THE EFFECT OF EXERCISE AND EXTENDED-RELEASE NIACIN ON
C-REACTIVE PROTEIN AND LIPOPROTEIN (A) LEVELS IN INDIVIDUALS
WITH TYPE II DIABETES
A RESEARCH PAPER
SUBMITTED TO THE GRADUATE SCHOOL
IN PARTIAL FULFILLMENT OF THE REQUIREMENTS
FOR THE DEGREE
MASTER OF ARTS
BY
ALVITO REGO
DR. LEONARD KAMINSKY‐ ADVISOR
BALL STATE UNIVERSITY
MUNCIE, INDIANA
JULY, 2012
AKNOWLEDGEMENTS
This project would not have been possible without Dr. Kaminsky. I am genuinely
and eternally indebted to you for your patience, guidance and endless support in trying to
get it done. Words cannot describe the feeling of completing this degree and finally being
a member of the Human Performance Lab. Hope to call you Lenny soon.
To my parents, you have always allowed me to pursue my dreams and I am
thankful. The man I am today has been highly influenced, by God and the strong values
you instilled, not quite sure how it took me eight years to finish this chapter. To Alton
and Ailis, asante sana. This would not have been possible without your help.
Finally, the silver lining to this journey has to be Ashley. Life brought me to
Muncie, ten years ago and my life hasn’t been the same. You started as a friend, only to
become my best friend and now my life partner. Thanks for standing by me all these
years; this is as much yours as it is mine. Aiden is truly our gift and hope to teach him not
to make the same mistakes.
TABLE OF CONTENTS
Acknowledgements………………………………………………………………………i
Table of Contents………………………………………………………………………..ii
Chapter I – Introduction
Hypothesis ………………………………………………………………….…..5
Significance of the problem………………………………………………….....5
Definitions ……………………………………………………………….……..5
Chapter II – Review of Literature
Diabetes Mellitus ……………………………………………..………………..6
Niacin …………………………………………………………………………..8
Lipoprotein (a) …………………………………………………………………12
C –Reactive Protein ……………………………………………………………13
Exercise Training ………………………………………………………………16
Chapter III – Methods
Subjects ……………….……………………………………………………….18
Quiet Testing …………………..………………………………….…………...18
Exercise Testing ………………………..……………………………….…..…19
Blood Work……………………………………..………………………..…….20
Exercise Program ………………………………………..……………………..22
Medication ……………………………………………………………….…….23
Statistical Analysis …………………………………………………………….24
Chapter IV – Results …………………………………………………………………25
Chapter IV – Discussion …………………………………………………………….. 29
ii
References …………………………………………………………………………..33
Chapter I
Introduction
In the United States, the American Diabetes Association reports, 24 million
Americans have diabetes. Of this number, 18 million have been diagnosed, but a
staggering 6 million cases of type II diabetes have gone undiagnosed. Approximately 9095% of these cases are Type II diabetics [1]. Type II diabetes, also known as non-insulin
dependent diabetes mellitus (NIDDM) is a metabolic disease associated with varying
levels of insulin resistance and impaired insulin secretion [2-4]. NIDDM is associated
with obesity, hypertension, hyperglycemia and dyslipidemia[2-5].
Over the past three decades, obesity rates have been rapidly increasing, and are
estimated at 44.3 million as of 2002 [5]. The prevalence of obesity has reached epidemic
proportions, mainly related to sedentary lifestyles and poor nutrition. Eighty percent of
NIDDM cases are obese. Obesity is closely linked with hypertension, dyslipidemia,
glucose intolerance, and insulin resistance, which increases the risk of arteriosclerosis. In
individuals with diabetes, this corresponds to an associated threefold increased risk of
coronary artery disease (CAD)[10,15,16]. NIDDM is associated with increased risk of
macrovascular and microvascular disease, and diabetic neuropathy. Due to this risk, the
American Heart Association (AHA) and the National Cholesterol Educational Program
(NCEP) now recognize diabetes to be a coronary heart disease (CHD) risk
equivalent[17,20]. People with diabetes have a greater risk of mortality from coronary
3
heart disease and stroke. Despite advances in medicine and technology, coronary heart
disease is the leading cause of death in the United States [17-20].
Epidemiological studies have recognized major independent contributing risk
factors in NIDDM patients such as cigarette smoking, high serum cholesterol,
hypertension and other predisposing risk factors including sedentary lifestyle, obesity and
advancing age[8,15]. Recently the development of C-reactive protein (CRP) and
lipoprotein (a) [Lp (a)] are drawing great attention as coronary disease markers [26,31].
Lipoprotein (a) is a sub-fraction of lipoproteins (LDL) and structurally similar to
plasminogen. Hence Lp(a) interferes with the process of fibrinolysis and causes
impairments in plasminogen activation and fibrinolysis [26]. Lp(a) has been shown to
have marked elevation after acute ischemic coronary syndromes, and oxidized Lp(a)
promotes atherosclerosis. The Framingham Study and Lipid Research Clinic have both
shown a 2.3x higher risk for coronary heart disease with Lp(a) levels >10mg/dl [31,34].
According to NCEP, 37% of individuals who possess high risk profiles for CAD,
also have elevated levels of Lp(a) compared to those with low risk profiles . Research has
shown increased concentrations of Lp(a) to be an established risk factor for coronary
heart disease [26,35,39,41], hence a better understanding of Lp(a) and importance to
assess Lp(a) levels in this high risk population. Lp(a) is primarily genetically determined
and varies between racial groups, an observation which has added to the controversy for
screening and therapy.
Since the 1990s, CRP has been strongly associated with prediction of future
coronary events. CRP is an acute-phase protein, which is a systemic marker of
inflammation and tissue damage. In the recent past, CRP has become an
4
emerging/independent risk factor for prediction of myocardial infarction, stroke and
arteriosclerosis [44-49]. CRP levels are measured in assays (hs-CRP) and can be used to
assess cardiovascular risk in conjunction with other factors such as cholesterol levels.
Recently, AHA/CDC released a position statement stating that hs-CRP assays are the best
marker of inflammation at this time [53-54]. This study used these assays to quantify
CRP.
Ridker et al. has shown the relationship between elevated CRP levels and future
cardiovascular events are independent of age, smoking, cholesterol and diabetes. In one
study, 27,000 women followed over eight years showed CRP to be a better indicator of
risk CAD events and atherosclerosis, than LDL cholesterol levels [53].
There is a direct correlation between Body Mass Index (BMI) and CRP. The
Third National Health and Nutritional Examination Survey found higher levels of CRP in
overweight (25-29.9 kg/m²) and obese (30 kg/m²) individuals than in normal weight
individuals. Hence, this investigation looked at the effect of exercise and weight loss on
CRP levels. In addition, CRP levels are thought to be affected by smoking, age, sex,
adiposity and inactivity [45,47,49].
Niacin is well recognized for treating dyslipidemia in adults because of its wide
variety of effectiveness. Niacin has been shown to increase high-density lipoproteins
(HDL) cholesterol as well as decrease triglycerides (TG) and Lp(a) [21-24]. In the past
the prescription of niacin has been discouraged in diabetic populations due to potential
glucose elevation [21-23]. Extended release (ER) niacin (Niaspan®; Abbott Laboratories,
Chicago, IL), specially formulated to reduce side-effects compared to immediate release
or over the counter formulas now available.
5
The ADVENT study showed the best therapy for Lp(a) reduction is niacin. In the
study, a majority of Type II diabetics taking 1500 mg of niacin can successful reduce
Lp(a) and increase HDL cholesterol without much change in glucose levels. Presently,
statin medications are the preferred therapy for treating dyslipidemia, due to their
powerful lowering of LDLs, but there is only a modest effect on HDL cholesterol and TG
[24]. The extended release niacin at doses of 1500mg seems to be the ideal dosage for
less flushing and effective lipid control [22].
