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Several outcomes studies have examined whether pharmacologic interventions in combination, early in the disease process, can prevent progression from impaired glucose tolerance or impaired fasting glucose to type 2 diabetes. Other outcomes studies examining monotherapy failure in the newly diagnosed patient with type 2 diabetes and the relationship between macrovascular events and glucose control are under way. A recent Veterans Administration study examines whether expensive new therapies for diabetes are cost-effective. This program discussed the impact of these studies, with a focus on three: DREAM, ADOPT, and VADT. Program Introduction
Alan J. Garber, MD, PhD
Dr. Garber discussed a variety of completed trials with varied results, but all showing that early intervention can improve some outcomes in some patients at high risk for development of diabetes. In the TRoglitazone In the Prevention Of Diabetes (TRIPOD) study, troglitazone reduced the incidence of diabetes by 55% in Hispanic women with a history of gestational diabetes. Women who were protected during the trial remained protected 8 months later and had stable β-cell function over 54 months. The Pioglitazone In Prevention Of Diabetes (PIPOD) was an open-label study of pioglitazone, 45 mg/d, given to women who completed TRIPOD. The risk of diabetes was lowest in women with the largest reduction in total intravenous glucose tolerance test insulin area after 1 year of treatment. Comparison of changes in β-cell compensation for insulin resistance across the TRIPOD and PIPOD studies revealed that pioglitazone stopped the decline in β-cell function that occurred during placebo treatment in the TRIPOD study and maintained the stability of β-cell function that had occurred during troglitazone treatment in the TRIPOD study. These data support a class effect of thiazolidinedione drugs to enhance insulin sensitivity, reduce insulin secretory demands, and preserve pancreatic β-cell function, all in association with a relatively low rate of type 2 diabetes, in Hispanic women with prior gestational diabetes.
The PROactive (PROspective pioglitAzone Clinical Trial In macroVascular Events) study was a randomized, double-blind, placebo-controlled outcome trial that determined the effects of pioglitazone on mortality and morbidity associated with cardiovascular disease progression. It included more than 5000 high-risk patients with type 2 diabetes and added pioglitazone to “standard treatment” (antihypertensives such as angiotensin-converting enzyme inhibitors and β-blockers; metformin, sulfonylureas, and insulin; antiplatelet drugs such as aspirin; and statins and fibrates). PROactive had two key endpoints: the primary endpoint, seven macrovascular events, was reduced by 10%, but this reduction was not significant by the end of the study. However, the principal secondary endpoint of life-threatening events showed that pioglitazone significantly reduced the combined risk of nonfatal myocardial infarction (MI), stroke, and deaths by 16% (P = 0.027). The 5-year FIELD study (Fenofibrate Intervention and Event Lowering in Diabetes), which included almost 10,000 patients, produced mixed results, with a reduction in nonfatal MI but no effect on coronary heart disease.
The IDEAL (Incremental Decrease in Endpoints through Aggressive Lipid lowering) study, one of a number of trials in the past few years addressing the "lower-is-better" hypothesis of cholesterol lowering, produced mixed results. Intensive lipid lowering with atorvastatin 80 mg/d did not result in a significant reduction in the primary endpoint of major coronary events when compared with usual-dose simvastatin in patients with previous MIs. Intensive lipid lowering did reduce the risk of other composite secondary endpoints and significantly reduced the risk of nonfatal MI.
In contrast, PROVE-IT (PRavastatin Or atorVastatin Evaluation and Infection Therapy), which included patients recently hospitalized with acute coronary syndrome, showed that intensive lipid lowering with atorvastatin 80 mg/d provided greater protection from death and cardiovascular events than pravastatin 40 mg/d.
DREAM
Hertzel C. Gerstein, MD, MSc, FRCPC
The DREAM (Diabetes REduction Assessment with ramipril and rosiglitazone Medication) trial was designed to determine whether treatment with either ramipril and/or rosiglitazone can reduce the incidence of diabetes in persons with impaired glucose tolerance. As these two interventions have very different mechanisms of action, the effects are likely to be independent and potentially complementary.
Ramipril prevents or delays cardiovascular disease and death in high-risk individuals. However, this trial excluded patients at high cardiovascular risk but included those at low risk.
