ABSTRACT: Low-density lipoproteins are the most common atherogenic particles in diabetic dyslipidemia; therefore statins, which dramatically reduce low-density lipoprotein (LDL) cholesterol, are first-line therapy for patients with diabetes. These agents produce equivalent relative risk reductions in those with and without diabetes but confer greater absolute risk reduction because of the increased incidence of ischemic cardiovascular events in those with diabetes. The LDL cholesterol goal for patients with diabetes who do not have coronary heart disease is below 100 mg/dL. For secondary prevention, the goal is below 70 mg/dL. High-dose statin therapy may be required to achieve these goals. Fibric acids are a reasonable initial option for patients with triglyceride levels above 200 mg/dL and high-density lipoprotein (HDL) cholesterol levels below 40 mg/dL; in such patients they reduce risk as effectively as statins. Intermediate-release niacin raises HDL cholesterol levels; the effect is enhanced when niacin is combined with a statin.
The greatly increased risk of coronary heart disease (CHD) and its sequelae in patients with diabetes demands that all modifiable risk factors be addressed. In the past 10 years, the ability to control risk factors for atherosclerosis in these patients has improved significantly with the availability of more varied and more powerful agents to control blood pressure, lipids, and glucose. Such efforts, which can produce relative risk reductions of up to 50%, must be used aggressively and continuously to reverse the long-term morbidity and early fatal consequences of diabetes. In this article, I focus on managing the dyslipidemia associated with insulin resistance in type 2 diabetes, an essential component of treatment.
THE CASE FOR INTERVENTION
Evidence has shown that the life span of patients in whom diabetes is diagnosed in their 40s and 50s is shortened by 6 to 8 years; the major cause of death in these patients is ischemic heart disease.1 Even when a diabetic patient survives a first myocardial infarction (MI), his or her prognosis is worse than that for a person without diabetes. One study that included 1700 patients with diabetes who had been hospitalized with unstable angina or MI found that the mortality in these patients was nearly double that of patients without diabetes.2
Other evidence, however, underscores the fact that intervention can improve outcomes for these patients. The Steno-2 study showed that an intensive multifactorial intervention in patients with diabetes and microalbuminuria resulted in a 50% relative risk reduction (20% absolute risk reduction) in the combined end point of MI, death from CHD, stroke, amputation, and revascularization, as well as measures of microvascular disease.3
Insulin-resistant type 2 diabetes is associated with the dyslipidemic triad of an increase in triglyceride levels, a decrease in high-density lipoprotein (HDL) cholesterol levels, and a preponderance of smaller, denser low-density lipoprotein (LDL) particles.4 As reported 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.5 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.
Some studies have shown that metformin and thiazolidinediones, which decrease insulin resistance, also produce beneficial changes in lipid levels.6,7 However, these changes have not translated into major preventive clinical benefits. In the UKPDS, although there was a significant reduction in relative risk of macrovascular disease events in patients who received metformin versus those receiving usual care, there was no significant risk reduction when these patients were compared with diabetic patients treated intensively with insulin or a sulfonylurea.8
In the PROspective pioglitAzone Clinical Trial In macroVascular Events (PROactive), at 34.5 months, although the aggregate primary cardiovascular end point was not reduced significantly, the more commonly used, prespecified secondary end point of all-cause mortality, nonfatal MI, and stroke was reduced by 16% (P = .027) with an absolute risk reduction of 2.1%.9 These preventive results of insulin-sensitizing drugs can be compared with the more dramatic preventive effects of the lipid- altering drugs discussed next.
Statins are first-line lipid-altering drugs because of their extensively documented preventive benefits. These agents produce equivalent relative risk reductions in those with and without diabetes but confer greater absolute risk reduction because of the increased incidence of ischemic cardiovascular events in those with diabetes.
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 patients with this condition. In addition, the more potent statins (simvastatin, atorvastatin, and rosuvastatin) reduce triglyceride levels by 12% to 28%.
All statins raise HDL cholesterol levels 3% to 7%; rosuvastatin raises them 7.5% to 9.5%.10
Evidence from the trials. A meta-analysis of lipid-lowering therapy in type 2 diabetes included primary and secondary prevention trials that measured results with statins in a wide variety of patients (Tables 1, 2, and 3).11 In the individual trials, some diabetes subgroup analyses showed statistically significant preventive effects; others did not. However, the meta-analysis, with vastly increased numbers of participants and usually including end points of MI, CHD death, cerebrovascular accident (CVA), and coronary revascularization, showed a primary preventive relative risk reduction of 22% and absolute risk reduction of 3% during 4.3 years of treatment. Secondary prevention 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 testing periods.
