PERKEMBANGAN TERKINI PENATALAKSANAAN DIABETES MELLITUS

Type 1 diabetes, -cell destruction, usually leading to absolute insulin deficiency Immune mediated or idiopathicType 2 diabetes mellitus - 90%Other specific types, drug induced, endocrino- pathies, disease of the exogen pancreas, etcDiabetes mellitus gestationalDiabetes Care. 1997; 20: 1183 - 1197 CLASSIFICATION OF DIABETES MELLITUS

Type 2 diabetes

Adapted from IDC, MinneapolisDiabetes duration (years)-20-10 0 10 20 30Obesity IGT Diabetes [uncontrolled] PlasmaGlucose(mg/dl)-cellfunction(%)126100PostprandialFastingInsulin ResistanceInsulin LevelType 2 Diabetes: a chronic progressive disease

CRITERIA FOR THE DIAGNOSIS OF DIABETES MELLITUS1. Symptoms of diabetes Casual plasma glucose concentration > 200 mg/dlor 2. Fasting plasma glucose > 126 mg/dl. FPG, no caloric intake for at least 8 hoursor 3. 2-h post-OGTT > 200 mg/dl 75 gram glucose dissolved in water

KENAPA DIABETES MELITUS HARUS DI TERAPI ??

A1C (%)Semua penyebab kematian (%)5 - 5.45.4 6.9DM< 5> 7Penelitian EPIC Norfolk 76543210Hubungan antara kadar A1C dengan semua penyebab kematian pada penelitian EPIC-Norfolk. DM = diabetes mellitus; EPIC = European Prospective Investigation of cancer and nutrition; A1c = glycated hemoglobin. Khaw et al. BMJ 2001; 322: 15 18

THE HONOLULU HEART PROGRAMThe Honolulu Heart Program. Diabetes Care 22:1262-1265,1999

Chart1

1351.7

145.92

20.48.83.7

28.814.16.3

Total Mortality

CHD Incidence

CHD Mortality

Sheet1

Total MortalityCHD IncidenceCHD MortalityTotal MortalityCHD IncidenceCHD mortality

Low Normal (120 mg/dl)1351.71351.7

High Normal (181mg/dl)145.92145.92

Asymptomatic Hyperglycemia (262* mg/dl)20.48.83.720.48.83.7

Known Diabetes (254* mg/dl)28.814.16.328.814.16.3

Sheet1

Total Mortality

CHD Incidence

CHD Mortality

Sheet2

Sheet3

Cumulative incidence of a sustained change in retinopathy in patients with type 1 diabetes in the primary prevention cohort. Adapted from the diabetes control and complications research group. N Engl J Med 1993; 329: 977 - 98601234567890605040302010Time after beginning of study (years)Percentage of patientsConventionalIntensiveConventional: n = 348 324 128 79Intensive: n = 354 335 136 93The Diabetes Control and Complications Trial (DCCT)Retinopathy primary prevention

01234567890605040302010Time after beginning of study (years)Percentage of patientsConventionalIntensiveCumulative incidence of a sustained change in retinopathy in patients with type 1 diabetes in the secondary intervention cohort. Adapted from the diabetes control and complications research group. N Engl J Med 1993; 329: 977 - 986Conventional: n = 348 324 128 79Intensive: n = 354 335 136 93The Diabetes Control and Complications Trial (DCCT)Retinopathy secondary intervention

Percentage of patientsYear of study302520151050Percentage of patientsYear of studyp < 0.04p = 0.4ABCumulative incidence of urinary albumin excretion.300 mg per 24 hours (Dashed line) and 40 mg per 24 hours (solid line) patients with IDDM receiving intensive or conventional therapy.

10-year follow-up of intensive glucose control in type 2 diabetesHolman RR, Paul SK, et al. N Engl J Med 2008; 359: 1577 1589

A. Microvascular diseaseHazard ratio1.41.21.00.80.60.4199719992001200320052007p = 0.01p = 0.0011.41.21.00.80.60.4199719992001200320052007p = 0.052p = 0.01B. Myocardial infractionHazard ratio

C. Death from any causeHazard ratioHazard ratios for four prespecified aggregate clinical outcomes.Hazard ratios for patients in the United Kingdom Prospective Diabetes Study who had microvascular disease (panel A), myocardial infraction (panel B), and who died from any cause (panel C) are shown for the sulfonylurea-insulin group versus the conventional-therapy group for the metformin group versus the conventional therapy group. The overall values at the end of the study , in 1997, are shown (red squares), along with the annual values during the 10-year post-trial monitoring period (blue diamonds). Hazard ratios below unity indicate a favorable outcome from sulfonylurea or metformin therapy. Numbers of first events in an aggregate outcome that accumulated in each group are shown at 2-year intervals. The vertical bars resresent 95% confidence intervals. UKPDS 33. lancet 1998; 352: 837 853.

