Διαβητική δυσλιπιδαιμία...atherosclerosis 239 (2015) 483-495 cell cycle 7:20,...
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Διαβητική δυσλιπιδαιμία
Παθοφυσιολογία και αντιμετώπιση
Βασίλης Τσιμιχόδημος, Παθολόγος-Διαβητολόγος
Αναπληρωτής Καθηγητής Παθολογίας, Πανεπιστήμιο Ιωαννίνων
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Roper AN et al. BMJ 2001;322:1389-93
Το προσδόκιμο επιβίωσης μειώνεται 8 χρόνια
όταν ο ΣΔ διαγνωσθεί στα 40 έτη.
Ο ΣΔ τύπου 2 μειώνει το προσδόκιμο επιβίωσης
Μείωση του προσδόκιμου επιβίωσης σε έτη,Ανάλογα με την ηλικία διάγνωσης του ΣΔ.
Year
s
Ηλικία διάγνωσης (έτη)
0
10
8
6
4
2
40 45 50 55 60 65 70 75 80
Άνδρες
Γυναίκες
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0
2
4
6
8
10
12
14
16
18
Annual CH
D D
eath
sper
1000 P
ers
ons
Kannel WB, McGee DL. JAMA. 1979;241:2035-2038.
Framingham Study: DM and CHD Mortality20-Year Follow-up
17
8
17
4
Men Women
DM
Non-DM
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ΕΠΙΠΤΩΣΗ ΚΑΡΔΙΑΓΓΕΙΑΚΗΣ ΝΟΣΟΥ KΑΙ ΘΝΗΤΟΤΗΤΑΣ ΣΕ
ΔΙΑΒΗΤΙΚΟΥΣ ΚΑΙ ΜΗ, ΜΕ Η΄ ΧΩΡΙΣ ΕΜΦΡΑΓΜΑ ΜΥΟΚΑΡΔΙΟΥ
379.000 άτομα με ΣΔ vs. 9.018.082 xωρίς ΣΔ, FU:6 έτη
Booth G. et al. Lancet 2006; 368: 29-36
Age (years)
Nu
mb
er
of
eve
nts
pe
r 1
00
0 p
ers
on
/ ye
ars
20 40 60 80
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ΣΔ τύπου 2 : Διαδρομή νόσου
Adapted from Kendall DM, Bergenstal RM. Am J Manag Care 2001;7:S327-43
Ris
k r
ela
tive
to g
ene
ral po
pula
tion
Έτη ΣΔ
5
6
4
3
2
1
0
-20 -15 -10 -5 0 5 10 15 20
Μικροαγγειακές επιπλοκές*
ΚΑ νόσος
Αντίσταση στην ινσουλίνη
Δυσλιπιδαιμία
Υπέρταση
Υπεργλυκαιμία
* Nephropathy,Neuropathy, Retinopathy
.
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Influence of Multiple Risk Factors* on CVD Death Rates in Diabetic and Nondiabetic Men: MRFIT Screenees
*Serum cholesterol >200 mg/dl, smoking, SBP >120 mmHg
Stamler J, et al. Diabetes Care. 1993;16:434-444.
0
20
40
60
80
100
120
140
None One onlyAge-a
dju
ste
d C
VD
death
rate
per
10,0
00 p
ers
on-y
ears
All three
No diabetes Diabetes
Two only
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0
1
2
3
4
5
6
TotalCholesterol
Triglycerides HDL-C LDL-C
Normal
IFG
IGT
IFG/IGT
Diabetes
Impaired Fasting Glucose and Impaired Glucose Tolerance Have Distinct Lipoprotein and Apolipoprotein Changes: The Insulin Resistance Atherosclerosis Study
J Clin Endocrinol Metab 98: 1622–1630, 2013
mm
ol/
l
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ΕΠΙΠΕΔΑ ΛΙΠΙΔΑΙΜΙΚΩΝ ΠΑΡΑΜΕΤΡΩΝ ΣΕ ΑΣΘΕΝΕΙΣ ΜΕ
ΜΕΤΑΒΟΛΙΚΟ ΣΥΝΔΡΟΜΟ ΚΑΙ ΣΠΛΑΧΝΙΚΗ ΠΑΧΥΣΑΡΚΙΑ
mg/dl Ασθενείς (n=105)
Ομάδα ελέγχου(n=70)
p
TCHOL 237 226 NS
LDL CHOL 145 143 NS
HDL CHOL A 42Γ 52
5163
<0.001<0.001
TRG 213 124 <0.001
Αpo A1 Α 117Γ 124
135145
<0.001<0.001
Apo B 112 98 <0.01
I Gazi et al: Metabolism 2006;55:885-891
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Selby JV et al. Am J Manag Care. 2004;10(part 2):163-70.
