Diabetic

Dyslipidemia
Hidden Faces of Diabetes

1
2
3
 What types of lesions
cause MI ?
Coronary stenosis severity prior to MI
100 100
14%

80 80
Coronary stenosis (%)

18%

60 60 68%

40 40

20 20

0 0
Ambrose Little Nobuyoshi Giroud All four
1988 1988 1991 1992 studies
<50% 50%-70% >70%
Falk E, et al. Circulation. 1995;92:657-671.
4
 What types of lesions
cause MI ?
Coronary stenosis severity prior to MI
100 100

si s 14%

80 o 18%
80
n
Coronary stenosis (%)

ste
60
o f 60 68%
ee
gr
40
e de 40

t th
No
20 20

0 0
Ambrose Little Nobuyoshi Giroud All four
1988 1988 1991 1992 studies
<50% 50%-70% >70%
Falk E, et al. Circulation. 1995;92:657-671.
5
 CV Risk Factors in
Diabetes
12
10.0
10

8
Odds Ratio

6.5
6
3.2
4
2.3
2

0
Microalbuminuria Smoking Diastolic BP Cholesterol

Eastman RC, Keen H. Lancet 1997;350 Suppl 1:29-32.

6
Causes of death in
Diabetes

7
Diabetes = Coronary
AD
Why is it so ?

8
DM – Strongest RF for CVD

DM = CHD
9
Duration of T2DM and CVD
48%

29%
24%
21%
15%

≤2 3-5 6-9 10-14 15+

Years after DM Diagnosis

Harris, S et al.; Type 2 Diabetes and Associated Complications in Primary Care in 
Canada: The Impact of Duration of Disease on Morbidity Load. CDA 2003.

10
 Duration of DM - CV
Mortality
4 p for trend <0.001
3.5
Relative Risk

3
2.5
2
1.5
1
0.5
0
<5 6 to 10 11 to 15 16 to 25 26 +

Duration of Diabetes (years)

Cho, et al. J Am Coll Card 2002:40:954.
11
 Life Expectancy with
Diabetes
Years
DM
90 No DM 1600
80 1400
70 1200
60 Diabetes
1000 No Diabetes
50
800
40
600
30
400
20
10 200
0 0
Men Women Mortality rate/100,000

Hux JE, et al. Diabetes in Ontario, an ICES Practice Atlas 2003.

12
Cardiovascular Disease
and T2DM
20%
Prevalence of CV Disease

Diabetes
15%
No Diabetes

10%

5%

0%
Hypertension Heart Disease
Hux JE, et al. Diabetes in Ontario, an ICES Practice Atlas 2003.

13
 Clinical Outcome for
Diabetes
4-year Follow-up
14
12
10
8
%
6
4
2
0
CV Death MI Stroke Dialysis

HOPE / MICRO­HOPE.  Lancet 2000;355:253.

14
 ACS and Diabetes – Up to
25
1 Year
P<0.0001
No Diabetes
20 21.3
% of patients

N = 3429
Diabetes P<0.0001
15 N = 1149
14.4 14.1
P=0.035
10
8.9 7.9
P<0.0001 7.
5 1
3.9
1.8
0
In-Hospital Non-fatal MI 1-y All-Cause 1-y
Mortality Mortality Mortality/MI

Yan R, et al. Can J Cardiol 2003;19(suppl A):260A.

15
 OASIS Study: Total
0.25 Mortality
Diabetes/CVD +, (n = 1148)
RR = 2.88 (2.37-3.49)
Diabetes/CVD -, (n = 569)
0.20 No Diabetes/CVD +, (n = 3503)
No Diabetes/CVD -, (n = 2796)
Event rate

0.15 RR=1.99 (1.52-2.60)

0.10 RR=1.71 (1.44-2.04)

0.05
RR=1.00

0.0

Months  3 6 9 12 15 18 21 24
Malmberg K, et al. Circulation 2000;102:1014–1019.
16
Predictors of CV Risk in DM
Age; But Gender looses
its power
MAU (Microalbuminuria)
W/H Ratio (Abdominal
Obesity)
LP(a) (Lipoprotein small
‘a’)
LDL Cholesterol
Not the Glycemic
levels !!

