Diabetes mellitus (DM) is a growing problem. According to the Centers for Disease Control and Prevention (CDC), in the United States there were an estimated 23.6 million cases in 2005 as compared to nearly 17 million cases in the year 2000 with the number expected to be greater than 30 million cases by 2030. Worldwide millions die annually from cardiovascular disease (CVD) for which diabetes and the associated co-morbidities are the major contributing factors. The most prevalent form, Type 2 diabetes mellitus (T2DM), accounts for over 90% of all cases. Consequently, what this means to the practitioner is that not only will the patient population with T2DM increase, but the patients will also be diagnosed earlier in life and most concerning are the cardiac complications that are associated with having the disease (CDC, 2007).
Although characterized as a chronic condition of hyperglycemia, T2DM causes a number of other medical complications, most common being cardiovascular disease. Fisher (2001, p.1) poignantly stated over 14 years ago that a better clinical definition of diabetes is "a state of premature cardiovascular death associated with chronic hyperglycemia and may also be associated with blindness and renal failure." Dyslipidemia is a key factor contributing to the high risk of cardiovascular disease (CVD) inÂ diabetesÂ and appropriate management is fundamental in order to prevent, stop, or reverse the progression of dyslipidemia.
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Confirming the idea that dyslipidemia is under or mistreated, Dr. Abraira and colleague determined from a polling of nearly one thousand primary care physicians, on the most effective means in the prevention of cardiovascular disease in the diabetic patient, the majority, 65% got it wrong. The physicians overwhelmingly believe because diabetes was diagnosed and monitored based on blood glucose levels that it also was the best strategy in the prevention of cardiovascular disease, followed by hypertension management, and then lipid management. A meta-analysis published around the same time concluded exactly the opposite findings, the most effective management in the prevention of cardiovascular events was by targeting lipid levels first, hypertension next and glycemic intervention being non-contributory to cardiovascular outcomes (Abraira, & Duckworth, 2003).
Type 2 diabetes treatment cannot center solely on glucose control, there are a myriad of reasons to focus on minimizing the microvascular damage resulting from chronic hyperglycemia, however diabetics do not die from cardiovascular disease due to those changes. This is supported by the fact that there are no clinical studies to date that have been conducted on diabetics that have proven to reduce cardiovascular outcome as a primary endpoint, in this patient population. Glucose management only minimally reduces macrovascular complications, so therefore it is essential to control the three traditional, treatable , and preventable risk factors for cardiovascular disease which are blood pressure, dyslipidemia, and smoking. These risk factors are not unique in the diabetic population; however, because it is amplified to a larger degree that makes it much more important to control. Diabetic patients that fail to manage their glucose levels, blood pressure, and lipid levels, will die earlier and suffer the devastating complications because the mortality rate from CVD doubles in patients with T2DM with one additional risk factor, and more than triples with three additional risk factors.(AHA, 2007; Campbell, & Martin, 2009 Cefalu,2008)
Providers have to identify the components that are clinically relevant and consider aggressive or combination therapy to target aspects of the lipid profile to reduce cardiovascular events. Lipid lowering therapy is proven to reduce morbidity and mortality yet primary efforts are directed at achieving desirable HbA1c levels. The cornerstone of preventing or delaying the progression of macrovascular complications of diabetes is aggressive management of lipid disorders to prevent or reduce atherosclerosis, myocardial infarction (MI), stroke, and peripheral vascular disease. The most serious complications are the macrovascular sequela- myocardial infarction and stroke. It is the leading cause of death among diabetic patients and it also predicts further deleterious events that include re-infarction, heart failure, and death. (Bourassa & Jean-Claude, 2007, CDC 2007).
There must be a shift away from the treatment of individual cardiovascular risk factors to managing the cumulative and amplified effect of those risks with overlapping interventions, tailored to each patient. According to the CDC, diabetes was captured as the seventh leading cause of death in the U.S. and contributed to over 230,000 deaths in 2005 alone, more than half of patients with diabetes die from heart disease or stroke, and death rates are 2 to 4 times higher in patients with diabetes compared with those without the disease. To achieve the recommended targets, a combined approach that focuses on intensive medical nutrition, exercise, behavior, and drug therapy is required. The average patient with diabetes will need complex regimens involving multiple anti-diabetic, antihypertensive, and lipid-lowering agents to achieve these recommended targets. (Bazaldua, et al,2008 ).
