DIABETES MELITUSPUSAT DIABETES DAN LIPIDRSUP. Dr. WAHIDIN SUDIROHUSODOSUB BAGIAN ENDOKRIN METABOLIK BAGIAN ILMU PENYAKIT DALAM FK-UNHASMakbul M Aman

DefinitionDiabetes mellitus is a group of metabolic diseases characterized by hyperglycemiaresulting from defects in insulin secretion, insulin action, or both (Expert Committee on the Diagnosis and Classification of Diabetes mellitus 2002)Long-term damage, dysfunction, and failure of various organs especially the eyes, kidneys, nerves, heart, and blood vessels

The diabetes epidemic:171 million in 2000 to 366 million people in 2030IndiaChinaUSAIndonesiaPakistanBrazilBangladeshJapanPhilippinesEgyptCountry203079.442.330.321.313.911.311.18.97.86.7People with diabetes (millions)IndiaChinaUSAIndonesiaJapanPakistanRussian Fed.BrazilItalyBangladeshCountry200031.720.817.78.46.85.24.64.64.33.2People with diabetes (millions)12345678910RankingWild S et al. Diabetes Care 2004;27:104753Status of diabetes management

Symptoms :PolyuriaPolydipsiaWeight lossSometimes polyphagiaBlurred vision

50% of type 2 diabetes patients have complications at the time of diagnosisRetinopathy, glaucoma or cataractsNephropathyNeuropathyMICROVASCULARMACROVASCULARCerebrovascular diseaseCoronary heart diseasePeripheral vascular diseaseUKPDS Group. UKPDS 33. Lancet 1998; 352:837853.

Current recommendationsDiabetes must be diagnosed earlier. And once diagnosed, all types of diabetes must then be managed much more aggressively Canadian Diabetes Association

Therefore, the results of the UKPDS mandate that treatment of type 2 diabetes include aggressive efforts to lower blood glucose levels as close to normal as possible American Diabetes AssociationCanadian Diabetes Association. Can J Diabetes 2003; 27 (Suppl 2): 1163;American Diabetes Association. Diabetes Care 2003; 26: S2832.

ADA definition of hyperglycaemic statesADA = American Diabetes AssociationOGTT 2-h post-load glucose < 140 mg/dl (7.8 mmol/l) normal glucose tolerance140199 mg/dl (7.811.1 mmol/l) impaired glucose tolerance 200 mg/dl (11.1 mmol/l) diabetesAdapted from American Diabetes Association. Diabetes Care 2004; 27:S5S10. Criteria for the diagnosis of diabetes Symptoms of diabetes plus casual plasma glucose 200 mg/dl (11.1 mmol/l) 126 mg/dl (7.0 mmol/l) diabetes FPG< 100 mg/dl (5.6 mmol/l) normal fasting glucose100125 mg/dl (5.66.9 mmol/l) impaired fasting glucoseoror

IDF: Indications for OGTTMost screening programmes use either fasting or random glucose as the first stepOGTT should be performed on all people withFPG of 5.65.9 mmol/l orrandom plasma glucose of 5.611.0 mmol/lNOTEOGTT is not a test of controlHbA1c should not be used for the diagnosis of DiabetesAsian-Pacific Type 2 Diabetes Policy Group. Type 2 diabetes: Practical targets and treatment 4th edn. Hong Kong: Asian-Pacific Type 2 Diabetes Policy Group, 2005.

PENJARINGAN DM TIPE 2Idealnya untuk mendeteksi DM tipe 2 harus dilakukan skrining populasi, kenyataan sulit oleh karena, biaya mahalOleh karena itu penjaringan hanya dilakukan pada mereka dengan resiko tinggi DM

KELOMPOK RESIKO TINGGI DMUmur diatas 45 tahunKegemukan > 120% BB idaman atau IMT > 27 kg/m2), Hipertensi >140/90 mmHg, Riwayat keluarga DM, Pernah melahirkan anak BB lahir bayi >4000 gram, Riwayat DMG, Dislipidemi, HDL 250 mg/dl, Pernah TGT atau GPPT

