Complications ofÂ DM

CHRONIC COMPLICATIONS INCHRONIC COMPLICATIONS INDIABETES MELLITUSDIABETES MELLITUS

CHRONIC COMPLICATIONS INCHRONIC COMPLICATIONS INDIABETES MELLITUSDIABETES MELLITUS

CPT Thomas Oliver, M.D.CPT Thomas Oliver, M.D.

Endocrinology, Diabetes and Endocrinology, Diabetes and

Metabolism ServiceMetabolism Service

Walter Reed Army Medical CenterWalter Reed Army Medical Center

DM COMPLICATIONSDM COMPLICATIONSDM COMPLICATIONSDM COMPLICATIONS

PREVENTIONPREVENTION PREVENTIONPREVENTION PREVENTIONPREVENTION PREVENTIONPREVENTION PREVENTIONPREVENTION PREVENTIONPREVENTION MANAGEMENTMANAGEMENT

DM COMPLICATIONSDM COMPLICATIONS - EPIDEMIOLOGY - EPIDEMIOLOGYDM COMPLICATIONSDM COMPLICATIONS - EPIDEMIOLOGY - EPIDEMIOLOGY

MAJOR DETERMINING FACTORSMAJOR DETERMINING FACTORS

DurationDuration

Glycemic ControlGlycemic Control

Type 1 vs. Type 2Type 1 vs. Type 2

DM COMPLICATIONSDM COMPLICATIONS - GLYCEMIC CONTROL IN TYPE 1 - GLYCEMIC CONTROL IN TYPE 1 DM COMPLICATIONSDM COMPLICATIONS - GLYCEMIC CONTROL IN TYPE 1 - GLYCEMIC CONTROL IN TYPE 1

DIABETES CONTROL AND DIABETES CONTROL AND

COMPLICATIONS TRIAL (DCCT)COMPLICATIONS TRIAL (DCCT)

1441 pts. with type 1 DM1441 pts. with type 1 DM

726 within 5 years of onset = 0 comp’s726 within 5 years of onset = 0 comp’s

Comparison of intensive therapy vs.... Comparison of intensive therapy vs....

conventional therapyconventional therapy

Mean follow-up 6.5 years (4-9) with 98% Mean follow-up 6.5 years (4-9) with 98%

data collectiondata collection

DM COMPLICATIONSDM COMPLICATIONS - GLYCEMIC CONTROL IN TYPE 1 - GLYCEMIC CONTROL IN TYPE 1DM COMPLICATIONSDM COMPLICATIONS - GLYCEMIC CONTROL IN TYPE 1 - GLYCEMIC CONTROL IN TYPE 1

DIABETES CONTROL AND DIABETES CONTROL AND

COMPLICATIONS TRIAL (DCCT)COMPLICATIONS TRIAL (DCCT)

INTENSIVE THERAPY MEANSINTENSIVE THERAPY MEANS

Subcutaneous Continuous Insulin Injection (pump) Subcutaneous Continuous Insulin Injection (pump)

OROR

Multiple daily injections Multiple daily injections ANDAND

Monthly clinic visitsMonthly clinic visits


DCCT RESULTS:DCCT RESULTS:

INTENSIVE GROUP:INTENSIVE GROUP: HgA1c avg........ 7.2%HgA1c avg........ 7.2%

FS avg........ 155 mg/dlFS avg........ 155 mg/dl

CONVENTIONAL GROUP:CONVENTIONAL GROUP: HgA1c avg......... 9.1%HgA1c avg......... 9.1%

FS avg.......... 231 mg/dlFS avg.......... 231 mg/dl


DCCT RESULTS:DCCT RESULTS: In Intensive GroupIn Intensive Group:: Retinopathy progressed by 3 steps in Retinopathy progressed by 3 steps in

70.3% fewer patients.70.3% fewer patients. Initial appearance of retinopathy was Initial appearance of retinopathy was

reduced by 27%.reduced by 27%. Need for laser photocoagulation reduced Need for laser photocoagulation reduced

by 56%. by 56%.


