2. Introduction
.
Dr. Joslin in 1927 said :
I believe the chief cause of premature development of atherosclerosis in
diabetes, save for advancing age, is an excess of fat, an excess of fat in the body, an
excess of in the diet, and an excess of fat in the blood. With an excess of fat diabetes
begins, and with an excess of fat
diabetics die, formerly of coma
and recently of atherosclerosis.
And nowadays, NAFLD, NASH,and NAFPD. ( liver and pancreas).
3. DM mortality
.
Type 2 diabetic patients have 2-5 age-adjusted mortality
from CAD.
CAD is responsible for 70% of mortality in diabetic
patients.
1st attack is fatal in 50% in diabetic patients.
5. Non traditional /Conditional or/
Emerging risk factors:
Triglyceride – rich lipoproteins
(VLDL,IDLP,remnant particles).
Small dense LDL particles.
Homocystien.
Oxidative milieu.
Procoagulant state.
High-sensitivity C- reactive protein (CRP).
Intercellular adhesion molecules.
6. DM = CAD equivalent
Microvascular complications: linked strongly
to hyperglycemia.
All studies confirmed benefit of intensive ttt of
hyperglycemia in its prevention.
Macrovascular complications: linked to
insulin resistance , starts years before onset
of DM, less strong, equivocal(UKPDS) or
even paradoxical (ACCORD,ADVANCE)
outcome in the intensive arm of most studies.
7. Spectrum of Diabetic Dyslipidemia
Diabetic dyslipidemia:
( quantitative and qualitative)
8. Quantitative changes:
High TGs
Reduced HDL cholesterol
Total and LDL cholesterol are usually similar
to non diabetic
High remnant particles.
High levels of small dense LDL particles (
readily oxidized and very atherogenic ) .
Increased postprandial lipemia.
Increased coagulant factors: fibrinogen, F VII,
and plasminogen activator- inhibiting factor 1.
9. Qualitative / compositional changes:
oxidized lipoproteins.
Glycated lipoproteins
Oxidized, glycated, or small –sized
lipoprotein particles are poor ligands for LDL
receptors and are shifted to the non receptor
( scavenger pathway)….penetrate artery wall
and form foam cells…. More atherogenic
potential.
10. Hyperytriglyceridemia and CAD?
In general population, TGs have proved to be
independent risk for CAD .
Not all patients with high TGs are at increased risk. Till
now nobody can separate the two groups ( atherogenic
TGs from non atherogenic TGs ).
The concept is that those patients with high TGs with
prevailing small particle size are at risk.
In diabetics, TGs and low HDL have
more strong and consistent relation
to CAD than cholesterol.
12. VLDL HDL
(CETP)
LDL
SD
LDL
TG
Apo B
VLDL
Hepatic lipase
or lipoprotein lipase
(remove PL&TG)
TGCE
Fat Cells Liver
FFA
Kidney
Lipid-poor
Apo A-1
IR X
Insulin
(CETP)
CE
TG
CETP=cholesterol ester transfer protein.
↑CE on
TGRL ↓HDL
↑SD LDL
“Atherogenic Dyslipidemia” of
DM-2 1
2
3
Ginsberg HN. J Clin Invest. 2000;106(4):453-457.
13. Drug induced dyslipidemia
Diuretics, β blockers, glucocorticoids, retinoic acid derivatives.
Interferons α, β, and γ are well known to increase serum triglycerides.
Cyclosporine can increase LDL cholesterol levels,
Sirolimus and HIV 1 protease inhibitors can cause severe
hypertriglyceridemia.
Bexarotene, a new retinoid X receptor selective retinoid, causes
hypertriglyceridemia in up to 80% of patients .
Tamoxifen, by virtue of its estrogenic effects, can also cause severe
hypertriglyceridemia in susceptible individuals but reduces LDL
cholesterol levels.
Aromatase inhibitors can modestly raise LDL cholesterol levels,
especially in comparison with tamoxifen .
Severe hypertriglyceridemia has also been reported anecdotally with
the use of asparaginase, capecitabine, and propofol .
16. RECOMMENDATIONS: LIPID MANAGEMENT
In adults not taking statins, a screening lipid profile is reasonable (E):
At diabetes diagnosis
At the initial medical evaluation
And every 5 years, or more frequently if indicated
Obtain a lipid profile at initiation of statin therapy, and periodically
thereafter. E
American Diabetes Association Standards of Medical Care in Diabetes.
