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Milestones for Management of Diabetes• 1552 B.C. - describe in EgyptianPapyrus• 1869 – Paul Langerhans• 1870 – Bouchardat• 1921 – Banting’s• 1922 – 1 st patient (LeonardThompson ) treated by insulin

Milestones for Management of Diabetes• 1955 – OHA introduced• 1960 – HBGM devices• 1993 – Discovery of IDX-1 1 gene• 1993 – DCCT• 1998 – UKPDS10 Jan 2007 US Congress passed theresolution and recognized DM asglobal threat

GLOBAL PROJECTIONS FORTHE DIABETES EPIDEMIC: 2000-2010201014.2 14.217.5 17.523% 23%9.4 9.414.1 14.150% 50%26.5 26.532.9 32.924% 24%84.5 84.5132.3 132.357% 57%15.6 15.622.5 22.544% 44%World2000 = 151 million2010 = 221 millionIncrease 46%1.0 1.01.3 1.333% 33%

Barriers to quality diabetes care• > 50% undiagnosed• 40-50 % of patients are non-compliant• FACTORS• Illness• Patient• Doctor

ILLNESS• Absence of symptoms• Incurable chronic PROGRESSIVEillness

Natural Progression of Type 2 DiabetesDiagnosisGlucose(mg/dl)35030025020015010050Post-MealGlucoseFastingGlucoseRelativebeta-cellfunction (%)250200150100500Obesity IGTInsulinLevelBeta-cell FailureDiabetesInsulin ResistanceUncontrolledhyperglycemiaClinicalFeaturesMacrovascular changesMicrovascular changesYears -10 -5 0 5 10 15 20 25 30

UKPDS demonstrated loss of glycemiccontrol with all agents studied9HbA 1c(%)87ConventionalGlyburideChlorpropamideMetforminInsulin600Overweight patientscohort, median values2 4 6 8 10Years from randomizationUpper limit of of normal = 6.2%UK Prospective Diabetes Study (UKPDS) Group. Lancet 1998; 352:854–865.

The UKPDS demonstrated progressivedecline of β-cell function over time100β-cell function (%)80604020Start of treatmentP < 0.00010–10 –9 –8 –7 –6 –5 –4 –3 –2 –1 1 2 3 4 5 6Time from diagnosis (years)HOMA model, diet-treatedn = 376Adapted from Holman RR. Diabetes Res Clin Pract 1998; 40 (Suppl.):S21–S25.

UKPDS 35 - Association of glycemia with macrovascularand microvascular complications of type 2 diabetes:prospective observational study• Result:• The incidence rates of diabetes complications weresignficantly associated with glycemia• There was no threshold of risk observed for anycomplicationAdjusted incidence per1,000 person year (%)140120100806040205 6 7 8 9 10 11Updated mean haemoglobin A 1Cconcentration (%)Irene M Stratton, Amanda I Adler, H Andrew W Neil, et al BMJ. 2000;321;405-412.

UKPDS 35 - Association of glycemia with macrovascularand microvascular complications of type 2 diabetes:prospective observational study• Result:• Each 1% reduction in HbA 1cis associated with• 21% for any end point relatedto diabetes ( (P < 0.0001)• 21% for deaths relatedto diabetes (P

Lessons from the UKPDS• Too few patients achieved target HbA 1clevels, and progression to combinationtherapy was almost inevitable 1• After 3 years of monotherapy, , 50% ofpatients required combination therapy 1• Progression of type 2 diabetes was associatedwith deterioration of glycemic control 2• No therapy studied reduced diseaseprogression 21 Turner RC, et al. JAMA 1999; 281:2005–2012. 2 UK Prospective Diabetes Study. Lancet 1998; 352:837–853.