This investigation is the first to test the role of exercise and niacin with NIDDM
individuals. Exercise is a vital component in the treatment of Type II diabetes.
Therefore, the emphasis must be placed on regular physical activity in order to control
blood glucose levels and prolong the onset of microvascular, macrovascular and neural
complications [4]. Regular exercise has also been shown to have favorable effects on
HDL and TG levels. Other benefits of regular aerobic exercise include weight loss,
improved aerobic capacity and improved psychological status.
Purpose of the Investigation:
The purpose of this study was to determine the effect of regular aerobic exercise
and extended release niacin on C-reactive protein levels and lipoprotein (a) levels in
individuals with type II diabetes in the management of dyslipedemia.
Hypothesis:
This investigation hypothesis was: 1) CRP levels to decrease after a 16-week
aerobic exercise program in Type II diabetics taking extended release niacin; 2) Lp (a)
levels decrease in Type II diabetics, exercising and taking extended release niacin.
6
Significance of Problem:
The epidemic prevalence of 97 million Americans who are overweight or obese
continues to rise [5]; these individuals are pre-disposed to NIDDM due to sedentary
lifestyles and excess body fat. According to the CDC, the total cost of diabetes mellitus in
the United States in 2002 was $132 billion. Dyslipidemia is directly correlated with
diabetes. There is a need to examine the potential benefits of extended release niacin and
aerobic exercise as treatment in this specific population.
Definitions:
1. Type II Diabetes: A chronic metabolic disease characterized by diminished insulin
secretion or tissue resistance to insulin.
2. C-Reactive Protein (CRP): Is a plasma protein and acute phase reactant released into
the bloodstream as a result of inflammation. CRP is exclusively made in the liver and
released by the body in response to acute injury, infection, or other inflammatory stimuli.
3. Lipoprotein (a):Lp (a) is a low-density lipoprotein produced in the liver with structural
similarity to plasminogen. Increased concentrations are a risk factor for myocardial
infarction and coronary disease.
CHAPTER II
REVIEW OF LITERATURE
Cardiovascular disease is the leading cause of mortality in diabetes patients in the
United States. Already, an estimated 24 million Americans have diabetes and a
furthermore 6 million have been undiagnosed [1]. An estimated 80% of these patients
develop or die of macrovascular disease (CVD) [7]. The combination of an increasing
aging population, obesity epidemic and sedentary lifestyle, the enormity of the disease is
epidemic. This epidemic is associated with an annual medical expense of approximately
$174 billion annually, both direct and indirectly [3]. Once physicians identify greater risk
for CVD, aggressive measures encompassing both long term lifestyle modification and
drug therapy must be the primary goal. The development of type II diabetes has
numerous risk factors ranging from age, race, hypertension, dyslipidemia, obesity, family
history and even socio-economic background [5-6,8]. Majority of these risks are
modifiable through lifestyle changes and pharmacological intervention. Research has
shown a decrease in mortality with the aggressive treatment of these risk factors.
Diabetes Mellitus
Of the 24 million Americans with diabetes, only 5-10% are categorized as having
Type I diabetes. This is caused by B-cell destruction resulting in an absolute deficiency
of insulin production. In these individuals, insulin must be administered by regular
injections or pumps. The other major category is Type II diabetes, which covers 90-95%
8
of all diabetic cases. Although the diagnosis of this metabolic disease usually comes after
the age of 40 due to the increase in obesity levels, inactivity, and diet, there is epidemic
within children and adolescences. According to present figures from the Centers for
Disease Control and Prevention (CDC), among children and teens aged 9-16, 9% of the
population which equates to 9 million are overweight [1].
Type II diabetes is characterized by insulin resistance and reduction of insulin
secretion, which simply means a state of reduced sensitivity of the body tissues to the
action of insulin [8-10]. Insulin resistance has been attributed to hereditary disposition of
the disease, causing mutations of insulin receptors, glucose transporter, and signaling
proteins, coupled with environmental factors such as physical inactivity, diet,
hyperglycemia (glucose toxicity) and the aging process [8-12].
Decades of epidemiological and observational studies, have firmly established
that Type II diabetes is independently correlated to CVD. Besides mortality and
morbidity associated with nephropathy, retinopathy and neuropathy, cardiovascular
disease remains the leading cause of death in type II diabetes [2,15]. In conjunction to
these disease states, other predisposing factors such as obesity, hypertension,
hyperlipidemia, physical inactivity and aging compound the disease. In the Framingham
Study and Heart Study, individuals with diabetes with CVD are at three-fold increased
risk of CVD, compared with non-diabetics without CVD [2-3,6,5-7,10]. According to
Geiss et al CVDs is listed as the cause of death in 65% of persons with diabetes and CVD
mortality was equal between men and women [15].
The pathogenesis of hyperglycemia is not fully understood, but can contribute to
endothelial cell dysfunction which could hasten the development of atherosclerosis.
9
The endothelial cells produce nitric oxide which acts as a vasodilator and prevents
smooth muscle proliferation [3,9,18,13]. Compelling data on endothelial dysfunction has
been noted in patients with diabetics, hypertension and dyslipidemia, but also in
non-diabetics with insulin resistance. This dysfunction inhibits vasodilation and increases
vascular smooth muscle proliferation and thrombogonesis [3,10-13].
The pathophysiology of diabetes is characterized by peripheral insulin resistance,
impaired regulation of hepatic glucose production, and declining Beta-cell function,
eventually leading to Beta-cell failure [3,13,18-19). Skeletal muscle is the main state of
insulin-dependent glucose deposit. Resistance to insulin-dependent glucose uptake and
phosphoralation in muscle is primary in type 2 diabetes. This causes disruption of the
insulin-sensitive glucose transporter Glut 4 in muscle, causing reduction of glucose
transport resulting in increased glucose levels [4,18,20]. Insulin resistance is also found
in hypertension, hyperlipidemia and CVD. This raises the issue if, insulin resistance
occurs from different processes or is unique to type 2 diabetes [2-3,6].
Hyperglycemia can impair both insulin can also cause glycosylation. The process
of glycation occurs due to oxidation of lipoproteins to form complex and irreversible
function to the arterial wall, producing arterial changes leading to susceptibility to
atherosclerosis and possibly ischemia [10,17-20].
Niacin:
Niacin or vitamin B³ is a water soluble vitamin. According to National Cholesterol
Education Program (NCEP) Adult Treatment Panel III (ATP III) guidelines, niacin has
been shown to have a clinically important effect on lipids and lipoproteins [22,31].
Niacin (Nicotinic Acid), in the management of dyslipidemia, has proven to have
10
significant and beneficial effects on most lipoprotein profiles for decades. Clinical trials
have shown niacin to effectively reduce triglycerides, lipoprotein (a), low-density
lipoprotein (LDL), and most importantly increasing high-density lipoprotein cholesterol
(HDL) (17,22,25). To add to the favorable lipid management, niacin has shown to
consistently reducing levels of Lp a by 20-25%, better than any other lipid managing
therapy [23-24].
The advantageous ability to increase HDL is a major contributing factor in reducing
morbidity and mortality for coronary heart disease. This unique ability to increase HDL
offers an important advantage not available with other dyslipidemia therapies [22-27].
Niacin works by inhibiting the release of free fatty acids from adipose tissue
leading to reductions in triglycerides and very- low density-lipoproteins (VLDL)
cholesterol synthesis. It is thought that, niacin inhibits synthesis and secretion of
apolipoprotein B directly reducing triglyceride levels and enhancing VLDL catabolism
[31-32]. During reverse cholesterol transport, the liver absorbs the cholesterol carried by
HDL particles which reduces catabolism of HDL. This increases HDL cholesterol and
makes the main therapeutic benefit of niacin, enhanced HDL levels [29-32].
