Diabetes Mellitus and Hypertension

Management in Clinical Practices

The Role of DPP4i and ARB

Pembicara :
Dr.Ketut Swastioni

PC-ID-100461 abcd
Epidemiology of Type 2 DM

425 MILLION 3.7 MILLION

living with diabetes, globally1 deaths due to diabetes and high glucose2

2.2 MILLION
deaths caused by complications of
diabetes, including:2
CARDIOVASCULAR DISEASE
CHRONIC KIDNEY DISEASE
629
million people

425
million people
1.5 MILLION
deaths caused by
diabetes directly2

Present 2040

This will rise to 629 million by 2045*1

Prevalence of DM in Indonesia 8-10% (Riskesdas 2018)
*For people aged 20–79 years old
1. International Diabetes Federation. IDF Diabetes Atlas. 8th Edition. 2017 http://www.diabetesatlas.org; 2. World
Health Organization (WHO). Global Report on Diabetes. 2016 abcd
http://apps.who.int/iris/bitstream/10665/204871/1/9789241565257_eng.pdf (both accessed January 2019)
There is a need for glucose-lowering medications with proven CV and kidney safety
Ada kebutuhan untuk obat penurun glukosa dengan CV dan keamanan ginjal yang terbukti

Good glycaemic control No dose adjustment

Weight-neutral CV safety

Low risk of hypoglycaemia Kidney outcomes

Balfour PC, Rodriguez CJ, Ferdinand KC. Curr Hypertens Rep 2014;16:455
Bakris GL, Williams M, Dworkin L, et al. AJKD 2000.;36(3):646-61
McFarlane SI, Sica DA, Sowers JR. J Clin Hypertens 2005;7(5):286-92 abcd
Rosenstock J, Perkovic V, Johansen OE, et al. JAMA 2019;321(1):69-79
Linagliptin has the highest DPP-4 inhibition potency compared with other DPP-4is
Linagliptin memiliki potensi penghambatan DPP-4 tertinggi dibandingkan dengan DPP-4is
lainnya

120
DPP-4 enzyme activity, % control

100 Linagliptin Mean IC50* [nM]

Alogliptin
Sitagliptin Linagliptin 1
80
Saxagliptin Alogliptin 24
60 Vildagliptin
Sitagliptin 19
40
Saxagliptin 50
20 Vildagliptin 62

0
- 12 - 10 -8 -6
Log dose [M]
Highest potency of linagliptin in
inhibiting DPP-4 enzyme activity

*Concentration of compound needed to inhibit 50% of DPP-4 activity, i.e. the lower the IC50, the higher the potency
to inhibit DPP-4 activity
DPP-4, dipeptidyl peptidase-4; DPP-4i, dipeptidyl peptidase-4 inhibitor; IC50, half maximal inhibitory concentration abcd
Adapted from: Thomas L et al. J Pharmacol Exp Ther 2008;325:175
Start your metformin-uncontrolled patients with TRAJENTA DUO® for powerful HbA1c reductions
Mulailah pasien Anda yang tidak terkontrol metformin dengan TRAJENTA DUO® untuk pengurangan HbA1c yang
kuat
Placebo-adjusted mean HbA1c change from baseline at 24 weeks1

Perubahan HbA1c rata-rata yang disesuaikan dengan plasebo dari awal pada 24 minggu1

Haak T et al. Diabetes Obes Metab 2012;14;565-74 abcd

TRAJENTA DUO® provides powerful HbA1c reductions for high baseline
patients
Placebo-adjusted mean HbA1c change from baseline at 24 weeks*
Open-label arm:
Linagliptin 2.5 mg bid + Linagliptin 2.5 mg bid + linagliptin 2.5 mg bid +
0.0
metformin 500 mg bid metformin 1000 mg bid metformin 1000 mg bid 3.7%
in HbA1c at 24 weeks (%)

reduction
Adjusted mean change

in open-
-1.0 label arm
-1.3
-2.0
-1.7
-3.0

-4.0 -3.7
n 137 140 66†
Mean baseline 8.7 8.7 11.8
HbA1c (%)
Open-label arm: patients with poor glycaemic control: mean; full analysis set, observed cases (n=48)
*24-week, double-blind, placebo-controlled, phase III trial. Two arms received linagliptin 2.5 mg bid + either low (500
mg) or high (1000 mg) dose metformin bid. Four arms received linagliptin 5 mg qd, metformin 500 mg or 1000 mg bid
or placebo. Patients with HbA1c ≥11.0% were not eligible for randomisation and received open-label linagliptin +
high-dose metformin. High baseline defined as HbA1c >8.5% to <11.0%; †56 of the 66 patients randomised to open-
label treatment of linagliptin 2.5 mg bid + metformin 1000 mg bid completed treatment. HbA1c, glycated abcd
haemoglobin Haak T et al. Diabetes Obes Metab 2012;14:565
The long-term glucose-lowering efficacy of TRAJENTA DUO® is
comparable with that of glimepiride + metformin
Adjusted* change from baseline HbA1c over time (baseline HbA1c: 7.24%)
7.5

