DPP-4 inhibitor
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Oral Agents for Diabetes - OADs for Pts with T2DM (PDCI: Terapi Oral Individual) 2015 33-1082-M 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 PRACTITIONERS PDCI Partnership for Diabetes Control in Indonesia ASKES / BHAKTI HUSADA, MoH, PERKENI, ADA, SANOFI TUBAN (MUSTIKA HOTEL), 18-20 DECEMBER 2015 ASK-SDNC 1 2 TUJUAN PEMBELAJARAN PDCI-WORKSHOP • DAPAT MENGETAHUI “Pharmacological Agents”: “Oral Agents for Diabetes” (OADs) YANG PADA SAAT INI TERSEDIA DI INDONESIA • DAPAT MENGETAHUI KEAMANAN DAN EFIKASI DARI BERBAGAI VARIASI GOLONGAN OBAT ANTI DIABETIK oral (OAD) ASK-SDNC DICTIONARY OF ORAL ANTI DIABETES (OAD) IN DAILY PRACTICE 3 (Summarized : Tjokroprawiro 1996-2015) I 1 SUs : Gliquidone, Glipizide, Gliclazide, Glibenclamide, Glimepiride 2 NON-SUs (Metaglinides : Nateglinide, Repaglinide) 3 DPP-4 Inhibitors 4 GLIMIN (new tetrahydrotriazine-containing class) : IMEGLIMIN (1500 mg twice/day) : Insulin, Muscle glucose uptake, HGP 5 GPR40 Agonist (TAK-875) : 50-200 mg once/day. The long-chain FAs amplify glucose-stimulated insulin secretion, GLP-1 6 GPR119 Agonist 7 GPR120 Agonist 8 GPR142 : Insulinotropic and -cell Proliferation (ADA 2015) II INSULIN SENSITIZERS INSULIN SECRETAGOGUES (Rosi-*), Pio-, Neto-, Dar-glitazone) 1 THIAZOLIDINEDIONES (TZDs): Glitazone Class *) Withdrawn 2 NON-TZDs : a Glitazar Class (Mura-*), Raga-, Ima-, Tesa-, Saroglitazar**) : MRITS **) A Novel dual PPAR / agonist approved in India for Tx Diabetic Hyper TG b Non-Glitazar Class (Metaglidasen : Non Edema and Non Weight Gain) 3 BIGUANIDE : METFORMIN, DLBS-3233 (Inlacin®) METFORMIN, METFORMIN XR (Glucophage XR), 3-Guanidinopropionic-Acid 4 5 Dopamine-2 Agonists (Bromocriptime) : Activates Dopaminergic Receptors ( Insulin Sensitivity & No Hypoglycemia, ?CVD Events) 6 DPP-4 Inhibitors 7 Methazolamide (ALT and Weight Loss) 8 Berberine (Chinese Herb) ***) : Insulin Sensitizer and Incretin Enhancer 1 2 III INTESTINAL ENZYME INHIBITORS IV INCRETIN-ENHANCERS (Gliptin – Class) V FIXED DOSE COMBINATION (FDC) TYPES Glucophage XR, DPP-4 INHIBITORS : 13 Sita-, Vilda-, Saxa-, Lina- , Alo-, Dena-, Duto-, Melo-, Teneli-, Omari-, Gosogliptin, SYR-322, TA-666 Glucovance®, VI OTHER SPECIFIC (OS) TYPES -Glucosidase Inhibitor (AGI): Acarbose -Amylase Inhibitor (AMI): Tendamistase Amaryl-M®, Janumet® , Xigduo * Glyxambi® (empaglifozin + linagliptin) (dapa + met) Invokamet® (cana + met) XR Galvusmet®, Kombiglyze®XR, Trajenta®Duo, Actosmet® 1 Sodium GLucose co Transporter-2 (SGLT2)-Inhibitors (12): Dapagliflozin (Farxiga® 10 mg, FDA-2014), Canagliflozin (Invokana® 100mg, 300mg, FDA-filed), Empaglifozin (Jardiance® 10mg, 25mg, Phase-III), Ipragliflozin (Ph-III), Tofogliflozin (Ph-III), BI 44847 (Ph-II), LX-4211 (Ph-II), PF-04971729 (Ph-II), TS-071 (Ph-II), ISIS 388626 (Ph-I), Seragliflozin (?), Remogliflozin (?), YM-543, BI 10773, 3 Oxphos-Blocker 4 FBPase – Inhibitor KGT-1681, ASP1941, AVE-2268 2 Glucokinase Activator (GKA): MTBL1, MK-0941. 5 INCB13739 (11HSD1–inhibitor) 6 Berberine ***) : Rhizomacoptidis ASK-SDNC Increased Glucagon Secretion Islet- cell LIVER Decreased Glucose Uptake 4 MUSCLE 2 PANCREAS 3 4 TZDs MET TZDs (PIPOD), SU, GLP-1RA, DPP4-i Decreased Insulin Secretion 1 Islet-β cell Neurotransmitter Dysfunction 7 DPP4-i 5 GLP1-RA TZDs ADIPOSE 6 KIDNEY Increased Glucose (DeFronzo 2009, Provided : Tjokroprawiro 2015) Reabsorption THE OMINOUS OCTET INTESTINES Decreased Incretin Effect SGLT2-I BRAIN (Hepatic Glucose Product) MET TZDs HYPERGLYCEMIA 8 Increased HGP Increased Lipolysis CURRENT AVAILABLE OADS AND NON-INSULIN INJECTABLES IN INDONESIA 1 METFORMIN 2 SULFONYLUREAS (SUs) AND GLINIDES 3 ΑLPHA-GLUCOSIDASE INHIBITORS (AGIS) PIPOD : Pioglitazone In Prevention Of DM (Xiang et al 2006) ASK-SDNC 4 THIAZOLIDINEDIONES (TZDs) 5 DIPEPTIDYL PEPTIDASE-4 INHIBITORS (DPP4-Is): ORAL (DPP-4 INHIBITORS : DPP-4Is=INCRETINS) 6 GLP-1 RA : SC INJECTION THE TRIUMVIRATE : PANCREAS, MUSCLE, LIVER PATOFISIOLOGI DMT2 : THE OMINOUS OCTET 5 (De Fronzo 2009) Insulin Secretion Glucose Production Glucose Uptake α Glucagon Secretion Lipolysis Glucose Reabsorption ASK-SDNC HYPERGLYCEMIA Incretin Effect Neurotransmitter Function β 6 Mekanisme Kerja Obat Anti Diabetes oral Insulin Glucose Production α Glucagon Secretion Metformin GLP-1s DPP-4Is Sulfonylureas TZDs GLP-1s DPP-4Is Insulin TZDs Metformin Glucose Uptake GLP-1s Incretin Effect NORMOGLYCEMIA DPP-4Is Lipolysis TZDs GLP-1s Glucose Reabsorption ASK-SDNC Insulin Secretion SGLT2-Is Neutransmitter Function β TERAPI ANTIHIPERGLIKEMIK DMT2 REKOMENDASI UMUM (Diabetes Care, Diabetologia. 19 April 2012 [Epub ahead of print]) Makanan Yang Sehat, Kendali Berat Badan, Aktifitas Fisik OBAT MONOTERAPI PERTAMA METFORMIN Efikasi (HbA1c) Tinggi Hipoglikemia Risiko Rendah Berat Badan Tetap / Berkurang Efek samping Saluran Cerna / Asidosis Laktat Biaya ASK-SDNC Rendah 7 TERAPI ANTIHIPERGLIKEMIK DMT2 REKOMENDASI UMUM 8 Diabetes Care, Diabetologia. 