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Macrovascular complications, which carry the highest risk of mortality, are cerebrovascular stroke and myocardial infarction. The microvascular complications retinopathy, neuropathy, and nephropathy, with the exception of end stage renal disease, pose the least risk for mortality. Diabetes not only complicates but amplifies cardiovascular disease through several complex metabolic pathways that are exacerbated by the presence of each other. Having these abnormal metabolic features of insulin resistance, hypertension, atherosclerosis, dyslipidemia, and vascular damage, creates this vicious cascade of events which ultimately leads to premature death from cardiovascular complications.
Hyperglycemia is only one of several abnormalities found in Type 2 Diabetes Mellitus patients (T2DM) and even though maintaining glucose levels is an absolute requirement, poor control results in abnormal changes to the lipid profile, particularly triglycerides which further contribute to atherosclerosis and CVD. Findings of the ACCORD trial, glucose arm, have demonstrated that tight glycemic control alone does little to affect the lipid panel and was actually terminated early due to increased mortality when subjects were aggressively managed. The impact of this translates to finding alternate or combined therapies to reduce cardiovascular related deaths beyond primary management of glucose alone. The multifactorial etiology of diabetes consequently would imply that the ideal treatment of people with T2DM would include correction of lipid abnormalities while simultaneously controlling glucose levels, in addition to therapeutic lifestyle changes, and smoking cessation in the primary or secondary prevention of atherosclerosis.
Diabetes is considered a coronary artery disease equivalent and those with diabetes have a disproportionately higher prevalence for CVD. This finding is supported by the Adult Treatment Panel III guidelines which defines this condition a CVD risk equivalent and also directs further therapy aimed at reducing the lipid risk factors for low HDL, high triglycerides, that also confer their own risk factor contributing to CVD. The increased risk is related to simultaneous diabetic pathology and the typical clustering of other modifiable risk factors predominantly, obesity, dyslipidemia and hypertension. Cardiovascular disease, the number one complication and cause of death in T2DM patients, is also preventable with aggressive treatment which can reverse complications and reduce the long-term medical problems associated with the disease (Ali, Fazio, & Mac Rae, 2008; Haffner, 2006; Ahmed,et al,2010 ).
It is macrovascular disease changes, not the microvascular process that contributes significantly to the mortality in people with Type 2 diabetes. The results of the ACCORD and ADVANCE studies on improved glycemic control suggest that it has no affect on mortality from CVD. Further understanding of the macrovascular disease process may help to target appropriate therapy for patients and to reduce the severity of the condition on morbidity and mortality.
Consideration of the pathophysiology of vascular disease in type 2 diabetes indicates the need for an integrated therapeutic approach in the clinical management of dyslipidemia, the process behind atherosclerosis. Recent findings show that dyslipidemia plays a key role in the development of macrovascular disease associated with T2DM. Therapeutic intervention to correct both the quantitative and qualitative changes characteristic of diabetic dyslipidemia should be viewed as a priority for reducing both macrovascular risk (Haffner, 2006; JACC, 2008; Tomkin, 2008)
The specific pathogenesis of diabetic dyslipidemia is not entirely known, however an association between insulin resistance is thought to play a central role, and a thorough knowledge of the atherosclerotic process is necessary in order to prevent or reduce the rate of progression once the process has started. Atherogenic dyslipidemia in T2DM is characterized by three distinct features: moderately increased LDL cholesterol, increased triglycerides, and decreased HDL cholesterol.
Dyslipidemia, largely an asymptomatic disorder, is an abnormal condition of lipoprotein metabolism that can be due to genetics, secondary causes or the combination. The usual secondary causes are those that normally can be modified such as intake, hypothyroidism, steroid treatment, oral contraceptives, obesity, and T2DM. It can manifest in several ways, hypercholesterolemia, hypertriglyceridemia and as decreased high density lipoproteins (HDL). As seen in diabetics the most common pattern is elevated triglycerides, decreased HDL, and normal to moderately elevated LDL, this distinct pattern is also known as atherogenic dyslipidemia. Atherogenic dyslipidemia is the result of elevated in the number (quantity) or the composition (quality) of specific lipoproteins is important in determining the appropriate drug therapy. Type 2 diabetic patients have relatively normal LDL levels, but they are abnormally smaller and denser particles, which are associated with an increase in atherogenicity, a condition which predisposes them to increased atherosclerotic deposits. Due to the relatively normal concentration of LDL providers fail to recognize and ultimately treat diabetics for the reason that in their non-diabetic counter parts this would be considered benign. (Nesto, 2008).