BAGAIMANA PENATALAKSANAAN DIABETES MELITUS

TIGA PILAR UTAMA PENATALAKSANAAN DIABETESNon-farmakologis perencanaan makan olah raga dan perencanaan makanObat-obatan obat oral dan insulinEdukasi penderita memantau gukosa darah sendiri

Dilatih melakukan sendiri

BAGAIMANA PENATALAKSANAAN DIABETES MELITUSPerlu dibuat suatu kesepakatan umum sebagai pegangan bagi para dokter praktekKesepakatan yang ada adalah EASD ADADasar membuat algoritma: - dari penelitian yang sudah ada - efektif untuk menurunkan glukosa darah - mudah dilaksanakan oleh dokter - terjangkau oleh penderita

*Page *ADA/EASD: Metabolic Management of Type 2 DiabetesNathan DM et al. Diabetes Care 2009; 32(1) : 194-203

* Check HbA1cevery 3 months until HbA1c

Step One: Lifestyle and Metformin Lifestyle interventions: - Weight loss, exercise, - Diet should be implemented by regis- tered dieticiansNathan DM et al. Diabetes Care 2009; 32(1) : 194-203

Step One: Lifestyle and Metformin, contd Since lifestyle interventions fail in most patients, initiate metformin at diagnosis Metformin is recommended due to its: Effect on glycemia Absence of weight gain and hypoglycemia Generally low level of side effects High level of acceptance Relatively low costNathan DM et al. Diabetes Care 2009; 32(1) : 194-203

Nathan DM et al. Diabetes Care 2009; 32(1) : 194-203

Step Two: Adding a Second Agent After 2 - 3 months, if Step 1 fails to achieve glyce- mic goals, add one of the following: - Basal insulin (most effective) - Sulfonylurea (least expensive) - TZD (no hypoglycemia) - pioglitazone

Choice of medication depends on HbA1c Choose insulin for HbA1c level >8.5 or with symptoms secondary to hypergly- cemia

Nathan DM et al. Diabetes Care 2009; 32(1) : 194-203

Data from our Diabetes Clinic :* 791 patients had A1C A1C < 7,0% = 145 or 18,3% A1C > 7,0% - < 8,5% = 152 or 19,2% A1C > 8,5% = 494 or 62,5%Around 60% of our diabetic patients attending our Diabetic Clinic needed combination therapy either two oral agents or oral agent plus insulin* John MF Adam (Makassar) CONTROLLED AND UNCONTROLLED DIABETES BASED ON A1C

Nathan DM et al. Diabetes Care 2009; 32(1) : 194-203

If Step 2 fails to achieve glycemic goals after 2 3 months .. Start or intensify insulin (preferred choice) - Usually means adding short or rapid acting insu- lin before selected meals to reduce PPG excur- sions - Discontinue use of sulfonylureas or glinides when short - or rapid - acting insulin injec- tions are started (not considered synergistic) If HbA1c is close to goal (

Efficacy-Cost Ratio of Adding a Third OralTherapy vs. Switching to Insulin + Metformin HbA1c values at study endpoint (Week 24)0%10%20%30%40%50%60%70%Portion of patients achievingHbA1c (%) at study endpoint HbA1c < 7%HbA1c < 8%p=n.sp=n.sTriple oral therapy ($10.40/day)Insulin + metformin ($3.20/day) Schwartz S et al. Diabetes Care 2003;26:2238 - 2243

Considerations for Selecting Combination Therapy Glucose - lowering effect Secondary characteristics of the medications - e.g., weight gain or loss, GI side effects, injection, frequency, expense, other side effects Synergy- In general, different mechanisms of action will have the greatest synergy Nathan DM et al. Diabetes Care 2009; 32(1) : 194-203

