1. Diabetic Dyslipidemia and Atherosclerosis Henry Ginsberg, MD

2. Interrelation Between Atherosclerosis and Insulin Resistance
Hypertension
Obesity
Hyperinsulinemia
Diabetes
Hypertriglyceridemia
Small, dense LDL
Low HDL
Hypercoagulability
Insulin Resistance
Atherosclerosis
Interrelation Between Atherosclerosis and Insulin Resistance
Insulin resistance is associated with a panoply of abnormalities, including hypertension, hyperinsulinemia, hypertriglyceridemia with small, dense low-density lipoprotein (LDL) and low high-density lipoprotein (HDL), and hypercoagulability. Of course, insulin resistance is a major risk factor for the development of diabetes. Obesity plays a role both in exacerbating insulin resistance and as an independent risk factor for atherosclerosis. Therefore, any patient with insulin resistance has numerous reasons to be at very high risk for atherosclerosis.

3. Insulin Resistance and Hyperinsulinemia: Clinical Clues
Abdominal obesity
 TG +  HDL-C
Glucose intolerance
Hypertension
Atherosclerosis
Ethnicity
Insulin Resistance and Hyperinsulinemia: Clinical Clues
Clues for the identification of hyperinsulinemic or insulin-resistant patients include abdominal obesity and the presence of hypertriglyceridemia and low HDL cholesterol. Glucose intolerance can sometimes be identified by the fasting glucose level, which may be between 100 and 125 mg/dL. Other characteristics of insulin-resistant individuals are hypertension and the presence of atherosclerotic cardiovascular disease. Also, certain ethnic groups, such as those from Southeast Asia and Native Americans, have very high genetic predispositions to develop insulin resistance.

4. Dyslipidemia in the Insulin Resistance Syndrome
Elevated total TG
Reduced HDL-C
Small, dense LDL-C
Dyslipidemia in the Insulin Resistance Syndrome
Dyslipidemia in patients with the insulin resistance syndrome is characterized by an elevated level of total triglyceride, a reduced level of HDL cholesterol, and the presence of heterogeneity within LDL particles, with an increased proportion of LDL found as small, dense, cholesterol-poor particles.

5. Dyslipidemias in Adults with Diabetes Framingham Heart Study
MEN
WOMEN
Normal DM
Normal DM
Increased cholesterol
Increased LDL
Decreased HDL
Increased triglycerides
14%
11%
12% 9%
13% 9%
21%
19%
21%
16%
10% 8%
24%
15%
25%
17%
Dyslipidemias in Adults with Diabetes: Framingham Heart Study
In an analysis from the Framingham Heart Study, lipid levels in men and women with and without diabetes were compared to levels in the overall U.S. population. For total cholesterol, LDL cholesterol, and triglycerides, the slide portrays the percentage of normal and diabetic men and normal and diabetic women who have values above the 90th percentile for those parameters, and for HDL cholesterol, the data show the proportion of normal and diabetic men and women in Framingham who are below the 10th percentile for the U.S. population. As you can see, for total cholesterol and LDL cholesterol, there were no differences between normal and diabetic men or between normal and diabetic women. However, the diabetic men and women had about twice the prevalence of low HDL cholesterol levels and about twice the prevalence of high triglyceride levels as did their nondiabetic counterparts.
Reference:
Garg A, Grundy SM. Management of dyslipidemia in NIDDM. Diabetes Care 1990;13:
Garg A et al. Diabetes Care 1990;13:

6. Mean Plasma Lipids at Diagnosis of Type 2 Diabetes - UKPDS
MEN
WOMEN
Type 2
Control
Type 2
Control
Number of Pts
TC (mg/dl)
LDL-C (mg/dl)
HDL-C (mg/dl)
TG (mg/dl)
2139
213
139
39**
159* 52
205
132 43
103
1574
224
151*
43*
159*
143
217
135 55 95
Mean Plasma Lipids at Diagnosis of Type 2 Diabetes—UKPDS
In a comparison of diabetic men and women from the United Kingdom Prospective Diabetes Study (UKPDS) and normal healthy control subjects, total cholesterol levels did not differ between the diabetics and the control subjects. For LDL cholesterol, there was also no difference among the men; however, women with type 2 diabetes in UKPDS had slightly but significantly higher LDL cholesterol levels than their normal counterparts. The data are more striking, however, for both HDL cholesterol, which was lower in the diabetics for both genders, and for triglycerides, which were higher in the diabetic subjects than in the normal control subjects.
Reference:
U.K. Prospective Diabetes Study Group. U.K. Prospective Diabetes Study 27: plasma lipids and lipoproteins at diagnosis of NIDDM by age and sex. Diabetes Care 1997;20:
* P<0.001, ** P<0.02 comparing type 2 vs. controll
UKPDS Group. Diabetes Care 1997;20:

7. Relation Between Insulin Resistance and Hypertriglyceridemia
625
500
400
300
200
100
r = 0.73
P <
Plasma TG (mg/dL)
Relation Between Insulin Resistance and Hypertriglyceridemia
Data to support the relation between insulin resistance and diabetic dyslipidemia include the strong correlation between insulin response to an oral glucose challenge and plasma triglyceride levels, as found in this analysis of a large number of subjects studied many years ago at Stanford University. The r value of 0.73 indicates that about half the variability in plasma triglyceride levels in this group could be explained by variability in their insulin resistance as measured by insulin response to oral glucose.
Reference:
Olefsky JM, Farquhar JW, Reaven GM. Reappraisal of the role of insulin in hypertriglyceridemia. Am J Med 1974;57:
100
200
300
400
500
600
Insulin Response to Oral Glucose*
* Total area under 3-hour response curve (mean of 2 tests).
Olefsky JM et al. Am J Med. 1974;57:

8. Association Between Hyperinsulinemia and Low HDL-C
Hyperinsulinemic
Normoinsulinemic
P<0.005
P<0.005
HDL-C (mg/dL)
Association Between Hyperinsulinemia and Low HDL-C
In another study done at Stanford University, Reaven and colleagues found an association between hyperinsulinemia and low HDL cholesterol. In both nonobese and obese subjects, those who had insulin levels above the median had lower HDL cholesterol levels than did those with insulin levels below the median.
Reference:
Reaven GM. Insulin resistance and its consequences: non–insulin-dependent diabetes mellitus and coronary heart disease. In: LeRoith D, Taylor SI, Olefsky JM, eds. Diabetes Mellitus: a Fundamental and Clinical Text. Philadelphia: Lippincott-Raven, 1996:
Nonobese
Obese
Reaven GM. In: LeRoith D et al., eds. Diabetes Mellitus. Philadelphia: Lippincott-Raven,1996:

9. Mechanisms Relating Insulin Resistance and Dyslipidemia
Fat Cells
Liver
FFA X IR
Mechanisms Relating Insulin Resistance and Dyslipidemia (I)
The pathophysiologic basis for diabetic dyslipidemia and its relation to insulin resistance is presented over the next four slides. In the first, we see that insulin-resistant fat cells undergo greater breakdown of their stored triglycerides and greater release of free fatty acids into the circulation. This is a common abnormality seen in both obese and nonobese insulin-resistant subjects and those with type 2 diabetes. Increased fatty acids in the plasma leads to increased fatty acid uptake by the liver; in the fed state and in the presence of adequate glycogen stores, which is the common situation in patients with type 2 diabetes that is reasonably well controlled and certainly the case in the insulin-resistant nondiabetic subject, the liver takes those fatty acids and synthesizes them into triglycerides.
Insulin

10. Mechanisms Relating Insulin Resistance and Dyslipidemia
Fat Cells
Liver
FFA
 TG
 Apo B
 VLDL
VLDL X IR
Mechanisms Relating Insulin Resistance and Dyslipidemia (II)
The presence of increased triglycerides stimulates the assembly and secretion of the apolipoprotein (apo) B and very low density lipoprotein. The result is an increased number of VLDL particles and increased level of triglycerides in the plasma, which leads to the rest of the diabetic dyslipidemic picture.
Insulin

11. Mechanisms Relating Insulin Resistance and Dyslipidemia
Fat Cells
Liver
FFA CE
(hepatic lipase)
 TG
 Apo B
 VLDL
VLDL
(CETP)
HDL X IR TG
Apo A-1
Mechanisms Relating Insulin Resistance and Dyslipidemia (III)
In the presence of increased VLDL in the plasma and normal levels of activity of the plasma protein cholesteryl ester transfer protein (CETP), VLDL triglycerides can be exchanged for HDL cholesterol. That is, a VLDL particle will give up a molecule of triglyceride, donating it to the HDL, in return for one of the cholesteryl ester molecules from HDL. This leads to two outcomes: a cholesterol-rich VLDL remnant particle that is atherogenic, and a triglyceride-rich cholesterol-depleted HDL particle. The triglyceride-rich HDL particle can undergo further modification including hydrolysis of its tryglyceride, probably by hepatic lipase, which leads to the dissociation of the structurally important protein apo A-I. The free apo A-I in plasma is cleared more rapidly than apo A-I associated with HDL particles. One of the sites of clearance is the kidney. In this situation, HDL cholesterol is reduced, and the amount of circulating apo A-I and therefore the number of HDL particles is also reduced.
Kidney
Insulin

