Studies examining nonglycemic therapies

Revascularization interventions

Table 3 details other interventions under investigation. In the initial BARI trial, among the diabetic subgroup a dramatic advantage of coronary artery bypass graft surgery (CABG) was observed compared with percutaneous coronary intervention (PCI) with angioplasty; the benefit was seen primarily in the more than 80% of patients who had an internal mammary artery graft [23]. Since then, several advances have been made in the management of the acute coronary syndrome [24,25], the medical management of coronary disease [26], and the techniques of PCI (eg, stents and, most promisingly, drug-eluting stents) [27-30].

This leaves questions regarding the appropriate management of the patient who has diabetes mellitus and flow-limiting coronary disease. Two trials will explore these issues robustly. The BARI 2D trial will explore whether intensive medical management or intensive medical management plus bypass surgery or PCI improves survival in patients who have type 2 diabetes mellitus [15,16].

The FREEDOM trial (Future Revascularization Evaluation in Patients with Diabetes Mellitus: Optimal Management of Multivessel Disease) will compare CABG to PCI using the drug-eluting stents in diabetic patients who have multivessel disease, following the patients for 5 years to examine mortality as the primary endpoint. Investigators at 100 sites will recruit 2300 patients who have diabetes mellitus and at least two stenotic lesions in at least two major epicardial coronary arteries amenable to either PCI or surgical revascularization over 18 months. Intermediate endpoints, quality of life, neurocogni-tive function, and cost-effectiveness also will be examined. FREEDOM is planned to be complete in 2010 [31]. The CARDia trial (Coronary Artery Revascularization in Diabetes) is a smaller study of 600 individuals in the United Kingdom and Ireland that began recruitment in 2002 and is similar in intent to FREEDOM. CARDia addresses the hypothesis that optimal PCI is not inferior to modern CABG in patients who have diabetes with multivessel or complex single-vessel coronary disease assuming that the PCI 1-year event rate is 9%. The primary endpoint of death, nonfatal MI and nonfatal stroke will be assessed at 1 year and the population followed for a total of 5 years for a broad range of secondary endpoints [32].

Lipid interventions

No area of CVD research in diabetes has received more attention than lipid management. Numerous studies in primary prevention and secondary intervention with statins and fibrate lipid-lowering agents are underway [33]. The guidelines regarding lipid management are in flux based on the rapidly evolving landscape of clinical trials that have recently and soon will be reported. Recent guidelines discussed elsewhere in this issue reinforce prior recommendations that in high-risk patients like those who have type 2 diabetes mellitus, the low-density lipoprotein cholesterol (LDL-C) goal is less than 100 mg/dL, but suggest that in the highest risk patients, such as those who have acute coronary syndrome or diabetes mellitus and clinical CVD, further lowering to an LDL-C level of 70 mg/dL or less is ''a therapeutic option, ie, a reasonable clinical strategy'' [34].

A remaining question is how low should one go in managing lower risk patients who have diabetes mellitus? Several trials addressing this will report in the near future: HPS II (Heart Protection Study II), IDEAL (Incremental Decrease in Endpoints through Aggressive Cholesterol Lowering) [35], SEARCH (Study of the Effectiveness of Additional Reductions in Cholesterol and Homocysteine) [36], and TNT (Treating to New Targets) [37]. Each examines the effect of different levels of low-density lipoprotein (LDL) control with high and moderate doses of one agent (HPS II, SEARCH, and TNT) or different levels of control obtained in comparisons of two agents (IDEAL). Approximately 40,000 patients are randomized in those studies, which will report starting in 2005.

Despite fairly robust demonstration of the role of gemfibrozil in the management of CV risk, issues have arisen regarding the safety of combining statins and fibrates. Thus, with many statin trials documenting the usefulness of statins to reduce CVD in virtually every clinical situation, questions exist regarding the appropriate role of fibrates in the management of CVD risk in diabetes mellitus. The FIELD trial (Fenofibrate Intervention and Event Lowering in Diabetes) randomized 9795 people who had type 2 diabetes with average total cholesterol (115-250 mg/dL) and elevated triglyceride to high-density lipopro-tein cholesterol (HDL-C) ratio (> 9.2) or triglyceride level greater than 88 mg/dL to fenofibrate or placebo. FIELD is expected to report on the primary endpoint, CVD death and nonfatal MI, in 2005 [38]. FIELD should establish the role of fenofibrate, a newer fibrate with fewer issues regarding drug interactions with statins.

