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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

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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


Lipid disorders and their management in type 1 diabetes mellitus l.jpg
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 mellitus3 l.jpg
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 l.jpg
Patients with Type 1 Diabetes in DCCT Mellitus

p

Conventional

Intensive

Purnell, J.Q. et al Diabetes 44: 1220, 1995


Slide6 l.jpg
Lipid Levels Adjusted for Age and Waist/Hip Ratio in MellitusMale Type 1 Diabetic and Control Subjects: CACTI

* p < 0.001 for all

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 l.jpg
Lipid Levels Adjusted for Age and Waist/Hip Ratio in MellitusFemale Type 1 and Control Subjects: CACTI

* p < 0.01 for all

Wadwa P et al, Diabetes Care, In Press


Lipid and lipoprotein abnormalities in type 1 diabetes l.jpg
Lipid and Lipoprotein Abnormalities in Type 1 Diabetes Mellitus

  • 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 l.jpg

Cholesterol Metabolism in Type 1 Diabetes Mellitus

Miettinen TA et al, Diabetes Care 27:56, 2004


Fractional escape rates of ldl and albumin in type 1 diabetes and controls l.jpg

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

Konnerup K et al, Atherosclerosis 170:163, 2003


Intracellular l.jpg

TG TG Diabetes and Controls

CE TG TG

TG TG

FC

FC

Extracellular

Intracellular

Apo A-1

Synthesis

(liver, intestine)

HDL2

Phospholipid

(PL)

Recycling

CE rich

HDL

Free

Cholesterol

(FC)

Synthesis

FC

SR-B1

mediated

selective

uptake of CE

CE

CE

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

FC

Lipolysis

Uptake by

liver and

other tissue

Chol

Ester (CE)

Droplet

FC

Transfer

of FC and PL

Apo B

VLDL


Hdl in type 1 diabetes l.jpg
HDL in Type 1 Diabetes Diabetes and Controls

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 l.jpg

* Diabetes and Controls

*p<0.001

*

A-I/A-II Apolipoprotein Ratios in Men and Women with Type 1 Diabetes

Men

Women

Eckel, RH et al. Diabetes 30:134-135, 1981


Factors related to lipid and lipoprotein levels in diabetes l.jpg
Factors Related to Lipid and Lipoprotein Levels in Diabetes Diabetes and Controls

  • 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 mellitus21 l.jpg
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 l.jpg
Renal Disease, Lipids and Diabetes Mellitus 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 l.jpg
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 l.jpg
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 l.jpg
Incidence of CHD in Type 1 Diabetes: Effect of Nephropathy Macro- vs Normoalbuminuria

Tuomilehto, J. et al, Diabetologia 41:786, 1998


Incidence of stroke in type 1 diabetes effect of nephropathy l.jpg
Incidence of Stroke in Type 1 Diabetes: Effect of Nephropathy

Tuomilehto,J. et al, Diabetologia 41:786, 1998


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Don’t forget about lipids and lipoproteins in type 1 diabetes and their to retinopathy and nephropathy!



Is lpl in the sciatic nerve affected by diabetes l.jpg
Is LPL in the sciatic nerve in type 1 diabetesaffected by diabetes?


Slide35 l.jpg

Male Sprague Dawley Rats in type 1 diabetes

STZ injection SQ

(55 mg/Kg)

Vehicle

Sample nerve at different time points

and measure LPL activity and mRNA and MNCV


Plasma glucose l.jpg
Plasma Glucose in type 1 diabetes

30

20

Glucose (mM)

10

0

STZ

Vehicle

Ferreira LDMC-B et al, Endo 143:1213, 2002


Slide37 l.jpg

1 in type 1 diabetes

0

Motor Nerve Conduction Velocity Measurement

*, P<0.001

0

*

8

0

6

0

MNCV (m/sec)

4

0

2

0

0

Control

STZ

n=4

n=5

Ferreira LDMC-B et al, Endo 143:1213, 2002


Sciatic nerve lpl activity l.jpg

STZ in type 1 diabetes

6

4

LPL

2

0

0

5

10

15

20

25

30

35

Days

Sciatic Nerve LPL Activity

* vs control, p<0.05

Vehicle

(nmoles FFA/min/g)

*

*

*

*

*

Ferreira LDMC-B et al, Endo 143:1213, 2002


Plasma glucose vs sciatic lpl activity l.jpg
Plasma Glucose vs Sciatic LPL Activity in type 1 diabetes

r=0.623

p<0.001

6

LPL activity

(nmoles FFA/min/g)

4

2

0

0

10

20

30

Glucose (mM)

Ferreira LDMC-B et al, Endo 143:1213, 2002


Plasma glucose40 l.jpg
Plasma Glucose in type 1 diabetes

30

20

Glucose (mM)

10

0

Vehicle

STZ + Ins

STZ

Ferreira LDMC-B et al, Endo 143:1213, 2002


Lpl activity after insulin treatment l.jpg
LPL Activity After Insulin Treatment in type 1 diabetes

* vs STZ, p<0.05

10

*

LPL

(nmoles FFA/min/g)

*

5

0

STZ

STZ + Ins

Vehicle

Ferreira LDMC-B et al, Endo 143:1213, 2002


Slide42 l.jpg

7 in type 1 diabetes

*

6

5

LPL activity (nmoles FFA/min/g)

4

# *

# *

3

2

1

0

Veh

STZ

Insulin

Phloridzin

# p<0.05 vs Insulin

* p<0.05 vs Vehicle

Is It Glucotoxicity or Insulin Deficiency?


