Complications of Complications of DiabetesDiabetes

영양병원 내과 영양병원 내과 이준엽이준엽

ClassificationsClassifications

Acute complicationsAcute complications1) Hypoglycemia1) Hypoglycemia2) comas (DKA Vs HHS)2) comas (DKA Vs HHS)

Chronic complicationsChronic complications1) Diabetic microvascular Cxs. 1) Diabetic microvascular Cxs. (retinopathy, nephropathy, (retinopathy, nephropathy, neuropathy) neuropathy)2) Diabetic macrovascular Cxs. 2) Diabetic macrovascular Cxs. (coronary, cerbral a. , foot ulcers, (coronary, cerbral a. , foot ulcers, HTN) HTN)

Acute ComplicationsAcute ComplicationsComplications Cause Early Signs Prevention

Diabetic Ketoacidosis (DKA)

- Insulin deficit causing severe  metabolic alterations

Weight loss • Increased

urination • Increased thirst • Vomiting • Rapid breathing

- Insulin must be  given

Hyperosmolar Hyperglycemic Nonketotic

Coma (HHNK)

- Excessive blood glucose  concentration

Increased urination • Increased thirst • Fatigue • Lethargy

- Maintaining blood glucose within lower  range

Hypoglycaemia - Blood glucose drops significantly  below healthy range and can not recover naturally because of  diabetes medications.

Lightheaded • Dizzy • Shakey • Hungry • Weak, Tired

- Carbohydrate food intake is balanced  with medication and  activity

Chronic ComplicationsChronic Complications

Systems Effected

Disease Health  Concern

Eyes • Retinopathy • Glaucoma • Cataracts

• Blindness

Blood Vessels • Coronary artery disease • Cerebral vascular disease • Peripheral vascular disease • Hypertension

• Heart attack • Stroke • Poor circulation in feet

and  legs • Heart attack, stroke,

kidney  damage Kidneys • Renal insufficiency

• Kidney failure • Insufficient blood filtering • Loss of ability to filter 

blood

Nerves • Neuropathies • Autonomic neuropathy

• Chronic pain • Poor nerve signaling to

organ  systems

Skin,  Muscle, Bone

• Advanced infections • Cellulitis • Gangrene

• Amputation

Acute Complications Acute Complications - Hypoglycemia- Hypoglycemia

1.1. IV or Oral glucosesIV or Oral glucoses

2.2. evaluations of causeevaluations of cause (drug overdose? (drug overdose? – PO Vs Insulin– PO Vs Insulin, other cause?), other cause?)

3.3. managements?managements?

Acute ComplicationsAcute Complications- Comas- Comas

1.1. ** Hydrations ** Hydrations (ex. N/S 1 L full dropping)(ex. N/S 1 L full dropping)

2.2. ** Insulin?? ** Insulin?? (ex. N/S 500 + HR 100 IU)(ex. N/S 500 + HR 100 IU)

3.3. EEvaluations and Causes? valuations and Causes? (DKA Vs HHS) (DKA Vs HHS)

4.4. ManagementsManagements(Key points: (Key points: deficiency of deficiency of insulin)insulin)

Chronic ComplicationsChronic Complications

1)1) Diabetic microvascular Cxs. Diabetic microvascular Cxs. (retinopathy, nephropathy, (retinopathy, nephropathy, neuropathy) neuropathy)

2)2) Diabetic macrovascular Cxs. Diabetic macrovascular Cxs. (coronary, cerebral a. , foot ulcers, (coronary, cerebral a. , foot ulcers, HTN) HTN)

Glycemic control and microvascular complications

Blood pressure control and microvascular

complications

Other preventive and therapeutic measures

Follow-up and specific treatment of nephropathy

Follow-up and specific treatment of retinopathy

Glycemic control and microvascular complications

Blood pressure control and microvascular

complications

Other preventive and therapeutic measures

Follow-up and specific treatment of nephropathy

Follow-up and specific treatment of retinopathy

Prevention and treatment Prevention and treatment of microvascular of microvascular complicationscomplications

Prevention and treatment Prevention and treatment of microvascular of microvascular complicationscomplications