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It is important to understand the pathophysiology concerning atherogenic dyslipidemia in order to understand the approach tried by researchers to control the progression of the disease. Cholesterol is found everywhere in the body and is used for several processes. It can either be produced inside the body, endogenous pathway, that involves the liver in synthesis or it can be consumed , exogenous pathway, thru digestion and absorption via the intestine.. Cholesterols can be classified by their composition into five categories based on size. Chylomicrons are the largest least dense, followed by Very Low Density Lipoprotein (VLDL), Intermediate density Lipoprotein (IDL), Low Density Lipoprotein (LDL), and finally High Density Lipoprotein (HDL).
Drug therapy offers several options with every drug class targeting specific areas of the lipid profile associated with dyslipidemia. Since LDL levels aren't affected by euglycemic control, the primary target of intervention focuses on management of LDL levels and is the first step in treating diabetics. The commonly accepted guidelines provide target goals at achieving levels to < 100 mg/kg but allow further reduction to target achieving levels to below 70 mg/kg to further reduce long term mortality and cardiovascular events in those patients with several risk factors.
LDL carries the majority of the body's cholesterol in the bloodstream where it is used for several processes. LDL is atherogenic and what does not get used remains circulating and eventually gets deposited on the walls of the arteries and penetrates into the subendothelial tissue. Due to this tendency it has earned a reputation as being bad cholesterol. Lowering of LDL levels reflects a decreased cardiovascular risk.
Primary therapy must be directed at lowering LDL levels first. It is necessary to treat dyslipidemia with pharmacological intervention because the high incidence of mortality for T2DM patients with their first myocardial infarction. Subsequently, in persons with multiple risk factors, pharmacological intervention is absolutely necessary for additional benefit. The following studies have proven statistically significant for use of statins to alter this lipid profile.
The Collaborative Atorvastatin Diabetes study (CARDS), the only primary prevention trial designed specifically for the diabetic population, studied the effect of 10 mg daily atorvastatin therapy. The population consisted of type 2 diabetic patients without a previous history of cardiovascular disease, but who had at least 1 cardiovascular risk factor. The study had such a profound reduction in cardiovascular events, 37% risk reduction, that it was terminated after only 3.9 years. Overall CARDS determined atorvastatin as being safe and efficacious in reducing the risk of CVD events including MI and stroke in T2DM patients without elevated LDL cholesterol (Betteridge, et al., 2004;Tomkin, 2008). This study is important in that it highlights the concept of treating dyslipidemia before it presents clinically and that risk reduction is achieved through modification of LDL and not glycemic intervention.
The Scandinavian Simvastatin Survival Study (4S), which was a double blinded, secondary prevention study, demonstrated that treatment of patients suffering from coronary heart disease with simvastatin had a lowering effect on mortality and morbidity. They examined a total of 4,444 patients divided into 2,223 patients who received aÂ placeboÂ and 2,221 that were assigned Simvastatin treatment for a mean period of 5.4 years. They achieved a 30% relative reduction in the risk of death with simvastatin treatment. The absolute coronary heart disease-mortality was reduced from 8.5% to 5.0%, making theÂ number needed to treatÂ to be 30 (Betteridge, et al., 2004;Faergeman , et al. 1998; Scandinavian Simvastatin Survival Group, 2000). The 4S proves that even in T2DM patients with cardiovascular disease, a reduction in mortality could be achieved by once more targeting the LDL panel to reduce overall mortality.
Another statin monotherapy study, the Cholesterol and Recurrent Events trial (CARE), a double blinded, randomized, placebo controlled study followed the effect of treating 4,159 patients with prior myocardial infarction patients with pravastatin 40 mg daily, or placebo, over a 5-year event follow-up. Diabetic patients only accounted for 14.1% of the patient population. CARE achieved a statistically significant- 30% reduction in LDL, and had a 25% relative risk reduction in incidence of coronary events. These results show that the benefit of cholesterol-lowering therapy can extend to the majority of patients with previously diagnosed coronary disease that also have average cholesterol levels (Howard et al. 1998; Moye et al., 1996). Care reinforces treating dyslipidemia in diabetics once more through modification of LDL levels in diabetics can be useful in halting the progression and reversing the CVD associated with dyslipidemia.