III. Klasifikasi Etiologis DM1. Diabetes Tipe-1 (destruksi sel beta)AutoimunIdiopatik2. Diabetes Tipe-2 ( resistensi insulin disertai defek sekresi insulin atau sebaliknya)3. Diabetes Tipe lainA. Defek genetik fungsi sel beta MODY 1,2,3. DNA mitokondriaB. Defek genetik kerja insulinC. Penyakit eksokrin pankreas; Pankreatitis, tumor pankreas, pankreatektomi, pankreopati fibrokalkulus

D. EndokrinopatiAcromegali, sindroma Cushing, Feokromositoma, hipertiroidismeE. Karena obat/zat kimia Vacor, pentamidin, asam nikotinat, Glukokortikoid, hormontiroid, tiazid, Dilantin, interferon alfaF. Infeksi : rubellakongenital, CMVG. Sebab imunologi yang jarang : Antibodi anti insulinH. Sindroma genetik lain: Sindroma Down, Klinefelter, Turner dll.4. Diabetes Gestasional

Type 2 diabetes: a growing problemA serious, progressive diseaseCharacterised by two fundamental defects:insulin resistance-cell dysfunctionAccounts for 90% of diabetes cases worldwideAssociated with serious microvascular and macrovascular complicationsRepresents a significant disease burdenRepresents a considerable economic burdenDefinition, Diagnosis and Classification of Diabetes Mellitus and its Complications. World Health Organization, 1999. Diabetes Mellitus. Fact Sheet No 138. World Health Organization, 2002.

LIVERADIPOSE TISSUEPancreasInsulin supply or actionG L UC O S EG LYCOGENGLUCONEOGENESISThe Pathophysiology of Type 2 DMLIPOLYSISFFA +

Management A. Aim

Prinsip Dasar Terapi Diabetes Mellitus1PENGATURAN MAKANLATIHANOBAT HIPOGLIKEMIKPENYULUHANCANGKOK PANKREASKonsensus Perkeni, 19982354Pengaturan makanOlahragaPenyuluhanObat hipoglikemikCangkok Pankreas

Lifestyle interventionRepresents the first step in treating type 2 diabetesIn the Belfast Diet Study, dietary management was initially associated with reductions in FPG and weightHowever, after 6 years, a progressive rise in FPG was observed, associated with declining -cell functionMost patients required oral pharmacotherapy within a few years of diagnosisLevy J et al. Diabet Med 1998; 15: 2906.

Exercise

30 minutes: 3 - 4 times / weekContinuousRhytmicalIntervalProgressiveEndurance training

Nutrient Composition of Diabetic Diet

PERKENI A D A and B D A(Indonesian Soc.of Endoc.)

20-25%10-15%60-70%Diet/Nutrition Therapy/Meal planning30%10-15%55%

OBAT HIPOGLIKEMIK ORAL

Adipose tissueSites of Action of Antihyperglycemic AgentsPancreas1. Insulin GLUCOSEGLUCONEOGENESISHGP-Intestine2. Insulin secretagogue4. Acarbose3. MetforminTZD3. MetforminTZD++-++

Oral Hypoglycemic Drugs Available in Indonesia Initial dose Maximal dose Frequency of mg/day mg/dayadministration /daySulphonylureaGlibenclamide2,515-201-2 XGliclazide802401-2 XGlipizide : 5202-3 XGliquidone30120 1 XChlorpropamide 50500 1 XGlimepiride0,56 1 XMeglitinideRepaglinide1.5 mg8 mg 3XNateglinide120 mg360 mg 3XMetformin 50030001-3 XAlpha glucosidase inhibitor Acarbose50300 3 XDerivat ThiozolidindionesPioglitazoneRoziglitazoneFix Dose ( Campuran )Glucovance1,25/2502,5/5001-2 x

MonotherapyInsulin therapyCombination oral therapyLifestyle modificationExpected HbA1c (time allotted)1% (3 months) 1 to 2%(13 months) 1 to 2% fall peradditional OHA(13 months) Unlimited T2DM treatment strategies**Individualise

Adapted from Bergenstal RM. In: De Fronzo RA, et al (eds). International Textbook of Diabetes Mellitus. 3rd ed. Chichester, New York: John Wiley & Sons; 2004:9951015.