17
 DM = CAD - Because
• CVD is responsible for 60 - 75% of mortality in
T2DM
• CVD is 4 times more prevalent in diabetes; CADI
is more
• CVD prevalence increases with age, so is T2DM
• CVD in DM is often severe, silent, poor prognosis
and fatal
• Diabetes ↑ mortality, 50% pre adm / recurrent MI
and ACS
• Diabetes erases the protection conferred to
women 18
The Lipid Profile

How to interpret ?

19
 Lipoproteins
HDL LDL

C C
T TG
G
A I, A II B 100

VLDL CM

TG TG
C
B 100 + E B 48+E+C
+C
20
 Atherogenic Particles
Non-HDL-C
Measurements Apolipoprotein B

VLDL VLDLR IDL LDL SDL

TG rich particles Cholesterol rich

21
 The Good, Bad, Ugly and
Deadly
• Total Cholesterol < 200
• ‘Good’ Cholesterols (HDL)
– HDL 1, HDL 2, HDL 3 > 50
• ‘Bad’ Cholesterols (Non HDL) <
150
– LDL, IDL < 100
– VLDL, VLDL-R < 30
– Lp(a), Small LDL < 20
HDL 1 and HDL 2 are protective
22
 Today’s Safer Values
 Total Cholesterol < 200
 Triglycerides < 150
 LDL Cholesterol < 100
preferably < 70
 HDL Cholesterol > 50 (for
women 55)
 Bad Cholesterols the lower the
better
 Good Cholesterols the higher
the better 23


Dyslipidemia in
Diabetes
What are the
Mechanisms ?

24
Atherosclerosis and Insulin
Resistance
Hypertension
Obesity
Hyperinsulinemia
Diabetes
Insulin
Insulin Atherosclerosis
Atherosclerosis
Resistance
Resistance Hyper triglyceridemia
Small, dense LDL
Low HDL
Hyper coagulability

25
Insulin Resistance - Clinical
Clues
• Abdominal obesity
• ↑ TG + ↓ HDL-C
• Glucose intolerance
• Hypertension
• Atherosclerosis
• Ethnicity (Indians, Negroid
races)
26
Dyslipidemia in DM and IRS
• Elevated total TG
LDL Level
• Reduced HDL of
• Small, dense LDL 180 to 220
mg
• ↑ HDL 3 and ↓ HDL1 and HDL

• LDL is not usually high

• Postprandial Hyper lipemia 27
Dyslipidemia in DM and IRS
Increase Decreas
d ed
• Triglycerides • HDL

• VLDL • Apo A-I

• LDL, sLDL

• Apo B

28
Dyslipidemia based on TG
and LDL

29
Dyslipidemia based on TG
and Apo B

30
 Mechanisms of DM
Dyslipidemia
Fat Cells Liver
FFA

IR X

Insulin

31
 Mechanisms of DM
Dyslipidemia
Fat Cells Liver
FFA

 TG VLDL
 Apo B
IR X  VLDL

Insulin

32
 Mechanisms of DM
Dyslipidemia
Fat Cells Liver
FFA CE

 TG (hepatic
VLDL (CETP) HDL
 Apo B lipase)
IR X  VLDL TG
Apo A-
1
Kidney
Insulin

33
 Mechanisms of DM
Dyslipidemia
Fat Cells Liver
FFA CE

 TG (hepatic
VLDL (CETP) HDL
 Apo B lipase)
IR X  VLDL TG
Apo A-1
CE (CETP) TG
Kidney
Insulin
SD
LDL
LDL
(lipoprotein or hepatic lipase)
34
 IR and TG Increase
625
r = 0.73
500 P < 0.0001
Plasma TG (mg/dL)

400
300
200
100

100 200 300 400 500 600

Insulin Response to Oral Glucose
Olefsky JM et al. Am J Med. 1974;57:551-560.

35
 DM, IRS and HDL
Hyperinsulinemi
P < 0.005 c
Normoinsulinemi
HDL-C (mg/dL)

cP < 0.005

Non-obese Obese
Reaven GM. In: Le Roith D et al., eds. Diabetes Mellitus.1996:509-519.

