Lipid Disorders and Their
Management
in Type 1 Diabetes Mellitus
Robert H. Eckel, M.D.
University of Colorado at Denver and Health
Sciences Center
Lipid Disorders and Their Management
in Type 1 Diabetes Mellitus



Lipid and lipoprotein metabolism in
type 1 diabetes
Relationship between lipids and
lipoproteins and complications of
type 1 diabetes
Management of lipid and lipoprotein
disorders in type 1 diabetes
Lipid Disorders and Their Management
in Type 1 Diabetes Mellitus



Lipid and lipoprotein metabolism in
type 1 diabetes
Relationship between lipids and
lipoproteins and complications of
type 1 diabetes
Management of lipid and lipoprotein
disorders in type 1 diabetes
Patients with Type 1 Diabetes in DCCT
Conventional
Intensive
p
HbA1c (%)
9.2
7.3 <0.00001
TG (mg/dl))
87
80
<0.01
LDL-C
114
111
0.05
Apo B
86
83
0.01
12.5
10.7
0.03
25
27
1x10-14
Lp(a)
BMI (kg/m2)
Purnell, J.Q. et al Diabetes 44: 1220, 1995
Lipid Levels Adjusted for Age and Waist/Hip Ratio
in Male Type 1 Diabetic and Control Subjects:
CACTI
250
Lipids (mg/dl)
200
* p < 0.001 for all
150
Non-DM
T1-DM
100
50
0
TC
LDL
HDL
Trig
Wadwa P et al, Diabetes Care, In Press
Lipid Levels Adjusted for Age and Waist/Hip
Ratio in Female Type 1 and Control Subjects:
CACTI
200
180
160
Lipids (mg/dl)
140
* p < 0.01 for all
120
Non-DM
100
T1-DM
80
60
40
20
0
TC
LDL
HDL
Trig
Wadwa P et al, Diabetes Care, In Press
Lipid and Lipoprotein
Abnormalities in Type 1 Diabetes
Hypertriglyceridemia (VLDL, IDL, remnants,
apo B)
  HDL cholesterol
 Lipoprotein composition


TG
  cholesterol/lecithin
 Lp(a) (renal disease)
 Glycation/oxidation

Cholesterol Metabolism in Type 1
Diabetes
Miettinen TA et al, Diabetes Care 27:56, 2004
Fractional Escape Rates of LDL and
Albumin in Type 1 Diabetes and Controls
Konnerup K et al, Atherosclerosis 170:163, 2003
FC
Extracellular
Intracellular
Phospholipid
(PL)
Free
Cholesterol
(FC)
Synthesis
Apo A-1
Synthesis
(liver, intestine)
Recycling
CE rich
HDL
FC
FC
FC
ABCA1
FC
HDL2
FC
CE
CE
CE
Lipid poor
apo A1
Transfer
of CE
LDL
+ LCAT
CE
FC
HDL3
Recyling
from Lipoproteins
Chol
Ester (CE)
Droplet
CE
FC
FC
Transfer
of FC and PL
CE
CE
FC CE
CE
CE
SR-B1
mediated
selective
uptake of CE
Lipolysis
FC TG
CE
TG
TG
TG
VLDL
TG
TG
Apo B
Uptake by
liver and
other tissue
HDL in Type 1 Diabetes
HDL cholesterol is typically normal
or increased in type 1 diabetes!
A-I/A-II Apolipoprotein Ratios in Men and
Women with Type 1 Diabetes
5
*
*p<0.001
*
A-I/A-II
4
3
2
1
0
Non-DM
T1-DM
Men
Non-DM
T1-DM
Women
Eckel, RH et al. Diabetes 30:134-135, 1981
Factors Related to Lipid and
Lipoprotein Levels in Diabetes








Glycemia
Obesity
Diet (Quantity and Composition)
Route of insulin administration
Genetic hyperlipidemia
Drugs
Alcohol and cigarette smoking
Nephropathy (Proteinuria and CRF)
Lipid Disorders and Their Management
in Type 1 Diabetes Mellitus



