Professional Documents
Culture Documents
Sidartawan Soegondo
dr.SpPD,KEMD, DTM&H, FINASIM, FACE.
1. Type 1 diabetes
(due to autoimmune beta-cell destruction, usually leading to absolute insulin deficiency)
2. Type 2 diabetes
(due to a progressive loss of beta-cell insulin secretion frequently on the background of insulin resistance)
3. Gestational diabetes mellitus (GDM)
(diabetes diagnosed in the second or third trimester of pregnancy that was not clearly overt diabetes prior
to gestation)
4. Specific types of diabetes due to other causes,
e.g., monogenic diabetes syndrome (such as neonatal diabetes and maturity-onset diabetes of the young
[MODY]),
diasese of the exocrine pancreas, such as cystic fibrosis), and
drug or chemical-induced diabetes (such as with glucocorticoid use,treatment of HIV/AIDS, or after organ
transplantation)
Diabetes Care 2017;40(Suppl.1):S11-S24 | DOI: 2337/dc17-S005
Diabetes is not a single
homogeneous disease but
composed of many diseases
with hyperglycaemia as a
common feature.
“4” factors to identify this diversity:
1.Age at onset
2.Degree of loss of beta cell function
3.Degree of insulin resistance
4.Presence of DAA.
Two major types,
Type 1 DM and Type 2 DM,
are based on these factors,
apparently they do not precisely capture the
different disease forms.
There has been a repositioning of the
understanding of diabetes
Current
Diabetes Classification System
T1DM
LADA
T2DM
Age Metabolic TCF7L2 Systemic C-peptide
syndrome FTO inflammation
Lacks Foundation That
Readily Incorporates Advances
Understanding
Disease and its Treatment
Articles
Summary
Background Diabetes is presently classified into two main forms, type 1 and type 2 diabetes, but type 2 diabetes in Lancet Diabetes Endocrinol 2018
particular is highly heterogeneous. A refined classification could provide a powerful tool to individualise treatment Published Online
regimens and identify individuals with increased risk of complications at diagnosis. March 1, 2018
http://dx.doi.org/10.1016/
S2213-8587(18)30051-2
Methods We did data-driven cluster analysis (k-means and hierarchical clustering) in patients with newly diagnosed
See Online/Comment
diabetes (n=8980) from the Swedish All New Diabetics in Scania cohort. Clusters were based on six variables http://dx.doi.org/10.1016/
(glutamate decarboxylase antibodies, age at diagnosis, BMI, HbA1c, and homoeostatic model assessment 2 estimates S2213-8587(18)30070-6
of β-cell function and insulin resistance), and were related to prospective data from patient records on development *Contributed equally
of complications and prescription of medication. Replication was done in three independent cohorts: the Scania Lund University Diabetes
Diabetes Registry (n=1466), All New Diabetics in Uppsala (n=844), and Diabetes Registry Vaasa (n=3485). Cox Centre, Department of Clinical
regression and logistic regression were used to compare time to medication, time to reaching the treatment goal, and Sciences, Lund University,
Skåne University Hospital,
risk of diabetic complications and genetic associations. Malmö, Sweden
(E Ahlqvist PhD, P Storm PhD,
Findings We identified five replicable clusters of patients with diabetes, which had significantly different patient M Dorkhan PhD, P Vikman PhD,
characteristics and risk of diabetic complications. In particular, individuals in cluster 3 (most resistant to insulin) had R B Prasad PhD, D M Aly MSc,
P Almgren MSc, Y Wessman MSc,
