Hyperlipidemia in diabetes-etiology, consequences and treatment

Edward Shahady MD

Athero-thrombosis in diabetes
Our concept of atherosclerosis and cardiovascular events has changed significantly over
the last few years. At one time, we believed that gradual narrowing of arteries over time
led to cardiovascular events like stroke and myocardial infarction. We now understand
atherosclerosis as a more dynamic process where plaque instability and plaque rupture
are the primary culprits in cardiovascular events. The arterial endothelium is the site of
plaque formation and endothelium is now the target for therapeutic interventions. A
healthy endothelium contains the enzyme nitric oxide synthase (NSO) that converts L-
arginine into nitric oxide. NO is a powerful vasodilator and it protects the endothelium
from many of the abnormalities that contribute to plaque formation like cell adhesion and
penetration of LDL. Multiple entities like diabetes, hypertension, hyperlipidemia and
smoking damage the endothelium and cause decrease in NOS and therefore NO.
Atherosclerosis is an inflammatory disease where metabolic risk factors like LDL interact
with immune mechanisms to threaten the structural integrity of plaque. The small dense
LDL (SMDLDL) that is increased in the metabolic syndrome and diabetes stimulate
inflammatory cells to secrete degrading enzymes that deplete collagen in the intima of the
arterial wall. This leads to plaque instability and susceptibility to rupture. The key to
plaque stability is the fibrous cap that forms the roof of the cap. Figure 2 demonstrates
the difference between a stable and unstable plaque.
Figure 2
Fibrous cap
Fibrous Cap
Smooth Muscle Cell
Inflammatory Cell Characteristics of Stable and Characteristics of Stable and
Unstable Plaque in the blood Unstable Plaque in the blood
vessel vessel
Activated Macrophage
Foam Cell
Unstable Plaque-eroded endothelium
and thin Fibrous cap
Stable Plaque-non eroded
endothelium and thick Fibrous cap
Atheroma
Atheroma
Adapted from Libby P. Circulation. 1995;91:2844-2850.

The thicker the fibrous cap the more stable the plaque. Integrity of the fibrous cap of the
arterial plaque is dependent on the balance of synthesis and breakdown of the matrix
materials in the cap. Inflammatory forces shift this balance towards the breakdown of
matrix materials and plaque rupture. Thin fibrous caps have an increased amount of
inflammatory cells and are more susceptible to rupture. Therapeutic lifestyle changes and
medications like statins, ACE inhibitors, aspirin and thiazolidinediones (TZDs) stabilize
plaque and reduce the chance of rupture.
Insulin resistance aids in creating the environment for inflammation. The fat cells
(adipocytes) are dysfunctional because of the insulin resistance and are not inhibiting the
release of free acid into the plasma. This increase in circulating FFA contributes to an
increase in hepatic triglycerides. This increased hepatic triglyceride content contributes to
an increase in the production of more atherogenic small dense LDL. The dysfunctional
fat cell also releases other inflammatory cytokines like tissue necrosis factor and
interleukin-6 and the pro-coagulation PAI-1. Figure 3 illustrates all of the abnormalities.
Figure 3
Clotting Clotting
B/P B/P
Triglycerides Triglycerides
Appetite Appetite
Inflammation Inflammation
Inflammation Inflammation

Inflammation
Chronic inflammation and coagulation/fibrinolysis abnormalities are associated with and
predict insulin resistance, type 2 diabetes, and cardiovascular disease. Markers for
inflammation like C-Reactive Protein, interleukin 6 and coagulation/fibrinolysis
abnormality markers like plasminogen activator inhibitor-1 (PAI-1) and fibrinogen (FIB)
can be used to assess the presence of inflammation and abnormalities of the coagulation
system. (39-41)
Vascular impact of the dysfunctional fat cell
Free fatty acids (FFA) are stored as triglycerides in adipocytes and serve as an energy
source during fasting conditions. Insulin is a potent anti-lipolytic hormone and restrains
the release of FFA (lypolysis) from the adipocyte by inhibiting the enzyme lipase. The
impact of insulin resistance on the adipocyte is just as important if not more important
than its impact on muscle and liver. The fat cells of type 2 diabetics and patients with the
metabolic syndrome are resistant to the inhibitory effect of insulin on lypolysis. This
leads to a release of large amounts of FFA into the serum. The FFA increase produces
lipid abnormalities; the most common is increased triglycerides and decreased HDL (the
so called atherogenic dyslipidemia). (38)
The increased triglycerides lead to an increased production of small dense lipoproteins
(SDLDL). The small dense particles contribute to endothelial dysfunction and
inflammation. White cells accumulate and become adherent to the endothelium and along
with the SDLDL enter through the endothelium into the blood vessel intima. Atheroma
and plaque are now formed. This leads to the cardiovascular disease that is associated
with the metabolic syndrome and T2 diabetes. (43) The major driving force for coronary
atherosclerosis in patients with T2 diabetes resides in the triad of low HDL, high
Triglycerides, and small, dense LDL particles. These abnormalities are significantly
predictive of CV events. (44)
Patients with T2 diabetes have increased lipid abnormalities that contribute to higher
rates of CVD. Lipid management aimed at lowering LDL cholesterol, raising HDL
cholesterol, and lowering triglycerides has been shown to reduce macrovascular disease
and mortality in patients with type 2 diabetes.(50) Lifestyle intervention including diet,
increased physical activity and weight loss will help reduce the lipid abnormalities.
Dietary therapy should focus on the reduction of saturated and transfats. At best dietary
therapy can only provide a 30% reduction in lipid levels. Medication will be needed for
further reduction. Glycemic control will lower triglycerides significantly.
The priority of pharmacological therapy is to lower LDL cholesterol or non-HDL
cholesterol if the triglycerides are greater than 200. For LDL lowering in diabetics statins
are the drugs of choice. (43) Other drugs that lower LDL include nicotinic acid,
ezetimibe, bile acid sequestrants, and fenofibrate.