Lipid and lipoprotein metabolism in
type 1 diabetes
Relationship between lipids and
lipoproteins and complications of
type 1 diabetes
Management of lipid and lipoprotein
disorders in type 1 diabetes
Renal Disease, Lipids and
Diabetes Mellitus
Microalbuminuria
Often indicates or predicts lipoprotein
abnormalities
 Gross proteinuria
 LDL,  HDL,  VLDL,  Lp(a)
 CRF
 VLDL,  HDL,  Lp(a)

Difference Plot for Lipoproteins: Type 1
Diabetics with Micro- vs Normoalbuminuria
Sibley, S.D. et al, Diabetes Care 22:1167, 1999
Difference Plot for Lipoproteins: Type 1
Diabetics with Macro- vs Normoalbuminuria
Sibley, S.D. et al, Diabetes Care 22:1167, 1999
Incidence of CHD in Type 1
Diabetes: Effect of Nephropathy
Tuomilehto, J. et al, Diabetologia 41:786, 1998
Incidence of Stroke in Type 1
Diabetes: Effect of Nephropathy
Tuomilehto, J. et al, Diabetologia 41:786, 1998
Don’t forget about lipids and
lipoproteins in type 1 diabetes
and their to retinopathy and
nephropathy!
What about lipid and
lipoprotein metabolism
and neuropathy in type
1 diabetes?
Is LPL in the sciatic nerve
affected by diabetes?
Male Sprague Dawley Rats
STZ injection SQ
Vehicle
(55 mg/Kg)
Sample nerve at different time points
and measure LPL activity and mRNA and MNCV
Plasma Glucose
Glucose (mM)
30
20
10
0
STZ
Vehicle
Ferreira LDMC-B et al, Endo 143:1213, 2002
Motor Nerve Conduction Velocity
Measurement *, P<0.001
MNCV (m/sec)
10 0
80
*
60
40
20
0
Control
STZ
n=4
n=5
Ferreira LDMC-B et al, Endo 143:1213, 2002
Sciatic Nerve LPL Activity
LPL
(nmoles FFA/min/g)
* vs control, p<0.05
Vehicle
STZ
6
4
0
*
*
2
0
5
*
*
10
15
20
25
30
*
35
Days
Ferreira LDMC-B et al, Endo 143:1213, 2002
(nmoles FFA/min/g)
LPL activity
Plasma Glucose vs Sciatic LPL Activity
r=0.623
6
p<0.001
4
2
0
0
10
20
30
Glucose (mM)
Ferreira LDMC-B et al, Endo 143:1213, 2002
Plasma Glucose
Glucose (mM)
30
20
10
0
Vehicle STZ + Ins STZ
Ferreira LDMC-B et al, Endo 143:1213, 2002
LPL
(nmoles FFA/min/g)
LPL Activity After Insulin Treatment
* vs STZ, p<0.05
10
5
*
*
0
Vehicle STZ + Ins STZ
Ferreira LDMC-B et al, Endo 143:1213, 2002
LPL activity (nmoles FFA/min/g)
Is It Glucotoxicity or Insulin
Deficiency?
# p<0.05 vs Insulin
* p<0.05 vs Vehicle
7
*
6
5
4
#*
3
#*
2
1
0
Veh
STZ
Insulin
Phloridzin
“With an excess of fat
diabetes begins and from an
excess of fat diabetics die . . .”
EP Joslin, 1927
Cumulative Coronary Artery Disease
Mortality in Type 1 Diabetes
Krolewski, A.S. et al, Am J Card 59:750, 1987
Atherosclerosis and Type 1
Diabetes
 mortality
 9x in men, 14x in women
 Associated with


age
duration of disease
 nephropathy
 hypertension
 lipid abnormalities

 Atherosclerosis in Type 1 Diabetes

Is it simply glucose?

AGES


Oxidative stress
Endothelial dysfunction?
Precursor
 Associated pathophysiology


Hypertension?

Nephropathy
Genetics?
 Metabolic syndrome?


