[Postgraduate Medicine]
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[SYMPOSIUM]

SYMPOSIUM ON DYSLIPIDEMIA

Cholesterol lowering in diabetes

New evidence supports aggressive LDL-C targets

Robert S. Rosenson, MD

VOL 117 / NO 4 / APRIL 2005 / POSTGRADUATE MEDICINE

CME learning objectives

  • To understand the rationale for aggressive strategies to lower low-density lipoprotein cholesterol levels in diabetic patients
  • To recognize the lipoprotein abnormalities of insulin resistance
  • To learn the use of specific classes of lipid-lowering agents in the treatment of diabetic dyslipidemia

Dr Rosenson has received grant or research support from Abbott, AstraZeneca, GlaxoSmithKline, Kos, Pfizer, Merck, and Takeda; is a consultant for LipoScience and Takeda; is on the speakers' bureau for Abbott, AstraZeneca, Bristol-Myers Squibb, GlaxoSmithKline, Kos, LipoScience, Merck, Merck/Schering Plough, Sankyo, and Takeda; and holds stock or options in LipoScience. He discloses no unlabeled uses of any product mentioned in this article.

Preview: Recent guidelines for treating patients with diabetes categorize the disorder as a coronary heart disease (CHD) equivalent and urge aggressive treatment of modifiable risk factors, such as plasma levels of low-density lipoprotein cholesterol (LDL-C). In this article, Dr Rosenson discusses the rationale for cholesterol lowering in patients with diabetes, the lipoprotein abnormalities that accompany insulin resistance, and the prognostic significance of high LDL particle numbers. He also highlights major findings from recent clinical trials to explore statin therapy and other treatment strategies for lowering lipoprotein levels in this patient population.
Rosenson RS. Cholesterol lowering in diabetes: new evidence supports aggressive LDL-C targets. Postgrad Med 2005;117(4):17-27

Cardiovascular disease is the principal cause of illness and disability in patients with diabetes, and in the United States, it accounts for more than 70% of all deaths in this population (1). Until 5 years ago, it was debated whether patients with type 2 diabetes should be treated as aggressively for risk factor modification as patients with CHD. In the second revision of the National Cholesterol Education Program (NCEP) guidelines (2), diabetes was considered no more important than other major CHD risk factors. Subsequently, it was shown that incident cardiovascular events were comparable in type 2 diabetic patients without previous myocardial infarction (MI) and nondiabetic patients with prior MI (3).

In the third revision of the NCEP guidelines (4), diabetes is considered a CHD risk equivalent, and this information provides the rationale for treating cardiovascular risk factors as aggressively in patients with diabetes as in patients with CHD. Recently, diabetic patients with cardiovascular disease were categorized as being at very high risk, which prompted even more aggressive targets for one major modifiable risk factor--the plasma concentration of LDL-C (5).

Cardiac events in patients with diabetes

Diabetic patients without prior MI have a 7-year incidence of MI (20.2%) comparable to that of nondiabetic patients with prior MI (18.8%) (3). The incidence of sudden cardiac death after the onset of chest pain is nearly twice as high in diabetic men as in nondiabetic men (5.5% versus 3.0%, P<.001) and 3.5 times higher in diabetic women than in nondiabetic women (7.6% versus 2.2%, P<.001) (6). The higher mortality rate in patients with diabetes persists after hospitalization. In the initial year after a first MI, mortality rates are 1.4 times higher in diabetic men than in nondiabetic men (45.1% versus 32.6%, P<.001) and 1.8 times higher in diabetic women than in nondiabetic women (38.5% versus 22.0%, P<.0001). Patients with CHD and diabetes are at especially high risk for recurrent events; their incidence of MI at 7 years is nearly 50% (3). These data establish the need for aggressive therapies to reduce initial and recurrent cardiovascular events in patients with diabetes.

