CLINICAL USE OF INSULIN IN DAILY PRACTICE (PDCI: MEMULAI DAN INTENSIFIKASI INSULIN)
2015 34-1083-K Presented and Provided by : Prof. Dr. dr. Askandar Tjokroprawiro Sp.PD, K-EMD, FINASIM SURABAYA DIABETES AND NUTRITION CENTRE - Dr. SOETOMO TEACHING HOSPITAL FACULTY OF MEDICINE AIRLANGGA UNIVERSITY, SURABAYA
SANOFI PDCI WORKSHOP FOR GENERAL PRACTITIONS
PDCI Partnership for Diabetes Control in Indonesia ASKES / BHAKTI HUSADA, MoH, PERKENI, ADA, SANOFI TUBAN (MUSTIKA HOTEL), 18-20 DECEMBER 2015 ASK-SDNC
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TUJUAN PEMBELAJARAN PDCI-WORKSHOP 1. Memahami Peran Insulin dalam Pengendalian Glukosa Darah
2. Meningkatkan Kemampuan dalam Memulai dan Mentitrasi Dosis Insulin, Menggunakan Insulin Basal dan Premixed 3. Mampu Melakukan Monitoring dan Evaluasi Penggunaan Insulin
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Pancreatic Islet Cells: Cell, Cell, Cell, Cell, PP-Cell. APA ITU INSULIN?
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(Molina 2010, Masharani et al 2011, Summarized : Tjokroprawiro 2015)
Insulin
• Hormon yang disekresikan oleh sel Beta Pankreas ( Cell) • Cell Types in Adult Human Pancreatic Islet of Lengerhans, in approximately % of Islet volume : Cell (25%, Glucagon, Proglucagon), Cell (55%, Insulin, C Peptide, Proinsulin, IAPP, GABA), Cell (10%, Somatostatin-14), Cell (3%, Ghrelin), PP-Cell (5%, Pancreatic Polypeptide) • First-Phase Secretion (a period of minutes, < 5%) and SecondPhase Secretion (over an hour or more, > 95%) • Disekresikan sebagai Respon terhadap Glukosa atau Rangsangan lainnya, seperti Asam Amino
60 40 20
0 ASK-SDNC
Sarapan
Makan siang
Makan malam
TINJAUAN TERHADAP PROFIL FISIOLOGIS INSULIN (Molina *2010, Summarized : Tjokroprawiro 2015) 50
Saat makan, insulin meningkat dengan cepat, durasi pendek (First Phase Secretion, <5%*)
Serum Insulin (mU/L)
40
30
Halus, Stabil Profil Insulin Basal (Second Phase Secretion, > 95%*)
20
10 0
0800 1200 1600 2000 2400 MAKAN PAGI MAKAN SIANG MAKAN MALAM BP=blood pressure; QOL=quality of life Adapted from Kruszynska Y et al. Diabetologia 1987;30:16.
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0400
0800
Daly A, Power MA. Medical Nutrition Therapy. Diabetes Mellitus and Related Disorders; Medical Management of Type 2 Diabetes, 7th Edition. American Diabetes Association, 2012.
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TYPE 2 DIABETES IS PROGRESSIVE DIAGNOSIS
100
β-cell Function, %
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MONOTHERAPY
80
COMBINATION ORAL THERAPY
60 40
T2DM Phase-I
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INSULIN T2DM Phase-II
0 -12
-6
0
T2DM Phase-III
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12
Time, Years HbA1c Not at Target: < 7.0% Based on data from UKPDS. Diabetes. 1995;44:149-1258(1); Kendall DM, et al. Am J Med. 2009; 122:S37-S50(2); Kendall DM, et al. Am J Manag Care. 2001;7:S327-S343(3) ASK-SDNC
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MEKANISME KERJA INSULIN (PDCI-2014, Provided 2014-2015)
INSULIN
GLUCOSE
INSULIN RECEPTORS
GLUT4
β β
ACTIVE
INACTIVE A B
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MAPK – PATHWAY GENE EXPRESSION GROWTH REGULATION ATHEROGENIC & MITOGENIC
A1
P13K – PATHWAYS SIGNAL TRANSDUCTION A2
GLUCOSE UTILIZATION + GLYCOGEN / LIPID / PROTEIN SYNTHESIS METABOLIC & ATHEROPROTECTIVE
THE 6 SITES OF ACTIONS OF INSULIN RESISTANCE
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(Kim et al 2008, Circ Res. 2008;102:401-414, Provided : Tjokroprawiro 2014-2015) 1
INSULIN RECEPTOR
3 DEGRADATION
IRS-1/2
2 SERINE PHOSPHORYLATION
Pi 3-Kinase 6A ACTIVATION Akt
PDK-1
4 PTP-1B 5 PTEN
PKB FOXO1 G6P /PEPCK Gluconeogenesis
LIVER
eNOS NO Vasodilation HEART, ENDOTHELIUM
FOXO1 inhibits β Cell Survival & Proliferation Akt inhibits FOXO1
6B ACTIVATION aPKC
PKC GLUT4 Glukose Uptake ADIPOSE TISSUE, HEART, SKELETAL MUSCLE
MOLECULAR MECHANISM OF INSULIN RESISTANCE : (1) 1 decreased activation of receptor binding 2 increased serine phosphorylation of IRS proteins (Zick 2005); (3) 3 increased degradation of IRS proteins (Zhande et al 2002); increased activity of phosphatases including (src homology 2 domain containing inositol 5-phosphatase 2 [SHIP2], 4 4 phospho-tyrosine phosphatase 1B [PTP-1B]), and 55 phosphatase tensin homolog deleted on chromosome ten [PTEN] (Egawa et al 2001); (5) 6 decreased activation of insulin receptor downstream signaling molecules including 6A Akt and 6B atypical PKC (Stratford et al 2004) ASK-SDNC
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HAMBATAN DALAM INISIASI INSULIN MASALAH KLINIS Klinisi mengkhawatirkan kondisi hipoglikemia, kenaikan berat badan
MASALAH PASIEN Takut suntikan / jarum Takut hipoglikemia
Kesalahpahaman bahwa peningkatan insulin meningkatkan risiko kardiovaskular
Menganggap insulin sebagai tanda kegagalan pasien pribadi untuk mengendalikan penyakit
Rumit dan labor-intensive
Rumit dan labor-intensive
Kurangnya pengetahuan/pengalaman
Mahal
Tidak cukup waktu untuk edukasi pasien
Takut kualitas hidup menurun Keuangan Teknis (buta dan hidup sendiri)
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KAPAN INSULIN DIPERLUKAN? (PERKENI Consensus Guidelines, 2015)
1. 1 2. 2 3 3. 4. 4 5. 5 6. 6 7 7. 8 8.
