SMBG: Self Monitoring of Blood Glucose

In existing type 2 diabetes, how can patients adapt their lifestyle to lower the risks of complications?

No Control
Age (yr) Sex (% male) Diabetes Duration (yr) BMI (kg/m2) FBG (mM) HbA1c (%) 56.3 + 1.1 59 12.7 + 0.1 27.0 + 0.5 10.8 + 0.5 8.2 + 0.3

SMUG
54.9 + 1.2 72 13.3 + 0.8 26.0 + 0.4 10.8 + 0.4 8.6 + 0.3

SMBG
54.5 + 1.3 53 12.2 + 0.8 27.1 + 0.5 10.7 + 0.4 8.2 + 0.3

Fontbonne, Diab Metab 15: 255-260, 1989

250 Patients with Type 2 Diabetes

BMI > 25 kg/m2 HbA1c > 7,5 and < 10% no previous insulin therapy age 45-70 years Type 2 diabetes > 3 months participation in diabetes education program within the previous 2 years capable of maintaining an eating diary and of documenting thier state of well being no previous SMBG during past 6 months

223 included in per-protocol analysis

Control (n = 478)

SMBG (n = 510)

Schwedes, Diabetes Care 25: 1928-1932, 2002

 visits every 4 weeks nonstandardised counseling with focus on diet and lifestyle Patient Wellbeing Questionare Diabetes Satisfaction Questionare

Run 4 4 4 4 4 4 in weeks weeks weeks weeks weeks weeks 6 weeks

6 months follow-up

24 weeks

HbA1c, weight , questionares Intervention in SMBG group at least 6 capillary assays on 2 different days of a week (on Sunday) recording blood glucose values combined with eating habits information about adjustment of diet and lifestyle based on SMBG Schwedes, Diabetes Care 25: 1928-1932, 2002

Control 0.54%
p= 0.0086

SMBG 1.0%

Schwedes, Diabetes Care 25: 1928-1932, 2002

Control SMBG

Schwedes, Diabetes Care 25: 1928-1932, 2002

SMBG as an integral part of the diabetes therapy

SMBG

no SMBG
Increased awareness of disease, concern about complications

+
+

Patient adjusts daily routine according to BG values

More therapy adjustments

+
+

More training/counselling by physician

More attention from physician

First step: Do several blood glucose profiles within one week

Date

Before breakfast

1 -2 h after breakfast

Before lunch

1 -2 h after Lunch

before dinner

1 -2 h after dinner

before sleep

Second step: Visualise BG profiles to understand them

300 250 200 150 100 50
Before breakfast 1 -2 h after breakfast Before lunch 1 -2 h after lunch Before dinner 1 -2 h after dinner Before sleep

Third step: Modify lifestyle and determine effect on BG

Before and 1.5-2 h after good/bad meal or drink Before and after physical activity Impact of 15 min walk before a meal Impact of evening walk on fasting BG in the morning

Fourth step: Maintenance by individual measurements per day and BG profiles from time to time (more tests if insulin treated, less intense if oral drugs or diet)

Please note: SMBG is effective also in patients on diet only

Therapeutical Strategies in Diabetes mellitus Type 2

HbA1c (%) 10 HbA1c (%)

female, born 1939 164 cm

10

male, born 1958 180 cm

4
Dec 04 Mar 05 Jun 05 Sep 05

4
Mar 05 Apr 05 May 05 Jun 05

SMBG versus Controls

Welschen, Diabetes Care 28: 1510-1517, 2005

89 Patients with Type 2 Diabetes

currently enrolled or on entrance into the Diabetes Management Care Program Type 2 diabetes > 3 months participation in diabetes education program within the previous 2 years not taking insulin capable of maintaining an eating diary and of documenting thier state of well being no previous SMBG during past 6 months