Lipids, lipoproteins, and major cardiovascular events

High plasma cholesterol levels are a strong predictor of cardiovascular events in patients with diabetes (7,8). The cardiovascular mortality rate is 2.83 to 4.46 times higher in diabetic men than in nondiabetic men at various levels of serum cholesterol (7). In the UK Prospective Diabetes Study (9), high levels of LDL-C were the lipid levels that most highly correlated with cardiovascular events. However, low levels of high-density lipoprotein cholesterol (HDL-C) were almost equally significant.

LDL-C levels do not account for the heterogeneity in LDL and other lipoprotein subclasses that characterizes insulin resistance. As a result, the cardiovascular risk in diabetic patients with metabolic syndrome is underestimated when these levels are used as predictors (10). Lipoprotein subclass abnormalities that accompany insulin resistance are characterized by large, triglyceride-enriched very low-density lipoprotein (VLDL) particles; small, cholesterol-depleted LDL particles; and small HDL particles (10). In addition, more severe states of insulin resistance have been associated with progressively higher numbers of VLDL particles, intermediate-density lipoprotein particles and, most important, LDL particles (11).

Lipid-altering therapies

Therapies to address the increased cardiovascular risk in patients with diabetes include lifestyle changes and treatment with statins, fibric acid derivatives, and niacin. Combination therapy with these agents may also prove effective.

Therapeutic lifestyle changes
Therapeutic lifestyle changes address the principal causes of metabolic syndrome--obesity and physical inactivity--and should be the first intervention and the foundation for any cardiovascular risk reduction program (4). The increased cardiovascular risk in patients with diabetes is higher yet in those with metabolic syndrome than in those without it.

Weight loss and aerobic exercise improve insulin sensitivity and lower blood glucose levels in patients with diabetes. In two clinical trials (12,13), therapeutic lifestyle changes in patients with impaired fasting glucose reduced the incidence of diabetes by nearly 60%. These interventions used similar strategies to achieve a weight loss of 5% to 7%. The lifestyle interventions included reduced intake of total and saturated fat and moderate-intensity aerobic exercise for 3 to 3.5 hours weekly.

The effects of a Mediterranean-style diet on endothelial dysfunction and inflammatory markers were investigated in a controlled trial (14) in patients with metabolic syndrome as defined by the NCEP Adult Treatment Panel III (ATP III). Patients in the intervention group received instructions on how to implement a Mediterranean diet by increasing their daily intake of whole grains, fruits, vegetables, nuts, and olive oil; others were given instructions on a "prudent" diet of 50% to 60% carbohydrates, 15% to 20% protein, and less than 30% total fat. After 2 years, patients with metabolic syndrome assigned to the Mediterranean diet had improved glycemic status and endothelial function and reduced prevalence of cardiovascular risk markers (table 1).

The effects of physical activity on cardiovascular outcomes were evaluated in 3,058 men with diabetes who participated in the Health Professionals' Follow-up Study (15). After 14 years of follow-up, the investigators concluded that higher levels of physical activity were associated with lower cardiovascular risk. The relative risks of cardiovascular disease that correlated with walking at a normal pace (2-2.9 mph), brisk pace (3-3.9 mph), and very brisk pace (>4 mph) were 0.82, 0.58, and 0.17 (95% confidence interval [CI], 0.04-0.71; P for trend, <.001), respectively, compared with a slower pace.

Statins
Cholesterol lowering with statin therapy has been accompanied by a reduction in cardiovascular events among subsets of diabetic patients enrolled in primary and secondary prevention trials (3,16-21) (table 2). One study (3) showed that statins afford more cardioprotection in patients who have CHD and diabetes than in patients who have CHD without diabetes. In the Scandinavian Simvastatin Survival Study (16), the incidence of major CHD events was reduced by 55% (95% CI, 26%-73%; P=.002) in diabetic patients with CHD compared with 32% (95% CI, 23%-40%; P<.0001) in nondiabetic patients with CHD.

