Diabetes en de postmenopauzale vrouw Christophe De Block, MD PhD
Diabetologie-Endocrinologie, UZA & UA 4 februari 2012
Inhoudsweergave
Metabool syndroom en menopauze Type 2 diabetes
Prevalentie Risicogroepen Behandeling Genezing ? Preventie ?
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: 3143-3421).
Risicofactoren voor het MS
NHANES III: 1988-1994:
leeftijd postmenopauzale status BMI roken laag inkomen hoge koolhydraat intake geen alcohol consumptie fysische inactiviteit
Park YW et al. Arch Intern Med 2003; 163: 427-436
Metabool syndroom en menopauze
Prevalentie stijgt vanaf menopauze.
Mogelijke verklaringen:
toename intra-abdominaal vet shift naar meer atherogeen lipidenprofiel (↑LDL, ↑TG, ↓HDL) ↑ insuline en glucoseconcentraties: insulineresistentie
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; 88:2404-2411
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; 88:2404-2411
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; 88:2404-2411
Karelis et al. Diab Obes Metab 2006; 8:336-341
Menopauze, metab syndroom en adipocytokines
Chu et al. Am J Obstet Gynecol 2006; 194:100-104
Metabool syndr. (NCEP-ATPIII crit.) en cardiovascul. aandoeningen
Ford et al. Diabetes Care, 2005
Metabool Syndroom (NCEP-ATPIII) en type 2 diabetes
Ford et al. Diabetes Care, 2005
Type 2 diabetes: pathogenese Islet-cell Dysfunction Glucagon (α cell)
Islet
Alpha cell produces excess glucagon
Pancreas
Hepatic glucose output
Insulin (β cell)
Beta cell produces less insulin
Insulin resistance Glucose uptake
Hyperglycemia Liver
Muscle Adipose tissue
Adapted with permission from Kahn CR, Saltiel AR. Joslin’s Diabetes Mellitus. 14th ed. Lippincott Williams & Wilkins; 2005:145–168; Del Prato S, Marchetti P. Horm Metab Res. 2004;36:775–781; Porte D Jr, Kahn SE. Clin Invest Med. 1995;18:247–254.
5
Toenemende prevalentie van diabetes in België
Diabetes Atlas, 3rd edition. International Diabetes Federation, 2006. GGT: Gestoorde glucose tolerantie
Diagnose van diabetes mellitus
Diabetes Care 2010
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
>27.4
<27.4
<24.4
<22.7
0
<21.1
600
BMI
Carey et al, 1997
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
MetS komt frequent voor bij diabetici en pre-diabetici Metabolic Syndrome Prevalence
Age-adjusted prevalence of metabolic syndrome in the US population over 50 years of age categorized by glucose intolerance
100% 86,0% 71,3%
75%
50% 33,1% 25,8%
25%
0% NFG
IGT
IFG
DM
Alexander CM et al, Diabetes 2003;52:1210-1214
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
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; 352:837–853.
CVD
Luscher TF et al. Circulation 2003; 108: 1655-1661 Reilly MP and Rader DJ. Circulation 2003; 108: 1546-1551
behandeling
Gewichtsreductie
Lichaamsbeweging Dieet (arm aan verzadigde vetten en snelabsorbeerbare koolhydraten)
Rookstop Behandeling van hypercholesterolemie Behandeling van hypertensie
behandeling
Lifestyle: voeding
behandeling
Nutritie
Fysische activiteit:
verzadigde vetten < 7% van totale calorie-intake cholesterol < 200 mg/dag twee maal vis per week stop alcohol gebruik rookstop
30 min/d aerobe oef. gewichtsreductie
Normoglycemie
behandeling
Lifestyle:
Effect van fitness bij 906 vrouwen met angor die coronaro ondergingen: ↓ TG, insulin, CRP, gewicht
Wessel et al. JAMA 2004; 292:1179-1187
Better Control Equals Reduced Risk of Complications EVERY 1% reduction in HBA1C
1%
REDUCED RISK*
Deaths from diabetes
-21%
Heart attacks
-14%
Microvascular complications
-37%
Peripheral vascular disorders
-43% *p<0.0001
UKPDS 35. BMJ 2000; 321: 405-12.