1 lost of follow up

88 included in per-protocol analysis

Control (n = 45)
Davidson, Am J Med 118: 422-425, 2005

SMBG (n = 43)

 diatary councelling at visits every 2-4 weeks specific treatment algorithm FBG every 2 weeks

2 2 weeks weeks 6 weeks

4 weeks

4 weeks

3 months

6 months

HbA1c

HbA1c

HbA1c

HbA1c

Intervention in SMBG group at least 6 capillary assays on 6 days of a week recording what they ate

Davidson, Am J Med 118: 422-425, 2005

Treatment Algorithm
1st Goal:
Fasting Plasma Glucose (measured every 2 weeks) < 130 mg/dl
Stepwise increase of metformin or SU every 2 weeks until maximum dose

Second drug was added with subsequent stepwise increase every 2 weeks

2nd Goal:
HbA1c (Measured every 2 months) < 7.5 %
Add maximal dose of thiazolidinedione

Stop of thiazolidinedione and bedtime NPH insulin

Control
Age (yr) Sex (% male) BMI (kg/m2) Diabetes Duration (yr) Use of OAD (%) HbA1c (%) 49.8 + 11.2 33 31.7 + 6.7 5.5 + 4.7 96 8.4 + 2.1

SMBG
50.9 + 11.0 21 33.4 + 7.0 5.8 + 5.8 100 8.5 + 2.2

Davidson, Am J Med 118: 422-425, 2005

80 70 60
% Patients

50 40 30 20 10 0
before after before after

Control SMBG

Metformin and/or SU

Triple OAD or Insulin

Davidson, Am J Med 118: 422-425, 2005

p = 0.58

p = 0.56

Change of HbA1c (%) or weight (kg)

-0.1 -0.2 -0.3 -0.4 -0.5 -0.6 -0.7 -0.8

Control SMBG

HbA1c

Weight

Davidson, Am J Med 118: 422-425, 2005

Arterial glucose level Highest Venous glucose level Lowest Capillary glucose level (4-30%) higher than venous

Plasma glucose: Whole blood glucose {1,0-(0,0024 x Hct)} Table Whole BG Plasma G at different HCT levels

HCT 25 35 45 55 65

Whole BG 100 100 100 100 100

Plasma Glucose 106,4 109,2 112,1 115,2 118,5

Condition that affect hematocrit

Lower: Pregnancy Cancer AIDS Anemia Hemorraghe Fluid infusion Dialysis Raise: - Polycythemia - Dehydration

Substances interfered meter accuracy: Uric acid Glutathione Ascorbic acid Contamination or insufficiency of the blood sample (unwashed hand, unclean test strips or meters) decrease accuracy meter readings The clinician must take note of the meters operating range for Hct level

CHRONIC COMPLICATION Of DIABETES MELLITUS

Effects of Elevated Glucose

Non Enzymatic glycosylation Aldose Reductase activity DAG & B2 PKC activity

AGE receptors & Structural proteins

Sorbitol Myoinositol Na+/K+ ATP ase

Sorbitol Myoinositol Na+/K+ ATP ase

STRUCTURAL CHANGES Changes in the Vessel Of the eye, (+) Hemorraghe Retinopathy

Nerve Damage

Intraglomerular pressure Mesangial cell proliferation Nephropathy

Neuropathy

DAG: Diacylglycerol PKC: Proteinkinase AGE: Anvantage Glycosylated End product

Myoinositol Aldose reductase Na-K ATPase result Na retention, cell swelling, osmotic regulation , changes in cell function Glycosilation of protein Glucose 1-Amino-1-deoxyketose Aminoguanidine Glycosylation End product deposisition of protein in the basement membrane, increase vascular cell proliferation and permeability AGEP also destroy endothelial derived Nitric Oxide Protein Kinase Activity Glucose Diacylglycerol PKC activation altergen transcription of subtances deposit in the endothelial cells and the nerve and activates cytokines