2015 [Epub ahead of print] Makanan Yang Sehat, Kendali Berat Badan, Aktifitas Fisik OBAT MONOTERAPI PERTAMA KOMBINASI DUA OBAT METFORMIN + SGLT-2 Inhibitor GLP-1-R Agonis Insulin (Umumnya Basal) Sulfonilurea Thiazolidinedion DPP-4 Inhibitor Tinggi Tinggi Sedang Rendah Tinggi Tertinggi Hipoglikemia Risiko Sedang Risiko Rendah Rendah Rendah Risiko Rendah Risiko Tinggi Berat Badan Meningkat Meningkat Tetap Menurun Menurun Meningkat Hipoglikemia Edema, HF Angiodema Dehidrasi Saluran Cerna Hipoglikemia Sedang Sedang Tinggi Tinggi Tinggi Bervariasi Efikasi (HbA1c) Efek Samping Biaya Jika diperlukan untuk mencapai target A1C tertentu setelah ~3 bulan, dapat diberikan kombinasi dua obat (urutan kolom tabel diatas tidak berarti urutan prioritas pilihan) ASK-SDNC TERAPI ANTIHIPERGLIKEMIK DMT2 REKOMENDASI UMUM 9 (Diabetes Care, Diabetologia. 2015 [Epub ahead of print]) Makanan Yang Sehat, Kendali Berat Badan, Aktifitas Fisik OBAT MONOOTERAPI PERTAMA KOMBINASI DUA OBAT KOMBINASI TIGA OBAT METFORMIN + SGLT-2 Inhibitor GLP-1-R Agonis Insulin (Umumnya Basal) Sulfonilurea Thiazolidinedione DPP-4 Inhibitor + TZD + SU + SU +SU + SU + TZD Atau DPP-4-i atau DPP-4-I Atau TZD Atau TZD atau TZD Atau DPP-4-i Atau SGLT-2-i Atau SGLT-2-I Atau SGLT-2-I Atau DPP-4-i Atau insulin Atau SGLT-2-i Atau GLP-1-RA Atau GLP-1-RA Atau Insulin Atau Insulin Atau Insulin atau Insulin atau GLP-1-RA Jika diperlukan untuk mencapai target A1C tertentu setelah ~3 bulan, dapat diberikan kombinasi tiga obat (urutan kolom tabel diatas tidak berarti urutan prioritas pilihan) ASK-SDNC TERAPI ANTIHIPERGLIKEMIK DMT2 REKOMENDASI UMUM 10 (Diabetes Care, Diabetologia. 2015 [Epub ahead of print]) Makanan Yang Sehat, Kendali Berat Badan, Aktifitas Fisik OBAT MONOTERAPI PERTAMA KOMBINASI DUA OBAT KOMBINASI TIGA OBAT METFORMIN + SGLT-2 Inhibitor GLP-1-R Agonis Insulin (Umumnya Basal) Sulfonilurea Thiazolidinedione DPP-4 Inhibitor + TZD + SU + SU +SU + SU + TZD Atau DPP-4-i atau DPP-4-I Atau TZD Atau TZD atau TZD Atau DPP-4-i Atau SGLT-2-i Atau SGLT-2-I Atau SGLT-2-I Atau DPP-4-i Atau insulin Atau SGLT-2-i Atau GLP-1-RA Atau GLP-1-RA Atau Insulin Atau Insulin Atau Insulin atau Insulin atau GLP-1-RA Strategi Insulin Yang Lebih Kompleks Insulin (Dosis Multipel) ASK-SDNC Jika kombinasi terapi termasuk didalamnya basal insulin gagal mencapai HbA1c setelah 3-6 bulan, dapat dimulai strategi insulin yang lebih kompleks, biasanya dikombinasi dengan 1-2 agen non insulin Obat Anti Diabetes oral (OAD) di Indonesia Kelas Sulfonilurea Generik Durasi kerja (jam) Frek/ hari 1.5 Keduanya Keduanya 12-24 1-2 Glipizid 5-10 5-20 12-16 1 30,60,80 30-320 24 1-2 30 30-120 6-8 2-3 1,2,3,4 0.5-6 24 1 Repaglinid 1 1.5-6 3 1-1.5 Nateglinid 120 360 3 0.5-0.8 GDPP 15-30 15-45 50-100 100300 5-10 5-10 Pioglitazon 18-24 1 Tidak tergantung asupan makanan 0.5-1.4 GDP 3 Bersama suapan pertama 0.5-0.8 GDPP 1 Tidak tergantung asupan makanan 0,8-1,0 TZD Acarbose Dapagliflozin SGLT -2 Inhibitor GDP vs. GDPP 2.5-15 Gliklazid 24 Sebelum makan Penurun an A1C 2.5-5 Glimepiride α-Glucosidase Inhibitor (AGI) Waktu Glibenklamid Glikuidon Glinid Dosis Harian (mg) Mg/tab 11 Konsensus PERKENI : Pengelolaan dan Pencegahan Diabetes Melitus Tipe 2, Guidelines 2015 ASK-SDNC Obat Anti Diabetes oral (OAD) di Indonesia 2,5/500 Biguanid DPP-IV Inhibitor Generik ASK-SDNC Dosis harian (mg) Durasi kerja (jam) Frek/ hari Metformin 500-850 500-3000 6-8 1-3 Metformin XR 500-750 500-2000 24 1 Vildagliptin 50 50-100 12-24 1-2 Sitagliptin 25,50,100 25-100 24 1 5 5 24 1 12-24 1-2 Saxagliptin Linagliptin Obat Fixed Dose Combination (FDC) Mg/tab Metformin+ Glibenclamide 25-500/ 1.25-5 Glimepiride + Metformin 1-2/ 250-500 Pioglitazone+ Metformin 15-30/ 500-850 Sitagliptin + Metformin 50/ 500-1000 Vildagliptin + Metformin 50/ 500-1000 Saxagliptin + Metformin 5/500 1 Litagliptin + Metformin 2,5/500 2,5/850 2 1-2 Mengacu dosis maksimum masing – masing komponen 18-24 1 2 12-24 2 12 Penurunan A1C GDP vs GDPP Bersama atau sesudah makan 1.5 GDP Tidak tergantung asupan makanan 0.6-0.8 Kedua nya Waktu Bersama atau sesudah makan Bersama, atau sesudah makan 13 ALGORITME PENGOBATAN Panduan Dalam Memilih Intervensi Terapi Yang Tepat ASK-SDNC Profil Pengelolaan Diabetes di Indonesia DiabCare Asia 2008 (Soewondo Med J Indones 2010;19:235-244 ) VARIABEL PENGELOLAAN • Diet • Insulin Monoterapi • Insulin & OAD Kombinasi • OAD Monoterapi • Herbal • Tanpa Pengobatan *n = 1785 ASK-SDNC n (%)* 317 (17.31) 356 (19.44) 1133 (61.88) 5 (0.27) 20 (1.09) 14 Profil Pengelolaan Diabetes di Indonesia DiabCare Asia 2008 (Soewondo Med J Indones 2010;19:235-244 ) VARIABEL n (%)* JENIS OAD • Biguanide • Sulfonilurea • Meglinitide 1085 (59.26) 1036 (56.58) 8 (0.44) • Alfa Glucosidase Inhibitor (AGI) • TZD • OAD Lainnya 461 (25.18) 51 (2.79) 48 (2.62) • Tradisional Herbal • Kombinasi Dua Obat (Fixed Dose Combination=FDC) 5 (0.27) 88 (4.81) ASK-SDNC 15 MEKANISME KERJA OBAT ANTI DIABETES ORAL 16 (DeFronzo 1999, Provided : 2013-2015) AGENTS • SULPHONYLUREAS • GLINIDS • INCRETINS* (GLP-1 & GIP) • BIGUANIDES • THIAZOLIDINEDIONES • -GLUCOSIDASE INHIBITORS (AGIs)) • THIAZOLIDINEDIONES • BIGUANIDES • DPP-4 INHIBITORS ASK-SDNC SITE OF ACTION MOA INSULIN SECRETION INSULIN* AND GLUCAGON* HEPATIC GLUCOSE PRODUCTION SLOW CARBOHYDRATE DIGESTION PERIPHERAL INSULIN SENSITIVITY 17 BIGUANID JENIS – Metformin – Metformin Hydrochloride Lepas Lambat (Metformin XR) FARMAKOLOGI – Mengurangi Produksi Glukosa di Hati – Meningkatkan Ambilan Glukosa (Dengan Mediasi Insulin) di Perifer ASK-SDNC BIGUANID 18 EFIKASI – Menurunkan Gula Darah Puasa 60 – 70 mg/dL (3.3-3.9 mmol/L) – Menurunkan A1C 1.0 – 2.0% PERTIMBANGAN – Menekan Nafsu Makan – Diare dan rasa tidak nyaman di perut (sering hilang timbul) – Asidosis Laktat (MALA : Metformin Associated Lactic Acidosis) – Sedikit penurunan kolesterol LDL dan trigliserida – Tidak menyebabkan kegemukan (kemungkinan penurunan berat badan ringan-sedang) – DAPAT TERKAIT DENGAN DEFISIENSI VITAMIN B12 – Harus hati-hati pada pasien dg gangguan ginjal Kontraindikasi jika kreatinin serum > 1.4 mg/dL pd wanita dan 1.5 mg/dL pada pria (US. FDA-2011), atau lebih tepatnya bila GFR sama/kurang dari 30 mL/menit (most accepted) ASK-SDNC Nathan DM et al. Diabetes Care 2009; 32(1):193-203. 19 METFORMIN : MODE OF ACTION The Primary Effects of METFORMIN are to DECREASE HGP and INCREASE insulin-mediated PERIPHERAL GLUCOSE UPTAKE INTESTINE Anaerobic Glucose Metabolism LIVER MUSCLE Gluconeogenesis Glucose Uptake Glucose Uptake Glycogenolysis Glucose Oxidation Glucose Oxidation Oxidation of FA Glycogenesis ADIPOSE TISSUE Oxidation of FA FA: Fatty Acids HGP : Hepatic Glucose Product Krentz, Bailey. Drugs 2005;65:385–411 ASK-SDNC SC = SERUM CREATININE eGFR S THE FORMULA OF COCKROFT – GAULT : eGFR (estimated GFR) CREATININE CLEARANCE Other FORMULA : MDRD (Modification of Diet in Renal Disease) (Summarized : 2010-2015) (140-AGE) X BODY WEIGHT (Kg) eGFR (o ) = (mL/min.) PLASMA CREATININE (mg/dL) x 72 (140-AGE) X BODY WEIGHT (Kg) eGFR ( o+ ) x 0.85 = (mL/min.) PLASMA CREATININE (mg/dL) x 72 ASK-SDNC 20 The 3 Main Cardioprotective Properties of Metformin 21 (Wang et al 2006, Piwkowska et al 2010, Viollet et al 2012, Illustrated : Tjokroprawiro 2013-2015) METFORMIN ENERGY SUPPLY Metabolic Switch from Lipid to Glucose (Glucose Requires Lower O2 than Lipid) Circulating FFA in Hyperadrenergic States (Notably – Cardiotoxic Action) CARDIAC FIBROSIS AMPK : Smad3 Phosphorylation, Downstream Effector of TGF-β1 Cardiac Fibrosis eNOS phosphorylation : TGF-β1 and βFGF in Circulation and Myocardium Cardiac Fibrosis THE HEART CARDIAC APOPTOSIS CARDIOPROTECTIVE Effects of METFORMIN AMPK: eNOS Phosphorylation results in Plasma NO, Myocardial NO, Improved Endothelial Function, Preserved EF, LV Dilatation, LV End-Diastolic Pressure, Myocardial Autophagy, Cardiac Apoptosis METFORMINand andHEART HEART FAILURE: FAILURE: NEVER METFORMIN NEVERSAY SAYNEVER NEVERAGAIN AGAIN 1 Metformin Reduced Incidence of New Heart Failure and Cardiovascular Mortality 2 Metformin Improved Survival in Patient with HF (Heart Failure) THUS, THE ARGUMENT FOR METFORMIN PRESCRIPTION IN HF IS QUITE STRONG (Papanas et al 2012) ASK-SDNC THE 3 MAIN POSSIBLE RENOPROTECTIVE PROPERTIES OF METFORMIN 22 (Wang et al 2006, Piwkowska et al 2010, Viollet et al 2012, Illustrated: Tjokroprawiro 2013-2015) 1 REDUCED HIF-1 CHRONIC HYPOXIA as the CONSEQUENCY OF INCREASING HIF-1DIABETIC NEPHROPATHY (DN) METFORMIN REDUCES HIF-1 RENAL CHRONIC HYPOXIA METFORMIN RENAL CHRONIC HYPOXIA RENAL FIBROSIS DN 1 METFORMIN 3 REDUCED LIPOTOXICITY Metformin Reduces Kidney TG Content 3 (Lipotoxicity) by Decreasing SREBP-1, FAS and ACC Expression in the Kidney DN is Correlated with Kidney TG Content NEPHROPATHY METFORMIN RENOPROTECTIVE PROPERTIES 2 SUPPRESSED GLUCOTOXICITY 2 AMPK NADPH OXIDASE ROS IN PODOCYTES DIABETIC NEPHROPATHY 1. HIF-1 (Hypoxiainducible Factor-1) CHRONIC HYPOXIA: the initiation and progression of RENAL FIBROSIS and DIABETIC NEPHROPATHY (DN). Metformin Decreaes Renal Oxygen Consumption 2. GLUCOTOXICITY (hyperglycemia). Metformin ACTIVATES AMPK and DECREASES the NADPH oxidase activity, ultimately leading to a Decreased ROS production in RENAL PODOCYTES, thus preventing to the Development of DN 3. LIPOTOXICITY (Increased Kidney TG Content). The Reduction in RENAL LIPOTOXICITY by METFORMIN, by Decreasing SREBP-1, FAS and ACC expression in the Kidney could thus be a NEW STRATEGY FOR THE PREVENTION of DN ASK-SDNC STAGES OF CHRONIC KIDNEY DISEASE (CKD) 23 (ADA-2015) 1 Kidney Damage with Normal or Increased GFR > 90 Stage 1. mL/min/1.73 m2 2 Kidney Damage with Mildly Decreased GFR 60-89 Stage 2. mL/min/1.73 m2 3 Moderately Decreased GFR 30-59 mL/min/1.73 m2 Stage 3. 4 Severely Decreased GFR 15-29 mL/min/1.73 m2 Stage 4. Stage 5. 