Challenges in type 2 diabetes Hypoglycemia is a frequent acute complication of treatment
High risk1
Low risk1,2
Insulin
Metformin
Sulphonylureas
α-glucosidase inhibitors
Meglitinides
Thiazolidinediones GLP-1 receptor agonists DPP-4 inhibitors
1. Nathan DM, et al. Diabetologia. 2009;52:17-306. 2. Cefalu WT. Nature. 2007;81:636-49.
Challenges in type 2 diabetes Weight increases with time
Selecting the Appropriate Therapeutic Agent for Individual Patients Selecting Specific Diabetes Interventions
Glycemic effects
o o o o
Reduction in HbA1c Risk of hypoglycemia Insulin secretory capacity Safety profile
Nathan DM, et al. Diabetes Care 2009; 32:193-203.
Nonglycemic effects
o o o o o o
Changes in body weight CV risk factors Safety profile Tolerability Ease of use Cost
De voordelen van metformine bij patiënten met overgewicht en diabetes type 2 0
Diabetesgerelateerde eindpunten
Diabetesgerelateerde sterfgev.
Mortaliteit alle gevallen
Myocardinfarct
Risicovermindering (%)
5 10 15 20 25 30 35 40
32% 36% p = 0,0023
39% 42%
p = 0,011 p = 0,01
45
p = 0,017
p-waarden in vergelijking met de groep die een conventionele behandeling krijgt Aangepast naar United Kingdom Prospective Diabetes Study (UKPDS) Group. Lancet 1998; 352: 854–865.
ADVANCE Intensieve behandeling : daling van de HbA1c tot 6.5%, behouden op lange termijn 10.0
Standaard Intensieve (op basis van Uni Diamicron)
Gemiddelde HbA1c (%)
9.5 9.0
Gem. HbA1c laatste bezoek
8.5 8.0 7.5
Δ 0.67% (95% CI 0.64 - 0.70); p<0.001
7.0
7.3 % 6.5%
6.5 6.0 5.5 5.0 0
6
12
18
24
30
36
42
48
54
60
66
Opvolging (maanden) NEJM 2008;358;24:2560-72
ADVANCE Intensieve behandeling Gecumuleerde incidentie van microen macrovasculaires events (%)
beschermt tegen de belangrijkste complicaties 25
(micro- & macrovasc.)
Standaard Intensieve (op basis van Uni Diamicron)
20 15
Relatieve risicoreductie 10%
10
(95% CI: 2 to 18%; p=0.013)
5
0 0
6
12
18
24
30
36
42
48
54
60
66
Opvolging (maanden)
Patel A et al. ADVANCE collaborative group; NEJM 2008
Incretines en DPP-IV inhibitoren Ingestion of food Pancreas
GI tract
Release of gut hormones — incretins* Active GLP-1 & GIP
DPP-4 inhibitor
X
*Incretins are also released throughout the day at basal levels. Adapted from Kieffer TJ, Habener JF. Endocr Rev. 1999;20:876–913; Ahrén B. Curr Diab Rep. 2003;2:365–372; Drucker DJ. Diabetes Care. 2003;26:2929–2940; Holst JJ. Diabetes Metab Res Rev. 2002;18:430–441.
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physiological actions of GLP-1
Baggio & Drucker. Gastroenterology 2007; 132: 2131-2157
DPP-4 Inhibitors: efficacy
Green BD, et al European Endocrinology 2010
Incretines: GLP-1 Rec agonisten
Change in Weight (kg)
Change in HbA1c (%)
BYETTA® vs Insulin: Changes in HbA1c and Weight in 3 Head-to-Head Studies Heine, et al1
Nauck, et al3
9 8 ADA
7 GOAL -1.1% 6 8 6 4 2 0 -2 -4 -6 QD = once daily
1. 2. 3.
