Pengantar: Pengobatan Rasional Rustamaji Pusat Studi Farmakologi Klinik dan Kebijakan Obat UGM 2017

Tujuan Difinisi Pengobatan Rasional dan mengidentifikasi besarnya masalah yang ditimbulkan Memahami mengapa terjadi pengobatan yang tidak rasional Mendiskusikan strategi intervensi unutk memperbaiki masalah Mendiskusikan pedoman pengobatan

Definisi The rational use of drugs requires that patients receive medications appropriate to their clinical needs, in doses that meet their own individual requirements for an adequate period of time, and at the lowest cost to them and their community. WHO conference of experts Nairobi 1985

Ciri pengobatan rasional Tepat dalam pemilihan obat Obat digunakan sesuai indikasi Obat memenuhi kriteria kemanfaatan klinkk, keamanan, kecocokan dengan kondisi pasien, dan biaya Tepat dosis, cara pemberian, dan lama terapi Tidak ada kontraindikasi pada pasien Pemberian obat yang tepat (termasuk informasi yang cukup agar pasien dapat mengikuti program pengobatan dengan benar)

Ketepatan dalam diagnosis

% Ketaan terhadap Pedoman Pengobatan

What are we spending to promote rational use of medicines ? Global sales of medicines 2002-3 (IMS): US$ 867 billion Drug promotion costs in USA 2002-3: US$ >30 billion Global WHO expenditure in 2002-3: US$ 2.3 billion Essential Medicines expenditure 2% (of 2.3 billion) Essential Medicines expenditure on promoting rational use of medicines 10% (of 2%) WHO expenditure on promoting rational use of medicines 0.2% (of 2.3 billion)

Advantages of Standard Treatments Patients Consistency among prescribers Most effective treatments prescribed Improved drug supply Providers Provides expert consensus Provider can concentrate on diagnosis Quality of care standard Basis for monitoring and supervision

Advantages of Standard Treatments Supply Management Staff Performance standard for drug supply Allows pre-packs of common items Drug demand more predictable Health Policy Makers Funds used more efficiently Assess and compare quality of care Therapeutic integration of special programs

Key Features 1. Simplicity 2. Credibility 3. Same standards for all levels 4. Drug supply based on standards 5. Introduced in pre-service training 6. Dynamic—regular updates 7. Durable pocket manuals

PENGOBATAN DIABETES MELLITUS TYPE 2 Rustamaji

Homeostasis Kadar Gula darah

Patologi Anatomi Sel Islet Pankreas DM tipe 2 Sel islet pankreas normal Deposit amyloid pada DM

Kriteria Diabetes Melitus

Tujuan Terapi

Obat Hiperglikemia

A1C 6.5 – 7.5%** A1C 7.6 – 9.0% A1C > 9.0% Monotherapy Drug Naive Under Treatment Symptoms No Symptoms Monotherapy Dual Therapy 8 MET † DPP4 1 GLP-1 TZD 2 AGI 3 MET + GLP-1 or DPP4 1 or TZD 2 SU or Glinide 4,5 INSULIN ± Other Agent(s) 6 MET + GLP-1 or DPP4 1 ± SU 7 TZD 2 ± TZD 2 INSULIN ± Other Agent(s) 6 2 - 3 Mos.*** Dual Therapy MET + GLP-1 or DPP4 1 TZD 2 Glinide or SU 5 TZD GLP-1 or DPP4 1 Colesevelam AGI 3 2 - 3 Mos.*** Triple Therapy 9 * May not be appropriate for all patients ** For patients with diabetes and A1C < 6.5%, pharmacologic Rx may be considered *** If A1C goal not achieved safely † Preferred initial agent 1 DPP4 if  PPG and  FPG or GLP-1 if  PPG 2 TZD if metabolic syndrome and/or nonalcoholic fatty liver disease (NAFLD) 3 AGI if  PPG 4 Glinide if  PPG or SU if  FPG 5 Low-dose secretagogue recommended 6 a) Discontinue insulin secretagogue with multidose insulin b) Can use pramlintide with prandial insulin 7 Decrease secretagogue by 50% when added to GLP- 1 or DPP-4 8 If A1C < 8.5%, combination Rx with agents that cause hypoglycemia should be used with caution 9 If A1C > 8.5%, in patients on Dual Therapy, insulin should be considered MET + GLP-1 or DPP4 1 + TZD 2 + SU 7 TZD 2 AACE/ACE Algorithm for Glycemic Control Committee Cochairpersons: Helena W. Rodbard, MD, FACP, MACE Paul S. Jellinger, MD, MACE Zachary T. Bloomgarden, MD, FACE Jaime A. Davidson, MD, FACP, MACE Daniel Einhorn, MD, FACP, FACE Alan J. Garber, MD, PhD, FACE James R. Gavin III, MD, PhD George Grunberger, MD, FACP, FACE Yehuda Handelsman, MD, FACP, FACE Edward S. Horton, MD, FACE Harold Lebovitz, MD, FACE Philip Levy, MD, MACE Etie S. Moghissi, MD, FACP, FACE Stanley S. Schwartz, MD, FACE 2 - 3 Mos.*** Triple Therapy 2 - 3 Mos.*** MET + GLP-1 or DPP4 1 + TZD 2 Glinide or SU 4,7 INSULIN ± Other Agent(s) 6 2 - 3 Mos.*** INSULIN ± Other Agent(s) 6 Available at www.aace.com/pub © AACE December 2009 Update. May not be reproduced in any form without express written permission from AACE