significantly higher risk of diabetic kidney disease than individuals in clusters 4 and 5, but had been prescribed
1. SAID
Severe autoimmune diabetes
• 6.4% of patients
• Early onset disease / Relatively young
• All GADA positive = T1D+LADA
• High HbA1c (poor metabolic control)
• Relatively lean/low BMI
• Insulin deficiency
2. SIDD
Severe Insulin-Deficient Diabetes
• 17.5% of patients
• High HbA1c (poor metabolic control)
• Relatively lean (low BMI)
• Relatively young / early onset
• Low insulin secretion
3. SIRD
Severe Insulin-Resistant Diabetes
• 15.3 % of patients
• Low HbA1c
• Obese (High BMI)
• Relatively old
• High insulin resistance (HOMA2-IR high)
4. MOD
Moderate Obesity-Related Diabetes
• 21.6% of patients
• Low HbA1c
• Very obese
• Relatively young
• Low risk of complications
5. MARD
Moderate Age-Related iDabetes
• 39.1% of patients
• Low HbA1c
• Relatively lean
• Old
• Low risk of complications
• Three severe forms of diabetes
- Autoimmune (SAID)
- Insulin deficient (SIDD)
- Insulin resistant (SIRD)
-
Lipids Food
additives
Epigenetics
Beta cell
Environment secretion/mass
FINAL COMMON
DENOMINATOR
Polygenic
Monogenic
Endocrine
Gut Biome
disrupters
Decreased
Incretin Effect
Increased
Impaired Lipolysis
Insulin Secretion
Increased Glucose
Reabsorption
Increased
HGP Decreased Glucose
Uptake
Neurotransmitter
Dysfunction
Three Additional
Mediating Pathways
Colon /
microbiome Changes in Gut Microbiota
Immune
dysregulation/ Systemic Low- grade
inflammation
Inflammation
Amylin Reductions in Amylin
Production
1. Pancreatic Beta-cells
8. Beta-cell function
Colon / Islet β-cell
microbiome Beta-cell mass
INSULIN
FINAL COMMON
9. DENOMINATOR
Immune
dysregulation/
inflammation
Amylin
HYPERGLYCEMIA
10. Stomach/
small intestine
1. Pancreatic Beta-cells
8. Colon/ biome
Abnormal microbiota; Beta-cell function 7. Brain
Islet β-cell
possible decreased Increased appetite
GLP-1 secretion Beta-cell mass
Decreased morning
dopamine surge
INSULIN Increased sympathetic tone
FINAL COMMON
DENOMINATOR
9. Immune
Insulin Resistance
dysregulation/
inflammation
6. Liver
Increased
Amylin glucose
2. incretin effect 3.alpha cell defect production
Glucagon
5. Muscle
Decreased
peripheral muscle
HYPERGLYCEMIA uptake
10. Stomach/
small intestine 11. Kidney
Increased rate of Increased glucose 4. Adipose
glucose absorption reabsorption Increased lipolysis
Inflammation/
Immune Regulation
Beta cell
secretion/mass
β-Cell
FINAL COMMON secretion/mass
DENOMINATOR
FINAL COMMON
DENOMINATOR
8. Colon/
microbiome
6. Liver
2. Incretin effect 3.alpha cell defect
Increased
Amylin glucose
Incretins
production
Glucagon
treatable mediators of HYPERLYCEMIA Incretins 5. Muscle
resulting from Beta-cell Damage Pramlintide Decreased
peripheral
10. Stomach/ HYPERGLYCEMIA muscle uptake
small intestine
GLP-1 agonists
11. Kidney 4. Adipose
Pramlintide
AGI Increased lipolysis
SGLT-2 inhibitors
Treatments provide rational choices for
Personalized therapies that
Target the individual
Mediating pathways of hyperglycemia
At work in any given patient.
Targeted Treatments for Mediating Pathways of Hyperglycemia
8. Colon/
microbiome 1. Pancreatic Beta-cells 7. Brain
Probiotics
Incretins Beta-cell function Incretins
Metformin Dopamine agonist-QR
Beta-cell mass Appetite suppressants
Incretins
9. Immune INSULIN Ranolazine
dysregulation/ FINAL COMMON
inflammation DENOMINATOR
Incretins,
Anti-inflammatories
Immune modulators
INSULIN RESISTANCE
"50
Multiple Defects Contribute to the Pathophysiology of T2D
