Treating Dyslipidemia: Recommendations for Type 2 Diabetics

Type 2 diabetes affects an estimated 21 million people in the Unites States¹; 70% to 80% of diabetics will die of cardiovascular disease.^2,3 Patients often have had diabetes for up to 10 years prior to diagnosis and many present with cardiovascular disease (CVD) at diagnosis.⁴ In addition, studies have found that patients with diabetes have the same risk of having a future myocardial infarction (MI) as a nondiabetic who has already suffered a MI.⁵ Furthermore, diabetics also have a higher mortality rate from MIs than nondiabetics.⁶ 

Nondiabetic women generally have a much lower rate of CVD than their male counterparts. However, diabetic women have a similar rate of CVD as diabetic men, with up to a 15-fold increase in CVD versus nondiabetic women.⁷

Lipid-reducing therapy is one of the principal methods for decreasing the risk of CVD and its complications. Studies on treating dyslipidemia have historically excluded diabetics, but many recent studies have changed their target demographic. This article reviews some of the most pertinent new studies and discusses how they affect current recommendations for the treatment of dyslipidemia in type 2 diabetics.

DIABETIC DYSLIPIDEMIA

Most type 2 diabetics have a type of dyslipidemia that is related to insulin resistance. This profile is consist with decreased high-density lipoprotein (HDL), increased triglycerides, slightly increased low-density lipoprotein (LDL), and LDL particles that are smaller and more dense.⁸ Type 2 diabetics also have increased amounts of intermediate lipid particles, including very low-density lipoprotein (VLDL) and intermediate density lipoprotein (IDL). This can lead to an increased non-HDL cholesterol level—which is associated with an even higher risk of CVD than increased LDL levels in type 2 diabetics.⁹ VLDLs increase production of small dense LDLs which, along with IDLs, are very athrogenic. 

Additionally, Type 2 diabetics exhibit increased C-reactive protein levels and other markers of inflammation and thrombogenesis. This contributes to type 2 diabetics having 2 to 4 times the risk of CVD of similar age and risk-controlled patients.¹⁰

Currently, 70% to 80% of diabetics die of CVD; therefore, cardiovascular risk reduction should be a central part of diabetic management.

NONLIPID INTERVENTIONS

Before considering various lipid treatments for diabetics, it is crucial to maximize other interventions to reduce CVD. The United Kingdom Prospective Diabetes Study found that tight control of blood pressure in diabetics can have as much or more of an effect in CVD as LDL reduction.¹¹ In addition, the Heart Outcomes Prevention trial demonstrated that treatment with an angiotensin-converting enzyme (ACE) inhibitor reduced both overall mortality and CVD in hypertensive patients at high risk for CVD.¹² A daily aspirin reduces CVD by 25% to 50%.¹³ 

Smoking cessation is vital in reducing the risk of CVD. Therapeutic lifestyle change (TLC) can also have a significant effect on LDL levels and other markers of CVD risk. In fact, a very stringent, vegetarian diet with viscous fiber, plant sterols, soy protein, and almonds lowered LDL and C-reactive protein levels to the same degree as 20 mg of lovastatin a day.¹⁴ Additionally, physical activity is pivotal in the treatment of diabetes. Observational studies have shown that diabetics with the highest level of physical activity have a 40% to 45% reduction in CVD compared to those with the lowest levels of physical activity.¹⁵ There is no magic pill to prevent CVD in diabetes, but when all of these interventions are combined, the reduction in CVD achieved is much greater than that from lipid treatment alone.

PAST RECOMMENDATIONS

Adults

In 2001, the National Cholesterol Education Panel released the third Adult Treatment Panel (NCEP ATP III).¹⁶ For the first time, diabetes was considered a coronary heart disease (CHD) equivalent (Table). The goals for dyslipidemia treatment in all diabetics were defined as:

•A LDL <100 mg/dL. 

•Medication should be initiated at LDL levels above 130 mg/dL if this level was not achieved by 3 to 6 months of TLC. For LDL levels between 100 mg/dL and 130 mg/dL, TLC was recommended and drug therapy was optional. 

Children and Adolescents with Type 2 Diabetes

Children and adolescents with type 2 diabetes have similar dyslipidemia and insulin resistance as adults.¹⁷ In 2002, the American Diabetes Association (ADA) published new recommendations for dyslipidemia in children and adolescents. They recommended:

•A lipid panel screening of all type 2 diabetics at diagnosis, including children.¹⁸ Autopsy studies show that atherosclerosis is commonly seen before the age of 20.¹⁷ The LDL goal in this group is the same as adults: <100 mg/dL. 