THE POLYOL PATHWAY Glucose Sorbitol

Diabetic Retinopathy
Important: blindness 20-74 years age 20 times in DM comparison with non DM Manifestations: blurring vision, darkened or distorted vision, floaters vision field until loss of vision Type 1DM > type 2 DM Patient with Diagnosed DM after 30 years age < younger when diagnosed DM Increased severity & incidence of DM retinopathy associated with poorer glucose control

Risk factor of retinopathy

Elevated blood glucose Age Duration of DM Hypertension Dyslipidemia Glucose +sorbitol + formation AGEP,s + activity PKC vascular permeability & thickening basement membrane of retinal capillaries vascular occlusion & microaneurysms Response decreased perfusion a.v.shunt proliferation endothelial cells Hemorraghe into inner retinal dot shape Bleeding in superficial layer flame shape Leakage of proteins & lipids from damaged capillaries exudat

Classification of DM retinopathy
I. Nonproliferative Diabetic Retinopathy Microaneurysma only Mid/moderate nonproliferative Severe nonproliverative Very severe nonproliverative

II. Proliferative Diabetic Retinopathy Mild/moderate proliferative retinopathy High risk proliferative Presence 3 of 4 of the following: - pressence new vessel in the eye - presence of new vessel on/near of optic disc - moderate or severe new vessel (>1/4 disc area) - Vitreous Hemorraghes
III. IRMA (Intra Retinal Microvascular Abnormalities)

Nonproliferative: earliestclinical manifestasion, has no effect visual aquity, but edema macula & vitreus hemorraghes decrease visual aquity Proliferative: more severe new vessel, fibrous proliferation and pre retinal and vitreous hemorraghes if no treatment blindness ADA recommendation comprehensive eye examination by opthalmologist shortly after diagnosis DM Pregnant women + DM must be examination the first trimester accelerate changes in vascular permeability in the retina

Management Retinopathy DM
Glycemic control (UKPDS 6, 9 years risk reduction 17% retinopathy DM) Blood pressure control (beta blockers & ACE inhibitors) Antiplatelet treatment (aspirin, dipyridamol & ticlodipin) Laser photocoagulation Vitrectomy Refferal to opthalmologist as soon as Dx

Diabetic Nephropathy
RISK FACTOR: Insulin resistance Hypertension Glycosylated Hemoglobin Cholesterol Smoking Advance age High protein diet Male Microalbuminuria

History of Nephropathy
Stage I: Hyperglycemia vasodilatation & GFR Kidney enlarged Stage II: silent phase Stage III: microalbuminuria important 30-299mg/day, base membrane thickened parenchymal damage Hypertension without interfentin specific 20-40% overt nephropt Stage IV: overt nephropathy >300mg/day urinary albumin, GFR treatment in this stage only slow down the rate of decline function and delay the need for renal replacement therapy Stage V: ESRD by 20 years onset nephropathy 20% will have progressed to ESRD

Screening for Nephropathy

Test for Microalbuminuria YES (+) microalbuminuria NO (-) microalbuminuria

Check for infection Congestive Heart Failure Marked Hypertension Hematuria YES Repeat test twice In/or 3-6 months

NO

NO
NO 2 or 3 positif YES Start treatment for Microalbuminuria Repeat sreening for micro Albuminuria Annually

DEFINITION OF ALBUMIN SECRETION

Normal <30 <30 <30 Microalb 30-299 30-299 20-199 Macroalb >300 >300 >200

Spot collect (Ug/mg) 24hr collect (mg/24hr) Timed Collect (ug/mg)

Albumin excretion not measure:

After exercise During ketoacidosis UTI Fever CHF Marked Hypertension Hematuria ADA recommendation to yearly screening in type 2 DM

MANAGEMENT OF ND
Glycemic control (UKPDS 9,12, 15 year risk reduction 24%, 33%, 30% microalb) Blood Pressure Control (Aggressive slow progression of ND): Life style (weight loss, salt reduction, alcohol, exercise ACE inhibitors and ARBs

ALGORITHM ON MICROALBUMINURIA TREATMENT IN TYPE 2 DM PATIENT

(+) Microalbuminuria YES

Glycemic control Adequate?