DCCT RESULTS:DCCT RESULTS: In Intensive GroupIn Intensive Group:: Nephropathy (albuminuria > 300 mg/d) Nephropathy (albuminuria > 300 mg/d)

reduced by 54%. reduced by 54%. Neuropathy (Nerve conduction Neuropathy (Nerve conduction

abnormalities + clinical sx.) reduced abnormalities + clinical sx.) reduced by 64%.by 64%.


DCCT RESULTS:DCCT RESULTS:

In Intensive GroupIn Intensive Group::

Macrovascular events (cardiac & Macrovascular events (cardiac &

peripheral) reduced; though not to peripheral) reduced; though not to

statistically significant level.statistically significant level.

Significant LDL elevation (>160 mg/dl) Significant LDL elevation (>160 mg/dl)

reduced by 35%.reduced by 35%.


DCCT looked at Type 1 DCCT looked at Type 1 onlyonly!! Can we apply findings to type 2?Can we apply findings to type 2? Studies:Studies:

Small Japanese study with 110 patients Small Japanese study with 110 patients shows results similar to DCCT.shows results similar to DCCT.

UKPDSUKPDS

UKPDSUKPDS

Microvascular DiseaseMicrovascular Disease Delayed retinopathyDelayed retinopathy Delayed nephropathyDelayed nephropathy

Macrovascular DiseaseMacrovascular Disease No effect on:No effect on:

Cardiovascular diseaseCardiovascular disease Diabetes-related deathsDiabetes-related deaths All-cause mortalityAll-cause mortality Difference in HGB-A1C(0.9%)Difference in HGB-A1C(0.9%)

UKPDSUKPDS

Macrovascular DiseaseMacrovascular Disease Metformin +Sulfonylurea detrimentalMetformin +Sulfonylurea detrimental

Metformin monotherapy showed significant Metformin monotherapy showed significant benefit on:benefit on: Cardiovascular diseaseCardiovascular disease Diabetes-related deathDiabetes-related death All cause mortalityAll cause mortality

DM COMPLICATIONSDM COMPLICATIONS - MECHANISMS - MECHANISMSDM COMPLICATIONSDM COMPLICATIONS - MECHANISMS - MECHANISMS

Many different tissues involved - Many different tissues involved -

nerves, skin, retina, kidney, heart, nerves, skin, retina, kidney, heart,

brain.brain.

Common to all of these are:Common to all of these are:

BLOOD VESSELSBLOOD VESSELS


Microvascular Damage Affects:Microvascular Damage Affects:

RetinasRetinas

GlomeruliGlomeruli

NervesNerves


Microvascular Damage Causes:Microvascular Damage Causes:

BlindnessBlindness

End-Stage Renal DiseaseEnd-Stage Renal Disease

Neuropathy >>> AmputationsNeuropathy >>> Amputations


Macrovascular Damage Affects Large Macrovascular Damage Affects Large

(Named) Arteries:(Named) Arteries:

Coronary ArteriesCoronary Arteries

Carotid/Cerebral ArteriesCarotid/Cerebral Arteries

Lower Extremity ArteriesLower Extremity Arteries


Macrovascular Damage Causes:Macrovascular Damage Causes:

Angina, Myocardial Infarction, Sudden Angina, Myocardial Infarction, Sudden

DeathDeath

StrokesStrokes

Poor Healing from Wounds or Poor Healing from Wounds or

Infections >>> AmputationsInfections >>> Amputations


So So HOWHOW does diabetes damage blood does diabetes damage blood vessels?vessels?

Best understood mechanism is by non-Best understood mechanism is by non-enzymatic glucosylation (glycation) of proteins enzymatic glucosylation (glycation) of proteins and other macromolecules. and other macromolecules.

Other mechanisms postulated include changes Other mechanisms postulated include changes in NADP+ and NADH levels associated with in NADP+ and NADH levels associated with

alternative glucose metabolic fatesalternative glucose metabolic fates when when usual pathways are saturated.usual pathways are saturated.


Chronic hyperglycemia causes Chronic hyperglycemia causes increased glycation of proteins, increased glycation of proteins, resulting in resulting in AAdvanced dvanced GGlycation lycation EEndproducts (ndproducts (AGEAGEs)s)

These can cause damage through loss These can cause damage through loss of function, turning on/off signal of function, turning on/off signal pathways within cells, or alteration in pathways within cells, or alteration in gene expression.gene expression.


