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Prof.Dr.

Sidartawan Soegondo
dr.SpPD,KEMD, DTM&H, FINASIM, FACE.

Director, Indonesia Diabetes Institute


Past President, Indonesian Diabetes Association
Past President, Indonesian Endocrine Society
Combined approach of
clinical experience,
Best Optimal personalisation,
Management and
of T2DM
application of the
information in the
guidelines as
clinically appropriate.
!4
Classification and Diagnosis of Diabetes

ADA Position Statement


CLASSIFICATION 2017

Diabetes can be classified into the following general categories:

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

Diabetes Care 2016;39:179–186 | DOI: 10.2337/dc15-1585


Diagnosis and Treatment

Type 1 DM, Type 2 DM,

Latent Autoimmune Diabetes of Adults (LADA)


Not HLA Auto- Insulin
T cells
obese DQBI antibodies treatment

T1DM

LADA

T2DM
Age Metabolic TCF7L2 Systemic C-peptide
syndrome FTO inflammation
Lacks Foundation That
Readily Incorporates Advances
Understanding
Disease and its Treatment
Articles

Novel subgroups of adult-onset diabetes and their association


with outcomes: a data-driven cluster analysis of six variables
Emma Ahlqvist, Petter Storm, Annemari Käräjämäki*, Mats Martinell*, Mozhgan Dorkhan, Annelie Carlsson, Petter Vikman, Rashmi B Prasad,
Dina Mansour Aly, Peter Almgren, Ylva Wessman, Nael Shaat, Peter Spégel, Hindrik Mulder, Eero Lindholm, Olle Melander, Ola Hansson,
Ulf Malmqvist, Åke Lernmark, Kaj Lahti, Tom Forsén, Tiinamaija Tuomi, Anders H Rosengren, Leif Groop

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)
-

• SIDD has the highest risk of diabetic retinopathy


• SIRD has the highest risk of diabetic kidney disease

• Two moderate forms of diabetes


- Obesity-related (MOD)
- Age-related (MARD)
-

• Classification can be done at diagnosis based on ANDIS clusters and could be


useful in the clinic to predict risk of complications and guide choice of medication
New Approach
Classification of DM
Insulin Resistance

Lipids Food
additives

Epigenetics
Beta cell

Environment secretion/mass
FINAL COMMON
DENOMINATOR

Polygenic
Monogenic

Endocrine
Gut Biome
disrupters

Inflammation / Immune Regulation

CLASSIFY PATIENT BY CAUSE(s) of Beta-Cell Dysfunction in EACH Individual

Diabetologia (2016) 59:13–20 DOI 10.1007/s00125-015-3789-z

Diabetes Care 2016;39:179–186 | DOI: 10.2337/dc15-1585


Factors Contribute to β-cell
Stress, Dysfunction, or Loss
Distinct Pathways
Root and Crossroads
Multiple Mediating Pathways in
Hyperglycemia.

More Logical Rationale
8 core defects of
Ominous Octet.

Ominous Octet
Islet β-cell

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

Diabetes Care 2016;39:179–186 | DOI: 10.2337/dc15-1585


Beta-cell Centric Construct:
Egregious Eleven

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

Diabetes Care 2016;39:179–186 | DOI: 10.2337/dc15-1585


The new model
recognizes a total of 11
interlocking pathways
that contribute to
hyperglycemia.
Current anti-diabetes armamentarium
broader applicability
across the spectrum of DM
than is currently utilized.
Beta-Cell Centric Classification of DM:
SEGUE INTO THERAPY
INSULIN
RESISTANCE

One CORE Defect- the Beta-Cell


Polygenic
Monogenic
GENE Epigenetic
s
Environment

Inflammation/
Immune Regulation

Beta cell
secretion/mass
β-Cell
FINAL COMMON secretion/mass
DENOMINATOR
FINAL COMMON
DENOMINATOR

8. Colon/
microbiome

(at least) treatable Causes of Probiotics 1. Pancreatic Beta-cells


Incretins 7. Brain
Metformin Beta-cell function Increased appetite
Beta-Cell Damage / HYPERGLYCEMIA Beta-cell mass Decreased morning
dopamine surge
increassed symphatic
INSULIN
9. Immune
dysregulation/ FINAL COMMON
inflammation DENOMINATOR
Incretins, INSULIN RESISTANCE
Anti-inflammatories
Immune modulators

