Rosiglitazone effective diabetes monotherapy
ADOPT shows drug delays progression with long-term glucose control
A recently completed diabetes trial indicates the higher relative, single-therapy efficacy of a newer class of glucose-lowering agents-the thiazolidinediones (TZDs), particularly rosiglitazone maleate-in delaying the progression of type 2 diabetes through long-term blood-sugar control in newly diagnosed patients.
Compared with two other hypoglycemic drugs, rosiglitazone is shown to have a more durable treatment effect over five years-vis-a-vis the progressive nature of type 2 diabetes-by better reducing the risk of monotherapy failure. Monotherapy failure in this case was initially defined as confirmed level of fasting plasma glucose of more than 180 mg/deciliter. Researchers found similar results at a lower fasting glucose threshold (140 mg/deciliter) which is the more current therapeutic benchmark.
A Diabetes Outcome Progression Trial (ADOPT), an international study concluded in 2006 involving 4,360 patients, found that rosiglitazone reduced risk by as much as 32 percent compared with metformin and 63 percent compared with glyburide, a sulfonylurea. Its results were published in the New England Journal of Medicine and presented at the recent 19th World Diabetes Congress of the International Diabetes Federation in South Africa.
Per subgroup, rosiglitazone's efficacy versus metformin was more pronounced among older patients (more than 50 years old) and those with larger waist circumference, while it is generally more effective than glyburide across all subgroups.
The first subgroup comparison might be significant in the Philippines where diabetes is highest among Filipinos 50 to 59 years old. By 2030, the country is also set to rank ninth worldwide in the number of projected diabetes cases.
Other complementary findings were consistent with the primary outcome. The level of glycated hemoglobin or the chemical linkage of glucose and hemoglobin molecules was maintained at less than seven percent for a longer period with rosiglitazone than with the other medications. Rosiglitazone also accounted for the slowest decline of beta-cell function and greatest improvement in insulin sensitivity. Loss of beta-cell function is viewed as probable cause for the increase of glucose levels over time in type 2 diabetes, despite lifestyle and pharmacologic interventions.
Dr. Peter J. Grant, a leading British researcher on diabetes and vascular disease who was in Manila recently, said that ADOPT is the latest in the recent series of major clinical trials examining the utilization of TZDs. "It's a very busy time for diabetes. We've moved from an awareness of complications, through major epidemiologic studies in the early part of the 1990s, to what causes those complications."
He added that over the last 18 months, there have been three major trials on these drugs. ADOPT comes at the heels of an earlier study, the Diabetes Reduction Approaches with ramipril and rosiglitazone Medications (DREAM), which associated rosiglitazone with a 64-percent decrease in the conversion of impaired glucose tolerance, a precursor condition of diabetes, to type 2 diabetes over three years.
However, studies like ADOPT and DREAM are not yet likely to lead to a change in treatment guidelines in terms of first-line therapy recommendations, said Grant. Based on parameters of some international guidelines, he notes that a new drug would have to exhibit better cardiovascular benefits than metformin, a drug currently enshrined in guidelines as a first-liner from its long history of use.
Although ADOPT was not designed to evaluate cardiovascular disease outcomes, it nevertheless showed that it was glyburide which is associated with a lower risk of cardiovascular events (including congestive heart failure) than either rosiglitazone and metformin which share a similar cardiovascular risk level.
"The surrogate cardiovascular effects of the different glucose-lowering-type oral agents are about the same so that in itself is not about to change guidelines," Grant explained. "But what the ADOPT and DREAM trials have done, more than change guidelines, is make us aware of their efficacy. And that I think is important and shouldn't be underestimated."
With a three- to fivefold higher risk of myocardial infarction in type 2 diabetes, he pointed out that future studies are likely to look more closely into the association of diabetes with vascular disease. "In the presence of insulin resistance, a cluster of classical (hyperglycemia, dyslipidemia, hypertension) and nonclassical (inflammatory, thrombotic) risk factors develop to increase vascular risk. The tight relationship between insulin resistance and vascular outcomes suggests that management of insulin resistance would prevent type 2 diabetes and cardiovascular disease," he said. M Grace Roxas
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