Lecture DM dr Bowo Pramono.ppt

R. Bowo PramonoR. Bowo Pramono

Endocrinology Subdivision of Endocrinology Subdivision of

Internal Medicine DepartmentInternal Medicine Department

Faculty of MedicineFaculty of Medicine

Gadjah Mada UniversityGadjah Mada University

YOGYAKARTAYOGYAKARTA

Recent Update Diabetes Mellitus Recent Update Diabetes Mellitus ManagementManagement

Definition and Description of Diabetes Mellitus

• DM is a group of metabolic diseases characterized by hyperglycemia resulting from defects in insulin secretion, insulin action, or both.

• The chronic hyperglycemia of diabetes is associated with long-term damage, dysfunction, and failure of various organs, especially the eyes, kidneys, nerves, heart, and blood vessels.

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By 2030, By 2030, 7 of the 107 of the 10 Countries with the Countries with the Most Diabetic Patients Will Be in AsiaMost Diabetic Patients Will Be in Asia

IndiaChinaUSAIndonesiaPakistanBrazilBangladeshJapanPhilippinesEgypt

Country

2030

79.442.330.321.313.911.311.18.97.86.7

People with diabetes (millions)

IndiaChinaUSAIndonesiaJapanPakistanRussian Fed.BrazilItalyBangladesh

Country

2000

31.720.817.78.46.85.24.64.64.33.2

People with diabetes (millions)

12345678910

Ranking

Wild S et al. Diabetes Care 2004;27(5):1047-53.

EPIDEMIOLOGY

WHO Estimation: Indonesia have people with DM (2030):

Rural : 7,2 % from adult (>20 years old)• Urban: 14,7 % from adult

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Type 1 diabetesType 1 diabetes, , ββ--cell destruction, usually cell destruction, usually leading leading

to absolute insulin deficiencyto absolute insulin deficiency

Immune mediated or idiopathicImmune mediated or idiopathic

Type 2 diabetes mellitus - 90%Type 2 diabetes mellitus - 90%

Other specific types, Other specific types, drug induced, endocrino-drug induced, endocrino-

pathies, disease of the exogen pancreas, epathies, disease of the exogen pancreas, etctc

Diabetes mellitus gestationalDiabetes mellitus gestationalDiabetes Care. 1997; 20: 1183 - 1197 Diabetes Care. 1997; 20: 1183 - 1197

CLASSIFICATION OF CLASSIFICATION OF DIABETES DIABETES MELLITUSMELLITUS

Multiple Factors Contribute to T2DM

1. Bode BW. Postgrad Med. 2009;121:82-93.2. DeFronzo RA. Ann Intern Med. 1999;131:281-303.3. DeFronzo RA. Diabetes. 2009;58:773-795.

Decreased

glucose uptake

Progressive -cell

dysfunction

Hepatic glucose production

Lack of α cells

glucagon suppression

Impaired incretin signaling

Increased renal

glucose transport

Type 2 Diabetes

Increased lipolysis

Hungry & stressHungry & stress

βcell dysfunction

Insulin resistance

Type 2 diabetes

DeFronzo et al. Diabetes Care 1992;15:318-68DeFronzo et al. Diabetes Care 1992;15:318-68

Diabetes mellitus is a group of metabolic Diabetes mellitus is a group of metabolic diseases characterized by hyperglycemia diseases characterized by hyperglycemia

resulting fromresulting from defect of insulin action, defect of insulin action, insulin secretion or bothinsulin secretion or both

PATHOGENESIS OF TYPE 2 DIABETESPATHOGENESIS OF TYPE 2 DIABETES

CRITERIA FOR THE DIAGNOSIS OF CRITERIA FOR THE DIAGNOSIS OF DIABETES MELLITUSDIABETES MELLITUS

1. 1. Symptoms of diabetes Symptoms of diabetes Casual plasma glucose concentration > Casual plasma glucose concentration > 200 200 mg/dlmg/dl

or or 2. 2. Fasting plasma glucose Fasting plasma glucose >> 126 mg/dl. 126 mg/dl. FPG, no caloric intake for at least 8 hourFPG, no caloric intake for at least 8 hourss

oror 3. 3. 2-h post-OGTT 2-h post-OGTT >> 200 mg/dl 200 mg/dl 75 gram glucose dissolved in water75 gram glucose dissolved in water

Natural History of Type 2 Diabetes

IR phenotypeAtherosclerosisobesityhypertensionHDL,TG,HYPERINSULINEMIAEndothelial dysfunctionPCO,ED

