CLINICAL MANAGEMENT OF TYPE 2 DIABETES : Matching Therapy to PatophysiologyDjoko Wahono SoeatmadjiDiabetes and Endocrinology Section, Department of Internal Medicine, Faculty of Medicine, Brawijaya University, Malang2004 (4)

VALUATIONS OF THERAPEUTIC GOALS By professionals Qualtity of Life By patients3

2

1123Quality of LifePerspective in Life(Secondary and tertiary prevention)Expectation of LifeDreyer,1997

GOALS OF DIABETES MANAGEMENTReliev symptomsMaintain normal weightAchieve normal activityMaintain normal blood glucose levels (70 140 mg%)Achieve acceptable HbAIc (< 7%)Prevent long-term and short-term complicationsPrevent hypoglycemic and hyperglycemic reactions

The New Paradigm of Type 2 Diabetes TreatmentAggressive Treatment Driven by Target (AIC < 7%)Early Combinations Early Insulin Treatment

Tighter Glycaemic Control

Blood pressureLipids - LDL - Triglycerides - HDL < 130/80 mmHg

< 100 mg% < 150 mg% > 40 mg%

Correlation Between AIC level and Mean Plasma GlucoseRohlfing CL et al. Diabetes Care 25; 275:, 2002

AIC (%)Mean Plasma Glucosemg%mmol/L67891011121331702052402753103457.59.911.513.515.517.519.5

Prevalence of retinopathy by deciles of the distribution of FPG, 2-h PG, and HbA1c in Pima Indians (A) described by McCance et al. (129), in Egyptians (B)

Treatment of DMNutrition Therapy, Exercise, Lifestyle ChangesPharmacological Treatment - Insulin - Oral diabetes medicationsPancreas/Islet-cell transplantationsEducation

Nutrition Therapy, Exercise, Lifestyle ChangesNutrition therapydecrease fat content and total caloriesdecrease saturated fatdecrease salt for hypertensionhealthy dietweight reduction in obese patientsExerciseincrease energy expenditure with moderate-intensity exerciseLifestyle changes to reduce cardiovascular risk factors (eg, smoking cessation)Training in self-management and SMBG

Oral Diabetic MedicationsPHARMACOTHERAPY

Treatment Based on the Pathophysiology of Hyperglycemia in Type 2 Diabetes

Insulin resistance-cell dysfunctionInsulin SecretagoguesInsulin Sensitizer

Treatment Based on the Pathophysiology of Hyperglycemia in Type 2 Diabetes

Prandial HyperglycemiaFasting Hyperglycemia Insulin basal Sulfonylureas Metformin Insulin prandial Glinide Glitazones (-Glucosidase inhibitors)

Causes of Hyperglycemia in Type 2 Diabetes : Site of action of oral agentsGlucoseLiverMusclePancreasReceptor + postreceptor defectGlucose production Fasting plasma glucoseImpaired insulin secretionInsulin resistanceInsulin resistancePeripheral TissuesInsulin secretagoguesFat GlitazonesMetformin Glucose uptake Prandial plasma glucose

Insulin Secretagogues

MECHANISM OF ACTION

Sulfonylureas: EfficacyApproximately 50% of patients with newly diagnosed type 2 diabetes achieve acceptable glycemic controlAbout 15%-20% of patients have little or no glycemic responseLebovitz HE. In: Joslin's Diabetes Mellitus. 1994:508-529.1997 PPS

Nateglinide Controlled Postprandial Spikes

Nateglinide Controlled Postprandial Spikes

INSULIN SENSITIZER Predominant Action in the Liver (Metformin) Predominant Action in the Peripheral Insulin- Sensitive Tissues (Thiazolidine diones)

METFORMIN

Metformin Monotherapy:Effects on LipidsDeFronzo RA et al. N Engl J Med. 1995;333:541-549.*P

Model for the mechanism by which metformin mediates effects on lipid and glucose metabolism (Zhou G et al. JCI; 2001: 108, 1167-1174)

Genes regulated by SREBPsDHCR, 7-dehydrocholesterol reductase; FPP, farnesyl diphosphate; GPP, geranylgeranyl pyrophosphate synthase; CYP51, lanosterol 14-demethylase; G6PD, glucose-6-phosphate dehydrogenase; PGDH, 6-phosphogluconate dehydrogenase; GPAT, glycerol-3-phosphate acyltransferase (Horton et al. JCI 2002; 109; 1125)

Effects of Metformin Monotherapy or Combination Therapy With GlyburideDeFronzo RA et al. N Engl J Med. 1995;333:541-549.*P

Adjunctive Metformin Therapy in Insulin-Treated Patients With Type 2 Diabetes and Suboptimal Glycemic Control-100-50050100FPGPlaceboMetforminPlaceboMetforminHbA1c (%)-3-2-1012Change aftertreatment(mg/dL)ChangeaftertreatmentP

The New Paradigm of Type 2 Diabetes TreatmentAggressive Treatment Driven by TargetEarly Combinations (Oral-oral/Oral-Insulin)Early Insulin Treatment

