Diabetes type 2 Kortrijk, 6 september 2004

Diabetes: A Growing Global Crisis 189 million people in 2003 324 million projected for 2025 72% increase 38.2 44.2 16% 81.8 156.1 91% 25.0 39.7 59% 18.2 35.9 97% 13.6 26.9 98% 10.4 19.7 88% 1.1 1.7 59% Adapted from Zimmet P et al. Diabet Med. 2003;20:693-702.

Diabetes : pandemie Wereldwijd : 150 000 000 patienten meer dan 50% in India, China en VS Europa : 10 000 000 patienten Belgie : type 1 : 35000 type 2 : 230 000 gediagnosticeerd 450 000 geschat. Men verwacht tegen 2025 300 miljoen type 2 patienten In Belgie tegen 2010 bijna 600 000 type 2 patienten

Estimated Lifetime Risk of Developing Diabetes in the United States for Those Born in 2000 Men: 33% Women: 39% Hispanics are at greatest lifetime risk Men: 45% Women: 53% When diagnosed at age 40 years: Men lose 12 life-years and 19 quality-adjusted life-years Women lose 14 life-years and 22 quality-adjusted life-years Narayan KMV et al. JAMA. 2003;290:1884-1890.

Diabetes Diabetes Mellitus in the US: Health Impact of the Disease 6th leading cause of death Renal failure* Life expectancy 5 to 10 yr ­ Blindness* Diabetes Cardiovascular disease ­ 2X to 4X Nerve damage in 60% to 70% of patients Amputation* *Diabetes is the no. 1 cause of renal failure, new cases of blindness, and nontraumatic amputations Diabetes Statistics. October 1995 (updated 1997). NIDDK publication NIH 96-3926. Harris MI. In: Diabetes in America. 2nd ed. 1995:1-13.

Impact of Type 2 Diabetes Lifestyle implications heart disease, kidney failure, blindness and foot ulceration Increased risk of mortality risk of death more than doubled Heavy burden on healthcare resources approximately 8% of total healthcare budgets in the developed world Balkau, 1999; WHO, 1998

What about Belgium ? Bron IMS Health CODE 2 in BIGE N°28 maart 2000 3000 Euro per patiënt / jaar totaal : 1 miljard Euro per jaar = 6,7% van het totale gezondheidsbudget

Oral anti-diabetic drugs Most of the costs of diabetes are related to hospitalization Oral anti-diabetic drugs 2–7% Ambulatory 18% Hospitalizations 55% Other drugs 20–25%

Socio-economische impact Kostprijs ( The Economic Impact of the Diabetic Foot, Van Acker K )

Increased HbA1c and SBP Are Associated With Increased Morbidity and Mortality Microvascular end points1,2 Myocardial infarction1,2 70 50 60 HbA1c 40 HbA1c 50 SBP 30 40 Incidence (per 1000 PY) 30 SBP 20 20 10 10 5.0 110 7.0 130 9.0 150 11.0 170 5.0 110 7.0 130 9.0 150 11.0 170 HbA1c (%) SBP (mm Hg) HbA1c (%) SBP (mm Hg) SBP=systolic blood pressure; PY=person-year. Stratton IM et al. BMJ. 2000;321:405-412. Adler AI et al. BMJ. 2000;321:412-419.

1% Lessons from UKPDS: Better control means fewer complications EVERY 1% reduction in HBA1C REDUCED RISK* 1% -21% Deaths from diabetes -14% Heart attacks -37% Microvascular complications -43% Peripheral vascular disorders *p<0.0001 UKPDS 35. BMJ 2000; 321: 405-12

ADA criteria voor diagnose diabetes mellitus (1997)

Casus 1 Wat doen ???? Therapeutische richtlijnen Man, 45 jaar, roker VG : appendectomie, AHT R/Amlor 5 mg Familiale voorgeschiedenis : moeder : DM2 vader: overleden na AMI Klinisch onderzoek : BMI : 32 Bloeddruk : 145/85 Abd omtrek : 105 cm Nu jaarlijks routine labo Wat doen ???? Therapeutische richtlijnen

Casus 1 Labo : Glucose N 120 mg/dl HbA1c : 6.2 ¨% chol : 220 mg/dl TG: 250 mg/dl LDL chol : 145 mg/dl HDL chol : 42 mg/dl Insuline : 24 mU/L

Casus 1 Labo : Glucose N 120 mg/dl HbA1c : 6.2 ¨% chol : 220 mg/dl TG: 250 mg/dl LDL chol : 145 mg/dl HDL chol : 42 mg/dl Insuline : 24 mU/L Diagnose IFG Metabool syndroom abd. Omtrek Ins. Resistentie Dyslipidemia AHT M.O. familiaal +

Casus 1 Therapie : 1. Risicofactoren : roken gewicht beweging 3 X30’ BD familie ?