Proposed New Treatment Paradigm for Type 2 DiabetesMedical Nutrition Therapy, Exercise , Education and SMBGHbA1c < 7 %HbA1c 7- 8 %HbA1c > 8 %Consider oralmonotherapyAdd insulin sensitizer or secretagoqueAdd insulin sensitizer and secretagoqueTarget not MetTarget not MetTarget not MetStart Insulin or add Third oral agentFull Insulin therapy With Or without Oral agent(s)

New treatment paradigms for type 2 diabetesDiet/ exerciseOral monotherapyOral combinationInsulinEarly aggressive combination therapyStepwise treatmentOral +/- insulin

SulphonylureasHave been a mainstay of type 2 diabetes treatment for > 40 yearsBind to an SU receptor (SUR) on the b-cell which leads to depolarisation of b-cell membrane and stimulates insulin secretionFirst generation : chlorpropamideSecond generation : glibenclamide, glipizide, gliclazideThird generation : glimepirideAttention : Hypoglycemia (less in glipizide GITS and glimepiride)

Depola-risationCa 2+Voltage DependentCa 2+Channel (VDCC)ProinsulinClosedATP SensitiveK+ ChannelSS 01OpenCa 2+INSULIN C-PEPTIDESUSURATPADPATPADPGlucose Am. acid Glucokinase MetabolismMode of Action of Sulphonylureas

LIVERADIPOSE TISSUEThe Suppression Hepatic Glucose ProductionPancreasInsulin GLUCOSEGLUCONEOGENESISHGPGLYCOGENOLYSIS-

LIVERADIPOSE TISSUEThe Stimulation of Glucose UptakePancreasInsulin GLUCOSEGLUCONEOGENESISHGP-GLYCOGENOLYSISG LYCOGENG L UC O S E+

LIVERADIPOSE TISSUEThe Stimulation of Lipogenesis in Adipose TissuePancreasInsulin GLUCOSEGLUCONEOGENESISHGP-GLYCOGENOLYSISG LYCOGENG L UC O S E+Lipogenesis+FFA

Evaluate 4-8 wksEvaluate 4-8 wks

Type 2 DM Overweight Not Overweight Severe metab. decompensationStressing onMeal planning ExerciseMetformin or AcarboseM / A + SUM +A + SUSU or AcarboseSU + A / MSU + A + MUncontrolledDepends on the response: Diet or OHAInsulin C O N T I N U E C O N T I N U EEducationMeal planningExerciseEducationMeal planningExercisecontrolledUncontrolledUncontrolledUncontrolledUncontrolledUncontrolledUncontrolledUncontrolledUncontrolledcontrolledcontrolledcontrolledcontrolledcontrolledcontrolledcontrolledcontrolled

ADA Treatment Goals for Glycemic ControlGlycemia Normal Goal Further Action Required* Average Preprandial

Current ADA treatment targetsHbA1c < 7%Blood pressure < 130/80 mmHgLDL-cholesterol < 100 mg/dl (2.6 mmol/l)HDL-cholesterol Men> 40 mg/dl (1.1 mmol/l)Women > 50 mg/dl (1.3 mmol/l)Triglycerides < 150 mg/dl (1.7 mmol/l)American Diabetes Association. Diabetes Care 2004; 27 (Suppl 1): S1535.