Penurunan berat badan secara drastis Hiperglikemia berat diikuti dengan ketosis Ketoasidosis Diabetes (KAD) Kondisi hiperglikemia Hiper Osmolar Non Ketotik (HONK) Hiperglikemia diikuti dengan laktat asidosis Kegagalan kombinasi OAD dengan dosis optimal Infeksi sistemik, pembedahan mayor, Miokardiak Infark Akut, stroke Gestational DM dengan kadar gula darah yang tidak terkendali dengan diet. 9 Kerusakan berat fungsi ginjal dan hati 9. 10. 10 Kontraindikasi dan/atau hipersensitivitas terhadap OAD ASK-SDNC
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PRACTICAL INDICATIONS OF BASAL INSULIN FORMULA : PBB (ESWL), 2-4-9-9, HOMA-B 35 (Clinical Experiences : Tjokroprawiro 2003-2015) PRIMARY INDICATIONS OF BASAL INSULIN
(When Any of the Six Following Items are Exceeded)
LIFE STYLE MODIFICATION
1 PBB*) Means: Penurunan Berat Badan*) (Kg) > 10% (within 3 months) 2 2 Means: FPG > 200 mg/dL 3 4 Means: 1h-PG > 400 mg/dL 4 9 Means: A1C
*) or ESWL / 3 months Estimated Significant Weight Loss > 10%
> 9%
5 9 Means: A1C for Naïve T2DM > 9% 6 HOMA-B 35 Means: HOMA-B < 35% (Normal : 70-150%) SOMETIMES EARLY INSULINIZATION IS INITIATED if : HOMA-B < 50% ASK-SDNC
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INSULIN DI INDONESIA (PERKENI, Petunjuk Praktis Terapi Insulin pada pasien DM, 2015) JENIS INSULIN
AWITAN (ONSET)
PUNCAK EFEK
LAMA KERJA
KEMASAN
Kerja pendek (Insulin manusia, Insulin regular) Humulin® R Actrapid® Insuman®*
30-45 menit
2-4 jam
6- 8 jam
Vial Penfill
4-6 jam
Vial/pen Flexpen Pen/vial
8-12 jam
Vial Penfill Vial
Kerja cepat (Insulin Analog) Insulin lispro (Humalog®) Insulin aspart (Novorapid®) Insulin glulisin (Apidra®) Kerja menengah (Insulin manusia, NPH) Humulin N® Insulatard® Insuman Basal®* ASK-SDNC
5-15 menit
1,5-4 jam
1-2 jam
4-10 jam
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INSULIN DI INDONESIA (LANJUTAN) (PERKENI, Petunjuk Praktis Terapi Insulin pada pasien DM, 2015) JENIS INSULIN
Kerja panjang (Insulin Analog) Insulin glargine (Lantus®) Insulin detemir (Levemir®) Kerja ultra-panjang (Insulin Analog) Degludec (Tresiba®)* Glargine U300 (Lantus XR, Toujeo)*
AWITAN PUNCA (ONSET) K EFEK
1-3 jam
Hampir tanpa puncak
LAMA KERJA
KEMASAN
12-24 jam
Pen/vial 100 IU/mL Pen 100 U/mL
30 -60 menit
Hampir Sampai 48 tanpa jam puncak 1-3 jam Tanpa 24 jam puncak
NPH: Neutral Protamine Hagedorn;. *belum tersedia di Indonesia ASK-SDNC
Pen
Pen 300U/mL
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INSULIN DI INDONESIA (LANJUTAN) (PERKENI, Petunjuk Praktis Terapi Insulin pada pasien DM, 2015) JENIS INSULIN
Campuran (Premixed, Insulin Manusia) Humulin® 30/70 (30% Regular, 70% NPH) Mixtard® 30/70 (30% Regular, 70% NPH) Campuran (Premixed Insulin Analogue) Humalog® Mix75/25TM (75% Protamin Lispro, 25% Lispro) NovoMix® 30 (30% Aspart, 70% Protamin Aspart) 50/50 PreMix
AWITAN PUNCAK LAMA EFEK KERJA (ONSET)
30 – 60 menit
12-30 menit
3-12 jam
Vial 30/70 Penfill
1-4 jam
Vial 10 mL, Pen 3 mL Penfill/ flexpen
NPH: Neutral Protamine Hagedorn;. *belum tersedia Indonesia ASK-SDNC
KEMASAN
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INSULIN IN CLINICAL USE Lee et al 1998, Hirsch 1998, Bolli et al 1999, Gillies et al 2000 Heinemann 1996, Fineberg et al 2003, Malone et al 2000, 2004 (Summarized : Tjokroprawiro 2003-2015)
PAST AND PRESENT
PRESENT AND FUTURE
NATIVE HUMAN INSULINS Clinical Use : Since 1922s
INSULIN ANALOGUES Recombinant Human Insulin: Since 1980s
ACTRAPID,INSULATARD-MONOTARD,MIXTARD
Regular-Semilente, NPH-Lente, Ultralente THE 3 OF 34 PROPERTIES OF INSULIN 1 ANTI-INFLAMMATION 2 ANTI-OXIDANT 3 ANTI-APOPTOSIS (Brain, Heart, -Cell) ASK-SDNC
RAPID-ACTION : 7
LONG ACTION : 8
1 Lispro : LysB28, ProB29 1 Glargine (Lantus®, 2003) (Humalog®, 2006) 2 Insulin Aspart 70/30 2 AspB9 (NovoMix30®, 2006) 3 AspB10 3 Humalog Mix25® (2006) 4 Asp B28-Aspart (NovoRapid®, 2007) 4 Detemir (Levemir®, 2007) 5 Glu B21 5 Degludec (Expected 2016?) 6 Glu B27 6 Novo Sol BASAL 8 C16-HI 7 Glulisine 7 W99-S32 9 Glargine 300U (Apidra®, 2007)
(Toujeo)
PHARMACOKINETICS OF HUMAN INSULIN AND INSULIN ANALOGUES
