene

Diabetics are prone to develop gangrene, especially of the toes and feet, as result circulatory embarvassment incident to atherosclerotic vascular disease. A minor injury or local dermatitis may be the immediate cause. Prompt and vigorous treatment of the diabetics as well as the local lesions is indicated.

NeuropathyNeuropathyApproximately 80% of lower extremity amputations (LEA) have a preliminary finding of PERIPHERAL NEUROPATHY– $27,000+ for LEA– $21,000+ for rehabilitation

50% of LEA’s could have been prevented with proper foot careIt is estimated that 15%–25% of diabetes patients will have a foot ulcer at some time over the course of their disease

NeuropathyNeuropathy

Peripheral neuropathy can precipitate foot ulcers

Vascular Disease inhibits healing

Hyperglycemia inhibits healing

NeuropathyNeuropathy

4 mechanical ways to damage feet– Direct Injury– Ischemia– Repetitive Stress– Infection

Avoid Iodine, hydrogen peroxide, astringentsControl blood glucose levelsSmoking cessation

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NeuropathyNeuropathyFoot ExaminationFoot Examination

Sensory Foot Examination– Semmes-Weinstein 5.07 nylon monofilament

has been standardized to deliver 10g force when apply properly

Footwear Assessment– assess the patient’s shoes – inside for foreign objects– outside for deformities– assess the patient’s socks

Vibration SensationPatient Education—daily inspection of feet

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NeuropathyNeuropathyFoot ExaminationFoot Examination

– Sensory Foot Exam Form---Filled Out for at least One Foot

– Pedal Pulses: Yes or Nonote on back of form

– Vibration Sensation: Yes or Nonote on back of form

– Footwear Inspection

Renal Complications of Renal Complications of Diabetes:NephropathyDiabetes:Nephropathy

Assessment of serum creatinine and urinary proteinIntensify glycemic controlNormalize blood pressure => 130/80 mm Hg

– Caution with calcium channel blockers, beta blockers

Use of ACE inhibitors/ARB’s– Role of angiotensin II– Reduced progression to ESRD

Dietary counseling: low protein diet

Medications Used to Treat Medications Used to Treat Diabetes ComplicationsDiabetes Complications

Tricyclic antidepressants, SSRI’s (Cymbalta)Aspirin, NSAIDS, Anti Convulsants (Lyrica)Vitamin C, Vitamin E, MgCl, glucose tabsReglan, Erythromycin, Antacids, PPI’s, Capsaicin, Histamine 2 blockersACE inhibitors, ARB’s, diuretics, Trental, PlavixCa channel blockers, tadalafil or sildenafilLipid lowering meds (Zetia, Crestor, Lipitor)Hypoglycemic meds (oral agents and insulin)

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Meds to Treat/Prevent CV Meds to Treat/Prevent CV Disease in Diabetes PatientsDisease in Diabetes PatientsAspirinACE Inhibitors or ARBS or bothStatins plus Coenzyme CQ-10Ezetimibe and/or FibratesAnti-Oxidants and other micro-nutrients, especially Magnesium, folic acid + B vitaminsNormalize blood glucose levels with a good treatment regimen

Pharmacologic Management Pharmacologic Management of Symptomatic DPNof Symptomatic DPN

Nonsteroidal drugs occasionally help.Tricyclic Antidepressants: may be first line drugs but are rapidly being replaced by other agents like tramadoland gabapentin.Imipramine or amitriptyline at 25-150 mgm have some proven efficacy if drug levels are maintained.

Pharmacologic Management Pharmacologic Management of Symptomatic DPN (cont)of Symptomatic DPN (cont)Mexiletine: Dosage up to 450 mg/day but has many side effects and should be used short term only.Carbamazepine: this anticonvulsant drug has shown benefit but adverse effects are common.New agents with proven efficacy include: Duloxetine, pregabalin, gabapentin, topiramate, lanotrigine and tramadol.