Treatment Priorityof Type 2 DMMicrovascular diseaseMacrovascular disease

CardiovasculardiseaseIntervention/ControlControl of Insulin Resistance

1a. Insulin Insulin actions include :Ability of insulin to lower circulating glucose concentrations

Suppress glucose production : liverStimulate glucose utilization : muscle plus fat

Additional metabolic, vascular & mitogenic actions

JENIS INSULIN Jenis insulin menurut cara kerjaMulai KerjaKerja MaksimalLama Kerja(Jam)(Jam)(Jam)Actrapid0,52,5 - 54 - 8Humulin R0,52,5 - 54 - 8Monotard1 - 24 - 68 - 24Insulatard1 - 24 - 168 - 24Humulin N1 - 24 - 88 - 22Kerja LamaUltratard

2 - 48 - 2428Lama KerjaNama InsulinKerja SingkatKerja Sedang

Indications of Insulin Treatment

Indication for the use of insulin in Type 2 DMIn severe metabolic decompensationKetoacidosisHyperosmolar non ketotic coma Lactic acidosis Severe stress :Systemic infectionMajor surgeryWeight loss within a short period of timePregnancy if diet does not succeed to control glycemiaOHA failure or contra-indication of OHA

Combination Therapy in T2DM:Insulin Plus Oral Hypoglycemic AgentsInsulin Plus Sulphonylurea - BIDS Some insulin is endogenous, with natural secretory patternBiguanide Plus InsulinReduces hepatic insulin resistanceMay achieve better control with less insulinCan reduce weight gainAlpha Glucosidase Inhibitor Plus InsulinReduces posotprandial glucose levelThiazolidinedione Plus InsulinReduces peripheral insulin resistanceReduces insulin requirementMust balance TZD and insulin carefully to minimize weight gain

Benefits of Insulin and Oral Agents CombinationImproves glycemic controlTreats multiple physiologic abnormalitiesLess insulin is needed to achieve good glycemic controlReduces potensial for weight gainPatients: more practical and less frightening improved psychological acceptance, patients continue the oral drugs less / minimal education is needed treatment can be started in an outpatients-setting better compliance, and cost may be less

Complications :

KetoacidosisNonketotic Hyperosmolar syndromeRetinopathyNephropathyNeuropathyMacroangiopathyChronic :Acute :MicroangiopathyCADPVDStroke

KOMPLIKASI AKUTMetabolik Ketoasidosis diabetikKoma hiperglikemik hiperosmoler non-ketotikHipoglikemiAsidosis laktat2. Infeksi berat

KETOASIDOSIS DIABETIK (1)Klinis- Dehidrasi, kesadaran menurun sampai koma, hipotensi-syok, pernafasan Kussmaul, panas

2. Laboratorium - Hiperglikemi, GDS > 300 mg/dl- Asidosis, pH arteri

KETOASIDOSIS DIABETIK (2) PENATALAKSANAANCairan- Infus NaCl 0.9% sebanyak 500 ml selama 15 menit pertama, diteruskan sesuai kebutuhan - Bila GDS < 250 mg/dl, NaCl 0.9% diganti Dextrose 5%Insulin- Pada awal diberikan 10 U insulin kerja singkat i.v secara bolus (Actrapid, Humulin R) diteruskan dengan insulin drips 6 U/jamPotassium - Pada pemberian insulin biasanya kalium plasma menurun oleh karena itu perlu diberikan tambahan potassiumAntibiotik bila ada infeksi

KETOASIDOSIS DIABETIK (3) KomplikasiInfeksi

2. Gagal ginjal akut

KOMA HIPERGLIKEMIKHIPEROSMOLER NON-KETOTIK (KHHNK) (1)Klinis- Dehidrasi, koma, hipotensi-syok.- Beda dengan ketoasidosis, oleh karena tanpa asidosis tidak ada Kussmaul- Orang tua > 60 tahun

2. Laboratorium - Hiperglikemi, GDS > 400 mg/dl- Osmolalitas plasma >= 315 mmol/kg DIAGNOSIS

KOMA HIPERGLIKEMIKHIPEROSMOLER NON-KETOTIK (KHHNK) (2)CairanSama dengan ketaosidosis, hanya biasanya penderita dalam keadaan syok sehingga perlu pemberian NaCl 0.9% cepat. Untuk seterusnya diberikan cairan NaCl 0.45%Insulin sama dengan ketoasidosis PotassiumAntibiotik kalau perlu PENATALAKSANAAN

Pada DM reaksi hipoglikemi terjadi bila GDS < 50 mg/dl Penyebab : Insulin berlebihan, OHO berlebihan, gagal ginjal kronik mendapat OHO