β
Glucose production Insulin secretion
Glucagon secretion α
To help improve glycemic control, treatments with
Glucose uptake
Chronic
to be used in combination2
Lipolysis Incretin effect
Insulin β
secretion
Glucose
production
Glucose
uptake
α Glucagon
secretion Hyperglycemia
Incretin
effect
Lipolysis
Neurotransmitter
function
Glucose
reabsorption
Pathophysiology of Type 2 Diabetes:
Therapies
Metformin
Glucose
production
TZDs TZDs Glucose
Insulin uptake
Metformin
α Glucagon GLP-1s
secretion
Normoglycemia
GLP-1s Incretin
DPP-4s
effect
DPP-4s
Lipolysis TZDs
Neutransmitter
GLP-1s
function
Glucose
reabsorption
SGLT2s
Current Antihyperglycemic Medications
Sulfonylureas TZDs
Glinides
Generalized insulin Reduce
Restore secretagogue peripheral insulin Biguanide
alpha-Glucosidase postprandial resistance
inhibitors
insulin patterns Reduces hepatic
Delay CHO absorption insulin resistance
Gejala ( - ) Gejala ( + )
Monoterapi* dengan Kombinasi 2 obat dengan
kombinasi 2 obat
salah satu dibawah ini mekanisme kerja yang berbeda
"60
Look at the
HbA1c
"61
Adjust to
PERKENI 2015
Guidelines
"62
Algoritma Pengelolaan DM Tipe-2 di Indonesia, KONSENSUS
PERKENI 2015
Kombinasi 2 obat
Monoterapi* dengan salah Kombinasi 2 obat* dengan
satu dibawah ini mekanisme yang berbeda Insulin ± obat lain
Kombinasi 3 obat
- Metformin - Agonis GLP1 Kombinasi 3 obat
- SU / Glinid
- Tiazolidindion - Kolesevelam** Mulai pemberian insulin atau lakukan
- Kolesevelam** intensifikasi insulin
- Sulfonilurea - Bromokriptin QR**
- Bromokriptin
- Glinid - Penghambat
QR**
glukosidase alfa Keterangan:
- Penghambat
glukosidase alfa * Obat yang terdaftar, pemilihan dan
penggunaannya disarankan
Jika HbA1C belum mempertimbangkan faktor keuntungan,
mencapai sasaran dalam kerugian dan ketersediaan sesuai **
3 bulan, tambahkan obat Jika HbA1C belum
ke-2 (kombinasi 2 obat) Kolesevelam belum tersedia di Indonesia dan
mencapai sasaran dalam
3 bulan, tambahkan obat Bromokriptin QR umumnya digunakan pada
Jika HbA1C belum mencapai
ke-3 (kombinasi 3 obat) sasaran dalam 3 bulan, mulai
terapi insulin atau intensifikasi
terapi insulin
PERKENI, 2015
Target
HbA1c
"64
Approach to the Management of hyperglycemia
A1c 7 %
Patient / Disease features
More Stringent Less Stringent
Disease Duration
Newly diagnosed Long-standing
Life Expectancy
Long Short
• Efficacious
• Protect remaining beta cell function
• Minimize hypoglicemic riks
• Minimize weight gain
• Minimize adverse effects and drug interactions
• Cardiovascular benefit
!67
HbA1c < 7.5%
!68
Mono therapy ?
"69
Choose SU plus/minus Metformin
to add on.
"70
HbA1c < 7.5%
Monoterapi* dengan
salah satu dibawah ini
• Metformin
• Agonis GLP-1
• Penghambat DPP-IV
• Penghambat Glikosidase Alfa
• Penghambat SGLT-2**
• Tiazolidindion
• Sulfonilurea
• Glinid Satu Obat*
!71
HbA1c > 7.5%
!72
Dual Therapy ?
"73
HbA1c > 7.5%
• Agonis GLP-1
• Penghambat DPP-IV
• Tiazolidindion
• Penghambat SGLT-2
• • Insulin basal
• SU/Glinid
• Kolesevelam**
• Bromokriptin-QR Dua Obat *
• Penghambat Glukosidase Alfa
!74
HbA1c > 9%
!75
Triple Therapy ?
"76
HbA1c > 7.5%
KOMBINASI 3 OBAT
• Agonis GLP-1
• Penghambat DPP-IV
Metformin / obat lini pertama yang lain
• Tiazolidindion
Obat lini kedua
• Penghambat SGLT-2
•
• Insulin basal
!77
HbA1c > 9%
GEJALA
Tidak Ada
kombinasi 2 obat
Insulin +/-
Obat jenis
lain
kombinasi 3 obat
!78
There are now 9 results of such trials:
3 assessing safety of DPP- 4 inhibitors,
4 testing the safety of GLP1-RA, and
2 (SGLT)-2 inhibitors.