Perbandingan Obat Diabetes

Perbandingan Obat Antidiabetika Oral

Perbandingan Obat Antidiabetika parenteral

Kenaikan HbA1c setelah beberapa tahun terapi 8.0 7.6 7.2 6.8 6.4 6.0 0 1 2 3 4 5 Time (Years) HbA1c (%) Rosiglitazone Metformin Glybenclamide ADOPT study Key Points T2DM is initially managed with lifestyle modifications and OHAs. However, the progressive decline in pancreatic -cell secretory capacity means that OHAs have limited efficacy, even at high doses, and insulin will be required to reach and sustain target glycemic levels. OHA failure was demonstrated in ‘A Diabetes Outcome Progression Trial’ (ADOPT) – a multicentre, randomized, double-blind, controlled clinical trial designed to evaluate long-term glycemic control in patients receiving OHA monotherapy. Rosiglitazone, metformin, and glyburide were evaluated as initial treatment for patients recently diagnosed with T2DM (n=4360), treated for a median of 4 years. OHA monotherapy was unable to maintain HbA1c <7% over time. Kaplan-Meier analysis showed a cumulative incidence of monotherapy failure at 5 years of 15% with rosiglitazone, 21% with metformin and 34% with glyburide, despite patients receiving maximal doses. Kahn SE et al. Glycemic durability of rosiglitazone, metformin, or glyburide monotherapy. N Engl J Med 2006;355:2427-43. ADOPT: Kahn SE et al. N Engl J Med 2006;355:2427-43.

Insulin

Early Addition of Insulin Can Optimize Glycemic Control Conventional Insulin Alone SU ± Insulin 50 25 p=0.011 Proportion of Patients with HbA1c <7% at 6 Years (%) n=242 n=245 n=339 Early addition of insulin when OAD is inadequate can improve glycemic control without weight gain or hypoglycemia Key Points The requirement for early initiation of insulin was demonstrated in the UKPDS 57, in 826 patients with T2DM who were randomly assigned to a conventional glucose control policy, primarily with diet (n=242), or an intensive policy with insulin alone (n=245) or in combination with a sulfonylurea (SU) (n=339). In patients receiving SU therapy, insulin was added if FBG remained >6 mmol/L (>108 mg/dL), despite maximal doses of SU. After 6 years, approximately 50% of patients receiving SU therapy required additional insulin therapy, and significantly more patients in the SU ± insulin group had an HbA1c <7% than those in the group receiving insulin alone (47% versus 35%, respectively; p=0.011). These results suggest that early addition of insulin when maximal SU therapy is inadequate can significantly improve glycemic control. Wright A et al. Sulfonylurea inadequacy: efficacy of addition of insulin over 6 years in patients with type 2 diabetes in the U.K. Prospective Diabetes Study (UKPDS 57). Diabetes Care 2002;25:330-36. SU = sulfonylurea UKPDS 57: Adapted from Wright A et al. Diabetes Care 2002;25:330-6.