The attractiveness of niacin has been overshadowed by poor tolerance and low
compliance amongst patients. At present there are three variations of niacin available,
immediate-release (IR), sustained-release (SR) and extended release (ER) formulations,
each with their own distinct safety and efficacy profiles. Over the counter, formulations
have shown to have a lower tolerance level, and adverse reactions such as cutaneous
flushing, rashes, nausea and gastrointestinal effects [27] The American Heart Association
does not recommend these because their efficacy, safety, and tolerability are not
11
established [26]. Niacin has shown other adverse effects including cardiac arrhythmias,
hypotension, dizziness, chills migraine and activation of peptic ulcer disease, but only 5%
of users have been forced to discontinue treatment due to severe symptoms [12,24,27].
According to Capuzzi et al [23] niacin is metabolized by two pathways: the conjugate
pathway in which there is lower affinity and saturation producing nicotinic acid which in
turn causes cutaneous flushing, while the nonconjugate pathway shows higher affinity
and saturation, but results in hepatotoxicity. In comparison the extended release version
(Niaspan; Abbott Laboratories, Chicago, IL) demonstrates a balance between the two
pathways, resulting in fewer incidence of adverse effects and safety.
In the type II diabetic population, hyperglycemia and dyslipidemia are two main
CVD risk factors. The common characteristic in the lipid profile is excessively high
triglycerides and low HDLs. Although niacin has been shown to be the most potent drug
to increase HDLs, it has also been shown to have modest increase blood glucose in
diabetic patients versus non-diabetics. It is estimated that 10-30% of patients with
diabetes have some increase in glucose levels, but only 10% would require to discontinue
niacin [11,23]. According to Grundy et al, HbA1c levels increased 0.07% and 0.29%, but
of no significance [23]. Therefore, there has been reluctance from health providers of
prescribing niacin despite the advantages for reduced CVD risk in treatment of
dyslipidemia in this population. According to Arterial Disease Multiple Intervention
Trial (ADMIT), levels of HbA1c were unchanged from baseline to follow-up [62-63]
while the Assessment of Diabetes Control and Evaluation of the Efficacy of Niaspan
Trial (ADVENT), showed that 10-30% of patients encountered increased blood glucose,
but 70% had no change in glucose levels [23]. These short-term alterations in glycemic
12
control can occur with niacin, less is known on the effect of Niaspan’s glycemic control
with extended absorption times [61-63].
Hence, it is possible for similar diabetic patients to take niacin and it not
contradictive to managing or preventing adverse effects associated with its use. More
research is required to determine whether the rise in blood sugar levels caused by niacin
can be offset by exercise. Health care providers must weigh the risk versus benefits of
using niacin in this population. Majority of diabetic patients can successfully take niacin
without increases in glucose levels. It is possible for clinicians to increase hypogylcemic
therapy, as long as patients are adhering with the tolerance of flushing [14,23].
The greatest challenge facing clinicians is poor adherence with dyslipidemia
therapy, in particular niacin. Niacin has its own unique adverse effects, but mainly
flushing. It is important to mention, that patient education is important to fully achieve
compliance. In order to aid with reduced flushing, aspirin has been introduced to reduce
potential flushing. The flushing caused by niacin is due to prostaglandins, and as acetyl
salicylic acid (aspirin) is a highly effective inhibitor of prostaglandin synthesis [28-29].
Besides, the strategy to reduce potential side effects, which could affect patient
compliance, aspirin has been recommended by the American Diabetes Association as a
primary and secondary prevention measure. As previously documented people with
diabetes are two to fourfold risk of CVD and risk of cardiac events. The Early Treatment
Diabetic Retinopathy Study (ETDRS) and the Hypertension Optimal Treatment (HOT)
Trial have shown that aspirin reduced cardiovascular events as a secondary strategy is
beneficial, in addition to the favorable outcomes it provides to patients on niacin [28,29].
13
Lipoprotein (a)
Lipoprotein(a) also known as Lp(a) is a highly complex macromolecular structure
from the lipoprotein(LDL) class found in human plasma [35-36]. Lp(a) is made up of two
components, a low-density lipoprotein B-100 and glycoprotein apolipoprotein (a)
[apo(a)] attached by a disulphide linkage. Due to the structural complexity of Lp(a), the
physiological and mechanism of action are not completely understood. This is part has
lead to the difficult treatment in the clinical setting. This lipoprotein in only found in
several mammals, including some primates and hedgehogs [40].
Since the early 60’s when Kare Berg first discovered the new lipid class, Lp(a)
has been researched and linked to being a risk factor in CAD, in particular peripheral
vascular disease and cerebrovascular disease[41]. Despite numerous supportive studies, it
is still considered an “emerging” factor compared to conventional risk factors including
smoking and hypertension [39]. The glycoprotein subfraction apo (a) is highly
structurally similar to plasminogen and competes for binding sites to fibrin and
endothelial cells; it may reduce fibrinolysis and encourages thrombosis and
atherosclerosis (39-40). It is also well documented that Lp(a) accumulates on sites of
vascular injury and in vessels with gradient mechanism resulting in the formation of
atherosclerotic plaque [35-39].
Lp(a) levels seems to be genetically linked, and have shown great variability
between individuals and gender, hormones and glycemic control have been shown to
effect levels depending on the apo (a) genotype [42]. Most research on Lp(a) have been
done on Caucasians, but African-Americans and Asians have shown higher levels [38].
Howard et al found African-Americans has 72-118% higher concentrations of Lp(a) than
14
Caucasians. Numerous studies have shown that individuals with high levels of Lp(a)
(>300 mg/dl), to be independent predictor of death [40-43]. Hence, due to poor
outcomes, these patients can be identified and treated aggressively with medication [26].
In other studies, especially the Copenhagen City Heart Study high levels in conjunction
with other risk factors like hypertension, smoking and hypercholestremia, the risk of
myocardial infarction was doubled and ten year myocardial infarction risk was >20%.
There is some controversy in regards to the role of Lp(a) in development of CVD
in the diabetic population. Danesh and Rees et al have shown a correlation, but some
studies have shown no significance. However, there is a balk of evidence linking Lp(a)
with vascular diseases, in particular peripheral artery disease in type II diabetics [31].
Many studies have shown that regular exercise can have beneficial effects in lipid
profiles, hence decreasing CVD mortality and atherosclerosis risk [33]. Investigation into
existing literature regarding exercise training on Lp(a), suggest no affect. Present studies
show single bouts of exercise [55], long-duration exercise and resistance training have
little impact [56]. However, there are a few studies, that have shown elevated Lp a with
high volume weight lifting and prolonged distance running [56,64]. It is theorized that
this elevation on Lp(a) levels in high volume weight lifting, could possibly attributed to
Lp(a) association with tissue damage and repair[55]. Dufaux et al also found that these
elevated levels returned to normal after several days of post-exercise [64]. A possible
explanation for this could be Lp(a) acts as an acute reactant in muscle damage and repair.
C - reactive protein:
The importance of predicting cardiovascular risk and events has lead to the
importance of C-reactive protein (CRP) in the past two decades. Multiple
15
epidemiological studies, have demonstrated a predictive relationship between CRP and
myocardial infarction, stroke, peripheral artery disease and sudden cardiac death [4449,70-71]. So much so, the Center for Disease Control and Prevention (CDC) in
conjunction with the American Heart Association (AHA) published a scientific paper
regarding inflammation markers in the clinical and public practice. The AHA has
acknowledged that CRP is independent of age, smoking, cholesterol and diabetes. Ranges
for CRP are <1.0 mg/l, 1.0-3.0 mg/l and >3.0 mg/l are associated with low, intermediate
and high risk respectively [70]. The average CRP levels in a healthy young adult are 0.8
mg/l[70].