A subsequent major primary prevention trial, the Collaborative Atorvastatin Diabetes Study (CARDS), enrolled only diabetic patients aged 40 to 75 years with at least 1 other risk factor--retinopathy, hypertension, current smoking, or albuminuria.12 Baseline LDL cholesterol of 118 mg/dL in the atorvastatin group fell to 84 mg/dL but 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% in MI, CHD death, CVA, and coronary revascularization.
A more recent meta-analysis of 90,056 participants in 14 primary and secondary statin/placebo randomized clinical trials showed a 21% reduction in major cardiovascular events (MI, CHD death, stroke, or coronary revascularization) per 1- mmol (about 40 mg/dL) reduction in LDL cholesterol in those with and without diabetes.13 Of note, this included participants with baseline LDL cholesterol levels below 100 mg/dL. In absolute terms, a 1-mmol reduction in LDL cholesterol resulted in 4.8% fewer major cardiovascular events in those with CHD and 2.5% fewer in those without CHD during a 5-year period. In comparison, the absolute rate reduction in diabetic patients without CHD in the CARDS trial was 3.7%, which demonstrates the increased baseline risk of cardiovascular events in these patients.
High-dose therapy. A meta-analysis of several trials of more intensive LDL cholesterol lowering that compared usual lower-dose statin therapy with highest-dose therapy revealed a difference in LDL cholesterol of 101 versus 75 mg/dL.14 CHD death and MI were reduced 16% (absolute risk reduction, 1.4%) in the high-dose group. When coronary revascularization, stroke, and hospitalization for unstable angina were combined with CHD death and MI, the relative risk reduction remained 16%, but the absolute risk reduction increased to 3.5%. Overall mortality trended downward by 6%, but there were not enough deaths to show statistical significance. Combining the preventive results to be expected from a low- or moderate-dose statin with the additional effects of raising the dosage, the overall effect of high-dose statin versus placebo was a reduction inthe incidence of cardiovascular events by about 40%, or a 1% relative risk reduction for each 1.8 mg/dL reduction in LDL cholesterol level. Each of these trials had diabetic patients, but relevant subanalyses were not performed.
Current lipid goals. An LDL cholesterol level below 70 mg/dL in diabetic patients with CHD was an "optional" goal in the 2004 National Cholesterol Education Program (NCEP) update.15 This goal was upgraded to "reasonable" 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.16 The NCEP recommendation for the LDL cholesterol goal in those with diabetes but without CHD remains less than 100 mg/dL. This recommendation is based primarily on the preventive effects seen with reduction of LDL cholesterol levels from 124 to 84 mg/dL in CARDS.
An LDL cholesterol level less than 100 mg/dL in diabetic patients without overt cardiovascular disease and an optional goal of less than 70 mg/dL in those with overt cardiovascular disease has also been recommended by the American Diabetes Association.17
Other lipid goals include the following:
To achieve these goals, high-dose statin therapy may be necessary and is recommended for patients with CHD. The safety of these drugs at the standard and at the highest doses in 2 meta-analyses has been clearly demonstrated over a 2- to 5-year period with no increases in noncardiovascular deaths or cancers. Rare side effects included creatine phosphokinase values that were more than 10 times the upper limit of normal (0 to 0.4%), rhabdomyolysis (0 to 0.13%), and transaminase levels more than 3 times the upper limit of normal (3%).13,14
Fibric acids raise HDL cholesterol levels and lower LDL and triglyceride levels in patients with diabetic dyslipidemia and decrease the incidence of cardiovascular events. In patients with triglyceride levels higher than 200 mg/dL and low HDL levels, fibric acids may be a reasonable initial option; they reduce risk as effectively as statins in these patients.
Evidence from the trials. A number of trials have demonstrated the efficacy of fibric acids in patients with insulin resistance and/or diabetes (Tables 4, 5, and 6). The Veterans Administration HDL Intervention Trial (VA-HIT)18 randomly assigned gemfibrozil, 600 mg bid, or placebo to 2531 veterans with an HDL cholesterol level of 40 mg/dL or lower, LDL cholesterol level of 140 mg/dL or lower, and triglyceride level of 300 mg/dL or lower. These middle-aged men were overweight; 25% had diabetes and 57% had hypertension. Overall, there was a 22% relative risk reduction in CHD death and MI (P = .006). In a subanalysis of those with baseline diabetes versus those without, relative risk reduction of MI, CHD death, and stroke was 32% versus 18%, with absolute risk reductions of 9.9% versus 3.3%.19 Those without diabetes but in the upper quartile of fasting insulin concentration, or most insulin resistant, were the only non-diabetic group with a statistically significant relative decrease in CHD death, MI, and stroke of 35%.
