Hôpitaux Universitaires de Genève Lipides, métabolisme des hydrates de carbonne et maladies cardio-vasculaires

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1 Hôpitaux Universitaires de Genève Lipides, métabolisme des hydrates de carbonne et maladies cardio-vasculaires Prof. J. Philippe

2 Effect of estrogens on glucose metabolism : Fasting Glucose, HbA1c and C-Peptide C in subjects with NIDDM after treatment with estradiol and placebo according to (8) Variable Baseline After treatment p-value Glucose (mmol/l) Estradiol 12.1 ±.4.9 ±.4 P <.1 Placebo 12.2 ± ±.4 HbA1c (%) Estradiol 8.7 ± ±.2 P <.1 Placebo 8.5 ±.2 9. ±.3 C-Peptide (nmol/l) Estradiol 1.29 ± ±.11 P <.1 Placebo 1.21 ± ±.13

3 Glucose level and coronary heart disease rates in the Honolulu Heart Study (12-Year Follow-up)* Postchallenge Glucose Level Fatal Coronary Heart Disease mmol/l % Total Coronary Heart Disease * The study included 6394 Japanase-American men (exclusion criteria were previous cardiovascular disease, treated hypertension, and known diabetes) and had a 12-year, age-adjusted incidence rate per 1.

4 Crude 22 years cardiovascular and noncardiovascular mortality according to fasting blood glucose quartiles. Error bars indicate 95 % CI 25 Cardiovascular mortality Non-cardiovascular mortality 2 22 Years Mortality (%) Quartile I : mg/dl Quartile II : mg/dl Quartile III : 8-85 mg/dl Quartile IV : mg/dl Fasting Blood Glucose

5 n Mean All subjects Men Women Non menopausal Menopausal Men Age n Mean All subjects Age n Mean Women Age n Mean

6 Anthropometric variables and blood pressure before and after treatment with estradiol and placebo (mean ± SEM; n = 25) 2 mg 17β-estradiol 3 months - 1 mg norethisterone acetate 1d Variables Baseline After treatment P - val Body weight (kg) Estradiol 82.1 ± ± 3.2 P <.1 Placebo 83.5 ± ± 3.2 Body fat (kg) Estradiol 38. ± ± 2. P <.5 Placebo 4.1 ± ± 2.2 Lean body mass (kg) Estradiol 43.9 ± ± 1.4 ns Placebo 43.5 ± ± 1.4 Waist/hip ratio Estradiol.96 ±.2.96 ±.2 ns Placebo.96 ±.2.96 ±.2 SBP (mmhg) Estradiol 139 ± ± 3 ns Placebo 14 ± ± 3 DBP(mmHg) Estradiol 73 ± 2 72 ± 72 ns Placebo 74 ± ± 2 SBP, Systolic blood pressure; DBP, diastolic blood pressure, ns, not significant p-values for comparison between changes during estradiol treatment vs. placebo treatment

7 Incidence rate/ Fasting plasma glucose Quintiles Incidence rate/ hour plasma glucose P < Quintiles Incidence of CVD according to fasting and 2-hour 2 plasma glucose and insulin concentrations Fasting plasma insulin 2- hour plasma insulin Incidence rate/ Quintiles Incidence rate/ P < Quintiles

8 Cumulative hazard curves for ADA fasting glucose criteria and WHO 2h glucose criteria adjusted by age, sex, and study center Fasting glucose classification Known diabetes Diabetes by ADA criteria Impaired fasting glucose Normal 2 h glucose classification Known diabetes Diabetes by ADA criteria Impaired fasting glucose Normal Cumulative hazard Cumulative hazard Follow-up (years) Follow-up (years)

9 Age adjusted 22 years cumulative cardiovascular mortality comparing fasting blood glucose quartiles I-III I III ( ( 85 mg/dl) with quartile IV (> 85 mg/dl) 22 years cumulative cardiovascular mortality (%) Years of follow-up

10 The relationship between non-diabetic glycemia and ischaemic heart disease (IHD) mortality in men ( );( premenopausal women ( );( and postmenopausal women ( ).( Non-diabetic men and women aged 4-79 years were followed for an average of 14 years. (Schwidt-Nave et al. Am J Epidemiol 1991; 133: )

11 The significance of glucose concentrations as a risk factor for chronic disease. Plasma glucose concentrations above the diabetic cut off are associated with an increasing risk of cardiovascular and microvascular disease; levels above the IGT cut off are associated with an increasing risk of diabetes; and elevated levels above some, s as yet undefined, "dysglycaemic"" cut off are associated with an increasing risk of cardiovascular disease.