The Cholesterol and Recurrent Events trial (17,21) showed that pravastatin sodium (40 mg/day) was equally efficacious in diabetic and nondiabetic patients. Among diabetic patients with low LDL-C levels, defined as less than 125 mg/dL (3.24 mmol/L), pravastatin therapy was accompanied by a 44% reduction in cardiovascular events (17). In contrast, pravastatin was ineffective in reducing recurrent events among nondiabetic patients with CHD and low LDL-C levels.

In the Heart Protection Study (HPS) (19), simvastatin (40 mg/day) reduced the risk of vascular events in 5,963 patients with diabetes, regardless of baseline LDL-C levels. In the cardiovascular subgroup, simvastatin reduced the absolute risk of a major cardiovascular event in patients with CHD by 4.4 percentage points (33.4% versus 37.8%) and in patients without CHD by 7.3 percentage points (25.6% versus 32.9%). In the 2,912 patients with diabetes who did not have diagnosed cardiovascular disease, simvastatin therapy reduced the risk of major vascular events by 4.2 percentage points (9.3% versus 13.5% in placebo-treated subjects) for a relative risk reduction of 33% (95% CI, 17%-46%; P=.0003).

The Collaborative Atorvastatin Diabetes Study (CARDS) (20) was a randomized, placebo-controlled clinical trial that evaluated the effect of atorvastatin calcium (10 mg/day) on initial cardiovascular events in 2,838 type 2 diabetic patients with LDL-C levels less than or equal to 160 mg/dL (4.14 mmol/L) and triglyceride levels less than or equal to 600 mg/dL (6.77 mmol/L). The study was stopped 2 years earlier than expected because of a significant 37% (95% CI, 17%-52%) reduction in the rate of major cardiovascular events.

This trial provides important information concerning the effectiveness of statin therapy in primary prevention of cardiovascular disease in patients with type 2 diabetes. Additionally, it extends the benefits of statin therapy to type 2 diabetic patients with baseline LDL-C levels that are considered optimal. The findings in CARDS are consistent with the primary prevention data from HPS (19). Yet it remains unclear whether this therapy is empirical (fixed dose) or whether it should be guided by the LDL-C concentration.

Subgroup analyses from clinical trials of cholesterol-lowering therapy have shown that patients with diabetes are at higher risk for initial and recurrent cardiovascular events than patients without diabetes (10). Although diabetic patients derived significant benefit from statin therapy, the event rate remained higher than in nondiabetic patients who were randomly assigned to placebo. This higher risk in patients treated with statins has raised several issues about which strategy is best for treating cardiovascular risk in patients with diabetes: aggressive reduction of LDL-C levels or a comprehensive approach that addresses LDL-C, triglyceride, and HDL-C levels. The Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial (22) will evaluate the effectiveness of a strategy for lowering LDL-C levels (using simvastatin) versus comprehensive lipid-altering treatment (using simvastatin and fenofibrate) on cardiovascular outcomes in 10,000 patients with well-controlled diabetes.

Fibric acid derivatives
In patients with metabolic syndrome who have high fasting triglyceride levels and low levels of HDL-C, therapy with fibric acid derivatives (gemfibrozil, bezafibrate [an agent not available in the United States]) has been shown to reduce the risk of initial and recurrent cardiovascular events (23,24). The Veterans Affairs High-Density Lipoprotein Cholesterol Intervention Trial (25) evaluated the effects of gemfibrozil (1,200 mg/day) on nonfatal MI or death from coronary causes in patients with CHD and low levels of HDL-C. As expected, these patients had many characteristics of metabolic syndrome, shown by the high prevalence of hypertriglyceridemia (mean fasting triglyceride level, 161 mg/dL [1.82 mmol/L]), low HDL-C levels (median, 32 mg/dL [0.83 mmol/L]), hypertension (in 57% of subjects), and diabetes or impaired fasting glucose (in 43% of subjects). At 5.1 years, the relative risk of nonfatal MI and CHD death was reduced by 22% (P=.006). A follow-up analysis showed that among nondiabetic patients, gemfibrozil was more effective than placebo in those with hyperinsulinemia (fasting plasma insulin, >265 pmol/L) (26). The incidence of CHD deaths was reduced by 41% (P=.02) in diabetic patients treated with gemfibrozil.