!80
Large CV Outcomes Trials in Diabetes (Non-Insulin)
Study SAVOR EXAMINE TECOS CAROLINA CARMELINA
A L
Comparator
TR
Placebo PlaceboAL
R AL
Placebo
R
Sulfonylurea Placebo
U T
NE UT U
N 16,500 NE
5,400 NE14,000 6,000 8,300
+ +
GLP1-RA Liraglutide Lixisenatide Semaglutide Exenatide LR Dulaglutide
Comparator Placebo A
Placebo
L Placebo Placebo Placebo
R
UT
N 16,500 NE6,000 6,000 5,400 8,300
+ +
SGLT-2i Empagliflozin Canagliflozin Dapagliflozin Ertugliflozin
EMPAGLIFLOZIN
MACE -14% vs placebo
hHF -35% vs placebo LIRAGLUTIDE
CV death -38% vs placebo MACE -13% vs placebo
hHF -35% vs placebo
CV death -22% vs placebo
Dapagliflozin ? Dulaglutide ?
Albiglutide ?
Dapagliflozin ? Dula? Albi?
CANAGLIFLOZIN SEMAGLUTIDE
MACE -14% vs placebo MACE -26% vs placebo
hHF -33% vs placebo Non-fatal stroke -39% vs
placebo
hHF - NS
2018 Standards of Care - Resources
At diagnosis, initiate lifestyle management, set A1C target, and initiate
pharmacologic therapy based on A1C:
Start with Monotherapy unless: A1C is greater than or equal to 10%, blood glucose is greater than or equal to 300 mg/dL.
or patient is markedly symptomatic, consider Combination Injectable Therapy.
Monotherapy Metformin
Efficacy* high
Costs* low
If A1C target not achieved after approximately 3 months of monotherapy, proceed to 2-drug combination (order not
meant to denote any specific preference - choice dependent on a variety of patient- & disease-specific factors).
Metformin +
GLP-1 RA Insulin (basal)
Dual Therapy Sulfonylurea Thiazolidinedione DPP-4 inhibitor SGLT2 inhibitor
If A1C target not achieved after approximately 3 months of dual therapy, proceed to 3-drug combination (order not
meant to denote any specific preference - choice dependent on a variety of patient- & disease-specific factors).
Metformin +
Triple Therapy Sulfonylurea Thiazolidinedione DPP-4 inhibitor SGLT2 inhibitor GLP-1 RA Insulin (basal)
TZD SU SU SU SU TZD
or Insulin or Insulin
If A1C target not achieved after approximately 3 months of dual therapy and patient on oral combination, move to basal insulin or GLP-1RA, add basal insulin or on
optimally titrated basal insulin, add GLP-1RA or mealtime insulin. Metformin therapy should be maintaned, while other oral agents may be discontinued on an
individual basis to avoid unncessarily complex or costly regimens.
A1C is less than or equal to 10%, blood glucose is greater than or equal to 300 mg/dL, or patient is markedly
symptomatic, consider Combination Injectable Therapy.
Neutral: lixisenatide,
Pharmacologic Approaches to Glycemic
GLP-1 RAs exenatide extended release
Neutral Treatment:
Standards of Medical Care in Diabetes -
Benefit:
liraglutide 2018. Diabetes Care 2018; 41 (Suppl. 1):
S73-S85
Potential Risk:
DPP-4 Inhibitors Neutral saxagliptin,
alogliptin
Potential Benefit:
Thiazolidinediones Increased Risk
pioglitazone
Human
Insulin Neutral Neutral
Analogs
Drug-specific and patient factors to consider when selecting antihyperglemic treatment in adults with type 2 diabetes
Weight
Efficacy* Hypoglycemia CV Effects Cost Oral/SQ Renal Effects Additional Consideraitions
Change ASCVD CHF Progression of DKD Dosing/Use considerations
High No Neutral Potential Benefit Neutral Low Oral Neutral • Contraindicated with eGFR <30 • Gastrointestinal side effects common (diarrhea,
nausea)
(potential for • Potential for B 12 deficiency
modest Loss)
Metformin
Intermediate No Loss Benefit: Benefit: High Oral Benefit: • Canaglliflozin: not recommended with eGFR <45 • FDA Black Box: Risk of amputation (canagliflozin)
• Dapagliflozin: not recommended with eGFR <60; contraindicated with • Risk of bone fractures (canagliflozin)
canagliflozin,
eGFR <30 • DKA risk (all agents, rare in T2DM)
canagliflozin, canagliflozin, empagliflozin
• Empagliflozin: contraindicated with eGFR <30 •
•
Genitourinary infections
Risk of volume depletion, hypotension
SGLT-2 Inhibitors
High No Loss Neutral: Neutral High SQ Benefit: • Exenatide: not indicated with eGFR <30 • FDA Black Box: Risk of thyroid C-cell tumors (liraglitude,
