The Dyslipidemia of Type 2 Diabetes: Treatment Strategies

                    Focus on Cardiometabolic Risk                    

ABSTRACT: In non-urgent settings, lifestyle changes are the initial line of therapy for patients with diabetic dyslipidemia. Statins, which reduce ischemic cardiovascular events, are the first choice of lipid-altering medication. Fibric acids are a reasonable initial option for patients with triglyceride levels above 200 mg/dL and high-density lipoprotein (HDL) cholesterol levels below 35 mg/dL; in such patients, they reduce risk as effectively as statins. Niacin raises HDL cholesterol to a greater degree than other lipid-altering agents and when given by itself in high doses decreases ischemic cardiovascular events. When added to statin therapy, niacin does not reduce events in patients who have only minor changes in HDL cholesterol and/or non-HDL cholesterol with treatment. Fish oils lower triglycerides; recent studies, however, have shown no reduction in ischemic cardiovascular events and thus should only be the last medication ordered in a multi-lipid-altering drug regimen.

Key words: diabetes, dyslipidemia, low-density lipoprotein cholesterol, statins, fibrates, niacin

During the past 30 years, the ability to control risk factors for atherosclerosis in persons with diabetes has improved significantly with more varied and powerful agents to control blood pressure, lipids, and glucose. But such agents must be used aggressively and continuously to reverse the long-term morbidity and early fatal consequences of diabetes. As a result of the accelerated atherothrombotic processes associated with diabetes, a person who receives a diagnosis of type 2 diabetes at age 55 has a reduction in lifespan of 5 years.

This article will focus on treating the dyslipidemia associated with insulin resistance in type 2 diabetes.

DIABETIC DYSLIPIDEMIA: AN OVERVIEW

Insulin-resistant type 2 diabetes is often associated with the dyslipidemic triad of:

•An increase in triglycerides (mainly present in very low-density lipoprotein [VLDL] remnants).

•A decrease in high-density lipoprotein (HDL) cholesterol.

•Smaller, denser low-density lipoprotein (LDL) particles.

As seen in the United Kingdom Prospective Diabetes Study (UKPDS), adults with new-onset diabetes have triglyceride levels about 60 mg/dL higher than persons without diabetes; HDL cholesterol levels are 5 mg/dL lower in men and more than 10 mg/dL lower in women than in age-matched persons without diabetes.² Elevated triglyceride levels (150 mg/dL or higher) and decreased HDL cholesterol levels (less than 40 mg/dL in men and less than 50 mg/dL in women) are criteria in most definitions of insulin resistance.³ In addition, men with diabetes have 50% small, type B LDL particles compared with 25% in nondiabetic men⁴; women with diabetes have 36%, compared with 6% in nondiabetic women.⁵

NON-HDL CHOLESTEROL AS A TREATMENT GOAL IN DIABETIC DYSLIPIDEMIA

Smaller LDL particles are more rapidly taken up into the vascular subendothelial space, more avidly associate with the proteoglycans in the subendothelial space, are more rapidly oxidized than large LDL, and thus are ultimately more atherogenic.⁶ In addition, for two persons with the same serum LDL cholesterol level, the person with dyslipidemia who has a smaller LDL particle volume must have more LDL particles. Thus, the LDL cholesterol level as measured by the standard lipid profile in diabetic populations with elevated triglycerides underestimates the LDL particle number as measured by apoB or by LDL particle number using nuclear magnetic resonance (NMR) spectroscopy.⁷

