Comprehensive approach to Early

Address Need in T2DM: Treatment on

Glycemic Control and Beyond

Wira Gotera
Indonesia A1c condition: very poor glycaemic control

• Indonesian HbA1c is the

highest compare with other
participant countries in
DISCOVER study, even after
initiating second line of therapy
(mean+SD = 9.2+2%)1, almost
70% patient >8%).2

1. Wahono DS et al. 2nd ICE on IMERI, 7 November 2017, Jakarta, Indonesia

2. Ji L et al. 53rd EASD, 11–15 September 2017, Lisbon, Portugal.

3
Even after initiating 2nd
line therapy, prevalence
of macrovascular
complications in T2DM
patient still very high1

Indonesia –
Higher proportion of macrovascular
than overall Asia Pacific data2

77.4%

17.2%
1. Shestakova et al. 53rd EASD, 11–15 September 2017, Lisbon, Portugal
Any Macrovascular Any Microvascular 2. Soeatmadji DW et al. 2nd ICE on IMERI, 7 November 2017, Jakarta, Indonesia
Disease Disease
 Renal and CV disease are closely interconnected

Renal and cardiac systems are linked1 CKD patients are more likely to die of
heart disease than advance to ESRD2

Rate per 100 person-years

0.5

ESRD CV
death

Renal and cardiac systems should be considered together

CKD, chronic kidney disease; CV, cardiovascular; ESRD, end-stage renal disease
1. Ronco C, et al. J Am Coll Cardiol 2008;52:1527-1539; 2. Dalrymple L, et al. J Gen Intern Med 2011;26:379-385
INTERNAL MEDICAL USE ONLY
 87,5% of Cost of Diabetes Treatment Are for Complications
Meanwhile Drug cost are only 0,54%
81

87.5% of cost of diabetes treatment are for complication,

meanwhile drug cost are only 0.54%1

Cost in referral health care

Until June 2016

1%
0,54%

12%
12,5
%

Non complication Drug cost

Complication Non drug cost

88%
87,5%
99,56%
99%

1. Budi Hidayat. Diabetes Medical Cost for Secondary and Tertiary Care. Presented during Round Table Meeting PERKENI and MoH. Bali, 26 Oktober 2018.

INTERNAL MEDICAL USE ONLY

 Declining renal function is associated
with incident HF
Incidence rates of HF are higher in those with CKD Incidence rates of HF are higher in those with
compared to those without microalbuminuria compared to those without

8% 8%

CKD HFrEF Microalbuminuria HFrEF

CKD HFpEF Microalbuminuria HFpEF
No CKD HFrEF No microalbuminuria HFrEF
6% No CKD HFpEF 6% No microalbuminuria HFpEF
Cumulative incidence of HF

Cumulative incidence of HF
4% 4%

2% 2%

0% 0%
0 2 4 6 8 10 12 0 2 4 6 8 10 12

Years Years

CKD, chronic kidney disease; HF, heart failure; HFpEF, heart failure with preserved ejection fraction; HFrEF, heart failure with reduced ejection fraction.
7
Nayor M, et al. Eur J Heart Fail. 2017;19:615-623.
HF was the first manifestation of T2D-related
CV disease more often than was MI or stroke

Cohort study of patients (n=1.9 million) with T2D

and incidence of CV disease

16.2%
• In this large cohort, PAD and HF were the
14.1% two most common first presentations of
% event as first CV event

T2D-related CV disease
11.5% • Yet, myocardial infarction and stroke
10.3% continue to be chosen as primary outcomes
of major type 2 diabetes trials, as part of
the MACE endpoint
• This suggests that future studies should
assess CV events that occur earlier in
4.2% patients with T2D such as HF and PAD