The Diabetes Atherosclerosis Intervention Study (27) evaluated the effects of fenofibrate (200 mg/day) on angiographic progression of coronary stenoses in patients with type 2 diabetes. After 3 years, patients treated with fenofibrate had reduced rates of localized CHD as shown by less progression in minimum luminal diameter and percent stenosis. In this coronary angiography-based study of 418 patients with diabetes, fenofibrate therapy was more effective (P=.029) than diet therapy in arresting the progression of high-grade stenoses. The effects of fenofibrate on CHD events in nearly 10,000 patients with diabetes is under investigation in the Fenofibrate Intervention and Event Lowering in Diabetes study (28).

Niacin
Niacin (Niaspan, Nicor) has not been considered useful in patients with metabolic syndrome or type 2 diabetes because of its effects on insulin resistance. However, in two studies of patients with type 2 diabetes (29,30), niacin worsened glycemic status only when taken at moderately high doses. In the Arterial Disease Multiple Intervention Trial (29), crystalline niacin taken at a dose of 3,000 mg per day for 48 weeks increased HDL-C levels by 29% and reduced levels of triglycerides by 23% and LDL-C by 8% in patients with diabetes (P<.001 for all data). In patients treated with niacin, fasting glucose levels increased by 8.7 mg/dL (0.48 mmol/L), but levels of hemoglobin A1c were unchanged. This study showed that a transient increase in blood glucose occurred when the niacin dose was increased to 3,000 mg per day, but the glucose level returned to baseline with continued niacin use.

The Assessment of Diabetes Control and Evaluation of the Efficacy of Niaspan trial (30) showed that compared with placebo, 4 months of therapy with extended-release niacin at daily doses of 1,000 mg and 1,500 mg was accompanied by a dose-dependent increase (19% to 24%, P<.05) in HDL-C levels and a reduction (13% to 28%, P<.05) in triglycerides. The therapy had no effect on the lowering of glycemic control. Of the patients receiving 1,500 mg of extended-release niacin, 29% required a change in hypoglycemic therapy.

Combination therapy for complex lipoprotein disorders

Complex lipoprotein disorders in patients with diabetes may require therapy that combines a statin and a fibric acid derivative (31) or a statin and niacin (32).

One study (32) has shown that in patients with CHD and low levels of HDL-C, combination therapy with simvastatin (10-20 mg/day) and niacin (500-3,000 mg/day) slowed rates of coronary disease progression and reduced cardiovascular events by 90%. In this trial, there was a transient increase in glucose concentration that returned to pretreatment levels with continued therapy.

The potential benefits of combined lipid-altering therapy that includes a statin must be tempered by the measurable risks of myopathy (33). Risk factors for myopathy include older age (especially in women), renal insufficiency, untreated hypothyroidism, and alcohol abuse.

Risk factors specific to statin therapy include use of a lipophilic, soluble statin (simvastatin [Zocor] or lovastatin [Mevacor]) in moderate to high doses; renal excretion of statin metabolites that depends on glucuronidation; and concomitant therapy with other medications metabolized by the cytochrome P-450 3A4 system. Although the most important clinical trials of fibric acid derivative therapy have used gemfibrozil, this agent is a competitive inhibitor of the 1A1 and 1A3 glucuronidation elimination pathway for statins (34). In patients treated with gemfibrozil, plasma levels of statins increased anywhere from 1.9-fold with rosuvastatin calcium to 2.8-fold with simvastatin (34). In contrast, fenofibrate uses a different set of glucuronidation pathways (1A9 and 2B7) for metabolism, and therefore statin levels are unchanged.