liraglutide • Lixisenatide: caution with eGFR <30 albiglutide, dulaglutide, exenatide extended release)
• Gastrointetinal side effects common (nausea, vomiting, diarhea)
lixisenatide, • Increased risk of side effects in patients with renal
impairment
•
•
Injection site reactions
Acute pancreatitis risk
exenatide
GLP-1 RAs extended
Benefit:
release
liraglutide
High Oral Neutral • Renal dose adjustment required; can be used in renal • Potential risk of acute pancreatitis
Intermediate No Neutral Neutral Potential Risk: impairment • Joint pain
saxagliptin,
alogliptin
DPP-4 Inhibitors
Low Oral Neutral • No dose adjustment required • FDA Black Box: Congestive heart failure [pioglitazone,
rosiglitazone]
High No Gain Potential Increased • Generally not recommended in renal impairment due to
potential for fluid retention
•
•
Fluid retention (edema; heart failure)
Benefit in NASH
Benefit: Risk •
•
•
Risk of bone fractures
Bladder cancer (pioglitazone)
LDL cholesterol (rosiglitazone)
pioglitazone
Thiazolidinediones
Low Oral Neutral • Glyburide: not recommended • FDA Special Warning on increased risk of
High Yes Gain Neutral Neutral • Glipizide & Glimepiride: initiate conservatively to avoid cardiovascular mortality based on studies of an older
sulfonylurea (tolbutamide)
hypoglycemia
Sulfonylureas
(2nd Generation)
Higest Yes Gain Neutral Neutral Neutral • Lower insulin doses required with a decrease in eGFR;
titrate per clinical response
•
•
Injection site reactions
Higher risk hypoglycemia with human insulin (NPH or
Human premixed formulations) vs. analogs
Insulin
Low SQ
Weight
Efficacy* Hypoglycemia CV Effects Cost Oral/SQ Renal Effects Additional Consideraitions
Change ASCVD CHF Progression of DKD Dosing/Use considerations
High No Neutral Potential Benefit Neutral Low Oral Neutral • Gastrointestinal side effects
• Contraindicated
(potential for common (diarrhea, nausea)
modest Loss) with eGFR <30 • Potential for B 12
Metformin deficiency
Intermediate No Loss Benefit: Benefit: High Oral Benefit: • Canaglliflozin: not • FDA Black Box: Risk of
canagliflozin, canagliflozin, canagliflozin, recommended with eGFR amputation (canagliflozin)
empagliflozin <45 • Risk of bone fractures
empagliflozin empagliflozin
• Dapagliflozin: not (canagliflozin)
SGLT-2 Inhibitors recommended with eGFR • DKA risk (all agents, rare in
<60; contraindicated with T2DM)
eGFR <30 • Genitourinary infections
• Empagliflozin: • Risk of volume depletion,
contraindicated with eGFR hypotension
High No Loss Neutral: Neutral High SQ Benefit: • Exenatide: not indicated with • FDA Black Box: Risk of
lixisenatide, liraglutide eGFR <30 thyroid C-cell tumors
• Lixisenatide: caution with (liraglitude, albiglutide,
exenatide eGFR <30
GLP-1 RAs dulaglutide, exenatide
extended • Increased risk of side effects
Benefit: extended release)
release
liraglutide in patients with renal
• Gastrointetinal side effects
impairment
common (nausea, vomiting,
diarhea)
High Oral Neutral • Renal dose adjustment • Potential risk of acute
Intermediate No Neutral Neutral Potential Risk: pancreatitis
required; can be used in
saxagliptin, • Joint pain
renal impairment
alogliptin
DPP-4 Inhibitors
Higest Yes Gain Neutral Neutral Neutral • Lower insulin doses required • Injection site reactions
Human
Insulin Low SQ with a decrease in eGFR; • Higher risk hypoglycemia
Pharmacologic Approaches to Glycemic Treatment:
with human insulin (NPH or
titrate per clinical response
Standards of Medical Care in Diabetes - 2018. Diabetes Care 2018; 41 (Suppl. 1): S73-S85 premixed formulations) vs.
Insulin analogs
Analogs
High SQ
Monitoring
Contribution of past blood glucose to
HbA1c and Glycated Albumin (GA) values
Collection of Blood
17days 1 month 2 months 4 months
Functions determined
Againts by the plasma glucose level during the 1-month
period before this month, and the
Preceding Plasma
glucoseGlucose
level during the remaining 25% was determined by