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1 THIAZOLIDINEDIONES (TZDs): Glitazone Class *) Withdrawn 2 NON-TZDs : a Glitazar Class (Mura-*), Raga-, Ima-, Tesa-, Saroglitazar**) : MRITS **) A Novel dual PPAR / agonist approved in India for Tx Diabetic Hyper TG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