Envir.+ Other Disease

Obesity (visceral)Poor Diet Inactivity

Insulin Resistance

Risk of Dev. Complications

ETOHBPSmoking

EyeNerveKidney

Beta Cell Secretion

Genes

BlindnessAmputationCRF

Disability

Disability

MICVAAmp

Age 0-15 15-40+ 15-50+25-70+

Macrovascular Complications

IGT/IFG Type II DM

Microvascular Complications

DEATHFBS>5.5,ppg>7.8

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Type 2 diabetes is NOT a mild disease

DiabeticRetinopathyLeading causeof blindnessin working ageadults1

DiabeticNephropathyLeading cause of end-stage renal disease2

CardiovascularDisease

Stroke2 to 4 fold increase in cardiovascular mortality and stroke3

DiabeticNeuropathyLeading cause of non-traumatic lower extremity amputations5

8/10 diabetic patients die from CV events4

1 Fong DS, et al. Diabetes Care 2003; 26 (Suppl. 1):S99–S102. 2Molitch ME, et al. Diabetes Care 2003; 26 (Suppl. 1):S94–S98. 3 Kannel WB, et al. Am Heart J 1990; 120:672–676. 4Gray RP & Yudkin JS. In Textbook of Diabetes 1997.

5Mayfield JA, et al. Diabetes Care 2003; 26 (Suppl. 1):S78–S79.

Target on Management of DM

• A : HbA1c• B : Blood Pressure• C : Ch0lesterol

PERKENI 2011

04/17/23 Page 14

ADA/EASD: Metabolic Management of Type 2 Diabetes

Nathan DM et al. Diabetes Care 2009; 32(1) : 194-203

* Check HbA1c every 3 months until HbA1c <7%, and then at least every 6 months.** Preferred based on effectiveness and expense.

Add basal insulin(most effective)

Add sulfonylurea(least expensive)

Add TZD(no hypoglycemia)

If HbA1c> 7%*

Add basal or intensify insulin

Add TZDIntensify insulin**

Add basal insulin**

Add sulfonylurea

Intensive insulin + metformin +/- TZD

If HbA1c > 7%

If HbA1c > 7%

ADA/EASD CONCENSUS…Lifestyle intervention and metformin

Nathan DM et al. Diabetes Care 2009; 32(1) : 194-203

•Monotherapy•Metformin•Pioglitazone•GLP-1 agonist•DPP-4 Inhibitor•(or AGI)

Dual Combination• Metformin• Pioglitazone• GLP-1 agonist• DPP-4 Inhibitor(or AGI / secretagogue /

colesevelam)

AGI = alpha glucosidase inhibitor

Triple Combination• Metformin• Pioglitazone• GLP-1 agonist• DPP-4 Inhibitor(or AGI / secretagogue /

colesevelam)

Insulin*• +/- Other

agents*Insulin analogsNot NPH/regular If over 9.0% or above

and symptomaticIf triple combo fails

6.5% 7.5% 9.0 HbA1c Continuum – if not at goal, advance Rx 12%

Asymptomatic

Symptomatic

Principles of the AACE Guidelines / A1C Goal less than or equal to 6.5%

1. Minimize risk/severity of Hypoglycemia 5. Lifestyle Modification Essential and NO SMOKING

2. Minimize risk/severity of Weight gain6. Combination frequently required; Complimentary mechanisms of action

3. Fast therapeutic changes (2-3 months, earlier even better)

7. When using insulin, add an insulin-sensitizing agent if possible

4. Address fasting and postprandial glucose 8. Cost is important but, safety and efficacy trump cost

Therapeutic Choice Should Match The Drug With Patient CharacteristicsDiet and Exercise

Provided by Dr. Stanley S. Schwartz.

Therapeutic Strategies for Improving B-cell function, treating Prediabetes, PPG, DM

Central dec. Dopasym.tone,inc HGP, PPG Fast-acting bromocryptine

Correlation between HbA1c level and mean plasma glucosa levels on multiple testing

over 2-3 months

HbA1c Mean plasma glucose (mg/dL)

6 135

7 170

8 205

9 240

10 275

11 310

12 345

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Management of Diabetes Mellitus

• Education (what, why, how to manage)• Diet (BMI, schedule, kind of fo food, amount)• Exercise (30’, CRIPE)• Farmakologi • SMBG (Self Monitor/Management Blood

Glucose)

MetforminMetformin

How it works • Decreases hepatic glucose output • Lowers fasting glycemia

Expected HbA1c reduction

~ 1.5%

Adverse events • GI side effects• Lactic acidosis (quite rare)

Weight effects Weight stability or modest weight loss

CV effects Unconfirmed beneficial effect demonstrated in UKPDS

Nathan DM et al. Diabetes Care 2006;29(8):1963-72.

