1 DIABETES DIABETES COMPLICATIONS COMPLICATIONS By R. Keith Campbell RPh, FASHP, CDE Distinguished Professor of Pharmacy Wash. State Univ. College of Pharmacy Clinical Impact of Clinical Impact of Diabetes Diabetes 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. 2 nd ed. 1995. Wingard DL et al. In Diabetes in America. 2 nd ed. 1995. Kuller LH. In Diabetes in America. 2 nd ed. 1995. Status of Diabetes Status of Diabetes Management Management 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. 2 nd ed. Diabetes Healthcare System Diabetes Healthcare System Problems Problems Managed Care Places Barriers to Optimal Managed Care Places Barriers to Optimal Care 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 ADA Standards of Care Physician 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 Complications Complications 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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Clinical Impact of DIABETES Diabetes COMPLICATIONS zJan 23, 2006 · Clinical Impact of Diabetes zMajor cause of premature death and disability in the United States zLeading cause
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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
• 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 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
• 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
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
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
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
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.
• 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
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.
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
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
• 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