Gambaran klinisKeringat dingin, takhikardi, rasa lapar, pusing, penglihatan kabur, kesadaran menurun sampai koma HIPOGLIKEMI (1)

HIPOGLIKEMI (2)Segera hentikan insulin atau OHOBila masih sadar segera berikan teh gula Dalam keadaan koma berikan Dextrose 40% sebanyak 50 ml i.v langsungDilanjutkan dengan infus Dextrose 10% selama 48 jam PENATALAKSANAN

KOMPLIKASI KRONIKKomplikasi vaskuler Makrovaskular Penyakit jantung koroner, strok, pembuluh darah perifer Mikrovaskular Retinopati,nefropatiKomplikasi neuropati Neuropati sensorimotorik,Neuropati otonomik Gastroparesis, diare diabetik, buli-buli neurogenik, Impotensi, gangguan refleks kardiovaskular Campuran vaskuler-neuropati Ulkus kakiKomplikasi pada kulit

RETINOPATI DIABETIK (1)Dikenal empat bentuk yaitu :Tipe backgroundTipe pre-proliferatifTipe proliferatifMakulopatiTipe background adalah paling ringan, sedang tipe proliferatif penyebab kebutaan

RETINOPATI DIABETIK (2)

RETINOPATI DIABETIK (3)

Kendali glukosa darah sebaik mungkin (HbA1c < 7%)Pengobatan terhadap hipertensi, dislipidemia bila adaHentikan merokokAspirin RETINOPATI DIABETIK (4)Pengobatan

NEFROPATI DIABETIK (1)Merupakan penyebab utama gagal ginjal terminal di negara maju

2.Diperkirakan 40% DM tipe 1 menjadi nefropati diabetik setelah menderita DM 20 tahun dan 5-10% pada DM tipe 2 dengan riwayat DM 20 tahun

NEFROPATI DIABETIK (2)Pengertian proteinuriNormo-albuminuri (Albustix negatif) Ekskresi albumin per menit < 20 ug atau jumlah albumin < 30 mg/24 jamMikro-albuminuri (Albustix negatif) Ekskresi albumin per menit 20-200 ug atau jumlah albumin 30-300 mg/air seni 24 jamMakro-albuminuri = proteinuri klinik (Albustix positif) Ekskresi albumin per menit > 200 atau jumlah albumin > 300 mg/air seni 24 jam

NEFROPATI DIABETIK (3)Diagnosis Adanya proteinuri menunjukkan nefropati diabetikNefropati diabetik klinik bila tes Albustix posistif sedikitnya 3 kali dengan interval beberapa miliNefropati diabetik dini bila ditemukan mirkroalbuminuri 2 sampai 3 kali pemeriksaan dalam 6 bulan

PengobatanKendali glukosa darah sebaik mungkin (HbA1c < 7%)Pengobatan terhadap hipertensi, dislipidemia bila ada Obat anti hipertensi sebaiknya ACE inhibitorHentikan merokokCatatan : TD sistolik < 135 mmHg, diastolik =< 80 mmHg NEFROPATI DIABETIK (4)

NEFROPATI DIABETIK (5)Hemodialisa

2.Transplantasi ginjal Pengobatan gagal ginjal terminal :

We are not getting older

We are getting better

The prevalence of diabetes worldwide is estimated to increase from 2.8% of the population in 2000 to 4.4% in 2030

ReferenceWild S et al. Diabetes Care 2004;27:104753

In the UKPDS, 50% of patients had a diabetes-related complication at diagnosis.1Neuropathy affects around 70% of those with diabetes at the time of diagnosis, leading to 55,00060,000 amputations in the USA each year.2Retinopathy, glaucoma or cataracts occur in around 10% of people after 15 years of diabetes. Blindness affects around 2%.2Nephropathy is the leading cause of end-stage renal disease.2Coronary heart disease (CHD) affects 7.520% of all people with diabetes over 45 years of age in the USA. The risk of CHD is two to four times higher than for those without diabetes.2Cerebrovascular disease: the risk of stroke is two to four times higher in people with diabetes. Fifteen percent of people with type 2 diabetes die from stroke.2The risk of peripheral vascular disease is four to eight times higher in people with type 2 diabetes.2