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(Summarized : Tjokroprawiro 2008-2015)
INSULIN PREPARATION SHORT ACTING *)
ONSET OF ACTION
PEAK OF ACTION (HRS)
DURATION OF ACTION (HRS)
30-60 mins 5-15 mins 5-15 mins 5-15 mins
2-4 1-2 1-2 1-2
6-8 3-4 3-4 3-4
RAPID ACTING **)
Regular Human Insulin = RHI*) INSULIN GLULISINE : APIDRA **) Insulin Aspart : Novorapid **) Insulin Lispro : Humalog **)
INTERMEDIATE-ACTING 1-3 hrs 5-7 13-16 NPH 1-3 hrs 4-8 13-20 Lente LONG-ACTING INSULIN GLARGINE (LANTUS) 1-3 hrs No Peak 24 Detemir (Levemir) 1-3 hrs No Peak 24 Ultralente 2-4 hrs 8-14 22-24 hrs Ultra-long-acting insulin DEGLUDEC : New Gen. Basal Ins. that forms Soloble Hexamers upon SC inj. PREMIXED = Biphasic Insulin Lispro 75/25 (Humalog Mix25)
Insulin Aspart 70/30 (Novomix30)
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10 mins 10 mins
1-4 1-4
10-20 16-20
MEMULAI DAN MENTITRASI INSULIN BASAL
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(Nathan et al. Diabetes Care 2009;32:193-203, Provided : Tjokroprawiro 2013-2015)
Mulai dgn insulin basal suntikan tunggal, contoh: pagi hari insulin glargine
Malam hari atau Pagi hari (lebih baik) • Insulin kerja panjang (siang dan malam dengan OAD) • Malam Insulin kerja menengah )) ), Slide Dosis harian: 10 U atau 0.2 U/kg*) (atau Formula atau Formula 1/3**1/3** 19, 20, 21
Cek GDP perhari Naikkan dosis 2 U per 3 hari (Formula 3.3.5), Slide Slide 21 19 sampai (Formula 3.3.5**), GDP 3.9–7.2 mmol/L (80–130 mg/dL) Jika GDP >10 mmol/L (>180 mg/dL), Naikkan dosis 4 U per 3 hari
Lanjutkan regimen dan cek HbA1c tiap 3 bulan ASK-SDNC
Jika terjadi hipoglikemia atau GDP <3.9 mmol/L (<80 mg/dL), kurangi dosis insulin di pagi hari ≥4 unit, atau 10% jika >60 unit
*) Body Weight Oriented **) Blood Sugar Level Oriented
PENYESUAIAN DOSIS INSULIN MENURUT ADA-2006 Jika A1C tidak tercapai setelah 2-3 bulan pengobatan dan GDP masih dlm rentang target, tambahkan suntikan sesuai kadar glukosa darah sebelum makan (pre-meal) – GD pre-meal makan siang yg meningkat: Tambahkan insulin rapid-acting saat makan pagi – GD pre-meal makan malam yg meningkat: Tambahkan NPH saat makan pagi atau insulin rapid-acting saat makan siang* – GD sebelum tidur yg meningkat: Tambahkan insulin rapidacting saat makan malam
Premixed insulin tidak dianjurkan pd penyesuaian dosis; namun dapat digunakan sebelum makan pagi dan/atau makan malam jika proporsi kerja singkat-menengah nya sama dg proporsi campuran yg tersedia Nathan DM et al. Diabetes Care 2006;29:1963-72. ASK-SDNC
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PENYESUAIAN DOSIS INSULIN MENURUT ADA-2006 Periksa kembali glukosa darah sebelum makan untuk melihat apakah diperlukan suntikan lagi. Jika A1C tetap tidak tercapai, cek glukosa darah 2 jam, atau 1 jam (Tjokroprawiro 2014) setelah makan dan sesuaikan dengan insulin kerja singkat
Nathan DM et al. Diabetes Care 2006;29:1963-72. ASK-SDNC
CTOI with FORMULA 1/3 for DISCHARGED-PATIENTS
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(Clinical Experiences : Tjokroprawiro 2007-2015)
1 INPATIENTS TREATED with APIDRA 3x 20 Units per Day: Total dose of APIDRA® 60 units per Day CTOI : Combined Therapy USE FORMULA 1/3 *) *) Blood Sugar Oriented Oral-Insulin METHOD- A OR B METHOD- A (Since-2003)
- LANTUS : 20 units (1/3 of 60) Mornings - APIDRA : Formula X2 - AMARYL-M® : Mornings, or Mornings and Evenings
or - LANTUS : 20 units Evenings METHOD- B - APIDRA : Formula X2 (Widely Withdrawn) - AMARYL-M® : Mornings, or Mornings and Evenings
PERKENI-CONSENSUS 2006 : Insulin Dose > 30 Units/day in CTOI is not Recommended ASK-SDNC
STOP OAD, and Give PREMIX® Twice Daily (ADA/EASD-2012)
Continued
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CTOI with FORMULA 1/3 (LANTUS®) for DIABETIC-OUTPATIENTS (Clinical Experiences : Tjokroprawiro 2007-2015)
2 DIABETIC OUTPATIENTS FAILED with 2-4 OADs*):
depending on 1-h PG (One Hour Plasma Glucose) , and Special attention to
the figures of the first two fe. : 1-h PG 450 mg/dL , the First two is 45 *) 1-h PG Oriented