The Heart Protection Study (HPS),Â a prospective double blind randomized controlled trial,Â studied the affect of simvastatin 40 mg daily. HPS included a subgroup analysis of the 5,900 diabetic patients, and found during the 5 years of follow-up, that simvastatin prevented 49 patients per 1000 from having a major coronary event. Patients were able to achieve approximately a 31% reduction in LDL and the benefit of therapy was demonstrable regardless of the patient's baseline cholesterol level. Although this study has been used as the source for recommending that all patients with diabetes receive a statin, HPS does not provide evidence that diabetic patients with a baseline LDL is <100 mg/dL could benefit from simvastatin therapy (Brown et al, 2006). Overall, this study supports reducing LDL as an effective means to reduce cardiovascular events in diabetics across.
The Long-Term Intervention with Pravastatin in Ischemic Disease (LIPID) trial, a double-blind randomized trial, compared the effects of pravastatin 40 mg daily in 9,014 patients who were 31 to 75 years of age with a known CHD over those of a placebo over a mean follow-up of 6.1 years. The focus of the study was to determine mortality from coronary heart disease. LIPID showed that pravastatin significantlyÂ reduced mortality and coronary heart disease (CHD) events. Pravastatin reducedÂ the risk of fatal CHD or nonfatal myocardialÂ infarction by 24% and the expanded end point of fatal CHD, nonfatal myocardialÂ infarction, unstable angina, or coronary revascularization byÂ 17%Â (The Long-Term Intervention With Pravastatin in Ischaemic Disease (LIPID) Study Group, 1998)
These Clinical trials of statins support aggressive treatment of dyslipidemia in diabetics and changes in the lipid levels explain all orÂ most of the observed benefit. These studies reveal clinically significant improvement in the lipid profile and reduction of cardiovascular risk; however, LDL lowering alone will unlikely reduce the remaining risk or that more intensive reduction will result in greater benefit.
Although the statins are the cornerstone of lipid-lowering therapy, they may not adequately contribute to clinically significant increases in the levels of HDL-cholesterol. Other cardiovascular medications have been studied as being able to delay or prevent cardiovascular disease by improving the lipid panel. Fibrates are another class that has shown to be of benefit especially in diabetics, that target the HDL profile, consequently another aspect of atherogenic dyslipidemia. Low HDL-cholesterol, an independent risk factor for CVD, may require the addition of drugs effective in raising those levels. Fibrates and niacin based therapies may provide a strategy for reducing cardiovascular risk to a level below what is possible with a statin alone (Barter, & Rye, 2006).
Fibrates target lipids by lowering triglycerides to a much greater extent than statins, raising HDL levels, and decreasing the number of small, dense atherogenic LDL particles. A limited number of studies have evaluated the effects of fibrates in diabetic patients and the results of these studies are presented.
The outcome of the largest intervention study ever conducted for the prevention of cardiovascular disease in people withÂ diabetes,Â the FenofibrateÂ Intervention andÂ EventÂ Lowering inÂ Diabetes (FIELD) study, showed that patients treated with fenofibrate had a reduced rate of total cardiovascular events. Populations of 9,795 T2DM patients were given fenofibrate 200 mg daily, or placebo, over a 5-year event follow-up. FIELD evaluated the effect of fenofibrate on patients who were not taking a statin and after a median of 4.9 years. The study failed to meet the primary endpoint which was composed of CHD death or nonfatal MI. The reason for the lack of benefit from fenofibrate therapy is attributed to a disproportionately higher number of patients in the placebo group that were taking a statin by the end of the study (36% placebo vs. 19% fenofibrate) (Backes, et al. 2007; Barter, & Rye, 2006).