Pioglitazon + sulfonilurea Pioglitazon Tahap 1 Tahap 2 Tahap 3 Gaya hidup + Metformin + Insulin basal Gaya hidup + Metformin + Insulin intensif Saat diagnosis: Gaya hidup + Metformin Gaya hidup + Metformin + Sulfonilurea Well validated core therapies Gaya hidup + Metformin + Pioglitazon + sulfonilurea Gaya hidup + Metformin + Pioglitazon Gaya hidup + Metformin + GLP-1 agonis Gaya hidup + Metformin + insulin basal Less well validated core therapies Nathan DM et al, Diabetes Care 32:193–203, 2009

Sejarah Perkembangan insulin  1921 : penemuan insulin  s/d 1983 : era insulin hewan Menggunakan ekstrak pankreas hewan (sapi / babi)  1983 : era Human insulin Menggunakan rDNA manusia untuk menghasilkan insulin  1999 : era insulin modern (analog) dimulai Menggunakan teknologi bioengineering untuk memodifikasi rantai DNA human insulin untuk membuat insulin baru yang lebih baik dalam hal farmakologi Saccharomyces cerevisiae Insulin analog adalah merupakan penemuan terbaru di bidang insulin. Oleh karena itu insulin analog sering juga disebut insulin modern (modern insulin). Insulin mengalami inovasi dari waktu ke waktu. Dimulai dari tahun 1921, ketika insulin baru ditemukan dan diujicobakan pada seekor anjing yang bernama Majorie, saat itu insulin dihasilkan dari ektrasi pankreas binatang, sapi dan kemudian babi. sampai dengan tahun 1983, dimana mulai berkembang bioengineering yang mampu menghasilkan insulin dari recombinant DNA manusia yang kemudian disebut Human Insulin. Tahun 1999, tekhnologi bioengineering ini semakin berkembang, dimana kemudian dilakukan penelitian untuk melakukan rekayasa pada rantai rDNA manusia tersbut untuk menghasilkan insulin jenis baru yang lebih baik efikasinya. Akhirnya ditemukanlah insulin analog yang saat ini merupakan insulin paling mutakhir dan memiliki banyak kelebihan dibanding human insulin atau insulin regular. Insulin analog sering disebut sebagai insulin modern. Banting dan Best, Mehring dan Minkowski

Pembagian Insulin menurut masa kerjanya

Profil farmakokinetika Insulin

Profil Farmakokinetika Human Insulin vs normal insulin Period of unwanted hyperglycemia Normal insulin secretion at mealtime Human insulin Period of unwanted hypoglycemia Change in serum insulin Human Insulin  disuntikkan 30 menit sebelum makan Baseline level Time (h) SC injection

A More Physiologic Insulin Normal insulin secretion at mealtime Insulin analog Change in serum insulin . Baseline Level Time (h) SC injection

Glycemic Control: Recommended goals Measurement Normal IDF1 ADA/EASD2 AACE3 PERKENI A1c* <6% <6.5% <7% Fasting Gluc <100 <110 90-130 80-110 PP (2h) Gluc <140 <155 <180 80-145 * Realistic Target: Lowest A1c possible without unacceptable adverse effects Key Points The most recent HbA1c target set by the American Diabetes Association (ADA) is <7%, with the aim of restoring HbA1c to normal values (<6%) without significant hypoglycemia.1 A consensus statement from the ADA and the European Association for the Study of Diabetes (EASD) recommends that an HbA1c value ≥7% should prompt the initiation or adjustment of treatment. The goal of treatment should be to achieve an HbA1c value as close to the healthy range (<6%) as possible or, at a minimum, decrease HbA1c to <7%.2 The ADA and EASD recognize that this goal is not appropriate or practical for some patients, and advocate an assessment of the potential risks and benefits of an intensified regimen for each individual patient.2 1. ADA. Standards of Medical Care in Diabetes. Diabetes Care 2006;29(Suppl 1):S4-42. 2. Nathan DM et al. Management of hyperglycaemia in type 2 diabetes: a consensus algorithm for the initiation and adjustment of therapy : A consensus statement from the American Diabetes Association and the European Association for the Study of Diabetes. Diabetologia 2006;49:1711-21. IDF = International Diabetes Federation ADA = American Diabetes Association. AACE = American Association of Clinical Endocrinology Global guideline for type 2 diabetes clinical guidelines taskforce (Brussels: IDF,2005) Nathan DM et al. Diabetologia 2006;49:1711-21. http://www.aace.com/pub/odimplementation/roadmap.pdf 31