FORMULA 1/3 (based on the figures of the first two , that is 45): Thus, the Initial Dose : 1/3 of 45 = 15 Units - LANTUS : 15 Units Mornings (At the Same Time of the Day) METHOD- A - APIDRA : Formula X2 Since-2003 & 2007 - AMARYL-M® : Mornings, or Mornings and Evenings
or - LANTUS : 15 units Evenings (At the Same Time of the Day) METHOD- B - APIDRA : Formula X2 Widely Withdrawn - AMARYL-M® : Mornings, or Mornings and Evenings ASK-SDNC
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STEP-UP FORMULA : 3-3-5 (Clinical Experiences : Tjokroprawiro 2003-2015)
I STEP-UP FORMULA 3-3-5 WITH LANTUS THE 1st 3 INDICATES DAY , whereas the 2nd & 3rd 3 & 5 INDICATE LANTUS® DOSE
INCREASING INSULIN DOSE : 3 or 5 units after 3 DAY-EVALUATION INCREASING INSULIN DOSE OF 3 UNITS IF
FPG (Morning-Glucose) : 130-200 mg/dL INCREASING INSULIN DOSE 5 UNITS IF
FPG (Morning-Glucose) : > 200 mg/dL DECREASING INSULIN DOSE 3 UNITS IF FPG (Morning-Glucose) : < 80 mg/dL (ADA-2015) ASK-SDNC
Continued
STEP-DOWN FORMULA : 2-2 , 2-1 , 1-2 , 1-1
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(Clinical Experiences : Tjokroprawiro 2003-2015)
II
STEP-DOWN FORMULAS TO END LANTUS INJECTION THE 1st FIGURE ( 2 or 1 ) INDICATES DAY , whereas : THE 2nd FIGURE ( 2 or 1 ) INDICATES DECREASE in LANTUS® DOSE
FORMULA 2-2 : Every 2 Days FORMULA 2-1 : Every 2 Days
2 U Decrease ,until LANTUS INJECTION OFF 1 U Decrease , until LANTUS OFF
FORMULA 1-2 : Every Day
2 U Decrease , until LANTUS OFF
FORMULA 1-1 : Every Day
1 U Decrease , until LANTUS OFF
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LANGKAH-LANGKAH PENDEKATAN TERAPI DMT2 (KONSENSUS PERKENI, 2011; Raccah. Diabetes Ob Met 2008;10:76-82) ADA-2015 ADA-2015 A1C <7.0% Glukosa plasma sebelum makan 80–130 mg/dL Puncak glukosa plasma kapiler setelah makan (1 jam postprandial) <180 mg/dL
INSULIN BASAL OAD MONOTERAPI ATAU KOMBINASI DIET DAN LATIHAN FISIK
Sehari 1x (sampai optimal)
A1C Tdk terkendali
BASAL PLUS-1 1 suntikan prandial utk asupan karbohidrat terbesar
2 suntikan prandial utk asupan karbohidrat & terbesar
A1C tdk terkendali, GDP sesuai target GDPP > 180 mg/dL
Waktu ASK-SDNC
BASAL PLUS-2
BASAL BOLUS Basal + 3 Suntikan Prandial BASAL PLUS
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INTENSIFIKASI INSULIN (Konsensus PERKENI, 2011)
Dari BASAL ke BASAL-PLUS kemudian BASAL-BOLUS : Ketika INSULIN BASAL (Suntikan ke-1) ditambahkan pada OAD TIDAK MENCAPAI TARGET A1C, maka :
Lakukan langkah-langkah PENAMBAHAN SHORT ATAU RAPID INSULIN (Stepwise) pada MEALTIME • BASAL +1 : SUNTIKAN ke-2 sebelum sebelum LARGEST LARGEST MEAL MEAL nd MEAL • BASAL +2 : SUNTIKAN ke-3 sebelum sebelum 22nd MEAL
• BASAL +3 (BASAL-BOLUS) : SUNTIKAN ke-4 sebelum 3rd MEAL ASK-SDNC
CTOP : Combined Therapy Oral and Premix
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CTOP with FORMULA 1/3 for DIABETIC-OUTPATIENTS (Clinical Experiences : Tjokroprawiro 2007-2015)
DIABETIC OUTPATIENTS FAILED with 2-3 OADs*): depending on 1-h PG (One Hour Plasma Glucose) , and Special attention to
the figures of the first two fe. : 1-h PG 450 mg/dL , the First two is 45 *) 1-h PG Oriented
FORMULA 1/3 (based on the figures of the first two , that is 45): Thus, the Initial Dose or PREMIX : 1/3 of 45 = 15 Units - PREMIX : 15 Units MORNINGS (at Breakfast) (If Insulin Dose < 20U/day) - OAD : LUNCH and DINNER
PREMIX-A
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CTOP WITH PREMIX A , AB , AND ABC FOR DIABETIC OUTPATIENTS PREMIXED-INSULIN REGIMEN IN DAILY PRACTICE (Clinical Experiences : Tjokroprawiro 2014-2015)
FORMULA 1/3 (Formula < 20) : PREMIX-A If Premix Dose < 20 U/day : Breakfast FORMULA 60-40 : PREMIX-AB
IF PREMIX DOSE (20-40 U/day): Breakfast and Dinner (Example : 30 U/day Breakfast 18 U, Dinner 12 U)
60% = 18 U Breakfast (A) – 40% = 12 U Dinner (B) FORMULA 50-20-30 : PREMIX-ABC
IF PREMIX (>40 U/day) : Breakfast, Lunch, Dinner (Example : 50 U/day Breakfarst : 25 U, Lunch 10 U, Dinner 15 U)
50% = 25 U Breakfast (A), 20% = 10 U Lunch (B), 30% = 15 U Dinner (C) ASK-SDNC