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

2. Incretin effect 3.alpha cell defect 6. Liver


Amylin Incretins
Metformin
TZDs
Glucagon
Incretins 5. Muscle
Pramlintide
10. Stomach/ TZDs
small intestine HYPERGLYCEMIA Metformin

GLP-1 agonists 4. Adipose


Pramlintide 11. Kidney
AGI TZDs
Metformin
SGLT-2 inhibitors

Diabetes Care 2016;39:179–186 | DOI: 10.2337/dc15-1585


Pathophysiology Base Treatment ?

"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


complementary mechanisms of action should be considered Hyperglycemia

to be used in combination2
Lipolysis Incretin effect

Glucose reabsorption Neurotransmitter function

T2DM=type 2 diabetes mellitus.


. DeFronzo RA. Diabetes. 2009;58:773-795.
. Garber AJ et al. Endocr Pract. 2013;19:536-557.
Pathophysiology of Type 2 Diabetes:
The Ominous Octet

Insulin β
secretion

Glucose
production
Glucose
uptake

α Glucagon
secretion Hyperglycemia
Incretin
effect

Lipolysis
Neurotransmitter
function

Glucose
reabsorption
Pathophysiology of Type 2 Diabetes:
Therapies

GLP-1s DPP-4s Insulin β


secretion
Insulin Sulfonylureas

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

DPP-4 Inhibitors SGLT-2 Inhibitors

Restore GLP-1 Block renal glucose


reabsorption
Level

Different groups with different mechanisms of


action
GLP-1 Analogs Bromocriptine

Stimulate beta-cells Colesevelam Hypothalamic


Insulin
Suppress glucagon pituitary reset
Replacement Amylin Analog Bile acid
Therapy
sequestrant
Suppresses
glucagon
"55
Why and When ?
"56
Algoritme Pengelolaan DM Tipe 2 di Indonesia
KONSENSUS PERKENI 2015
Modifikasi Pola Hidup Sehat

HbA1c > 9.0%


HbA1c < 7.5% HbA1c > 7.5%

Gejala ( - ) Gejala ( + )
Monoterapi* dengan Kombinasi 2 obat dengan
kombinasi 2 obat
salah satu dibawah ini mekanisme kerja yang berbeda

Insulin +/- Obat


jenis lain
• Metformin
• Agonis GLP-1
Metformin / obat lini pertama yang lain +

Kombinasi 3 obat kombinasi 3 obat

• Penghambat DPP-IV • Agonis GLP-1


• Penghambat Glikosidase • Penghambat DPP-IV

Metformin / obat lini pertama yang lain +


Alfa • Tiazolidindion
• Agonis GLP-1
• Penghambat SGLT-2** • Penghambat SGLT-2
• Penghambat DPP-IV
• Tiazolidindion • Insulin basal Mulai atau intensifikasi insulin

Obat lini kedua +


• Tiazolidindion
• Sulfonilurea • SU/Glinid
• Penghambat SGLT-2
• Glinid • Kolesevelam**
• Insulin basal
• Bromokriptin-QR Keterangan
• Kolesevelam** *Obat yang terdaftar pemilihan dan
• Penghambat penggunaannya disarankan
• Bromokriptin-QR mempertimbangkan faktor
Jika HbA1c > 6.4% dalam 3
Glukosidase Alfa
• Penghambat keuntungan,kerugian, biaya dan
bulan tambahkan obat ke 2 ketersediaan sesuai tabel-11.
(kombinasi 2 obat) Glukosidase Alfa
** Kolesevelam belum tersedia di
Indonesia. Bromocriptin QR
umumnya digunakan pada terapi
tumor hipofisis.
Jika belum memenuhi sasaran
dalam 3 bulan, masuk ke Jika belum memenuhi sasaran dalam
kombinasi 3 obat 3 bulan, mulai terapi insulin /
intensifikasi terapi insulin
!58
Key Points to Consider When Selecting
Pharmacotherapy for T2DM