So what do we use when the standard LDL cholesterol measurement may underestimate cardiovascular risk? Although lipidologists will occasionally look at the apo B or NMR LDL particle number, non-HDL cholesterol is also a better goal-setting measure than LDL cholesterol in the presence of elevated triglycerides or lowered HDL cholesterol. Goals for non-HDL cholesterol are 30 mg/dL higher than goals for LDL cholesterol, and are being reported by more laboratories in the standard lipid profile results. A recent meta-analysis of persons in long-term placebo-controlled statin trials found that persons achieving LDL-C greater than or equal to 100 mg/dL but non-HDL-C goal less than 130 mg/dL had no increased risk of cardiovascular events compared with those achieving both LDL-C less than 100 mg/dL and non-HDL-C goal less than 130 mg/dL. However, persons achieving the LDL-C goal of less than 100 mg/dL but with non-HDL-C goal still greater than or equal to 130 mg/dL had an increased event rate of 30% (HR 1.32, 95% CI 1.17 – 1.50).⁸ In talking with patients, if the non-HDL cholesterol (“not-healthy cholesterol”) is not on the report, I calculate the level with the patient and then go over ways in which we are going to achieve that goal.

TREATMENT OF DIABETIC DYSLIPIDEMIA

Lifestyle changes. In a patient with an elevated triglyceride level (but less than 1000 mg/dL) and a low HDL cholesterol level who has no recent history of an ischemic cardiovascular event, by far the most powerful therapy is lifestyle modification. I recommend the following four interventions:

•Discontinuation of all sugar-containing beverages, particularly fruit juices, which supply the fructose for fatty acid synthesis. Always ask the patient what he or she drinks with meals and also between meals. Most adults consider fruit juices healthy or at least harmless, but this is not true for a patient with diabetic dyslipidemia. Consumption of sugar-containing beverages must be stopped, and sugar-free beverages or water should be substituted.

•Weight loss, even 10 to 15 lb. I tell patients that by losing weight, they lose intra-abdominal fat, which supplies the free fatty acids to the liver with which
it synthesizes triglycerides and VLDL particles.

•Regular exercise. Advise patients to begin a scheduled exercise program 3 times per week. If they start with a reasonably timed amount and type of exercise with which they are comfortable, the amount of exercise done will increase naturally. Exercise increases the activity of lipoprotein lipase, which hydrolyzes circulating triglycerides for storage in adipose and muscle tissues.

•Heavy alcohol consumption must be modified to no more than 2 drinks per day, ie, alcohol without accompanying sugar-containing liquids, such as tonic water or orange juice. No sweet liqueurs should be consumed, and beer must be light. Some lipidologists prefer only 1 alcoholic beverage per day or none at all.

It is better to try lifestyle changes without giving a lipid-altering agent for at least 8 weeks before re-measuring the lipid profile. For patients who make any effort, triglycerides will start to decrease and they will learn very clearly the specific benefit of lifestyle change. In addition, glucose must be controlled in those with hyperglycemia, or triglycerides may never normalize.

Hypoglycemic agents. Some hypoglycemic agents that decrease insulin resistance have been shown to improve baseline lipid levels.⁹ However, the beneficial lipid changes associated with metformin and the thiazolidinediones have not necessarily translated into major preventive clinical benefits. In the UKPDS, patients who received metformin had a relative risk reduction of 30% (absolute risk reduction over 10 years of 1.4%) in macrovascular ischemic events compared with those who received dietary therapy only, but no significant risk reduction was found when the metformin group was compared with other intensive therapy groups.¹⁰ In the PROspective pioglitAzone Clinical Trial In macroVascular Events (PROACTIVE) trial, all-cause mortality, non-fatal myocardial infarction, and stroke were reduced by 16% (P 5 .027), with an absolute risk reduction of 2.1%, in obese patients with type 2 diabetes and previous ischemic macrovascular disease who received pioglitazone.¹¹

Although mildly positive preventive effects on ischemic cardiovascular disease can be seen with hypoglycemic agents, these effects are not great, and side-effect concerns about pioglitazone have curtailed its use in many patients. The UKPDS study does illustrate the importance of excellent glucose control for cardiovascular prevention.

