DIABETES COMPLICATIONS

Clinical Impact of Diabetes

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By R. Keith Campbell RPh, FASHP, CDE Distinguished Professor of Pharmacy Wash. State Univ. College of Pharmacy

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Major cause of premature death and disability in the United States Leading cause of new cases of blindness in working-aged adults 50% 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 Management

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

fasting serum glucose levels of ≥ 200 mg/dL

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HbA1C levels of 9%-10%

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Postprandial blood glucose levels average ~300 mg/dL

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

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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 Problems Managed Care Places Barriers to Optimal Care Greater than 90% of patients are seen only by primary care physicians 70% of patients receive little or no diabetes education Up to 70% of patients do not receive annual eye exams Less 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 Care z

Physician Visits

2-4 per year

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HbA1C Measurement

2-4 per year

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Fasting Glucose Measurement/ (SMBG)

4-6 per year/daily

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Foot Exams

Every Visit

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Aspirin

Daily

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Urine Protein Measurements

Yearly

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Blood Pressure

As needed to achieve goals

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Lipid Levels

As needed to achieve goals

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Dilated Pupil Eye Exam

Yearly

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Flu and Pneumovax

As needed

Causes of Diabetes Complications z

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Health care delivery problems: lack of implementation of ADA standards of diabetes care; acute healthcare system Cultural, language, access barriers Genetic factors Sustained hyperglycemia resulting in pathophysiological changes and damage to small and large blood vessels

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Harmful Effects of Hyperglycemia • 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 polyol pathway • Increased aldose reductase • Faulty lipid metabolism yields hypercholesterolemia and hypertriglyceridemia • Increased neonatal morbidity and mortality OXIDATIVE STRESS with increased levels of Reactive Oxygen Species (ROS) results from 4 major pathways

• Increased blood pressure • Hemorrheologic factors affected

adversely:

Increased platelet adhesiveness Increased serum fibrinogen levels Increased blood viscosity Decreased red blood cell flexibility Increased coagulation factors like plasminogen activator inhibitor-1 (PAI-1) Increased lipoprotein A Increased 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 blood Increased Coronary Artery Disease Increased dental cavities and gum disease Increased weight Increased incidence of cataracts Skin disorders DEPRESSION

Harmful Effects of Hyperglycemia 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 polyol pathway • Increased aldose reductase • OXIDATIVE STRESS resulting in increased levels of Reactive Oxygen Species (ROS) z

The Polyol Pathway Glucose + NADPH Aldose Reductase Sorbitol + NADP

Sorbitol + NAD Sorbitol Dehydrogenase Fructose + NADH

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

Faulty lipid metabolism yields hypercholesterolemia and hypertriglyceridemia Increased neonatal morbidity and mortality Increased blood pressure Hemorrheologic factors affected adversely: Increased platelet adhesiveness Increased serum fibrinogen levels Increased blood viscosity Decreased red blood cell flexibility Increased coagulation factors like plasminogen activator inhibitor-1 (PAI-1) Increased lipoprotein A INCREASED CRP (INFLAMMATION)

Harmful Effects of Hyperglycemia (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

Dyslipidemias and Diabetes z z

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Retinopathy:

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Nephropathy:

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

Inhibitors

Normalize Blood Glucose, ACE

TREATMENT: STATINS (Crestor or Lipitor)

Major Chronic Complications of Diabetes z z z z z z z

Treating Diabetes Complications

Enhanced VLDL Secretion Increased Small Dense LDL Production Hypertriglyceridemia Decreased HDL Secretion

Accelerated Macrovascular Disease Retinopathy Neuropathy Nephropathy Dermopathy Foot Problems Numerous Other

Cardiovascular Risk Factors in Patients with Diabetes Hypercoagulability Glucose Intolerance or Diabetes

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

normalize glucose, statins, ACE-I, aspirin, anti-oxidants

Obesity

Dyslipidemia/ Atherosclerosis

LIFESTYLE Genetics Hypertension

Insulin Resistance Hyperinsulinemia Other (Inflammation)

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Glucose Intolerance/Diabetes 7-year incidence of CHD and Stroke

LIFESTYLE Major Contributor to: z z z z z

by HbA1C Grouping

Obesity Smoking Hypertension Dyslipidemia Insulin resistance/NIDDM

30%

20%

25% 15%

20% 15%

10%

10% 5%

5% 0%

0% 10.7%

All CHD events

Coronary Events and Stroke are positively correlated with HbA1C levels

AgeAge-adjusted 77-Year Incidence of CHD Mortality and CHD Events

Lipid Abnormalities z

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Total Cholesterol

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 HDL Triglycerides are usually elevated in type 2 diabetes and increase the risk at any LDL/HDL combination CRP is emerging as a major risk factor

30% 20% 10% 0% < 230 40%

230-275

>275

Triglycerides 35% 30% 25% 20% 15% 10% 5% 0% 2.6

HDL Cholesterol Dark color = All CHD Events

30% 20%

Light color = Fatal CHD Events

10% 0% 130

> 400

Borderline 100-129

35-45

200-399

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Lower

>45

50

Obesity z

35 inches

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AgeAge-adjusted Cardiovascular Mortality rates by Systolic BP

Hypertension z

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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.