12. Mechanisms Relating Insulin Resistance and Dyslipidemia
Fat Cells
Liver
FFA CE
(hepatic lipase)
 TG
 Apo B
 VLDL
VLDL
(CETP)
HDL X IR TG
Apo A-1
(CETP) CE TG
Mechanisms Relating Insulin Resistance and Dyslipidemia (IV)
On the last slide in this series, we see a similar phenomena leading to small, dense LDL. Increased levels of VLDL triglyceride in the presence of CETP can promote the transfer of triglyceride into LDL in exchange for LDL cholesteryl ester. The triglyceride-rich LDL can undergo hydrolysis by hepatic lipase or lipoprotein lipase, which leads to a small, dense, cholesterol-depleted—and, in general, lipid-depleted—LDL particle.
Kidney
Insulin
SD LDL
LDL
(lipoprotein or hepatic lipase)

13. Dyslipidemia in Diabetes
Increased
Decreased
Triglycerides
VLDL
LDL and small dense LDL
Apo B
HDL
Apo A-I
Dyslipidemia in Diabetes
As described in the preceding slides, high triglyceride and high VLDL levels lead to low HDL, fewer HDL particles, and small, dense LDL.

14. LDL Subclass Phenotypes in Diabetes Mellitus
Int B
Men* Diabetic Nondiabetic
Women** Diabetic Nondiabetic
29 87
54 543
28 47
34 85
Percent
21 29
30 9
51 24
36 6
LDL Subclass Phenotypes in Diabetes Mellitus
An increased proportion of LDL particles are small and dense—that is, characteristic of the intermediate and B phenotypes—in both diabetic men and diabetic women compared to their nondiabetic counterparts.
References:
Feingold KR, Grunfeld C, Pang M, Doerrler W, Krauss RM. LDL subclass phenotypes and triglyceride metabolism in non-insulin-dependent diabetes. Arterioscler Thromb 1992;12:
Selby JV, Austin MA, Newman B, Zhang D, Quesenberry CP Jr, Mayer EJ, Krauss RM. LDL subclass phenotypes and the insulin resistance syndrome in women. Circulation 1993;88:
* Feingold KR et al. Arterioscler Thromb 1992; 12:
** Selby JV et al. Circulation 1993; 88:

15. Small Dense LDL and CHD: Potential Atherogenic Mechanisms
Increased susceptibility to oxidation
Increased vascular permeability
Conformational change in apo B
Decreased affinity for LDL receptor
Association with insulin resistance syndrome
Association with high TG and low HDL
Small, Dense LDL and CHD: Potential Atherogenic Mechanisms
Data from in vitro and in vivo studies suggest that small, dense LDL may be particularly atherogenic. In vitro, small, dense LDL appears to be more susceptible to oxidative modification. Because they are smaller, these particles appear to penetrate the endothelial layer of the arterial wall more easily. The apo B molecule in small, dense LDL undergoes a conformational change that leads to decreased affinity for the LDL receptor, therefore allowing this LDL particle to remain in the circulation longer and be more liable to oxidative modification and uptake into the vessel wall. Finally, in population studies and small clinical studies, small, dense LDL is associated with the insulin-resistance syndrome as well as with high triglycerides and low HDL cholesterol.
Reference:
Austin MA, Edwards KL. Small, dense low density lipoproteins, the insulin resistance syndrome and noninsulin-dependent diabetes. Curr Opin Lipidol 1996;7:
Austin MA et al. Curr Opin Lipidol 1996;7:

16. Hypertriglyceridemia and CHD Risk: Associated Abnormalities
Accumulation of chylomicron remnants
Accumulation of VLDL remnants
Generation of small, dense LDL-C
Association with low HDL-C
Increased coagulability
-  plasminogen activator inhibitor (PAI-1)
-  factor VIIc
- Activation of prothrombin to thrombin
Hypertriglyceridemia and CHD Risk: Associated Abnormalities
One should not focus extensively on the atherogenic potential of small, dense LDL to the exclusion of considering hypertriglyceridemia as a risk factor. There are a number of reasons to consider hypertriglyceridemia as at least a marker of increased atherogenic potential. First of all, hypertriglyceridemia is associated with the accumulation of chylomicron remnants, which we know can be atherogenic, and accumulation of VLDL remnants, which are also atherogenic. As previously discussed, hypertriglyceridemia generates small, dense LDL and is the basis for low HDL in the general population. Hypertriglyceridemia is also associated with increased coagulability and decreased fibrinolysis, as shown by its association with increased levels of plasminogen activator inhibitor 1 (PAI-1) and factor VII and its activation of prothrombin to thrombin.