SulfonylureasSulfonylureas

How they work Enhance insulin secretion


~ 1.5%

Adverse events Hypoglycemia (but severe episodes are infrequent)

Weight effects ~ 2 kg weight gain common when therapy initiated

CV effects UGDP suggested potential cause of increased CVD mortality; not substantiated by UKPDS


INCREASED INSULIN SECRETIONSulfonylurea Length of

actionBegins ofaction

Daily dose(mg)

Route of excretion

Glibenclamide 16 – 24h 2 – 4h 1,25 – 15 R = 50%, B = 50%

Gliclazide 10 – 24h 2 – 4h 40 – 320 R = 70%, B = 30%

Glipizide 6 – 24h 2 – 4h 2,5 – 40 R = 80%, B =20%

Chlorpramide 24 – 72h 2 – 4h 100 – 500 Renal

Tolbutamide 6 – 10h 2 – 4h 100 – 1000 Renal

Glimepiride 24h 2 – 4h 1 - 6 R = 40%, B =60%

gliquidon 18 - 24h 2 - 4h 30 - 120 R = 5%, B = 95%

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GlinidesGlinidesHow they work Stimulate insulin secretion (but

differently from sulfonylureas)


~ 1.5% (repaglinide)

Adverse events Hypoglycemia (may be less frequent than some sulfonylureas)

Weight effects ~ 2 kg weight gain common when therapy initiated

CV effects None mentioned in ADA recommendations


Dipeptidyl Peptidase IV InhibitorsDipeptidyl Peptidase IV Inhibitors

How they work Inhibit degradation of endogenous GLP-1


~0.8%

Adverse events Minimal

Weight effects Neutral

CV effects Unknown


-Glucosidase Inhibitors-Glucosidase Inhibitors

How they work ↓ rate of digestion of polysaccharides in proximal small intestine (primarily lowering PPG levels without causing hypoglycemia)


0.5–0.8%

Adverse events • Increased gas production

• GI symptoms

Weight effects Weight neutral

CV effects Unconfirmed report of reduction of severe outcomes in one clinical trial


ThiazolidinedionesThiazolidinediones

How they work Increase sensitivity of muscle, fat, and liver to endogenous and exogenous insulin


0.5–1.4%

Adverse events Weight gain and fluid retention

Weight effects • Increase in subcutaneous adiposity• Redistribution from visceral deposits

CV effects • New / worsened CHF or peripheral edema (due to fluid retention)

• Reduction in some secondary CV endpoints demonstrated in PROactive study


Glucagon-like Peptide 1 AgonistGlucagon-like Peptide 1 Agonist (exenatide)(exenatide)

How it works Stimulates insulin secretion

Expected HbA1c

reduction

0.5–1%

Adverse events GI side effects (nausea, vomiting, diarrhea)

Weight effects Weight loss of ~ 2–3 kg over 6 months (may be result of GI effects)



Dipeptidyl Peptidase IV InhibitorsDipeptidyl Peptidase IV Inhibitors

How they work Inhibit degradation of endogenous GLP-1


~0.8%

Adverse events Minimal

Weight effects Neutral

CV effects Unknown


Amylin Agonists (pramlintide)Amylin Agonists (pramlintide)

How it works Synthetic amylin analogue that inhibits glucagon production in a glucose-dependant fashion


0.5–0.7%

Adverse events GI effects (nausea)

Weight effects Weight loss ~ 1–1.5 kg over 6 months (may be due to GI effects)



Years From Diagnosis

T2 DMphase I

T2 DMphase II

Stages of Type 2 Stages of Type 2 DiabetesDiabetes

Lebovitz, 2000

T2 DM phase III

-12 -10 -6 -2 0 2 6 10 14

100

75

50

25

0

Beta CellFunction

(%)IGT Postpandrial

Hiperglycemi T-2 DM phase IBeta Cell function 50 %

30

InsulinInsulin

How it works Direct compensation for lack of insulin sensitivity


1.5–2.5%

Adverse events Hypoglycemia

Weight effects Weight gain of ~ 2–4 kg

CV effects • Beneficial effect on TG and HDL• Weight gain may have an adverse effect on CV risks


Effectiveness of Type 2 Diabetes Therapy

Diet & Exercise

Diet & Exercise

1% 1% <7%

TZDAlpha-glucosidase

Inhibitors

TZDAlpha-glucosidase

Inhibitors

Metformin Insulin

Secretagogues

Metformin Insulin

Secretagogues

1.5-2% 1.5-2%

1-1.5% 1-1.5%

<8%

CombinationOral

Agents

CombinationOral

Agents 3-4% 3-4% <8-10%

InsulinInsulin 5% or more 5% or more >10%

Starting HbA1c

Acute complications(Emergency on DM)

• Medical emergencies, complications are these spark medical emergencies requiring immediate attention.