Thiazolidinediones (Glitazones)

Fasting and Postprandial Blood Glucose and HbA1c Responses to Pharmacologic Treatment in Patients With Type 2 Diabetes

Tissue uptake of glucose in nondiabetic and diabetic subjects during hyperinsulinemic-euglycemic clamp (Diabetes 1998; 37: 667)The Triumvirate : -cell, muscle, liver. A collusion responsible for NIDDM

The New Paradigm of Type 2 Diabetes TreatmentAggressive Treatment Driven by TargetEarly Oral-agents CombinationsEarly Insulin Treatment

ORAL DIABETIC MEDICATION HAS ITS LIMITATIONS

Cross-sectional and 10-Year Cohort Data: Patients on SU/Insulin vs Conventional Treatment07896100200UKPDS Group. Lancet. 1998;352:837-853.FPG60391215Median FPG (mg/dL)HbA1c60391215Median HbA1c (%)Time from randomization (y)Time from randomization (y)180160140120

UKPDS Cross-sectional and 10-Year Cohort Data: HbA1c: Intensive (Metformin) vs Conventional TreatmentUKPDS Group. Lancet. 1998;352:837-853.All patients assigned to regimenConventionalPatients followed for 10 yearsConventionalIntensiveTime from randomization (y)003691215Median HbA1c (%)9876Cross-sectional10-year cohort

ORAL AGENT FAILURE RATESFeingloss,1999

-Cell function decline steadily in type 2 diabetes. The process begins 10 12 years before diagnosis

The New Paradigm of Type 2 Diabetes TreatmentAggressive Treatment Treat to TargetEarly Oral-agents CombinationsEarly Insulin Treatment

Lifestyle (dietary and activity)Add 1st OHA (SU or Metformin) Titrate dose

Add 2nd OHA (Combo) Titrate dose

Add 3rd OHA (Combo)

Begin Insulin (Continue 1 OHA) Titrate doseCOMBO (SU + Metformin) Titrate dose

Begin Insulin (Continue 1 OHA) Titrate dosemonthsyearsAcceleratedAlgorhytm of Type 2 Diabetes Treatment PASTRECENT

RULE OF COMBINATION2 Drugs (or more ?) With Different Mechanisms of ActionSULFONYLUREA + METFORMINMETFORMIN + THIAZOLIDINEDIONEINSULIN + ANY OTHER DRUGS

Patients who fail to respond to monotherapy with an oral agent are treated with combination of twoWhen this fails, combination of three oral agents are unlikely to be effectiveWilliams G. Lancet 1994; 343: 95 -100ADA 1998: 56 - 72

Treatment Based on the Pathogenesis of Type 2 Diabetes

Insulin resistance-cell dysfunctionInsulin SecretagoguesInsulin SensitizerGlibenclamideMetformin

The New Paradigm of Type 2 Diabetes TreatmentAggressive Treatment Driven by TargetEarly Oral-agents CombinationsEarly Insulin Treatment

Lifestyle (dietary and activity)Add 1st OHA (SU or Metformin) Titrate dose

Add 2nd OHA (Combo) Titrate dose

Add 3rd OHA (Combo)

Begin Insulin (Continue 1 OHA) Titrate doseCOMBO (SU + Metformin) Titrate dose

Begin Insulin (Continue 1 OHA) Titrate dosemonthsyearsBegin Insulin1 OHA Titrate doseAcceleratedAlgorhytm of Type 2 Diabetes Treatment PASTRECENT

THANK YOU FOR YOUR ATTENTION

Treatment Targets for Type 2 Diabetes(European diabetes Policy Group)(European Diabetes Policy Group. Diabetes Med 1999; 16: 716-30)

Treatment Targets for Type 2 diabetes(American Diabetes Association)

Dual defect of type 2 diabetes: treating a moving targetInsulinResistanceHyperglycaemiaInsulinConcentrationInsulin ActionEuglycaemiab-cell FailureNormalIGT ObesityDiagnosis of type 2 diabetesProgression of type 2 diabetesDeFronzo et al. Diabetes Care 1992;15:318-68

Glucovance tablet technology:engineered to optimise drug delivery25%50%75%Metformin soluble matrixGlibenclamide particle rangeDonahue et al. Clin Pharmacokinet 2002;41:1301-9.

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.Glucovance tablet technology: engineered to optimise drug deliveryIn addition to providing a straightforward means of delivering combination therapy, the Glucovance tablet is engineered to optimise the delivery of metformin and glibenclamide.A freely-soluble matrix of metformin contains glibenclamide particles in a precisely controlled range of sizes, offering a metered release into the bloodstream. This supports the efficacy of Glucovance on both fasting and postprandial glycaemia.

Donahue SR, Turner KC, Patel S. Pharmacokinetics and pharmacodynamics of glyburide/metformin tablets (Glucovance) versus equivalent doses of glyburide and metformin in patients with type 2 diabetes. Clin Pharmacokinet 2002;41:1301-9.