get to target diabetes control with dual combination

It's not easy to reach glucose targets in diabetes management. A combination of two drugs in one pill can improve adherence for diabetic patients.

1. OPTIMIZATION OF TYPE 2 DM TREATMENT WITH DUAL COMBINATION Nanang Miftah Fajari Internist - Endocrinologist Divisi Endokrinologi Metabolik dan Diabetes Dept Ilmu Penyakit Dalam – FK ULM Banjarmasin

2. Introduction Type 2 DM is Progressive disease Progressive loss of beta cell function is observed during the natural course of the disease DM in Asian Region is more beta cell dysfunction rather than insulin resistance . Need Guideline acceptance for Specific population

3. Asian Population is not similar to other Population in Western

4. Asian Phenotypes T2DM Patients Adapted from Chan JCN, Yeung R, Luk A. Diabetes Voice 2014. March 14, Volume 59

5. Diabetes Spectrum in Asian Region

6. 8 Management of T2DM Old Paradigm Diet + Exercise Oral drugs Insulin 1 2 3 ‘ Step-Care ’ Glycemic targets not met Monotherapy is not durable Fails to address dual defect Perpetuates failure of Rx. Glucotoxicity ↓ response

7. 9 Stage Management Today ’ s Paradigm IR Alone IR + ID Frank ID 1 2 3 Metabolic Basis Metformin is the sheet anchor HbA1c target of < 7  OAD Combination. OAD choice based on patient type Early insulin therapy, Basal Insulin ABC control; not glycemia alone Prevention of complications - a must

8. Expected HbA1c reduction according to intervention Intervention Expected ↓ in HbA 1c (%) Lifestyle interventions 1 to 2% Metformin 1 to 2% Sulfonylureas 1 to 2% Insulin 1.5 to 3.5% Glinides 1 to 1.5% 1 Thiazolidinediones 0.5 to 1.4%  - Glucosidase inhibitors 0.5 to 0.8% GLP-1 agonist 0.5 to 1.0% Pramlintide 0.5 to 1.0% DPP-IV inhibitors 0.5 to 0.8% 1. Repaglinide is more effective than nateglinide Adapted from Nathan DM, et al. Diabetes Care 2009;32:193-203.

9. OAD is More Frequent for Drug Prescribed in Asia Diabetes Management Variable n (%)* Type of OAD Therapy Biguanides 1085 (59.26) Sulphonylureas 1036 (56.58) Meglinitides 8 (0.44) Alpha glucosidase inhibitors 461 (25.18) TZDs 51 (2.79) Other OADs 48 (2.62) Traditional herbal medicines 5 (0.27) Double drug fixed dose combination 88 (4.81) Kobayashi M, et al. Diabetes Res. Clin. Pract. 73: 198–204 Soewondo P. Med J Indones 2010;19(4):235-244 OAD Prescription in Indonesia Japan Diabetes Clinical Data Management Study Group (JDDM)

10. Differences in Type 2 Diabetes Guidelines IDF guidelines 2016 metformin 1 st line sulphonylurea (SU) 2 nd line ADA/EASD guidelines 2015 metformin 1 st line multiple options 2 nd line AACE guidelines 2016 metformin 1 st line Use with caution of SU, TZD, GLN ADA – EASD guidelines 2021 metformin 1 st line Identify ASCVD, overt or not

11. Korean J Intern Med. 2017;32(6):947-958

12. Titel der Präsentation | DD.MM.YYYY 16

13. 17 Treatment algorithm for people with T2DM IDF Clinical Guidelines Task Force. Global Guideline for Type 2 Diabetes, 2012. www.idf.org/sites/default/files/IDF-Guideline-for-Type-2-Diabetes.pdf

14. Combination Therapy in Type 2 DM

15. Early Combination VS Mono Therapy According guideline : Fixed dose Combination : Pills burden >> Patients adherence << High Cost Initial combination therapy is proposed to better and faster achievement of glycemic impede clinical inertia possibly slow the deterioration of β- cell function. Simplify the treatment regimen Reduced pill burden compared to same combination delivered as separate pills J Family Med Prim Care.  2020 Nov; 9(11): 5450–5457

16. Rationale for choosing fixed-dose combinations  • Drugs in combination should have different mechanisms of action.  • The pharmacokinetics of drugs must not be too different from each other.  • The combination should not have additives that can induce supra-additive toxicity.  • The combination can be chosen based on the recommendations of treatment guidelines J Family Med Prim Care.  2020 Nov; 9(11): 5450–5457 The present systematic review of FDCs of various oral hypoglycemic agents suggests that these are beneficial to patients with T2DM in order to achieve their target glycemic levels by effectively controlling hyperglycemia

17. Pro and Contra of Fixed Dose Combination Simpler dosage improves therapy adherence and treatment outcome Reduced medication error Lower cost and similar ED Sinergistic Combination due to pathophysiology of DM Improve Glycemic Control PRO CONTRA No dosing flexibility Need to discontinue if a patient is allergic to even one component of the FDC Drugs Interaction