5 Kidney Failure <15 or Dialysis The terms “MICROALBUMINURIA” (30–299 mg/24 h) and “MACROALBUMINURIA” (>300 mg/24 h) will will no no longer longer be be used used , since albuminuria occurs on a continuum. ALBUMINURIA IS DEFINED AS UACR >30 mg/g. ASK-SDNC UACR : Urine Albumin to Creatinine Ratio METFORMIN (Met) : INDICATION AND CONTRA INDICATION 24 (Multiple Sources, Summarized : Tjokroprawiro*) 1994-2015) INDICATION OBESE PERSONS, OBESE-DM, NON OBESE-DM, WITH “HEALTHY” : HEART, LUNG, KIDNEY, and LIVER. INDICATION SHOULD BE NO TISSUE HYPOXIA , such as : INFECTION, GANGRENE, Etc. CONTRAINDICATION 1 CHEST : CONGESTIVE HEART FAILURE (HF) needing Drug Treatment HF with Ejection Fraction (EF) < 50%, but not for ISOLATED HF COPD 2 ABDOMEN : a KIDNEY : a. • if eGFR < 60 mL/min : be caution! • Stop Met. if S-CREATININE > 1.5 mg/dL for men, and > 1.4 mg/dL for women, or if eGFR <50mL/min (US. FDA-2011) • CDA (Canadian Diabetes Association)-2008, Most Accepted : Stop Metformin if eGFR<30mL/min b LIVER : SGOT/SGPT > 2-3 x Normal Value b. 3 OTHERS a. a ANY INFECTION (ACTIVE CELLULITIS/GANGRENE, UTI, ETC) b. b TISSUE HYPOXIA and Its ASSOCIATED CONDITIONS c. d. d INTRAVENOUS CONTRAST AGENTS c BREAST FEEDING PRECAUTION 1 AGE > 80 YEARS (SELECTIVE) 4 ALCOHOL INTAKE 4. 3 PREGNANCY 2 ACUTE MYOCARDIAL INFARCTION 3. 5 SURGICAL PROCEDURES 5. : No Met. XR/Day (Contraindication!) CLINICAL EXPERIENCES *) on CKD eGFR < 30 eGFR 30 – 40 : 500 mg Met. XR/Day Renal Function : eGFR mL/min eGFR 40 – 50 : 750 mg Met. XR/Day Met: Metformin Metformin XR (Met. XR) is eGFR 50 – 60 : 1000 mg Met. XR/Day Recommended eGFR > 60 : 1000 mg–1500 mg Met. XR/Day (CKD-St2) ASK-SDNC 25 SULFONILUREA JENIS SULFONILURIA – – – – – GLIMEPIRID GLIBENKLAMID GLIPIZID GLIKAZID GLIKUIDON FARMAKOLOGI – MENINGKATKAN SEKRESI INSULIN ENDOGEN – MEMPERBAIKI SENSITIVITAS INSULIN (GLIBENKLAMID, GLIMEPIRID) ASK-SDNC 26 MEKANISME KERJA SULFONILUREA (Provided : Tjokroprawiro 2013-2015) GLUCOSE GLUT2 SUCCINATE ESTERS SULFONYLUREAS, REPAGLINIDE, NATEGLINIDE, KAD1229 K+ATP CHANNEL (SUR-Kir6.2)4 GLUCOKINASE GLUCOSE METABOLISM PROINSULIN BIOSYNTHESIS PKA cAMP 2-ADRENOCEPTOR ANTAGONISTS GLP1, EXENDIN-4 ASK-SDNC INSULIN ATP RATIO DEPOLARIZATION ADP Ca2+-SENSITIVE PROTEINS Ca2+CHANNEL 2 1 3 EXOCYTOSIS PDE INHIBITORS INSULIN PANCREATIC B-CELL Trends in Pharmacological Sciences SULFONILUREA (Nathan DM et al. Diabetes Care 2009; 32:193-203) EFIKASI – Menurunkan Gula Darah Puasa 60-70 mg/dL (3.3-3.9 mmol/L) – Menurunkan A1C 1.0-2.0% PERTIMBANGAN KEAMANAN – Hipoglikemia – Kegemukan – Tidak berpengaruh pada Lipid Plasma (?) dan Tekanan Darah ASK-SDNC 27 ® EFFECT of AMARYL on ADIPONECTIN (Apn) LEVEL in NÄIVE T2DM (Surabaya Diabetes and Nutrition Centre: Adi, Tjokroprawiro, Ulfa Kholili 2007) HMW Adiponectin level (ng/mL) 1200 p=0.004 1000 942 800 600 681 400 Apn Apn 200 Before AMARYL® After AMARYL® BASELINE (WEEK-0) (WEEK-12) 0 n=20, 12 WEEK TREATMENT with AMARYL® ASK-SDNC 28 ADIPONECTIN WITH CARDIOPROTECTIVE PROPERTIES 29 Ouchi et al 2000-2001, Yamauchi et al 2001-2003, Arita et al 2002, Kobayashi et al 2004, Multiple Sources, Illustrated : Tjokroprawiro 2007-2015 ANTI INSULIN RESISTANCE I 1 II 1 ENDOTHELIUM : ACTIVATE AMPK 2 UPREGULATE INSULIN SIGNALING 3 ACTIVATE PPAR ANTI ATHEROSCLEROSIS A the Expression of Adhesion Mol. 5 ROLES OF ADIPONECTIN 4 TISSUE TG CONTENT : ICAM-1, VCAM-1, E-selectin; also TNF-induced NFB Activation B Endothelial Cell Apoptosis via AMPK Activation by HMW multiform of Adiponectin 2 MACROPHAGE : SRA-1, Uptake of Ox-LDL, Foam Cell 3 SMC : Cell Proliferation Migration V IV III ANTI APOPTOSIS BRAIN, HEART, -CELL ANTI INFLAMMATION INFLAMMATORY MARKERS ANTI OXIDANT OXIDATIVE STRESS ASK-SDNC THE 14 BENEFITS OF GLIMEPIRIDE ON CARDIOVASCULAR RISK (With 3 SUPPORTING COMPONENTS : A, B, C) 30 (Summarized and Illustrated : Tjokroprawiro 2012-2015) EVENTS OF ATHEROSCLEROSIS: Monocyte Adherence, 14 Differentiation of Mo, SMC Migration, OxLDL, Foam Cell, CIMT Pancreatic β-cells Specific (SUR1, Etc) Improvement of CVD A 1 A1C 2 ADIPONECTIN 3 PPAR 4 TNF INFLAMMATORY MARKERS ( hsCRP, IL-6, TNF) 13 NF-B ACTIVATION (Amaryl®) 12 ANTIOXIDANT ENZYME GENES (PARAOXONASE, SOD, CATALASE) 11 PAI-1 10 LESS HYPOGLYCAEMIA B ASK-SDNC GLIMEPIRIDE 14 BENEFITS ON CV RISK A-B-C 9 Insulin Resistance ( HOMA-R) 5 INSULIN RESISTANCE 6 LDL- C 7 Ox-LDL 8 PLATELET AGREGATION C MODEST WEIGHT GAIN REPAGLINIDE or DEXANORM® in BRIEF 31 UK Drug Information Pharmacists Group – May 1999, Kajosaari 2006, Hasslacher 2003, Schmoelzer 2006, Hoelscher et al 2008, Aoyagi 2009, AACE 2011, Summarized : Tjokroprawiro 2014-2015 1 2 3 4 REPAGLINIDE (DEXANORM®) A Short Acting Insulin - Secretagogue Repaglinide Should be Taken shortly Before main Meal Not to be taken if a Meal is Missed Repaglinide Excretion : Almost Entirely by Biliary & Faecal Routes SUITABLE for Pts with MILD/MODERATE RENAL IMPAIRMENT Repaglinide is Particularly Useful for DM Patients with PmH (Postmeal Hyperglycemia) 5 6 Reduction of PmH by Repaglinide may suppress ENDOTHELIAL DYSFUNCTION and OTHERS (as mentioned in PmH-IDF 2007) in a Glucose Dependent Manner DEXANORM® : ā1 mg or ā2 mg. Initially 0.5 or 1 mg before Main Meal. Maximum Single Dose @4 mg. Maximum Total Daily Dose 16 mg. ASK-SDNC 32 THIAZOLIDINEDIONE (TZD) JENIS TZD – Pioglitazone – Rosiglitazone (sudah ditarik dari peredaran) FARMAKOLOGI – Memperbaiki Sensitivitas Insulin – Menurunkan Resistensi Insulin dengan membuat