Casus 1 Therapie : 1. Risicofactoren : roken gewicht beweging 3 X30’ BD familie ? Andere vragen ? Diabetes dieet ? Statine ? Aspirine ? Metformine ? Glucometer ? CONTINUUM RISICOFACTOREN

Slechts de top van een grote ijsberg Diabetes Slechts de top van een grote ijsberg HOGE GLYCEMIE ?

A progressive metabolic disorder What is Type 2 diabetes? A progressive metabolic disorder characterised by: Type 2 diabetes Insulin resistance -cell dysfunction Adapted from: Beck-Nielson H et al. J Clin Invest 1994;94:1714–1721 and Saltiel AR, Olefsky JM. Diabetes 1996;45:1661–1669

Insulin Resistance and the development of Type 2 diabetes Glucose Evolution Insulin production Time IGT Overt diabetes

The Insulin Resistance Syndrome Type 2 diabetes or impaired glucose tolerance Obesity Dyslipidaemia ­ Blood pressure Insulin resistance Hyperinsulinaemia (initially) Atherosclerosis DeFronzo, Ferrannini. Diabetes Care 1991; 14 (3): 173-94

Conditions Associated With Insulin Resistance Atherosclerosis Central obesity Dyslipidemia Hypertension Type 2 diabetes Impaired fibrinolysis Hyperinsulinemia Microalbuminuria Adapted from DeFronzo. Diabetes Care 1991; 14(3): 173-94.

NCEP: Clinical Identification of the Metabolic Syndrome* Risk Factor Defining Level Abdominal obesity Waist circumference Men >102 cm (>40 in) Women >88 cm (>35 in) TG 150 mg/dL HDL-C Men <40 mg/dL Women <50 mg/dL BP 130/85 mm Hg Fasting glucose 110 mg/dL *The metabolic syndrome comprises 3 risk factors. Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults. JAMA. 2001;285:2486-2497.

Dr. DeFronzo (Berlin 2004) Other definition 1. Fasting plasma insulin > of = 21 or BMI > of = 28.9 kg/m² 2. Fasting plasma insulin > of = 16 and BMI > 27.5

Prevalence of Complications at Time of Diagnosis United Kingdom Prospective Diabetes Study (UKPDS) Complication Any complication Retinopathy Abnormal ECG Absent foot pulses ( 2) and/or ischemic feet Impaired reflexes and/or decreased vibration sense Myocardial infarction/angina/claudication Stroke/transient ischemic attack Prevalence (%)* 50 21 18 14 7 ~2-3 ~1 *Some patients had more than 1 complication at diagnosis Adapted from UKPDS VIII. Diabetologia 1991; 34: 877-890.

Strategie Preventie van diabetes type 2 Vroege argwaan en vroege behandeling (ICEBERG theorie) Belang van totale behandeling van de patient dwz. Alle risicofactoren : 1+1 = 2 Rationele behandeling Op die manier verbetering van cardiovasculaire prognose en microvasculaire complicaties

Systolic blood pressure (mmHg) ‘Double jeopardy’: type 2 diabetes and hypertension and cardiovascular risk 250 No diabetes Diabetes 200 150 (per 10,000 person-year) CVD death rate 100 50 < 120 120–139 140–159 160–179 180–199  200 Systolic blood pressure (mmHg)

Goals HbA1c lager dan 6.5% Bloeddruk lager dan 130/80 mm Hg Lipiden LDL cholesterol onder de 100 mg/dl HDL cholesterol hoger dan 40/50 (vrouwen) mg/dl triglyceriden lager dan 150 mg/dl Aspirine (bij alle patienten ouder dan 40 jaar) BMI < 25 kg/m² ROOKSTOP !!!! LICHAAMSBEWEGING!!!!DIEET!!!!