PAD HF* NFMI CVA CV death

*Heart failure post MI was not included in this definition of HF

CV, cardiovascular; CVA, cerebrovascular accident; HF, heart failure; NFMI, nonfatal myocardial infarction; PAD, peripheral arterial disease; T2D, type 2 diabetes.
Shah AD, et al. Lancet Diabetes Endocrinol. 2015;3:105-113, Appendix.
PATOFISIOLOGI GANGGUAN CARDIOVASKULAR
 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 HbA1C > + Monoterapi dalam 3
7% bulan HbA1C > 7%
Gejala (-) Gejala (+)

Monoterapi* dengan salah Kombinasi 2 obat* dengan Kombinasi 2 obat

satu dibawah ini mekanisme yang berbeda
Insulin ± obat lain
- Metformin - Agonis GLP1 Kombinasi 3 obat Kombinasi 3 obat
Metformin atau obat lini pertema yang lain

- Agonis GLP1 - Penghambat DPP4 Metformin atau obat lini pertema yang lain - Agonis GLP1
- Penghambat DPP4 - Tiazolidindion - Penghambat DPP4
- Penghambat - Penghambat
- Tiazolidindion
SGLT2 *
glukosidase alfa - Penghambat
- Insulin basal SGLT2 *
- Penghambat
2 Obat lini kedua

- SU / Glinid - Insulin basal

SGLT2 * Mulai pemberian insulin atau
- Kolesevelam** - SU / Glinid lakukan intensifikasi insulin
- Tiazolidindion
- Bromokriptin - Kolesevelam**
- Sulfonilurea
QR** - Bromokriptin
- Glinid Keterangan:
- Penghambat QR**
Jika HbA1C belum glukosidase alfa * Obat yang terdaftar, pemilihan dan penggunaannya
- Penghambat
mencapai sasaran disarankan mempertimbangkan faktor keuntungan,
dalam 3 bulan, Jika HbA1C belum glukosidase alfa
kerugian dan ketersediaan sesuai tabel 11.
tambahkan obat ke-2 mencapai sasaran dalam
Jika HbA1C belum mencapai ** Kolesevelam belum tersedia di Indonesia dan
(kombinasi 2 obat) 3 bulan, tambahkan obat
sasaran dalam 3 bulan, mulai Bromokriptin QR umumnya digunakan pada terapi
ke-3 (kombinasi 3 obat)
terapi insulin atau intensifikasi tumor hipofisis
terapi insulin
 2019 ACC/AHA Guideline on the Primary Prevention of
Cardiovascular Disease

• Recommendation for adults with type 2 diabetes mellitus

COR LOE Recommendation

I A For all adults with T2DM, a tailored nutrition plan focusing on a heart
healthy dietary pattern is recommended to improve glycemic control,
achieve weight loss if needed, and improve other ASCVD risk factors
(S4.2-1, S4.2-2).
I A Adults with T2DM should perform at least 150 minutes per week of
moderate-intensity physical activity or 75 minutes of vigorous-intensity
physical activity to improve glycemic control, achieve weight loss if
needed, and improve other ASCVD risk factors (S4.2-3, S4.2-4).
IIa B-R For adults with T2DM, it is reasonable to initiate metformin as first-line
therapy along with lifestyle therapies at the time of diagnosis to
improve glycemic control and reduce ASCVD risk (S4.2-5–S4.2-8).
IIb B-R For adults with T2DM and additional ASCVD risk factors who require
glucose lowering therapy despite initial lifestyle modifications and
metformin, it may be reasonable to initiate a sodium-glucose
cotransporter 2 (SGLT-2) inhibitor or a glucagon-like peptide-1
receptor (GLP-1R) agonist to improve glycemic control and reduce
CVD
Arnett et al.. 2019 ACC/AHA Guideline riskPrevention
on the Primary (S4.2-9–S4.2-14).
of Cardiovascular Disease
SGLT2 Inh.(Dapaglifozin )
CV Safety and in Real World Clinical Setting
 SGLT2 inhibition blocks the proximal reabsorption of sodium and glucose,
resulting in urinary glycosuria and changes in several risk factors1-4