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THE 3 (THREE) FORMULAS OF PREMIX IN CTOP
PREMIX- A – PREMIX- AB – PREMIX- ABC (Clinical Experiences : Tjokroprawiro 2014-2015)
PREMIX-A (IF < 20 /d) PREMIX-AB (IF 20-40 /d) PREMIX-ABC (IF >40 /d) DOSE: 60% (A) and 40% (B) DOSE: 50%-20%-30% DOSE 1/3 (A) (A), (B), (C)
PREMIX-A : 1X Breakfast Only
PREMIX-AB : 2X Breakfast 60% (A) Dinner 40% (B)
(CTOP = Combined Therapy Oral Premixed Insulin) ASK-SDNC
PREMIX-ABC : 3X Breakfast 50% (A) Lunch 20% (B) Dinner 30% (C)
THE SUMMARIZED USE OF FORMULAS PREMIX-A, AB, ABC
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(Clinical Experiences : Tjokroprawiro 2015)
• PREMIX-A (100% of insulin daily dose) : if the daily insulin dose < 20 Unit. Injection of premix (<20 U/day) only once injection per day at breakfast.
• PREMIX-AB (see Slide 26) (60% at breakfast, 40% at dinner) : if the daily insulin dose between 20-40 Unit, for example 30 unit/day
Injection of premix twice daily. Premix-A 60% (60% of 40 U) : 18 Unit at breakfast and premix-B 40% (12 Unit) at dinner.
• PREMIX-ABC PREMIX-ABC (see Slide 26) (50% at breakfast, 20% at lunch, 30% at dinner) If the daily insulin dose >40 Unit, for example 50 Unit/day, Injection of premix-A (50% of 60 U) : 25 Unit at breakfast, premix-B (20% of 10 U) : 12 unit, and premix-C (30% of 60 U) : 15 unit at dinner ASK-SDNC
Pendekatan dalam Memulai dan Menyesuaikan Insulin pada DMT2 Number of injections
(usually with metformin +/- other noninsulin agent)
Flexibility ASK-SDNC
If not controlled after FBG target is reached (or if dose >0,5 U/kg/day), treat PPG excursions with mealtime insulin. (Consider initial GLP-1-RA trial.)
• Start: 4 U, 0.1 U/kg, or 10% basal dose. If HbA1c <8% consider reducing basal by same amount. • Adjust: Increase dose by 1-2 U or 10-15% once-twice weekly until SMBG target reached. • For hypo: Determine and address cause; reduce corresponding dose by 2-4 U or 10-20%
If not controlled, consider basal-bolus
3+
low
• Start: 10 U/day or 0.1-0.2 U/kg/day • Adjust: 10-15% or 2-4 U once-twice weekly to reach FBG target. • For hypo: Determine and address cause; reduce dose by 4 U or 10-20%
Add 1 rapid insulin injection before largest meal (Basal Plus 1 or 2, Basal Bolus)
2
Regimen complexity
BASAL INSULIN
1
Change to premixed insulin twice daily (Premix-A, AB, or ABC)
• Start: Divide current basal dose into 2/3 AM, 1/3 PM or 1/2AM, 1/2 PM. • Adjust: Increase dose by 1-2 U or 10-15% once-twice weekly until SMBG target reached. • For hypo: Determine and address cause; reduce corresponding dose by 2-4 U or 10-20%
ADD ≥ 2 RAPID INSULIN* INJECTIONS BEFORE MEALS (“BASAL-BOLUS”)
mod.
If not controlled, consider basal-bolus
• Start: 4 U, 0.1 U/kg, or 10% basal dose/meal. If HbA1c <8% consider reducing basal by same amount. • Adjust: Increase dose by 1-2 U or 10-15% once-twice weekly until SMBG target reached. • For hypo: Determine and address cause; reduce corresponding dose by 2-4 U or 10-20%
More flexible
29
high
Less flexible Inzucchi SE, et al. Diabetes Care 2015;38:140–149
CORRELATION OF A1C WITH AVERAGE GLUCOSE
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A calculator for converting A1C results into eAG (estimated Average Glucose), in either mg/dL or mmol/L, is available at http://professional.diabetes.org/GlucoseCalculator.aspx
A1C 6 7 8 9 10 11 12 ASK-SDNC
MEAN PLASMA GLUCOSE mg/dL mmol/L 126 7.0 154 8.6 183 10.2 212 11.8 240 13.4 269 14.9 298 16.5 Diabetes Care 35, Supplement 1, January 2012
MEMBERIKAN PENGOBATAN YANG TEPAT PADA PASIEN YANG TEPAT
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KARAKTERISTIK PASIEN – – – – – –
Profil Glucosa Darah Pasien Faktor Psikososial dan Budaya Pilihan Pasien Usia Penyakit Komorbid Keinginan untuk Mematuhi Pengobatan
KARAKTERISTIK INSULIN – – – – ASK-SDNC
Kemampuannya utk Menyamai Sekresi Insulin Endogen Potensi Efek Samping Biaya Kompleksitas Komposisinya
Meneghini L. South Med J 2007;100:164-74. Mooradian AD et al. Ann Intern Med 2006;145:125-34. Hirsch IB et al. Clin Diabetes 2005;23:78-86.