18. G. Reach. Diabetes & Metabolism, Volume 40, Issue 4, 2014, Pages 241-245,

19. Adapted from Han S et al . Curr Med Res Opin. 2012;28(6):969-77. CDT = coadministered dual therapy; FDC = fixed-dosed combination Study Blonde L et al , 2003 Thayer S et al , 2010 Thayer S et al , 2010 Duckworth W et al , 2003 Raptis AE et al , 1990 Overall Mean difference of A1C (95% CI) Weight (%) Baseline A1C -0.53% (-0.80, -0.26) 28.0% 9.1–9.2% -0.31% (-0.66, -0.04) 22.7% 8.0–8.1% -0.45% (-0.77, -0.13) 24.7% 7.3–7.8% -0.60% (-0.97, -0.23) 21.4% 8.3% -2.30% (-3.65, -1.00) 3.2% 10.6% -0.53% (-0.78, -0.28) 100% -4 -3.5 -3 -2.5 -2 -1.5 -1 -0.5 0.5 Mean difference in HbA1C (FDC – CDT) Favours FDC Fixed-dose Combination Therapy is Associated with Improved Glycemic Control

20. FDC vs. Free Tablet Combinations Avandamet Same profile Met + Rosiglitazone Competact Same profile Met + Pioglitazone Janumet Same profile Met + Sitagliptin Eucreas Same profile Met + Vildagliptin Glucovance ® Improved profile Met + Glibenclamide Clinical Equivalence Fixed-Dose Tablet Combination Free Tablet Combination Titel der Präsentation | DD.MM.YYYY 28

21. Mitos dan Fakta Penggunaan SU dalam Terapi Diabetes Kontrol Glikemik Pasien Diabetes Lebih banyak pilihan terapi diabetes tipe 2, berarti kontrol glikemik semakin baik . MITOS Reference: 1. Nathan, D.M., et al. Diabetes Care. 2009. Jan; 32(1):193-203, 2. Inzucchi , S.E., et al. Diabetes Care. 2015; 38(1): 140-9 Perbandingan penurunan HbA1c antara golongan agen anti- hiperglikemik oral 1,2 Metformin dan Sulfonilurea merupakan OAD* dengan penurunan HbA1c terbesar (1-2%) dibandingkan dengan OAD* golongan lainnya . FAKTA

22. Mitos dan Fakta Penggunaan SU dalam Terapi Diabetes Profil Keamanan Sulfonilurea OAD * molekul baru memiliki profil keamanan yang lebih baik daripada OAD * molekul lama. MITOS Reference: 1. Lipska KJ et al. Trends in Drug Utilization, Glycemic Control, and Rates of Severe Hypoglycemia, 2006-2013. Diabetes Care. 2017;40(4):468-475. Kejadian hipoglikemia per 100 pasien 1 Penurunan penggunaan SU dalam terapi diabetes ≠ penurunan kejadian hipoglikemia . FAKTA Kejadian hipoglikemia 1 : Secara keseluruhan, tingkat kejadian hipoglikemia berat tetap sama (1,3 per 100 orang- tahun ; p=0,72) Tingkat kejadian hipoglikemia tetap tinggi di antara mereka yang memiliki dua atau lebih penyakit penyerta (3,2 hingga 3,5; p=0,36) Tingkat kejadian hipoglikemia sedikit menurun di antara pasien tertua ( dari 2,9 menjadi 2,3; p<0,001)

23. SU + Metformin : Effective combination for t2dm American Diabetes Association.Approaches to glycemic treatment. Sec. 7.In Standards of Medical Care in Diabetesd2015. Diabetes Care 2015;38(Suppl. 1):S41–S48 Metformin + Sulfonylurea What is the rationale? Increases insulin secretion Extensive experience Reduces microvascular risk (UKPDS) Economis

24. SU-Metformin Combination Uses two of the most widely used and experienced medicines Targets dual defects effectively Cost effective Allows smaller effective doses for each drug at less possible side effect

25. Glucovance: Dikembangkan untuk membantu pasien mencapai target Hb A 1c Bukan sekedar FDC seperti pada umumnya

26. Glucovance dikembangkan untuk membantu mencapai target Hba1c Bukan sekedar FDC seperti pada umumnya Donahue SR, et al. Clin Pharmacokinet 2002;41:1301–1309 Glucovance Tablet Technology: Engineered to deliver optimal drug release

27. 35 Memperbaiki Efikasi Membantu lebih banyak pasien mencapai target kontrol A1c (<7.0%) Blonde L et al., Diabetes, Obesity and Metabolism 2003; 5: 424-31 (n=950) (n=471) Studi kohort dari 1421 pasien AS, dengan rerata follow-up 128 hari untuk Glucovance dan 135 hari untuk kombinasi bebas. A1c pada baseline: 9.2% (Glucovance) 9.1% (kombinasi bebas) Lebih banyak pasien yang mencapai target A1c dengan Glucovance ® dibandingkan Yang mendapat kombinasi bebas

