Diabetes en de postmenopauzale vrouw

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1 Diabetes en de postmenopauzale vrouw Christophe De Block, MD PhD Diabetologie-Endocrinologie, UZA & UA 4 februari 2012

2 Inhoudsweergave Metabool syndroom en menopauze Type 2 diabetes Prevalentie Risicogroepen Behandeling Genezing? Preventie?

3 Metabool Syndroom: NCEP-ATPIII criteria Diagnosis is established when >3 of these risk factors are present Risk Factor Abdominal obesity (Waist circumference ) Men Women TG HDL-C Men Women Blood Pressure Fasting glucose Defining Level >102 cm >88 cm >150 mg/dl <40 mg/dl <50 mg/dl >130/85 mm Hg >110 mg/dl * NCEP Expert Panel on Detection, Evaluation and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III). Final report. Circulation 2002; 106: ).

4 Risicofactoren voor het MS NHANES III: : leeftijd postmenopauzale status BMI roken laag inkomen hoge koolhydraat intake geen alcohol consumptie fysische inactiviteit Park YW et al. Arch Intern Med 2003; 163:

5 Metabool syndroom en menopauze Prevalentie stijgt vanaf menopauze. toename intra-abdominaal vet shift naar meer atherogeen lipidenprofiel ( LDL, TG, HDL) insuline en glucoseconcentraties: insulineresistentie Mogelijke verklaringen: direct effect van ovarian failure indirect gevolg van centrale vetdistributie bij oestrogendeficiëntie Metab syndroom, type 2 DM en CVD stijgen na menopauze Carr MC. JCEM 2003; 88:

6 Effect van menopauze op lichaamssamenstelling toename intra-abdominaal vet Oestrogenen bevorderen accumulatie van vet gluteofemoraal (peer-type) = gynoide obesitas Oestrogen-deficiëntie na menopauze: centrale vetdistributie (appel-type) = androide obesitas Carr MC. JCEM 2003; 88:

7 Effect van menopauze op insulineresistentie menopauze abdominale obesitas insuline-resistentie compensatoir hyperinsulinisme VVZ perifere glucose-uptake hepatische gluconeogenese hepatische klaring van insuline Carr MC. JCEM 2003; 88: Karelis et al. Diab Obes Metab 2006; 8:

8 Menopauze, metab syndroom en adipocytokines Chu et al. Am J Obstet Gynecol 2006; 194:

9 Metabool syndr. (NCEP-ATPIII crit.) en cardiovascul. aandoeningen Ford et al. Diabetes Care, 2005

10 Metabool Syndroom (NCEP-ATPIII) en type 2 diabetes Ford et al. Diabetes Care, 2005

11 Type 2 diabetes: pathogenese Hepatic glucose output Liver Islet-cell Dysfunction Glucagon (α cell) Pancreas Insulin (β cell) Hyperglycemia Alpha cell produces excess glucagon Islet Insulin resistance Glucose uptake Muscle Adipose tissue Beta cell produces less insulin Adapted with permission from Kahn CR, Saltiel AR. Joslin s Diabetes Mellitus. 14th ed. Lippincott Williams & Wilkins; 2005: ; Del Prato S, Marchetti P. Horm Metab Res. 2004;36: ; Porte D Jr, Kahn SE. Clin Invest Med. 1995;18:

12 Toenemende prevalentie van diabetes in België Diabetes Atlas, 3rd edition. International Diabetes Federation, GGT: Gestoorde glucose tolerantie

13 Diabetes Care 2010 Diagnose van diabetes mellitus

14 Incidentie van DM2 volgens BMI en middelomtrek Log Age-Adjusted Incidence/100,000 person-years >86.4 <86.4 <78.7 Waist (cm) <73.7 <70 <21.1 <22.7 <24.4 <27.4 >27.4 BMI Carey et al, 1997

15 Televisie kijken, overgewicht en T2 DM Sedentaire levensstijl, voornamelijk TV kijken is geassocieerd met sterk verhoogd risico op obesitas en type 2 diabetes. Each 2 h/day increment in TV watching was associated with 23% increase in obesity and 14% increase in risk of diabetes. Hu FB et al, JAMA 2003

16 MetS komt frequent voor bij diabetici en pre-diabetici Metabolic Syndrome Prevalence 100% 75% 50% 25% 0% Age-adjusted prevalence of metabolic syndrome in the US population over 50 years of age categorized by glucose intolerance 25,8% 33,1% 71,3% 86,0% NFG IGT IFG DM Alexander CM et al, Diabetes 2003;52:

17 Diabetes mellitus: predictie : Wie heeft er risico op diabetes (type 2)? personen > 65 j personen > 45 j als volgende risicofactoren : diabetes bij 1ste graad familieleden algemene obesitas (BMI > 27 kg/m²) abdominale obesitas (buikomtrek M > 94, V > 80 cm) vroeger zwangerschapsdiabetes of baby > 4.5 kg gebruik van diabetogene farmaca (vb. corticoïden) vroeger gestoord glucosemetabolisme (vb. bij chirurgie) hyperlipidemie : HDL-Chol < 35 of TG > 250 mg/dl hypertensie 140/90 mm Hg

18 chronische complicaties: prevalentie 50% type 2 diabetici vertonen reeds complicaties bij diagnose MICROVASCULAR MACROVASCULAR Retinopathy, glaucoma or cataracts Cerebrovascular disease Nephropathy Coronary heart disease Neuropathy Peripheral vascular disease UK Prospective Diabetes Study Group. UKPDS 33. Lancet 1998; 352:

19 CVD Luscher TF et al. Circulation 2003; 108: Reilly MP and Rader DJ. Circulation 2003; 108:

20 behandeling Gewichtsreductie Lichaamsbeweging Dieet (arm aan verzadigde vetten en snelabsorbeerbare koolhydraten) Rookstop Behandeling van hypercholesterolemie Behandeling van hypertensie

21 behandeling Lifestyle: voeding

22 behandeling Nutritie verzadigde vetten < 7% van totale calorie-intake cholesterol < 200 mg/dag twee maal vis per week stop alcohol gebruik rookstop Fysische activiteit: 30 min/d aerobe oef. gewichtsreductie Normoglycemie

23 behandeling Lifestyle: Effect van fitness bij 906 vrouwen met angor die coronaro ondergingen: TG, insulin, CRP, gewicht Wessel et al. JAMA 2004; 292:

24 Better Control Equals Reduced Risk of Complications EVERY 1% reduction in HBA 1C Deaths from diabetes REDUCED RISK* -21% Heart attacks -14% 1% Microvascular complications -37% Peripheral vascular disorders -43% UKPDS 35. BMJ 2000; 321: *p<0.0001

25 Challenges in type 2 diabetes Hypoglycemia is a frequent acute complication of treatment High risk 1 Low risk 1,2 Insulin Sulphonylureas Meglitinides Metformin α-glucosidase inhibitors Thiazolidinediones GLP-1 receptor agonists DPP-4 inhibitors 1. Nathan DM, et al. Diabetologia. 2009;52: Cefalu WT. Nature. 2007;81:

26 Challenges in type 2 diabetes Weight increases with time

27 Selecting the Appropriate Therapeutic Agent for Individual Patients Selecting Specific Diabetes Interventions Glycemic effects Nonglycemic effects o Reduction in HbA1c o Risk of hypoglycemia o Insulin secretory capacity o Safety profile o Changes in body weight o CV risk factors o Safety profile o Tolerability o Ease of use o Cost Nathan DM, et al. Diabetes Care 2009; 32:

28 De voordelen van metformine bij patiënten met overgewicht en diabetes type 2 0 Diabetesgerelateerde eindpunten Diabetesgerelateerde sterfgev. Mortaliteit alle gevallen Myocardinfarct 5 Risicovermindering (%) % p = 0, % p = 0,017 36% p = 0,011 39% p = 0,01 p-waarden in vergelijking met de groep die een conventionele behandeling krijgt Aangepast naar United Kingdom Prospective Diabetes Study (UKPDS) Group. Lancet 1998; 352:

29 ADVANCE Intensieve behandeling : daling van de HbA1c tot 6.5%, behouden op lange termijn Standaard Intensieve (op basis van Uni Diamicron) Gemiddelde HbA 1c (%) Δ 0.67% (95% CI ); p<0.001 Gem. HbA 1c laatste bezoek 7.3 % 6.5% Opvolging (maanden) NEJM 2008;358;24:

30 ADVANCE Intensieve behandeling beschermt tegen de belangrijkste complicaties (micro- & macrovasc.) Gecumuleerde incidentie van microen macrovasculaires events (%) Standaard Intensieve (op basis van Uni Diamicron) Opvolging (maanden) Relatieve risicoreductie 10% (95% CI: 2 to 18%; p=0.013) Patel A et al. ADVANCE collaborative group; NEJM 2008

31 Incretines en DPP-IV inhibitoren Ingestion of food Pancreas GI tract DPP-4 inhibitor Release of gut hormones incretins* Active GLP-1 & GIP X *Incretins are also released throughout the day at basal levels. Adapted from Kieffer TJ, Habener JF. Endocr Rev. 1999;20: ; Ahrén B. Curr Diab Rep. 2003;2: ; Drucker DJ. Diabetes Care. 2003;26: ; Holst JJ. Diabetes Metab Res Rev. 2002;18:

32 physiological actions of GLP-1 Baggio & Drucker. Gastroenterology 2007; 132:

33 Green BD, et al European Endocrinology 2010 DPP-4 Inhibitors: efficacy

34 Incretines: GLP-1 Rec agonisten

35 BYETTA vs Insulin: Changes in HbA1c and Weight in 3 Head-to-Head Studies Change in HbA1c (%) Change in Weight (kg) ADA GOAL Heine, et al 1 Barnett, et al 2 * Nauck, et al 3-1.1% -1.1% -1.4% -1.4% -0.9% -1.0% +1.8 kg +2.3 kg +2.9 kg -2.3 kg -2.2 kg BYETTA Insulin aspart, 70/30 BID Glargine QD -2.5 kg QD = once daily Comparable glycaemic control for BYETTA and insulin Weight loss for BYETTA vs weight gain for insulin 1. Heine R, et al. Ann Int Med. 2005;143: Barnett A, et al. Clin Ther. 2007;29: Nauck M, et al. Diabetologia. 2007;50:

36 LEAD programme: reductions in HbA 1c with liraglutide # Change in HbA1c (%) Monotherapy LEAD-3 51% 43% -0.9 Metformin combination LEAD-2 SU combination LEAD-1 Met + TZD combination LEAD-4 Met + SU combination LEAD-5 Baseline A1c % * -1.3* * -1.5* -1.5* -1.5* -1.6* Liraglutide 1.2 mg Liraglutide 1.8 mg Glimepiride 8 mg Rosiglitazone 4 mg Glargine Significant *vs. comparator; # Change in HbA 1c from baseline for overall population (LEAD-4,-5) add-on to diet and exercise failure (LEAD-3); or add-on to previous OAD monotherapy (LEAD-2,-1). Marre et al. Diabetic Medicine 2009;26; (LEAD-1); Nauck et al. Diabetes Care 2009;32;84 90 (LEAD-2); Garber et al. Lancet 2009;373: (LEAD-3); Zinman et al. Diabetes Care 2009;32: (LEAD-4); Russell-Jones et al. Diabetologia 2009;52: (LEAD-5);

37 Liraglutide: effect on weight Marre et al. Diabetic Medicine 2009;26; (LEAD-1); Nauck et al. Diabetes Care 2009;32;84 90 (LEAD-2); Garber et al. Lancet 2009;373: (LEAD-3); Zinman et al. Diabetes Care 2009;32: (LEAD-4); Russell-Jones et al. Diabetologia 2009;52: (LEAD-5); Buse et al. Lancet 2009;374 (9683):39 47 (LEAD-6)

38 insulinetherapie, glulisine, Levemir Hirsch I, NEJM

39 behandeling Lipids: LDL < 70 mg/dl: statines TG < 150 mg/dl: fibraten, nicotinezuur BP: 130/80 mmhg

40 Kunnen we type 2 diabetes genezen?

41 Weight Change during a 15-y Period According to the Method of Bariatric Surgery Sjostrom L et al. N Engl J Med 2007;357:

42 Incidence of Diabetes among Subjects in the SOS Study over 2- and 10-Year Periods Sjostrom L et al. N Engl J Med 2004;351:

43 Diabetes remission at 2 years Hofsø D et al. Eur J Endocrinol 2010

44 IDF consensus March 2011 The achievable goal is not cure, but remission, of the diabetic state HbA1c < 6% No hypoglycemia Total cholesterol < 154 mg/dl, LDL < 77 mg/dl Triglyceriden < 150 mg/dl BP < 135/85 mmhg > 15% weight loss Without medication or with reduced medication

45 Preventie type 2 diabetes

46 FDPS: Effect of Interventions on Weight Control Intervention Weight loss relative to basal (kg) YEAR 1 YEAR 2 Tuomilehto J, N Engl J Med 2001;344:

47 Finnish Diabetes Prevention Study Cumulative probability of remaining free of diabetes Control (n=257) Intervention (n=265) p< % Study year Tuomilehto J, N Engl J Med 2001;344:

48 DPP: Effect of Interventions on Weight 3234 individuals, FPG <126 mg/dl and IGT 0 Placebo Metformin Lifestyle Change in weight (kg) Time (months) Knowler WC, N Engl J Med 2002;346:

49 Diabetes Prevention Program Cumulative incidence of diabetes (%) Placebo Metformin Lifestyle RR* 31% RR 58% Year *Reduction in risk of progressing to type 2 diabetes versus placebo DPP.N Engl J Med. 2002; 346:

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