Conclusion : Every 3 out of 4 diabetic suffers from dyslipidemia
Globally, dyslipidemia is a widespread condition in diabetics
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• Elevated total TG
• Postprandial Hyperlipemia
• LDL-C is not usually high
• Small, dense LDL
• Reduced HDL-C
• ↑ HDL 3 and ↓ HDL1 and HDL 2
Dyslipidemia in DM and IRS
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Adipose Tissue Is an Endocrine Organ:Its Function in Health and Disease
Reprinted in adapted form from Trayhurn P, Wood IS. Br J Nutr.2004;92:347–355, with permission of Cambridge University Press. | Eckel RH, et al. Lancet. 2005;365:1415–1428. | Lyon CJ, et al. Endocrinology. 2003;144:2195–2200.
CRP = C-reactive protein; IL-6 = interleukin-6; TNFα = tumor necrosis factor-alpha
Inflammation Atherogenic Dyslipidemia
Type 2 Diabetes
Thrombosis
Atherosclerosis
Hypertension Lipoprotein lipase
Angiotensinogen IL-6
CRP
Plasminogen
activator inhibitor-1
(PA-1)
Insulin
Lactate
Resistin
Leptin
Adiponectin
TNF
Adipsin
(Complement D)
Free Fatty Acids
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Mechanisms of DM Dyslipidemia
Fat Cells Liver
Insulin
IR X
FFA
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Fat Cells Liver
Insulin
IR X
TG
Apo B
VLDL
VLDL
FFA
Mechanisms of DM Dyslipidemia
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(hepatic
lipase)
Fat Cells Liver
Kidney
Insulin
IR X
(CETP)
CE
TG
Apo B
VLDL
HDL
TGApo A-1
FFA
VLDL
Mechanisms of DM Dyslipidemia
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(hepatic
lipase)
Fat Cells Liver
Kidney
Insulin
IR X
(CETP)
CE
TG
Apo B
VLDL
(CETP)
HDL
(lipoprotein or hepatic lipase)
sd LDLLDL
TGApo A-1
TGCE
FFA
VLDL
Mechanisms of DM Dyslipidemia
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Plasma lipoprotein profile of a nonobese or obese individual with functional adipose tissue versus the profile of a viscerally obese individual with ectopic
fat and dysfunctional adipose tissue.
André Tchernof, and Jean-Pierre Després Physiol Rev 2013;93:359-404
©2013 by American Physiological Society
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Atherosclerosis 239 (2015) 483-495
Cell Cycle 7:20, 3162-3170; 15 October 2008
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Atherosclerosis 239 (2015) 483-495
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Atherosclerosis 239 (2015) 483-495
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Mean (±SEM) time course of fractional hepatic de novo lipogenesis (DNL) during the fasting period (between 10 h and 17.5 h fasted) and after intake of the meal (0–240 min) in the lean
(◯; n = 6) and overweight (•; n = 7) men.
Iva Marques-Lopes et al. Am J Clin Nutr 2001;73:253-261
©2001 by American Society for Nutrition
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FoxO1 integrates insulin signaling to VLDL production
Cell Cycle 7:20, 3162-3170; 15 October 2008
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Atherosclerosis 239 (2015) 483-495
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Apolipoprotein C-III and hepatic triglyceride-rich lipoprotein production.Yao, Zemin; Wang, Yuwei
Current Opinion in Lipidology. 23(3):206-212, June 2012.DOI: 10.1097/MOL.0b013e328352dc70
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Atherosclerosis 239 (2015) 483-495
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Insulin
-
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Intestinal lipid synthesis and lipoprotein biogenesis in the small intestine of insulin-sensitive and insulin-resistant obese subjects.