Inflammation and pro-thrombotic state included
Intensive Insulin Treatment and BMI:
DCCT
Purnell, J.Q. et al, JAMA 280:142, 1998
Lipid Levels at Follow-up By Quartile of
Weight Gain in Intensively Treated
Individuals: DCCT
Lipid Level (mg/dl)
250
200
Total Cholesterol
LDL
Triglycerides
HDL
150
100
50
0
First
Second
Third
Fourth
Quartile
Purnell, J.Q. et al, JAMA 280:142, 1998
Lipoprotein Cholesterol Distribution after
Intensive Insulinization : Effect of Change in BMI
Purnell, J.Q. et al, JAMA 280:145, 1998
Coronary Artery Calcium in Type 1 Diabetes
• University of Colorado Health Sciences Center
Department of Preventive Medicine & Biometrics
Department of Medicine
• University of Colorado Hospital
General Clinical Research Center
Division of Cardiology
• The Barbara Davis Center for Childhood Diabetes
• Colorado Heart Imaging Center
Goals
Determine the prevalence of coronary
calcification in Type 1 Diabetes
Identify risk factors for coronary
calcification in Type 1 Diabetes
Measure progression of coronary
calcification in Type 1 Diabetes
Normal Coronary Calcification
Severe Coronary Calcification
Coronary Calcium Score

Peak density and
area in each location
in each coronary
artery is measured.

The Calcium Score
is the total of area
and density of each
calcified lesion.
Baseline Lipids/Lipoproteins/Apo B
and CAC Progression: CACTI
(mg/dl)
CAC Progressors
(n=101)
Controls
(n=205)
102 (32-400)
97 (25-584)
HDL cholesterol
50 ± 13
51 ± 15
LDL cholesterol
109 ± 31
108 ± 31
Apo B
99 ± 24
97 ± 26
Triglycerides
Maahs DM et al, Circulation 111:747, 2005
Is an increasing CAC
score always progression
of CAD?
Predictors of Combined Carotid IMT
Progression in Type 1 Diabetes over Six
Years: DCCT
Univariate






Treatment group
Smoking
Hypertension
LDL/HDL cholesterol
Log AER
HbA1c
Multivariate Adjusted
for Variables not
Affected by Rx





Age
Sex
Smoking
Systolic blood pressure
Treatment Group as a
function of age
DCCT Research Group NEJM 348:23, 2003
Cardiovascular Disease in Type 1
Diabetes: EURODIAB vs EDC
Variable
EURODIAB
EDC
‘n’, gender
608 M
607 F
18.5 yr
286 M
281 F
20.0 yr
8.6% M
7.4% F
8.0% M
8.5% F
(x age, 28)
Diabetes
duration
CVD
prevalence
Orchard, T.J. et al, Int J Epid 27:976, 1998
Multivariate Models of CVD in
Men with Type 1 Diabetes
Std ‘r’
EURODIAB
Age
0.36
HDL chol
-0.38
EDC
Triglycerides 0.23
Hypertension 0.49
p value
0.007
0.008
0.02
0.0001
Orchard, T.J. et al, Int J Epid 27:980, 1998
Multivariate Models of CVD in
Women with Type 1 Diabetes
EURODIAB
Age
HbA1c
Hypertension
EDC
Age
HbA1c
Proteinuria
Std ‘r’
p value
0.21
-0.29
0.16
0.008
0.008
0.032
0.32
0.27
0.31
0.01
0.03
0.006
Orchard, T.J. et al, Int J Epid 27:980, 1998
 Atherosclerosis in Type 1 Diabetes
Metabolic Syndrome
Glycemia
Genetics
Lipid Disorders and Their Management
in Type 1 Diabetes Mellitus



Lipid and lipoprotein metabolism in
type1 diabetes
Relationship between lipids and
lipoproteins and complications of
type1 diabetes
Management of lipid and
lipoprotein disorders in type 1
diabetes
Prevalence, Awareness, Treatment and Control
of Dyslipidemia in Type I- Diabetes: CACTI
60
50
40
Non-DM
T1DM
*
30
20
(45)
(6)
(109)
(41)
(150)
(442)
10
(157)
*
(304)
Percentage
*
*
0
Prevalence
*p<0.05, (n)
Aware
Treated
Controlled
Wadwa P et al, Diabetes Care, In Press
Lifestyle Recommendations
 Exercise

and diet
Prescription based on
metabolic control
 weight goal (e.g. BMI < 25 kg/m2)
 microvascular complications
 macrovascular complications


In general,
predominantly aerobic exercise
 restriction of saturated and trans fat,
cholesterol +/- Kcal

