Διαβητική δυσλιπιδαιμία

Παθοφυσιολογία και αντιμετώπιση

Βασίλης Τσιμιχόδημος, Παθολόγος-Διαβητολόγος

Αναπληρωτής Καθηγητής Παθολογίας, Πανεπιστήμιο Ιωαννίνων

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

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

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

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

.

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

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

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

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

• 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

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

Mechanisms of DM Dyslipidemia

Fat Cells Liver

Insulin

IR X

FFA

Fat Cells Liver

Insulin

IR X

TG

Apo B

VLDL

VLDL

FFA

Mechanisms of DM Dyslipidemia

(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

(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

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

Atherosclerosis 239 (2015) 483-495

Cell Cycle 7:20, 3162-3170; 15 October 2008

Atherosclerosis 239 (2015) 483-495

Atherosclerosis 239 (2015) 483-495

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

FoxO1 integrates insulin signaling to VLDL production

Cell Cycle 7:20, 3162-3170; 15 October 2008

Atherosclerosis 239 (2015) 483-495

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

Atherosclerosis 239 (2015) 483-495

Insulin

-

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.

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.

Intestinal Lipoprotein Secretion: Incretin-Based Physiology and

Pharmacology Beyond Glucose

Diabetes 2015;64:2338–2340

GLP-1- -

Gut Peptides Are Novel Regulators of Intestinal Lipoprotein Secretion:

Experimental and Pharmacological Manipulation of Lipoprotein Metabolism

Diabetes 2015;64:2310–2318

New and emerging regulators of intestinal lipoprotein secretion

Atherosclerosis, Volume 233, Issue 2, 2014, 608–615

Atherosclerosis 239 (2015) 483-495

ΗΠΑΡ

CE

ΧΟΛΗ

VLDL/LDL

CETP

ΕΞΩΗΠΑΤΙΚΟΙ

ΙΣΤΟΙ:

ΕΛΕΥΘΕΡΗ

ΧΟΛΗΣΤΕΡΟΛΗ

LCATHDL

UCSR-B1 υποδοχείς

LDL-RCE (2)

CE

UC

(2)

(1)

Diabetes 54:2198–2205, 2005

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

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.

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

Biol Chem. 2015 Jun;396(6-7):573-83

Structural changes in HDL during acute phase response

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)

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.

European Heart Journal 2019

JCI Insight. 2019;4(12):e128308

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

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

Petros Karystinos

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

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

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

Lancet Diabetes Endocrinol 2016

Lancet Diabetes Endocrinol 2017

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)

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

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

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

Diabetes Obes Metab. 2018

A systematic review and meta-analysis of metabolic and cardiovascular outcomes in patients with diabetes

Cardiovascular Risk Reduction with Icosapent Ethyl for Hypertriglyceridemia

DOI: 10.1056/NEJMoa1812792

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