Alain Veilleux et al. Arterioscler Thromb Vasc Biol. 2014;34:644-653
Copyright © American Heart Association, Inc. All rights reserved.
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Intraduodenal coinfusion of glucose with Intralipid increases triglyceride-apolipoprotein B48 (TRL-apoB48) concentrations (A), Fractional catabolic rate (FCR) and production rate (PR) (B).
Changting Xiao et al. Arterioscler Thromb Vasc Biol. 2013;33:1056-1062
Copyright © American Heart Association, Inc. All rights reserved.
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Intestinal Lipoprotein Secretion: Incretin-Based Physiology and
Pharmacology Beyond Glucose
Diabetes 2015;64:2338–2340
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GLP-1- -
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Gut Peptides Are Novel Regulators of Intestinal Lipoprotein Secretion:
Experimental and Pharmacological Manipulation of Lipoprotein Metabolism
Diabetes 2015;64:2310–2318
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New and emerging regulators of intestinal lipoprotein secretion
Atherosclerosis, Volume 233, Issue 2, 2014, 608–615
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Atherosclerosis 239 (2015) 483-495
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ΗΠΑΡ
CE
ΧΟΛΗ
VLDL/LDL
CETP
ΕΞΩΗΠΑΤΙΚΟΙ
ΙΣΤΟΙ:
ΕΛΕΥΘΕΡΗ
ΧΟΛΗΣΤΕΡΟΛΗ
LCATHDL
UCSR-B1 υποδοχείς
LDL-RCE (2)
CE
UC
(2)
(1)
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Diabetes 54:2198–2205, 2005
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Effect of AGE-BSA on the selective uptake of HDL-CE by HepG2 cells.
Nobutaka Ohgami et al. J. Biol. Chem. 2001;276:13348-13355
©2001 by American Society for Biochemistry and Molecular Biology
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Inhibition of ICAM-1 and VCAM-1 expression in HCAECs by (A-IN) rHDL and (A-IGlyc in vitro) rHDL.
Estelle Nobécourt et al. Arterioscler Thromb Vasc Biol. 2010;30:766-772
Copyright © American Heart Association, Inc. All rights reserved.
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Diabetic HDL is less efficient in stimulating EC proliferation.
Pan B, Ma Y, Ren H, He Y, Wang Y, et al. (2012) Diabetic HDL Is Dysfunctional in Stimulating Endothelial Cell Migration and
Proliferation Due to Down Regulation of SR-BI Expression. PLoS ONE 7(11): e48530. doi:10.1371/journal.pone.0048530
http://127.0.0.1:8081/plosone/article?id=info:doi/10.1371/journal.pone.0048530
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Biol Chem. 2015 Jun;396(6-7):573-83
Structural changes in HDL during acute phase response
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Clinical Manifestations of Insulin Resistance
Insulin Resistance
Glucotoxicity; Lipotoxicity; Adiponectin
Atherosclerosis
HDL = high-density lipoprotein; hs-CRP = high-sensitivity C-reactive protein; LDL = low-density lipoprotein; PAI-1 = plasminogen activator inhibitor-1
Visceral Adiposity
▪ Type 2 Diabetes
▪ Glycemic Disorders
▪ Dyslipidemia
-Low HDL
-Small, dense LDL
-Hypertriglyceridemia
▪ Hypertension
-Endothelial dysfunction/ inflammation (hs-CRP)
-Impaired thrombolysis
(PAI-1)
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Stepwise Selection of Risk Factors* in 2693 White Patients with Type 2 Diabetes with Dependent Variable as Time to First Event: UKPDS
Variable
Low-Density Lipoprotein Cholesterol
High-Density Lipoprotein Cholesterol
Hemoglobin A1c
Systolic Blood Pressure
Smoking
P Value
<0.0001
0.0001
0.0022
0.0065
0.056
Coronary Artery Disease (n=280)
Position in Model
First
Second
Third
Fourth
Fifth
*Adjusted for age and sex.
Turner RC, et al. BMJ. 1998;316:823-828.