The Diabetes Control andThe Diabetes Control andComplications Trial (DCCT)Complications Trial (DCCT)

Multicenter, randomized study of type Multicenter, randomized study of type 1 diabetes patients1 diabetes patients

To assess effect of intensive glycemiTo assess effect of intensive glycemic control vs conventional therapy on:c control vs conventional therapy on: development and progression of retin development and progression of retinopathy and other long-term complicatiopathy and other long-term complicationsons

Results of this trial led to similar studResults of this trial led to similar studies of type 2 diabetes patientsies of type 2 diabetes patients

DCCT Research Group. N Engl J Med. 1993;329:977-986.

Overall Results of Overall Results of the DCCT Trialthe DCCT Trial

Intensive control of blood glucose reduced risk of diabetic complications

1) retinopathy onset ↓76% in patients with no retinopathy at baseline (P≤0.002)2) retinopathy progression ↓54% in patients with mild retinopathy at baseline (P≤0.002)3) nephropathy ↓54% (P<0.04)4) neuropathy ↓60% (P≤0.002)

There was, however, a 2- to 3-fold greater incidence of severe hypoglycemia

DCCT Research Group. N Engl J Med. 1993;329:977-986.

Relative Risk of Progression Relative Risk of Progression of Diabetic Complicationsof Diabetic Complications

Possible molecular Possible molecular mechanisms mechanisms

of diabetes-related of diabetes-related complications. complications.

Harrison's Principles of Internal Medicine, 16th Edn

Mechanisms of Glucose Mechanisms of Glucose Related ComplicationsRelated Complications

ReuschJEB: J ClinInvest 2003;112:986-988

Consequences of hyperglycemia-induceConsequences of hyperglycemia-induced activation of d activation of

protein kinase C (PKC)protein kinase C (PKC)

Vascular Health and Risk Management 2007:3(6):823-832

Diabetic retinopathyDiabetic retinopathy

AAnnually ophthalmic examnnually ophthalmic exam

Retinal Anatomy and Retinal Anatomy and Mechanisms of Diabetic Mechanisms of Diabetic

Retinopathy. Retinopathy.

N Engl J Med 350:48, January 1, 2004 Review Article

Diabetic retinopathyDiabetic retinopathy

실 명

Follow-up of retinopathy

No

Bckg

0

Prolif.

Pre-Prolif.

Advanced

Control commonCV risk factors

Identify and correctreversible factors

Optimal glycemic control (HbA1c < 7%)Target blood pressure (< 130/80 mm Hg)Monitor FO 12 monthlyMonitor FAG every 2 yrsPhotocaogulation only in case of macular edema

Optimal glycemic control (HbA1c < 7%)Target blood pressure (< 130/80 mm Hg)Monitor FO 12 monthlyFAG only if FO suspect

Optimal glycemic control (HbA1c < 7%) with gradual ameliorationTarget blood pressure (< 130/80 mm Hg)Monitor FO 6 monthlyFAG in preparation for photocaogulation Photocaogulation

Optimal glycemic control (HbA1c < 7%) with gradual ameliorationTarget blood pressure (< 130/80 mm Hg)Monitor FO 3-6 monthlyFAG pre- and post- photocaogulationPhotocaogulation

Optimal glycemic control (HbA1c < 7%) with gradual ameliorationTarget blood pressure (< 130/80 mm Hg)Monitor FO 3-6 monthlyFAG pre- and post- photocaogulationPhotocaogulationSurgery

Photocoagulation

focal grid

panphotocoagulation panphotocoagulation + grid

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Diabetic nephropathyDiabetic nephropathy

Annually 24hr urine proteinAnnually 24hr urine protein

Stages of Renal Involvement According Stages of Renal Involvement According to the Urinary Albumin Level in Patients to the Urinary Albumin Level in Patients

with Type 2 Diabetes Mellitus. with Type 2 Diabetes Mellitus.

N Engl J Med 346:1145, April 11, 2002 Clinical Practice

Recommended Interventions to Slow Recommended Interventions to Slow the Progression of Renal Disease the Progression of Renal Disease in Patients with Type 2 Diabetes. in Patients with Type 2 Diabetes.