36
 Effects of  TG on CV Risk
• Accumulation of chylomicron
remnants
• Accumulation of VLDL remnants
• Generation of small, dense LDL
• Association with low HDL
• Increased coagulability
•  PAI-1, and  factor VIIc
• Activation of prothrombin to
thrombin 37
Small Dense LDL and CHD
Potential Atherogenic Mechanisms
• Increased susceptibility to oxidation
• Increased vascular permeability
• Conformational change in Apo B
• ↓ Affinity for LDL receptor (↓
clearance)
• Association with insulin resistance
syndrome
Austin MA et al. Curr Opin Lipidol 1996;7:167-171.
• Association with high TG and low HDL
38
Research on DM
Dyslipidemia
What the studies
say ?

39
 Lipid-Lowering Therapy
Accounted for >70% of CV Risk Reduction in Diabetes

80 Steno-2 study
Risk Reducton in CVD Events
Percent of Total Calculated

60 Multfactorial therapy in type 2 DM , to achieve :

BP <130/80, HbA1c < 6.5%, total cholest < 175 mg/dL
40

20

0
Lipids HbA1c Blood Pressure

The most of the CV benefit was attributable to the use of lipid-lowering therapy

Adapted from Gaede P, Pedersen O. Diabetes. 2004;53 (suppl 3):S39–S47.

41
42
43
 c t
e
E f
v e
t i
c a
l i
i p
l t
u
M
44
Clear Excess mortality in DM

45
 CARDS: Type 2 diabetes
outcomes trial
CARDS was a multicenter, randomized, double-blind study

Patient population
 Type 2 diabetes, no
clinically evident CHD Atorvastatin 10 mg/day
 ≥1 other CHD risk
factor (smoking, HTN,
albuminuria, n=2838
retnopathy)
 LDL-C ≤160 mg/dL Placebo
 TG ≤600 mg/dL
 Aged 40–75 years
3.9-year median follow-up

 Primary endpoint: Time to first occurrence of a major CV event, defined as acute CHD
events (ie MI including silent MI, unstable angina, acute fatal CHD, resuscitated
cardiac arrest), coronary revascularizaton, or stroke

46
CARDS, Collaborative AtoRvastatin Diabetes Study Colhoun HM, et al. Lancet. 2004;364:685–696
 CARDS: Efficacy results in patients
with
type 2 diabetes
 CARDS: Atorvastatin 10 mg provided a significant reduction in CV events in
patients with type 2 diabetes and ≥1 risk factor compared with placebo
Incidence of major CV events*
15 Placebo (n=1410); final LDL-C=121 mg/dL Fatal/non-
Stroke fatal MI
Atorvastatin 10 mg (n=1428); final LDL-C=82 mg/dL
Cumulatve incidence (%)

10 37% 48% 42%

RRR RRR RRR
95% CI 95% CI 95% CI
0.17–0.52 0.31–0.89 0.39–0.86
(p=0.001) 1 (p=0.016) 2 (p=0.007) 3
5 ARR=3.2% ARR=1.3% ARR=1.9%

0 //
2.0 0.03.0 1.0 3.9
Time (years)
CARDS was stopped ~2 years early due to significant CV benefits with atorvastatin
Reprinted from The Lancet, 364, Colhoun HM, Betteridge DJ et al. Primary prevention of cardiovascular disease with atorvastatin in type 2
diabetes in the Collaborative Atorvastatin Diabetes Study (CARDS): multicentre randomised placebo-controlled trial, 685–96., Copyright (2004),
1. Colhoun HM, et al. Lancet. 2004;364(9435):685–696; 2. Hitman GA, et al. Diabet Med.with2007;24(12):1313–1321;
47
permission from Elsevier
*Primary endpoint 3. Lipitor Highlights of US Prescribing Information, 2013
 Atorvastatin Study Group in Korea:
Atorvastatin improves dyslipidemia in T2DM

Reduction in LDL-C with atorvastatin 10–40 mg

Atorvastatin Atorvastatin Atorvastatin

10 mg (n=62) 20 mg (n=18) 40 mg (n=69)

Success rate in
achieving target LDL-C at 90.3% 88.9% 91.3%
Week 4

Percent change in LDL-C

–42.5% –52.9% –58.7%
from baseline to Week 8

Atorvastatin 20 mg reduced LDL-C ≥ 50% in T2DM

Asian patients

Atorvastatin Study Group in Korea. Korean J Intern Med 2008;23:22–29

Vascular Protection in
DM
A New Paradigm !!!