One of the proteins which is glycated One of the proteins which is glycated is Hemoglobin. Because it is found in is Hemoglobin. Because it is found in the blood, it is convenient to measure the blood, it is convenient to measure as HgA1c.as HgA1c.

Because RBCs (and thus Hg) survive Because RBCs (and thus Hg) survive in the blood for 90-120 days, the in the blood for 90-120 days, the HgA1c provides a means to assess HgA1c provides a means to assess glycemic control over this period.glycemic control over this period.


The Role of InsulinThe Role of Insulin

High insulin levels as seen in insulin High insulin levels as seen in insulin

resistance MAY be contributory to the resistance MAY be contributory to the

development of:development of:

HypertensionHypertension

AtherosclerosisAtherosclerosis


The Role of InsulinThe Role of Insulin Hyperglycemia causes complicationsHyperglycemia causes complications Insulin causes complicationsInsulin causes complications

Type 1 Type 1 Usually not hyperinsulinemic; therefore Usually not hyperinsulinemic; therefore

concentrate on controlling hyperglycemia.concentrate on controlling hyperglycemia. Type 2 (Actively under investigation)Type 2 (Actively under investigation)

Unclear whether increasing insulin to achieve Unclear whether increasing insulin to achieve normal sugars overall benefit!!! normal sugars overall benefit!!!

DM COMPLICATIONSDM COMPLICATIONS - EYE DISEASE - EYE DISEASEDM COMPLICATIONSDM COMPLICATIONS - EYE DISEASE - EYE DISEASE

8,000 new cases of blindness due to DM 8,000 new cases of blindness due to DM

per year in the US.per year in the US.

12% Cases of new blindness due to DM.12% Cases of new blindness due to DM.

Leading Cause of new Blindness in Leading Cause of new Blindness in

working-aged Americans.working-aged Americans.


Early Changes (normal exam)Early Changes (normal exam)

Loss of Autoregulation of blood flow.Loss of Autoregulation of blood flow.

Decreased blood flow.Decreased blood flow.

Loss of pericytes (supporting cells).Loss of pericytes (supporting cells).


Nonproliferative Changes:Nonproliferative Changes: Dot & blot hemorrhagesDot & blot hemorrhages Cotton-wool spotsCotton-wool spots Venous LoopsVenous Loops Venous TortuosityVenous Tortuosity

100% incidence at 15 years100% incidence at 15 years Increased retinal blood flow.Increased retinal blood flow. Capillary DropoutCapillary Dropout


Proliferative ChangesProliferative Changes Neovascularization - most prominent Neovascularization - most prominent

at border between perfused and at border between perfused and nonperfused retina.nonperfused retina.

Vitreous hemorrhage due to fragility Vitreous hemorrhage due to fragility of new vessels.of new vessels.

Contraction of co-existing glial tissue Contraction of co-existing glial tissue may lead to retinal detachment.may lead to retinal detachment.


Quiescent StageQuiescent Stage End of Proliferative changes; vision End of Proliferative changes; vision

usually stable at whatever level of loss usually stable at whatever level of loss was sustained during proliferative phase.was sustained during proliferative phase.

Laser photocoagulationLaser photocoagulation seems to seems to accelerate transition from proliferative accelerate transition from proliferative phase to quiescent phase. Intent is to phase to quiescent phase. Intent is to arrive at quiescent phase with minimal arrive at quiescent phase with minimal loss of vision.loss of vision.


Macular EdemaMacular Edema In DM, retinal vessels are more permeable.In DM, retinal vessels are more permeable. Fluid leakage from vessels to retina can Fluid leakage from vessels to retina can

cause localized edema.cause localized edema. If present in the macula, can cause If present in the macula, can cause

reduction in VA (20/20 > 20/50).reduction in VA (20/20 > 20/50). Affects 300,000 pts/year.Affects 300,000 pts/year. Risk can be decreased with laser rx.Risk can be decreased with laser rx.