+ + Basic Steps in the Management of Type 2 Diabetes insulin oral plus insulin + oral combination + oral monotherapy diet & exercise

Reduces hepatic glucose output Reduce Insulin Resistance Treatments for Type 2 Diabetes Glucose (G) Carbohydrate Glucose DIGESTIVE ENZYMES Insulin (I) I G Acarbose Reduces absorption - Sulphonylurea Repaglinide Stimulates pancreas + Metformin Reduces hepatic glucose output (??muscle/fat effects) Thiazolidinediones Reduce Insulin Resistance

DeFronzo, Ferrannini. Diabetes Care 1991; 14 (3): 173-94 Reducing insulin resistance may be the key to controlling type 2 diabetes and its cardiovascular complications DeFronzo, Ferrannini. Diabetes Care 1991; 14 (3): 173-94

Typical HbA1c Reduction, % Oral Anti-diabetic Drugs Differ by Mode of Action and Results Class Main Actions Typical HbA1c Reduction, % Insulin secretagogues (sulphonylureas, glitinides) Potentiate insulin secretion 1.0-2.0 Biguanides (metformin) Inhibit hepatic glucose production Thiazolidinediones Enhance insulin action at liver, fat, and muscle 0.5-1.0 -Glucosidase inhibitors Delay GI absorption of carbohydrates GI=gastrointestinal. Adapted from Nathan DM. N Engl J Med. 2002;347:1342-1349.

Orale antidiabetica Insulin-augmenting agents Insulin-assisting agents Sulfonylurea Biguanides (Metformin) “Glinides” Alpha-glucosidase inhibitoren Thiazolidinediones

Biguaniden Docmetformi (°Docpharma) : 500-850 mg Glucophage (°Merck) : 500-850 mg Merck-metformine (°Merck) : 500-850 mg Metformax (°Menarini) : 850 mg deelbaar !! Metformiphar (°Unicophar) Actiemechanisme : verhogen gevoeligheid lever en perifere weefsels verhogen van GLUT 4 transporters inhibitie gluconeogenese verhoging glycogeen synthese

Biguaniden Andere effecten : verlagen LDL, TG en FFA Gewichtsverlies Dosis : zo maximaal mogelijk tot max. 3 maal 850 mg Nevenwerking : 1. GI 2. Lactaaintolerantie 3. CI : lever en nierfalen (creat >1.4 bij vr en bij man > 1.5), 4. 5.5 % is intolerant M.O.- Bij nevenwerkingen terug naar vorige dosis en na 2 weken opnieuw pogen op te drijven - Bij contraststof onderzoek of operatie pas opnieuw starten als 2 dagen normale nierfunctie

Thiazolidinediones: wie en wat? Produkten Troglitazone ( Rezulin ) ° Parke Davis (uit de handel genomen omwille van hepatotoxiciteit ) Pioglitazone ( Actos ) ° Eli Lilly 15-30 mg Rosiglitazone ( Avandia ) °GSK 4-8 mg werken in op de insulineresistentie PLEIOTROOP effect : insuline sensitizer thv lever, vetcel en spier minder circulerend insuline geen hypo’s bewaren van de pancreatische insulinesecretie

Thiazolidinediones = PPAR  agonisten (PPAR) = Peroxisome Proliferator Activator Receptoren zijn Nucleaire Receptoren (proteine) Verbetert expressie & translocatie GLUT4 differentiatie van adipocyten opname FFA’s en lipogenese Vermindert productie TNF⍺ aanmaak leptine productie resistine Retinoid X receptor AVANDIA DNA PPre Nucleair receptor ppar  PPAR response elements = gene expression

PPAR : Primary Downstream Tissue-Specific Effects Fat - Adipocyte differentiation - Glucose uptake by muscle - Expression of TNFα Pancreatic β-Cells - Cell morphology and structure Vascular - VSMC size, type, migration - Endothelial function - Atherogenicity of lipids Muscle - Glucose uptake and utilization Liver - Glucose and VLDL synthesis - Hepatic insulin resistance - Glomerular function and structure Kidneys Desvergne B, Wahli W. Endocrine Reviews 1999;20(5):649-688. Rosen ED, Spiegelman BM. J Biol Chem 2001;276(41):37731-37734. Kelly D. Circ Res 2001;89:935-937. Benson S, et al. AJH 2000;13:74-82. Guan YF, Breyer MD. Kidney Intl 2001;60:14-30. Buchan KW, Hassal DG. PPAR agonists as direct modulators of the vessel wall in cardiovascular disease. Wiley&Sons, 2000, pp. 350-366.

