Trials examining glycemic management techniques

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The second fundamental question in diabetes management is whether particular glucose-lowering approaches, and more specifically insulin sensitizers, provide benefits beyond glucose lowering in managing CV risk. The possibility first was suggested based on the notion that insulin resistance is linked epidemiologically with components of the metabolic syndrome including dyslipidemia, dysglycemia, hypertension, a procoagulant state, vascular inflammation, endothe-lial dysfunction, and premature vascular disease [13,14]. Several small and medium-sized studies have supported the idea that insulin-sensitizing approaches could be superior to approaches that supplement deficient insulin secretion, suggesting improvements in markers of CV risk during treatment with metformin and thiazolidinediones when compared with other therapies. Furthermore, in the UKPDS, among overweight subjects, those randomly assigned to initial therapy with metformin (but not to insulin or sulfonylurea) demonstrated a reduction in diabetes mellitus-related deaths and MI compared with those treated with lifestyle intervention; the validity of this observation has been challenged because of the relatively limited sample size and the unusual responses in a subsequent subrandomization [7].

BARI 2D

Arguably the BARI 2D study (Bypass Angioplasty Revascularization Investigation in Type 2 Diabetes) will offer the most straightforward assessment of this controversy. This multicenter study will recruit 2800 patients who have type 2 diabetes mellitus. Important inclusion criteria include age over 25 years and a coronary arteriogram showing one or more vessels amenable to revascu-larization with at least a 50% or greater stenosis and either objective documentation of ischemia or typical angina with at least a 70% coronary stenosis. Patients will be randomized in a 2 x 2 factorial design to examine two treatment strategies: one cardiac-related (coronary revasculariza-tion plus aggressive medical therapy versus aggressive medical therapy alone) and one diabetes-related (comparing insulin-providing versus insulin-sensitizing therapy). The diabetes treatment randomization will be to treatment focusing on providing more insulin, either endogenously, stimulated through the use of insulin secreta-gogues, or exogenously, administered through subcutaneous insulin injections, versus a strategy of increasing sensitivity to insulin by using metformin and/or one of the commercially available thiazoli-dinediones, pioglitazone or rosiglitazone. All patients will be treated with a target HbAlc level of < 7%. For those unable to achieve an HbAlc level less than 8% with one treatment strategy, crossover to combined treatment approaches will be used. The other randomization will examine two approaches to manage CVD: elective revasculari-zation using surgery or catheter-based therapies combined with aggressive medical therapy versus aggressive medical therapy alone. The primary outcome for this trial is CV mortality. Additional outcomes include MI, angina, quality of life, employment, cost, and cost-effectiveness. Recruitment is expected to be complete in 2004, with results reporting in 2007 [15,16].

PROactive

Several pharmaceutical industry-sponsored clinical trials will examine the effect of various specific agents on CV outcomes. Little published information on these trials is available. One exception is the PROactive study (Prospective Pioglitazone Clinical Trial in Macrovascular Events), which has reported its design and baseline characteristics. PROactive has randomized 5238 patients from 19 countries who have type 2 diabetes mellitus and a history of macrovascular disease to the addition of pioglitazone versus placebo onto existing baseline antidiabetic therapy. The primary endpoint is the time from randomization to occurrence of a new macrovascular event or death. The study was expected to reach its prespecified follow-up period depending on the rate of accrual of events in 2005 [17].

RECORD

The RECORD study (Rosiglitazone Evaluated for Cardiac Outcomes and Regulation of Glycae-mia in Diabetes) will randomize 6000 patients who have type 2 diabetes mellitus failing either sulfonylurea or metformin. Patients entering the study on metformin will be randomized to combination with sulfonylurea or rosiglitazone and patients entering the study on sulfonylurea will be randomized to combination with metformin or rosiglitazone. At 18 months, an interim analysis will examine glycemic control between arms. Patients will be followed for 6 years on rosiglita-zone plus metformin or sulfonylurea versus met-formin plus sulfonylurea or acarbose for combined CV endpoints [18].

ORIGIN

The ORIGIN trial (Outcome Reduction with Initial Glargine Intervention) is a multicenter international study that will randomize in a 2 x 2 factorial design 10,000 people 50 years of age or older at high risk for CVD who have early type 2 diabetes mellitus as defined by an HbAlc level less than 9% if drug nai've or a lower Alc if treated with one oral antidiabetic agent. Persons who have prediabetes with either impaired fasting glucose (IFG) or with impaired glucose tolerance (IGT) will also be included. For the first randomization, patients will be assigned to treatment with insulin glargine titrated to normalize fasting glucose to < 95 mg/dL versus standard care, which generally will involve metformin or sulfonylurea therapy, at least in patients who have fasting hyperglycemia with sequential conventional tactics aiming at achieving Alc < 7%. Patients also will be randomized to a supplement of omega-3 polyunsatu-rated fatty acids versus placebo. The primary endpoint is combined CV morbidity and mortality outcomes, with projected study completion in late 2008 [19].

