Diabet Reglasyonu ve zlemProf. Dr. mit Karayaln Akdeniz niversitesi Tp Fakltesi

Diabet Reglasyonu ve zlemGlisemik kontrol hedefleri

Genel tedavi yaklam

Pratik inslin tedavi klavuzu

ntensif tedavi

ntensif tedavi-klinik almalar

Diabet- GenelPrevalans : Erikinde %7 (TURDEP)

WHO: Bulac olmayan pandemi2000: 175 milyon / 2010: 240 milyon

4. srada lm nedeni (Erken KAH)

En skKrlkBbrek yetmezliiAmputasyon

Salk harcamalar (ABD: 98 milyar $/yl)

Glisemik Kontrol HedefiADA 2005

HbA1c < %7

Alk/pre-prandial 90-130 mg/dl

Post-prandial (2.saat) < 180 mg/dl

Diabet TedavisiDiabetik hasta eitimi

Diyet ve egzersiz

Farmakolojik tedaviOral anti-diabetiklernslin

Diabet Tedavisi- Dnm Noktalar nslin Glarjin

nslinin KefilksulfonilrelerNPHinslinLente inslinlerMetforminnslin pompasnslin AnaloglarUKPDS199819201940196019802000HbA1CDCCT1993Diabetik Hasta Eitimi ( DESG 1979, UDEP 1994)

SHGM (Kapiller kan ekeri ile monitorizasyon)

HbA1c (Glikozile hemoglobin)Son 2-3 aylk glisemik kontrol

Normal: %4-6

>%7 mikro ve makrovaskler komplikasyon

Ortalama Plazma Glukoz - HbA1c (DCCT)Rohlfing CL et al. Diabetes Care. 2002;25:275-278.

Chart1

6135

7170

8205

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10275

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Approximate MPG for clinical use

Regression-estimated MPG

A1C (%)

OPG (mg/dL)

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6135

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9240

10275

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Sheet1

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Approximate MPG for clinical use

Regression-estimated MPG

A1C (%)

MPG (mg/dL)

Sheet2

Sheet3

HbA1c- Komplikasyon Korelasyonu (UKPDS)Stratton IM et al. Br Med J. 2000;321:405-412. HbA1Cdeki %1lik azalma ile risk azalmasAmputasyon3721211443Risk Azalmas (%)MikrovasklerDiyabetle likili Her Trl Son Noktalm Akut MITip 2 DM

HbA1c - Mikrovaskler Komplikasyon Riski (DCCT)

DCCT. Diabetes. 1995;44:968-983.Greceli RiskA1C (%)15131197531678910111220

Tip 2 Diyabet Progresyonu (UKPDS)

UKPDS Group. Lancet. 1998;352:837-853.Sre (yl)Konvansiyonel Tedavi (n=1138)ntensif Tedavi (n=2729)9876ADA hedefi003691215 HbA1c (%)

Tip 2 Diabet- nslin Sekresyon Bozukluu ve Direnci

Oral Antidiabetiklernslin sekresyonunu SulfonilrelerRepaglinid, nateglinid

nslin direncini MetforminThiazolidindionlar

Glikoz absorbsiyonunu Akarboz

ntensif Tedavi ?

DCCT : Gnde 3-4 kere SC nslin

UKPDS : En dk HbA1c salayan tedavi

Agresif tedaviHiperglisemi + dislipidemi + hipertansiyon

ntensif Tedavi Hedefleri

HbA1c < %7KB 40 mg/dl

Makro ve mikro-vaskler komplikasyon riski

Hiperglisemi- Zararl EtkilerAkutOksidatif stres Endotel disfonksiyonuKoaglasyon sistemi aktivasyonu

KronikProtein glikozilasyonu AGE birikimi ve organ disfonksiyonuProtein kinaz C aktivasyonuYa asitlerinde art, inslin direnciSorbitol birikimi

Endojen nslin Sekresyonu-Bazal-Prandial nslin TedavisiSAGPrandialBazalEndojen

Tip 2 diabetik hastada ayaktan inslin tedavisi ?Gnlk ihtiya: 0.4-1 nite/kg

%50 bazal, %50 blnm prandial dozlar

Hipoglisemi riski: Dk doz 0.2-0.5 nite/kg

Hastaya gre doz ayarlamas

Konvansiyonel / ntensif tedavi

nslin ve Analoglarnn Farmakokinetii

nslin Etki Maksimum Etki Preparat Balangc Etki Sresi

Prandial/ek inslin ok hzl etkili 5-15 dakika 1-2 saat 2-4 saat (Lispro,aspart) Ksa etkili 30-45 dakika 2-4 saat 6-8 saat (Kristalize)

