Prevention of Cardiovascular Outcomes in Type 2 Diabetes Mellitus Trials on the Horizon

John B. Buse, MD, PhDa*, Julio Rosenstock, MDb c aDivisions of Endocrinology and General Medicine and Clinical Epidemiology, Diabetes Care Center, University of North Carolina School of Medicine, CB #7110, 5039 Old Clinic Building, Chapel Hill, NC 27599-7110, USA bDalla,s Diabetes and Endocrine Center, 7777 Forest Lane, C-618, Dallas, TX 75230, USA cUniversity of Texas Southwestern Medical School, Dallas, TX, USA

Type 2 diabetes mellitus is a clinical syndrome characterized by hyperglycemia in which early cardiovascular (CV) death is the predominant clinical outcome. In the last 20 years several clinical trials have demonstrated unequivocally techniques that reduce the risk for CV events in patients who have diabetes mellitus; these studies form the basis for current guidelines regarding management of patients who have diabetes mellitus, specifically in the areas of lipid modification, blood pressure reduction, modulation of the renin-angiotensin system, antiplatelet therapy, and invasive revascu-larization procedures.

Despite the many published clinical trials, reviews, and guidelines on diabetes mellitus and cardiovascular disease (CVD), large untested areas of accepted clinical practice remain. Although interventional trials strongly support the notion that more intensive glycemic control is associated with a reduction in microvascular complications, there is only epidemiologic basis for the causal link between glucose control and CVD. Outcomes from the adequately powered

This article was originally published in Endocrinology and Metabolism Clinics of North America 34:1, 2005.

Dr. Buse is supported in part by National Institutes of Health Grants RR00046, HC9961, and DK061223.

* Corresponding author.

E-mail address: [email protected] (J.B. Buse).

clinical trials addressing the relationship between intervention to lower glucose and CV events are awaited with great interest. Furthermore, no outcomes studies have been conducted with insulin analogs or thiazolidinediones. Clinical practice is informed by the best available data, but epidemiologic studies can lead one astray, as was the case with hormone replacement therapy as a technique to reduce CVD [1].

This article focuses on the continuing clinical trials in patients who have diabetes mellitus and prediabetes in which CVD outcomes—specifically CV death, myocardial infarction (MI), and stroke—are examined as primary outcomes. These trials were identified using three approaches:

1. Searching www.clinicaltrials.gov, a National Institutes of Health (NIH)-funded website that provides ''regularly updated information about federally and privately supported clinical research in human volunteers" with almost 200 diabetes mellitus trials posted [2];

2. Hand-searching titles and abstracts for over 3000 citations identified in the National Library of Medicine PubMed System describing clinical trials in diabetes mellitus cited over the prior 5 years; and

3. Querying thought leaders in diabetes mellitus and CVD as well as representatives of the NIH's National Heart Lung and Blood Institute and National Institute on Diabetes, Digestive and Kidney Diseases.

This is undoubtedly an incomplete representation of the work being conducted in this regard and the authors recognize in advance the potential intellectual risk of any oversights. Many additional studies examine only intermediate surrogate outcomes (eg, intravascular ultrasound, carotid intimal thickness, and CV risk markers), but unfortunately, there is little published information about them. Various search engines were used to identified design details from study websites and press releases, which are referenced to the extent that they provided additional details.

For purposes of discussion these trials have been grouped based on general themes:

• Trials that examine glycemic targets,

• Trials that examine interventional techniques of glucose lowering, and

• Trials that examine nonglycemic interventions.

Some studies involve designs (eg, factorial designs) in which more than one intervention is examined. In those cases, the theme of the study will be introduced in the earlier section and additional details regarding other interventions in subsequent sections.

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