N Engl J Med 346:1145, April 11, 2002 Clinical Practice

Suggested Medications for Suggested Medications for Hypertension in Patients with Type 2 Hypertension in Patients with Type 2

Diabetes. Diabetes.

N Engl J Med 346:1145, April 11, 2002 Clinical Practice

Follow-up of nephropathy

Normo

Micro

0

30 mg

300 mg

Macro & GFR

Macro &= GFR

Macro &ESRD

Control commonCV risk factors

Identify and correctreversible factors

Optimal glycemic controlTarget blood pressureControl UAE irrespective of BP with RAS blockadeMonitor UAE 6 monthlyMonitor GFR 12 monthly

Optimal glycemic control (HbA1c < 7%)Target blood pressure (< 130/80 mm Hg)Monitor UAE 12 monthlyMonitor GFR 12 monthly

Optimal glycemic controlTarget blood pressure (< 125/75 mm Hg)Control UAE irrespective of BP with RAS blockadeRestrict dietary protein (to 0.8 g/ kg bw/d) in selected casesMonitor UAE 3 monthlyMonitor GFR 6-12 monthly

Refer to renal teamOptimal glycemic control, but avoid hypoglycemiaTarget blood pressure Maintain RAS blockade, except in patients with GFR>15 ml/min Restrict dietary protein (to 0.8 or even 0.6 g/kg bw/d), but avoid malnutritionRestrict P (add binders), K & NaControl Hb with EPO & FeMonitor UAE 3 monthly Monitor GFR 3 monthly

Refer to renal teamRRT education and modality selection Access creation (no temporary)Start RRT early in diabeticsAvoid malnutritionOptimise Hb and Ca/P control

Renal replacement therapy

50

30

15

10

5

50

30

15

10

5

Options

Transplant ?No Yers

HD PD Kidney Kidney +pancreas

cadaveric living

Access

StartHD

StartPD

Waitinglist

Waitinglist

Trapianto

GFR GFR

Diabetic neurophathyDiabetic neurophathy

Every visit, foot examEvery visit, foot exam

Sensory Foot Exam Sensory Foot Exam FindingsFindings

Diabetic foot ulcersDiabetic foot ulcers

Diabetic foot ulcersDiabetic foot ulcers

Consensus guidelines: treatment planning options. Mayo Clin Proc. 2006;81[4 suppl]:S12-S25.

Monitoring Parameters for Monitoring Parameters for Control of ComplicationsControl of Complications

Every visitEvery visit Blood PressureBlood PressureFoot Exam (55% achieve goal)Foot Exam (55% achieve goal)

______________________________________________________________________________________________________________

3-6 months3-6 months A1CA1C- Every 3 months if treatment changes or - Every 3 months if treatment changes or

not meeting goals not meeting goals- Every 6 months if stable- Every 6 months if stable

_______________________________________________________ _______________________________________________________

AnnualAnnual Dilated Eye Examination (63% achieve goal)Dilated Eye Examination (63% achieve goal)Lipid Levels*Lipid Levels*MicroalbuminMicroalbumin

______________________________________________________________________________________________________________*Every 2 years if levels fall in lower risk categories*Every 2 years if levels fall in lower risk categories

Macrovascular complicationsMacrovascular complications

Coronary A. diseasesCoronary A. diseases Cerebral A. diseasesCerebral A. diseases Foot ulcersFoot ulcers HypertensionsHypertensions

Causes of Death in People with Diabetes

Causes of Death in People with Diabetes

Geiss LS, et al. In: Diabetes in America, 2nd ed. 1995. Bethesda, MD: NIH; 1995

00

1010

2020

3030

4040

5050

IschaeIschaemic mic

Heart Heart DiseaseDisease

Other Other Heart Heart

DiseaseDisease

DiabeteDiabetess

CancerCancer StrokeStroke InfectionInfection OtherOther

% deaths

Hypertension Impaired fibrinolysis

Hyperglycaemia(Insulin resistance)