Intervention for multiple risk factors

Intensive hypoglycemic therapy and treatment of modifiable risk factors are more effective than less intensive risk factor modification in reducing cardiovascular complications of hyperglycemia in type 2 diabetes. In the Steno-2 Study (35), a multifactorial intervention of behavior modification and pharmacologic therapy targeted hyperglycemia, hypertension, dyslipidemia, and microalbuminuria in 160 patients with type 2 diabetes and microalbuminuria. Intensive lipid control included reduction in levels of total cholesterol (<175 mg/dL [4.52 mmol/L] versus <190 mg/dL [4.91 mmol/L]) and triglycerides (<150 mg/dL [1.69 mmol/L] versus <180 mg/dL [2.03 mmol/L]).

Isolated hypercholesterolemia or combined hyperlipidemia was treated with atorvastatin (maximum, 80 mg/day), and isolated hypertriglyceridemia (fasting triglyceride level, >350 mg/dL [3.95 mmol/L]) was treated with a fibric acid derivative. One patient received combined statin-fibric acid derivative therapy. Intensive intervention involving multiple risk factors reduced the risk of macrovascular cardiovascular events (death from cardiovascular causes or nonfatal MI) by 53% (95% CI, 22%-74%; P=.01).

Goals of therapy

Lipid guidelines for patients with diabetes emphasize the importance of lowering LDL-C levels. For diabetic patients, an LDL-C level of less than 100 mg/dL (2.59 mmol/L) has been advocated by the ATP III (4). Recently, the NCEP issued a revised algorithm for lowering LDL-C levels for a new category of very high-risk patients (5), for whom an LDL-C level of less than 70 mg/dL (1.81 mmol/L) was advised. Although this specific recommendation remains unproven by randomized clinical trials that investigate intensive versus very intensive therapy (36), subgroup analyses from placebo-controlled trials indicate that a lower LDL-C level is associated with a lower cardiovascular event rate.

Several studies have evaluated rates of success in achieving recommended LDL-C targets. Among patients with CHD-equivalent risk who were enrolled in the Statin Therapies for Elevated Lipid Levels Compared Across Doses to Rosuvastatin trial (37), an LDL-C goal of less than 100 mg/dL was attained in 80% of patients treated with rosuvastatin (40 mg/day), 70% of those treated with atorvastatin (80 mg/day), 53% of those treated with simvastatin (80 mg/day), and 8% of those treated with pravastatin (40 mg/day). This study showed that many patients at high risk were unable to achieve the previously defined optimal LDL-C concentration. The newly advocated LDL-C goal of less than 70 mg/dL raises new challenges that may not be overcome by many patients at very high risk, even if they receive the statin therapy most potent for lowering LDL-C levels (36).

Nevertheless, it remains unresolved whether patients with diabetes gain more benefit from LDL-C lowering or from combined therapy directed at abnormally high fasting and postprandial triglyceride levels or low levels of HDL-C. In patients with CHD who have low HDL-C levels and metabolic syndrome, combined therapy with simvastatin and niacin was accompanied by a 90% reduction in major cardiovascular events (32). The ACCORD trial is specifically investigating whether combined statin-fibric acid derivative therapy in 10,000 patients with diabetes is accompanied by fewer cardiovascular events than statin monotherapy. Taken together, these ongoing trials should provide further insights into appropriate management and therapeutic goals in these very high-risk patients.

Because LDL-C measurements do not accurately account for the abnormalities in LDL composition and LDL particle concentration in patients with diabetes (10), it is my practice to quantify risk through advanced lipoprotein testing. In the Framingham Offspring Study (38), 73% of patients with metabolic syndrome and LDL-C levels less than 100 mg/dL (20th percentile) had an LDL particle number greater than or equal to 1,100 nmol/L, or above the 20th percentile. For diabetic patients with metabolic syndrome and LDL particle numbers greater than or equal to 1,100 nmol/L, intensification of therapy for lowering LDL-C levels may be warranted.