28. Formula si Ukuran Parti kel Karakteristik Standard 2.5 mg Micronised 1.75 mg Glucovance® 500/2.5 mg 10  100 µ <6 µ <21 µ for 75% of particles Absorp si lamban Lamban mencapai konsentrasi maks Diberikan sebelum makan Absorp si sangat cepat Cepat mencapai konsentraksi maks Diberikan bersama makan Absorp si cepat tetapi paparan sistemik yang ekuivalen Diberikan bersama makan Tablet Glibenclamide

29. Klinis Formulasi Perbaikan Formulasi untuk Menghasilkan Manfaat Klinis Glibenclamide Standard : Glibenclamide Lebih Baik Donahue SR, et al. Clin Pharmacokinet 2002;41:1301–1309

30. 25% 50% 75% Donahue SR, et al. Clin Pharmacokinet 2002;41:1301–1309 Glibenclamide Metformin Soluble Matrix 250 mg 500 mg 500 mg Tablet Tablet Tablet 1.25 mg 2.50 mg 5.00 mg  Metformin Glibenclamide Particle Distribution 38 Glucovance ® Tablet d en g a n Tekhnologi  Dikembangkan u n t u k Mengoptimalkan Pelepasan Obat

31. Glucovance ® Efektif Menurunkan Glukosa Post Prandial p=0.012 24% Penurunan Ekskursi Glukosa Postprandial Donahue SR, et al. Clin Pharmacokinet 2002;41:1301–1309 20 40 60 80 100 120 140 Met + Glib Glucovance Ekskursi Glukosa Postprandial (mg/dl) Glucovance ® vs. Metformin + Glibenclamide

32. Glucovance ® vs. Metformin + Glibenclamide Tablet Terpisah  HbA 1C Glib (mg/ hari ) 17 15 17 15 Met (mg/ hari ) 1607 1750 1624 1743 HbA 1C Rata-rata (%) Semua pasien (n=72) -0.6% p<0.01 HbA 1C Rat-rata (%) Baseline HbA 1C  8% (n=37) -1.3% p<0.001 ® ® Duckworth W, et al. J Manag Care Pharm 2003;9:256 –2 62

33. (1) Blonde L et al., Diabetes, Obesity and Metabolism 2003; 5: 424-31 41 Glucovance ® vs Kombinasi bebas Metformin + Glibenclamide  HbA 1C

34. 42 Glucovance® vs. Metformin + Glibenclamide Tablet Terpisah Pada pasien yang Beralih ke Glucovance ® Duckworth et al. JMCP 2003; 9: 256-62 Glib (mg/day) 17 15 17 15 Met (mg/day) 1607 1750 1624 1743 HbA 1C Rata-rata (%) Semua pasien (n=72) -0.6% p<0.01 HbA 1C Rata-rata (%) Base HbA 1C > 8% (n=37) -1.3% p<0.001 ® ® 6 7 8 9 10 Met + SU Glucovance 6 7 8 9 10 Met + SU Glucovance Duckworth W, et al. J Manag Care Pharm 2003;9:256 –2 62

35. Pasien dengan Glucovance ® memiliki risiko lebih rendah mengalami hipoglikemia dibandingkan dengan yang diberikan kombinasi bebas metformin dan sulfonilurea Sebagian besar episode hipoglikemia dengan Glucovance ® ringan hingga sedang dan tidak memerlukan intervensi medis. Marre M et al., Diabetic Medicine 2002, 19: 673–80. (2) DeFronzo RA et al., N Engl J Med 1995 31;333(9):541-9. (3) Charpentier G et al., Diabet Med 2001;18(10):828-34. Study 1 (1) Marre et al, 2002 Study 2: (2) DeFronzo et al, 1995 Study 3: (3) Charpentier et al, 2001 Ris i k o H i pogl ikemia 43

36. Glucovance : Meningkatkan Kepatuhan Pasien

37. Memulai Terapi Glucovance ® Titrasi mulai dengan dosis kecil & sekali sehari Pasien gagal dengan diet Mulai dengan 1 tablet Glucovance 1.25 / hari Pengganti monoterapi Mulai dengan 1 tablet Glucovance 2.5 mg / hari Pengganti kombinasi metformin & glibenclamide Mulai dengan 1-2 tablet Glucovance 2.5 / hari Product information

38. Setiap 1-2 minggu : titrasi dosis sesuai respons terapi & toleransi Dosis maksimal glibenclamide dose = 20mg Pemberian Glucovance : bersama makan Frekuensi pemberian : 2 x sehari : pagi & sore dengan interval 10 – 12 jam Mengoptimalkan Terapi Glucovance ® Product information

39. Conclusion Because of the progressive nature of T2DM, first-line therapy often fails to provide effective glycemic control, necessitating the addition of add-on therapy. FDCs can play a crucial role in achieving glycemic targets effectively. Understanding the difference between rational and irrational combinations is necessary from the safety, efficacy, and tolerability perspective.

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