Type 2 DiabetesImplications of Progressive Beta-Cell Loss100%Diabetes DxMonotherapyFailureInsulinRequiringβ-cellFunctionMonotherapy MonotherapyDual Dual drug drugregimensMultidrudrugMulti-comb comb+/- +/-Insulin InsulinInsulin InsulinBased BasedRegimens0%IGT0 10 years 15-25 years

Stages to reach and maintain thetargets• Diet and exercise• Oral hypoglycaemic agents – monotherapy• Oral hypoglycaemic agents – combination therapy• OHA s + Nocte Insulin therapy• OHAs (IS) + Insulin Therapy

OADs – 5 classificationsSulphonylureas (SU)Prandial GlucoseRegulators (PGRs)Insulin SecretagoguesBiguanidesInsulin SensitisersThiazolidinediones(TZDs)α-GlucosidaseInhibitors

Oral antidiabetic agents:physiological effectsInsulinsecretagoguesMetforminα-glucosidaseinhibitorsTZDsEffect on FPG/HbA 1c↓↓↓↓Effect on plasma insulin↑ ↓ -↓Effect on LDL-cholesterol - ↓ - ↑Effect on HDL-cholesterol - ↑/- - ↑Effect on triglycerides - ↓ - ↓/-Adapted from DeFronzo RA. Ann Int Med 1999; 131(4):281–303 .

Oral antidiabetic agents: sideeffectsInsulinsecretagoguesMetforminα-glucosidaseinhibitorsTZDsRisk of hypoglycemia---Weight gain--GI side-effects--Lactic acidosis-*--Edema---Anemia - - *Observed in patients with renal impairmentAdapted from DeFronzo RA. Ann Int Med 1999; 131(4):281–303.

OHA FOR DIABETESClassEfficacy in HbA1C reductionα1-glucosidase inhibitors 0.5 - 1%Sulphonylureas 1 - 2%Biguanides 1 - 2%Thiazolidinedione 1 - 2%

Monotherapy and Combination TherapyBeta-cell functionInsulinOral agentsDiet and exercise

A consensus statement from theAmerican Diabetes Association andthe European Association for theStudy Of Diabetes

DiagnosisLifestyle intervention + metforminNo HbA1c≥7% Yes acAdd basal insulin- most effectiveAdd sulfonylurea- least expensiveAdd glitazone- No hypoglycaemiaNoHbA1c≥7%NoHbA1c≥7%Yes aNoHbA1c≥7%Yes aNoHbA1c≥7%NoYes a Yes a Yes aIntensify insulin c Add glitazone b Add basal insulin Add sulfonylurea bHbA1c≥7%Add basal or intensify insulin cIntensive insulin + metformin +/- glitazone

New Treatment• GLP-1• Amylin analog• Dual PPAR agonist• Inhibition of release or action of counterregulatory hormones• Inhibition of gluconeogenesis

Incretins: augment insulin secretionGive a glucose loadIV or oralMatch glycemic profile intravenousor oral with glucose load“Incretins”•GLP-1 (7-36)•GIP•? Other incretinsPlasma glucoseIVoralWith oral glucose loadPlasma InsulinWith intravenousglucose loadTime

The Main Incretin• GIP (Glucose-dependent InsulinotropicPeptide)• GLP (Glucagon Like Peptide)

The Incretin : Where they go?• Both peptides are rapidly cleaved (andthus inactivated) by enzymes• DPP-IV (Dipeptidyl peptidase)• Serum T ½ of GIP = 7 mins• Serum T ½ of GLP-1 1 = 2 mins

GLP-1: regulation and actionsDelayedGastricEmptyingMeal bolusNeuralinnervationGI TractGLP-1GLP-1 NeuroendocrineCells in Ileum↑InsulinSkeletal muscleGlucoseuptake80400500400300200100MealGLP-1InsulinPancreatic islet00 30 60 120 180 240CNS↓ Food Intake/BW↓ Glucagon↓ HGP

GLP-1: effects on the β-cellGlucose-dependent: no stimulationof insulin release when hypoglycemiainducedGLP-1Increased insulin synthesisFunctional improvements in β-cellβ-cell? inhumansβ cell neogenesisLong-term improvementsin glycemic control?

What does GLP-1 1 do?• Enhance insulin secretion• Decrease glucagon secretion• Decrease rate of gastric emptying• Diminish food intake (and obesity)• Enhance differentiation of progenitor cellsto insulin producing cells –neogenesis ofß-cells in the islets

Incretin-based therapies• GLP-1 1 Agonist• Exenatide• Liraglutide• CJC-1131• DPP-IV Inhibitor• LAF-237• MK-0431• ZP-10

Correlation between HbA1c & Plasma GlucoseHbA1c % Mean plasma glucose6 7.57 9.58 11.59 13.510 15.511 17.512 19.5