In patients with metabolic syndrome and low LDL particle numbers, treatments for increasing low levels of HDL-C and lowering high levels of triglycerides may be considered. When the fasting triglyceride levels are high to very high and the HDL-C levels are low, a fibric acid derivative is a reasonable option, and this therapy can be more safely implemented with fenofibrate than with gemfibrozil. In recipients of kidney and other organ transplants who are treated with cyclosporine, fenofibrate lowers serum cyclosporine levels. Thus, gemfibrozil therapy is preferable in these patients. Also, because fibric acid derivatives are primarily excreted by the kidneys, the dose and dosing interval should be reduced to avoid myositis.

In patients with HDL-C levels that are low and triglyceride levels that are normal to borderline high, low doses of niacin may be an effective option. The major concerns with niacin therapy in patients with type 2 diabetes are a worsening of insulin resistance and a deterioration of glycemic control. In a randomized, placebo-controlled trial of 148 patients with diabetes (30), low-dose niacin therapy (extended-release niacin, 1 g/day) did not worsen glycemic status, whereas high doses of niacin (extended-release niacin, 1.5 g/day) worsened glycemic control in nearly 30% of patients.

It is my recommendation that niacin be considered for raising HDL-C levels when used in combination with a statin in patients with metabolic syndrome and type 2 diabetes. However, regular monitoring (at 3-month intervals) of glycemic status is essential for the identification of patients prone to worsened insulin resistance.

Conclusion

There are two strategies for treating the dyslipoproteinemia of insulin resistance: aggressive lowering of LDL-C levels and combined treatment of LDL-C, triglyceride, and HDL-C levels. Until the optimal approach has been established in a clinical trial, the primary emphasis of lipid-lowering therapy is reduction in LDL-C levels and, more specifically and accurately, in the number of LDL particles.

It must be emphasized that a majority of patients with diabetes remain at high risk despite achieving optimal levels of LDL-C and normal control of other major risk factors. Although aggressive treatment of the dyslipoproteinemia of insulin resistance may require combined use of lipid-altering agents, the potential risk for myopathy may be higher in these patients with diabetes because they are often older and have reduced renal function. Judicious selection of both the specific statin and fibric acid derivative and the dosage of these agents is necessary to maintain safety.

Nevertheless, results of randomized clinical trials have firmly established that lowering LDL-C levels, specifically with statin agents, affords cardioprotection across a broad range of LDL-C levels.