Sel Otot dan Lemak lebih Sensitif terhadap Insulin – Menekan Produksi Glukosa di Hati ASK-SDNC MEKANISME KERJA THIAZOLIDINEDIONES (TZDs) INSULIN 33 GLUCOSE INSULIN RECEPTOR SYNTHESIS GLUT 4 PPAR PPRE PROMOTER ASK-SDNC mRNA RXR TRANSCRIPTION CODING REG Modified from Howard L. Foyt et al. Thiazolidinediones. Diabetes Mellitus: a Fundamental and Clinical Text, 2nd Ed. 34 THIAZOLIDINEDIONE (TZD) EFIKASI – Menurunkan Glukosa Darah Puasa : ~35-40 mg/dL (1.9-2.2 mmol/L) – Menurunkan A1C ~0.5-1.0% – Memerlukan 66 MINGGU MINGGU untuk mendapatkan Efek Maksimal ASK-SDNC THIAZOLIDINEDION (TZD) PERTIMBANGAN KEAMANAN – Kontraindikasi jika ALT (SGPT) >2.5 Diatas Batas Atas Normal – Kegemukan Ringan – Kontraindikasi jika terdapat Gagal Jantung Kongestif – Hipoglikemia – Edema Makula – Meningkatkan Risiko Fraktur The RECORD Study secara random menemukan bahwa rerata fraktur ekstremitas atas dan bawah meningkat pada perempuan yang menggunakan ROSIGLITAZON 1 ALT: alanine transaminase 1Home PD et al. Rosiglitazone evaluated for cardiovascular outcomes in oral agent combination therapy for type 2 diabetes (RECORD): a multicentre, randomised, open-label trial. Lancet. 373: 9681; 2125-2135, 2009. ASK-SDNC 35 36 ALFA-GLUCOSIDASE INHIBITOR (AGI) JENIS AGI (lihat Slide-3) – Acarbose (-Glucosidase Inhibitor =AGI) – Tendamistase (-Amylaze Inhibitor =AMI) – Miglitol FARMAKOLOGI – Memblok enzim yang Menyerap / Mencerna Oligosakarida di Usus Halus – Memperlambat Penyerapan Karbohidrat ASK-SDNC 37 MEKANISME KERJA ALFA-GLUCOSIDASE INHIBITOR ALPHA GLUCOSIDASE INHIBITOR (AGI) : ACARBOSE WITHOUT ACARBOSE WITH ACARBOSE STOMACH CARBOHYDRATE ABSORPTION UPPER SMALL INTESTINE CARBOHYDRATES LOWER SMALL INTESTINE CARBOHYDRATE ABSORPTION To be Administered After the 1st or 2nd Spoon of the Meal ASK-SDNC ALFA-GLUCOSIDASE INHIBITOR (AGI) 38 EFIKASI – Menurunkan Puncak Glukosa Darah Prandial : 40-50 mg/dL (2.2-2.8 mmol/L) – Menurunkan Glukosa Darah Puasa 20-30 mg/dL (1.4-1.7 mmol/L) – Menurunkan A1C 0.5-1.0% PERTIMBANGAN KEAMANAN – Kembung dan Rasa tidak Nyaman di Perut – Tidak berpengaruh pada Lipid Plasma & Tekanan Darah – Tidak menyebabkan Kegemukan – Kontraindikasi : Inflammatory Bowel Disease (IBD), Sirosis ASK-SDNC WORLDWIDE INITIATIVE FOR DIABETES EDUCATION (WIDE) 39 Calling for Fast Application of Emerging Incretin Therapies GLIPTINS : IN EARLY STAGE OF DIABETES MELLITUS (Rodring 2007, Summarized : Tjokroprawiro 2009-2015) GLP-1R AGONIST : GLP-1 RA SC INJECTION 1 Exenatide (Byetta) : Synthetic Incretin-Mimetic Isolated from Lizard Venom Synthetic Exendin-4, SC, bid (FDA, April 2005) 2 Exenatide Extended Release (Bydureon®), Once Weekly dosing and no titration 3 Lixisenatide *, (EMA, Feb 2013) SC (AVE0010) : Once-Daily 4 Liraglutide** (Victoza®) (FDA, 25 Jan 2010): Once-Daily 5 Dulaglutide (Trulicity®, Once-Weekly) 6 Semaglutide, Once Weekly **Saxenda® : for Obesity 7 Albiglutide (Tanzeum®) 9 LY2189265 8 Taspoglutide : Investigational 10 VRS-859 RESISTANT TO DPP-4, DUE TO : *) **) DPP-4 INHIBITOR : DPP-4i ORAL AGENTS 1 Sitagliptin @ 50, 100 mg (Januvia) : FDA 18 October 2006 Janumet® @ 50 mg : Metformin 500, 1000 mg (Available : INA 2011) 2 Vildagliptin @ 50 mg; bid 50 mg a. Galvus® : 50 mg (FDA 18 October 2008) b. Galvusmet® @ 50 mg : Metformin 500, 850 mg (FDA 2 November 2009) 3 a. Saxagliptin 5 mg (Onglyza®, FDA : 31 July 2009) b. Kombiglyze XR® @ 5 mg : Metformin 500mg (FDA: 5 November 2010) 4 a. Linagliptin (Trajenta® 5 mg, FDA:5 May 2011) b. TrajentaDuo® @ : Linagliptin 2.5 mg plus Met. Metformin 500, 850, 1000 mg 5 Alogliptin (Nesinal®) @ 6.25, 12.5, 25 mg (Japan 2010) 6 Denagliptin, 7 Dutogliptin, 8 Melogliptin 9 Teneligliptin 10 Omarigliptin 11 Gosogliptin 12 SYR-322 13 TA-666 SUSCEPTIBLE TO DPP-4 *) C-terminal Modification with six (6) Lysine Residues and one (1) Proline Deletion **) Lysine is Replaced with Arginine at Position 34, and Fatty Acid is Added at Position 26, Heptamer Formation, and Albumin Binding ASK-SDNC LIRAGLUTIDE (GLP-1RA) HAS BEEN APPROVED BY: 1 The European Medicines Agency (EMA) on 3 July, 2009 2 The U.S. Food and Drug Administration (FDA) on 25 January, 2010 3 The FDA (26 January 2010) Approved Liraglutide as a New Treatment for T2DM 40 DPP-4 INHIBITORS (DPP-4Is) JENIS DPP-4I – SITAGLIPTIN (Januvia® @ 50, 100 mg) – VILDAGLIPTIN (Galvus® @ 50 mg) – SAXAGLIPTIN (Onglyza® @ 5 mg) – LINAGLIPTIN (Trajenta® @ 5 mg) FARMAKOLOGI – Glucose-dependent Insulin Secretion – Glucagon Suppression ASK-SDNC MEKANISME KERJA DPP-4 INHIBITOR T2DM Diminished Incretin Response Insulin Further impaired HYPERGLYCEMIA islet function Glucagon DPP-4 inhibitor Prolonged Incretin Activity Insulin IMPROVED Improved islet GLYCEMIC CONTROL function Glucagon DPP-4=dipeptidyl peptidase-4 T2DM=type 2 diabetes mellitus Adapted from Unger RH. Metabolism. 1974; 23: 581–593. Ahrén B. Curr Enzyme Inhib. 