•Treatment with TLC is recommended as first-line treatment. If the patient is older than 10 years and has a LDL >160 mg/dL after TLC, pharmacotherapy is recommended. For a LDL between 130 mg/dL and 160 mg/dL, drug treatment should be considered based on the patient’s CVD risk profile. A statin is the usual treatment of elevated LDLs. If the triglycerides are above 1000 mg/dL, a fibrate should be used. The ADA recommends the use of aspirin after the age of 40. 

•Other risk factors such as tobacco use, hypertension, tight glucose control, weight control, and exercise should be addressed.

The original ATP III recommendations were similar for a diabetic with chronic heart disease (CHD) and a diabetic without the disease. Thus, the LDL goal for all diabetics was <100 mg/dL. Treatment was only recommended if the  LDL remained above 130 mg/dL after 3 to 6 months of TLC. Since the ATP III was released, many lipid treatment trials have specifically included diabetic patients, both for primary and secondary CVD prevention. These trials have added significant information to the treatment of dyslipidemia in diabetics.

RECENT TRIALS

HPS

The Heart Protection Study (HPS) examined statin treatment in 20,536 patients at high risk for CVD with borderline lipids. The average baseline lipids were a cholesterol of 228 mg/dL and a LDL of 131 mg/dL.¹⁹ The study included 3,982 patients with diabetes and CVD and 1,981 patients with diabetes and no known CVD.²⁰ Patients were randomized to placebo or 40 mg of simvastatin a day. There was a statistically significant reduction in CVD events by 25% in the treatment group despite the low pretreatment LDL level. 

A similar reduction of 27% in the diabetic subset of the study was also statistically significant. Even diabetics with baseline LDLs <116 mg/dL demonstrated a significant reduction in CVD events, both those with prior CVD events and those without. 

Patients with a baseline LDL <100 mg/dL (diabetics and nondiabetics) exhibited a significant decrease in CVD events as well. The average post-treatment LDL in this group was 65 mg/dL. 

This study suggests that all diabetic patients, both with and without known CVD, should be treated with a statin. It also suggests that a LDL goal of <70 mg/dL should be considered.

PROVE-IT TIMI 22

The Pravastatin or Atorvastatin Evaluation and Infection Therapy–Thrombolysis in Myocardial Infarction 22 (PROVE-IT TIMI) trial²¹ further confirmed the benefit of more aggressive statin treatment to reach a lower LDL goal. A total of 4,162 patients were randomized to 40 mg of pravastatin a day or 80 mg of atorvastatin a day within 10 days of hospital admission for acute coronary syndrome (ACS). The study included 734 diabetics, although separate analysis was not done for this group. 

The mean pretreatment LDL was 106 mg/dL and treatment resulted in mean LDLs of 95 mg/dL for pravastatin and 65 mg/dL for atorvastatin. The primary outcome was a major CVD event. The atorvastatin group showed a clinically significant decrease of 16% at 24 months compared to the pravastatin group. The study was scheduled to run for 5 years, but was stopped early due to the significant positive treatment effect. There was a trend towards decreased overall mortality that may have been reached with longer study duration. 

This trial suggests that aggressive treatment of ACS patients with a high-dose, high-potency statin yields a greater protective effect against future CVD events by attaining a VLDL (65 mg/dL in this study).

VA-HIT 

The Veterans Affairs High-Density Lipoprotein Intervention Trial (VA-HIT) studied 2,531 older men with a history of CVD. A lipid profile common to type 2 diabetics was average LDL cholesterol, high triglycerides, and low HDL cholesterol. They were treated with 1200 mg a day of gemfibrozil or placebo. There was a 22% reduction in MI or CVD death among all treated patients and a 24% reduction in the 627 diabetics, both clinically significant. The average LDL was 140 mg/dL at the time of randomization.²² A subgroup analysis of patients with insulin resistance demonstrated a statistically significant 28% reduction in CHD events.²³ 

This study suggests that a fibrate may be the best treatment for patients with CVD, low LDL, low HDL, high triglycerides, and either diabetes or insulin resistance. 

ASCOT-LLA

The Anglo-Scandinavian Cardiac Outcomes Trial—Lipid Lowering Arm (ASCOT-LLA)²⁴ trial randomized 19,342 hypertensive patients with 3 other risk factors to 10 mg of atorvastatin a day plus blood pressure treatment or placebo plus blood pressure treatment. These patients did not have known CVD and had a moderately elevated LDL, averaging 132 mg/dL. The trial was stopped early due to an observed 36% reduction of nonfatal MI and fatal CHD at 3.3 years in the atorvastatin group.²⁴ 

In the diabetic subgroup of 2,532 patients, there was a 16% reduction in CHD events. This observation did not reach statistical significance, possibly because of the short duration, small number of participants, and lower incidence rate in the placebo group (16%) compared to other studies.²⁴ 

This study further supports the conclusion from the HPS in that statin therapy provides effective primary prevention of CVD for patients with moderately elevated LDLs and moderate risk of CVD.