Linagliptin + metformin (n=233)

Mean HbA1c over time, % (SE)

Glimepiride + metformin (n=271)

7.0
-0.6%
at 104
weeks
6.5

6.0
0 4 8 12 16 20 24 28 32 36 40 44 48 52 56 60 64 68 72 76 80 84 88 92 96 100 104
Treatment duration (weeks)
*Model includes treatment, baseline HbA1c and number of prior glucose-lowering therapies
HbA1c, glycated haemoglobin
Gallwitz B et al. Lancet 2012;380:475
abcd
With TRAJENTA DUO®, more patients achieve target HbA1c levels without hypoglycaemic events* or weight gain compared with glimepiride + metformin†
Dengan TRAJENTA DUO®, lebih banyak pasien mencapai level target HbA1c tanpa kejadian hipoglikemik * atau penambahan berat badan dibandingkan dengan
glimepiride + metformin †
Proportion of patients achieving
HbA1c target <7% after 2 years

80 Proporsi pasien yang mencapai target HbA1c <7% setelah 2

tahun

76% 76%
60 76% 76%
Proportion of patients, %

Proportion of patients achieving

54% HbA1c target <7% after 2 years:
40 • Without hypoglycaemic events
• Without weight gain
Proporsi pasien yang mencapai target HbA1c <7%
setelah 2 tahun:
• Tanpa kejadian hipoglikemik
• Tanpa penambahan berat badan
20
23% OR (95% CI):
3.86 (2.63, 5.68)
p<0.0001 23% 54%
0
Glimepiride + Linagliptin +
metformin metformin
(n=271) (n=233)
*As defined by the American Diabetes Association Workgroup on Hypoglycemia2; †Study performed using a free
combination of linagliptin and metformin
1. Gallwitz B et al. Lancet 2012;380:475; 2. American Diabetes Association Workgroup on Hypoglycemia. Diabetes abcd
Care 2005;28:1245
    
Linagliptin is the DPP-4i with extensive CVOT data  

   
Confirmed kidney safety
DPP-4i CVOT trials Confirmed profile through Hospitalisation
CV safety profile for heart failure
hard outcomes

Vildagliptin None Not investigated No Not investigated

Saxagliptin1 1 Yes No Increased risk
Sitagliptin4 1 Yes No Safety confirmed

Linagliptin5 2 Yes Yes Safety confirmed

*Incidence of hospitalisation for heart failure increased in patients receiving alogliptin in the EXAMINE CV outcome
trial, prompting the FDA to accordingly include a warning in the Nesina® US Prescribing Information. However, it
should be noted that the increased incidence of hospitalisation for heart failure was numerical only and was not
statistically significant6 CVOT, cardiovascular outcomes trial; DPP-4i, dipeptidyl peptidase-4 inhibitor
1. Scirica BM et al. N Engl J Med 2013;369:1317; 2. White WB et al. N Engl J Med 2013;369:1327; 3. Zannad F et al.
Lancet 2015;385:2067;
4. Green JB et al. N Engl J Med 2015;373:232; 5. Rosenstock J et al. JAMA 2019;321:69; 6. Takeda. Nesina® (alogliptin) abcd
Prescribing Information. 2016
Linagliptin: The only approved DPP4i that does not require dose reduction based on renal function
Linagliptin: Satu-satunya DPP4i yang disetujui yang tidak memerlukan pengurangan dosis berdasarkan fungsi ginjal

Require DPP4i dose with declining renal function

1. Glucophage summary of product characteristics, January 2017 available at: https://www.medicines.org.uk/emc

2. Trajenta Duo summary of product characteristics, 2019
3. Trajenta summary of product characteristics, 2018

abcd
4. Janumet summary of product characteristics, 2018
5. Kombiglyze summary of product characteristics, 2017
6. Galvusmet summary of product characteristics, 2017
7. Vipdomet summary of product characteristics, 2018
Interlink between Type 2 Diabetes & Hypertension
Keterkaitan antara Diabetes Tipe 2 & Hipertensi
• Hypertension and type 2 diabetes are common comorbidities.
• Hypertension is twice as frequent in patients with diabetes compared with
those who do not have diabetes.
• Patients with hypertension often exhibit insulin resistance and are at
greater risk of diabetes developing than are normotensive individuals.
• The major cause of morbidity and mortality in diabetes is cardiovascular
disease, which is exacerbated by hypertension.
• Accordingly, diabetes and hypertension are closely interlinked because of
similar risk factors and substantial overlap in the cardiovascular
complications.