Dyslipidaemia

LowHDL-C

Small, denseLDL-C

Endothelialdysfunction

Central obesity

TYPE 2 DIABETES

CVD

Proinflammatory state

Hypertriglycaeridemia

HbAHbA1c1c <7.0%<7.0%

3.5-

yr I

nci

den

ce (

%)

3.5-

yr I

nci

den

ce (

%)

Relationship Between Glycemic Control Relationship Between Glycemic Control and Coronary Heart Disease Events in and Coronary Heart Disease Events in

Type 2 Diabetes Patients (Ages 65 to 74)Type 2 Diabetes Patients (Ages 65 to 74)

Duration of Diabetes (yr)Duration of Diabetes (yr)

Kuusisto J et al. Diabetes. 1994;43:960-967.

HbAHbA1c1c 7.0%7.0%

<6<6 6600

55

1010

1515

2020

2525

Relative riskRelative riskreduction reduction (95% CI)(95% CI)

0.0090.009

0.170.17

0.010.01

0.130.13

0.170.170.020.02

0.0050.005

P ValueP Value

0.63 (0.44–0.89)0.63 (0.44–0.89)Microvascular Microvascular complicationscomplications

0.51 (0.19–1.37)0.51 (0.19–1.37)Peripheral vascular Peripheral vascular diseasedisease

0.56 (0.35–0.89)0.56 (0.35–0.89)StrokeStroke

0.82 (0.63–1.08)0.82 (0.63–1.08)All-cause mortalityAll-cause mortality

0.79 (0.59–1.07)0.79 (0.59–1.07)Myocardial infarctionMyocardial infarction

0.68 (0.49–0.94)0.68 (0.49–0.94)DM-related deathsDM-related deaths

0.76 (0.62–0.92)0.76 (0.62–0.92)

Relative risk Relative risk for tight control for tight control

(95% CI)(95% CI)

Any DM-related Any DM-related endpointendpoint

UKPDS Impact of Tight*UKPDS Impact of Tight* vs Less Tightvs Less Tight†† Blood Pressure C Blood Pressure Control on Diabetes-Related Endpointsontrol on Diabetes-Related Endpoints

0.1 1 10Favors tight

controlFavors less tight control

*n=758 (mean achieved blood pressure of 144/82 mmHg)†n=390 (mean achieved blood pressure of 154/87 mmHg)

Adapted from UKPDS Group. BMJ. 1998;317:703–713.

Relative Risk Reduction With Relative Risk Reduction With ACEIsACEIs in ABCD, CAPPP and FACETin ABCD, CAPPP and FACET

-24

-43

-63

-51

-70

-60

-50

-40

-30

-20

-10

0

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ela

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isk r

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on

Pahor M, et al. Diabetes Care. 2000;23:888-892.

Acute Myocardial Infarction

Cardiovascular Event Stroke

All-cause Mortality

P<0.001

P<0.001

P=0.01

NS

DIABETIC HYPERTENSIONDIABETIC HYPERTENSION

Combinations of two or more drugs are usually needed to achieve the target goal of <130/80 mmHg.

Thiazide diuretics, BBs, ACEIs, ARBs, and CCBs are beneficial in reducing CVD and stroke incidence in

patients with diabetes.

ACEI- or ARB-based treatments favorably affect the progression of diabetic nephropathy and reduce

albuminuria, and ARBs have been shown to reduce progression to macroalbuminuria.

The seventh Report of the Joint National Committee on Prevention, Detection, Evaluationof High Blood Pressure, May 2003

Intensive blood pressure control in diabetic patients

criteriaof

choice

hypotensiveeffect

influence onglycolipid

metabolism

protectionof targetorgans

sideeffects

Functionkidney: RPF ( Re>Ra) = GFR P proteinuria retina: capillary P; endothelial dysfunction vessels: constr. (resp. ET-1) dilat (NO)heart: myocardial function & coronary flow

Structure kidney, retina vessels & heart remodeling x cell growth & matrix production

Carbohydrate metabolism or = insulin secretion & sensitivity

= response to hypoglycemia

Lipid metabolism

or = LDL-C & TG

or = HDL-C

Intensive blood pressure control in diabetic patients

2003 ADA Clinical Practice Recommendations

Nephropathy RetinopathyCoronaric

eveltsStroke

Thiazidic diuretics Unknown Unknown Favorable (A) Favorable (A)