The ACCORD study has a lipid substudy in which approximately 5800 participants also will be randomized to fenofibrate or placebo in the context of therapy with simvastatin to achieve LDL levels of approximately 100 mg/dL or lower. The ACCORD lipid study will answer whether a treatment strategy that uses a fibrate to raise HDL-C and lower triglycerides and a statin to treat LDL reduces the rate of CVD events compared with a strategy that uses only a statin for treatment of LDL-C, establishing the safety and efficacy of statin-fibrate combination therapy [12].

Finally, several studies will examine the role of lipid management in particular clinical situations common in patients who have diabetes mellitus, such as the SPARCL study (Stroke Prevention by Aggressive Reduction in Cholesterol Levels), which will evaluate the effects of atorvastatin in the setting of transient ischemic attack [39], and the SHARP study (Study of Heart and Renal Protection), which will examine the effect of simvastatin versus simvastatin/ezetimibe combination therapy in dialysis patients [40].

Blood pressure interventions

Many have argued that blood pressure management is the most important aspect of diabetes care because it has tremendous impact on the risk for microvascular and macrovascular complications [41]. Strictly speaking, the current systolic blood pressure goal of less than 130 mm Hg has not been tested formally in clinical trials because that level has not been achieved and sustained in studies; the diastolic goal of less than 80 mm Hg is better studied.

ACCORD's second substudy will randomize 4200 participants to two levels of blood pressure control to answer whether, in the context of good glycemic control, a therapeutic strategy that targets a systolic blood pressure (SBP) of < 120 mm Hg reduces the rate of CVD events compared with a strategy that targets a SBP of < 140 mm Hg. The ADVANCE trial also has a blood pressure substudy in which patients will be randomized to a fixed low-dose combination of the ACE inhibitor perindopril and the thiazide diuretic indapamide or matching placebo to produce a difference in blood pressure between arms.

NAVIGATOR and DREAM will examine the roles of valsartan, an angiotensin-receptor blocker, and ramipril, an ACE inhibitor, on CVD.

Lifestyle interventions

Another crucial question in diabetes management is whether lifestyle intervention can affect CVD outcomes. Lifestyle management is a critical component of all diabetes management. Short-term studies of medical nutrition therapy, physical activity, and comprehensive lifestyle approaches have improved the control of classic CVD risk factors as well as intermediate markers of CVD risk, such as C-reactive protein. However, no long-term large-scale study of intentional weight loss has been powered to examine CVD endpoints.

Look AHEAD (Action for Health in Diabetes) will examine CVD events for up to 11.5 years in patients 45 to 74 years of age who have type 2 diabetes mellitus and a body mass index > 25 kg/ m2 [40]. Patients will be randomized to a 4-year intensive weight-loss program (calorie restriction and physical activity) or to ''diabetes support and education.'' With planned recruitment of 5000 patients at 16 centers over 2.5 years, the study is designed to provide a 0.90 probability of detecting an 18% difference in major CVD event rates between arms.

Miscellaneous interventions

Finally, a related topic is whether antioxidant vitamins, B-vitamin supplementation to lower homocysteine, or various fatty acids can promote CV health in diabetes mellitus. All have been associated with lower risk in epidemiologic analysis, although no consistent findings have emerged from large-scale randomized trials in people who have diabetes mellitus [42-44]. The ORIGIN trial will evaluate the effect of omega fatty acids in patients who have diabetes mellitus and predia-betes and CVD risk factors; ASCEND (A Study of Cardiovascular Events in Diabetes) also will do so in patients who have diabetes mellitus in the setting of primary prevention in a 2 x 2 factorial design in which the second randomization will be to aspirin, 100 mg/d, versus placebo [45]. SEARCH and HPS II will randomize subjects to various vitamin supplements or placebo to examine whether these relatively inexpensive interventions provide clinical benefit to reduce CVD as well.

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