Statins. These are first-line lipid-modifying drugs because of their extensively documented preventive benefits. Low-density lipoproteins are the most common atherogenic lipid particles in diabetic dyslipidemia; statins, which dramatically reduce LDL cholesterol, have thus become the drugs of choice for treating it. In addition, the more potent statins (simvastatin, atorvastatin, and rosuvastatin) reduce triglyceride levels by up to 28%.¹² All statins raise HDL cholesterol levels by 3% to 7%; rosuvastatin raises them 7.5% to 9.5%.¹²

A meta-analysis done for the American College of Physicians of lipid-lowering therapy in type 2 diabetes included primary and secondary prevention trials that used statins in a wide variety of patients.¹³ The meta-analysis showed a primary preventive relative risk reduction of 22% and absolute risk reduction of 3% during 4.3 years of treatment. Secondary prevention trials produced a similar relative risk reduction of 24% but a doubling of the absolute risk reduction to 7% during 4.9 years of treatment, which demonstrated the relatively more powerful effect in higher-risk patients during these relatively short periods.

The trial I discuss most often with patients is a subsequent major primary prevention trial, the Collaborative Atorvastatin Diabetes Study (CARDS), which enrolled only diabetic patients with at least one other risk factor.¹⁴ Subjects were randomized to atorvastatin or placebo with a primary combined endpoint of first coronary heart disease (CHD) event, coronary revascularization, or stroke. Baseline LDL cholesterol of 118 mg/dL was lowered in the atorvastatin group to 84 mg/dL and increased to 124 mg/dL in the placebo group by year 4. The trial was stopped 2 years early with a 3.9-year 37% relative risk reduction and absolute risk reduction of 3.7%.

I tell patients with no history of an ischemic cardiovascular event that the most likely serious health consequence of diabetes will be just that, a myocardial infarction (MI), stroke, or stent/bypass, and that they can reduce their risk by more than one third by taking a low-dose powerful statin. However, on their first visit, I do not try to control glucose, lipids, and blood pressure at the same time with medications for all three conditions. A statin can be introduced during the second or third visit as glucose and blood pressure are being controlled; the key is to focus on one risk factor at a time.

A more recent meta-analysis, including CARDS, performed by the Cholesterol Treatment Trialists’ (CTT) Collaboration of statin therapy in primary and secondary trials showed a 20% reduction in major cardiovascular events (major coronary event, stroke, or coronary revascularization) per 1 mmol (about 40 mg/dL) reduction in LDL cholesterol in those with and without diabetes—and importantly in those with baseline LDL cholesterol levels of less than 100 mg/dL (2.6 mmol/L).¹⁵

An LDL cholesterol of less than 70 mg/dL in diabetic patients with CHD was an “optional” goal in the 2004 National Cholesterol Education Program (NCEP) update¹⁶ and more recently was upgraded to a “reasonable” recommendation in the 2006 guidelines of the American Heart Association and the American College of Cardiology, and endorsed by the National Heart Blood and Lung Institute.¹⁷ The NCEP guidelines for the LDL cholesterol goal in those with diabetes but without CHD remains less than 100 mg/dL. The reduction of LDL cholesterol from 124 to 84 mg/dL, which produced preventive effects in the CARDS trial, has been the major clinical evidence supporting this goal. The American Association of Clinical Endocrinologists has recommended an LDL cholesterol goal of less than 70 mg/dL for diabetic persons both with and without CHD who have at least one cardiovascular risk factor.¹⁸

The Heart Protection Study also demonstrated that an LDL cholesterol level of less than 100 mg/dL may be preventive.¹⁹ Even in those whose baseline LDL cholesterol was less than 100 mg/dL, the reduction in ischemic cardiovascular events was 25%, which suggests that an LDL cholesterol goal of significantly less than 100 mg/dL is evidence-based. Thus, lower LDL cholesterol goals for persons with diabetes may be appropriate and in the future may be more data-based. Certainly, given the results of the meta-analyses and CARDS, obtaining an LDL cholesterol level substantially below 100 mg/dL in those with diabetes, and with any other cardiovascular risk factors or previous ischemic disease, has well-documented preventive benefits.