Nevenwerkingen : Klasse effect 1. Oedeem dubbel blind tr(mono, comb metf.) bij patienten onder Avandia 4 tot 5 % oedeem metformine 2,2 % , placebo 1,3 % dubbel blind bij patienten onder Actos 4,8 % ( mono) vs 1,2 % placebo comb met Insuline (15,3 % vs 7 % ) mild oedeem, goed beantwoordend aan diuretica bij ernstig oedeem stop TZD

Nevenwerkingen : Klasse effect 2. Hemoglobine troglitazone : 5 % lager dan normale waarde Rosiglitazone : - 1 g/dl pioglitazone : - 1 g/dl 3. Gewichtstoename door vocht retentie en meer subcut vet hoge dosis : gewichtstoename tot 3 kg/jaar 4. Lipiden

Nevenwerkingen : Unieke effecten 1. Hepatotoxiciteit troglitazone : 48 leverfalen : 28 doden en 15 levertransplantatie achteraf gezien bleek dat ook in vitro troglitazone hepatotoxisch was voor levercellen conc troglit 15 tot 20 X hoger in lever dan in plasma rosiglitazone 100 X potenter dan Trog en 10 X meer dan pio kort T1/2 ( 4 h ) ( trog : 16-34 h) accumuleert niet in de lever Advies monitoren ALT na 2 maanden R

Nevenwerkingen : Unieke effecten 2. Myalgie pioglitazones (33/606) : 5,4 %-2,7 % placebo 3. Rosiglitazone minder potentie tot drug interactie

Insulin augmenting agents : SU Short acting (administration before meals): Diamicron-Glurenorm Long acting (once daily): Amarylle, Uni-Diamicron Reason for choice short/long: compliance of patient When: failing of insulin secretion- high glucose +++, adding to metformin, intolerance of metformin

Characteristics of commonly used sulfonylurea Generic name Brand name Posology Duration of action Excretion (h) (Tolbutamide) Rastinon (Tolazamide) Tolinase (Chlorpropamide)Diabinese 125-250mg/d 60 Renal Glibenclamide Daonil 5 2.5-15mg/d 60 Renal Euglucon 5/Bevoren 5 Glipizide Glibenese 5 2.5-20mg/d < 24 Renal 80% Minidiab 5 Gliquidone Glurenorm 30 30-90mg/d 7 Hepatic 95% Gliclazide Diamicron 80 Merck Gliclazide 40-160mg/d < 24 Renal 70% Glimepiride Amarylle 2/3/4 1-8mg/d 24 Renal 60%

Long acting SU’s Amarylle (Aventis) glimepiride 1-8 mg/dag werkt 24 uur 60 % renale excretie Uni Diamicron (Servier) 30 mg dagelijks 1 tot 4 co in 1 orale inname duur 12 uur switch 1 tablet 80 mg DM = 1 co UniDiamicron

Casus 2 Zelfde man Nu klacht van droge mond Labo : glycemie N : 240 mg/dl hbA1c : 8 % chol : 220 mg/dl LDL : 140 mg/dl HDL chol : 42 mg/dl Trig : 480 mg/dl Insuline : 34 mU/L Wat ?

Casus 2 Diagnose diabetes Type ? D/C peptide, GAD as Therapie : Diabetes dieet Beweging Gewicht Rookstop Aspirine TG ? SUR/Met/TZD/ins ? Hoeveel ? Glucometer ? Dagprofielen !!!! Wanneer controle ? Verder : AS ? urine oftalmologie

Casus 3 Man 54 jaar Familiale VG : CABG vader DM 2 moeder Med Vg : R/ 2 co Diamicron HP : AMI HbA1c 7.8 % Insuline ?