Modulation of traditional risk factors

Using dapagliflozin
Glucose
Reabsorptio
n ↑ in T2D 0.89% decrease from baseline
HbA1c at 24 weeks1

Weight ~3 kg weight loss from baseline

at 24 weeks2,3

Proximal tubule
5.1 mm Hg reduction from baseline
SBP at 24 weeks4

Glucose
Filtration ↑
in T2D
SGLT2 Impact on renal function with
dapagliflozin
Glucose

Sodium UACR Improves albuminuria (-33%) on

top of ACEi/ARB at 12 weeks6

eGFR Remains stable out to 4 years5

SGLT2, sodium–glucose cotransporter-2; SBP, systolic blood pressure; T2D, type 2 diabetes.
1. Ferrannini E, et al. Diabetes Care. 2010;33:2217-2224. 2. Sugiyama S, J Atheroscler Thromb. 2018;25:467-476. 3. Henry RR, et al. Int J Clin Pract. 2012;66(5):446-456. 4. Bailey CB, et al.
15 Lancet. 2010;375:2223-2233. 5. Del Prato S, et al. Diabetes Obes Metab. 2015;17(6):581-590
 The cardio-renal benefits likely results from different but
yet to be confirmed mechanisms for SGLT-2 inhibitors

Natriuresis

Improved cardiac Reduction in interstitial

bioenergetics edema

SGLT2
Inhibition
Inhibition of cardiac Reduced preload and
sodium–hydrogen afterload and reduction
exchange in LV wall stress

Improved renal function

and cardiorenal
physiology

LV, left ventricular; SGLT2, sodium-glucose co-transporter-2.

Adapted from Farkouh ME, Verma S. J Am Coll Cardiol. 2018;71:2507-2510.
INTERNAL MEDICAL USE ONLY
 Renal and CV disease are closely interconnected

Renal and cardiac systems are linked1 CKD patients are more likely to die of
heart disease than advance to ESRD2