49
Glycemic control alone

is hopelessly
inadequate !!

50
The A B C of Diabetes
Management
A A1c (Hb A1c)
B Blood pressure
(goal)
C Cholesterol (all
lipids) 51
 Ticking Clock of T2DM
1. Micro-vascular (DR, DKD, DPN,
DAN)
 At the onset of hyperglycemia
 Control of hyperglycemia
essential
 The A1c target of less than 7
must (A)
2. Macro-vascular (CAD, CVD, PVD)
 At the onset of insulin resistance
 Blood pressure goal of 130/80 (B) 52
53
 Goals inT2DM for VP
Risk Factor Goal or Target
Glycemia Hb A1c < 6.5%
Blood Pressure < 130/80 mm Hg
LDL target < 100 mg%; better <
70
HDL target > 40 men, > 50
women
TG target < 150 mg%
BMI < 25 kg/m2
Physical activityADA, CDA,
AtIDF,
least
WWD 5 days - 2
km/day 54
From Blood Sugar to Blood
Vessel
ACEi (Ramipril) Vasoprotective, anti HT, ↓ ED
ASA (75 to 150 mg Anti inflamm., Anti Platelet
%)
Statin (Powerful, ↓ LDL, TG, Corrects ED,
full) Inflam
BP Goal Vascular damage, LVH, CVA
Glycemic control ↓ Micro vascular ?
Macrovascular
Physical activity ED, ↓ Inflammation, ↑ HDL
Diet and TLC ↓ TG, LDL, Glycemia, Weight
Smoking cessation ↓ ED and Inflammation
55
 ACEi in T2DM - VP
• Antihypertensive, vasoprotective,
antithrombotic, and anti-inflammatory
properties – Inevitable in DM
• Reduce CV events, Reduce atherosclerosis

• Reduce renal disease which is a strong CV

risk factor
• Metabolically ‘friendly’ drugs that prevent
rises in glucose & prevent diabetes
56
• Well-tolerated with few side effects
Treatment of DM
Dyslipidemia
Recommendations

57
 MNT and Dyslipidemia
• Total CHO to be reduced < 50% of
calories
• Saturated fat must reduced to< 7% of
calories
• MUFA and PUFA up to 15% of calories

• Protein in take to be increased – 25% of

cal.
58
• Dietary fiber > 20 g/day -Soy protein,
 Priorities for Treatment
 If all lipid values are normal
1.Lifestyle interventions (TLC)
MNT, Physical Activity, Weight and Waist
reduction

2.Statin in a minimum dose of 10 mg o.d

3.Follow up every one year by full lipid
profile

59
 Priorities for Treatment
 LDL cholesterol lowering – First
priority
1. Lifestyle interventions (TLC)
2. Drugs - First choice – Statin with or
without
3. Cholesterol absorption inhibitors (EZ)
4. Second choice – Niacin and Fibrate
5. Add on – BAR (Bile acid binding
60
resins)
 Priorities for Treatment
 HDL cholesterol raising – Second
priority
1. Lifestyle interventions
2. First choice - Niacin ( doses <2 g/day)
3. Preferably short acting Niacin
4. Fibrates are second choice

61
 Priorities for Treatment
 Triglyceride lowering – Third
priority
1. First choice: Lifestyle interventions
2. Glycemic control is the best Rx for ↓TG
3. Fibrates
4. Niacin
5. High dose statins (if LDL is also high )
62
 Priorities for Treatment
 Triglyceride Lowering
(continued)