PREVENTION STRATEGIES:PREVENTION STRATEGIES:

Glycemic ControlGlycemic Control

Regular Eye ExamsRegular Eye Exams

Photocoagulation for Macular Photocoagulation for Macular

Edema or Neovascularization Edema or Neovascularization

DM COMPLICATIONSDM COMPLICATIONS - KIDNEY DISEASE - KIDNEY DISEASEDM COMPLICATIONSDM COMPLICATIONS - KIDNEY DISEASE - KIDNEY DISEASE

Leading Cause of Leading Cause of EEnd nd SStage tage RRenal enal

DDisease (isease (ESRDESRD) in developed nations.) in developed nations.

27.2% Dialysis Patients have DM.27.2% Dialysis Patients have DM.

36.4% NEW ESRD cases are related 36.4% NEW ESRD cases are related

to DM.to DM.

Familial clustering occurs.Familial clustering occurs.


Type 1 vs. Type 2Type 1 vs. Type 2

Previous studies suggested higher Previous studies suggested higher

rate of ESRD in Type 1 pts.rate of ESRD in Type 1 pts.

More recent studies suggest ESRD More recent studies suggest ESRD

rate in Type 2 pts. approaching rate in Type 2 pts. approaching

that in Type 1 pts.that in Type 1 pts.


To To B B (for biopsy) or not to (for biopsy) or not to BB Not needed in typical cases (~ 80%)Not needed in typical cases (~ 80%)

DM > 10 yearsDM > 10 years Other “opathies” presentOther “opathies” present Gradual progressionGradual progression

Helpful in atypical casesHelpful in atypical cases Within 10 yrs. onset of DMWithin 10 yrs. onset of DM Other indicators of inflammatory processOther indicators of inflammatory process Rapid ProgressionRapid Progression


Progression in Type 1 DMProgression in Type 1 DM

Glomerular HyperfiltrationGlomerular Hyperfiltration

RenomegalyRenomegaly

GFR up to 140% of normalGFR up to 140% of normal

Intermittent microalbuminuria (with Intermittent microalbuminuria (with

hyperglycemia)hyperglycemia)



Early Glomerular LesionsEarly Glomerular Lesions

Basement Membrane ThickeningBasement Membrane Thickening

Exercise-Induced MicroalbuminuriaExercise-Induced Microalbuminuria

Begins ~ 18-24 months after onsetBegins ~ 18-24 months after onset DM DM

Lasts 4-15 yearsLasts 4-15 years



Microalbuminuric StageMicroalbuminuric Stage

30 - 300 mg Albumin/Day30 - 300 mg Albumin/Day

GFR usually maintainedGFR usually maintained

Associated with other organ damageAssociated with other organ damage


Progression in Type 1 DMProgression in Type 1 DM Clinical nephropathyClinical nephropathy

> 300-500 mg/day> 300-500 mg/day Falling GFR (~1 ml/min/month)Falling GFR (~1 ml/min/month) Nephrotic Syndrome may occurNephrotic Syndrome may occur

* * >3500 mg/day>3500 mg/day ** Hypoalbuminemia Hypoalbuminemia

* * EdemaEdema ** Hyperlipidemia Hyperlipidemia



E nd S tage R enal D iseaseE nd S tage R enal D isease

Type 1 - 30-40% pts. after 20-30 Type 1 - 30-40% pts. after 20-30

years.years.

Onset within 2-3 years after Onset within 2-3 years after

nephrotic syndrome.nephrotic syndrome.


Progression in Type 2 DMProgression in Type 2 DM Not as well-defined as for Type 1 due Not as well-defined as for Type 1 due

to unknown onset in many individuals.to unknown onset in many individuals. 20-37% have microalbuminuria AT 20-37% have microalbuminuria AT

TIME OF DIAGNOSIS.TIME OF DIAGNOSIS. Subgroups at higher risk include Subgroups at higher risk include

African-Americans, Hispanics, and Pima African-Americans, Hispanics, and Pima Indians.Indians.