CRP is an acute-phase protein and sensitive marker of inflammation. CRP is
produced in response to infection, tissue injury and inflammation by hepatocytes in the
liver. This acute protein is non-specific marker of inflammation and circulates in the
plasma at low concentrations in healthy individuals [42-43]. Prospective epidemiologic
data signals that CRP is a more powerful predictor of risk than traditional blood lipid
panels especially LDLs [44-49,51]. Patients with near normal or mildly increased total
cholesterol are at 50% probability to experience myocardial infarctions [70-71]. Hence,
the need to screen for CRP in relatively healthy populations who do not have
hypercholesterolemia is necessary. Although the AHA guidelines specify testing for
intermediate and high risk, numerous studies state there is predictive value for future
cardiovascular events in healthy individuals with low to moderate levels [48]. According
to Ridker et al. CRP seems to be the most stable inflammation marker and its long plasma
half-life of 18-20 hours, with an established global standardization in testing, make it the
best predictor [51].
16
Atherosclerosis is defined as a chronic inflammatory disease of the arteries. The
mechanism of CRP in atherosclerosis is not fully understood. It is possible that CRP is
merely a marker for inflammation. Most theories suggest that CRP does play a role in the
evolution of atherosclerotic lesions because in is found in the lesions [51].
Atherosclerosis is an inflammatory process with known endothelial dysfunction. Injury to
the endothelium causes it to have procoagulant properties forming growth cells and
cytokine. This process can continue to progress causing macrophages and lymphocytes to
multiply releasing further cytokines and chemokines eventually causes rupture to the
lesion or death through ischemia [46,48-49]. In addition, smooth muscle proliferation can
occur and eventually obstruction of the lumen [46]. It should be noted, that CRP is
probably not responsible for this entire process, but a combination of several metabolic
pathways from diabetes, smoking, hypertension and genetics [49-51].
C-reactive protein is strongly linked to Body Mass Index (BMI) and weight loss
lowers CRP [44-46). In relation to BMI, several studies have linked the prediction of type
II diabetes [45-46,75]. This specific population is normally overweight and obese. A
theory is linked to adipose tissue which is the producer of 25% of the pro-inflammatory
cytokine interleukin (IL-6), which causes low grade inflammation. This would explain
the importance of exercise in this high risk population to help lower risk of cardiac
events. CRP has also been shown to be consistent among ethnic groups and sex, although
it should be noted in the Women’s Health Study, hormone replacement therapy and oral
contraceptives have significantly raised CRP levels, highly correlated to waist
circumference, BMI and fasting triglycerides [66-68,73].
17
Exercise Training:
Current evidence supports the view that exercise training (ET) has beneficial
effects on risk factors associated with diabetes and cardiovascular risk factor [77],
through the combination of both aerobic and strength training, benefits can include
lowering of body weight, resting blood pressure, improvements in blood lipids and
fasting glucose levels [4,77]. Research has shown individuals with type II diabetes have a
lower functional capacity than non-diabetics due to insulin resistant tissues, low capillary
density and other vascular complications especially among an older age group [5860,69].
Throughout this paper the repeated macrovascular complications related to
diabetes has been shown. There is also the association of hyperglycemia and
microvascular complications including retinopathy, nephropathy and neuropathy. ET has
been shown to effectively improve insulin sensitivity which leads to better glycemic
control in patients with type 2 diabetes [65-67]. The ADA suggests that both
cardiovascular and resistance training are both beneficial in the improvement of insulin
sensitivity and lowering HbA1c [4,67,69]. According to the American Diabetes
Association, the goal in the management of diabetes is maintaining glucose homeostasis.
HBA1c is an easily measured indicator of hyperglycemia and guidelines goals are <7%
or <6.5%.
Numerous physical activity studies have chosen one mode of exercise over the
other, with a lack of research combining the two. There is conflicting data, as to the
duration and intensity best suited for the diabetic population. Some studies have found
high intensity exercise has raised blood glucose levels, compared to the better controlled
18
levels with moderate intensity. Numerous studies have shown engaging in ET at mild to
moderate intensities decreases the cardiovascular risk and mortality. Helmrich et al
showed in a large prospective study, an increase of 500 kcal in energy expenditure
decreased incidence in type 2 diabetes by 6% [65,72]. In one study from Segal et al, the
combination of both ET reduced HbA1c compared to separate modes of exercise
compared to control groups [73]. The intensity of exercise has been widely investigated,
most studies showing mild to moderate intensity to be most beneficial.
Obesity is an independent risk factor of CVD, and directly linked to type II
diabetes. The common abdominal fat and subsequent loss of muscle mass are highly
associated with insulin resistance. Through both resistance and cardiovascular training a
decrease in abdominal adiposity, increase in lean mass and better glucose control should
significantly help reduce insulin resistance and increase sensitivity [65-66]. The initial
weight loss largely results in change of caloric intake compared to energy expenditure
from ET, but greatly aids in the maintenance of body weight.
Regular ET can improve glycemic control due to exercise on glucose metabolism.
Acute bouts of exercise increase skeletal muscle glucose uptake even if inhibited by
insulin resistance. Insulin stimulates increased glucose uptake by skeletal muscle and
activates glycogen synthase, the enzyme used for production of glycogen from
glucose [74]. Research has been established that ET regulates fat and glucose
metabolism, both resulting in increased insulin action [74]. There is a need for further
investigation on the mechanisms both aerobic and resistant training in individuals with
diabetes. It is the duty of clinician to educate patients on the importance of physical
activity and dietary restrictions to control blood glucose levels.
CHAPTER III
METHODOLOGY
The purpose of this study was to observe the effect of a 16-week aerobic exercise
program on C-reactive protein levels and lipoprotein (a) concentrations in individuals
with type II diabetes taking extended release niacin.
Subjects
Originally twenty seven subjects clinically diagnosed with type II diabetes were
recruited from Ball State University and the community of Muncie, IN. Nineteen subjects
fully completed the study requirements. Eight subjects were discontinued from the study
due to personal reasons, schedule conflicts, inadequate glucose control or flushing from
the medication. Subjects were recruited via flyers, brochures, and media releases.
Physicians in the Muncie area were contacted and informed of the study and the potential
recruitment of their patients. Subjects required written consent from their personal
physician and a prescription for Niaspan®. All subjects had the risks associated with the
study and the health benefits thoroughly explained to them. Subjects signed an
institutional approved informed consent form (Appendix C) prior to participating in the
study.
Quiet Testing
All subjects completed a health history questionnaire to provide medical history
information. The height and weight of each subject were measured and body mass index
20
calculated. Body composition was determined using the seven site method (Lange
skinfold caliper) and waist and hip girths were measured for calculation of waist-hip
ratio. Advanced body compositions were measured using the BOD POD (Life
Measurement Instruments, Concord, CA). Subjects were prepped with a standard 12 lead
electrocardiogram (ECG) ( Mac 5000 Resting ECG Analysis System, GE, Milwaukee,
WI) to record a supine and standing electrocardiogram(ECG) for presence of any
abnormalities contraindicated to exercise testing based on American College of Sports
Medicine (ACSM ) guidelines.
Exercise testing
All subjects were prepped for 12- lead ECG using the modified Mason-Likar
landmarks with disposable Quinton electrodes. Resting heart rates were measured in the
supine and standing position using the Marquette Case 16 (Marquette Electronics, Inc.,
Milwaukee, WI). Blood pressures obtained before and during exercise were measured
from the left arm using a sphygmanometer and the appropriate adult blood pressure cuff.
A graded exercise test was completed on the treadmill using the Bruce Ramp
protocol or Balke protocol in the presence of a physician, depending on individuals
estimated VO2max calculated from regression equations [44]. During the test, ECG was
continuously monitored and recorded by the Marquette cardiograph. Heart rate and rating
of perceived exertion (RPE) were recorded each minute, and blood pressure was recorded
every three minutes.