The importance of triglyceride lowering is demonstrated in the Veterans Affairs High-Density Lipoprotein Cholesterol Intervention Trial (VA-HIT) a randomized, double-blind, placebo-controlled clinical trial for the secondary prevention of coronary heart disease. The study had 2,531 men with coronary disease who were given gemfibrozil 1200 mg daily, or placebo, for a 5.1-year median event follow-up. The study demonstrates that gemfibrozil treatment significantly reduces the relative risk of major coronary events 22% and cardiovascular events by 24% in men with CHD and the lipid abnormality being low HDL cholesterol level. These findings suggest that, in a population with near optimal LDL levels by increasing HDL levels with a reduction in triglycerides can be an effective approach to decreasing the incidence of coronary events in secondary prevention. These results are impressive due to the improved outcomes being achieved without significantly lowering LDL cholesterol (Bazaldua, 2008; Grant & Meigs, 2007).
The Helsinki Heart Study (HHS), a double-blind, placebo-controlled 5 year trial focused on primary prevention evaluating Gemfibrozil 600 mg twice daily in an enrolled population of approximately 4,081 men without history of cardiac disease and with non-HDL-C levels >200 mg/dL. HHS was designed to confirm that coronary heart disease (CHD) can be prevented by gemfibrozil treatment and to analyze the long-term effect of the treatment. After 5 years, the study demonstrated a 34% decrease in the incidence of CHD events and the greatest reductions were noted for nonfatal myocardial infarction 37%, however, the rate of overall mortality was comparable to that with placebo. In addition, the HHS provided reassurance regarding the long term safety of fibrates (Barter & Rye, 2006; Frick, et al., 1987).
The effects of several lipid altering therapies in diabetics have been evaluated in clinical trials and the available data has proven adequate enough to promote an aggressive approach in the primary and secondary prevention of CVD. The concern is that there will still be those patients that have their risk factors treated and still die of CVD from residual risks. This is where studies that concentrate on increasing different areas of the lipid profile, HDL, have focused.
HDL, composed of triglyceride rich cholesterol, are small particles that exhibit an anti -atherogenic effect. They can prevent or reverse cholesterol deposits on arterial walls. They are involved with reverse cholesterol transport, a mechanism which removes deposits from arterial wall and foam cells and returns them to the liver to be processed. This aspect of removing harmful deposits has earned it a reputation as being good cholesterol. Higher levels of HDL are associated with a decrease in the risk of cardiovascular disease and their inverse relationship with triglycerides help serve as an indicator in abnormal chylomicrons and VLDL particles. Because of these properties several studies have focused on reducing cardiac risk by modifying this aspect of the dyslipidemia through the use of niacin products. Nicotinic acid raises HDL cholesterol more than fibrates, and its affect on triglycerides are similar, however it has greater effect on the reduction of LDL levels. A unique side effect of niacin causes flushing and itching, which had made its use undesirable but this became less of a problem with the extended release and sustained release forms. Unfortunately the different forms are still associated with increased blood glucose levels. The value and efficacy on the approach in the treatment of dyslipidemia will be covered in the following studies.
The Arterial Disease Multiple Intervention Trial (ADMIT), a prospective, randomized placebo-controlledÂ clinical trial conducted in 6 clinical centersÂ evaluated the effect of niacin on lipid levels in 468 patients with hypercholesterolemia of which 125 were diabetics. Â The average niacin dose was 3000 mg daily or the maximum tolerated dosage.
Niacin was associated with modest increases in fasting glucose in diabetic patients. Increases in fasting glucose were significantly greater with niacin than with placebo in both patients with and without diabetes. In addition, niacin was not associated with an increased frequency of use of oral antidiabetic drugs or insulin. Niacin use significantly increased HDL-C by 29% and 29% and decreased triglycerides by 23% and 28% and low-density lipoprotein cholesterol (LDL-C) by 8% and 9%, respectively, in participants with and without diabetes. Glucose levels were modestly increased by niacin in participants with and without diabetes. Levels of HbA1c were unchanged from baseline to follow-up in participants with diabetes treated with niacin. (Davis, et al., 2000;Watts, 2001)
The largest conducted study of niacin, the Assessment of Diabetes Control and Evaluation of the Efficacy of Niaspan Trial (ADVENT) a 16-week, randomized, double blind, placebo controlled study of 148 patients with type 2 diabetes highlights the therapeutic efficacy of Niaspan in managing lipid abnormalities in a population with a high risk of cardiovascular disease.