• This include low blood sugar, high blood sugar and excessive blood acids.

Symptoms

Adrenergic symptoms (catecholamine mediated): diaphoresis, palpitations, pallor, tachycardia apprehension, anxiety, sensation of hunger headache, weakness, restlessness

Neuroglycopenic symptoms: reduced intellectual capacity, irritability, confusion, abnormal behavior, convulsion, coma

Physiologic response in hypoglycemia

• Blood glucose 56-48 mg/dl * adrenalin secretion * diaphoresis, tremor * reduced function of central nervous system • Blood glucose <48-36 mg/dl * reduced consciousness • Blood glucose <36-18 mg/dl * coma, convulsion• Blood glucose <18 mg/dl * permanent brain damage

Risk factors

• Tight glycemic control• Age• Duration of diabetes• History of hypoglycemia• Sleeping• Alcoholism• Fasting• Increased insulin sensitivity: fitness, body weight• Clearance/metabolism of drugs: renal or hepatic

insufficiency

Mechanisms by which drugs increase the hypoglycemic effect of sulfonilureas

• Increase in half-life due to inhibition of metabolism or excretion rate:

ethanol, phenylbutazone, coumarin anticoagulants, chloramphenicol, doxycycline, sulfonamides, allopurinol

• Competition for albumin-binding sites: phenylbutazone, salicylates, sulfonamides

• Inhibition of gluconeogenesis, increase in glucose oxidation, or stimulation of insulin secretion:

ethanol, ß-adrenergic drugs, monoamine oxidase inhibitors, tranylcypromine,

Management of hypoglycemia

• Mild hypoglycemia when self treatment with oral carbohydrate suffices

• Sever hypoglycemia when external help is required to effect recovery

Management of hypoglycemia: Prevention

1. Early familiarization with the symptoms of hypoglycemia2. Do reviewing at intervals3. Explain the relationship between insulin administration,

timing of meals, and exercise4. Explain methods of self-treating hypoglycemia5. Choose appropriate insulin regimens, dose schedules with

appropriate therapeutic goals

Management of hypoglycemia: Treatment

• Mild hypoglycemia: oral glucose 15-20 g, wait 10-15 min then check blood glucose. If glucose level does not increase ≥18 mg/dl, give oral glucose again

• Severe hypoglycemia: solution 50 ml of dextrose 50% given intravenously, check blood glucose in 20 min. If it is still hypoglycemia administrate once again

• Glucagon 1.0 mg s.c/i.m/i.v. adverse effects include nausea, vomiting, and headache. Contraindicated to sulfonylureas-induced hypoglycemia. Ineffective in patient who is anorectic, or with protracted hypoglycemia

PATOFISIOLOGI KAD & HHS

Sign & symptom of DKA

• Deep, rapid breathing• Sweet, fruity smell on breath• Loss of appetite• Nausea • Vomiting• Fever• Stomach pain• Weight loss

• Fatigue• Weakness• Confusion• Drowsiness

Clinical presentation

• Lost more than 5% body weight• More than 35 breaths a minute• Can’t control blood sugar• Become confused• Nausea and vomiting

What should you do?

• Check ketones if feeling especially stressed or blood sugar persistently above 240mg/dL

• High ketones in blood ketones excreted in urine.

• High ketones in urine must treatment & stay in hospital

• DKA can lead into coma and posibly death.

Treatment

• Replenishing lost fluids through i.v. line• Insulin combined with glucose, injected into iv

stop making ketones• Gradually blood sugar level back to normal, if

quickly can produce swelling in the Brain

HHS

• Blood sugar reaches such a high level that blood become thick and syrupy (level >600 mg/dL)

• Cells can’t absorb much blood sugar, the sugar passed from blood to urine draws tremenous amounts of fluid from body and produces dehydration

• Common in type 2 DM, especially who don’t monitor blood sugar and who don’t know have DM

• Trigger factors: high-dose steroid, diuretics, infection, illness, stress or drinking excessive alcohol

HHS, sign & symptom

• Excesive thirst• Increased urination• Weakness• Leg cramps• Confusion• Rapid pulse• Convulsions• Coma

What should you do?

• Check blood sugar level (> 600mg/dL)• Emergency treatment can correct the problem

within hours• Give intravenous fluids to restore water to the

tissue • Short acting insulin to help cells can absorb

glucose• Without prompt treatment can be fatal

TERIMA KASIH

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Lecture DM dr Bowo Pramono.ppt