Future Future possiblepossible Medications to Medications to Treat Treat MicrovascularMicrovascular Diabetes Diabetes

ComplicationsComplicationsRuboxistaurin (Arxxant) is a PKC-Beta inhibitor. June 2005, Dr. Tuttle reported at ADA that it stopped the progression of kidney damage and reduced microalbuminuria by 25 %.Benfotiamine is a derivative of thiamine that blocks oxidative stress by activating transketolase.PARP (Poly-ADP-ribose Polymerase) inhibitors are being developed that block the 4 major pathways leading to oxidative stress and vessel damage.Superoxide desmutase will also block the oxidative stress pathways & hopefully will block complications.Aldose Reductase Inhibitors: epalrestat 300 mg/day improved retinopathy.Alpha Lipoic Acid: shows some promise with 2 large studies in progress.Pimagedine: inhibits AGE’s and showed positive effects in treating nephropathy.

Acute Complications:Acute Complications:Hypoglycemia– Blood Glucose < 60 mg/dl with symptoms– A common complication with intensified

blood glucose control– May not be recognized – Treat promptly with glucose tablets or

inject Glucagon if the patient isunconscious

Precipitating Factors– Medications, insulin activity timing– Exercise, Diet

Hypoglycemia Hypoglycemia HyperglycemiaHyperglycemia

• Sudden Onset• Staggering, Poor

Coordination• Anger, Bad Temper• Pale Color• Confusion,

Disorientation• Sudden Hunger• Sweating• Eventual Stupor or

Unconsciousness

• Gradual Onset• Drowsiness• Extreme Thirst• Very Frequent

Urination• Flushed Skin• Vomiting• Fruity or Wine-Like

Breath Odor• Heavy Breathing • Eventual Stupor or

Unconsciousness

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Type of Acute Diabetic Type of Acute Diabetic EmergenciesEmergencies

• Comas– Hypoglycemia– Ketoacidotic hyperglycemia– Nonketotic hyperosmolar

hyperglycemia (NKHH)– Lactic acidosis– Uremia– Nondiabetic comas

• Infection• Myocardial infarction• Stroke• Emergency surgery

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Suggested ReadingsSuggested ReadingsBrownlee M. The Pathobiology of Diabetic Complications. Diabetes. 2005; 54 (6):1615-25.Setter SM, Campbell RK, Cahoon CJ. “Biochemical Pathways for MicrovascularComplications of Diabetes Mellitus”. Ann Pharmacother 2003;37:1858-66.Duby JJ, Campbell RK, Setter SM, White JR, Rasmussen KA. “Diabetic Neuropathy”. Am J Health-Syst Pharm. 2004; 61:160-176.Duby JJ, Campbell RK. Treatment of Painful Diabetic Neuropathy: A Review of The Current Evidence. US Pharmacist, Vol. 29 (11). Pages HS-10-HS24.Fong DS, Aiello LP, Ferris FL, Klein R. Diabetic Retinopathy. DiabetesCare. 2004;27(10):2540-2553.Campbell RK, Bennett JA. Assessing Diabetes Patients' Healthcare Needs.

The Diabetes Educator. 2002;28(1):40-50.• Moghissi E. Hospital Management of Diabetes: Beyond the Sliding Scale. Cleveland Clinic

Journal of Med; 71(10) Oct. 2004:801-805.• Browning LA, Dumo P. Sliding Scale Insulin: An antiquated approach to glycemic control

in hospitalized patients. Am J Health-Syst Pharm. 2004; 61:1611-1614.• Ferrone M. Pharmacy Interventions in Chronic Kidney Disease. U.S. Pharmacist. Nov. 15,

2004, 29 (11).• Banarer S, Cryer PE. Hypoglycemia in type 2 Diabetes. Med Clin N Amer 88 (2004):1107-

1116.• Skyler JS. Effects of Glycemic Control on Diabetes Complications and on the Prevention of

Diabetes. Clinical Diabetes Vol 22 (4), 2004: 162-166.• Setter SM, Iltz JL, Fincham JE, Campbell RK, Baker DE. Phosphodiesterase 5 Inhibitors

for Erectile Dysfunction. Ann Pharmacother 2005;39: xxx.• I RECOMMEND THAT YOU JOIN THE ADA AND SUBSCRIBE TO DIABETES CARE,

DIABETES SPECTRUM AND CLINICAL DIABETES.