A 3 arm study, patients were randomly assigned to receive extended-release niacin 1 g daily, extended-release niacin 1.5 g daily, and placebo. Niaspan, alone or in combination with a statin, significantly improved lipid profiles in patients with type 2 diabetes and had minimal impact on blood sugar control, however, increased doses of antidiabetic drugs or the addition of a new antidiabetic drug was required in 16% of placebo patients, 24% of niacin 1 gram daily patients, and 29% of niacin 1.5 grams daily patients. Although the ADVENT study concluded that niacin could be safely used in diabetic patients, the need to add or increase doses of an antidiabetic drug as a result of niacin make it less optimal for most diabetes patients. (Grundy et al., 2002)
The Framingham Heart Study identified the major risk factors for CVD and established the relationship between cholesterol levels and heart disease. Since then subsequent studies designed specifically for diabetic patients have identified important clinical applications for primary and secondary prevention strategies (D'Agostino, et al, 2009).
In the prevention of macrovascular disease in patients with T2DM classic risk factors are as important as they are in non-diabetic subjects. In addition, high levels of triglycerides and low levels of HDL cholesterol should be a target of intervention. Finally, collective evidence indicates that poor metabolic control is associated with an increased risk for all manifestations of macrovascular disease. Therefore, the achievement of optimal glucose control should also be one of the cornerstones of treatment of diabetic patients, not only in the prevention of microvascular complications, but also in the prevention of atherosclerotic vascular disease (Goldberg, 2001).
All the collected studies recommend that the goal in management of the T2DM patient is to reduce their symptoms and improve the quality of life and that the mainstay of therapy should remain focused on glycemic control which is linked to microvascular disease processes. Managing microvascular complications should be considered in the primary management due to the synergistic effect on macrovascular pathology. This complication affects the role it has on smaller blood vessels and tight glycemic control has demonstrated to reduce these outcomes, however, dyslipidemia usually persists despite glycemic control alone.
More importantly is the prevention and treatment of macrovascular complications in diabetic patients. Under treatment of these complications is associated with increased morbidity and mortality. Reducing the morbidity and mortality associated with diabetes is an ongoing challenge. The key to diabetes management is multifaceted and requires the collaborative efforts of several healthcare disciplines, and most importantly compliance from the patient. The dynamic relationship with diabetes and the pathology of all the metabolic changes drive the management for treating all the conditions simultaneously and aggressively, as the combined metabolic processes don't operate independently in the body.
In conclusion, management of DM can no longer be focused solely on blood glucose. Aware of the clustering of risk factors, patients with diabetes and who also possess one or more cardiovascular risk factors-which predictably they all have- need to meet very strict goals for prevention and treatment. The challenge is to do a better job, both in diagnosing diabetes and monitoring patients for the development of dyslipidemia. The significance of addressing atherogenic dyslipidemia cannot be overemphasized in reducing their CVD risk. Once a patient has clinical diabetes, many therapies exist to treat the underlying abnormalities and allow us to help the patient to achieve the goals for both LDL and HDL. Many ongoing studies are being conducted that hopefully will shed new light on treatment modalities and further improve strategies for combating cardiac related morbidity and mortality, however, new research needs to focus on combination therapy. Modification of the lipid profile is a critical component to fully treat the process behind atherosclerosis, and reduce cardiovascular risk in patients with type 2 diabetes. As a result of the clinical benefit of lowering LDL cholesterol, statins are increasingly being used at higher doses, however, the residual risk of clinical events despite the use of statins supports the need to develop adjunctive therapeutic strategies to achieve ideal blood lipid levels for optimal reductions in cardiovascular risk.
on more aggressive lowering of cholesterol by reducing cardiovascular events through LDL levels. Treatment of LDL alone may be limited and further benefit may only be achieved through combination therapy. This has led to increased interest in targeting other lipid levels such as HDL cholesterol. Clinical trials (Bazaldua,et al, 2008; Grant, & Meigs, 2007) continues to show the cardiovascular benefits by reducing coronary events by treating the entire lipid profile are essential to reach goal and may soon become the standard of care.
As a person ages, levels of triglycerides and cholesterol have a tendency to rise. Elevation of triglyceride levels are thought to accompany other abnormalities that increase the development of cardiovascular disease which is why it is often measured with LDL and HDL.