Cardiovascular disease and risk management. Diabetes Care 2017; 40 (Suppl. 1): S75-S87
17. RECOMMENDATIONS: LIPID MANAGEMENT (2)
To improve lipid profile in patients with diabetes, recommend lifestyle
modification A, focusing on:
Weight loss (if indicated)
Reduction of saturated fat, trans fat, cholesterol intake
Increase of ω-3 fatty acids, viscous fiber,
plant stanols/sterols
Increased physical activity
American Diabetes Association Standards of Medical Care in Diabetes.
Cardiovascular disease and risk management. Diabetes Care 2017; 40 (Suppl. 1): S75-S87
18. Recommendations: Lipid
Management (3)
Intensify lifestyle therapy & optimize glycemic
control for patients with: C
Triglyceride levels >150 mg/dL
(1.7 mmol/L) and/or
HDL cholesterol <40 mg/dL (1.0 mmol/L) in
men and <50 mg/dL (1.3 mmol/L) in women
For patients with fasting triglyceride levels ≥ 500
mg/dL (5.7 mmol/L), evaluate for secondary causes
and consider medical therapy to reduce the risk of
pancreatitis. C
American Diabetes Association Standards of Medical Care in Diabetes.
Cardiovascular disease and risk management. Diabetes Care 2017; 40 (Suppl. 1): S75-S87
19. Age Risk Factors
Statin
Intensity*
<40
years
None None
ASCVD risk factor(s)
Moderate or
high
ASCVD High
40–75
years
None Moderate
ASCVD risk factors High
ACS & LDL ≥50 or in patients with
history of ASCVD who can’t tolerate
high dose statin
Moderate +
ezetimibe
>75
years
None Moderate
ASCVD risk factors
Moderate or
high
ASCVD High
ACS & LDL ≥50 or in patients with
Moderate +
Recommendations for Statin Treatment in People with Diabetes
American Diabetes Association Standards of Medical Care in Diabetes.
Cardiovascular disease and risk management. Diabetes Care 2017; 40 (Suppl. 1): S75-S87
20. RECOMMENDATIONS: LIPID MANAGEMENT (4)
In clinical practice, providers may need to adjust
intensity of statin therapy based on individual
patient response to medication (e.g., side effects,
tolerability,
LDL cholesterol levels). E
Ezetimibe + moderate intensity statin therapy provides
add’l CV benefit over moderate intensity
statin therapy alone; consider for patients with a
recent acute coronary syndrome w/ LDL ≥ 50mg/dL
A or in patients with a history of ASCVD who can’t
tolerate high-intensity statin therapy. E
American Diabetes Association Standards of Medical Care in Diabetes.
Cardiovascular disease and risk management. Diabetes Care 2017; 40 (Suppl. 1): S75-S87
21. RECOMMENDATIONS: LIPID MANAGEMENT (5)
Combination therapy (statin/fibrate) doesn’t improve
ASCVD outcomes and is generally not
recommended A.
Consider therapy with statin and fenofibrate for men
with both trigs ≥204 mg/dL (2.3 mmol/L) and HDL
≤34 mg/dL (0.9 mmol/L). B
Combination therapy (statin/niacin) hasn’t
demonstrated additional CV benefit over statins
alone, may raise risk of stroke & is not generally
recommended. A
Statin therapy is contraindicated in pregnancy. B
American Diabetes Association Standards of Medical Care in Diabetes.
Cardiovascular disease and risk management. Diabetes Care 2017; 40 (Suppl. 1): S75-S87
22. High- and Moderate-Intensity
Statin Therapy*
High-Intensity
Statin Therapy
Lowers LDL by
≥50%
Atorvastatin 40-80
mg
Raoشششsuvastatin
20-40 mg
Moderate-Intensity
Statin Therapy
Lowers LDL by 30 -
<50%
Atorvastatin 10-20 mg
Rosuvastatin 5-10 mg
Simvastatin 20-40 mg
Pravastatin 40-80 mg
Lovastatin 40 mg
Fluvastatin XL 80 mg
Pitavastatin 2-4 mg* Once-daily dosing. XL, extended release
American Diabetes Association Standards of Medical Care in Diabetes.