Management of Increased LDL
Cholesterol in Diabetes Mellitus
Goal: LDL cholesterol < 100 mg/dl





± Improve glycemia
± Weight reduction
± Exercise
Diet
Drugs
Dietary Treatment of Increased
LDL Cholesterol in Diabetes
Mellitus



Reduce saturated and trans fats to <
7% of Kcal
Reduce cholesterol to < 200 mg daily
Increase dietary fiber to > 25 g daily
Drug Treatment of Increased
LDL-Cholesterol in Diabetes Mellitus





HMG CoA reductase inhibitors
Stanol/Sterol esters
± Bile acid sequestrants (TG)
± Nicotinic acid (glycemia)
± Fibrates
Atorvastatin and Lipids/Lipoproteins
in Type 1 Diabetes
Baseline
Atorvastatin
(40 mg for 6 wk)
LDL cholesterol
117 ± 35 mg/dl
48 ± 10% 
Triglycerides
(mM)
85 ± 52 mg/dl
12 ± 26% 
Mullen MJ et al, JACC 36:310, 2000
Management of Increased
Triglycerides in Diabetes Mellitus
Goal: TG < 130 mg/dl





Improve glycemia
Weight reduction
Exercise
Diet
Drugs
Dietary Treatment of
Hypertriglyceridemia in Diabetes Mellitus




TG > 1000 mg/dl: < 10% fat; no ETOH
TG = 200-1000 mg/dl:
 Step II AHA diet
 if TG increase: CHO, monos
 ± ETOH
Fiber: > 25 g daily
Sucrose in moderation
Drug Treatment of Increased
Triglycerides in Diabetes Mellitus





Fibrates
Omega-3 fatty acids
HMG CoA reductase inhibitors
(high dose)
± Metformin, thiazolidinediones
± Nicotinic acid (glycemia)
Bezafibrate and Lipids/Lipoproteins in
Type 1 Diabetes + Hyperlipidemia
Baseline
LDL cholesterol
189 ± 12 mg/dl
Bezafibrate
(400 mg for 3
mo)
13 % 
Triglycerides
(mM)
158 ± 48 mg/dl
31 % 
Winocour PH et al, Diabet Med 7:736, 1990
Fish Oils and Lipids/Lipoproteins in Type 1
Diabetes
(2.7-7.7 grams of EPA+DHA/day)
Mori TA et al
 Jensen T et al
 Landgraf-Leurs
MM et al
 Bagdade JD et al
 Mori TA et al
 Bagdade JD et al
 Rossing P et al

Metabolism 1989
NEJM, 1989
Diabetes, 1990
Diabetes, 1990
Metabolism, 1991
Diabetologia, 1996
Diabetes Care, 1996
Plasma Triglycerides in Insulin-Dependent
Patients Fed Oil Supplements
2
* p < 0.05
Triglycerides (mg/dl)
1.5
1
0.5
0
Baseline
Values given as median ± range
Cod-Liver Oil
Olive Oil
Washout
Jensen, T. et al. NEJM 321:1575, 1989
Management of Reduced HDL
Cholesterol in Diabetes Mellitus
Goal: HDL cholesterol > 40 mg/dl
 ± Improve glycemia
 Weight reduction
 Exercise
 Diet
 Drugs
What is the evidence that
favorably modifying plasma
lipids and lipoproteins in
type 1 diabetes is beneficial?
Effects of Simvastatin on First Major
CVD Event in Diabetes: HPS
HPS Collaborative Group, Lancet 361:2010, 2003
Summary and Conclusions


Lipid and lipoprotein disorders in type 1 diabetes are less
common and better managed than in age/gender- matched
controls .
Dyslipidemia, when it occurs in type 1 diabetes relates to




Coronary artery disease and stroke occur earlier and are
major causes of morbidity and mortality in type 1 diabetes.


poor glycemic control
nephropathy
genetics or other acquired etiologies including central adiposity
Relationship to plasma lipids and lipoproteins remains uncertain.
Early evidence demonstrates potential benefit of lipid
altering therapy in favorably modifying microangiopathy.

Although unproven, preventive strategies should be aggressive, e.g.
LDL cholesterol < 100 mg/dl, weight control and triglycerides <
130 mg/dl to  the risk of ASCVD.