lecture dm dr bowo pramono.ppt
DESCRIPTION
DMTRANSCRIPT
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
Expected HbA1c reduction
~ 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
Nathan DM et al. Diabetes Care 2006;29(8):1963-72.
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)
Expected HbA1c reduction
~ 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
Nathan DM et al. Diabetes Care 2006;29(8):1963-72.
Dipeptidyl Peptidase IV InhibitorsDipeptidyl Peptidase IV Inhibitors
How they work Inhibit degradation of endogenous GLP-1
Expected HbA1c reduction
~0.8%
Adverse events Minimal
Weight effects Neutral
CV effects Unknown
Nathan DM et al. Diabetes Care 2006;29(8):1963-72.
-Glucosidase Inhibitors-Glucosidase Inhibitors
How they work ↓ rate of digestion of polysaccharides in proximal small intestine (primarily lowering PPG levels without causing hypoglycemia)
Expected HbA1c reduction
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
Nathan DM et al. Diabetes Care 2006;29(8):1963-72.
ThiazolidinedionesThiazolidinediones
How they work Increase sensitivity of muscle, fat, and liver to endogenous and exogenous insulin
Expected HbA1c reduction
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
Nathan DM et al. Diabetes Care 2006;29(8):1963-72.
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)
CV effects None mentioned in ADA recommendations
Nathan DM et al. Diabetes Care 2006;29(8):1963-72.
Dipeptidyl Peptidase IV InhibitorsDipeptidyl Peptidase IV Inhibitors
How they work Inhibit degradation of endogenous GLP-1
Expected HbA1c reduction
~0.8%
Adverse events Minimal
Weight effects Neutral
CV effects Unknown
Nathan DM et al. Diabetes Care 2006;29(8):1963-72.
Amylin Agonists (pramlintide)Amylin Agonists (pramlintide)
How it works Synthetic amylin analogue that inhibits glucagon production in a glucose-dependant fashion
Expected HbA1c reduction
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)
CV effects None mentioned in ADA recommendations
Nathan DM et al. Diabetes Care 2006;29(8):1963-72.
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
Expected HbA1c reduction
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
Nathan DM et al. Diabetes Care 2006;29(8):1963-72.
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