Rate per 100 person-years

0.5

ESRD CV
death

Renal and cardiac systems should be considered together

CKD, chronic kidney disease; CV, cardiovascular; ESRD, end-stage renal disease
1. Ronco C, et al. J Am Coll Cardiol 2008;52:1527-1539; 2. Dalrymple L, et al. J Gen Intern Med 2011;26:379-385
INTERNAL MEDICAL USE ONLY
Kasus A
• Laki 54 tahun diketahui menderita DM sejak 3
tahun, dengan gula darah sangat berfluktuasi
• Saat ini diterapi dengan insulin Glargin 30 unit,
insulin Aspart 3x 12 unit, Atorvastatin 20,
clopidrogel 75 mg, amlodipin 1x5 mg
• PF BMI 26, TD 130/80,
• HbA1c 9,2 Lain dbn, creatinin 0,86 mg%
• Albuminuria (-)
Kasus A (cont..1)
 Kasus A cont.. 2
• KIE
• Glargin XR 12, Metformin 2x500 mg
Liraglutide (GLP-1 RA) 1,2 mg dan
Dapaglifoxin 10 mg
Kasus A …cont 3
Kasus A … Cont 3
Hasil AkhirKasus A.. Cont 4
Hasil Akhir Kasus A
Kasus 1
• YW, 55 tahun, DM sejak 7 tahun
• Terapi dengan Lantus 16 unit , Glipizide MR,
Atovarstatin 20 mg, aspilet
• Selama ini pengobatan rutin dilakukan, tapi
diet tidak teratur. Olah raga teratur setiap hari
dengan jalan cepat ± 3 km
• Hasil pemeriksaan gula darah sangat
berfluktuasi
Cont 1
• HbA1C selama 1 tahun sebelumnya berkisar
masih diantara 8% dan 9%
• Pasien tidak bersedia menaikkan dosis terapi
karena takut berat badan naik
• Pernah memakai Liraglutide 1,2 mg sekali
sehari, karena malas menyuntik 2 kali sehari
akhirnya distop.
Cont 1
• Dua tahun yang lalu pasien diberikan
Dapaglifoxin 10 mg sehari, disamping
pengobatan rutin
• Bak bertambah banyak dan berat badan turun
dengan cepat. Dalam 3 bulan berat badan
turun 7 kg, tetapi tidak lemas seperti waktu
pertama diketahui menderita DM
• Saat terakhir diperiksa Gd puasa 120 dan
setelah makan dibawah 160 an
Cont 1
• Bak sudah normal lagi
• HbA1c setelah 6 bulan pemakaian Dapaglifoxin
menjadi 7,2% dan terakhir 6,9% (3 bulan yl)
• PF, Terakhir (5/2 2019 )
• BB 56 kg (sebelumnya 65) TD 120/80, lain dalam
batas normal, UL (glukosa Urin + 2)dan EKG dbn
• Obat saat ini Linagliptin, dan Dapaglifoxin 10 mg
 Kasus 3
• Laki 55 tahun dengan keluhan badan lemas
dan 3P sejak 1 bulan
• Tidak diketahui menderita DM sebelumnya
• Datang dengan membawa hasil Lab yang
dikatakan Gula darahnya tinggi
• Pemeriksaan fisik BMI 26 kg lain dbn
 Kasus 3 Cont1
• Hasil Lab
• GD puasa 220 mg%, Prandial 345 mg%
• LDL 170 mg% TGA 190 mg%
• Urin dbn
• Hba1c 9,2%
 Kasus 3 Cont 2
• Terapi:
• KIE perubahan gaya hidup
• Metformin 2x500 mg, dan Dapaglifoxin 10 mg
• Atorvastatin 1x 20 mg
• Aspirin 1x80 mg
 Kasus 3 cont3
• Dua minggu selanjutnya,
• GD puasa 120 mg% , Prandial 160mg%
• Pasien rencana kontrol 1 bln lagi
Real World Evidence (RWE) to evaluate CV safety of
dapaglifozin

CVD SGLT2i vs oGLDs in ~300.000 patients

REAL 1 (Europe and US population)

CVD
REAL Dapaglifozin vs DPP4-i in Norway,
Denmark, and Sweden population
Nordic

CVD SGLT2i vs oGLDs in ~400.000

REAL 2 patients (Asian population involved)

33
 Hospitalization for heart failure or
all-cause death primary analysis

P-value for SGLT2i vs other glucose-lowering drug: <0.001 Heterogeneity p-value: 0.166

SENSITIVITY
Data are on treatment, unadjusted.
ANALYSES
 Lower Risk of Cardiovascular Events and Death Associated with
Initiation of SGLT-2 Inhibitors versus Other Glucose Lowering Drugs -
Real World Data Across Three Major World Regions with More Than
400,000 Patients: The CVD-REAL 2 Study

Mikhail Kosiborod1, Carolyn Su Ping Lam 2, Shun Kohsaka3, Dae Jung Kim4, Avraham Karasik5, Jonathan Shaw6,
Navdeep Tangri7, Su-Yen Goh8, Marcus Thuresson9, Hungta Chen10, Filip Surmont11, Niklas Hammar12,13, Peter
Fenici14 on behalf of the CVD-REAL Investigators and Study Group
1Saint Luke's Mid America Heart Institute and University of Missouri-Kansas City, Kansas City, MO, USA; 2National

Heart Centre, Singapore and SingHealth Duke-NUS, Singapore; 3Keio University School of Medicine, Tokyo, Japan;
4Department of Endocrinology and Metabolism, Ajou University School of Medicine, Suwon, Republic of Korea; 5Tel