• How long the patient has had diabetes


• (duration of the disease-preservation of B cell function)
• Which blood glucose level is not at target
(eg,fasting,postprandial,both)
• The degree of A1c-lowering effect required to achieve goal
• The side-effect profile and the patient’s tolerability
• Minimize hypoglycemia
• Monitor weight gain
• Co-existing conditions (eg,CVD, depression,osteporosis)
Begin with the
Patient’s Profile

"60
Look at the
HbA1c

"61
Adjust to
PERKENI 2015
Guidelines

"62
Algoritma Pengelolaan DM Tipe-2 di Indonesia, KONSENSUS
PERKENI 2015

MODIFIKASI GAYA HIDUP SEHAT

HbA1C <7.5% HbA1C ≥7.5%


HbA1C >9.0%
Dalam 3 bulan + Monoterapi dalam 3 bulan
HbA1C > 7% HbA1C > 7% Gejala (-) Gejala (+)

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

- Agonis GLP1 - Penghambat


- Agonis GLP1
Metformin atau obat lini pertema yang lain

- Penghambat DPP4 DPP4


- Penghambat DPP4

Metformin atau obat lini pertema yang lain


- Penghambat - Tiazolidindion
- Tiazolidindion
glukosidase alfa - Penghambat
- Penghambat SGLT2 *
SGLT2 *
- Penghambat SGLT2 - Insulin basal
- Insulin basal
* - SU / Glinid
2 Obat lini kedua

- 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

Risks potentially associated with hypoglycaema,


other adverse events High
Low

Disease Duration
Newly diagnosed Long-standing

Life Expectancy
Long Short

Relevant Comorbidities Severe


Absent few/mild

Established Vascular Complications


Absent Severe
few/mild
Patient attitude and 

expected treatment efforts:
Highly motivated, adherent, excellent Less motivated, non-adherent,
self-care capacities poor self-care capacities

Resources, Support System


Readily available Limited

Diabetes Care 2017;40(Suppl.1):S11-S24 | DOI: 2337/dc17-S005


Selection of Pharmacotherapy
Desired drug effects

• 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%

Kombinasi 2 obat dengan


mekanisme kerja yang berbeda
Metformin / obat lini pertama yang lain +

• 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

• Kolesevelam** Tiga Obat *


• Bromokriptin-QR

• Penghambat Glukosidase Alfa

!77
HbA1c > 9%

GEJALA

Tidak Ada

kombinasi 2 obat

Insulin +/-
Obat jenis
lain

kombinasi 3 obat

Mulai atau intensifikasi insulin

!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

DPP4-i Saxagliptin Alogliptin Sitagliptin Linagliptin Linagliptin

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

Results 2013 2013 2015 2017 2017

Study LEADER ELIXA SUSTAIN 6 EXSCEL REWIND

+ +
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

Results 2016 2015 2016 2018 2019

Study EMPA-REG CANVAS DECLARE EXSCELNCT01986881

+ +
SGLT-2i Empagliflozin Canagliflozin Dapagliflozin Ertugliflozin

Comparator Placebo Placebo Placebo Placebo

N 7300 4300 22,200 3900

Results 2015 2017 2019 2020


New era of anti-hyperglycaemic therapies:
a POSITIVE IMPACT on cardiovascular outcomes

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:

A1C is less than 9%, consider Monotherapy.


A1C is less than 9%, consider Monotherapy.

A1C is less than or equal to 9%, consider Dual Therapy.

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.
Healthy eating, weight control, increased physical activity, and diabetes education

A1C is greater than or equal to 9%, consider Dual Therapy.

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

Hypo risk low risk ADA Position Statement

Weight neutral / loss 2017


Side effects GI / lactic acidosis

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

Efficacy* high high intermediate intermediate high highest


Hypo risk moderate risk low risk low risk low risk low risk high risk
Weight gain gain neutral loss loss gain

Side effects hypoglycemia edema,HF,fxs rare GU,dehydration, fxs GI hypoglycemia


low low high high high high
Costs*

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

DPP-4-i DPP-4-i TZD TZD TZD DPP-4-i


or or or or
or or

or SGLT2-i or SGLT2-i or SGLT2-i Insulin or SGLT2-i


or DPP-4-i or

or GLP-1-RA or GLP-1-RA or Insulin or Insulin or GLP-1-RA

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.