INSULIN DAN WAKTU PEMERIKSAAN GLUKOSA DARAH MANDIRI PEMBERIAN
MONITORING GULA DARAH
Sebelum atau setelah makan
Setelah makan
1-2 jam setelah suntikan atau segera sebelum makan
Sebelum makan
Diantara makan/makan berikutnya atau pada saat akan tidur
Segera sebelum makan berikutnya; biasanya 1-2 jam setelah suntikan
Kerja Menengah
Sebelum sarapan, Sebelum makan malam, pada saat akan tidur
Diantara makan siang/malam Diantara tengah malam/ sarapan, Diantara pukul 04:00/sarapan
Sebelum sarapan, sebelum tidur, midsleep, dan sarapan, sebelum sarapan
Kerja Panjang
Sebelum sarapan, atau pada saat akan tidur
Kebanyakan pada malam hari
Sebelum sarapan
(Pengalaman Klinik : Pagi Hari)
(Tergantung Jam Suntik)
INSULIN
Kerja Singkat
Regular
ASK-SDNC
WAKTU SUNTIKAN
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Medical Management of Type 2 Diabetes. 7th Edition. American Diabetes Association, 2012.
PRACTICAL INDICATIONS OF BASAL INSULIN FORMULA : PBB (ESWL), 2-4-9-9, HOMA-B 35 (Clinical Experiences : Tjokroprawiro 2003-2015) PRIMARY INDICATIONS OF BASAL INSULIN
(When Any of the Six Following Items are Exceeded)
LIFE STYLE MODIFICATION
1 PBB*) Means: Penurunan Berat Badan*) (Kg) > 10% (within 3 months) 2 2 Means: FPG > 200 mg/dL 3 4 Means: 1h-PG > 400 mg/dL 4 9 Means: A1C
*) or ESWL / 3 months Estimated Significant Weight Loss > 10%
> 9%
5 9 Means: A1C for Naïve T2DM > 9% 6 HOMA-B 35 Means: HOMA-B < 35% (Normal : 70-150%) SOMETIMES EARLY INSULINIZATION IS INITIATED if : HOMA-B < 50% ASK-SDNC
33
34
PRACTICAL TOOL FOR INSULIN RESISTANCE AND -CELL FUNCTION (Mathews et al 1985, Falutz et al 2002, Summarized : Tjokroprawiro 2005-2015)
HOMA-R
:
Fasting Insulin (U/mL) x FPG (mmol/L)
22.5
Insulin Resistance
HOMA-B
: -Cell Function
20 x Fasting Insulin (U/mL) FPG (mmol/L) – 3.5
Clinical Use in Daily Practice
HOMA-R and HOMA-B ASK-SDNC
:
(N: < 2.0)
(N: 70–150%)
1 RATIONALE TREATMENT 2 FOLLOW-UP OF TREATMENT
MECHANISMS BY WHICH HYPOGLYCAEMIA MAY AFFECT CARDIOVASCULAR EVENTS
35
(Desouza et al 2010, Provided : Tjokroprawiro 2013-2015) VEGF CRP IL6 INFLAMMATION
NEUTROPHIL ACTIVATION BLOOD COAGULATION ABNORMALITIES
1
4
PLATELET FACTOR VII ACTIVATION
HYPOGLYCEMIA
2
ENDOTHELIAL DYSFUNCTION Vasodilation
3 SYMPATHOADRENAL RESPONSE
RHYTHM ABNORMALITIES
ASK-SDNC
HEMODYNAMIC CHANGES Adrenaline Contractility Oxygen Consumption Heart Workload HEART RATE VARIABILITY
CLINICAL MANIFESTATIONS of POSTmeal HYPERGLYCEMIA (PmH) – IDF 2007
36
(IDF-2007, Summarized : Tjokroprawiro 2010-2015)
OTHER EVIDENCE of STATEMENT on POSTmeal HYPERGLYCEMIA 1 PmH causes OXIDATIVE STRESS, INFLAMMATION, and ENDOTHELIAL DYSFUNCTION
2 PmH is Associated with IMPAIRED COGNITIVE FUNCTION in ELDERLY PEOPLE with T2DM 3 PmH is Associated with : INCREASED RISK OF RETINOPATHY 4 PmH is Associated with INCREASED CIMT 5 PmH is Associated with MYOCARDIAL BLOOD VOLUME and REDUCED MYOCARDIAL BLOOD FLOW 6 PmH is Associated with INCREASED RISK OF CANCER ASK-SDNC
PROSEDUR PEMANTAUAN (MONITORING)
37
(Konsensus PERKENI-2015, Provided : 2015) 1 Tergantung dari tujuan pemeriksaan tes dilakukan pada waktu (B): 1. • Sebelum makan • 2 jam sesudah makan. Tjokroprawiro sejak 2014 (E) : 1 jam sesudah makan lebih akurat, based on Peak Prandial Plasma Glucose (ADA, 2015) • Sebelum tidur malam 2 Pasien dengan kendali buruk/tidak stabil dilakukan tes setiap hari 2. 3 Pasien dengan kendali baik/stabil sebaiknya tes tetap dilakukan secara rutin. 3. Pemantauan dapat lebih njarang (minggu sampai bulan) apabila pasien terkontrol baik secara konsisten 4 Pemantauan glukosa darah pada pasien yang mendapat terapi insulin, ditujukan 4. juga untuk penyesuaian dosis insulin dan memantau timbulnya hipoglikemia (E) 5 Tes lebih sering dilakukan pada pasien yang melakukan aktivitas tinggi , pada 5. keadaan krisis , atau pada pasien yang sulit mencapai target , atau (sering hiperglikemi/sering hipoglikemia ), juga pada saat perubahan dosis terapi *ADA menganjurkan pemeriksaan kadar glukosa darah malam hari (bed-time) dilakukan pada jam 22.00 ASK-SDNC