References

  1. Gu K, Cowie CC, Harris MI. Mortality in adults with and without diabetes in a national cohort of the US population, 1971-1993. Diabetes Care 1998;21(7):1138-45
  2. Summary of the second report of the National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel II). JAMA 1993;269(23):3015-23
  3. Haffner SM, Lehto S, Ronnemaa T, et al. Mortality from coronary heart disease in subjects with type 2 diabetes and in nondiabetic subjects with and without prior myocardial infarction. N Engl J Med 1998;339(4):229-34
  4. Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults. Executive Summary of the Third Report of the National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III). JAMA 2001;285(19):2486-97
  5. Grundy SM, Cleeman JI, Merz CN, et al; National Heart, Lung, and Blood Institute; American College of Cardiology Foundation; American Heart Association. Implications of recent clinical trials for the National Cholesterol Education Program Adult Treatment Panel III guidelines. Circulation 2004;110(2):227-39
  6. Miettinen H, Lehto S, Salomaa V, et al. Impact of diabetes on mortality after the first myocardial infarction. The FINMONICA Myocardial Infarction Register Study Group. Diabetes Care 1998;21(1):69-75
  7. Stamler J, Vaccaro O, Neaton JD, et al. Diabetes, other risk factors, and 12-yr cardiovascular mortality for men screened in the Multiple Risk Factor Intervention Trial. Diabetes Care 1993;16(2):434-44
  8. Rosengren A, Welin L, Tsipogianni A, et al. Impact of cardiovascular risk factors on coronary heart disease and mortality among middle aged diabetic men: a general population study. BMJ 1989;299(6708):1127-31
  9. Turner RC, Millns H, Neil HA, et al. Risk factors for coronary artery disease in non-insulin dependent diabetes mellitus: United Kingdom Prospective Diabetes Study (UKPDS: 23). BMJ 1998;316(7134):823-8
  10. Rosenson RS. New approaches in the intensive management of cardiovascular risk in the metabolic syndrome. Curr Probl Cardiol 2005 (in press)
  11. Garvey WT, Kwon S, Zheng D, et al. Effects of insulin resistance and type 2 diabetes on lipoprotein subclass particle size and concentration determined by nuclear magnetic resonance. Diabetes 2003;52(2):453-62
  12. Tuomilehto J, Lindstrom J, Eriksson JG, et al; Finnish Diabetes Prevention Study Group. Prevention of type 2 diabetes mellitus by changes in lifestyle among subjects with impaired glucose tolerance. N Engl J Med 2001;344(18):1343-50
  13. Knowler WC, Barrett-Connor E, Fowler SE, et al; Diabetes Prevention Program Research Group. Reduction in the incidence of type 2 diabetes with lifestyle intervention or metformin. N Engl J Med 2002;346(6):393-403
  14. Esposito K, Marfella R, Ciotola M, et al. Effect of a Mediterranean-style diet on endothelial dysfunction and markers of vascular inflammation in the metabolic syndrome: a randomized trial. JAMA 2004;292(12):1440-6
  15. Tanasescu M, Leitzmann MF, Rimm EB, et al. Physical activity in relation to cardiovascular disease and total mortality among men with type 2 diabetes. Circulation 2003;107(19):2435-9
  16. Haffner SM, Alexander CM, Cook TJ, et al. Reduced coronary events in simvastatin-treated patients with coronary heart disease and diabetes or impaired fasting glucose levels: subgroup analyses in the Scandinavian Simvastatin Survival Study. Arch Intern Med 1999;159(22):2661-7
  17. Goldberg RB, Mellies MJ, Sacks FM, et al. Cardiovascular events and their reduction with pravastatin in diabetic and glucose-intolerant myocardial infarction survivors with average cholesterol levels: subgroup analyses in the Cholesterol and Recurrent Events (CARE) trial. The Care Investigators. Circulation 1998;98(23):2513-9
  18. Keech A, Colquhoun D, Best J, et al; LIPID Study Group. Secondary prevention of cardiovascular events with long-term pravastatin in patients with diabetes or impaired fasting glucose: results from the LIPID trial. Diabetes Care 2003;26(10):2713-21
  19. Collins R, Armitage J, Parish S, et al; Heart Protection Study Collaborative Group. MRC/BHF Heart Protection Study of cholesterol-lowering with simvastatin in 5,963 people with diabetes: a randomised placebo-controlled trial. Lancet 2003;361(9374):2005-16
  20. Colhoun HM, Betteridge DJ, Durrington PN, et al; CARDS investigators. Primary prevention of cardiovascular disease with atorvastatin in type 2 diabetes in the Collaborative Atorvastatin Diabetes Study (CARDS): multicentre randomised placebo-controlled trial. Lancet 2004;364(9435):685-96