Loop diuretics Unknown Unknown Unknown Unknown

Central adrenergic agents Unknown Unknown Unknown Unknown

-blockers Favorable (A) Favorable (A) Favorable (A) Favorable (A)

-blockers Controversial Unknown Controversial Unknown

Ca-channel blockers (DHP) Controversial Unknown Controversial Favorable (A)

Ca-channel blockers (non-DHP) Favorable (C) Unknown Unknown Unknown

ACE-inhibitors Favorable (A) Favorable (A) Favorable (A) Favorable (A)

AT1 receptor antagonists Favorable (A) Unknown Favorable (A) Favorable (A)

Short-term studies with few patients

Effective on proteinuria (GFR ?)

Type A evidence referred to UKPDS

(low number of events)

CV events(mainly heart failure)

ALLHAT CV events(mainly coronaric)ABCD (nisoldipine)

metanalysis

(nifedipine)

Reduce GFR and doesn’t ameliorate

proteinuria(afferent arteriole

vasodilation)

Intensive blood pressure control in diabetic patients

Step 1 Low sodium diet (100 mEq/day), body weight

control, physical exercise, stop smoking

Step 1 Low sodium diet (100 mEq/day), body weight

control, physical exercise, stop smoking

Step 2 ACE-inhibitors or Ang-II

antagonists

Step 2 ACE-inhibitors or Ang-II

antagonists

Step 3 Ca-antagonist (non-DHP)Step 3 Ca-antagonist (non-DHP)

Step 4 Diuretics, -blockers or -

blockers

Step 4 Diuretics, -blockers or -

blockers

Step 5 Central adrenergic or vasodilatorsStep 5 Central adrenergic or vasodilators

Intensive blood pressure control in diabetic patients

BP target not reached

BP target not reached

other drugat low-dose

same drugat full-dose

monotheraphyat full-dose

combination

samecombinationat full-dose

other drugat low-dose

combinationof three drugsi

at full-dose

one drugat low-dose

two drugsat low-dose

Arterial hypertensionuntreated BP levelother risk factors

target organ damage

Intensive blood pressure control in diabetic patients

diureticis

-blockers

-blockers

CCBs

AT1RB

ACEi

Antiplatelet therapy

aspirin (tablets)81–325 mg/day

Primary prevention

DM1 and DM2 patients >30 years with high CV risk

CAD family history Smoking Hypertension Obesity (>120% BMI); BMI >27.8

kg/m2 M or >27.3 kg/m2 F Dislipidemia: TC >190 mg/dl; LDL-C

>100 mg/dl; HDL-C <45 mg/dl M or <55 mg/dl F; TG >150 mg/dl

Albuminuria (micro or macro)

Secondary prevention

DM1 and DM2 patients with clinical

history of cardiovascular disease

myocardial infarction or angina Stroke or TIA Peripheral vascular disease By-pass surgery

Contraindications

Allergy

Bleeding tendency

Anticoagulating treatment

Recent gastro-intestinal bleeding

Clinically active liver disease

Age <21 years ( Reye’s syndrome)

clopidogrelticlopidine

Reduce macrovascular complicaReduce macrovascular complicationstions

Good glycaemic controlGood glycaemic control LDL-Cholesterol <100 mg/dL (Statins)LDL-Cholesterol <100 mg/dL (Statins) BP <130/80 mm Hg (ACE inhibitors)BP <130/80 mm Hg (ACE inhibitors) Weight loss ~5% to 10% body weightWeight loss ~5% to 10% body weight AspirinAspirin No SmokingNo Smoking Realistic exerciseRealistic exercise

Key message Key message of Diabetic complications of Diabetic complications

IIntensive glucose controlntensive glucose control Restrictive BP control by using ACEIsRestrictive BP control by using ACEIs

(<130/80) (<130/80) SStop smokingtop smoking CControl dyslipidemiaontrol dyslipidemia EExams xams

(foot, OPH, Lab (foot, OPH, Lab …)…) AspirinsAspirins