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Diabetes type 2

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%.

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Diabetes type 2

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  1. Diabetes type 2 Kortrijk, 6 september 2004

  2. 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.

  3. 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

  4. 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.

  5. Diabetes Mellitus in the US: Health Impact of the Disease 6th leading cause of death Renal failure* Life expectancy 5 to 10 yr ­ Blindness* Cardiovasculardisease ­ 2X to 4X Diabetes 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.

  6. 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

  7. 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

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

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

  10. 5.0110 5.0110 7.0130 7.0130 9.0150 9.0150 11.0170 11.0170 Increased HbA1c and SBP Are Associated With Increased Morbidity and Mortality Microvascular end points1,2 Myocardial infarction1,2 70 50 60 HbA1c HbA1c 40 50 SBP 30 40 Incidence (per 1000 PY) 30 20 SBP 20 10 10 0 0 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.

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

  12. ADA criteria voor diagnose diabetes mellitus (1997)

  13. 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

  14. 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

  15. 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

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

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

  18. Diabetes Slechts de top van een grote ijsberg HOGEGLYCEMIE ?

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

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

  21. 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

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

  23. 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.

  24. 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

  25. 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.

  26. 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

  27. ‘Double jeopardy’: type 2 diabetes and hypertension and cardiovascular risk 250 No diabetes Diabetes 200 150 CVD death rate (per 10,000 person-year) 100 50 0 < 120 120–139 140–159 160–179 180–199  200 Systolic blood pressure (mmHg)

  28. 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!!!!

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

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

  31. 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

  32. Oral Anti-diabetic Drugs Differ by Mode of Action and Results GI=gastrointestinal. Adapted from Nathan DM. N Engl J Med. 2002;347:1342-1349.

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

  34. 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

  35. 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

  36. 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

  37. 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

  38. PPAR : Primary DownstreamTissue-Specific Effects - Adipocyte differentiation - Glucose uptake by muscle - Expression of TNFα Fat Vascular - Cell morphology and structure Muscle - VSMC size, type, migration - Endothelial function - Atherogenicity of lipids - Glucose uptake and utilization Pancreatic β-Cells - Glucose and VLDL synthesis - Hepatic insulin resistance Liver - 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.

  39. 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

  40. 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

  41. 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

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

  43. 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

  44. 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%

  45. 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

  46. 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

  47. 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 2

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