250 200

Rate per 10,000 person-yr

150 100

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

50 0 200

With Diabetes

Multiple Risk Factor Intervention Trial, Diabetes Care 1993:16

Chronic Complications: Hypertension z z

The Effect of Diabetes on Blood Coagulation Factors

Normalize blood pressure Use of antihypertensive drugs

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130 80 z

Patient education regarding exercise and the use of sodium and alcohol Weight management counseling

Increased Factor VII

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Increased vonWillebrand Factor (8)

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CONTROL NonNon-smokers Smokers IDDM NonNon-smokers* Smokers* IDDM NonNon-smokers Smokers+

1.0 1.3

On average, 25% of persons with diabetes smoke Smoking cessation programs vary from 3% to 22% long term effectiveness

1.9 6.0

Smoking

1.0 3.1

Increases the risk of nephropathy over 2.5X

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

Only of physicians counsel their on25% any given visit patients to quit smoking on any given visit

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Oklahoma ‘89 Direct medical costs related to smoking for those over 35 were $694 per person of which nearly 70% went to Hospital Care

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

Why is Diabetic Eye Disease Newsworthy?

Some Statistics on Smoking Odds of being hospitalized within the last 12 months

Also independently increased by smoking and age

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Increased Fibrinogen

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

Smoking increases the risk for deterioration of retinopathy 3 fold fold

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Risk of Complications in Type 1 Diabetes Renal failure Gangrene Blindness CHD Coronary death Stroke

Effect of Diabetes on Cardiovascular Disease (CVD) Death Rates Age--Adjusted CVD Death Rate Age Person--Years Per 10,000 Person

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15-20 x 20 x 15-20 x 2-6 x 2-3 x 2-3 x

Progression of Nephropathy in Diabetes

Nondiabetic patients

120

Diabetic patients

100 80

Glomerular filtration rate

60

Kidney failure

40 20

Plasma creatinine 0

None

One Only

Two Only

All Three

Microalbuminuria - Proteinuria

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

Prevalence of Retinopathy by Duration of Diabetes 100

Epidemiology of impaired vision in the elderly % % affected affected

80

B

B

B

B

60 %

J

40

J J J H

B

40

50

J

30

H H

20 0

Diabetologia 1994

JB JB H

1B

H

5Any

20

H H

10- 15- 20- 25Duration of diabetes J

Background

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30+ Proliferative

10 0 Diabetes

AMD

Glaucoma Progressive Myopia

Misc.

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Complications Pathogenesis

Hyperglycemia

Aldose-Reductase

AGE formation

De-novo DAG ->ß2 PKC

Diabetic complications

The Human Eye

Natural History of Diabetic Retinopathy

Cornea

Retina

60%

Pre-clinical DR Mild non proliferative DR

25%

Maculopathy

Optic nerve

Lens

10% 130/80 mm Hg –

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Use of ACE inhibitors/ARB’s – –

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Caution with calcium channel blockers, beta blockers Role of angiotensin II Reduced progression to ESRD

Dietary counseling: low protein diet

Medications Used to Treat Diabetes Complications z z z z

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Tricyclic antidepressants, SSRI’s (Cymbalta) Aspirin, NSAIDS, Anti Convulsants (Lyrica) Vitamin C, Vitamin E, MgCl, glucose tabs Reglan, Erythromycin, Antacids, PPI’s, Capsaicin, Histamine 2 blockers ACE inhibitors, ARB’s, diuretics, Trental, Plavix Ca channel blockers, tadalafil or sildenafil Lipid lowering meds (Zetia, Crestor, Lipitor) Hypoglycemic meds (oral agents and insulin)

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Meds to Treat/Prevent CV Disease in Diabetes Patients z z z z z

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Pharmacologic Management of Symptomatic DPN

Aspirin ACE Inhibitors or ARBS or both Statins plus Coenzyme CQ-10 Ezetimibe and/or Fibrates Anti-Oxidants and other micronutrients, especially Magnesium, folic acid + B vitamins Normalize blood glucose levels with a good treatment regimen

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Future possible Medications to Treat Microvascular Diabetes Complications

Pharmacologic Management of Symptomatic DPN (cont) z

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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.

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Ruboxistaurin (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.

Hypoglycemia Hyperglycemia

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

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

• • • • • • • •

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 Emergencies •

Comas – – – – – –

• • • •

Hypoglycemia Ketoacidotic hyperglycemia Nonketotic hyperosmolar hyperglycemia (NKHH) Lactic acidosis Uremia Nondiabetic comas

Infection Myocardial infarction Stroke Emergency surgery

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Suggested Readings z z z z z z • • • • • • •

Brownlee M. The Pathobiology of Diabetic Complications. Diabetes. 2005; 54 (6):161525. Setter SM, Campbell RK, Cahoon CJ. “Biochemical Pathways for Microvascular Complications 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):11071116. 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.

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