Lipids and Type 1 Diabetes Mellitus

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Lipid Disorders and Their Management in Type 1
Diabetes MellitusRobert H. Eckel,
M.D.University of Colorado at Denver and Health
Sciences Center
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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

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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

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Patients with Type 1 Diabetes in DCCT
p
Conventional
Intensive
Purnell, J.Q. et al Diabetes 44 1220, 1995
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Lipid Levels Adjusted for Age and Waist/Hip Ratio
in Male Type 1 Diabetic and Control Subjects
CACTI
p lt 0.001 for all
Wadwa P et al, Diabetes Care, In Press
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Lipid Levels Adjusted for Age and Waist/Hip Ratio
in Female Type 1 and Control Subjects CACTI
p lt 0.01 for all
Wadwa P et al, Diabetes Care, In Press
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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

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Cholesterol Metabolism in Type 1 Diabetes

• 
  Miettinen TA et al, Diabetes Care 2756, 2004

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Fractional Escape Rates of LDL and Albumin in
Type 1 Diabetes and Controls

• Konnerup K et al,
  Atherosclerosis 170163, 2003

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Intracellular
FC
Extracellular
Apo A-1 Synthesis (liver, intestine)
HDL2
Phospholipid (PL)
Recycling
CE rich HDL
Free Cholesterol (FC) Synthesis
FC
CE CE CE
SR-B1 mediated selective uptake of CE
Lipid poor apo A1
FC
FC
Transfer of CE
ABCA1
LDL
FC
LCAT
CE CE CE CE
FC
FC
HDL3
CE CE
FC
CE
Recyling from Lipoproteins
Lipolysis
FC
Uptake by liver and other tissue
Chol Ester (CE) Droplet
FC
Transfer of FC and PL
Apo B
VLDL
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HDL in Type 1 Diabetes

• HDL cholesterol is typically normal or increased
  in type 1 diabetes!

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A-I/A-II Apolipoprotein Ratios in Men and Women
with Type 1 Diabetes
Men
Women
Eckel, RH et al. Diabetes
30134-135, 1981
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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)

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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

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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)

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Difference Plot for Lipoproteins Type 1
Diabetics with Micro- vs Normoalbuminuria
Sibley, S.D. et al, Diabetes Care 221167, 1999
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Difference Plot for Lipoproteins Type 1
Diabetics with Macro- vs Normoalbuminuria
Sibley, S.D. et al, Diabetes Care
221167, 1999
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Incidence of CHD in Type 1 Diabetes Effect of
Nephropathy
Tuomilehto, J. et al, Diabetologia 41786, 1998
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Incidence of Stroke in Type 1 Diabetes Effect of
Nephropathy
Tuomilehto, J. et al, Diabetologia 41786, 1998
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Dont forget about lipids and lipoproteins in
type 1 diabetes and their to retinopathy and
nephropathy!
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What about lipid and lipoprotein metabolism and
neuropathy in type 1 diabetes?
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Is LPL in the sciatic nerveaffected by diabetes?
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Male Sprague Dawley Rats
STZ injection SQ (55 mg/Kg)
Vehicle
Sample nerve at different time points and
measure LPL activity and mRNA and MNCV
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Plasma Glucose
30
20
Glucose (mM)
10
0
STZ
Vehicle
Ferreira LDMC-B et al, Endo 1431213, 2002
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Motor Nerve Conduction Velocity Measurement
, Plt0.001
0

8
0
6
0
MNCV (m/sec)
4
0
2
0
0
Control
STZ
n4
n5
Ferreira LDMC-B et al, Endo 1431213, 2002
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Sciatic Nerve LPL Activity
vs control, plt0.05
Vehicle
(nmoles FFA/min/g)





Ferreira LDMC-B et al, Endo 1431213, 2002
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Plasma Glucose vs Sciatic LPL Activity
r0.623
plt0.001
6
LPL activity (nmoles FFA/min/g)

4
2
0
0
10
20
30
Glucose (mM)
Ferreira LDMC-B et al, Endo 1431213, 2002
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Plasma Glucose
30
20
Glucose (mM)
10
0
Vehicle
STZ
STZ Ins
Ferreira LDMC-B et al, Endo 1431213, 2002
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LPL Activity After Insulin Treatment
vs STZ, plt0.05
10

LPL
(nmoles FFA/min/g)

5
0
STZ
STZ Ins
Vehicle
Ferreira LDMC-B et al, Endo 1431213, 2002
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Is It Glucotoxicity or Insulin Deficiency?
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With an excess of fat diabetes begins and from
an excess of fat diabetics die . . .

• EP Joslin, 1927

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Cumulative Coronary Artery Disease Mortality in
Type 1 Diabetes
Krolewski, A.S. et al, Am J Card 59750, 1987
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Atherosclerosis and Type 1 Diabetes

• ? mortality
• 9x in men, 14x in women
• Associated with
• age
• duration of disease
• nephropathy
• hypertension
• lipid abnormalities

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? 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

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Intensive Insulin Treatment and BMI DCCT
Purnell, J.Q. et al, JAMA 280142, 1998
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Lipid Levels at Follow-up By Quartile of Weight
Gain in Intensively Treated Individuals DCCT
Purnell, J.Q. et al, JAMA 280142, 1998
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Lipoprotein Cholesterol Distribution after
Intensive Insulinization Effect of Change in
BMI
Purnell, J.Q. et al, JAMA 280145, 1998
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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

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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

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Normal Coronary Calcification
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Severe Coronary Calcification
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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.