SASARAN (TARGET) PENGENDALIAN DM
38
(Konsensus PERKENI-2015, Provided : 2015)
PARAMETER
SASARAN
IMT (kg/m2) Tekanan darah sistolik (mmHg) Tekanan darah diastolik (mmHg) Glukosa darah preprandial kapiler (mg/dL)
18,5 - < 23* < 140 (B) <90 (B) 80 – 130**
Glukosa darah (Peak Prandial Plasma Glucose, ADA-2015) 1-2 jam PP kapiler (mg/dL)
<180** Peak Prandial biasanya terjadi 1 jam Post Prandial ***)
HbA1c (%) Kolesterol LDL (mg/dL)
< 7 (atau individual) (B) <100 (<70 bila risiko KV sangat tinggi) (B)
Kolesterol HDL (mg/dL) Trigliserida (mg/dL)
Laki-laki: >40; Perempuan: >50 (C) <150 (C)
ASK-SDNC
Keterangan : KV = Kardiovaskular, PP = Post Prandial *The Asia-Pacific Perspective: Redefining Obesity and Its Treatment, 2000 ** Standards of Medical Care in Diabetes, ADA 2015 *** Tjokroprawiro sejak 2014
THE ROLES of
APIDRA
&
LANTUS
39
to TARGET HbA1c<7%
(Monnier et al 2003, Clinical Experience & Provided : Tjokroprawiro 2012-2015)
PPG
FPG
CONTRIBUTION (%)
100 80 60 40 20 0 <7.3 n=58
7.3–8.4 n=58
PPG APIDRA® ASK-SDNC
8.5–9.2 n=58
9.3–10.2 n=58
HbA1c, % APIDRA®
LANTUS®
>10.2 n=58
FPG LANTUS®
TARGET TREATMENT : STANDARDS OF MEDICAL CARE IN DIABETES ADA 2014-2015 (ADA-2015, PERKENI 2015,Summarized : Tjokroprawiro 2010-2015)
GLYCEMIC CONTROL (D) :
ADA 2015, PERKENI 2011
A1C (PRIMARY TARGET FOR GLYCEMIC CONTROL) PRE PRANDIAL CAPILLARY PLASMA GLUCOSE (PPG)
< 7% *) INA : < 7%
80-130 mg/dL PEAK PRANDIAL CAPILLARY PLASMA GLUCOSE (1hPG) < 180 mg/dL BLOOD PRESSURE-ADA 2015 (H) : < 140/90 mmHg **)
LIPIDS (L) :
LDL-C < 100 mg/dL ***)
Severe Hyper-TG (>1000 mg/dL): Immediate Tx with Fibric Acid Deriv or Fish Oil to Reduce the Risk of Acute Pancreatitis. If HDLChol < 40 mg/dL and LDL-Chol 100-129 mg/dL a Fibrate or Niacin might be used. CV Risk is more Important than LDL-C Target ***)
GA : Glycated Albumin (11-16%)
MAGE : PPG 80-130, 1hPG<180 Mean Amplitude of Glucose Excursion
TARGET : A1C < 7% Surabaya (outpatient clinic) (64.2 %, n : 500) Tjokroprawiro, 2010
* More or less stringent glycemic goals may be appropriate for individual patients. Goals should be individualized based on duration of diabetes, age/life expectancy, comorbid conditions, known CVD or advanced microvascular complications, hypoglycemia unawareness, and individual patient considerations. ** Based on patient characteristics and response to therapy, lower SBP targets may be appropriate. ***OVERT OVERTCVD: CVD:AALOWER LOWERLDL LDLCHOL. CHOL.GOAL GOALOF, OF 70 70 mg/dL, mg/dL, USING USINGAA HIGH HIGH DOSE DOSE OF OFAASTATIN, STATIN, IS IS AN AN OPTION OPTION *** DM––OVERT OVERTCVD CVDWITH WITHHIGH-INTENSITY HIGH-INTENSITYSTATIN STATINTHERAPY. THERAPY. DM CLINICAL PRACTICE RECOMMENDATIONS, FOCUS ON GDM – ADA 2015 1 GDM was defined as any degree of glucose intolerance with onset or first recognition during pregnancy. 1. 2 Women with diabetes in the First Trimester should receive a diagnosis of OVERT, not gestational, DIABETES. 2. 3. 3 The Diagnosis of GDM (“One Step” with 2-h 75-g OGTT) is made when ANY of the FOLLOWING PLASMA GLUCOSE VALUES in mg/dL (week 24-28) are EXCEEDED: Fasting > 92; 1 h > 180; 2 h > 153. (IADPSG consensus). IADPSG : International Association of Diabetes and Pregnancy Study Groups. 4. 4 TARGET TREATMENT of GDM : Preprandial <95, and either 1-h Postmeal < 140 or 2-h Postmeal < 120
ASK-SDNC
40
METHOD-A : AMGA MORNING LANTUS® , with AMARYL-M® Metformin, Gliptin, Amaryl-M 41 Lantus with AMGA : Amary-M, Metformin, Gliptin, Amaryl-M (Clinical Experiences : Tjokroprawiro 2003-2015)
LANTUS® plus AMGA (AMARIL-M® - METFORMIN – GLIPTIN – AMARYL-M®): SAFE FOR MCR *) OAD is Given if HOMA-B > 25%