NO

Check & manage Risk Factor

Start ACE

Continous Aggressive Management of Glucose Control

Adverse Effect?

Discontinue, shift to other Antihypertensive Medication

Repeat Albumin / Creatinin Every 3-6 months Goal

Stable GFR or Declining Mean Arterial Pressure BP < 120-130 / 80-85 mmHg

Use Antihypertensive Agent

Captopril prevent deterioration of renal function serum creatinin reduce 48% Enalapril offers long term reno-protection Losartan reduce risk ESRD by 28%, creatinin reduce 25%, delay need for dialysis 2 years Irbesartan reduce progression albuminuria and dimished the decline of GFR
PROTEIN RESTRICTION: Decrease glomerular perfusion rates and albuminuria Non pregnant DM limit their intake o,8 g/KG BW

REFFERAL to Nephrologist
GFR < 60mL/173 m2 GFR= ClCr (mL/min) = {[(140-age)xweight(kg)]/[72xser Creat(mg/dL)]} x 0,85 in woman Difficulty occur in the manage of Hypertension and Hyperkalemia and Patient has other concomitant diseases that could further aggravate the renal problems

DIABETIC NEUROPATHY
Slow Progression Prediction of earlyinvolvement of the longer axon The symptom begin in the feet Related with duration of DM

History
Loss of the myelin AGEs + sorbitol + PKC Damages perineural cappilaris altered function of the nerve first sensory fibres followed by motoric fibres

Damage on small fibres feel pain, loss of thermal sensation, reduced light touch & prick sensation Damage on largest fibres reduce fibration & position sense, weakness, muscle wasting, tendon reflex Risk factor: 4400 patients, following 25 years highest in DM with poored glucose control A1c correlation positive with neuropathy Hypertension, LDL , HDL , correlation with autonomyc neuropathy. Smoking habits neuropathy DM

Classification
Rapidly reversible
Hyperglycemic Neuropathies

Persistent Symmetrical Polyneuropathies

Distal Somatic Sensorimotor Autonomic Small fibres

Focal Neuropathies
Cranial Thoracoabdominal radiculopathies Focal Limbs Amyotrophy Compression/Entrapment

Mixed Form

Distal Somatic Sensorimotor muscle weakness of lower extremities, loss position sense, glove and stocking reduce pain & thermal sensation Focal/Mono neuropathies Bells Palsy, limbs are common acute onset, gradually improve, resolve without treatment Diabetic Autonomic Neuropathy (DAN) Posrural hypotension, gastric symptoms Cardiovascular autonomic Neuropathy (CAN) abnormal heart rate and rhythm Stroke, AMI, Sudden Death (5yrs MR 5x without CAN)

Clinical manifestation CAN

Response HR & BP during exercise Orthostatic Hypotension Silent Myocardial Ischemia Suddent Death Other autonomic Neuropathy Gastrointestinal Bladder dysfunction Erectile dysfunction Sweating abnormalities (esp. feet)

Screening & detection ND

Symptom profile Neurologic examination Quantitative sensory testing (QST) Nerve conduction Studies Quantitative autonomic function test/QAFT TEST: Resting heart rate, ECG, Valsava manuver, Heart rate response to standing, Systolic BP response to standing, Diastolic BP rise with exercise, QT interval on ECG Gastrointestinal, Bladder, Erectile, Sudomotor (sweating)

Drug preventing ND
Aldose Reductase inhibitor (Sorbinol, Zenarestat) Alpha-lipoic Acid Gamma-linoleic Acid Nerve Growth Factor Ganglioside Antiinflammatory and/or autoimmune Tx Myoinositol