Metabolic data was obtained during maximal exercise testing via standard open
circuit spirometry. Expired respiratory gases were collected through a mouthpiece
connected to a one-way valve. Nose clips remained in place throughout the test. Oxygen
21
consumption and carbon dioxide produced were determined using SensorMedics
Vmax229 Metabolic Cart (Yorba Linda, California). Standard reference gas tanks
containing oxygen and carbon dioxide were used for the calibration of the metabolic cart.
The metabolic cart calculated maximal oxygen uptake (VO2max). If the maximal
test was deemed positive due to ST-Segment depression greater than 1mm, subjects were
referred back to their physicians for further evaluation. Written physician approval was
required for such individuals to participate in the study. Once the graded exercise tests
were complete, maximal data was analyzed and interpreted.
Blood Work
Venous blood samples were taken prior to the exercise program, after four, eight,
twelve weeks and post exercise training. Participants were required to fast for 10-12
hours overnight prior to test. Blood was drawn from the arm using basic phlebotomy
procedures into one 5ml (13 x 100mm) Tiger Top serum tube. Sample was mixed
thoroughly by inverting tube 5-6 times. The specimen was allowed to clot for 20-30
minutes. Samples were then spun in a centrifuge for twenty minutes (at standard 2,500
rpm) and refrigerated. The serum from each sample was then pipetted into 1.5mL
microcentrifuge tubes until shipment time. A second sample of whole blood was taken in
non-clotting 3 mL vacutainer and refrigerated until shipment. The serum and whole
blood was sent on a monthly basis to University of Alabama at Birmingham for analysis
of glycosylated haemoglobin (HbA1c), glucose, serum glutamic oxaloacetic transaminase
(SGOT), lactate dehydrogenase (LDH), alanine transaminae (ALT), creatine
phosphokinase (CPK), Uric acid and bilirubin. Monthly, blood analysis was monitored to
avoid any hepatotoxicity, possibly related to the medication.
22
All pre and post specimens with appropriate paperwork were placed into an Atherotech®
Styrofoam container with absorbent material and pre-frozen cold pack. All packages were
labeled biohazard and express shipped to Atherotech Research Department, Birmingham
Alabama. Atherotech® carried out a Vertical Auto Profiles (VAP) procedure for
determining a cholesterol profile i.e. cholesterol content of all lipoprotein particles in the
blood. The VAP consists of three independent steps. 1) Lipoprotein classes are separated
using single vertical spin density gradient ultracentrifugation. This is an accurate way of
separating lipoproteins because lipoproteins are based upon their densities. 2) The
centrifugate containing bands of separated lipoproteins is continuously drained from the
bottom of the tube and mixed with enymatic cholesterol reagent in the VAP instrument
generating a cholesterol profile. The analog output of the spectrophometer representing
the cholesterol profile is recorded on the chart recorder and the digital output is recorded
in the computer. 3) Cholesterol concentrations of lipoprotein classes and subclasses are
quantified from the absorbance peaks of the spectrophotometer using proprietary
software. The blood was analyzed for C-reactive protein (CRP), Lipoprotoein(a) (Lp(a),
glycosylated haemoglobin (HbA1c) and blood fasting glucose (BFG). Results of the
blood work were faxed to the Adult Physical Fitness Program. Exercise testing and
venous blood sampling was carried out in the Human Performance Laboratory (HPL) in
the Adult Physical Fitness Program (APFP) Testing Laboratory at Ball State University.
Exercise sessions and fingertip blood sampling was carried out in the APFP Fitness
Laboratory in Irving Gymnasium.
23
Exercise Program
Subjects were given an individual interpretation in the Adult Physical Fitness
Programs fitness center of quiet and exercise tests results. During this consult, through
explanations covered body mass index (BMI), VO2MAX , description of blood lipids and
normal values, body composition, and importance of lifestyle changes. The
individualized exercise prescriptions were explained and education material regarding
Niaspan® as provided. Subjects were explained the program involved a warm up period
followed by aerobic activities such as treadmill walking, stationary cycling, stair
climbing, recumbent biking, NuSteps or rowing and concluded with a cool down. Each
participant was assigned a personalized exercise prescription for the first four weeks and
then progressed for the following four weeks based on exercise test results. Depending on
muscular or orthopedic limitations, subjects were prescribed the recumbent bike or
nuStep as preferred modes of exercise. During this time, subjects were given an
orientation to each mode of exercise and suitable speeds and grades to optimize slow and
safe progression during the first four weeks. The intensity and duration was prescribed
from the maximal exercise test data and approximate speeds and grades were calculated
using specific equations from ACSM guidelines. The exercise prescription was devised
using the heart rate reserve method and subjects were provided with polar heart
monitors to follow specific heart rates during the course of the 16 weeks. Each exercise
session was supervised by qualified personnel with intensity, duration and frequency set
to achieve caloric expenditure goals of 1000 calories per week by week four and 1500
calories per week by week eight. Initially, prior to exercise each subject’s blood pressure
was measured and blood glucose. Fitness facility was equipped with an emergency plan
24
and carbohydrates in cases of hypoglycemia. The exercise training program required an
attendance of three to five times weekly for 16 weeks in order to attain caloric goals.
Each participant could exercise during three specified periods during the day, convenient
with their schedule.
Medication
Niaspan® of Abbott Laboratories, (Chicago) provided the drug free of charge during the
course of the study. Subjects were provided with educational material on taking the drug
to minimize potential side effects and given toll free numbers of drug representatives in
case of any further questions. Dosages for Niaspan® gradually increased monthly. The
dosages for week: 1-4 = 500mg; week: 5-8= 1000mg; week: 9-12 = 1500mg; week: 1316 = 2000mg. Subjects were responsible for taking their own medication as directed
every night. Any side effects were self-reported at the beginning of the following exercise
week on participant’s weekly side-effect log. Three subjects who experienced extreme
flushing due to increase in dosage were maintained on the lower dosages until side effects
subsided. Flushing is common and it usually becomes less frequent within the first
several weeks of continued therapy. Subjects were then provided with increase in dosage
and closely monitored. After commencement of the study, participants were excluded if
they fail to adhere to the protocol or developed signs or symptoms that placed them at
greater risk as outlined in Box 2-1 of ACSM guidelines (Franklin et al., 2000) including
chest pain, dizziness or heart palpitations. One subject, after consultation with his
physician was discontinued due to adverse rise in fasting glucose levels greater than
200mg/dl fasting blood glucose.
25
Statistical Analyses:
A t-test was used to identify significant differences between pre training for all
dependent and independent variables. A t-test comparison was conducted to determine if
any differences existed pre to post training for each group for all dependent variables.
Chapter IV
Results
The purpose of this study was to assess the effect of niacin on Lp a, CRP and HbA1C
levels in individuals with type 2 diabetes who engaged in a 16 week exercise training
program. A total of 27 subjects originally enrolled of which 8 subjects were discontinued
from the study due to personal reasons, schedule conflicts, inadequate glucose control or
flushing from the medication. Of the 19 subjects, age 60 ± 10, 8 women and 11 men fully
completed the full requirements of the 16-week program. All 19 participants were
Caucasian and were assigned to an exercise training program and prescribed niacin.
There was no control group due to small sample size and unwillingness to be assigned to
control group.
Research has shown CRP and Lp a are both linked to increased risk of CVD, in
particular individuals with type 2 diabetes. The interventions did not significantly reduce
the cardiovascular risks factors or profiles. Table 4.1 shows CRP had no significant
changes across the whole group (p=0.48), but a sub-group (Table 4.2) was populated with
10 subjects with high risk levels at baseline (>3mg/L) according to the American Heart
Association. This sub-group showed significant decrease (p<0.014) after 16 weeks of
exercise training and niacin intervention.