• Hipertensi dan diabetes tipe 2 adalah penyakit penyerta yang umum.

• Hipertensi dua kali lebih sering terjadi pada pasien diabetes dibandingkan
dengan mereka yang tidak menderita diabetes.
• Pasien dengan hipertensi sering menunjukkan resistensi insulin dan berisiko
lebih besar terkena diabetes daripada individu normotensi.
• Penyebab utama morbiditas dan mortalitas pada diabetes adalah penyakit
kardiovaskuler, yang diperparah oleh hipertensi.
• Oleh karena itu, diabetes dan hipertensi sangat erat kaitannya karena faktor
risiko yang sama dan komplikasi kardiovaskular yang tumpang tin dih.

Petrie JR, et al. Canadian J Cardiology 2018:34;575-84 abcd

The number of people with hypertension continues to increase
Did you know in the world? Did you know in Indonesia?
the number of people with hypertension in the world the prevalence of hypertension in Indonesia is 34.1%
continues to increase every year in 2018 vs 25.8% in 2013

Estimated in 2025 The highest prevalence

there will be 1.5 billion of hypertension in South
people affected by Kalimantan 44.1%
hypertension

44.1%
1 in 3 People
in the world is 34.0%
diagnosed with Because
hypertension only 36.8% of Jakarta
hypertension patients The prevalence of hypertension
take their medication is 34.0%

WHO, RISKESDAS 2018 abcd

CCB + ARB: The Synergies of Counter-Regulation (1)

CCB
· Arteriodilation
· Peripheral oedema
· Effective in low-renin patients
· Reduces cardiac ischaemia
BP

CCB
Synergistic · RAS activation
BP reduction · No renal or CHF
Complementary benefits
clinical benefits

Mistry, et al. Expert Opin Pharmacother. 2006; 7: 575–581;

Sica. Drugs. 2002; 62: 443–462; Quan, et al. Am J Cardiovasc Drugs. 2006; 6: 103-113. abcd
CCB + ARB: The Synergies of Counter-Regulation (2)

CCB
· Arteriodilation ARB
· Peripheral oedema · RAS blockade
· Effective in low-renin patients · CHF and renal
· Reduces cardiac ischaemia benefits
BP

ARB
· Venodilation CCB
· Attenuates peripheral oedema Synergistic · RAS activation
· Effective in high-renin patients BP reduction · No renal or CHF
· No effect on cardiac ischaemia Complementary benefits
clinical benefits

Mistry, et al. Expert Opin Pharmacother. 2006; 7: 575–581; Sica. Drugs. 2002; 62: 443–462;
Quan, et al. Am J Cardiovasc Drugs. 2006; 6: 103-113. abcd
Telmisartan Has Unique Pharmacology Among ARBs
Telmisartan Memiliki Farmakologi Unik Diantara ARB

1. Chambers S. Telmisartan. Drugs in Context. 2008; 4(1): 1-14

2. Benson SC, et al. Hypertension. 2004; 43: 993-1002 abcd
Amlodipine - The longest half-life in-class
Amlodipine - Waktu paruh terpanjang di kelasnya

35

Plasma elimination half-life (h) 30

50

25

20
16
15
12
10 8
5
2 2
0
Nifedipine Nimodipine Nicardipine Nisoldipine Felodipine Amlodipine

Abernethy DR, Schwartz JB. The New England Journal of Medicine. 1999; 341 (9): 1447-57 abcd
Telmisartan + Amlodipine: Consistent BP reductions across hypertension severities to get patients to goa
Telmisartan + Amlodipine: Penurunan BP yang konsisten di semua tingkat keparahan hipertensi untuk membuat
pasien mencapai tujuanl

1. Suarez C. Drugs. 2011; 71 (17): 2295-2305

2. Neutel, et al. The Journal of Clinical Hypertension. 2012; 14: 206-215 abcd
Telmisartan + Amlodipine: Consistently high BP reductions in added-risk hypertensive patients
Telmisartan + Amlodipine: Penurunan tekanan darah tinggi secara konsisten pada pasien hipertensi risiko
tambahan

Neutel, et al. The Journal of Clinical Hypertension. 2012; 14: 206-215 abcd
Telmisartan + Amlodipine: Safety and tolerability profile similar to placebo
Telmisartan + Amlodipine: Profil keamanan dan tolerabilitas mirip dengan plasebo