Combination injectable theraphy


Basal insulin + Mealtime insulin or GLP-1-RA
Diabetes Care 2017;40(Suppl.1):S11-S24 | DOI:
2337/dc17-S005
Antihyperglycemic Therapy in Adults with Type 2 Diabetes
At diagnosis, initiate lifestyle management, set A1C target, and initiate pharmacologic
theraphy based on A1C:

A1C is less than 9%, consider Monotherapy.

A1C is less than or equal to 9%, consider Dual Therapy.

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.

Monotherapy Lifestyle Management + Metformin

Intiate metformin therapy if no contraindications*

A1C at target Yes: - Monitor A1C every 3-6 months


after 3 months
of monotherapy? No: - Assess medication-taking behavior
- Consider Dual Therapy

Dual Therapy Lifestyle Management + Metformin + Additional Agent

ASCVD? Yes: - Add agent proven to reduce major adverse


cardiovascular events and/or cardiovascular mortality

No: - Add second agent after consideration of drug-specific effects


and patient factors

Yes: - Monitor A1C every 3-6 months


A1C at target
after 3 months No: - Assess medication-taking behavior
of dual therapy? - Consider Triple Therapy

Triple Therapy Lifestyle Management + Metformin + Two Additional Agents

Add third agent based on drug-specific effects and patient factors.

A1C at target Yes: - Monitor A1C every 3-6 months


after 3 months
of triple therapy? No: - Assess medication-taking behavior
- Consider Combination Injectable Therapy

Combination Injectable Therapy


ASCVD
History of ACS, MI, Stable angina,
Coronary/other arterial revascularisation,
stroke,TIA, or PAD from atherosclerosis.
CV effects
ASCVD CHF

Metformin Potential Benefit Neutral

Drug-specific and patient factors to consider


Benefit:
Benefit:
when selecting antihyperglemic treatment in
SGLT-2 Inhibitors canagliflozin,
canagliflozin,
adults with type 2 diabetes
empagliflozin empagliflozin

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

Sulfonylureas Neutral Neutral


(2nd Generation)

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

empagliflozin empagliflozin • LDL cholesterol

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

Insulin Pharmacologic Approaches to Glycemic Treatment: 



Analogs Standards of Medical Care in Diabetes
High - 2018. SQ
Diabetes Care 2018; 41 (Suppl. 1): S73-S85
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 • 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

Low Oral Neutral • No dose adjustment • FDA Black Box:


High No Gain Potential Increased required Congestive heart failure
Benefit: Risk • Generally not recommended [pioglitazone,
pioglitazone rosiglitazone]
in renal impairment due to • Fluid retention (edema;
Thiazolidinediones potential for fluid retention heart failure)
• Benefit in NASH
• Risk of bone fractures
• Bladder cancer
Low Oral Neutral • Glyburide: not • (pioglitazone)
FDA Special Warning on
High Yes Gain Neutral Neutral increased risk of
recommended
• Glipizide & Glimepiride: cardiovascular mortality
based on studies of an
initiate conservatively to
Sulfonylureas older sulfonylurea
avoid hypoglycemia (tolbutamide)
(2nd Generation)

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

GA 50% 25% 25%

HbA1c 50% 25% 25%

K.Shima,Tokushima School of Medicine,Japan


ORIGINAL ARTICLE

In diabetic patients (21). The results


showed that 50% of the HbA1c level
Kinetics of HbA1c, Glycated was determined by the plasma
Albumin, and Fructosamine glucose level during the preceding 1-
50 % of the HbA1c
and Analysis of Their Weight level was month period, while 25% of its level
was determined by the plasma

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

Level the plasma glucose level during the

Yasuhiro Tahara, MD, PHD


preceding 1-month 2-month period before these 2
months. These data support the idea
Kenji Shima, MD, PHD
that the HbA1c level reflects the
OBJECTIVE - To examine the kinetics of HbA1c, glycated albumin weighted mean plasma glucose level
(GA), and fructosamine (FA) levels in response to plasma glucose
over the preceding 4 months.
change and their relationship with the preceding plasma glucose level.

Diabetes Care, volume 18, number 4, April 1995


This can be achieved with
Mean plasma glucose: ~150-160 mg/dL;
Fasting and premeal : < 130mg/dL.

Postprandial glucose : <180mg/dL.


• Fasting BG
• Glycated Albumin
• HbA1c