  21. Sacks FM, Pfeffer MA, Moye LA, et al. The effect of pravastatin on coronary events after myocardial infarction in patients with average cholesterol levels. Cholesterol and Recurrent Events Trial investigators. N Engl J Med 1996;335(14):1001-9
  22. Halimi S, Charpentier G, Grimaldi A, et al. Effect on compliance, acceptability of blood glucose self-monitoring and HbA(1c) of a self-monitoring system developed according to patient's wishes. The ACCORD study. Diabetes Metab 2001;27(6):681-7
  23. Frick MH, Elo O, Haapa K, et al. Helsinki Heart Study: primary-prevention trial with gemfibrozil in middle-aged men with dyslipidemia. Safety of treatment, changes in risk factors, and incidence of coronary heart disease. N Engl J Med 1987;317(20):1237-45
  24. Goldbourt U, Behar S, Reicher-Reiss H, et al. Rationale and design of a secondary prevention trial of increasing serum high-density lipoprotein cholesterol and reducing triglycerides in patients with clinically manifest atherosclerotic heart disease (the Bezafibrate Infarction Prevention Trial). Am J Cardiol 1993;71(11):909-15
  25. Rubins HB, Robins SJ, Collins D, et al. Gemfibrozil for the secondary prevention of coronary heart disease in men with low levels of high-density lipoprotein cholesterol. Veterans Affairs High-Density Lipoprotein Cholesterol Intervention Trial Study Group. N Engl J Med 1999;341(6):410-8
  26. Rubins HB, Robins SJ, Collins D, et al. Diabetes, plasma insulin, and cardiovascular disease: subgroup analysis from the Department of Veterans Affairs High-density Lipoprotein Intervention Trial (VA-HIT). Arch Intern Med 2002;162(22):2597-604
  27. Effect of fenofibrate on progression of coronary-artery disease in type 2 diabetes: the Diabetes Atherosclerosis Intervention Study, a randomised study. Lancet 2001;357(9260):905-10 [Erratum, Lancet 2001;357(9271):1890]
  28. Rosenson RS, Reasner CA. Therapeutic approaches in the prevention of cardiovascular disease in metabolic syndrome and in patients with type 2 diabetes. Curr Opin Cardiol 2004;19(5):480-7
  29. Elam MB, Hunninghake DB, Davis KB, et al. Effect of niacin on lipid and lipoprotein levels and glycemic control in patients with diabetes and peripheral arterial disease: the ADMIT study: a randomized trial. Arterial Disease Multiple Intervention Trial. JAMA 2000;284(10):1263-70
  30. Grundy SM, Vega GL, McGovern ME, et al; Diabetes Multicenter Research Group. Efficacy, safety, and tolerability of once-daily niacin for the treatment of dyslipidemia associated with type 2 diabetes: results of the Assessment of Diabetes Control and Evaluation of the Efficacy of Niaspan trial. Arch Intern Med 2002;162(14):1568-76
  31. Vega GL, Ma PT, Cater NB, et al. Effects of adding fenofibrate (200 mg/day) to simvastatin (10 mg/day) in patients with combined hyperlipidemia and metabolic syndrome. Am J Cardiol 2003;91(8):956-60
  32. Brown BG, Zhao XQ, Chait A, et al. Simvastatin and niacin, antioxidant vitamins, or the combination for the prevention of coronary disease. N Engl J Med 2001;345(22):1583-92
  33. Rosenson RS. The rationale for combination therapy. Am J Cardiol 2002;90(10B):2K-7K
  34. Prueksaritanont T, Tang C, Qiu Y, et al. Effects of fibrates on metabolism of statins in human hepatocytes. Drug Metab Dispos 2002;30(11):1280-7
  35. Gaede P, Vedel P, Larsen N, et al. Multifactorial intervention and cardiovascular disease in patients with type 2 diabetes. N Engl J Med 2003;348(5):383-93
  36. Rosenson RS, Lloyd-Jones D. Critical appraisal of revised cholesterol guidelines for the very high risk patient. Expert Rev Cardiovasc Ther 2005;3(2):173-8
  37. Jones PH, Davidson MH, Stein EA, et al; STELLAR Study Group. Comparison of the efficacy and safety of rosuvastatin versus atorvastatin, simvastatin, and pravastatin across doses (STELLAR* Trial). Am J Cardiol 2003;92(2):152-60
  38. Otvos JD, Cromwell W, Shalavrova I, Schaefer E. LDL particles, but not LDL cholesterol, are highly elevated in the metabolic syndrome: results from the Framingham Offspring Study. (Abstr) Circulation 2003;108(Suppl IV):740-1

Dr Rosenson is director, Preventive Cardiology Center, and associate professor, departments of medicine and preventive medicine, division of cardiology, Northwestern University, Feinberg School of Medicine, Chicago. Correspondence: Robert S. Rosenson, MD, Preventive Cardiology Center, Northwestern University, Feinberg School of Medicine, Galter Pavilion, Suite 11-120, 201 E Huron St, Chicago, IL 60611. E-mail: r-rosenson@northwestern.edu.

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