27
Table 4.1
Characteristics
Lpa (mg/dl)
HbA1C (%)
Glucose
CRP (mg/L -1)
Pre Intervention
5.74 ± 4.86
6.54 ± .88
122.11±30.59
5.37 ± 5.38
Post Intervention
6.73 ± 3.54
6.63 ± 0.87
117.86±31.91
4.29 ± 3.90
Table 4.2 Sub group of 10 subject with baseline CRP measurements > 3mg/L
Pre Intervention
Post Intervention
CRP(mg/L)
8.67 ± 5.63
5.84 ± 4.10*
*p<.05 Significant difference from pre and post interventions
No differences were noted from baseline (Table 4.3) noted in Lp(a) (p=0.47),
even though earlier research has shown that niacin is a unique therapeutic agent with the
ability to decrease Lp(a) levels(26,38). According to Framingham heart study, Lp (a)
levels greater than 10 mg/dl could be used as a predictor of greater risk of CAD. Only 3
subjects had these values at baseline and no significant changes noted with the
interventions.
Table 4.3 Subject with baseline Lp(a) measurements >3mg/L
Pre Intervention
Post Intervention
N=
19
19
Lp a
(mg/dL)
5.74± 4.86
6.74 ± 3.54
Table 4.4 shows monthly measurements for HbA1c. Seventeen subjects showed
no significant changes over the duration of exercise protocol and administration of
increased dosages of niacin (500- 2000mg) on monthly basis. Even though there was no
28
significant changes noted with blood glucoses, Figure 4.1 shows mean monthly blood
sugars declined over the course of the 4 months.
Table 4.4 Sub group of subjects with baseline HbA1c measurements %
Pre Intervention
17
N=
12
%=
6.67 ± 0.9
5.84 ± 0.9
Month 1
7
Month 2
Month 3
Post Intervention
11
6.4 ± 0.8
7.0± 1.1
17
6.7±1.0
Figure 4.1
All subjects during the exercise protocol increased their energy expenditure to 1000 Kcal
on a weekly basis. As seen in Table 4.5, there was no decrease in mean body weight over
the course of the 16 weeks, and no significant difference was noted in overall BMI
(p=0.96). There was a training effect noted (Figure 4.2). This shows heart rates pre and
29
post from 3 stages of exercise treadmill tests (Bruce Ramp or Balke). At post testing there
were no peak heart rates obtained, but submaximal testing was performed. A correlation
can be seen with training effect.
Figure 4.2
Table 4.6 Participant Clinical Characteristics:
Characteristics
Pre Intervention
Post Intervention
Weight (kg)
96.71 ± 15.56
96.04 ± 16.45
2
BMI (kg/m)
33.5 ± 6.1
33.4 ± 6.3
*p<.05 Significant difference from pre and post interventions
Chapter V
Discussion
This study investigated the effect of niacin and exercise training on CRP and
Lp(a) levels in previously sedentary individuals with type 2 diabetes mellitus. Exercise
training has been shown to decrease risk factors such as hypertension, body composition,
weight loss, improve plasma lipids and most important in individuals with diabetes,
improvement in glucose homeostasis [15,67-69,73-74].
Overweight and obesity are significantly associated with diabetes and CRP.
Recent investigations suggest exercise reduces CRP. The finding of this study showed
16-weeks of exercise training and niacin therapy did not improve CRP levels. Higher
levels of physical fitness and cardiorespiratory fitness are associated with 6-35% lower
CRP levels (7-48, 67-68). These findings are in contrast with those of several crosssectional reports that reported an inverse association between CRP levels and regular
physical activity [68]. There are conflicting results in respect to exercise reducing CRP.
This is consistent with the hypothesis that physical exercise acts predominantly by
reducing body composition and weight loss. There was no significant change in CRP
levels, but a subgroup of 10 subjects with high risk baseline values (>3mg/dl criteria from
American Heart Association), exhibited significant changes from baseline values
(p<0.014). This reflects several studies that have shown significant CRP improvements in
31
conjunction with significant weight loss through lifestyle interventions (75-76). This
could explain that even though caloric expenditure and compliance was met, minimal
changes in weight loss and no changes in CRP. This study showed there was a reduction
in higher levels than in individuals with normal values. It could be suggested that
exercise has an important role to play in reducing inflammation beyond weight loss. This
suggests that the anti-inflammatory effect of physical activity may counteract the CVD
associated with high CRP levels.
No significant difference in Lp a concentrations between pre and post intervention
was noted. In majority of studies, it has been shown there is no association between
physical activity or exercise training, but instead highly influenced by racial or ethnic
makeup and genetic factors such as age and sex [22-23,41]. However, conflicting reports
on high intensity exercise in elite athletes have shown to increase Lp a by 10-15% (57,
64). In contract, NCEP ATP III has identified niacin as a therapeutic drug in lowering
lipoproteins in particular Lp a (22), but after the 16- week duration no changes were
noted. There is no particular explanation except for possible lack of adherence from
subjects or the monthly increase in dosages was not long enough to see significant
changes.
The exercise training protocol did not significantly improve weight loss, body
composition, HbA1c or glucose control. The exercise program was designed to increase
energy expenditure (>1000Kcal) by week 3 and resistance training was introduced later
in the program. Adherence to the protocol was good, but possibly a longer intervention
with higher training intensities and volume might have produced greater changes with
32
these variables. Several studies have failed to show any improvements after 8-16 weeks
of training, but others have been more favorably for 6 months-1 year duration [78].
Although there were no significant changes in glucose, there was a trend in glucose levels
marginally decreasing over the 16 weeks. It is widely accepted that exercise training is
beneficial in improving glucose control as a result of enhanced insulin sensitivity [3-10 ].
Niacin has been associated with hyperglycemia. According to Grundy et al [21] 10-30%
of patients with diabetes see a rise in glucose levels with niacin therapy and possibly a
small increase in HbA1C levels. This study proved the importance of exercise training in
the diabetic population, but possibly countered any negative effects the niacin therapy
might have cause, but a slight decline in glucose levels was noted.
It must be noted this study had limitations such as the absence of a control group,
a relatively small number of subjects and a lack of heterogeneity. Some post intervention
testing such as VO2 testing was missing due to time constraints that could possibly have
shown significant cardiorespiratory improvements. There was also an improvement in
training effect; post submaximal exercise testing exhibited a trend in lower heart rates.
Despite these limitations, the study was one of few that incorporated exercise
training, in conjunction to a niacin intervention in a diabetic population. Sedentary
subjects were also introduced to a various modes of exercise and strength training. Since
there is a high correlation of diabetes and CRP, studies need to investigate a better
understanding of CRP in its value of predicting diabetes. Also, future designed studies
need to investigate larger diabetic populations and the role of niacin on HbA1c levels.
Moreover studies should emphasis longer interventions, incorporating interventions to
33
change in body composition and include dietary intervention, especially in this high risk
population.
In conclusion, even though this research project did not show any significant
changes across the variables, there was significant change in CRP levels in individuals
with high baseline levels. The benefit of exercise training in this high risk population
showed slight improvements in glucose control and a definite training effect. Therefore,
future studies should use larger populations and a control group.
34
References:
1.
Centers for Disease Control and Prevention. National diabetes fact sheet: general
information and national estimates on diabetes in the United States, 2007.
Atlanta, GA: U.S. Department of Health and Human Services, Centers for Disease
Control and Prevention, 2008
2.
Diabetes Control and Complications Trial Research Group. The effect of intensive
treatment of diabetes in the development and progression of long-term complications
in insulin-dependent diabetes mellitus. N Engl J Med.329:683-689,1993.
3.