Insulinetherapie ????? --.- % is the mean HbA1c of patients with type 2 being started on insulin -- % of patients with type 2 diabetes treated with SU need insulin by 6 years of follow up -- % of patients with type 2 diabetes treated with SU need insulin by 9 years of follow up

Insulinetherapie ???? 10.4 % is the mean HbA1c of patients with type 2 being started on insulin -- % of patients with type 2 diabetes treated with SU need insulin by 6 years of follow up -- % of patients with type 2 diabetes treated with SU need insulin by 9 years of follow up

Insulinetherapie ????? 10.4 % is the mean HbA1c of patients with type 2 being started on insulin 53 % of patients with type 2 diabetes treated with SU need insulin by 6 years of follow up -- % of patients with type 2 diabetes treated with SU need insulin by 9 years of follow up

Insulinetherapie ???? 10.4 % is the mean HbA1c of patients with type 2 being started on insulin 53 % of patients with type 2 diabetes treated with SU need insulin by 6 years of follow up 80 % of patients with type 2 diabetes treated with SU need insulin by 9 years of follow up

Insulin therapy in Type 2 DM BARRIERS TO INSULIN THERAPY Reassurance About Theoretical Concerns Insulin therapy in Type 2 DM Improves Insulin Sensitivity by Reducing Glucotoxicity Probably Reduces Cardiovascular Risk Causes Modest Weight Gain Rarely Causes Severe Hypoglycemia

Hoe insuline starten ? Verder orale aan dezelfde dosis Start 1 injectie insuline 10 U (bedtime) NPH (bedtime) Glargine (bedtime or with evening meal) in case of hypo Titreer de dosis wekelijks op basis van de nuchtere glycemie Increase 8 U if FPG > 180 mg/dL Increase 6 U if FPG 140-180 Increase 4 U if FPG 120-140 Treat to target (use FPG <120mg/dl) Verminder de dosis van de orale als hypo’s overdag Easiest way to start insulin

Initiating Basal Insulin Therapy: Treat-to-Target Trial Tactics Continue oral agent(s) at same dosage Add single daily insulin dose (10 IU) Glargine (morning, with evening meal, or at bedtime)* NPH (bedtime)† Titrate dose weekly according to fasting SMPG Increase by 8 IU if FPG >180 mg/dL (>10 mmol/L) Increase by 6 IU if FPG 140-180 mg/dL (7.8-10 mmol/L) Increase by 4 IU if FPG 120-140 mg/dL (6.7-7.8 mmol/L) Increase by 2 IU if FPG 120 mg/dL (6.7 mmol/L) Treat-to-target: usually FPG 100 mg/dL (5.6 mmol/L), unless hypoglycaemia prevents further titration Reduce insulin dosage (2-4 IU/d per adjustment) if serious hypoglycaemia occurs *Please see full prescribing information for insulin glargine (rDNA origin) injection. †Please see full prescribing information for NPH human insulin (rDNA origin) isophane suspension. NPH=neutral protamine Hagedorn; SMPG=self-monitored plasma glucose; FPG=fasting plasma glucose. Riddle MC et al. Diabetes Care. 2003;26:3080-3086.

Op basis van de streefwaarden : naar 2 of 4 injecties ….. En verder ??? Op basis van de streefwaarden : naar 2 of 4 injecties ….. als HbA1c 7 (6.5 %) niet wordt behaald……. Op moment van 2 injecties best stop SUR

Insulinetherapie onmiddellijk superieur in volgende gevallen Heel hoge HbA1c met onmiddellijk complicaties (micro en macrovasculair bij diagnose) : best onmiddellijk insuline (potentieel) Zwangere vrouwen Operaties gepland Patient wil zelf insuline Heel ernstig risicoprofiel

Treatment Milestones in Diabetes 1922 1946 1952 1960 1975 Late 1970s 1993 1996 1998 2000 NPH insulin HbA1c testing DCCT Insulin glargine Biguanides Insulin pump Insulin therapy Sulphonylurea therapy UKPDS Blood glucose self-monitoring Lente insulin therapy Rapid-acting insulin analogues NPH=neutral protamine Hagedorn; DCCT=Diabetes Control and Complications Trial; UKPDS=United Kingdom Prospective Diabetes Study. Data from Tattersall RB. In: Pickup JC, Williams G, eds. Textbook of Diabetes. 3rd ed. Boston, Mass: Blackwell Science; 2003. US FDA Center for Drug Evaluation and Research. Available at: http://www.fda.gov/cder/da/ddpa696.htm. Accessed 18 March 2003. Lantus Consumer Information. Available at: http://www.fda.gov/cder/consumerinfo/druginfo/lantus.htm. Accessed 18 March 2003.