With an excess of fat diabetes begins and from an excess of fat diabetics die l.jpg

“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 l.jpg
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 l.jpg
Atherosclerosis and Type 1 Diabetes Diabetes

  •  mortality

    • 9x in men, 14x in women

  • Associated with

    • age

    • duration of disease

    • nephropathy

    • hypertension

    • lipid abnormalities


Atherosclerosis in type 1 diabetes l.jpg
DiabetesAtherosclerosis 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 l.jpg
Intensive Insulin Treatment and BMI: DCCT Diabetes

Purnell, J.Q. et al, JAMA 280:142, 1998


Lipid levels at follow up by quartile of weight gain in intensively treated individuals dcct l.jpg
Lipid Levels at Follow-up By Quartile of Weight Gain in Intensively Treated Individuals: DCCT

Purnell, J.Q. et al, JAMA 280:142, 1998


Lipoprotein cholesterol distribution after intensive insulinization effect of change in bmi l.jpg
Lipoprotein Cholesterol Distribution after Intensive Insulinization : Effect of Change in BMI

Purnell, J.Q. et al, JAMA 280:145, 1998


C oronary a rtery c alcium in t ype 1 diabetes l.jpg
C Insulinization : Effect of Change in BMIoronary 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 ImagingCenter


Goals l.jpg
Goals Insulinization : Effect of Change in BMI

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


Slide55 l.jpg

Normal Coronary Calcification Insulinization : Effect of Change in BMI


Slide56 l.jpg

Severe Coronary Calcification Insulinization : Effect of Change in BMI


Slide57 l.jpg

Coronary Calcium Score Insulinization : Effect of Change in BMI

  • 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 l.jpg
Baseline Lipids/Lipoproteins/Apo B and CAC Progression: CACTI

Maahs DM et al, Circulation 111:747, 2005



Predictors of combined carotid imt progression in type 1 diabetes over six years dcct l.jpg

Univariate CACTI

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

Predictors of Combined Carotid IMT Progression in Type 1 Diabetes over Six Years: DCCT

DCCT Research Group NEJM 348:23, 2003


Cardiovascular disease in type 1 diabetes eurodiab vs edc l.jpg
Cardiovascular Disease in Type 1 Diabetes: EURODIAB vs EDC CACTI

Orchard, T.J. et al, Int J Epid 27:976, 1998


Multivariate models of cvd in men with type 1 diabetes l.jpg
Multivariate Models of CVD in Men with Type 1 Diabetes CACTI

Orchard, T.J. et al, Int J Epid 27:980, 1998


Multivariate models of cvd in women with type 1 diabetes l.jpg
Multivariate Models of CVD in Women with Type 1 Diabetes CACTI

Orchard, T.J. et al, Int J Epid 27:980, 1998


Slide68 l.jpg

CACTIAtherosclerosis in Type 1 Diabetes


Lipid disorders and their management in type 1 diabetes mellitus69 l.jpg
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


Prevalence awareness treatment and control of dyslipidemia in type i diabetes cacti l.jpg
Prevalence, Awareness, Treatment and Control of Dyslipidemia in Type I- Diabetes: CACTI

*

*

*

*

(6)

(157)

(150)

(109)

(442)

(304)

(41)

(45)

*p<0.05, (n)

Wadwa P et al, Diabetes Care, In Press


Lifestyle recommendations l.jpg
Lifestyle Recommendations in Type I- Diabetes: CACTI

  • 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 l.jpg
Management of Increased LDL Cholesterol in Diabetes Mellitus in Type I- Diabetes: CACTI

Goal: LDL cholesterol < 100 mg/dl

  • ± Improve glycemia

  • ± Weight reduction

  • ± Exercise

  • Diet

  • Drugs


Dietary treatment of increased ldl cholesterol in diabetes mellitus l.jpg
Dietary Treatment of Increased in Type I- Diabetes: CACTILDL 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 l.jpg
Drug Treatment of Increased in Type I- Diabetes: CACTILDL-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 l.jpg
Atorvastatin and Lipids/Lipoproteins in Type 1 Diabetes in Type I- Diabetes: CACTI

Mullen MJ et al, JACC 36:310, 2000


Management of increased triglycerides in diabetes mellitus l.jpg
Management of Increased in Type I- Diabetes: CACTITriglycerides in Diabetes Mellitus

Goal: TG < 130 mg/dl

  • Improve glycemia

  • Weight reduction

  • Exercise

  • Diet

  • Drugs


Dietary treatment of hypertriglyceridemia in diabetes mellitus l.jpg
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 l.jpg
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 l.jpg
Bezafibrate and Lipids/Lipoproteins in Type 1 Diabetes + Hyperlipidemia

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 l.jpg
Fish Oils and Lipids/Lipoproteins in Type 1 Diabetes Hyperlipidemia(2.7-7.7 grams of EPA+DHA/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


Plasma triglycerides in insulin dependent patients fed oil supplements l.jpg
Plasma Triglycerides in Insulin-Dependent Patients Fed Oil Supplements

* p < 0.05

Values given as median ± range

Jensen, T. et al. NEJM 321:1575, 1989


Management of reduced hdl cholesterol in diabetes mellitus l.jpg
Management of Reduced HDL Cholesterol in Diabetes Mellitus Supplements

Goal: HDL cholesterol > 40 mg/dl

  • ± Improve glycemia

  • Weight reduction

  • Exercise

  • Diet

  • Drugs


Slide86 l.jpg
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 l.jpg

Effects of Simvastatin on First Major CVD Event in Diabetes: HPS

HPS Collaborative Group, Lancet 361:2010, 2003


Summary and conclusions l.jpg
Summary and Conclusions HPS

  • 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 < 100 mg/dl, weight control and triglycerides < 130 mg/dl to  the risk of ASCVD.


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