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European Heart Journal 2019
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JCI Insight. 2019;4(12):e128308
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Peop
le s
uffering e
vents
(%
)SIMVASTATIN: MAJOR VASCULAR EVENTS by YEAR
in DIABETIC PATIENTS
Years of follow-up
PLACEBO
SIMVASTATIN
Benefit/1000(SE) -1(6) 13(8) 34(9) 47(10) 51(15) 58(48)
Logrank p<0.00001
0 1 2 3 4 5 60
5
10
15
20
25
30
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SIMVASTATIN: REVASCULARISATIONS andMAJOR VASCULAR EVENTS by prior DIABETES
SIMVASTATIN PLACEBO Rate ratio & 95% CI
STATIN better PLACEBO better
Vascular event& disease group (10269) (10267)
Revascularisations
Diabetes 260 309(8.7%) (10.4%)
No diabetes 679 896(9.3%) (12.3%)
All patients 939 1205(9.1%) (11.7%)24% SE 4reduction(2P<0.00001)
Major vascular events
Diabetes 601 748(20.2%) (25.1%)
No diabetes 1432 1837(19.6%) (25.2%)
ALL PATIENTS 2033 2585(19.8%) (25.2%)24% SE 3reduction(2P<0.00001)
0.4 0.6 0.8 1.0 1.2 1.4
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Petros Karystinos
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LDL-C and Lipid Changes
1 Yr Mean LDL-C TC TG HDL hsCRP
Simva 69.9 145.1 137.1 48.1 .8
EZ/Simva 53.2 125.8 120.4 48.7 3.3
Δ in mg/dL -16.7 -19.3 -16.7 +0.6 -0.5
Median Time avg
69.5 vs. 53.7 mg/dL
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Primary Endpoint — ITT
Simva — 34.7%
2742 events
EZ/Simva — 32.7%
2572 events
HR 0.936 CI (0.887, 0.988)
p=0.016
Cardiovascular death, MI, documented unstable angina requiring
rehospitalization, coronary revascularization (≥30 days), or stroke
7-year event rates
NNT= 50
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Simva† EZ/Simva†
Male 34.9 33.3
Female 34.0 31.0
Age < 65 years 30.8 29.9
Age ≥ 65 years 39.9 36.4
No diabetes 30.8 30.2
Diabetes 45.5 40.0
Prior LLT 43.4 40.7
No prior LLT 30.0 28.6
LDL-C > 95 mg/dl 31.2 29.6
LDL-C ≤ 95 mg/dl 38.4 36.0
Major Pre-specified Subgroups
Ezetimibe/Simva
Better
Simva
Better
0.7 1.0 1.3†7-year
event rates
*
*p-interaction = 0.023, otherwise > 0.05
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Lancet Diabetes Endocrinol 2016
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Lancet Diabetes Endocrinol 2017
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LDL-C επίπεδα(ITT† και On-Treatment‡ Ανάλυση)
†Όλες οι τιμές LDL-C, συμπεριλαμβανομένων εκείνων μετά από πρόωρη διακοπή της θεραπείας, τυφλή τιτλοποίηση ή τυφλή αλλαγή σε εικονικό φάρμακο‡Εξαιρούνται οι τιμές LDL-C μετά από πρόωρη διακοπή της θεραπείας ή τυφλή αλλαγή στο εικονικό φάρμακο (συμπεριλαμβάνονται οι LDL-C ύστερα από τυφή τιτλοποίηση alirocumab από την 75 στην 150 mg δόση). ITT, Ανάλυση με βάση την πρόθεση για θεραπεία;
Schwartz GG et al. N Engl J Med 2018 (epub ahead of print).
Οn-treatment ανάλυση: στους 4, 12, και 48 μήνες, ο μέσος όρος των LDL-C σε ασθενείς που ήταν σε θεραπεία με alirocumab ήταν 62.7%, 61.1%,
και 54.7% χαμηλότερα από τα αντίστοιχα επίπεδα στην ομάδα του εικονικού φαρμάκου.