NAVIGATOR

The NAVIGATOR trial (Nateglinide and Valsartan in Impaired Glucose Tolerance Outcomes Research) has randomized over 8000 individuals 55 years of age or older who have IGT in over 30 countries in a 2 x 2 factorial design to valsartan versus placebo and to the insulin secre-tagogue nateglinide versus placebo. Rate of progression from IGT to diabetes mellitus as an endpoint, will be examined 3 years after the last participant is randomized. After 1000 CV events have accrued, estimated to occur with 5 to 6 years of follow-up, composite CV morbidity and mortality outcomes will be examined as an endpoint [20,21].

DREAM

The DREAM study (Diabetes Reduction Assessment with Ramipril and Rosiglitazone Medication) is similar in design to NAVIGATOR, but only examines CVD endpoints and surrogate CV risk markers as secondary endpoints. It also uses a 2 x 2 factorial design to examine the primary outcome if treatment with an angiotensin-converting enzyme (ACE) inhibitor (ramipril) or a thiazolidinedione (rosiglitazone) versus matched placebo can delay or prevent the development of type 2 diabetes mellitus in people who have IGT or impaired fasting glucose (IFG). Follow-up is planned until 2006 in the 5269 patients who have been recruited; further details are published [22].

Table 2 provides an overview of these six studies. In particular, the BARI 2D study should answer the question of whether sensitizer-based therapy is superior to insulin-supplementing therapy. The others likely will be confounded somewhat by differences in levels of glycemic control. To the extent that the studies involving patients who have prediabetes and early diabetes unlikely will exhibit much in the way of elevated glucose, even in the placebo or usual care groups, the effect of differences in glycemia on CVD risk should be minimized, isolating nonglycemic effects of these therapies to some extent. As a body of work, these studies will provide substantial new guidance for

Table 2

Studies of techniques of glycemic control and effects on cardiovascular disease

Table 2

Studies of techniques of glycemic control and effects on cardiovascular disease

No. of

Estimated

Randomized treatments

Study [Ref.]

Population

participants

completion

1

2

BAR1 2D [15,16]

DM and

2800

2007

Insulin

Insulin

coronary

sensitizing

providing

lesion

PROACTIVE [17]

DM

5238

2005

Pioglitazone:

Placebo:

RECORD [18]

DM

6000

metformin +

metformin +

rosiglitazone ±

sulfonylurea ±

sulfonylurea

acarbose

ORIGIN [19]

DM and

10,000

2008

Glargine

Standard care

prediabetes

NAVIGATOR [20]

Prediabetes

8000

2006

Nateglinide

Placebo

DREAM [22]

Prediabetes

5269

2006

Rosiglitazone

Other interventions under study

Randomized treatments

Table 3

Other interventions under study

Randomized treatments

Study [Ref.]

i

2

BAR1 2D [15,16]

CABG or PCI + medical

Medical management

management

FREEDOM [31]

CABG

Sirolimus-eluting stent

HPS II, SEARCH [35,36]

High-dose simvastatin

Lower-dose simvastatin

TNT [37]

High-dose atorvastatin

Lower-dose atorvastatin

IDEAL [35]

High-dose atorvastatin

Moderate-dose simvastatin

FIELD [38]

Fenofibrate

Placebo

ACCORD-Lipid [12]

Simvastatin + fenofibrate

Simvastatin + placebo

ACCORD-BP [12]

SBP < HO mm Hg

SBP < 140 mm Hg

NAVIGATOR [20,21]

Valsartan

Placebo

DREAM [22]

Ramipril

Placebo

SPARCL (stroke) [39]

High-dose atorvastatin

Placebo

SHARP [40]

Simvastatin + ezetimibe

Simvastatin

ADVANCE [8,9]

ACE + thiazide

Placebo

Look AHEAD [42]

Lifestyle management

Diabetes support and

for weight loss

education

ORIGIN, ASCEND [19,46]

Omega fatty acid supplement

Placebo

SEARCH, HPS II [35,36]

Vitamins

Placebo

ASCEND [46]

Aspirin

Placebo

CARDia [32]

CABG

PCI

optimal treatment strategies in approaching gly-cemic targets in type 2 diabetes mellitus.

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