Drugs for treatment of symptom

Pain (Capsaicin) Gastroparesis (Erythromycin, Metocloperamide) Erectile dysfunction (Sildenafil, Tadalafil, Vardenafil) Eat healthy, fruit & vegetables and to limit alcohol, No smoking Postural hypotension may use body stocking, more fluid and salt intake Gastric problems, multiple small feeding, reduce fat intake, if diarrhea: tetracycline, cotrimoxazole, metronidazole

MANAGEMENT ND
Control blood glucose level Drug therapy to prevent or reverse condition Alleviation of distressing symptoms such as pain

MACROVASCULAR COMPLICATION
Atherosclerosis (Endothelial Dysfunction) Endothelial damage platetlet adhere thromboxanes + oxydation of LDL local inflammatory response accumulation of WBCs, smooth muscle proliferation & increased fibres atherosclerotic plaque Manifestation Cardiovascular Disease Peripheral Vascular Disease Cerebrovascular Disease

Pathway ENDOTHELIAL Dysfunct.

Hyperglycemia

Polyole pathway

Diacyl Glycerol (DAG) Positive effect

Advanced glycosilation End Product (AGE)

NADPH

Protein Kinase C

Oxidized LDL

Regeneration of Oxidation (ROS)

NO synthesized Endothelin

Glutathion Tocopherol

Ascorbate

Cardiovascular Risk Factor in DM

Hypertension Smoking Family history of heart disease at early age (<60 years) Dyslipidemia: Cholesterol >200 mg/dL LDL <130 mg/dL HDL >40 mg/dL Triglyserides >200 mg/dL Obesity

Clinical manifestation of CAD

Angina Pectoris Myocardial Infarction

Screening for CAD:

ECG Evaluation of Lipids Chest X Ray (cardiomegaly) Microalbuminuria (independent predictor)

Management of CAD
Glycemic control Blood Pressure control Lipid control Antiplatelet Therapy (aspirin, dipyridamole, sulfipyrazole)

Peripheral Vascular Disease

Occlusion PVD 15-20% of people 70 years old Increased in hypertension, dyslipidemia, DM and smokers Clinical manifestation PVD: Depending location Portion of blocked (if blocked pain, numbness,change in color) Extend of narrowing vessel Intermitten claudicatio, cramp in muscles

Screening PVD
Age >60 years Smokers > 10 years Type 2 DM Hypertension Obesity Hypercholesterolemia Inactive and bedridden Family history of heart attack or stroke Family history of aortic aneurysm

Ankle Brachial Index

Right ABI: Right Ankle Pressure Higher Right Arm Pressure

Left ABI:

Left Ankle Pressure Higher Left Arm Pressure

Severity of Disease Based on ABI value

ABI value Indication Risk of Mortality < 1.30 Non compressible 0% 0,91-130 Normal 0% 0,41-090 Mid to Moderate 15-20% in PAD 0,85-0,90 50% in <0,85 0,00-0,40 Severe Disease 70%

Management PVD
Smoking cessation Lipid control Glycemic control BP control Exercise Antiplatelet agents (aspirin, cilostazol, naftidofuryl) Revascularization

CEREBROVASCULAR disorders
Atherosclerotic plaque ruptur Hemorrhage from aneurysms RISK FACTOR Hipertension Cholesterol > 200 mg/dL Smoking Atrial Fibrillation

Classification of ischemic stroke

Thrombosis A. Atherosclerosis B. Arteritis C. Dissectin Carotid D. Hematologic Disorder Embolism A. Atherothrombotic B. Cardiac source
a. structural heart disease b. dysrhythmia c. infection

E. Cerebral mass
F. Miscellaneus

C. Unknown Source
a. healthy child or adult b. Associations: Carcinoma, eclampsia, contraception lupus etc.

Early symptom of Stroke

Sudden weakness or paralisys one side Severe headache Loss of balance and coordination fall Numbness on one side of the body Slurring of speech (dysartria) Monocular loss of vision MANAGEMENT of Stroke: Neurologist

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