Bazal Orta etkili (NPH) 1-2 saat 6-8 saat 10-12 saat Uzun etkili (Glargine) 1-2 saat Zirve yok 24 saat

Konvansiyonel nslin TedavisiSabah-akam miks (NPH-Kristalize) nslinSabahAkamKristalize NPH Endojen Hiperglisemi riski

ntensif nslin TedavileriYatarken NPH + Yemeklerden nce kristalizeKristalizeNPHEndojen Hiperglisemi

ntensif Tedavi Yararlar- Klinik almalar

DCCTEDICUKPDSOhkuboDIGAMISteno-2

ntensif Tedavi- Klinik almalar

DCCTOhkuboUKPDS(%9 7) (%97) (%87)

Retinopati -%63 -%69 -%21

Nefropati -%54 -%70 -%34

Nropati -%60

Makrovaskler hastalk -%41* -%16*

EDIC: Yararn Korunmas Retinopati

EDIC, Epidemiology of Diabetes Interventions and Complications DCCT/EDIC Research Group. N Engl J Med. 2000ylKmlatif nsidans(%)0.00.51.01.52.02.53.03.54.0024222018161412102468Konvansiyonel TedaviYoun TedaviTip 1 DM

Steno-2: Multipl Risk Faktrlerinin Agresif Tedavisi*= Makrovaskler komplikasyonlar, retinopati, nefropati, nropatiGaede Pl. N Engl J Med. 2003808072787074716663615919134144505963Riskli Says/Tedavi Konvansiyonel YounPrimer BileikSon Nokta* (%)zlem (ay)6050403020100P=.00701224364860728496Konvansiyonel TedaviYoun tedaviTip 2 DM

Hastanede Yatan Diabetik Hastada zlemHiperglisemi-mortalite likisi

Akut inme: >110 mortalite

Youn bakm hastalar: >103 mortalite

Dahiliye-Cerrahi: >220 enfeksiyon riski

Kalp Cerrahisi :

Hastanede OAD ? : ProblemlerSulfonilreEtki sresi uzunDzenli beslenemeyende hipoglisemiDoz ayarlamas zor

MetforminKOAH, KKY, Bbrek yetmezlii: Laktik asidoz riski

ThiazolidindionEtkisi 2-4 haftada balarDoz ayarlamas esnek deilntravaskler volm art- KKYHepatotoksisite- ALT takibi

Hastanede nslin: AvantajlarHzla deien ihtiyaca gre doz ayarlanabilirYoun bakm hastalarnda ksa dnem mortalite

SC nslin: Programlanm + ek inslin dozlarKristalize inslin ile sliding scale etkili deil(Komplians / hiper-hipo problemleri/ reaktif)

IV kristalize inslin enfzyonuDKA, hiperosmalar komaPre, intra, post Operatif dnemYoun bakm hastalarPO beslenemeyen hastalar

DIGAMI DIGAMI, Diabetes Mellitus Insulin Glucose Infusion in Acute Myocardial InfarctionMalmberg K 1997Tm Hastalar (N=620) %28 risk azalmaszlem (yl)Dk-Riskli ve nslin-Kullanmam Hastalar (n=272)%51 risk azalmaszlem (yl)0.00.30.20.40.70.10.50.6012345 0.00.30.20.40.70.10.50.6012345Mortalite Oran Standart Tedavi IV nslin (24 saat), sonra intensif inslin

Intensive insulin therapy in the critically ill patients. Van den Berghe, N Engl J Med 2001

Cerrahi youn bakm + Mekanik ventilasyon

nslin enfzyonu ile glisemi 80-110 mg/dl

Youn bakm mortalitesi (%8 4)

Yat mortalitesi %34

ACCORDAction to Control Cardiovascular Risk in Diabetes

Agresif tedavi hedefleri:HbA1c < %6Statin + fibrat ile HDL ykseltilmesiSistolik KB

ORIGINOutcome Reduction with Initial Glargine InterventionHasta Grubu:Yeni tan Tip 2 diabetBozulmu glikoz toleransBozulmu alk glikozu

Oral antidiabetik yerine inslin

Diabet progresyonu, komplikasyonlara etki ?

Diabet Tedavisi ntensif tedaviHiperglisemiHipertansiyon ACE, ARB, diretik,KKB,..Dislipidemi Statin / fibrat Aspirin

Makro ve mikrovaskler komp.