AEs > 1% incidence (%) Placebo (n = 46)

Amlodipine mono
Patients with

(n = 319)
Telmisartan +
Amlodipine
(n = 789)

Fatigue Oedema Sinusitis Naso- Upper Influenza Back Dizzi- Headache Peripheral
pharyngitis respiratory pain ness oedema
tract
infection

Littlejohn ,et al. J Clin Hypertens. 2009; 11: 207-213 abcd

Fixed Dose Combinations reduce resource utilization
Kombinasi Dosis Tetap mengurangi pemanfaatan sumber daya
p < 0.0001

Fixed Dose Combinations (n = 2,336)

Component therapy (n = 3,368)
Healthcare costs (US$)

p < 0.0001
p < 0.0001
p < 0.0001

NS

Hospital Other Ambulatory Drug Total

NS = not significant Rawat jalan
Dickson, Plauschinat. Am J Cardiovasc Drugs. 2008; 8: 45-50 abcd
Loose combination or Fixed Dose Combination?
Kombinasi longgar atau Kombinasi Dosis Tetap?

Fixed Dose Combination (FDC)

1. Reducing the number of pills to be taken daily improves adherence/patient compliance (Simplify
treatment regimens) 1,2,3
2. Provide superior BP-lowering efficacy2
3. Increases the rate of BP control1
4. Enhanced patient adherence2
5. Reducing healthcare costs3
6. Improved tolerability profile2
Kombinasi Dosis Tetap (FDC)
7. Mengurangi jumlah pil yang harus diminum setiap hari meningkatkan kepatuhan / kepatuhan pasien
(Sederhanakan rejimen pengobatan) 1,2,3
8. Memberikan khasiat penurun BP yang superior2
9. Meningkatkan tingkat kontrol BP1
10. Peningkatan kepatuhan pasien2
11. Mengurangi biaya perawatan kesehatan 3
12. Profil tolerabilitas yang ditingkatkan2

1. Mancia, et al. Journal of Hypertension. 2013; 31: 1281-1357

2. Suarez C. Drugs. 2011; 71 (17): 2295-2305
3. Cowart JB, Taylor AA. Curr Hypertens Rep. 2012; 14: 324-332
abcd
 Fixed Dose Combinations reduce non-compliance to medication

Kombinasi Dosis Tetap mengurangi ketidakpatuhan terhadap pengobatan

Non-compliance
to medication
regimens is
reduced by
24-26%
with fixed-dose
combinations
regimens

Ketidakpatuhan terhadap
Effect of fixed-dose combination vs free-drug combination on the risk of rejimen pengobatan adalah
medication non-compliance in cohort with hypertension dikurangi oleh
24-26%
Pengaruh kombinasi dosis tetap vs kombinasi obat bebas pada risiko
ketidakpatuhan pengobatan pada kohort dengan hipertensi dengan regimen kombinasi
dosis tetap
Bangalore S, et al. The American Journal of Medicine. 2007; 120: 713-719 abcd
Summary
Type 2 DM
• Trajenta Duo® provides powerful HbA1c reductions for high baseline patients
• With Trajenta Duo® more patients achieve target HbA1c levels without hypoglycaemic events* or weight gain compared with glimepiride + metformin
• Start your metformin-uncontrolled patients with Trajenta Duo® for powerful HbA1c reductions.
• Trajenta Duo® memberikan pengurangan HbA1c yang kuat untuk pasien dengan baseline tinggi
• Dengan Trajenta Duo®, lebih banyak pasien mencapai level target HbA1c tanpa kejadian hipoglikemik * atau penambahan berat badan dibandingkan
dengan glimepiride + metformin
• Mulailah pasien Anda yang tidak terkontrol metformin dengan Trajenta Duo® untuk pengurangan HbA1c yang kuat.
Hypertension
• Telmisartan Has Unique Pharmacology Among ARBs – Longest plasma half life, highest receptor affinity, most lipophilic and highest selective PPARγ
activation
• Twynsta: Consistent BP reductions across hypertension severities to get patients to goal
• Twynsta: Consistently high BP reductions in added-risk hypertensive patients
• Telmisartan Memiliki Farmakologi Unik Di Antara ARB - Paruh plasma terpanjang, afinitas reseptor tertinggi, aktivasi PPARγ selektif paling lipofilik dan
tertinggi
• Twynsta: Penurunan TD yang konsisten di seluruh tingkat keparahan hipertensi untuk membuat pasien mencapai tujuan
• Twynsta: Penurunan TD tinggi secara konsisten pada pasien hipertensi risiko tambahan

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