17. TG Metabolism in CHD: Studies in the Postprandial State
Corrected for Fasting TG Level*
Uncorrected
400
300
200
100
300
200
100
CHD Cases
CHD Cases
TG (mg/dL)
Controls
TG Metabolism in CHD: Studies in the Postprandial State
An area that has not been adequately discussed is the abnormalities of triglyceride metabolism in the insulin-resistant diabetic population that occur not only when the patients are fasting, but also after they have eaten a fat-containing meal. Postprandial hypertriglyceridemia has been shown to be a marker for the presence of coronary heart disease. In a study conduced by Patsch and his colleagues several years ago, patients with documented coronary heart disease by angiography were compared with those with normal angiograms. In those with coronary heart disease, there was greater postprandial triglyceride excursion after ingestion of a fat meal. In other studies, this abnormality of postprandial lipemia has been found to be an independent predictor of the presence of atherosclerotic cardiovascular disease independent even of fasting triglyceride levels.
Reference:
Patsch JR, Miesenbock G, Hopferwieser T, Muhlberger V, Knapp E, Dunn JK, Gotto AM Jr, Patsch W. Relation of triglyceride metabolism and coronary artery disease: studies in the postprandial state. Arterioscler Thromb 1992;12:
Controls 2 4 6 8 2 4 6 8
Hours after Test Meal
Error bars = SEM
Patsch JR et al. Arterioscler Thromb 1992;12:

18. Factors Promoting Thromboembolic Disease in Diabetes
Increased plasma fibrinogen
Increased plasminogen activator inhibitor 1
Increased platelet aggregability
Factors Promoting Thromboembolic Disease in Diabetes
Diabetes is associated with hypercoagulability and the predisposition for thromboembolic phenomena. Diabetics have increased fibrinogen, increased PAI-1 levels, and increased platelet aggregability; the latter is particularly a problem in the poorly controlled diabetic.
Reference:
Thompson SG, Kienast J, Pyke SD, Haverkate F, van de Loo JC, for the European Concerted Action on Thrombosis and Disabilities Angina Pectoris Study Group. Hemostatic factors and the risk of myocardial infarction or sudden death in patients with angina pectoris. N Engl J Med 1995;332:
Thompson SG et al. N Engl J Med 1995;332:

19. Adverse Effects on Balance Between Thrombosis and Fibrinolysis in Subjects with Diabetes
Predisposition to thrombosis
- Platelet hyperaggregability
- Elevated concentrations of procoagulants
- Decreased concentration and activity of antithrombotic factors
Predisposition to attenuation of fibrinolysis
- Decreased t-PA activity
- Increased PAI-1
- Decreased concentrations of 2-antiplasmin
Adverse Effects on Balance Between Thrombosis and Fibrinolysis in Subjects with Diabetes
Diabetic patients have an imbalance between thrombosis and fibrinolysis. The predisposition to thrombosis is reflected by platelet hyperaggregability, elevated levels of procoagulants, and decreased concentration and activity of antithrombotic factors. The predisposition to an attenuation of fibrinolysis is marked by decreased tissue plasminogen activator activity, increased PAI-1, and decreased concentrations of "2-antiplasmin.
Reference:
Sobel BE. Potentiation of vasculopathy by insulin: implications from an NHLBI clinical alert. Circulation 1996;93:
Sobel BE. Circulation 1996;93:

20. PAI-1 Activity in Blood in Patients with Type 2 Diabetes
No Diabetes
Diabetes
PAI-1 Activity (AU/mL)
PAI-1 Activity in Blood in Patients with Type 2 Diabetes
Data from McGill et al. showed that PAI-1 activity is elevated in the blood of patients with type 2 diabetes, whether they are lean or obese. Obese subjects both with and without diabetes had much higher levels of PAI-1 than the nonobese subjects. PAI-1 levels are increased with hyperinsulinemia as well as with hypertriglyceridemia.
Reference:
McGill JB, Schneider DJ, Arfken CL, Lucore CL, Sobel BE. Factors responsible for impaired fibrinolysis in obese subjects and NIDDM patients. Diabetes 1994;43:
Lean
Obese
PAI-1 = plasminogen activator inhibitor type 1
McGill JB et al. Diabetes. 1994;43:

21. Infusion of glucose and intralipid
Elevation of PAI-1 Induced by Hyperinsulinemia, Hyperglycemia, and Increased FFA in Blood of Normal Subjects *
Infusion of glucose and intralipid
PAI-I (mg/mL)
Elevation of PAI-1 Induced by Hyperinsulinemia, Hyperglycemia, and Increased FFA in Blood of Normal Subjects
Even in normal subjects, the induction of hyperinsulinemia and hyperglycemia along with increased free fatty acid levels, all of which were induced by an infusion of glucose and intralipid, resulted in a significant increase in plasma levels of PAI-1 over several hours.
Reference:
Calles-Escandon J, Mirza SA, Sobel BE, Schneider DJ. Induction of hyperinsulinemia combined with hyperglycemia and hypertriglyceridemia increases plasminogen activator inhibitor 1 in blood in normal human subjects. Diabetes 1998;47: 2 4 6 8 10 12
Time (h)
Values are mean + SD
*P<0.05 vs saline infusions in same subjects
Calles-Escandon J et al. Diabetes. 1998;47:

22. Pharmacologic Agents for Treatment of Dyslipidemia
Effect on lipoprotein
LDL
HDL
Triglyceride
First-line agents
HMG CoA reductase inhibitor
Fibric acid derivative
Second-line agents
Bile acid binding resins
Nicotinic acid
Pharmacologic Agents for Treatment of Dyslipidemia
In this slide, we can see a summary of the actions of the different classes of drugs available for treating the dyslipidemia of diabetes. The HMG-CoA reductase inhibitors, or statins, are very effective in lowering LDL cholesterol levels in patients with diabetes, have variable but often significant effects on triglyceride levels, and have a modest but potentially important ability to raise HDL cholesterol levels. The fibrates, of which gemfibrozil and fenofibrate are available in the United States, are very good at lowering triglycerides and raising HDL cholesterol levels. These effects of fibrates on triglycerides are usually better than those seen with statins. On the other hand, fibrates often have little effect on LDL cholesterol, and can even result in increased LDL levels in patients with more severe hypertriglyceridemia. Fenofibrate can lower LDL cholesterol significantly when used in patients with very high baseline LDL cholesterol levels. The bile acid–binding resins can achieve additional LDL cholesterol lowering when used with a statin, although GI side effects of the older resins may be particularly problematic in patients with diabetes. Newer, more potent bile acid sequestrants, such as colesevalem, may increase their efficacy in the diabetic population. Niacin is the best agent for raising HDL cholesterol and has significant effects on triglycerides and a modest ability to lower LDL cholesterol. Niacin appears to increase insulin resistance, however, and its use may require modification of the diabetic treatment regimen.
Reference:
American Diabetes Association. Management of dyslipidemia in adults with diabetes. Diabetes Care 2000;23(suppl 1):S57-S60.
In diabetic patients, nicotinic acid should be restricted to <2g/day. Short-acting nicotinic acid is preferred.
American Diabetes Association. Diabetes Care 2000;23(suppl 1):S57-S60.

23. Order of Priorities for Treatment of Diabetic Dyslipidemia in Adults*
LDL cholesterol lowering*
- First choice: HMG CoA reductase inhibitor (statin)
- Second choice: Bile acid binding resin or fenofibrate
HDL cholesterol raising
- Behavior interventions such as weight loss, increased physical activity and smoking cessation
- Glycemic control
- Difficult except with nicotinic acid, which is relatively contraindicated, or fibrates
Triglyceride lowering
- Glycemic control first priority
- Fibric acid derivative (gemfibrozil, fenofibrate)
- Statins are moderately effective at high dose in hypertriglyceridemic subjects who also have high LDL cholesterol
* Decision for treatment of high LDL before elevated triglyceride is based on clinical trial data indicating safety as well as efficacy of the available agents.
Order of Priorities for Treatment of Diabetic Dyslipidemia in Adults
This slide presents the priorities for treating abnormalities of lipid metabolism set by the American Diabetes Association. LDL lowering is the first priority, based on the clinical trials showing marked reductions in morbidity when statins lower LDL cholesterol in the subgroups with diabetes. Raising HDL cholesterol is the second priority, followed by lowering triglycerides. ADA goals for all diabetics include an LDL cholesterol less than or equal to 100 mg/dL, an HDL cholesterol greater than 45 mg/dl (possibly even higher in women), and a triglyceride level less than 200 mg/dL.
Reference:
American Diabetes Association. Management of dyslipidemia in adults with diabetes. Diabetes Care 2000;23(suppl 1):S57-S60.
Adapted from American Diabetes Association. Diabetes Care 2000;23(suppl 1):S57-S60.