• In case of severe hyper triglyceridemia

(> 1000 mg), severe fat restriction (<
10 % of calories ) in addition to
pharmacological therapy is necessary
to reduce the risk of pancreatitis and
lipemia effects 63
 Priorities for Treatment
 Combined Dyslipidemia
1. First choice: Glycemic control +
Statin
2. Glycemic control+ Statin +
Fibrate
3. Glycemic control+ Statin +
Niacin
64
 Drug Rx. – Effect on
Lipoproteins
Pharmacological
LDL HDL TG
Agents
Statins (HMG CoA
Reductase In)
    
Fibrates (PPAR- γ
Activators)    
BAR (Bile Acid Sequestering
Resins)
  

Niacin (Plain or SR)   

ADA. Diabetes Care 2003;26 (suppl 1):S 83-S 86

65
 Drugs for Dyslipidemia

Statins Fibric Acid Niacin

• Rosuvast • Fenofibra • Neasyn
atin te SR
• Atorvasta • Gemfibro • Neasyn
tin zil • Nialip
• Simvasta • Benzafibr • Neaspa
tin ate n
• Lovastati • Clofibrate
n • Ciprofibra
• Pravastat te 66
 Treatment of  LDL
High LDL

Therapeutic Lifestyle Change

Drug Therapy

Therapy of Choice: Statin

Add on drug - EZ , Niacin, BAR

67
Treatment of  HDL
Low HDL

Therapeutic Lifestyle Change

Drug Therapy

Therapy of Choice : Niacin

Add on drug - Finofibrate

68
 Treatment of  TG
High TG

Therapeutic Lifestyle Change

Drug Therapy

Therapy of Choice : Fibrate

Add on drug – Statin, Niacin

69
 Anti Diabetic Drugs and
Lipids
Anti Diabetic LDL
LDL HDL TG Size
Agents
Metformin (Mildly
favourable)
   
Pioglitazone (Very
favourable)    
Rosiglitazone (less
favourable)
   
Sulfonylureas
(Unfavourable)
   
Insulin (Not Atherogenic
at all)
   
70
 2014 NICE lipid guidelines recommend
atorvastatin in all settings where lipid
modification therapy is indicated
Atorvastatin:
• 2° prevention: 80 mg
• 1° prevention (including diabetes and CKD): 20 mg
• (Possibility to increase in some situations)

Type 2 diabetes Type 1 diabetes

(No established CVD) (No CVD)

Do not use a risk

QRISK2 assessment* assessment tool

Age >40 yr
Diabetes for >10 yr
Established nephropathy
10-year CVD risk ≥10% Other CVD risk factors

Offer Offer statin

atorvastatin 20 mg Start with atorvastatin 20 mg
National Institute for Health and Care Excellence
Lipid modification July 2014 http://www.nice.org.uk/Guidance/CG181
 2014 NICE lipid guidelines:
Statin intensity categories are based on LDL-
cholesterol reduction
Statin LDL-cholesterol reduction
Dose (mg/day) 5 10 20 40 80
Fluvastatn – – 21%1 27%1 33%2
Pravastatn – 20%1 24%1 29%1 –
Simvastatn – 27%1 32%2 37%2 42%3§
Atorvastatin – 37%2 43%3 49%3 55%3
Rosuvastatin 38%2 43%3 48%3 53%3 –

1
20–30% reduction in LDL-C: low-intensity statin
2
31–40% reduction in LDL-C: medium-intensity statin

3
>40% reduction in LDL-C: high-intensity statin (atorva 20, 40 or 80 mg)
§ Advice from UK Medicines and Healthcare products Regulatory Agency (MHRA). There is an increased risk of myopathy associated with high-dose (80
mg) simvastatin. The 80 mg dose should be considered only in patients with severe hypercholesterolemia and high risk of cardiovascular complications
who have not achieved their treatment goals on lower doses, when the benefits are expected to outweigh the potential risks

The information used to make the table is from Law MR et al BMJ 2003;326:1423

National Institute for Health and Care Excellence

National Institute for Health and Care Excellence
Lipid modification July 2014 http://www.nice.org.uk/Guidance/CG181 Lipid modification July 2014 http://www.nice.org.uk/Guidance/CG181
 NICE lipid guidelines: non-
statin drugs
• Because there is no evidence of benefit in non-statins:

• Do NOT routinely offer fibrates for primary or secondary

prevention of CVD

• Do NOT offer nicotinic acid (niacin), a bile acid sequestrant

(anion exchange resin) or omega-3 fatty acid compounds for
primary or secondary prevention of CVD

• Do NOT offer the combination of a bile acid sequestrant, fibrate,

nicotinic acid or omega-3 fatty acid compound with a statin for
primary or secondary prevention of CVD

• Heterozygous familial and non-familial hypercholesterolemia:

consider ezetimibe

73
National Institute for Health and Care Excellence
Lipid modification July 2014 http://www.nice.org.uk/Guidance/CG181
American Diabetes Association Standards of Care 2015
• Recommendations for statin treatment and lipid monitoring were revised after
consideration of 2013 ACC/AHA guidelines on the treatment of blood cholesterol
• In light of this fact, the 2015 ADA Standards of Care have been revised to recommend
when to initiate and intensify statin therapy (high versus moderate) based on risk profile
• Treatment initiation (and initial statin dose) is now driven primarily by risk status rather than
LDL cholesterol level

American Diabetes Association. Diabetes Care 2015;38(Suppl. 1):S49–S57

 ACC/AHA guidelines
for statin therapy
Moderate-intensity
High-intensity therapy* Low-intensity therapy‡
therapy†
Atorvastatin 40–80 mg Atorvastatin 10–20 mg Simvastatin 10 mg
Rosuvastatin 20–40 mg Rosuvastatin 5–10 mg Pravastatin 10–20 mg
Simvastatin 20–40 mg Lovastatin 20 mg
Pravastatin 40–80 mg Fluvastatin 20–40 mg
Lovastatin 40 mg Pitavastatin 1 mg
Fluvastatin XL 80 mg
Fluvastatin 40 mg BID
Pitavastatin 2–4 mg

Reprinted from J Am Coll Cardiol, ePub ahead of print, Stone NJ, Robinson J, Lichtenstein AH,
*LDL-C reduced by ≈≥50%; Bairey Merz CN, et al., 2013 ACC/AHA Guideline on the Treatment of Blood Cholesterol to
†
LDL-C reduced ≈30–50%; Reduce Atherosclerotic Cardiovascular Risk in Adults: A Report of the American College of
‡
LDL-C reduced ≈<30% 75
Cardiology/American Heart Association Task Force on Practice Guidelines. Copyright (2013),
BID, twice daily dosing with 2013
Adapted from Stone NJ, et al. J Am Coll Cardiol permission
Nov 7.from
EpubElsevier
ahead
of print
 A meta-analysis of statin trials suggests that
CV benefits outweigh the risk of NOD

• Statin therapy was associated with a 9% increased risk for incident diabetes, but this
does not show CAUSAL RELATIONSHIP
• This is retrospective data and did not consider number of Diabetes risk factors (such
as BMI, HbA1c, family history, lipid level, BP, etc) for both Statin & Placebo groups.
• Statins might be preferentially used in patients at higher risk of diabetes, thus NOD
might happen in those patients who already have risk factors of developing Diabetes,
not exclusively because of Statin usage itself
Anti HT Drugs and Lipids
Anti hypertensive
On Lipids
agents
ACEi and ARBS (Excellent) 
CCBs (Neutral on lipids) 
Diuretics (Unfavourable) 
 Blockers (Very
unfavourable)

 Blockers (Mildly
unfavourable)


77
 To Reiterate
 Glycemic goal alone is not
adequate at all
 CAD must be prevented at all costs

 The A, B, C of Diabetes must be

addressed

 Statins in full dose  Fibrate or

Niacin
78


Thank you all

79
• New-onset diabetes has been observed in
clinical trials and meta-analyses involving
statin therapy. To explain this association,
three major mechanisms have been
proposed and discussed in the literature.
First, certain statins affect insulin secretion
through direct, indirect or combined effects
80
on calcium channels in pancreatic β-cells.