The DREAM trial is an international (21 countries), multicenter (191 sites), randomized, double-blind, controlled trial. A total of 5269 participants with impaired glucose tolerance and mean age 55 years have been recruited. They have been randomly allocated to either ramipril and/or rosiglitazone using a 2 × 2 factorial design and followed for at least 3 years after randomization. Participants were assessed at regular intervals to ascertain the occurrence of the primary outcome (new-onset diabetes mellitus or all-cause mortality) and other secondary outcomes. Diabetes was defined as 2 consecutive plasma glucose levels exceeding the diagnostic thresholds (fasting plasma glucose [FPG] 126 mg/dL or a 2-hour plasma glucose ≥11.1 mmol/L (200 mg/dL) within 3 months. The secondary outcomes were composite cardiorenal events. The study was not powered for cardiovascular events. Results from the DREAM trial are not yet unblended. Outcome data will be presented at the (September) 2006 meeting of the European Association for the Study of Diabetes.
EpiDREAM, a substudy of DREAM, is expected to enroll approximately 15,000 high-risk subjects who are ineligible for DREAM. For the duration of DREAM, EpiDREAM participants will provide yearly updates on health status by telephone interview.
ADOPT
Steven M. Haffner, MD
ADOPT (A Diabetes Outcome Progression Trial) is a randomized, double-blind study comparing glycemic control and preservation of pancreatic β-cell function with rosiglitazone monotherapy, metformin, or a sulfonylurea (glyburide/glibenclamide) in patients with drug-naïve, recently diagnosed type 2 diabetes mellitus. A 4-week trial of diet/exercise identified patients who had insufficient control of their diabetes (FPG ≥126 mg/dL and ≤180mg/dL). These patients were randomly assigned to rosiglitazone, glyburide or glibenclamide, or metformin. The primary endpoint is time to monotherapy failure, which is defined as FPG >180 mg/dL when the patient is already on the maximum tolerated dose of study medication for at least 6 weeks.
ADOPT is testing the hypothesis that rosiglitazone preserves pancreatic β-cell function better than other drugs used as first-line therapy for type 2 diabetes mellitus, delaying or preventing deterioration in glycemic control. Pancreatic β-cell function will be assessed by an oral glucose tolerance test (OGTT). About 300 centers in North America and Europe have participated in ADOPT and data will be available in December 2006.
VADT Trial
Carlos Abraira, MD
About one fourth of patients treated by the Department of Veterans Affairs Health Administration have type 2 diabetes mellitus. The costs of care for the treatment are extremely high, both in expenditures for the metabolic disorder and care of end-organ complications. Macrovascular complications (coronary heart disease and peripheral vascular disease) are responsible for the overwhelming majority of the mortality, morbidity, and treatment costs in the American population of type 2 diabetics, even more so in the older VA diabetic population.
The Veterans Administration Diabetes Trial (VADT) is a prospective, 2-arm, randomized controlled trial to determine whether glycemic control, achieved through intensification of treatment, is effective in preventing clinical macrovascular complications in patients with type 2 diabetes no longer responsive to oral agents alone. The study consists of a 2-year accrual period and 5 years of follow-up of 1700 patients across 20 centers. The study is powered to detect a 25% reduction in the primary event rate. Additional study goals are to determine whether the expenditures, discomfort, and adverse effects associated with intensive intervention are justified in terms of their clinical benefits, considering both macrovascular and microvascular complications.
The primary hypothesis is that intensive glycemic control reduces major macrovascular morbidity and mortality compared with standard glycemic control in patients with type 2 diabetes who have failed simple therapy. The secondary hypothesis is that intensive glycemic control, compared with standard glycemic control, reduces other macrovascular morbidity and total mortality.
The intervention is aimed at normalization of hemoglobin (Hb)A1c. This will be achieved through stepped-care therapy, which will include lifestyle intervention, oral diabetes medications, and insulin. The comparison is standard control, aimed at achieving a HbA1c of 8%-9%. The same agents will be used, but at reduced doses. The sequence of steps is as follows: step 1, metformin (obese) or glimepiride (lean) in combination with rosiglitazone; step 2, insulin; step 3, increase doses in drugs used in steps 1 and 2 in the standard-therapy group. Since the intensive group is already at maximal doses of oral agents, insulin therapy will be intensified and acarbose/miglitol may be added; step 4, for standard, proceed as in step 3 and participants receiving intensive therapy will use multiple daily injections; step 5, "Tool Box"-miscellaneous agents, tailored to the individual patient.
The primary outcomes are time to major macrovascular events (MI, stroke, new or worsening congestive heart failure, amputation for ischemic gangrene, invasive intervention for coronary artery or peripheral vascular disease, inoperable coronary artery disease, or cardiovascular death). Secondary outcomes are angina, transient ischemic attack, intermittent claudication, critical limb ischemia, and total mortality.
The results of the VADT will open debate about the relevance of the outcomes from this older population to patients with new-onset diabetes.
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