12 Blood lipids before and after treatment with estradiol and placebo (mean ± SEM; n = 25) Variables Baseline After treatment P - val Cholesterol (mmol/l) Estradiol 5.7 ± ±.1 P <.1 Placebo 5.9 ± ±.2 HDL-C (mmol/l) Estradiol 1.1 ± ±.6 P <.1 Placebo 1.11 ± ±.5 LDL-C (mmol/l) Estradiol 3.74 ± ±.14 P <.1 Placebo 3.54 ± ±.15 Triglycerides (mmol/l) Estradiol 2.4 ± ±.17 ns Placebo 2.39 ± ±.26 HDL-C, High density lipoprotein cholesterol; LDL-C, low density lipoprotein cholesterol p-values for comparison between changes during estradiol treatment vs. placebo treatment

13 2 R=-6.4, p<.5 dhba1c (% ) 1-1

14 Changes in triglycerides in post-menopausal women receiving either no treatment, transdermal oestradiol-17 17β.5 mg daily with cyclical transdermal norethisterone acetate.25 mg daily, or oral conjugated equine oestrogens.625 mg daily with cyclical oral dl-norgestrel.15 mg daily. 3A, oestrogen alone phase; 3B, combined phase, 6, combined phase. (*p <.5). Control Transdermal Oral 2 15 * 1 % change Cycle : * E EP EP E EP EP Oestradiol+desogestrel Tibolone Danazol

15 Changes in high density lipoprotein (HDL) subfractions and apolipoproteins AI and AII in post-menopausal women receiving either transdermal oestradiol-17 17β.5 mg daily with cyclical transdermal norethisterone acetate.25 mg daily,or oral conjugated equine oestrogens.625 mg daily with cyclical oral dl-norgestrel.15 mg daily HDL2 HDL3 Transdermal Oral Transdermal Oral % change -5-1 % change Cycle : 3A 3B 6 3A 3B 6-2 Cycle : 3A 3B 6 3A 3B 6 3A : oestrogen alone phase - 3B : combined phase - 6 : combined phases ** p<.1; *** p<.1

16 Changes in high density lipoprotein (HDL) subfractions and apolipoproteins AI and AII in post-menopausal women receiving either transdermal oestradiol-17 17β.5 mg daily with cyclical transdermal norethisterone acetate.25 mg daily,or oral conjugated equine oestrogens.625 mg daily with cyclical oral dl-norgestrel.15 mg daily apo A1 apo AII Transdermal Oral Transdermal Oral % change -5-1 % change Cycle : 3A 3B 6 3A 3B 6-2 Cycle : 3A 3B 6 3A 3B 6 3A : oestrogen alone phase - 3B : combined phase - 6 : combined phases ** p<.1; *** p<.1

17 Changes in total cholesterol in post-menopausal women receiving either no treatment, trandermal oestradiol- 17β.5 mg daily with cyclical transdermal norethisterone acetate.25 mg daily,, or oral conjugated equine oestrogens.625 mg daily with cyclical oral dl-norgestrel.15 mg daily. Change from baseline (% ) Total cholesterol 3 6 3A 3B 6 3A 3B 6 3A : oestrogen alone phase - 3B : combined phase - 6 : combined phases *** p<.1

18 Cholesterol Months LDL-Cholesterol Months % Change in initial value % Change in initial value

19 HDL-Cholesteroll Months Apo A Months % Change in initial value % Change in initial value

20 Lipoprotein(a) Months Triglycerides Months % Change in initial value % Change in initial value

21 Effect of menopause on lipids and lipoproteins. HDL3 cholesterol HDL2 cholesterol HDL cholesterol LDL cholesterol Triglyce ride s Total cholesterol % change 542 healthy, non obese caucasian females 18-7 yrs LDL, low density lipoproteins; HDL, high density lipoproteins