ADA RECOMMENDED COMBINATIONS Insulin + metformin Insulin + TZD - However, fluid retention must be considered The combination of metformin and TZD has shown only modest HbA1c reductions (i.e., 0.3 - 0.8%)Schwartz S et al. Diabetes Care 2003;26:2238 - 2243

Insulin + MetforminAdapted from Yki-Jarvinen H, et al. Ann Intern Med 1999;130(5):389-3 9612-month reduction in HbA1c for bedtime Intermediate acting insulin + metformin (2 g)10987036912Time (mo)Glycosylated hemoglobin Value (%)n=19

Insulin + TZDStrowig SM, et al. 2004;27(7):1577- 83. * p

Only Modest HbA1c Reductions Seenwith Metformin and TZD Bailey CJ et al. Clin Ther 2005;27(10):1548-61 24-week reduction in HbA1cMET*RSG/MET*n=2720.0-0.1-0.2-0.3-0.4Mean change in HbA1cfrom baseline (%)-0.33-0.13

NASIHATPenderita kencing manis meninggal bukan kare-na gulanya tetapi akibat komplikasiKencing manis tidak dapat disembuhkan, tetapi anda dapat menghindari komplikasi dengan - kendali gula darah sebaik mungkin - kendali tekanan darah sebaik mungkin - kendali kolesterol sebaik mungkin Untuk itu perlu disiplin

RINGKASANPenatalasanaan DM tipe 2 mengacu pada algo- ritme yang ada saat ini Oleh karena sebagian besar penderita DM tipe 2 ke dokter dengan kendali buruk, metformin dapat segera dimulai terkecuali A1C < 8,0%, dapat non-farmakologisKombinasi metformin insulin paling efektif (insulin basal spt Levemir)Kombinasi metformin sulfonilurea murahKendali diabetes harus menggunakan kadar A1C

**Dual defect of type 2 diabetes: treating a moving targetThe pathophysiology of type 2 diabetes is complex, and characterised by remorseless progression of the dual metabolic defects of insulin resistance and b-cell dysfunction.Initially, insulin resistance causes the glucose-lowering actions of insulin to be blunted, so that the pancreas secretes more insulin to overcome the deficit. At this stage the subject may develop impaired glucose tolerance, but is not yet diabetic.As insulin resistance progresses, however, the pancreas is no longer able to secrete enough insulin to control glycaemia, and increased hepatic glucose output and reduced glucose disposal by muscle and fat contribute to the chronic fasting and postprandial hyperglycaemia characteristic of type 2 diabetes. Eventually, insulin secretion from the b-cell begins to decline and the severity of the hyperglycaemia increases further.

Adapted from DeFronzo RA, Bonadonna RC, Ferrannini E. Pathogenesis of NIDDM. A balanced overview. Diabetes Care 1992;15:318-68.****ADA/EASD: Metabolic Management of Type 2 DiabetesThis algorithm is part of a consensus statement by the ADA and European Association for the Study of Diabetes (EASD) for the management of hyperglycemia in patients with type 2 diabetes.Lifestyle modification is the most cost-effective means of controlling diabetes, but rarely effective long-term. Nevertheless, it should be included as a part of any diabetes management program unless contraindicated.The goal of this algorithm is based on achieving and maintaining glucose levels as close to the nondiabetic range as possible, initiating or changing therapy when the patients A1C level is 7%, and changing interventions, if necessary, as rapidly as titration of medications allow.Selection of antihyperglycemic agents is primarily based on their glucose-lowering efficacy. Exenatide, glinides, pramlintide, and a-glucosidase inhibitors are not included due to their lower overall efficacy in glycemic control, limited clinical data, and/or relative expense.Metformin therapy should be initiated at diagnosis (concurrent with lifestyle intervention) because of its efficacy in glycemic control (~1.5% expected decrease in A1C), low level of side effects, absence of hypoglycemia or weight gain, relatively low cost, and high level of acceptance. It should be titrated over 1 to 2 months to its maximally effective dose, as tolerated. If glycemic goals are not achieved or sustained within 2 to 3 months of treatment initiation, a second druginsulin, a sulfonylurea, or a thiazolidinedioneshould be added. There is no consensus on which of the 3 should be used. If the addition of a secondary medication does not achieve or sustain goal A1C, insulin therapy should be initiated or intensified. If A1C is close to goal (