These results supported those of the primary prevention Helsinki Heart Trial, which tested gemfibrozil, 600 mg bid, versus placebo in 4100 men aged 40 to 65 years who did not have CHD but whose non-HDL cholesterol level was higher than 200 mg/dL.20 In the group with triglyceride levels higher than 200 mg/dL and LDL/HDL cholesterol ratios higher than 5 at baseline, gemfibrozil decreased CHD events by 71%, significantly more than in any other group.21
The Bezafibrate Infarction Prevention (BIP) Study was a secondary prevention trial of 3090 patients with HDL cholesterol levels of 45 mg/dL or lower, triglyceride levels of 300 mg/dL or lower, and LDL cholesterol levels of 180 mg/dL or lower who were randomized to receive bezafibrate, 400 mg/d, or a placebo and monitored for a mean of 6.2 years.22The reduction in the primary end point of MI or sudden death was not statistically significant. However, in a post hoc subanalysis of those with triglyceride levels 200 mg/dL and higher, and especially in those with a concomitant HDL cholesterol level below 35 mg/dL, there was a 39.5% reduction in this primary end point.
The most recent clinical trial of a fibric acid was the Fenofibrate Intervention and Event Lowering in Diabetes (FIELD) study.23 This study enrolled 9800 patients with type 2 diabetes, aged 40 to 75 years, whose total cholesterol level was 115 to 250 mg/dL with either a total cholesterol/HDL cholesterol ratio of 4 or higher, or triglyceride levels between 89 and 443 mg/dL. Twenty-five percent of the patients had a history of CHD. Only 37% had the 2 qualifying lipid criteria for the metabolic syndrome: triglyceride levels higher than 150 mg/dL and HDL cholesterol less than 40 mg/dL in men or less than 50 mg/dL in women. Participants could not be taking lipid- altering therapy at baseline, but there was no restriction on lipid-lowering medications after the trial started.
The 11% reduction in the primary end point of MI and CHD death was not significant, partly because by the end of the study 36% of those in the placebo group but only 19% of those in the fenofibrate group had electively and independently started statin therapy. When the end point was adjusted for the differential on-trial statin use, the adjusted primary end point was decreased 19% (P = .01). The 11% decrease in all cardiovascular events was attributable to a significant 24% reduction in MI and 21% reduction in coronary revascularizations, with no significant decrease in stroke, CHD death, or total mortality. As seen in the Helsinki trial, the primary end point was reduced slightly more in the group with triglyceride levels above 150 mg/dL and HDL cholesterol less than 40 mg/dL in men and less than 50 mg/dL in women (14% relative risk reduction, P = .06). In the participants without a history of CHD, there was a significant 19% relative risk reduction in total cardiovascular events and a 2.0% absolute risk reduction. Surprisingly, no preventive benefit was seen in those with a history of CHD.
A number of studies have demonstrated preventive cardiovascular effects with fibric acids in patients with diabetes and those with insulin resistance. The benefits are always larger, and perhaps only become significant, in those with higher baseline triglyceride and lower HDL cholesterol levels. The sum of the effects in those with triglyceride levels higher than 200 mg/dL, especially when accompanied by HDL cholesterol levels of less than 40 mg/dL in men and less than 50 mg/dL in women, is as dramatic as the effects of statins in persons with diabetes.
Thus, although statins remain the first choice in patients with diabetes and dyslipidemia, fibric acids provide effective lipid-altering therapy for those with dyslipidemia of the metabolic syndrome and triglyceride levels higher than 200 mg/dL plus HDL cholesterol generally less than 40 mg/dL.
One obvious goal in treating the dyslipidemia of diabetes is to raise low HDL cholesterol levels. Although lifestyle changes, fibric acids in the presence of hypertriglyceridemia, and statins can raise these levels, the most significant increase is achieved with niacin (previously called nicotinic acid or vitamin B3). HDL cholesterol levels are raised in a dose- and time-dependent manner, with continuous increases seen in dosages of immediate-release niacin up to 2 g/d24 and with intermediate-release niacin at dosages of up to 2.5 g/d (at which point the effects plateau).25
Choosing the correct niacin formulation is critical. Inositol (non-flush niacin) preparations do not alter lipid profiles because of inadequate absorption.26 Slow-release niacin does not increase HDL cholesterol levels or decrease triglyceride levels as much as immediate-release niacin; it also increases hepatic enzyme levels more than immediate-release niacin.27 The HDL cholesterol-raising effects of intermediate-release niacin are equivalent to those of immediate- release niacin, but with fewer reported side effects.28,29
Niacin in dosages as high as 4.5 g/d significantly raises glucose levels,30 which is why its use was for many years discouraged 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 A1c at dosages of 1 to 3 g/d.31,32 An occasional patient may require increased dosages of hypoglycemic medications or may have to discontinue niacin because of major changes in glucose control.31 Uric acid levels may increase 10% to 15% with high-dose niacin, and patients with high baseline serum uric acid levels or a history of gout may risk an acute gouty attack.