Insulin excursions in a non-diabetic 70 Normal free insulin levels (Mean) Meals 60 50 Insulin (mU/l) 40 30 20 10 0600 0900 1200 1500 1800 2100 2400 0300 Time of day Breakfast Lunch Dinner Adapted from Polonsky et al. 1988

Insuline excursies bij vier injecties 70 Normal free insulin levels (Mean) Meals 60 50 Insulin (mU/l) 40 30 20 10 0600 0900 1200 1500 1800 2100 2400 0300 Time of day Breakfast Lunch Dinner Adapted from Polonsky et al. 1988

Limitations of today’s soluble human insulin Inability of s.c. injected soluble insulin to mimic the physiological pattern of endogenous insulin secretion observed in non-diabetic subjects after meals Delayed onset of action (30-60 min after injection) i.e. should be injected 30-60 min prior to a meal Prolonged duration of action (6-8 hrs after injection) The higher the dose - the longer the duration of action Absorption and duration of action dependent on injection site

Insulin Analogues Human Insulin Aspart1 Lispro2 Glargine3 A-chain Human Insulin Dimers and hexamers in solution B-chain Aspart1 Limited self-aggregation Monomers in solution Asp Lispro2 Limited self-aggregation Monomers in solution Lys Pro Glargine3 Soluble at low pH Forms microprecipitates at neutral (subcutaneous) pH, slow glargine release Gly Arg Arg Novolog [package insert]. Bagsvaerd, Denmark: Novo Nordisk Pharmaceuticals, Inc; 2004. Humalog [package insert]. Indianapolis, Ind: Eli Lilly and Company; 2002. Lantus [package insert]. Frankfurt, Germany: Aventis Pharma Deutschland GmbH; 2003.

Action Profiles of Insulin Analogues Aspart, lispro, glulisine, 2-5 h Regular, 6-8 h NPH, 13-16 h Ultralente, 18-24 h Glargine, 24 h Plasma insulin level 2 4 6 8 10 12 14 16 18 20 22 24 Time (h) NPH=neutral protamine Hagedorn.

(GIR profiles in 3 patients with type 1 diabetes) NPH insulin shows high within-subject variability (GIR profiles in 3 patients with type 1 diabetes) Dose at each injection: NPH insulin 0.4U/kg, tigh Data from study1450 (T. Heise et al. Diabetes 2003; 52 ( Suppl.1) A121)

Current insulin preparations and their pharmacokinetics following s. c Current insulin preparations and their pharmacokinetics following s.c. injection Onset of action 30-60 minutes 5-15 minutes 1-2 hours 1-3 hours 2-4 hours Peak of action 5-7 hours 4-8 hours 8-10 hours Duration of action 6-8 hours 4-5 hours 13-18 hours 13-20 hours 18-30 hours Insulin Soluble Lispro/Aspart NPH Lente Ultralente Glargine 1-2 hours peakless >24 hours Adapted from Burge and Schade. 1997

Structure of insulin detemir

Terugbetalingscriteria Lantus TERUGBETALING VOOR 1 JAAR Patient behoort tot groep 1 of 2 van diabetes conventie Patient met type 2 onder combinatie met orale OAD en 1 injectie Insuline EN 1 van de 2 volgende voorwaarden . HbA1c > 7.5 % onder combinatie van OAD en 1 injectie NPH, ULtratard, Humuline Long of Menginsulines . Ernstig hypoglycemie (nood aan hulp van derden) onder combinatie van OAD met 1 maal per dag NPH, Ultratard HM, Humuline long, Menginsulines VERLENGING VOOR 12 MAANDEN 1. conventiepatient groep 1 of 2 2. 1 injectie Lantus en OAD en HbA1c < 7 % op een test die de laatste 3 maanden is uitgevoerd (Bewijzen)