For type 2 diabetics the Heart Protection Study demonstrated a 25% reduction in the first
event rate for major coronary artery events independent of baseline LDL, preexisting
vascular disease, type or duration of diabetes, or adequacy of glycemic control. Similarly
in the Collaborative Atorvastatin Diabetes Study (CARDS), patients with type 2
diabetes randomized to atorvastatin 10 mg daily had a significant reduction in
cardiovascular events including stroke. Other studies \, in high risk groups have
demonstrated that more aggressive therapy with high doses of statins to achieve LDL
levels of <70 mg/dl leads to a significant reduction in further events. Diabetes is
considered a cardiovascular disease equivalent and in the views of many this fact should
encourage clinicians to reduce LDL to <70 mg/d; in all diabetics.
If statins and glycemic control are not successful in attaining goals for HDL and
triglycerides then combination therapy should be attempted. Nicotinic acid, ezetimibe,
bile acid sequestrants, and fenofibrate are agents that should be considered. This
combination is associated with an increased risk for abnormal liver transaminase,
myositis, or rhabdomyolysis. The risk of rhabdomyolysis is not as great when statins are
combined with fenofibrate rather than gemfibrozil. Close monitoring of liver enzymes
and clinical signs of myopathy and rhabdomyolysis is recommended when combining
drugs.
Lipid goals for patients with diabetes.
Lipid Measure Goal
Total Cholesterol <135
LDL <100 mg/dl <70 mg/dl with CVD
Non-HDL <130 mg/dl <100 mg/dl with CVD
Triglycerides <150 mg/dl
HDL >40 mg/dl men >50 mg/dl women
Two recent studies have demonstrated their ability to decrease the level of hsCRP the key
marker for inflammatory risk. Statins stabilize plaque and reduce the chance of rupture.
Statins
Several statins are available for use. Several statins have data to support the reduction in
mortality and morbidity associated with CVD.
Omega 3 Fatty Acids-Fish oils
Omega 3 polyunsaturated fatty acids (n-3 PUFAs) have been responsible for the low
incidence of cardiac disease. The American Heart Association (AHA) recommends
consumption of n-3 PUFAs in the form of oily fish and supplements for prevention of
CVD. These agents have been shown to decrease inflammatory markers of CVD and
protect the arterial endothelium. They can be used for elevated triglycerides. Prescription
Lovaza 4 grams a day in divided doses is recommended. It provides more predictable
results than over the counter fish oils.




Mozaffarian, D. et al. JAMA 2006;296:1885-1899.

Niacin
Long acting niacin in the form of Niaspan (500, 750, 1000 mg) can be used as an adjunct
to lowering LDL and triglycerides and raising HDL. Start with 500 mg and gradually
increase the dose to a maximum of 2000mg a day. Flushing is less with the longer acting
niacin but ASA 325 mg taken 30 minutes before the niaspan may decrease the flushing.
Either taken alone or when added to another lipid lowing medication it can cause
hepatotoxicity. LFTs should be obtained periodically
Fibrates
Fenofibrate (Tricor) is preferred over gemfibrozil (Lopid) because of the lower incidence
of side effects like hepatotoxicity and rhabdomyolysis. This is especially true when
combining a fibrate with a statin. Tricor when combined with a statin is much safer than
Gemfibrozil and a statin. Tricor is an excellent choice for the atherogenic dyslipedemia of
diabetes (high triglycerides and low HDL).
Ezetimibe
Ezetimibe (Zetia) is unique in its action. It inhibits cholesterol absorption in the small
intestine. Since only 1/3 of serum cholesterol is derived from gut absorption the overall
impact of Zetia is not as great as a statin. It is most effective when used in combination
with a statin. When patients are unable to take statins they can be of help. A recent study
in patients with Familial Hyperlipidemia demonstrated a reduction in LDL but no
reduction in carotid artery media thickness. This study calls into question the value of
decreasing LDL with Zetia.
Bile Acid Sequestrants
This class of drugs was the first to be used to demonstrate the decrease in cardiac
mortality with a lowering of cholesterol. They act by binding with intestinal bile acids.
WelChol (colesevelam) is the most commonly used of these agents. They can be used
alone or in combination with a statin to lower cholesterol. They can be very expensive
and create unpleasant GI side effects. Bile acids have recently been associated with a
reduction in blood sugar.
One advantage of this class of drugs is it is a class B drug in pregnancy compared to class
X or contraindicated for statins. If you have a patient who is of child bearing age that you
are not sure that pregnancy can be prevented then this class of drug would be the safest to
use. Once the patient becomes pregnant it may not be advisable to continue the drug.
Residual Risk
The existing statin trials reduce the risk of an event 31% compared to control.

This leaves a residual risk of 69% or greater. Some additional trials HATS, FATS, CLAS
that used a combination of drugs demonstrated risk reduction of up to 92%.. Combination
drugs are indicated when the HDL is low (Niaspan) or the triglycerides are high (fibrates
and Omega 3s). The combination drug with the best mortality profile is Niaspan.