Mahler, R.J., Adler, M.L. Type 2 Diabetes Mellitus: Update on Diagnosis,
Pathophysiology, and Treatment. The J of Clinical Endo &Metabolism. Vol 84:11651171, 1999.
4.
American College of Sports Medicine. Position Stand: Exercise and Type 2 Diabetes.
Med. Sci. Sports Exerc. 1345-1360, 2000.
5.
American Heart Association. Diabetes and Cardiovascular Disease: Pathogenesis of
Atherosclerosis in Diabetes (Position statement). Circulation, 2002, 138-143.
6.
Kannel, W.B., McGee, D. L. Diabetes and Cardiovascular Disease. The Framingham
Study. Journal of American Medical Association. 241:2035-2038, 1979.
7.
UK Prospective Diabetes Study Group: Tight blood pressure control and risk of
macrovascular and microvascular complications in type 2 diabetes: UKPDS. British
Med Journal, 11:670-677, 1994.
8.
Wingard DL, Barrett-Connor E: Heart disease and diabetes. In Diabetes in
America.2nd edition. Harris MI, ed. Bethesda, Md., National Institutes of Health
(NIH publication no. 95-1468), 429-48, 1995.
9.
Gu, K., Cowie, C.C, Harris, M.I. Diabetes and decline in heart disease mortality in
US adults. Journal of American Medical Ass.241:235-2038, 1998.
10.
Grundy, S. M., I. J. Benjamin, et al. "Diabetes and cardiovascular disease: a
statement for healthcare professionals from the American Heart Association."
Circulation 100(10): 1134-46, 1999.
11.
Egan, D. A., R. Garg, et al. "Rationale and design of the Arterial Disease Multiple
Intervention Trial (ADMIT) pilot study." Am J Cardiol 83(4): 569-575, 1999.
12.
Goldberg, J. Diabetic Dyslipidemia: Causes and Consequences. Clin.Endocrinol.
Metabolism. 52:731-40,2001.
35
13.
Eckel, R. H.-V. Diabetes and Cardiovascular Disease: Pathogensis of
Atherosclerosis in Disease. Circulation. 105:138-143, 2002.
14.
Garg, A, Grundy, S.M. Nicotinic acid as therapy for dyslipedemia in non-insulin
dependent diabetes mellitus. Journal of American Medical Association.264: 723-726,
1990.
15.
Geiss, L.S, Herman, W.H, Smith, P.J. National Diabetes Data Group, Diabetes in
American. NIH.95:233-257, 1995.
16.
Gazzaruso, C., A. Garzaniti, et al. "Assessment of asymptomatic coronary artery
disease in apparently uncomplicated type 2 diabetic patients: a role for lipoprotein(a)
and apolipoprotein(a) polymorphism." Diabetes Care 25(8): 1418-24, 2002.
17.
Haffner, S. M. "Dyslipidemia management in adults with diabetes." Diabetes Care
27 Suppl 1: S68-71, 2004.
18.
Alexander, C.M, Landsman, P.B. Teutsch, S.M. Diabetes mellitus, impaired fasting
glucose, atherosclerotic risk factors, and prevalence of coronary heart disease.
American J.Cardiology. 86:897-902, 2000.
19.
Gu, K, Cowie,C.C, Harris, M.I. Diabetes and decline in heart disease mortality in US
adults. Journal of American Medical Association.281:1291-1297, 1998.
20.
Redberg, R. F., P. Greenland, et al. "Prevention Conference VI: Diabetes and
Cardiovascular Disease: Writing Group III: risk assessment in persons with
diabetes." Circulation 105(18): e144-52,2002.
21.
Grundy, S. M., G. L. Vega, et al. "Efficacy, safety, and tolerability of once-daily
niacin for the treatment of dyslipidemia associated with type 2 diabetes: results of the
assessment of diabetes control and evaluation of the efficacy of niaspan trial." Arch
Intern Med 162(14): 1568-76, 2002.
22.
McKenney, J.M. Update on the National Cholesterol Education Program Adult
Treatment Panel III guidelines: getting to goal. Pharmacotherapy, 23: 26S-33S,2003.
23.
Capuzzi DM, Morgan JM, Brusco OA et al. Niacin dosing: relationship to benefits
and adverse effects. Curr Atheroscler Rep.2:64-71, 2000.
24.
Carlson, L.A, Hamsten, A. Asplund, A. Pronounced lowering of serum levels of
lipoprotein Lp(a) in hyperlipidemic subjects treated with nicotinic acid. Journal of
Internal Medicine.226:271-276, 1989.
36
25.
Grundy, S.M, Garg, A. Nicotinic acid as therapy for dyslipidemia in non-insulindependent diabetes mellitus. Journal of American Medical Ass.264:723-726, 1990.
26.
Marcovina, S.M., et al., Report of the National Heart, Lung, and Blood Institute
Workshop on Lipoprotein (a) and Cardiovascular Disease: recent advances and
future directions. Clin Chem, 49(11): 1785-96, 2003.
27.
Tavintharan, S, Kashyap, M.L. The benefits of niacin in atherosclerosis. Current
Atherosclerosis Report.3:74-82, 2001.
28.
Peterson, J.G, Topol, E.J, Sapp,S.K, Young. "Evaluation of the Effects of Aspirin
combined With Angiotensin-Converting Enzyme Inhibitors inPatients With Coronary
Artery Disease." American Journal of Medicine: 371-377, 2000.
29.
Colwell, J.A. Aspirin therapy in diabetes (Technical review). Diabetes Care
20:1767-1771, 1997.
30.
Souza, D. R. and M. V. Garcia "[Lipoprotein (a): variability and association with
coronary disease]." Arq Bras Cardiol 62(3): 187-94, 1994.
31.
Report of the National Heart, Lung, and Blood Institute Workshop on Liporotein (a)
and Cardiovascular Disease: Recent Advances and Future Directions. Clinical
Chemistry 2003.
32.
Piepho, R.W. The pharmacokinetics and pharmacodynamics of agent proven to raise
high-density lipoprotein cholesterol. American Journal of Cardiology, 86:35-40,
2001.
33.
Mackinnon, L. T. and L. M. Hubinger . "Effects of exercise on lipoprotein(a)." Sports
Med 28(1): 11-24,1999.
34.
Rath, M., A. Niendorf, et al. "Detection and quantification of lipoprotein(a) in the
arterial wall of 107 coronary bypass patients." Arteriosclerosis 9(5): 579-92, 1989.
35.
Utermann, G, Menzel, H, Kraft, H, Duba, H, Kemmleer, H, Seitz,C. Lp(a)
glycoprotein phenotypes: inheritance and relation to Lp(a) concentrations in plasma.
Journal of Clinical Investigation. 80:458-65, 1987.
36.
Scanu,A.M, Scandiani,L. Lipoprotein(a): structure, biology and clinical relevance.
Advanced Internal medicine.36:249-70, 1991.
37.
Cobbaert C, Mulder P, Lindemans J, Kesteloot H . Serum LP(a) levels in African
aboriginal Pygmies and Bantus, compared with Caucasian and Asian population
samples. J Clin Epidemiol 50(9):1045–1053, 1997.
37
38.
Howard BV, Le NA, Belcher JD et al. Concentrations of Lp(a) in black and white
young adults: relations to risk factors for cardiovascular disease. Ann Epidemol 4:
341-350, 1994.
39.
Danesh J, Collins R, Peto R . Lipoprotein(a) and coronary heart disease. Metaanalysis of prospective studies. Circulation.102 (10): 1082–5, 2000.
40.
Rader DJ, Cain W, Zech LA, Usher D, Brewer HB. "Variation in lipoprotein(a)
concentrations among individuals with the same apolipoprotein (a) isoform is
determined by the rate of lipoprotein(a) production". J. Clin. Invest. 91 (2): 443–447,
1993.
41.