Barnett, et al2*
-1.1%
-1.4%
-1.4%
-0.9%
-1.0%
BYETTA Insulin aspart, 70/30 BID Glargine QD
+2.9 kg
+2.3 kg
+1.8 kg
-2.3 kg
-2.2 kg
Comparable glycaemic control for BYETTA and insulin Weight loss for BYETTA vs weight gain for insulin
Heine R, et al. Ann Int Med. 2005;143:559-569. Barnett A, et al. Clin Ther. 2007;29:2333-2348. Nauck M, et al. Diabetologia. 2007;50:259-267.
-2.5 kg
LEAD programme: reductions in HbA1c with liraglutide
Baseline A1c %
Monotherapy LEAD-3
Metformin combination LEAD-2
SU combination LEAD-1
8.4
8.4 8.2
8.5
8.6 8.6
8.2
8.6
8.3
Met + TZD combination LEAD-4 8.5
8.6
8.4
Met + SU combination LEAD-5 8.3 8.1
#Change
in HbA1c (%)
0.0
-0.2 -0.4
51%
43%
-0.6
-0.5
-0.8
-0.8 -0.9
-1.0 -1.2 -1.4
-1.3 -1.3
-1.3* -1.4* -1.5*
-1.6
-1.6* Liraglutide 1.2 mg
-1.1
-1.1
-1.2*
Liraglutide 1.8 mg
-1.5* -1.5*
Glimepiride 8 mg
Rosiglitazone 4 mg
Glargine
Significant *vs. comparator; #Change in HbA1c 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;268–78 (LEAD-1); Nauck et al. Diabetes Care 2009;32;84–90 (LEAD-2); Garber et al. Lancet 2009;373:473–81 (LEAD-3); Zinman et al. Diabetes Care 2009;32:1224–30 (LEAD-4); Russell-Jones et al. Diabetologia 2009;52:20462055 (LEAD-5);
Liraglutide: effect on weight
Marre et al. Diabetic Medicine 2009;26;268–78 (LEAD-1); Nauck et al. Diabetes Care 2009;32;84–90 (LEAD-2); Garber et al. Lancet 2009;373:473–81 (LEAD-3); Zinman et al. Diabetes Care 2009;32:1224–30 (LEAD-4); Russell-Jones et al. Diabetologia 2009;52:2046-2055 (LEAD-5); Buse et al. Lancet 2009;374 (9683):39–47 (LEAD-6)
insulinetherapie , glulisine
, Levemir
Hirsch I, NEJM
behandeling
Lipids:
LDL < 70 mg/dl: statines TG < 150 mg/dl: fibraten, nicotinezuur
BP:
≤ 130/80 mmHg
Kunnen we type 2 diabetes genezen?
Weight Change during a 15-y Period According to the Method of Bariatric Surgery
Sjostrom L et al. N Engl J Med 2007;357:741-752
Incidence of Diabetes among Subjects in the SOS Study over 2- and 10-Year Periods
Sjostrom L et al. N Engl J Med 2004;351:2683-2693
Diabetes remission at 2 years
Hofsø D et al. Eur J Endocrinol 2010
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
Preventie type 2 diabetes
FDPS: Effect of Interventions on Weight
Weight loss relative to basal (kg)
Control
Intervention
YEAR 1
YEAR 2
8 4 0 -4 -8
Tuomilehto J, N Engl J Med 2001;344:1343-50
Finnish Diabetes Prevention Study
Cumulative probability of remaining free of diabetes
Control (n=257)
Intervention (n=265)
1.0 p<0.001
0.8
0.6
- 58%
0.4 0
1
2 3 Study year
4
5
6
Tuomilehto J, N Engl J Med 2001;344:1343-50
DPP: Effect of Interventions on Weight 3234 individuals, FPG <126 mg/dL and IGT Placebo
Metformin
Lifestyle
Change in weight (kg)
0 -2 -4 -6 Time (months)
-8 0
6
12
18
24
30
36
42
48
Knowler WC, N Engl J Med 2002;346:393-403
Diabetes Prevention Program 40
Cumulative incidence of diabetes (%)
Placebo RR* 31%
30
Metformin RR 58% Lifestyle
20
10
0 0
0.5
1.0
1.5
2.0 2.5 Year
*Reduction in risk of progressing to type 2 diabetes versus placebo
3.0
3.5
4.0
DPP.N Engl J Med. 2002; 346: 393-403
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