DCCT, EDIC,UKPDS, DIGAMI, STENO-2

1. Tattersall RB. The history of diabet mellitus. In: Pickup JC, Williams G, eds. Textbook of Diabet. 3rd ed. Blackwell Science; 2003.2.US Food and Drug Administration Center for Drug Evaluation and Research. Drug and device approvalsJune 1996. Available at: http://www.fda.gov/cder/da/ddpa696.htm. Accessed March 18, 2003.3.Lantus Consumer Information. Available at: http://www.fda.gov/cder/consumerinfo/druginfo/lantus.htm.Accessed March 18, 2003.It has been more than 80 years since the discovery of inslin, and as this timeline shows, there has been continuing progress. In fact, much of our current understanding of diabet, its devastating consequences, and its effective management has been attained during the latter part of this timeline. As this presentation will discuss, despite the progress of science, there are still many challenges to be overcomeResearchers at the University of Toronto discovered inslin in 19211The first sulphonylureas appeared during the early 1940s1Hans Christian Hagedorns delayed-action preparation, neutral protamine Hagedorn, appeared in 1946; we know it as NPH1The Lente series appeared in 19521Metformin became available (outside the United States) in 19601Portable inslin infusion pumps were introduced during the late 1970s1The Diabet Control and Complications Trial was published in 19931Rapid-acting inslin analogues became available in 19962The United Kingdom Prospective Diabet Study was published in 19981Lantus (inslin glargine; the first long-acting inslin analogue) received US Food and Drug Administration approval in 20003This slide shows mean plasma glucose (MPG) values at increasing levels of A1C derived from data from the Diabet Control and Complications Trial1Using fasting plasma glucose alone as a gauge of long-term glycaemia tended to progressively underestimate A1C and 7-point MPG at increasing plasma glucose levels1Postprandial plasma glucose contributes appreciably to A1C, although not all postmeal times are equal in their distribution; eg, postlunch levels and MPG show similar relationships to A1C levels, while postbreakfast levels markedly overestimate A1C11.Rohlfing CL, Wiedmeyer H-M, Little RR, England JD, Tennill A, Goldstein DE. Defining the relationship between plasma glucose and HbA1c: analysis of glucose profiles and HbA1c in the Diabet Control and Complications Trial. Diabet Care. 2002;25:275-278.The United Kingdom Prospective Diabet Study yielded:A continuous and quantifiable correlation between decreased A1C measurements and a lower likelihood of diabet-related macrovascular and microvascular complications, including peripheral vascular disease, stroke, and myocardial infarction1On average, each 1% reduction in A1C is associated with a 37% decrease in the risk of microvascular endpoints and a 21% decrease in the risk of any diabet-related endpoint or death; even patients with A1C levels only moderately above normal show an increased vulnerability to complications1These data demonstrate the value of clinicians efforts to bring patients A1C levels as near normal as possible. However, even moderate reductions in A1C levels have the potential to prevent deaths from complications related to diabet1.Stratton IM, Adler AI, Neil HAW, et al, on behalf of the UK Prospective Diabet Study Group. Association of glycaemia with macrovascular and microvascular complications of type 2 diabet (UKPDS 35): prospective observational study. Br Med J. 2000;321:405-412.Good glycaemic control is essential to reduce the risk of diabetic complicationsBased on the Diabet Control and Complications Trial data, the relative risk for microvascular complications such as diabetic retinopathy, nephropathy, neuropathy, and microalbuminuria increases with increasing levels of A1C1-3The relative risk of complications is set to 1 for an A1C of 6%1It is important to note that the risk gradient is continuous, with no glycaemic threshold for developing complications1