2005; 1: 65–73. ASK-SDNC 41 ENDOCRINE AND NEURAL PATHWAYS FOR GLP-1 MEDIATED ACTIONS 42 (Burcelin 2001, Dardevet 2005, Holst 2005, Lonut 2005, Combettes 2006, Provided : 2009-2015) 1 SATIETY HYPOTHALAMUS MEAL GLUCOSE, FFA, PEPTONES MUSCLE ADIPOSE TISSUE INCRETINS GLP-1 DPP-4 GLP-1 ASK-SDNC EMPTYING INACTIVE GLP-1 STOMACH PORTAL GLP-1 Intestinal Capillaries DPP-4 DPP-4 DPP-4 (INTESTINE) Active GLP-1 3 GASTRIC VAGUS NERVE L-Cell 100% 2 PERIPHERAL GLUCOSE DISPOSAL LIVER 25% Portal Circulation 40% Inactivated 15% Systemic Circulation 4 GLUCAGON, INSULIN SECRETION PANCREAS 43 DPP-4 Inhibitor EFIKASI DPP-4I – Menurunkan Glukosa Darah Puasa ~20 mg/dL (~1 mmol/L) – Menurunkan A1C ~0.7% PERTIMBANGAN KEAMANAN – Minimal Efek Diatas Placebo – Tidak menyebabkan Kegemukan – Meningkatkan Hipoglikemia yang berhubungan dengan Sulfonilurea ASK-SDNC Physiology of GLP-1 Secretion and Action on GLP-1 Receptors in Different organs and Tissues 44 (Drucker et al 2006, Summarized & Illustrated : 2015) BRAIN HEART Myocardial Contractility Heart Rate Myocardial Glucose Uptake 8 Ischemia-induced Myocardial Damage Neuroprotection Neurogenesis Memory 7 LIVER Glycogen Storage 6 H A E G T F T GLP-1 FAT CELLS 5 Glucose Uptake Lipolysis A A K KIDNEY Natriuresis Q G E L Y S S D V S PANCREAS New -cell Formation -cell Apoptosis Insulin Biosynthesis E F I A W L V K G R G 2 4 3 BLOOD VESSEL ASK-SDNC 1 Endothelium-dependent Vasodilation SKELETAL MUSCLE GLUCOSE UPTAKE GLP-1 Receptor Agonist (GLP-1RA) 45 PATOFISIOLOGI – Glucagon-like peptide-1 (GLP-1) agonist memperbaiki sekresi insulin, menurunkan sekresi glukagon, meningkatkan rasa kenyang, Berhubungan dengan penurunan berat badan – Mungkin memiliki efek yg baik untuk fungsi sel β – Mekanisme nya yg tergantung kepada glukosa membatasi risiko hipoglikemia – Dapat digunakan sbg monoterapi pada pasien yg tidak dapat mengkonsumsi metformin atau dapat digunakan sebagai kombinasi dengan metformin, TZD, dan Sulfonilurea Kelas Pengobatan ini (GLP-1RA: Liraglutide/Victoza) mulai available di Indonesia pada pertengahan tahun 2015 Spellman CW. Am Osteopath Assoc February 1, 2011;111(2 – Suppl 1): eS10-eS14 ASK-SDNC THE KIDNEYS FILTER AND REABSORB 180 Gram OF GLUCOSE PER DAY IN THE NEPHRONS BY ACTIVE TRANSPORT 46 (Wright 2001, Lee et al 2007, Brown 2000) 180 g GLUCOSE FILTERED EACH DAY GLOMERULUS PROXIMAL TUBULE S1 GLUCOSE FILTRATION SGLT2 90% COLLECTING DUCT S2 SGLT1 GLUCOSE REABSORPTION UP TO ~90% OF GLUCOSE IS REABSORBED FROM THE S1/S2 SEGMENTS DISTAL TUBULE ~10% OF GLUCOSE IS REABSORBED FROM THE S3 SEGMENT S3 Loop of Henle Minimal Glucose Excretion SPECIAL SGLTS ARE RESPONSIBLE FOR THIS REABSORPTION IN THE KIDNEYS ASK-SDNC 47 SGLT2-INHIBITOR (SGLT2-I) (Provided : Tjokroprawiro 2015) JENIS SGLT2-I 1. Dapagliflozin 5. Tofogliflozin 2. Canagliflozin 6. Seragliflozin 3. Empagliflozin 7. Remogliflozin 4. Ipragliflozin 8. Others : on Investigation FARMAKOLOGI – Menghambat Penyerapan Kembali Glukosa di Tubuli Proksimalis Ginjal ASK-SDNC 48 SGLT2-INHIBITOR (SGLT2-I) EFIKASI – Menurunkan A1C 0.8 – 1.0 % PERTIMBANGAN KEAMANAN – Tidak Menyebabkan Hipoglikemia – Menurunkan Berat Badan dan Efektif untuk Semua Fase DM ASK-SDNC MEKANISME KERJA SGLT2-INHIBITOR Hedinger MA, Rhoads DB , Physiol . Rev . 1994; 74:993 - 1826 SGLT2-INHIBITOR REVERSAL OF GLUCOTOXICITY Insulin sensitivity in muscle • GLUT4 translocation • Insulin signaling • Other Insulin sensitivity in liver • Glucose – 6 Phosphatase Gluconeogenesis • Decreased Cori cycle • PEP carboxykinase – Cell function ASK-SDNC 49 50 SGLT2-Inhibitors (f.e. Dapagliflozin) in Daily Practice IN COMBINATION WITH OTHER DRUGS INCLUDING INSULIN Based on Presentations at the 75th ADA Meeting, Boston 5-9 June 2015 (Summarized and Illustrated : Tjokroprawiro 2015) INSULIN 6 SAXA PLUS MET 5 SULFONILUREA PLUS METFORMIN (MET) 4 ASK-SDNC Dapagliflozin (FARSIGA) in COMBINATION for T2DM 1 MONOTHERAPY 2 METFORMIN XR 3 SAXAGLIPTIN (SAXA) RISIKO HIPOGLIKEMIA 51 (Bolen S et al. Ann Intern Med 2007;147:386-99) Drug 1 Less Harmful Pooled Effect Studles (95% CI) (Participants) Drug 1 More Harmful Met vs. Met + TZD 0.00 (-0.01 to 0.01) 3 (1557) SU vs. Repag 0.02 (-0.02 to 0.05) 5 (1495) Glyb vs. Other SU 0.03 (0.00 to 0.05) 6 (2238) SU vs. Met 0.04 (0.00 to 0.09) 8 (2026) SU + TZD vs. SU 0.08 (0.00 to 0.16) 3 (1028) SU vs. TZD 0.09 (0.03 to 0.15) 5 (1921) SU + Met vs. SU 0.11 (0.07 to 0.14) 8 (1948) SU + Met vs. Met 0.14 (0.07 to 0.21) 9 (1987) 0 0.5 0.1 0.15 Weighted Absolute Risk Difference ASK-SDNC 0.2 52 RISIKO KEGEMUKAN (Bolen S et al. Ann Intern Med 2007;147:386-99.) Drug 1 More Beneficial Drug 1 Less Beneficial Pooled Effect (95% CI) Studles (Participants) SU vs. Met (RCTs >24 wk) 3.5 (3.0 to 4.0) 4 (538) Met + SU vs. Met 2.4 (1.1 to 3.6) 9 (1871) SU vs. Met (RCTs <24 wk) 1.9 (1.4 to 2.4) 8 (1374) TZD vs. Met 1.9 (0.5 to 3.3) 6 (2143) SU vs. Acarbose 1.9 (0.2 to 4.0) 5 (397) TZD vs. SU 1.1 (-0.9 to 3.1) 3 (368) SU vs. Met + SU 0.05 (-0.5 to 0.6) 5 (1011) SU vs. Repag 0.03 (-1.0 to 1.0) 10 (2006) -2 ASK-SDNC -1 0 1 2 3 4 5 Weighted Mean Difference in Body Weight, kg ANTIHYPERGLYCEMIC THERAPY IN T2DM (ADA/EASD-2015) 53 (Inzucchi et al - ADA, Nauck et al – EASD; Diabetes Care, Volume 38, January 2015) INITIAL DRUG MONOTHERAPY HEALTHY