UKPDS Group. UKPDS 33. Lancet 1998; 352: 83753.World Health Organization/International Diabetes Federation. The economics of diabetes and diabetes care: a report of the Diabetes Health Economics Study Group. 1999 (WHO).Casual is defined as any time of day without regard to time since last meal.The classic symptoms of diabetes include polyuria, polydipsia, and unexplained weight loss.Fasting is defined as no caloric intake for at least 8 h.OGTT should be performed as described by WHO, using a glucose load containing the equivalent of 75 g anhydrous glucose dissolved in water.

American Diabetes Association. Diabetes Care 2004; 27: S5S10.

FPG = fasting plasma glucose IFG = impaired fasting glucose IGT = impaired glucose toleranceOGTT = oral glucose tolerance test

Epidemiological studies have shown that a significant number of people have isolated abnormalities of either the fasting or post-load state.

Asian-Pacific Type 2 Diabetes Policy Group. Type 2 diabetes: Practical targets and treatment 4th Edn. Hong Kong: Asian-Pacific Type 2 Diabetes Policy Group, 2005.

PENJARINGAN DIABETES MELITUS

Oleh karena diabetes mellitus tipe 2 sering tidak mempunyai keluhan yang khas, sebaiknya dilakukan skrining diabetes melitus pada semua orang dewasa. Hambatan untuk melakukan skrining semua orang dewasa antara lain biaya yang mahal, selain itu secara teknik sulit dalam pelaksanaannya. Oleh karena itu dianjurkan untuk melakukan skrining pada mereka yang dianggap mempunyai resiko tinggi diabetes melitus. Skrining demikian dapat dilakukan baik di praktek, poliklinik, maupun pada pemeriksaan kesehatan rutin.

Untuk menjaga agar kadar gula darah pada pasien tetap seimbang maka prinsip terapi DM disini ada 5 yaitu :1. Pengaturan makan (diet rendah lemak, karbohidrat dan protein)2. Latihan fisik sedang3. Penyuluhan ( supaya pasien berobat dengan teratur)4. Dan yang paling terpenting adalah pengobatan dengan obat hipoglikemik oral , karena seperti kita ketahui dari survei data epidemiologi bahwa 70% pasien DM akan selalu tergantung pada obat hipoglikemik oral untuk menjaga agar kadar gula darahnya tetap seimbang5. Cangkok pankreas , hanya dilakukan jika pankreas pasien sudah tidak mampu memproduksi insulinThe progressive nature of T2DM, caused by the decline in -cell function, means that oral hypoglycaemic agents have limited effectiveness and, despite being used to their maximum capacity, insulin will eventually be required to reach and sustain target glycaemic levels.

DeFronzo R, et al (eds). International Textbook of Diabetes Mellitus. 3rd ed. Chichester, New York: John Wiley & Sons; 2004:9951015.Stepwise approachThe traditional stepwise approach aims primarily to control acute symptoms.Dietary measures and exercise are not usually sufficient to control glycaemia beyond the first year of therapy. If oral monotherapy proves inadequate, combination therapy is usually started. If this also proves unsuccessful, conversion to insulin is the next step, either alone or in combination with an oral agent.In the majority of cases, the stepwise approach does not lead to sustained control.Many physicians intensify treatment only when symptoms of poor glycemic control become apparent, rather than when glycaemic targets are not reached.

Early, aggressive approachThis approach to type 2 diabetes management avoids the risk of early treatment failure by adopting an intensive therapeutic strategy immediately upon diagnosis. Combinations of agents with complementary modes of action targeting the dual defects underlying type 2 diabetes (insulin resistance and -cell dysfunction) are most likely to support tight, long-term glycaemic control.Furthermore, combination therapy should be considered earlier in the regimen to provide additional glycaemic control.

Campbell IW. Br J Cardiol 2000; 7: 62531.