1. Skyler JS. Diabetic complications: the importance of glucose control. Endocrinol Metab Clin North Am. 1996;25:243-254.2. The Diabet Control and Complications Trial Research Group. The effect of intensive treatment of diabet on the development and progression of long-term complications in inslin-dependent diabet mellitis. N Engl J Med. 1993;329:977-986.3.Diabet Control and Complications Trial Research Group.The relationship of glycemic exposure (HbA1C) to the risk of development and progression of retinopathy in the Diabet Control and Complications Trial. Diabet. 1995;44:968-983. United Kingdom Prospective Study (UKPDS) 33 was the largest study of newly diagnosed type 2 diabet patients ever undertaken to examine the outcomes of treatment strategies over timeMore than 4200 patients were eligible for randomisation to receive conventional or intensive treatment for 10 years1 Conventional therapy consisted of diyetary advice; in patients who developed marked hyperglycaemia, secondary slfonilre or inslin therapy was provided, with the additional option of metformin in overweight patientsIntensive therapy consisted of diyetary advice along with slfonilres or inslin therapy with once-daily Ultralente inslin or isophane inslinIn the UKPDS, A1C progressively increased over time, regardless of treatment strategy11.UK Prospective Diabet Study (UKPDS) Group. Intensive blood-glucose control with slfonilres or inslin compared with conventional treatment and risk of complications in patients with type 2 diabet (UKPDS 33). Lancet. 1998;352:837-853.Tip 2 diabet is a progressive disease1 characterised by coexisting inslin deficiency and resistance, often long-term2progressive decline in beta-hcresi function, resulting in lower levels of inslin secretion2Data from the United Kingdom Prospective Diabet Study 16 suggest that beta-hcresi function begins to decline prior to the diagnosis of type 2 diabet3A recent study has shown that beta-hcresi mass is decreased in patients with type 2 diabet. This is due to an increase in beta-hcresi apoptosis, while new islet formation and beta-hcresi replication is normal4Oral monotherapy addresses inslin resistance or deficiencynot both1

1.Bergenstal RM, Kendall DM, Franz MJ, Rubenstein AH. Management of type 2 diabet: a systematic approach to meeting the standards of care. In: DeGroot LJ, Jameson JL, Burger H, eds. Endocrinology. Philadelphia, Pa: W.B. Saunders Co; 2001:821-835.2.Skyler JS. nslin therapy in type 2 diabet mellitus. In: DeFronzo RA, ed. Current Therapies of Diabet Mellitus. St Louis, Mo: Mosby-Year Book Inc; 1998:108-116.3.UK Prospective Diabet Study (UKPDS) Group. Overview of 6 years therapy of type II diabet: a progressive disease (UKPDS 16). Diabet. 1995;44:1249-1258.4. Butler AE, Janson J, Bonner-Weir S, Ritzel R, Rizza R, Butler PC. Beta-hcresi deficit and increased beta-hcresi apoptosis in humans with type 2 diabet. Diabet. 2003;52:102-110. Aggressive therapy helps achieve control Treat to target requires a comprehensive approach: control of blood pressure and low-density lipoprotein cholesterol, and a concerted attack on A1C levelsTreat to target A1C levels reduces the risk of complications, thereby reducing the cost associated with these complicationsEarly diagnosis, along with effective therapeutic agents, may result in more patients reaching and maintaining target A1C goals, thereby maintaining a low-cost state for an extended period of time1.McCall AL. Insulin therapy and hypoglycemia. In: Leahy JL, Cefalu WT, eds. Insulin Therapy. New York, NY: Marcel Dekker, Inc.; 2002.In individuals with normal weight who do not have diabetes, 2 patterns of insulin output are seen: basal insulin, which is secreted at a fairly constant rate between meals and at night to maintain euglycaemia, and during early morning hours; and bolus insulin, which is meal-related1 The therapeutic challenge for patients with diabetes is to provide enough basal insulin to control between-meal hyperglycaemiawhich is due to hepatic glucose productionand enough bolus insulin to minimise hyperglycaemia immediately after meals. The provision of adequate levels of basal and bolus insulin may reduce risk for hypoglycaemia in individuals with erratic schedules or in those who have greater insulin requirements1