22 Effects of sex steroids on lipid metabolism. Width of lines indicate the rate of cholesterol traffic under influence of estrogen (L) or progestin/androgen (R). Question marks indicate effects for which documentation is uncertain or unclear ESTROGEN PROGESTIN / ANDROGEN LPL ( ) Bile Acids Chol Diet Chylomicrons Remnants? E HTGL B/E VLDL Remnants LDL LTP? HDL2 B/E FC HDL3 LPL (?) Bile Acids Chol Diet Chylomicrons Remnants? E HTGL VLDL Remnants B/E LDL LTP?? HDL2 B/E FC HDL3 CA/CDA +DC CA/CDA +DC

23 Effect of treatment with Placebo or 17β -Estradiol on concentrations of plasma lipids, lipoproteins, plasma nonesterified Fas,, C Peptide, and HbA1c (6 weeks) Placebo (n=2) Baseline Estradiol (n=2) Absolute and percentage changes after treatment p Placebo (n=2) Estradiol (n=2)= p TC, mmol/l 5.28 ±.66 ( ) LDL-C, mmol/l 3.36 ±.68 ( ) 5.25 ±.6 ( ) 3.3 ±.74 ( ).81.4 ±.46 (1%±9%).68.6 ±.38 (2 %±11%) -.28 ±.44 (-5%±8%) -48 ±.44 (-14 %±12 %).2 (.4).1 (.1) HDL-C, mmol/l 1.2 ±.3 ( ) 1.2 ±.47 ( ).88.3 ±.16 (3 %± 13 %).26 ±.18 (23 %±14 %).2 (.1) HDL 2 -C, mmol/l.36 ±.19 ( ).41 ±.29 ( ).89.2 ±.12 (11% ± 35 %).2 ±.17 (6%±44%).7 (.7) HDL 3 -C, mmol/l.84 ±.14 ( ).79±.21 ( ).47.2 ±.8 (3 % ± 9 %).7 ±.11 (11 % ± 15 %).14 (.1) VLDL-C, mmol/l.64 ±.35 ( ).69±.43 ( ) ±.2 (-11 % ±29 %) -.6 ±.25 (-11 % ± 37 %).61 (.7)

24 Effect of treatment with Placebo or 17β -Estradiol on concentrations of plasma lipids, lipoproteins, plasma nonesterified Fas,, C Peptide, and HbA1c (6 weeks) TGs, mmol/l VLDL TGs, mmol/l Placebo (n=2) 1.53 ±.83 ( ) 1.6 ±.63 ( ) ApoA-1, g/l 1.44 ±.18 ( ) ApoB, g/l 1.27 ±.28 ( ) Nonesterified Fas, mmol/l.36 ±.21 ( ) C peptide, nmol/l.54 ±.38 (-1.41) HbA1c, % 8.1 ± 1.6 ( ) Baseline Estradiol (n=2) 1.74 ±.95 ( ) 1.9 ±.83 ( ) 1.39 ±.28 ( ) 1.26 ±.36 ( ).47 ±.32 ( ).38 ±.39 (-1.68) 8.7 ± 1.5 ( ) Absolute and percentage changes after treatment p Placebo (n=2) Estradiol (n=2)= p.48.8 ±.48 (4 % ± 24 %).7.2 ±.32 (2 % ± 31 %).68.5 ±.1 (3 % ± 7 %).89.3 ±.14 (2 % ± 11 %).3.5 ±.29 (29 % ±113 %) ±.42 (8 %± 9 %) ±.45 (-4% ± 5 %).5 ±.62 (13 % ± 59 %) ±.32 (4 % ± 41 %).22 ±.13 (17 %± 1 %) -13±.13 (-9 % ± 9 %) -.2 ±.37 (37 % ± 15%) -.14±.33 (-16 % ± 89 %) -.66 ±.67 (-7 %± 7 %).65 (.66).85 (.67).1 (.1).4 (.1).79 (.62).26 (.1).2 (.3)

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