Berglund L, Ramakrishnan R . Lipoprotein(a): an elusive cardiovascular risk factor.
Arterioscler. Thromb. Vasc. Biol. 24(12): 2219–2226, 2004.
42.
Rees, A. “Lipoprotein (a): a possible link between lipoprotein metabolism and
thrombosis” British Heart Journal 65:2-3, 1991.
43.
Rainwater D, Macluer J, Stern M, VandeBerg J, Haffner S. Effects of NIDDM on
lipoprotein(a) and apolipoprotein(a) size. Diabetes 3:942-946, 1994.
44.
Han, T. S., N. Sattar, et al. (2002). "Prospective study of C-reactive protein in
relation to the development of diabetes and metabolic syndrome in the Mexico City
Diabetes Study." Diabetes Care 25(11): 2016-21.
45.
Blake, G. J. and P. M. Ridker . "Inflammatory bio-markers and cardiovascular risk
prediction." J Intern Med 252(4): 283-94, 2002.
46.
Duncan, B. B., M. I. Schmidt, et al. "Low-grade systemic inflammation and the
development of type 2 diabetes: the atherosclerosis risk in communities study."
Diabetes 52(7): 1799-805, 2003.
47.
Ford, E. S. "The metabolic syndrome and C-reactive protein, fibrinogen, and
leukocyte count: findings from the Third National Health and Nutrition Examination
Survey." Atherosclerosis 168(2): 351-358, 2003.
48.
Pradhan AD. C-reactive protein, interleukin 6, and risk of developing type 2 diabetes
mellitus. JAMA 286: 327–334, 2001.
49.
Dehghan A. Genetic variation, C-reactive protein levels, and incidence of diabetes.
Diabetes 56: 872-878, 2007.
38
50.
Gazzaruso, C., A. Garzaniti, et al. "Silent coronary artery disease in type 2 diabetes
mellitus: the role of Lipoprotein(a), homocysteine and apo(a) polymorphism."
Cardiovasc Diabetol 1(1): 5, 2002.
51.
King, D. E., P. Carek, et al. "Inflammatory markers and exercise: differences related
to exercise type." Med Sci Sports Exerc 35(4): 575-81, 2003.
52.
Ridker, P. M., M. Cushman, et al. "Plasma concentration of C-reactive protein and
risk of developing peripheral vascular disease." Circulation 97(5): 425-428, 1998.
53.
Rifai, N. and P. M. Ridker . "High-sensitivity C-reactive protein: a novel and
promising marker of coronary heart disease." Clin Chem 47(3): 403-11, 2001.
54.
Ridker, P.M. Clinical application of C-reactive protein for cardiovascular disease
detection and prevention. Circulation 107:363-369, 2003.
55.
Durstine L, Ferguson MA, Szymanski LM, Trost SG, Pate RR. Effect of a single
session of exercise on lipoprotein(a). Med Sci Sports Exerc 28:1277-1281, 1996.
56.
Hubinger L, MacKinnon LT. Lipoprotein (a) levels in middle aged male runners and
sedentary controls. Med Sci Sports Exerc 27:90-96, 1996.
57.
Cardoso GC, Posadas C, Orvananos OO et al. Long distance runners and bodybuilders exhibit elevated plasma levels of lipoprotein(a). Chem Phys Lipids 67:20721, 1994.
58.
Blair SN, Brodney S. Effects of physical inactivity and obesity on morbidity and
mortality: current evidence and research issues. Med Sci Sports Exerc 31:646-62,
1999.
59.
Blair SN, Cheng Y, Holder JS. Is physical activity or physical fitness more important
in defining health benefits? Med Sci Sports Exerc 33: 379-99, 2001.
60.
Laaksonen DE, Lindstrom J, Lakka TA et al. Physical activity in the prevention of
type 2 diabetes: the finnish diabetes study. Diabetes 54:158-65, 2005.
61.
Tuomilehto J, Linstron J, Eriksson JG et al. Prevention of type 2 diabtes mellitus by
changes in lifestyle among subjects with impaired glucose tolerance. New Eng J Med
344:1343-50, 2001.
62.
Goldberg RB, Jacobson TA.Effects of niacin on glucose control in patients with
dyslipidemia. Mayo Clinic Proceedings 84: 470-8, 2008.
39
63.
Elam MB, Hunninghake DB, Davis KB, Garg R, Johnson C, Egan D, Kostis JB,
Sheps DS, Brinton EA. Effect of niacin on lipid and lipoprotein levels and glycemic
control in patients with diabetes and peripheral arterial disease: the ADMIT study: A
randomized trial. Arterial Disease Multiple Intervention Trial. JAMA. 284:1263-70,
2000.
64.
Dufaux B. Order U. Muller R. Hollmann W. Delayed effects of prolonged exercise
on serum lipoproteins. Metabolism: Clinical & Experimental 35(2):105-9,1986.
65.
Horton, E. S. Exercise and physical training: effects on insulin sensitivity and
glucose metabolism. Diabetes/Metab. Rev. 2:1–17, 1986.
66.
Hubinger A., Frantzen A, and Gries A. Hormonal and metabolic response to
physical exercise in hyperinsulinemic and nonhyperinsulinemic type 2 diabetics.
Diabetes Res. 4:57– 61, 1987.
67.
Eriksson K, Lindgrade F. Prevention of type 2 diabetes mellitus by diet and physical
exercise. Diabetologia 34:891-898, 1996.
68.
Stewart LK, Earnest CP, Blair SN, Church T. Effects of different doses of physical
activity on c-reactive protein among women. Med Sci Sports Exerc 42:701-707,
2010.
69.
Sigal RJ, Kenny G, Fortier M, Reid, R et al. Effects of exercise training on physical
fitness in type II diabetes mellitus. Med Sci Sports Exerc 42:1439-1447.
70.
Markers of Inflammation and Cardiovascular Disease, Application to Clinical and
Public Health Practice. A Statement for Healthcare Professionals from the Centers
for Disease Control and Prevention and the American Heart Association. Circulation
107:499-511, 2003.
71.
Tataru MC, Heinrich J, Junker R, et al. C-reactive protein and the severity
of atherosclerosis in myocardial infarction patients with stable angina
pectoris. Eur Heart J. 21:1000–1008,2000.
72.
Helmrich SP, Ragland dr, Leung RW, et al(1991). Physical activity and reduced
occurrence of non-insulin-dependent diabtes mellitus. New Eng J of Med 325:17-52.
73.
Sigal RJ, Kenny G, Boule NG, et al (2007). Effects of aerobic training, resistance
training, or both on glycemic control in type 2 diabetes: a randomized trial. Ann
Intern Med. 147: 357-69.
74.
Richter EA, Garetto LP, Goodman M. Muscle glucose metabolism following
exercise in the rat: increased sensitivity to insulin. Clin Invest 69: 785-793, 1982.
40
75.
Villareal DT, Miller BV, Banks M, et al. Effect of lifestyle intervention on metabolic
coronary heart disease risk factors in obese older adults. Am J Clin Nutr 84:13171323, 2006.
76.
Nicklas BJ, Ambrosius W, Messier SP, et al. Diet-induced weight loss, exercise and
chronic inflammation in older adult. Am J Clin Nutr 79:544-51, 2004.
77.
Exercise and Physical Activity in the Prevention and Treatment of Atherosclerotic
Cardiovascular Disease .AHA Statement. Circulation 107:3109-3116, 2003.
78.
Balducci S, Zamuso S, Nicolucci A, De Feo P, Cavallo S, Cardelli P. Effect of an
intensive exercise intervention strategy on modifiable cardiovascular risk factors in
subjects with type 2 diabetes mellitus: a randomized controlled trial: the Italian
Diabetes and Exercise Study (IDES). Archn Intern Med 170:1794-803, 2010.