Target for Control? 6.5%? 7.0%Individualized

Target for ControlRisk versus benefit• Age• Life expectancy• Duration of disease• Presence of microvascular complication• Other co-morbidity• Psychosocial factors

STENO-2 STUDY160 patients with T2D and the metabolic syndrome,including microalbuminuria, randomised to eitherconventional therapy at their GPs, or intensive careat Steno Diabetes Centre.Conventional group at GPsn=1608080MicrovascularEndpointExaminationsMacrovascular4 Yrs 8 YrsIntensive group at Steno DiabetesCentreP. Gaede, P. Verdel, N. Larsen, et al. N Engl J Med. 2003;348

• Individualised risk assessment• Ambitious goal setting• More drugs/higher doses• Continued patient education/motivationDrug treatment: stepwise and target drivenHyperglycaemiaDyslipidaemiaMetformin - Gliclazide –– Insulin per chartsStatins – FibratesHypertension ACE Inhibitors - Angiotensin II blockers –Diuretics - Calcium antagonists - Beta-blockersAlbuminuriaOther CVD prevention AspirinACE Inhibitors

STENO-2: Follow up at 8 yrsConventionalIntensive• HbA 1C (%) 9.0 7.9• Systolic BP (mmHg) 146 131• Diastolic BP (mmHg) 78 73• Total chol (mM) 5.6 4.1• LDL chol (mM) 3.3 2.1• Triglycerides (mM) 3.0 1.7

Steno -2: Microvascular complications after8 yearsNephropathyRelative Risk0.39Retinopathy0.42AutonNeuropathy0.37Periph Neuropathy1.090 0.5 1.0 1.5 2.0 2.5In favour of intensiveIn favour of conventional

Steno -2: Cardiovascular endpointsafter 8 yearsProbability for primaryendpoint 0.665 CVD events in 35 ‘conventional’ patients (44%)33 CVD events in 19 ‘intensive’ patients (24%)0.5Conventional0.40.30.2Intensive0.100 12 24 36 48 60 72 84 96Months of follow-up

Fundamental message• Diabetes management - aggressive•Lifestyle is critical in ALL•Target all CVRF•ManageHyperglycaemia•Screen for and manage complicationsWe do not do a good job of reachingtargets in this conditionChallenge

PATIENT FACTORS• Poor acceptance of illness• Lack of knowledge• Health beliefs• Lack of motivation

DOCTORS FACTORS• Not listening to patient• Over/Under ambitious treatmentobjectives• Not realizing importance of education

MANAGEMENT• Patient education { doctor(latin): to teach}• Therapeutic• Correct health beliefs• Patient empowerment• Emphasize importance of self-care• Multidisciplinary approach• Diabetic centre

MULTIDISCIPLINARY CARE• Self care• Modify lifestyle• Maintain normal body weight• Perform self blood /urine monitoring• Attend regular medical follow-up• Learn abount diabetes

MULTIDISCIPLINARY CARE• Primary health care providers• Provide and reinforce education• Adjust medical therapy• Assess complication, cardiovascular risk andmetabolic control• Identify problems that require hospitalattention

MULTIDISCIPLINARY CARE• Diabetes Centre• Establish communication with primary health care• Provide ancillary care services, dietitian , podiatristsetc• Monitoring and quality assurance programmes withincommunity• Research for new treatment

Thank You

InterventionsExpecteddecrease inHbA1c (%)AdvantagesDisadvantagesSteps 1: initialLifestyle to decrease weightand increase activityMetformin 1.5 Weight neutral,inexpensiveStep 2: additional therapy1-2 Low cost, many benefits Fails for most in first yearInsulin 1.5-2.5 No dose limit, inexpensive,improved lipid profileGI side effects, rare lacticacidosisInjections, monitoring,hypoglycaemia, weight gainaSulfonylureas 1.5 Inexpensive Weight gain, hypoglycaemiaTZDs 0.5-1.4 Improved lipid profile Fluid retention, weight gain,expensiveOther drugsα -Glucosidase inhibitors 0.5-0.8 Weight neutral Frequent GI side effects, threetimes/ day dosing, expensiveExenatide 0.5-1.0 Weight loss Injections, frequent GI sideeffects, expensive, littleexperienceGlinidesb1-1.5 Short duration Three times/day dosing,expensivePramlintide 0.5-1.0 Weight loss Injections, three times/daydosing, frequent GI side effects,expensive, little experience

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