Μείωση της δόσης του alirocumab (ή αντικατάσταση με το εικονικό φάρμακο) δεν μπορούσε να πραγματοποιηθεί νωρίτερα από τον 4ο μήνα
Alirocumab ITT Alirocumab On Treatment Placebo ITT Placebo On Treatment
105
90
60
45
15
0
Μέσ
ηLD
L-C
(m
g/d
L)
0 4 48Μήνες μετά την τυχαιοποίηση
75
30
8 12 16 20 24 28 32 36 40 44
2.5
2.0
1.5
1.0
0.5
0
103mg/dL
101mg/dL
66mg/dL
53mg/dL
93mg/dL
96mg/dL
40mg/dL
48mg/dL
38mg/dL
42mg/dL
Μέσ
ηLD
L-C
(m
mo
l/L)
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Αθροιστική επίπτωση Πρωτεύοντος Καταληκτικού Σημείου
Schwartz GG et al. N Engl J Med 2018 (epub ahead of print).
100
90
60
40
10
0
Cu
mu
lati
ve in
cid
ence
(%
)
0 4
Χρόνια μετά την τυχαιοποίησηNumber at riskPlaceboAlirocumab
94629462
88058846
82018345
34713574
629653
70
30
1 2 3
80
50
20
16
12
9
6
3
01 2 3 4
HR 0.85 (95% CI, 0.78–0.93)
P<0.001
0
Kaplan–Meier ποσοστά για το πρωτεύον καταληκτικό σημείο στα 4 χρόνια:• 12.5% (95% CI: 11.5–13.5)
για alirocumab• 14.5% (95% CI: 13.5–15.6)
για εικονικό φάρμακο
Alirocumab Placebo
Για να προληφθεί ένα από τα πρωτεύοντα καταληκτικά συμβάντα, 49ασθενείς (95% CI: 28–164) πρέπει να θεραπευτούν για 4 χρόνια
*Για BL LDL-C ≥ 100
mg/dL, 16 ασθενείς (95% CI, 11 – 34) πρέπει να θεραπευτούν για 4 χρόνια
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Median (Q1, Q3) follow-up: 2.8 (2.3, 3.4) years
Relative risk reductionTreatment baseline glucometabolic status: Pinteraction = 0.98
Absolute risk reductionPinteraction = 0.0019
0.75 0.85 1.0
Alirocumab
n/N (%)
903/9462 (9.5)
HR (95% CI)
Overall
Diabetes
Prediabetes
Placebo
n/N (%)
0.85 (0.78, 0.93)
0.84 (0.74, 0.97)
0.86 (0.74, 1.00)
0.85 (0.70, 1.03)
Subgroup
Normoglycemia
1052/9462 (11.1)
380/2693 (14.1) 452/2751 (16.4)
331/4130 (8.0) 380/4116 (9.2)
192/2639 (7.3) 220/2595 (8.5)
Alirocumab Better
Placebo Better
MACE Incidence
0%1.6%3.2%
ARR (95% CI)
1.6% (0.7%, 2.4%)
2.3% (0.4%, 4.2%)
1.2% (0%, 2.4%)
1.2% (-0.3%, 2.7%)
Alirocumab Better
Placebo Better
x
0.75 0.85 1.0
Alirocumab
n/N (%)
903/9462 (9.5)
HR (95% CI)
Overall
Diabetes
Prediabetes
Placebo
n/N (%)
0.85 (0.78, 0.93)
0.84 (0.74, 0.97)
0.86 (0.74, 1.00)
0.85 (0.70, 1.03)
Subgroup
Normoglycemia
1052/9462 (11.1)
380/2693 (14.1) 452/2751 (16.4)
331/4130 (8.0) 380/4116 (9.2)
192/2639 (7.3) 220/2595 (8.5)
Alirocumab Better
Placebo Better
MACE Incidence
0%1.6%3.2%
ARR (95% CI)
1.6% (0.7%, 2.4%)
2.3% (0.4%, 4.2%)
1.2% (0%, 2.4%)
1.2% (-0.3%, 2.7%)
Alirocumab Better
Placebo Better
Relative and Absolute Risk Reduction with Alirocumab By Glucometabolic Status
Lancet Diabetes Endocrinol 2019; 7: 618–28
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Analysis method for A1c and fasting glucose: repeated-measures mixed effects model; random effects = slope, intercept; fixed effects = treatment, baseline value, and time. Only post-randomization values prior to initiation of diabetes medication were included in the analysis. *Without diabetes = prediabetes or normoglycemia.