Fibric acids. For patients with lifestyle- and statin-resistant hypertriglyceridemia and low HDL cholesterol, fibric acids can be very preventive. These agents improve lipid profiles of patients with type 2 diabetes and decrease clinical cardiovascular events; however, trial results have been increasingly disappointing and have indicated that fibric acids may be preventive only in those with sufficiently high triglycerides and low HDL cholesterol.

The Veterans Administration HDL Intervention Trial (VA-HIT) was one of the most successful trials of fibric acids.²⁰ More than 2500 men with CHD were randomly assigned to gemfibrozil or placebo. After about 5 years, there was an overall 22% relative risk reduction in CHD death and MI (P 5 .006) and a 4.4% absolute risk reduction. In a subanalysis of those with baseline diabetes, the relative risk reduction of MI, CHD death, and stroke was 32% with absolute risk reductions of 9.9%.²¹

These results are similar to those of the primary prevention Helsinki Heart Trial in which men without CHD who had non-HDL cholesterol levels higher than 200 mg/dL were randomized to gemfibrozil or placebo.²² The overall trial showed a reduction in CHD death and MI of 34% (P < .02). In a two-tiered subanalysis, the group with triglycerides greater than 200 mg/dL and LDL-C/HDL-C ratios greater than 5.0 (low HDL cholesterol) at baseline had a highly significant 71% reduction in CHD events, with non-significant reductions in all other groups.²³

An important clinical trial of another fibric acid was the Fenofibrate Intervention and Event Lowering in Diabetes (FIELD) study.²⁴ This study enrolled 9800 patients with type 2 diabetes whose total cholesterol level was 115 to 250 mg/dL with either a total cholesterol/HDL cholesterol ratio of 4 or higher, or triglycerides between 89 and 443 mg/dL. Twenty-five percent of the patients had a history of CHD. Participants could not be taking lipid-altering therapy at baseline, but there was no restriction on lipid-lowering medications that could be added after the trial started.

The 11% reduction in the primary endpoint of MI and CHD death was not significant largely because by the end of the study 36% of those receiving placebo but only 19% of those receiving fenofibrate had independently started statin therapy. When the end point was adjusted for statin use, it was significantly decreased 19% (P 5 .01). The 11% decrease in all cardiovascular events was due to a significant 24% reduction in MI and 21% reduction in coronary revascularizations with no significant decrease in stroke, CVD death, or total mortality. As seen in the Helsinki Trial, the primary endpoint was reduced slightly more in the group with triglyceride levels above 150 mg/dL and HDL cholesterol levels of less than 40 mg/dL in men and less than 50 mg/dL in women (14% relative risk reduction, P 5 .06).

Although regarded by many and by the FDA as a negative study for event reduction, correction for this differential use of statins increases the nonsignificant 11% decrease in the primary endpoint of MI and CHD death to a significant decrease of 19%. Thus, I tell patients with very high triglycerides that fenofibrate will improve their dyslipidemia (an FDA indication) and most likely decrease coronary risk 15% to 20% (not an FDA indication).

The Bezafibrate Infarction Prevention (BIP) Study was a secondary prevention trial in patients with HDL cholesterol of 45 mg/dL or lower, triglycerides of 300 mg/dL or lower, and LDL cholesterol of 180 mg/dL or lower randomized to receive either bezafibrate or placebo and followed for about 6 years.²⁵ The reduction in the primary endpoint of MI or sudden death was not statistically significant. However, in a post hoc subanalysis of those with triglycerides of 200 mg/dL and higher, and especially in those who also had an HDL cholesterol level lower than 35 mg/dL, there was a 39.5% reduction in this primary endpoint (P 5 .02). Subanalyses in those with 3 or more components of the metabolic syndrome—especially those with 4 or 5 components—significant relative risk reductions in events of 25% to 40% occurred.