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Baseline Lipids/Lipoproteins/Apo B and CAC
Progression CACTI
(mg/dl) CAC Progressors (n101) Controls (n205)
Triglycerides 102 (32-400) 97 (25-584)
HDL cholesterol 50 13 51 15
LDL cholesterol 109 31 108 31
Apo B 99 24 97 26
Maahs DM et al, Circulation 111747,
2005
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Is an increasing CAC score always progression of
CAD?
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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 34823, 2003
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Cardiovascular Disease in Type 1 Diabetes
EURODIAB vs EDC
Orchard, T.J. et al, Int J Epid 27976, 1998
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Multivariate Models of CVD in Men with Type 1
Diabetes
Orchard, T.J. et al, Int J Epid 27980, 1998
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Multivariate Models of CVD in Women with Type 1
Diabetes
Orchard, T.J. et al, Int J Epid 27980, 1998
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? Atherosclerosis in Type 1 Diabetes
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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

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Prevalence, Awareness, Treatment and Control of
Dyslipidemia in Type I- Diabetes CACTI




(6)
(157)
(150)
(109)
(442)
(304)
(41)
(45)
plt0.05, (n)
Wadwa P et al, Diabetes Care, In Press
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Lifestyle Recommendations

• Exercise and diet
• Prescription based on
• metabolic control
• weight goal (e.g. BMI lt 25 kg/m2)
• microvascular complications
• macrovascular complications
• In general,
• predominantly aerobic exercise
• restriction of saturated and trans fat,
  cholesterol /- Kcal

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Management of Increased LDL Cholesterol in
Diabetes Mellitus

• Goal LDL cholesterol lt 100 mg/dl
• Improve glycemia
• Weight reduction
• Exercise
• Diet
• Drugs

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Dietary Treatment of IncreasedLDL Cholesterol in
Diabetes Mellitus

• Reduce saturated and trans fats to lt 7 of Kcal
• Reduce cholesterol to lt 200 mg daily
• Increase dietary fiber to gt 25 g daily

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Drug Treatment of IncreasedLDL-Cholesterol in
Diabetes Mellitus

• HMG CoA reductase inhibitors
• Stanol/Sterol esters
• Bile acid sequestrants (TG)
• Nicotinic acid (glycemia)
• Fibrates

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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 36310, 2000
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Management of IncreasedTriglycerides in Diabetes
Mellitus

• Goal TG lt 130 mg/dl
• Improve glycemia
• Weight reduction
• Exercise
• Diet
• Drugs

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Dietary Treatment of Hypertriglyceridemia in
Diabetes Mellitus

• TG gt 1000 mg/dl lt 10 fat no ETOH
• TG 200-1000 mg/dl
• Step II AHA diet
• if TG increase CHO, monos
• ETOH
• Fiber gt 25 g daily
• Sucrose in moderation

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Drug Treatment of Increased Triglycerides in
Diabetes Mellitus

• Fibrates
• Omega-3 fatty acids
• HMG CoA reductase inhibitors (high dose)
• Metformin, thiazolidinediones
• Nicotinic acid (glycemia)

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Bezafibrate and Lipids/Lipoproteins in Type 1
Diabetes Hyperlipidemia
Baseline Bezafibrate (400 mg for 3 mo)
LDL cholesterol 189 12 mg/dl 13 ?
Triglycerides (mM) 158 48 mg/dl 31 ?
Winocour PH et al, Diabet Med 7736, 1990
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Fish Oils and Lipids/Lipoproteins in Type 1
Diabetes (2.7-7.7 grams of EPADHA/day)

• Mori TA et al Metabolism 1989
• Jensen T et al NEJM, 1989
• Landgraf-Leurs Diabetes, 1990
• MM et al
• Bagdade JD et al Diabetes, 1990
• Mori TA et al Metabolism, 1991
• Bagdade JD et al Diabetologia, 1996
• Rossing P et al Diabetes Care, 1996

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Plasma Triglycerides in Insulin-Dependent
Patients Fed Oil Supplements
p lt 0.05
Values given as median range
Jensen, T. et al. NEJM 3211575, 1989
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Management of Reduced HDL Cholesterol in Diabetes
Mellitus

• Goal HDL cholesterol gt 40 mg/dl
• Improve glycemia
• Weight reduction
• Exercise
• Diet
• Drugs

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What is the evidence that favorably modifying
plasma lipids and lipoproteins in type 1 diabetes
is beneficial?
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Effects of Simvastatin on First Major CVD Event
in Diabetes HPS

• HPS Collaborative
  Group, Lancet 3612010, 2003

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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
• poor glycemic control
• nephropathy
• genetics or other acquired etiologies including
  central adiposity
• Coronary artery disease and stroke occur earlier
  and are major causes of morbidity and mortality
  in type 1 diabetes.
• 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 lt 100
  mg/dl, weight control and triglycerides lt 130
  mg/dl to ? the risk of ASCVD.