1.Leahy JL. Intensive insulin therapy in type 1 diabetes mellitus. In: Leahy JL, Cefalu WT, eds. Insulin Therapy. New York, NY: Marcel Dekker, Inc.; 2002.2.Bolli GB, Di Marchi RD, Park GD, Pramming S, Koivisto VA. Insulin analogues and their potential in the management of diabetes mellitus. Diabetologia. 1999;42:1151-1167.3.Lantus (insulin glargine) US Prescribing Information. Bridgewater, NJ: Aventis Pharmaceuticals; 2002.A variety of human insulins that can be incorporated into a basal-bolus regimen that mimicks natural islet cell function are available1Genetically engineered short-acting human insulin preparations generally show a rapid onset of action and duration of action ranging from 3 to 4 hours1 Lantus (insulin glargine) activity is peakless and has an onset of action beginning 1 to 2 hours after subcutaneous injection1Lantus has demonstrated a duration of activity that is almost twice as long as that of NPH2The absorption of Lantus, which has a 24-hour duration of action, is prolonged without unwanted peaks3 and thus mimicks physiologic basal insulin more closely than does NPHThe regimen of twice-daily NPH and regular insulin attempts to mimick physiologic insulin secretion. However, this regimen results in many gaps in insulin coverage, during which the patient is at risk for hyperglycaemia, leading to poor long-term control1,2As a result, NPH and regular insulin profiles do not come close to matching the normal endogenous secretory pattern1,2Dawn phenomenon refers to the early morning fall in tissue insulin sensitivity counteracted by increased insulin secretion in individuals without diabetes but manifested as rising glycaemia in some patients with diabetes31.Leahy JL. Intensive insulin therapy in type 1 diabetes mellitus. In: Leahy JL, Cefalu WT, eds. Insulin Therapy. New York, NY: Marcel Dekker, Inc.; 2002.2.Bolli GB, DiMarchi RD, Park GD, Pramming S, Koivisto VA. Insulin analogues and their potential in the management of diabetes mellitus. Diabetologia. 1999;42:1151-1167.3.McCall AL. Insulin therapy and hypoglycemia. In: Leahy JL, Cefalu WT, eds. Insulin Therapy. New York, NY: Marcel Dekker, Inc.; 2002.The mixing of short-acting with intermediate-acting insulins has been used in patients with type 2 diabetes. This may consist of either a split-mixed insulin regimen or a multiple-dose regimen as represented in the graphs (3 or 4 injections of insulin per day, which may include an injection of short-acting insulin before meals). Another approach is a regimen of regular insulin before meals and NPH insulin at bedtime1 The periods of hyperglycaemia that develop during various multiple dose regimens demonstrate that these attempts to match insulin levels to endogenous needs do not adequately mimick normal endocrine pancreatic function21.Bergenstal RM, Kendall DM, Franz MJ, Rubenstein AH. Management of type 2 diabetes: a systematic approach to meeting the standards of care. In: DeGroot LJ, Jameson JL, eds. Endocrinology. 4th ed. Philadelphia, Pa: WB Saunders Co.; 2001:821-835.2.Leahy JL. Intensive insulin therapy in type 1 diabetes mellitus. In: Leahy JL, Cefalu WT, eds. Insulin Therapy. New York, NY: Marcel Dekker, Inc.; 2002.A reduction in risk for organ damage due to diabet was seen in 3 landmark trialsthe Diabet Control and Complications Trial (DCCT),1,2 Ohkubo,3 and the United Kingdom Prospective Diabet Study.4 In each, good glycaemic control, reflected by reductions in A1C levels (noted for each study at the head of each column), reduces the long-term incidence of microvascular complications Additionally, there was a strong trend toward reduction of macrovascular complications. The 41% reduction in macrovascular disease in DCCT was impressive, although it did not reach statistical significance due to the low number of events in the study1Thus, solid clinical evidence exists to support glycaemic control as a primary goal of therapy for patients with type 1 or 2 diabet

1.The Diabet Control and Complications Trial Research Group. The effect of intensive treatment of diabet on the development and progression of long-term complications in inslin-dependent diabet mellitus. N Engl J Med. 1993;329:977-986. 2.The Diabet Control Complications Trial Research Group. The relationship of glycemic exposure (HbA1c) to the risk of development and progression of retinopathy in the Diabet Control and Complications Trial. Diabet. 1995;44:968-983.3.Ohkubo Y, Kishikawa H, Araki E, et al. Intensive inslin therapy prevents the progression of diabetic microvascular complications in Japanese patients with non-inslin-dependent diabet mellitus: a randomized prospective 6-year study. Diabet Res Clin Pract. 1995;28:103-117.4.UK Prospective Diabet Study (UKPDS) Group. Intensive blood-glucose control with sulphonylureas or inslin compared with conventional treatment and risk of complications in patients with type 2 diabet (UKPDS 33). Lancet. 1998;352:837-853.The Epidemiology of Diabet Interventions and Complications trial (EDIC) consisted of patients with type 1 diabet in the Diabet Control and Complications Trial (DCCT) who were followed for an additional 4 years1Intensive therapy consisted of 3 injections of inslin daily or use of an inslin pump, combined with self-monitoring of blood glucose values, diet modification, and exercise. Conventional treatment consisted of 1 or 2 injections of inslin and 1 urine or blood glucose test each day1Those receiving intensive treatment during the DCCT/EDIC showed a lower risk of worsening retinopathy, including macular edema and proliferative retinopathy, and a need for laser therapy (P