Post-randomization A1c, Fasting Glucose, and New-onset Diabetes by Baseline Glucometabolic Status
Alirocumab Placebo Alirocumab Placebo Alirocumab Placebo0
5.5
5.6
5.7
5.8
5.9
6.0
Mean (
95%
CI)
HbA
1c, %
p=0.0008
All Patients
Without Diabetes
Normoglycemia
Prediabetes
HbA1c
Alirocumab Placebo Alirocumab Placebo Alirocumab Placebo0
5.3
5.4
5.5
5.6
5.7
5.8
5.9
Mean (
95%
CI)
Fasting G
lucose, m
mol/L
p=0.84
All Patients
Without Diabetes
Normoglycemia
Prediabetes
Fasting Glucose
Alirocumab Placebo Alirocumab Placebo Alirocumab Placebo
3
6
9
12
15
18
0
Incid
ence (
95%
CI)
, %
New Onset Diabetes
All Patients
Without Diabetes
Normoglycemia
Prediabetes
HR (95% CI) =
1.00 (0.89-1.11)
Alirocumab Placebo Alirocumab Placebo Alirocumab Placebo0
5.5
5.6
5.7
5.8
5.9
6.0
Mean (
95%
CI)
HbA
1c, %
p=0.0008
All Patients
Without Diabetes
Normoglycemia
Prediabetes
HbA1c
Alirocumab Placebo Alirocumab Placebo Alirocumab Placebo0
5.3
5.4
5.5
5.6
5.7
5.8
5.9
Mean (
95%
CI)
Fasting G
lucose, m
mol/L
p=0.84
All Patients
Without Diabetes
Normoglycemia
Prediabetes
Fasting Glucose
Alirocumab Placebo Alirocumab Placebo Alirocumab Placebo
3
6
9
12
15
18
0
Incid
ence (
95%
CI)
, %
New Onset Diabetes
All Patients
Without Diabetes
Normoglycemia
Prediabetes
HR (95% CI) =
1.00 (0.89-1.11)
Alirocumab Placebo Alirocumab Placebo Alirocumab Placebo0
5.5
5.6
5.7
5.8
5.9
6.0
Mean (
95%
CI)
HbA
1c, %
p=0.0008
All Patients
Without Diabetes
Normoglycemia
Prediabetes
HbA1c
Alirocumab Placebo Alirocumab Placebo Alirocumab Placebo0
5.3
5.4
5.5
5.6
5.7
5.8
5.9
Mean (
95%
CI)
Fasting G
lucose, m
mol/L
p=0.84
All Patients
Without Diabetes
Normoglycemia
Prediabetes
Fasting Glucose
Alirocumab Placebo Alirocumab Placebo Alirocumab Placebo
3
6
9
12
15
18
0
Incid
ence (
95%
CI)
, %
New Onset Diabetes
All Patients
Without Diabetes
Normoglycemia
Prediabetes
HR (95% CI) =
1.00 (0.89-1.11)
Lancet Diabetes Endocrinol 2019; 7: 618–28
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Diabetes Obes Metab. 2018
A systematic review and meta-analysis of metabolic and cardiovascular outcomes in patients with diabetes
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Cardiovascular Risk Reduction with Icosapent Ethyl for Hypertriglyceridemia
DOI: 10.1056/NEJMoa1812792
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ΔΙΑΒΗΤΙΚΗ ΔΥΣΛΙΠΙΔΑΙΜΙΑ
• Εξαιρετικά συχνή (και πρώιμη) επιπλοκή των καταστάσεων που
σχετίζονται με αντίσταση των ιστών στη δράση της ινσουλίνης
• Πολύμορφη, αν και συχνότερα έχει τα χαρακτηριστικά της μικτής
αθηρογόνου δυσλιπιδαιμίας
• Συμβάλλει στην παθογένεση των μακροαγγειακών επιπλοκών του
διαβήτη
• Η θεραπευτική αντιμετώπιση της οδηγεί σε σημαντική μείωση του
καρδιαγγειακού κινδύνου