EATING, WEIGHT CONTROL, INCREASED PHYSICAL ACTIVITY, AND DIABETES EDUCATION METFORMIN Efficacy (HbA1c) Hypoglycemia Weight Side effects Costs TWO DRUG COMBINATIONSa Efficacy (HbA1c) Hypoglycemia Weight Major Side effects Costs high low risk neutral/loss GI / lactic acidosis low IF HBA1c TARGET NOT ACHIEVED AFTER ~3 MONTHS OF MONOTHERAPY, PROCEED TO TWO-DRUG COMBINATION (order not meant to denote any specific preference – choice dependent non a variety of patient-and disease-specific factors) METFORMIN + METFORMIN + METFORMIN + METFORMIN + METFORMIN + METFORMIN + SULFONYLUREA THIAZOLIDINEDIONE DPP-4 INHIBITOR SGLT2 inhibitor GLP-1 Receptor Agonist INSULIN (basal) high moderate risk gain hypoglycemia low high low risk gain edema, HF,Fx’s high intermediate low risk neutral rare high intermediate low risk loss GU, dehydration high high low risk loss GI high highest high risk gain hypoglycemia variable IF HBA1c TARGET NOT ACHIEVED AFTER ~3 MONTHS OF DUAL THERAPY, PROCEED TO TWO-DRUG COMBINATION (order not meant to denote any specific preference – choice dependent non a variety of patient-and disease-specific factors) THREE DRUG COMBINATIONS METFORMIN + METFORMIN + METFORMIN + METFORMIN + SULFONYLUREA THIAZOLLDINEDIONE DPP-4 INHIBITOR SGLT2 inhibitor + + + + TZD DPP-4-i or or SGLT2-i or GLP-1-RA or INSULIN or MORE COMPLEX INSULIN STRATEGIES ASK-SDNC SU SU DPP-4-i or or SGLT2-i or GLP-1-RA or INSULIN METFORMIN + GLP-1 RECEPTOR AGONIST + SU TZD or or SGLT2-i or INSULIN METFORMIN + INSULIN (basal) + SU TZD TZD or TZD or DPP-4-1 or DPP-4-i or INSULIN or SGLT2-i or INSULIN or GLP-1-RA If HbA1c target not achieved after ~3 months of triple therapy and patient (1) on oral combination, move to injectables; (2) on GLP-1-RA, add basal insulin; or (3) on optimally titrated basal insulin, add GLP-1-RA or mealtime insulin. In refractory npatients consider adding TZD or SGLT2-i: Metformin + Basal Insulin + Mealtime Insulin or GLP-1-RA American Association of Clinical Endocrinologists-2015 LIFESTYLE MODIFICATION (Including Medically Assisted Weight Loss) MONOTHERAPY* SYMPTOMS DUAL THERAPY* TRIPLE THERAPY* LEGEND ENDOCRINE PRACTICE Vol 21 No. 4 April 2015 ASK-SDNC 54 RISK OF GENITAL INFECTIONS of SGLT2-I 55 (DAPAGLIFOZIN >< CANAGLIFOZIN) (Provided : 2015) DAPA vs. PLACEBO (2.5 mg-10 mg)* CANA vs. PLACEBO (50 mg-300 mg) OVERALL INCIDENCE (%) 4.8 vs. 0.9 3.0–8.0 vs. 2.0 INCIDENCE IN WOMEN (%) 5.8–8.4 vs. 1.5 13.0–25 vs. 3.0 INCIDENCE Note: Dapagliflozin and canagliflozin have not been studied in a head-to-head trial * these data are based on a pre-specified pooled analysis of 12 placebo-controlled dapagliflozin registration studies • With both SGLT2-inhibitors, increased incidence of genital infections was dose-independent • Vulvovaginal mycotic infection and vaginal infections most common genital infections with dapagliflozin (DAPA) • Vulvovaginal mycotic infection and vulvovaginal candidiasis most common genital infections with canagliflozin (CANA) • With both SGLT2-inhibitors, most infections were mild to moderate in intensity and resolved with standard anti-fungal therapy Forxiga PI, November 2012; Rosenstock et. al. Diabetes Care, 2012; Published online ahead of print: DOI: 10.2337/dc11-1926. FDA Committee Meeting; Dapagliflozin: Available at: http://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/EndocrinologicandMetabolicDrugsAdvisoryCommittee/UCM264314.pdf ASK-SDNC BENEFITS AND RISKS OF SGLT2-INHIBITOR (Data on File 2014, Provided and Illustrated : Tjokroprawiro 2015) 8 POTENTIAL BENEFITS INSULIN-INDEPENDENT 2 CALORIE LOSS DUE TO 2.2 DIURETIC EFFECTS GLUCOSE EXCRETION Hypovolemia FPG Hypotension PPG Dehydration A1C 3.3 BONE MINERAL METABOLISM BP 4.4 UTI VAT 5.5 VULVOVAGINITIS BW 6.6 BALANITIS 4 5 6 7 8 Glucuresis 6 POTENTIAL RISKS 1 3 DIRECT EXCRETION OF GLUCOSE AND ITS ASSOCIATED CALORIES 56 1.1 HYPOGLYCAEMIA FPG : Fasting Plasma Glucose UTI : Urinary Tract Infection PPG : Prandial Plasma Glucose BW : Body Weight BP : Blood Pressure VAT : Visceral Adipose Tissue http://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/Endocrinologic andMetabolicDrugsAdvisoryCommittee/UCM264314.pdf?utm_campaign=Google2&utm_source=fdaSear ch&utm_medium=website&utm_term=Dapagliflozin&utm_content=14 ASK-SDNC The 14 Selected Publications on Dapagliflozin (DAPA)-ADA 2015 57 (CV Safety, AT Inflammation, Cell, ROS, IR-IS in CVD, VAT-BW, Renal Lipid- DN, A1C, SBP) (Summarized & Illustrated : Tjokroprawiro 2015) Yeh et al 2015 14 Wang et al 2015 13 (DAPA: A1C, BW, SBP) IR : Insulin Resistance IS : Insulin Sensitivity AT : Adipose Tissue Met : Metformin 1 (DAPA – Met XR) 2 (SGLT2-I: Renal Lipid, Inflamm, DN) Rohwedder et al 2015 12 (DAPA + SAXA : Genitourinary Tract Infection) Parikh et al 2015 14 3 11 Nakamae et al 2015 10 Kosiborod et al 2015 9 (DAPA: BW via VAT Loss) SGLT2-Inhibitors The 75th ADA-2015 Dapagliflozin (Farxiga®) 4 ASK-SDNC Cefalu et al 2015 Efstathiou et al 2015 (DAPA : Adipose Tissue Inflamm., Arterial Stiffness) 5 Elkholm et al 2015 (Comb. DAPA + SAXA : Cell