CARDS

The Collaborative Atorvastatin Diabetes Study (CARDS)²⁵ trial is the most recent and most specific trial to diabetics.²⁵ The trial studied 2,838 diabetics without known CVD and at least one of the following comorbidities: hypertension, retinopathy, microalbuminuria, macroalbuminuria, or current smoking habit. Patients were randomized to 10 mg a day of atorvastatin or placebo for an average of 3.9 years. Baseline LDL was 117 mg/dL, decreasing to 81 mg/dL in the treatment group and remaining the same in the placebo group. This resulted in a statistically significant 37% reduction in major CVD events and a 27% reduction in overall mortality. 

This is the first statin trial to demonstrate a significant reduction in overall mortality in diabetics. This study was also stopped 2 years early due to the significant positive treatment effect.

SUMMARY OF NEW STUDIES

In general, observation studies and intervention studies support a log-linear relationship of LDL cholesterol levels and CVD incidence.²⁶ In simpler terms, for each 35 mg/dL decrease in LDL, there is a subsequent 50% decrease in CVD in population studies and a 25% decrease in intervention studies.²⁶ Recent studies seem to confirm that the effect is consistent across all baseline LDL cholesterol levels. At the time of the ATP III, there were no interventional trials studying the reduction of LDLs <100 mg/dL. There was also very limited data specifically applicable to diabetics regarding primary and secondary CVD prevention through lipid reduction. Recent trials have suggested that there is approximately a 25% reduction in CVD events for every 35 mg/dL reduction in LDL levels. This appears to be independent of the initial LDL level, relative risk of CVD, or whether treatment is for primary or secondary prevention.

A very practical variable that must always be considered for any prospective treatment is the pretreatment probability. For example, consider 2 different patients: a 65- year-old diabetic male with a history of MI, hypertension, and smoking, and a 30-year-old female without any CVD risks. Statin treatment reduces CVD event rate by the same 25% for both patients. Although the relative risk reduction is equal, the absolute risk reduction is markedly different because of the difference in pretest probability. Another way to look at it is the number of patients one needs to treat to prevent one CVD event. For the first patient, this would likely be >10. For the second, it would likely be >1,000 patients treated for 5 years to prevent one event.

WHAT WE LEARNED

•In all patients with ACS, including diabetics, the treatment target should be less than 100 mg/dL and achieving the goal might require a high-dose, high-potency statin.

•In very high risk patients, those with CVD, diabetes or both, a LDL goal of <70 mg/dL is optional.

•All diabetics, even those with LDL less than 100 mg/dL, should be on a statin, whether for primary or secondary CVD prevention. The caveat is that if a patient has a low LDL, low HDL, and high triglycerides, a fibrate should be considered as first-line treatment. With a borderline LDL, low HDL, and high triglycerides, a statin plus a fibrate should be considered. Fenofibrate is recommended when a fibrate is combined with a statin because it minimally increases the risk of muscle and liver toxicity when compared to other fibrates. Fenofibrate has been shown both alone and with atorvastatin to reduce intermediate markers of CVD.^27,28

•These studies did not include, and thus have not affected, recommendations for children and adolescents.

•There still is limited and inconclusive data for other medical interventions—including niacin, ezetimibe, and fish oils. These should primarily be used after statins and fibrates in patients unable to reach lipid goals or who do not tolerate the other medications.

These recommendations are very similar to the ADA’s and the NCEP ATP III’s recent revision of previous recommendations.^30,31

All type 2 diabetics should have their lipids profile at the time of their diagnosis. All diabetics should be on pharmacologic lipid-lowering therapy unless the patients are young, and at very low risk, or have an LCD cholesterol <70 mg/dL. At least a moderate dose of statin should be used, and the LDL level should be lowered by at least 30% to 40%. In the very high risk diabetic (including ACS), lowering the LDL to a goal of <70 mg/dL is optional.

Although lipid-lowering treatment has been proven to prevent at least 25% of CVD events, only one study showed a decreased mortality in diabetics.²⁵ All other intervention with a proven reduction in both CVD and mortality must be utilized. This includes TLC, aspirin in high-risk diabetics over 40, exercise, smoking cessation, tight blood pressure control, and ACE inhibitors in those at high risk for CVD. 

When proper lipid-lowering treatment is combined with modification of other CVD risk factors, providers can markedly reduce CVD and mortality in diabetics. In fact, a study of intensive treatment of all diabetic risk factors (including lipids) showed a >50% reduction in CVD, nephropathy, retinopathy, and autonomic neuropathy.³² Future research, including studies on adolescents and young adults, is needed to elucidate the effectiveness of fibrates for primary CVD prevention and their utility in conjunction with statins. ■

Thomas H. Clark, MD is a family practice physician working for Intermountain Healthcare. He specializes in diabetes, insulin resistance, and obesity treatmen

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