The results of VA-HIT, the Helsinki Heart Trial, the FIELD study, and the BIP study suggest that fibric acids have definite and measurable cardiovascular preventive effects in patients with diabetes and in those with insulin resistance. The preventive benefits are always greater, and perhaps only become statistically significant, in those with higher baseline triglycerides and lower HDL cholesterol levels. Thus, although statins remain the first choice in patients with diabetes, in diabetic patients with raised triglycerides (greater than 200 mg/dL) and low HDL cholesterol, treatment with a fibric acid as the first lipid-altering agent would most likely provide equivalent preventive effects.

The Action to Control Cardiovascular Risk in Diabetes (ACCORD) Lipid Trial demonstrated the benefit of adding a fibric acid (fenofibrate) to a statin (simvastatin) in a subgroup of patient with diabetes who had triglycerides higher than 200 mg/dL and HDL cholesterol lower than 35 mg/dL.²⁶ Subgroup analysis showed a trend for a decrease in events of about 30%. This study adds to the totality of evidence that fibric acids alone or with a statin may be most effective in the 10% to 20% of persons with diabetes who have the most severe triglyceride and HDL cholesterol abnormalities.

Niacin. One obvious focus in treating the dyslipidemia of diabetes is to raise the lowered HDL cholesterol. Although lifestyle changes, fibric acids, and statins will raise HDL cholesterol, the greatest increase is achieved with niacin. HDL cholesterol is raised in a dose- and time-dependent manner with continuous increases seen at dosages of niacin of up to 2 g/d²⁷ and with intermediate-release niacin at dosages of up to 2.5 g/d.²⁸

The choice of niacin formulation is highly important. Inositol preparations (non-flush niacin) produce no lipid changes because of inadequacy of absorption.²⁹ Slow, time-release niacin at high dosages produces less of an increase in HDL cholesterol or lowering of triglycerides than crystalline niacin and more hepatotoxicity.³⁰ However, it has fewer dermatologic side effects. Extended-release niacin has HDL cholesterol effects equivalent to those of crystalline immediate-release niacin with fewer adverse effects.³¹

To help patients with a history of flushing and pruritus tolerate extended-release niacin, I start them on an over-the-counter slow-release niacin 250 mg for 1 week, 500 mg for 1 week, 1000 mg for 2 weeks, and then switch to extended-release niacin 1000 mg for 4 weeks, and then 2000 mg for 8 weeks before checking blood test results of this intervention. I also recommend aspirin 325 mg, taken just before the nightly dosing, which is much more effective than 81 mg of aspirin in preventing dermatologic adverse effects of niacin.

Niacin in dosages as high as 4500 mg/d significantly raises glucose levels,³² which is why for many years its use was cautioned in those with diabetes. More recent studies, however, show smaller transient elevations in fasting glucose levels, and generally small or no increases (0.2% to 0.3%) in hemoglobin A_1c at dosages of 1 to 3 g/d.^33,34 A rare patient may require increased dosages of hypoglycemic medications or may have to discontinue niacin because of major changes in glucose control.³³ Uric acid levels may increase 10% to 15%, and patients with high baseline serum uric acid levels or a history of gout must be warned of the possibility of an acute gouty attack.

The Coronary Drug Project, a secondary prevention randomized, placebo-controlled study in 8300 men with CHD, demonstrated a 5-year 27% decrease in nonfatal MI, a 26% decrease in stroke and transient ischemic attack, and a 15-year 11% reduction in total mortality in those using 3 g/d of immediate-release, or crystalline, niacin.^35,36 No other niacin versus placebo studies have been done. More recent trials have studied statin/niacin combinations versus double placebo, or the addition of niacin versus placebo to a statin.