Function) 6 (DAPA : Efficacy & Safety in T2DM + HF) (DAPA: IR, IS in CVD) Bowering et al 2015 (DAPA to Met+SU) (DAPA to CVD : Efficacy & Safety) (DAPA : Uneffected by Albuminuria Level) Katz et al 2015 Bell et al 2015 Hansen et al 2015 (DAPA + SAXA to Met : I/GLS, GLU/GLS, I/GLU) 8 DN : Diabetic Nephropathy HF : Heart Failure SAXA : Saxagliptin ADA : American Diabetes Association 7 Hatanaka et al 2015 (DAPA: Oxidative Stress, DN) BENEFITS AND RISKS OF SGLT2-INHIBITOR (Data on File 2014, Cefalu et al 2015, Efstathiou et al 2015, Elkholm et al 2015; Hatanaka et al 2015, Katz et al 2015, Nakamae et al 2015, Wang et al 2015, Yeh et al 2015; Summarized and Illustrated : Tjokroprawiro 2015) 58 FIFTEEN (15) POTENTIAL BENEFITS OF SGLT2-INHIBITOR 1 INSULIN-INDEPENDENT 2 CALORIE LOSS DUE TO GLUCOSE EXCRETION 10 CELL FUNCTION 11 ROS 4 PPG 12 INSULIN SENSITIVITY 5 A1C 13 KIDNEY: LIPID, INFLAMMATION, DN 7 VAT 14 CV EFFICACY & SAFETY 8 BW 15 A1C, BW, SBP Data on File 2014 Glucuresis ARTERIAL STIFFNESS 3 FPG 6 BP DIRECT EXCRETION OF GLUCOSE AND ITS ASSOCIATED CALORIES 9 AT INFLAMMATION, ADA-Scientific Meeting, Boston 5-9 June 2015 FPG : Fasting Plasma Glucose AT : Adipose Tissue PPG : Prandial Plasma Glucose BW : Body Weight DN : Diabetic Nephropathy VAT : Visceral Adipose Tissue BP : Blood Pressure ADA : American Diabetes Association http://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/Endocrinologic andMetabolicDrugsAdvisoryCommittee/UCM264314.pdf?utm_campaign=Google2&utm_source=fdaSear ch&utm_medium=website&utm_term=Dapagliflozin&utm_content=14 ASK-SDNC 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 59 60 Askandar Tj. Alm. Soeharjono Alm. Hendromartono Ari Sutjahjo Agung Pranoto Sri Murtiwi Soebagijo Adi Sony Wibisono The 11 CORE STAFFS of SDNC 1986 - 2015 PLUS 52 EXPERT MEMBERS FROM MULTIPLE DISCIPLINES QUADRUPLE SYMPOSIUM : 1 SUMETSU 2 MECARSU 3 SOBU 4 SDU • NOS – 2 ...... OBELAR–MEETING SDW– 25 SDW PEPIC PEPIC- 3 DIAPIC DIAPIC–:Will WillBeBe Jongky Hendro Hermina Novida Rio Hermawan Susanto Wironegoro Deasy Ardiany OBELAR–MEETING EVERY TWO WEEKS Obesity, Biomolecular, Endothelium, Lipids, Atherosclerosis, Radicals Surabaya, 1 August 1986 – 1 August 2015 * EDUCATION * HEALTH SERVICE * INVESTIGATION: WDF, GIANT, ISIS, Etc SURABAYA DIABETES AND NUTRITION CENTER (SDNC) Dr. SOETOMO TEACHING HOSPITAL FACULTY OF MEDICINE AIRLANGGA UNIVERSITY, SURABAYA ASK-SDNC GULOH–SISAR : SEPULUH PETUNJUK POLA HIDUP SEHAT Prof. Dr. dr. Askandar Tjokroprawiro Sp.PD, K-EMD, FINASIM (1995-2015) Pusat Diabetes dan Nutrisi Surabaya, RSUD Dr. Soetomo – FK Universitas Airlangga, Surabaya 61 LAKSANAKAN POLA HIDUP SEHAT GULOH-SISAR dengan POLA MAKAN yang BERPEDOMAN : BNI (BATASI, NIKMATI, IMBANGI) DM : Diabetes Mellitus Non-DM : Bukan Diabetes Mellitus (Orang Normal) Revisi 5 Oktober 2015 1 G (GULA) : Pantang Gula bagi DM 6 S (SIGARET) : Stop Sigaret (Rokok) 2 U (asam URAT) : Batasi JAS-BUKKKET 7 I 3 L (LEMAK) : Batasi TEK-KUK-CS2 8 S (STRESS) : Usahakan Tidur Nyenyak 6-7 Jam/hari 4 O (OBESITAS): Target LP 9 A (ALKOHOL) : Stop Alkohol Bagi Non-DM Kurangilah Konsumsi Gula LP = Lingkar Pinggang Pria < 90 cm Wanita < 80 cm 5 H (HIPERTENSI): Untuk Pasien Hipertensi, Batasi Garam, Ikan Asin, Kacang Asin, dll JAS-BUKKKET 10 R (INAKTIVITAS): Hindarkan Inaktivitas, dan Rutinkanlah Latihan Fisik ± 300 kcal/hr atau Jalan 3 km/hari, atau SIT-UP 50-100 X/hr (REGULAR CHECK UP) : Usahakan Check Up Teratur dan Konsultasi Ahli Bagi yang Berumur > 40 th, setiap 3, 6,12 Bulan Jerohan, Alkohol, Sarden - Burung Dara, Unggas, Kacang, Kaldu, Kerang, Emping, Tape (10 macam makanan / minuman yang harus dibatasi/dipantang untuk pasien dengan kadar asam urat tinggi) TeK-KUK-CS2 Telor Keju - Kepiting, Udang, Kerang - Cumi, Susu, Santen (8 macam makanan yang harus di batasi /dipantang untuk pasien dengan kadar kolesterol / lemak darah tinggi) "MABUK" (Mengandung banyak Chromium) : Mrica, Apel, Brokoli, Udang, Kacang-kacangan Chromium (Cr) Dapat Memperbaiki Kerja Insulin (Menurunkan Gula). Ini berarti Cr bermanfaat bagi Pasien Diabetes BNI BNI BNI Makanan Suplemen yang Dianjurkan : Buncis, Bawang Putih, Teh Hijau, Merica, dan TKW-PJKA-BK TKW – PJKA – BK : Banyak Mengandung Antioksidan: Tomat, Kacang-kacangan, Wortel - Pepaya, Jeruk, Kurma, Apel - Brokoli, Kobis RESVERATROL didapatkan pada kulit anggur, raspberries, blueberries, kacang tanah, anggur merah dan “Pine Tree”. RESVERATROL: dapat memperbaiki kadar QUERCETIN : bahan makanan yang banyak terdapat pada capers, glukosa dan lemak darah, anti inflamasi, anti kanker, dan proteksi penyakit jantung dan ginjal. QUERCETIN lovage, apel, teh, bawang merah, sitrus, sayuran hijau dan buah berries. QUERCETIN bermanfaat untuk anti inflamasi dan anti kanker. NUTRACEUTICALS (bahan dalam buah / tanaman yang bermanfaat) lain selain RESVERATROL dan QUERCETIN adalah: bawang putih, bawang merah, biji wijen, dll; semuanya dapat berfungsi sebagai anti inflamasi, anti proliferasi, anti invasi, anti angiogenesis dan anti tumorigenesis (anti tumor dan penyebarannya). ASK-SDNC