The ROLE of HOMA-B in CTOI (N: 70-150%) 1. HOMA-B > 25% : Use Basal + Met + Gliptin + OAD*) FX2 : FORMULA X 2 or 2. HOMA-B > 25% : Use Basal Plus + Met + Gliptin + OAD*) ) F X 1: FORMULA X1 3. HOMA-B > 25% : Use Basal-Bolus + Met + Gliptin + OAD* 4. HOMA-B < 25% : Use Basal-Bolus + Met + Gliptin + No OAD*)
MCR: Metabolic, Cardioprotective, BREAKFAST : 6.30 am Renoprotective Fritsche et al 2003 MORNING LANTUS (METHOD – A) is BETTER than BEDTIME LANTUS (METHOD – B)
MORNING LANTUS® 6-30 u sc AMARYL-M® ASK-SDNC
LUNCH : 0.30 pm
DINNER : 6.30 pm
PRANDIAL APIDRA® ( FX2)
PRANDIAL APIDRA® ( FX2)
9.30 am
3.30 pm
9.30 pm
Snack
Snack
Snack
OPTIONAL Tx METFORMIN (MET), GLIPTIN
AMARYL-M®
LANTUS® in combination with AMARYL-M® in METHOD-A is the rationale theurapeutic regimen in the management of T2DM for better MCR: glycemic control (M), for risk reduction of CVDs (C), and for of cancer protection (C)
42
THE ROLES OF RUMUS KALI DUA : FORMULA X2 in RGC INDICATED FOR HYPERGLYCEMIA*) > 200 mg/dL IN DAILY PRACTICE (Clinical Experiences : Tjokroprawiro 2007-2015)
*) One Hour Post Prandial or Random Hyperglycemia RC : RAPID CONTROL
SC-INJECTION : FORMULA X2. RC with APIDRA ...Unit/Once (!) For Out- and In- Patients IF HYPERGLYCEMIA >200 mg/dL RGC : Rapid Glycemic Control Exp.: BS 240 mg/dL
APIDRA Dose (SC): 2 x 2 = 4u /once APIDRA
BS 380 mg/dL
APIDRA Dose (SC): 3 x 2 = 6u /once APIDRA
BS 450 mg/dL
APIDRA APIDRA
APIDRA® ASK-SDNC
Dose (SC): 4 x 2 = 8u /once
Onset of Action 5 – 15 Minutes, : Peak 1-2 Hours, Duration of Action 3-4 Hours
43
THE ROLES OF RUMUS KALI SATU: FORMULA X1 in RGC INDICATED FOR HYPERGLYCEMIA*) > 200 mg/dL IN DAILY PRACTICE (Clinical Experiences : Tjokroprawiro 2007-2015)
*) ONE HOUR POST PRANDIAL OR RANDOM HYPERGLYCEMIA
FORMULA X1 RC with S.C. Rapid - Ins : can be Repeated on Indication *) For Out- and In- Patients RGC : Rapid Glycemic Control IF HYPERGLYCEMIA >200 mg/dL Exp.:
BS 240 mg/dL
APIDRA®
Dose : 2 x 1 = 2u /once
BS 380 mg/dL
APIDRA®®
Dose : 3 x 1 = 3u /once
BS 450 mg/dL
APIDRA®
Dose : 4 x 1 = 4u /once
APIDRA®: ASK-SDNC
Onset of Action 5-15 Minutes, Peak 1-2 Hours, Duration of Action 3-4 Hours
The 34 ENDOCARDIOMETABOLIC PROPERTIES OF INSULIN (The Multitude of Insulin Effects)
44
(Summarized – Illustrated : Tjokroprawiro and Murtiwi 2009-2015) 25 24 23
Cell Cycle and Proliferation and Diff. of Cell Uric Acid Clearance Uric Acid Formation
RESTORE LH, FSH, TESTOSTERON
21 MATURATION OF ADIPOCYTE (mTORC1, CREB, C/ EBP, GPDH) 20
LIPOLYSIS via HSL (Hormone Sensitive Lipase)
19 LIPOGENESIS via LPL (Lipoprotein Lipase) 18
PROTEIN SYNTHESIS
17
FA & AA to Ketoacids AA Transport
16 15
GLYCOGEN SYNTHESIS BONE ANABOLIC ( OSTEOGENESIS)
ASK-SDNC
2
ANTI-INFLAMMATION IB, NFB, TNF, ICAM-1, MCP-1, CRP
4
Egr : TF, PAI-1, Ap-1 ( MMPs)
(Avogaro et al 2011)
27
HSP 70 / 72 / 90 (Wound Healing, Etc)
30 CORTICOSTERON-DEPENDENT INSULIN RESISTANCE
CARDIO-PROTECTION (ANIMALS, HUMAN)
3
29 EPCs SURVIVAL
ANDROGEN :
DHEAS, ANDROSTENE-DIONE, TESTO, DH TESTOSTERONE 22
1 GLYCEMIC CONTROL GLUT-4 Synt. & Transl, Glucose, A1C
ANTI-ATHEROSCLEROSIS 5 NADPH oxidase, ROS, IB, NFB ( ICAM, MCP, CRP) 6
PROFIBRINOLYSIS ( PAI-I)
7
VASODILATATION ( eNOS, iNOS, NO)
34 Mt Biogenesis, Oxidative Capacity, ATP
8
ANTI-PLATELET ( c-AMP)
33 Brain : Appetite & Energy Expenditure
9
34 INSULIN PROPERTIES
32 PLASMA ARGINASE ACTIVITY
10
ANTI-APOPTOSIS (Heart, Brain, Cell)
11
ANTI-OXIDANT ( ROS)
12
ADMA : PLASMA & END. ( NO : RENOFIBROSIS)
31 GLUCAGON SECRETION 14 GROWTH DEVELOPMENT HYPOTHETICAL WAY TO TUMOR VIA IGF1 – RECEPTOR ? 28 ARTERIAL VASODILATOR (SKELETAL MUSCLE VASCULAR BEDS)
ANTI-THROMBOSIS ( TISSUE FACTOR)
13
RONS ( RENAL FIBROSIS)
26 VASPIN mRNA IS INCREASED WITH INSULIN INJECTION IN SEVERE INSULIN RESISTANCE