Aviv University, Ramat Aviv, and Maccabi Healthcare Israel; 6Baker IDI Heart and Diabetes Institute, Melbourne,
Victoria, Australia; 7Department of Medicine, University of Manitoba, Winnipeg MB, Canada; 8Singapore General
Hospital, Singapore; 9Statisticon AB, Uppsala, Sweden; 10AstraZeneca, Gaithersburg, MD, USA; 11AstraZeneca, Luton,
UK; 12Karolinska Institutet, Stockholm, Sweden; 13AstraZeneca, Gothenburg, Sweden; 14AstraZeneca, Cambridge, UK
 Use of SGLT-2i: Proportion of Exposure Time

*In South Korea and Japan; †In Japan only. Kosiborod M et al. J Am Coll Cardiol 2018; S0735-1097(18)33528-9
 Composite of All-Cause Death or HHF

P-value for
SGLT2i vs. oGLD:
p<0.001

ITT, unadjusted analysis Heterogeneity p-value: p<0.001

Kosiborod M et al. J Am Coll Cardiol 2018; S0735-1097(18)33528-9

The 2018 ADA-EASD consensus report now reflects emerging evidence
from SGLT2 inhibitors and GLP-1 RA CVOTs

DECLARE results were

not yet available when
First-line therapy is metformin and comprehensive lifestyle modification
(including weight management and physical activity)
consensus written
If HbA1c above target, proceed as below

CONSENSUS RECOMMENDATIONS

Patients with T2D who have established

ASCVD:
SGLT2 inhibitors or GLP-1 RAs with proven
ASCVD HF or CKD
CV benefit recommended predominates predominates

Patients with ASCVD in whom HF

coexists or is of special concern: PREFERABLY
SGLT2 inhibitors recommended
EITHER/ SGLT2 inhibitor with evidence of reducing
OR HF and/or CKD progression in CVOTs,
if eGFR adequatec

Patients with T2D and CKD, with or

without CVD:
SGLT2 inhibitor OR
GLP-1 RA with proven
Consider SGLT2 inhibitor or, if with proven CVD benefita,
contraindicated/not preferred, GLP-1 RA CVD benefita if eGFR If SGLT2 inhibitor not tolerated or
shown to reduce CKD progression adequateb contraindicated or if eGFR less than
adequateb, add GLP-1 RA with
proven CVD benefita,d

aProven CVD benefit refers to a label indication of reducing CVD events. Hierarchy of evidence for CVD benefits: modestly stronger for EMPA>CANA for SGLT2 inhibitors
and strongest for LIRA>SEMA>EQW for GLP-1 RAs; bSGLT2 inhibitors vary by region and individual agent with regard to indicated level of eGFR for initiation and
continued use; cBoth EMPA and CANA have shown reduction in HF and reduction in CKD progression in CVOTs; d Caution with GLP-1 RA in ESRD.
ADA = American Diabetes Association; ASCVD = atherosclerotic cardiovascular disease; CKD = chronic kidney disease; CV = cardiovascular; CVD = cardiovascular
disease; CVOTs = cardiovascular outcome trials; EASD = European Association for the Study of Diabetes; eGFR = estimated glomerular filtration rate; ESRD = end-stage
renal disease; GLP-1 RA = glucagon-like peptide-1 receptor agonist; HbA1c = glycated haemoglobin; HF = heart failure; SGLT2 = sodium–glucose co-transporter 2; T2D =
type 2 diabetes.
Davies MJ et al. Diabetologia. 2018;61:2461-2498 © AstraZeneca 2019
Sekapur Sirih untuk dibawa Pulang ….
• Pendekatan yang komprehensif dan agresif haruslah
menjadi perhatian utama untuk menangani pasien DM
• Setiap Modulasi selalu harus mendapat manfaat dalam
koridor pencegahan kejadian CV
• SGLT2 Inh. (Dapaglifoxin) dapat dipertimbangkan sebagai
terapi lebih awal mengingat evek proteksi pada Ginjal dan
CV

© AstraZeneca 2019
Suksma ……