SAN FRANCISCO — Intensively lowering blood glucose levels did not significantly reduce cardiovascular risk in older patients with poorly controlled diabetes whose blood pressures and cholesterol levels were well controlled, a major long-term study found.
The 1,791-patient Veterans Affairs Diabetes Trial identified two predictors of cardiovascular risk—hypoglycemic episodes and the duration of diabetes—and included a secondary analysis of the safety of using rosiglitazone. The study found no increased risk for MI in patients on rosiglitazone. (See box.)
The VA Diabetes Trial is the third major randomized, controlled study to report no overall cardiovascular benefit from intensive glycemic control, following on the heels of the Action to Control Cardiovascular Risk in Diabetes (ACCORD) study, in which intensive glycemic control increased the risk of death, and the Action in Diabetes and Vascular Disease: Preterax and Diamicron Modified Release Controlled Evaluation (ADVANCE) study.
“Our patients had the worst glycemic control of the three trials,” with baseline hemoglobin A1c levels averaging 9.5%, Dr. Carlos Abraira said at a press conference at the annual scientific sessions of the American Diabetes Association.
The HbA1c levels fell to a median of 6.9% within 6 months with intensive therapy. The study was designed to maintain a 1.5% difference in HbA1c levels between the intensive and usual-care group, which reached an HbA1c level of 8.4%, to highlight any effects of intensive therapy.
Patients in the study averaged 60 years of age at enrollment, and 97% were male. About 40% had a history of prior cardiovascular events. At baseline, 80% had hypertension, 50% had lipid abnormalities, and most were obese. The trial strictly controlled blood pressure and cholesterol levels, achieving targets after 2 years of therapy that were maintained during the average 6-year follow-up, reported Dr. Abraira of the Miami Veterans Affairs Medical Center. Dr. Abraira is cochair of the VA Diabetes Trial and professor of medicine at the University of Miami.
Far fewer cardiovascular events occurred than were expected, totalling 231 events in the intensive group and 263 with usual care, probably because of the excellent control of blood pressure and lipids, improved diet and exercise, and treatment with aspirin, said Dr. William C. Duckworth, cochair of the trial and director of diabetes research at the Veterans Affairs Medical Center in Phoenix. Increases in levels of “good” HDL cholesterol in the study greatly decreased the chance of a cardiovascular event.
The study found cardiovascular benefits in patients who started intensive glycemic therapy early after diagnosis of diabetes, less likelihood of benefits for patients with longer-duration diabetes, and a suggestion of potential harm from intensive glycemic control in those with long-standing diabetes before starting the regimen, he said.
“Start intensively treating early after diagnosis, no matter how old they are,” Dr. Duckworth suggested.
An episode of severe hypoglycemia was associated with roughly a doubling in risk for a cardiovascular event within 3 months and a tripled risk for death from cardiovascular causes. The study may be the first to document the association between hypoglycemia and cardiovascular risk, which most physicians have assumed to be true, Dr. Duckworth added.
The trial will continue as an observational study for another 9 years.
Dr. Duckworth said the results so far illustrate the inadvisability of setting one glycemic target for all patients with diabetes.
Dr. Duckworth consults for, or has received research funds from, companies that make medications for diabetes, hypertension, or hypercholesterolemia including Sanofi Aventis, Novo Nordisk, Kos Pharmaceuticals, and Amylin Pharmaceuticals. Dr. Abraira has received research support from GlaxoSmithKline, which makes rosiglitazone, and from other companies that make medications for diabetes, hypertension, or hyperlipidemia.
No Increase in MI Seen in VA Trial of Rosiglitazone
Three secondary safety analyses of data from the VA Diabetes Trial found neutral effects or protection against cardiovascular events with use of the thiazolidinedione, rosiglitazone, contrary to previous findings.
“We feel that rosiglitazone is not causing any harm to the patients,” said statistician Thomas E. Moritz of the Hynes (Ill.) Veterans Affairs Hospital.
A meta-analysis of 42 randomized, controlled studies previously reported a significant 43% increase in the odds of developing an MI and a trend toward higher risk of death from cardiovascular causes in patients with type 2 diabetes treated with rosiglitazone, he noted (N. Engl. J. Med. 2007;356:2457–71). In response, the VA medical system removed the drug from its formulary and the Food and Drug Administration issued a black box warning about potential cardiovascular risks with rosiglitazone.
The meta-analysis findings prompted the VA Diabetes Trial investigators to take a hard look at their data on rosiglitazone. A retrospective case-control analysis matched patients who had cardiovascular events with similar patients who did not have events. “In every analysis we did, the frequency or dosage of rosiglitazone was increased in the group that did not suffer the event.”