Prevention Strategies:Prevention Strategies: Normalize Blood PressureNormalize Blood Pressure

Goal 120-130/80-85Goal 120-130/80-85 ACE inhibitors particularly beneficialACE inhibitors particularly beneficial

Dietary Protein RestrictionDietary Protein Restriction 0.6-0.8 gm/kg/day in established 0.6-0.8 gm/kg/day in established

macroalbuminuria or falling GFRmacroalbuminuria or falling GFR Glycemic ControlGlycemic Control Regular Monitoring for NephropathyRegular Monitoring for Nephropathy Avoid Nephrotoxins (NSAIDs, some abx)Avoid Nephrotoxins (NSAIDs, some abx)

DM COMPLICATIONSDM COMPLICATIONS - NEUROPATHIES - NEUROPATHIESDM COMPLICATIONSDM COMPLICATIONS - NEUROPATHIES - NEUROPATHIES

CNS Complications:CNS Complications: StrokeStroke

Increased Risk (independent of HTN, etc.)Increased Risk (independent of HTN, etc.) Worsened neurologic injuries/deficitsWorsened neurologic injuries/deficits

Diabetic EncephalopathyDiabetic Encephalopathy Subtle cognitive defects Subtle cognitive defects Possible increased risk from repeated Possible increased risk from repeated

episodes of severe hypoglycemiaepisodes of severe hypoglycemia CNS infections - MucormycosisCNS infections - Mucormycosis


Peripheral Neuropathies:Peripheral Neuropathies: Sensory LossSensory Loss

Pain ReceptionPain Reception Pain, ParesthesiasPain, Paresthesias Loss of Sensation, Occult Injuries/UlcersLoss of Sensation, Occult Injuries/Ulcers

Position/Vibratory SensePosition/Vibratory Sense AtaxiaAtaxia Increased Falls RiskIncreased Falls Risk


Peripheral Neuropathies:Peripheral Neuropathies:

Motor NeuronsMotor Neurons

Proximal Motor NeuropathyProximal Motor Neuropathy

Pain/Anesthesia anterior thighPain/Anesthesia anterior thigh

Difficulty rising from squat/ climbing stairsDifficulty rising from squat/ climbing stairs

Knee BucklingKnee Buckling


Autonomic Neuropathies:Autonomic Neuropathies:

CardiovascularCardiovascular Postural HypotensionPostural Hypotension

Resting TachycardiaResting Tachycardia

Painless MIPainless MI

RespiratoryRespiratory Sleep ApneaSleep Apnea



GastroIntestinalGastroIntestinal Esophageal DysmotilityEsophageal Dysmotility GastroparesisGastroparesis PylorospasmPylorospasm Intestinal - Diarrhea, SpasmIntestinal - Diarrhea, Spasm Gall Bladder ContractilityGall Bladder Contractility Anorectal Dysfunction - IncontinenceAnorectal Dysfunction - Incontinence



GenitoUrinaryGenitoUrinary Bladder DysfunctionBladder Dysfunction

Male ImpotenceMale Impotence

Ejaculatory DisordersEjaculatory Disorders

Reduced Vaginal Lubrication, Reduced Vaginal Lubrication,

DyspareuniaDyspareunia


Prevention StrategiesPrevention Strategies Glycemic ControlGlycemic Control Smoking CessationSmoking Cessation Regular Sensory ExamsRegular Sensory Exams Personal ProtectionPersonal Protection Consider RevascularizationConsider Revascularization Aggressive Treatment and Follow-Up of Aggressive Treatment and Follow-Up of

any Ulcersany Ulcers

DM COMPLICATIONSDM COMPLICATIONS - SUMMARY - SUMMARYDM COMPLICATIONSDM COMPLICATIONS - SUMMARY - SUMMARY

Diabetes is a leading cause of blindness, Diabetes is a leading cause of blindness,

kidney failure, amputation, heart kidney failure, amputation, heart

attack, stroke, and premature death.attack, stroke, and premature death.


These complications can be minimized!These complications can be minimized! Glycemic Control MattersGlycemic Control Matters

Early Diagnosis of DM Early Diagnosis of DM Glycemic Control MattersGlycemic Control Matters

Monitoring for complicationsMonitoring for complications Glycemic Control MattersGlycemic Control Matters

Aggressive treatment of co-risk factorsAggressive treatment of co-risk factors Glycemic Control MattersGlycemic Control Matters

Team approach - access to multiple Team approach - access to multiple specialistsspecialists


GlycemicGlycemic

ControlControl

MattersMatters**Thoughtfully applied in Type 2Thoughtfully applied in Type 2


PreventionPrevention

is more rewardingis more rewarding

thanthan

ManagementManagement

of Complicationsof Complications

Complications ofÂ DM

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