Cardiovascular disease and risk management. Diabetes Care 2017; 40 (Suppl. 1): S75-S87
23. How low is too low?
The Zero-LDL hypothesis
Clinical and pathophysiological evidence supporting the safety of
extremely low LDL levels—The zero-LDL hypothesis
Many patients on proprotein convertase subtilisin/kexin type 9 inhibitors
achieve extremely low low-density lipoprotein cholesterol (LDL-C)
levels.
Extremely low LDL-C levels are associated with even less
cardiovascular risk.
Extremely low LDL-C concentrations cause no clinically relevant side
effects.
Low LDL-C levels due to higher clearance are a marker of adequate
LDL-LDLreceptor function.
Unitat de Medicina Vascular i Metabolisme, Unitat de Recerca en Lipids i Arteriosclerosis, Sant Joan University
Hospital, IISPV, CIBERDEM, Universitat Rovira I Virgili, Reus, Spain , March 2018.
24. Statins and risk of DM?
Increased risk 9% to develop DM with statins
Rise to 12% with intensive ststin ttt
Age <65ys more prone to develop DM
Mechanism: unkown
Perhaps: statins uncover the predisposed pt. or
better survival increases the chance for DM
This modest risk should NOT change statin-
prescribing for DM.
25. Non-HDL Includes All
Atherogenic Lipoprotein Classes
Very low-density lipoprotein
Made in the liver
TG >> CE
Carries lipids from the liver to peripheral tissues
HDL
LDL
IDL
VLDL
AtherogenicLipoproteins
Non-HDL;ApoB100-containing
Intermediate-density lipoprotein
Formed from VLDL due to loss of TG
Also known as a VLDL remnant
Low-density lipoprotein
Formed from IDL due to loss of TG
CE>>TG
High-density lipoprotein
Removes cholesterol from peripheral tissues
Lp(a)
Lipoprotein (a)
Formed from LDL w/ addition of apo (a)?
Very atherogenic
26. 26
Time course of Statin effects
* Time course established
Days Years
LDL-C
lowered*
Inflammation
reduced
Vulnerable
plaques
stabilized
Endothelial
function
restored
Ischemic
episodes
reduced
Cardiac events
reduced*
27. Cardiometabolic Memory/ Legacy
effect
Superiority of beneficial effect of intensive
arm of ttt even years after cessation of ttt in:
hyperglycemia, hypertension, and
dyslipidemia.
Explained: ⇩AGES,⇩cardiac&vascular
remodelling, carry-over effect of life style
modification.
28. Emerging therapeutic strategies potentially
useful in diabetic dyslipidemia.
CETP inhibitors (anacetrapib,evacetrapib) :HDL↑ LDL↓ Inhibit the
transfer of cholesteryl esters and triglycerides between triglyceride-rich
lipoproteins and HDL as well as LDL;
ApoB antisense oligonucleotide ( mipomersen) : LDL↓, Lp(a) ↓ Bind to
apo B-100 mRNA, thereby blocking the translation of the gene product.
FDA approved for familial Hyperlipemia
MTP inhibitor (lomitapide): LDL↓ Inhibit the lipidation of apoB in liver
and enterocytes;FDA approved for familal hyperlipemia.
PCSK 9 antibodies: LDL↓, Lp(a) ↓ Inhibit the lysosomal degradation
of LDL receptors, consequently increasing their cell surface expression;
most promising.
ApoCIII antisense oligonucleotides : Triglyceride ↓ Bind to apoCIII
mRNA, thereby blocking the translation of the gene product and
consequently decrease the seretion of VLDL& chylomicrones.
29. conclusion
Cardiovascular risk is high in T2DM.
Diabetic dyslipidemia is a major link () T2DM
and CV risk.
Diabetic dyslipidemia is characterized by
⇪TG,⇩HDL,⇪small dense LDL,⇪Lp(a).
Diabetic dyslipidemia starts early with insulin
resistance, the CV risk ticks years before the
onset of DM.
Statins is the corner stone in modifying CV
risk besides life style and glucose control.
Almost all diabetic patients need statin
30. Take home message
All diabetic patients above 40ys are
candidates for moderate or
aggressive statin therapy.
The only exception from statin therapy is
patient below 40ys age, with NO other risk
factors.