The HDL-Atherosclerosis Treatment Study (HATS) was a small, double-blind quantitative coronary angiography imaging study of persons with CHD and low HDL cholesterol.³⁷ One group was randomized to simvastatin and immediate-release niacin, the other to double placebo. Plaque progression was only 0.2% in the group receiving simvastatin/niacin compared with 3.9% in those receiving placebo (P < .001). Although not powered as a clinical event reduction trial, there was a 90% reduction in coronary clinical events, including coronary revascularization, in the simvastatin/niacin versus placebo group (P 5 .003).

Two newer placebo-controlled, double-blind imaging studies (Arterial Biology for the Investigation of the Treatment Effects of Reducing Cholesterol [ARBITER] 2 and ARBITER 3 that measured carotid intimal medial thickness (IMT) explored the addition of intermediate-release niacin to ongoing statin therapy versus continuing the statin therapy alone in persons with CHD.^38,39 In both studies, intermediate-release niacin was associated with an increase in HDL cholesterol levels and a halt or reduction in the progression of carotid IMT; however, there was no difference in clinical events compared with statin therapy alone.

In ARBITER 6, persons with CHD who were receiving statin therapy were randomized to extended-release niacin or ezetimibe.⁴⁰ Although non-HDL cholesterol levels were the same in each group, the extended-release niacin group had significantly higher HDL cholesterol levels (8 mg/dL), decreased mean carotid IMT, and fewer ischemic cardiovascular events (MI, revascularization, and death).

In the recent Atherothrombosis Intervention in Metabolic Syndrome with Low HDL/High Triglycerides Impact on Global Health Outcomes (AIM-HIGH) trial, patients with cardiovascular disease were randomized to extended-release niacin or placebo (with a smaller dosage of extended-release niacin to keep the study blinded), while taking a statin and ezetimibe as needed.⁴¹ At 3 years with only a differential 9 mg/dL lowering of non-HDL cholesterol and 5 mg/dL raising of HDL cholesterol in the niacin/statin versus placebo/statin group, there was no difference in ischemic cardiovascular events. We await subgroup analysis results. The AIM-HIGH study does suggest that to match the preventive results of the previously cited trials, niacin added to a statin must achieve a greater differential rise in HDL cholesterol or lowering of non-HDL cholesterol than that achieved in this trial.

Based on the excellent results of the Coronary Drug Project and the mixed results seen in the HATS, ARBITER, and AIM-HIGH trials, here are my recommendations for diabetic patients with ischemic cardiovascular disease, hypertriglyceridemia, and reduced HDL cholesterol:

•For persons who have been taking statins and extended-release niacin for years with large increases in HDL cholesterol (more than 5 mg/dL), I do not discontinue their extended-release niacin at this point. However, if extended-release niacin has not had this HDL cholesterol-raising effect, then I would stop it, since the AIM-HIGH trial showed absolutely no benefit from a smaller HDL cholesterol increase.

•In patients who have progressive CHD with non-HDL cholesterol levels higher than 115 mg/dL, I would not hesitate to start extended-release niacin to treat their dyslipidemia (an FDA-approved indication) and I would aim to raise their HDL cholesterol by significantly more than 5 mg/dL and lower non-HDL cholesterol by 20 mg/dL if I wished to expect any clinical benefit.

Fish oil. Fish oils (eicosapentaenoic acid [EPA] and docosahexaenoic acid [DHA]) have an FDA indication to lower triglycerides. Three recent trials indicate that fish oils added to standard post-MI treatment, even in those with diabetes and/or impaired glucose tolerance, are ineffective in reducing ischemic cardiovascular events.^42-44 Although subanalysis data from the Japan EPA Lipid Study (JELIS) have shown a reduction in events using EPA 3000 mg/d in patients without previous CHD who had triglyceride levels of 150 mg/dL or higher and HDL cholesterol levels of less than 40 mg/dL,⁴⁵ ecologic concerns about declining fish populations suggest that a fibric acid or niacin be used first.