Penggunaan Insulin Indication: + insulin Permanent Not permanent Insulin had been reserved as the last line of therapy Considering the benefits of normal glycemic status, insulin can be initiated earlier, as soon as is required. Inadequate Lifestyle + 1 OAD 2 OAD 3 OAD insulin Indication: Permanent Not permanent T1DM Infection OAD failure Pregnancy OAD Contra Indication Hospitalized Diabetic Ketoacidosis Perioperative

Basic Recommendation If fasting blood glucose is elevated, start for basal insulin with long acting insulin (Levemir) 2. If prandial blood glucose is elevated, start for prandial /bolus insulin with rapid acting insulin 3. If fasting and post prandial are elevated : - Oral agent with basal insulin - premix insulin - basal/bolus as in multiple daily injection (MDI)

Treatment Based on Type of Hyperglycemia BASAL – PRANDIAL CONCEPT Fasting Hyperglycemia Prandial Treat fasting hyperglyc. first Continue oral agent SMBG is important Basal Insulin (Levemir) Prandial Insulin 34

PENDAPAT PASIEN YANG MENJADI KENDALA TERAPI INSULIN (1) “Sekali mulai terapi insulin, tidak bisa di stop lagi ” (Persepsi yang salah, seperti “kecanduan” obat ) Berikan insulin dengan masa perkenalan jangka pendek : “ Suntik insulin sangat merepotkan” ( Pasien merasa tidak sanggup suntik sendiri) Demonstrasikan kepada pasien cara melakukan suntikan insulin Sesuai indikasi, pilihlah insulin 1x /hari untuk mengurangi ketidaknyamanan Key Points Many patients worry that, once started, insulin can never be stopped and will lead to significant lifestyle restrictions that will prevent them from travelling, eating in restaurants, or any sudden change in activities. To overcome this barrier, physicians can shift control back to the patient by presenting insulin as a temporary trial, or by prescribing once-daily insulin that minimizes inconvenience and is easier to use. Many patients feel that taking insulin is too complicated and lack the self-confidence to determine proper timing and dosing of injections. By starting with a single injection per day, the patient can readily accept this simple procedure. Demonstrating insulin injection in the office and providing simple patient information tools will do much to boost confidence. Polonsky WH, Jackson RA. What's so tough about taking insulin? Addressing the problem of psychological insulin resistance in Type 2 diabetes. Clinical Diabetes 2004;22:147-50. Polonsky WH, Jackson RA. Clinical Diabetes 2004;22:147-50.

PENDAPAT PASIEN YANG MENJADI KENDALA TERAPI INSULIN (2) 3. “Kegagalan terapi adalah kesalahan saya” (suntikan insulin sebagai hukuman karena kegagalan pribadi) Jelaskan bahwa insulin diperlukan karena perjalanan penyakit DM, bukan karena kegagalan pasien mengelola penyakitnya) 4. “Famili saya disuntik insulin sebelum diamputasi kakinya” (Insulin diberikan bila Diabetes sudah berat) Jelaskan bahwa suatu saat insulin diperlukan karena perjalanan alamiah penyakit DM 5. “ Saya tidak berani suntik insulin sendiri, karena nyeri..! ” (Ketakutan terhadap suntik insulin) Berikan dorongan untuk melakukan penyuntikan sendiri Key Points Insulin therapy may be seen by some patients as an indicator of personal failure or as punishment for laziness or eating habits. Physicians should stress to these patients that they have done nothing wrong nor failed with their diabetes. Instead, the need for insulin is a function of the progressive nature of the disease: it is estimated that up to one-third of patients with type 2 diabetes will require insulin at some point. Similarly, many patients believe that insulin therapy signifies a dangerous or more serious change in the severity of their diabetes. Moreover, others are convinced that insulin will actually worsen their health or cause further health problems. Although it may be considered one of the largest contributors to fear of insulin, true injection phobia is rare. Instead, a stated fear of injections often reflects a more general reluctance to and negative impressions of insulin therapy. Framing the insulin message properly and early on in the course of treatment – emphasizing the progressive nature of diabetes and focusing on achieving glycemic control for optimal health protection – will help patients accept insulin as a natural choice when target glucose levels have not been met through lifestyle changes and oral agents. Polonsky WH, Jackson RA. What's so tough about taking insulin? Addressing the problem of psychological insulin resistance in Type 2 diabetes. Clinical Diabetes 2004;22:147-50. Polonsky WH, Jackson RA. Clinical Diabetes 2004;22:147-50.

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