Evidence from the trials. The Coronary Drug Project, a secondary prevention study in patients with CHD, demonstrated a 5-year 27% decrease in nonfatal MI and a 15-year 11% reduction in total mortality in the group that used immediate-release niacin, 3 g/d, versus placebo (Table 7).33 A recent substudy showed that although the niacin group at 1 year had a fasting plasma glucose level 5 mg/dL higher than the placebo group and a 1-hour post-glucose-challenge plasma glucose level 15 mg/dL higher, the decrease in relative risk was the same.34 This benefit was seen even in those with fasting glucose levels above 126 mg/dL--that is, patients with diabetes. Moreover, the preventive effects were the same no matter how great the glucose increase from baseline to year 1 in the fasting or 1-hour post-challenge glucose levels.
In the HDL-Atherosclerosis Treatment Study (HATS),35 immediate-release niacin was given in increasing dosages up to 4 g/d to raise HDL cholesterol by 10 mg/dL. Simvastatin was given simultaneously and was increased to attain an LDL cholesterol less than 90 mg/dL. Results included a major reduction in plaque progression on coronary angiography and a 60% reduction in coronary clinical events, including MI, death, and coronary revascularization in the group randomized to simvastatin and niacin versus placebo.
Two placebo-controlled, double-blind imaging studies (Arterial Biology for the Investigation of the Treatment Effects of Reducing Cholesterol [ARBITER]) that measured carotid intimal medial thickness (IMT) in 160 patients with CHD explored the addition of intermediate-release niacin, 1 g at night, to ongoing statin therapy versus continuing the statin therapy alone.36,37 In ARBITER 2, the niacin/statin combination raised HDL cholesterol levels from 39 to 47 mg/dL at 1 year. There was no progression of IMT in that group compared with progression in those taking the statin alone. However, there was no difference in clinical events.
In ARBITER 3, the patients in the placebo group could switch to intermediate-release niacin, 1 g, and those in the niacin group could continue it another 12 months.38 At 1 year, carotid IMT in those taking a statin alone progressed by 0.52 mm, while it regressed (20.027 mm) in those taking statin plus niacin.
The HATS and ARBITER trials are among the few that have compared statins alone with combination statin and niacin therapy on measures of CHD imaging or clinical events. A trial of combination therapy with lovastatin and intermediate- release niacin produced a 47% decrease in LDL cholesterol, a 41% decrease in triglycerides, and a 30% increase in HDL cholesterol.39
Statins and fibric acids in combination also produce better lipid results than statins alone. In a recent 12-week investigation in persons with triglycerides levels between 150 and 500 mg/dL and LDL cholesterol levels higher than 130 mg/dL, the addition of fenofibrate, 160 mg/d, to simvastatin, 20 mg/d, doubled the reduction in triglyceride levels com- pared with simvastatin alone (243% vs 220%, respectively). The addition of fenofibrate also doubled the increase in HDL cholesterol levels (19% vs 10%), further decreased LDL cholesterol levels (31% vs 26%), and halved the fraction of small LDL particles with no adverse side effects.40 Seventy percent of these patients had the metabolic syndrome or diabetes, and 40% had HDL cholesterol levels of less than 40 mg/dL. These results confirmed the beneficial lipid-altering effects of fibric acids in patients with hypertriglyceridemia and low HDL cholesterol levels.
Other studies of combinations of statins with fibric acids and statins with niacin are under way. Such studies set the stage for the next lipid- altering trials that will assess the benefits of raising HDL cholesterol levels while simultaneously lowering LDL cholesterol and triglyceride levels.
For persons with diabetes who have CHD or other cardiovascular risk factors, whose LDL cholesterol levels have reached a level significantly below 100 mg/dL but whose triglyceride levels remain higher than 200 mg/dL, the NCEP guidelines suggest the option of combination therapy.15 Certainly such combinations can be justified in those who have evidence of progression of CHD while taking a single lipid-altering agent.
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