Early type 2 treatment, high HDL prevent CV events

June 10, 2009

Patients treated early after a type 2 diabetes diagnosis, those with elevated high-density lipoprotein (HDL) levels, and those without a history of severe hypoglycemic episodes are most likely to benefit from intensive glucose control, according to subanalyses of data from the VA Trial of Glycemic Control and Complications in Diabetes Mellitus Type 2 (VADT).

Patients treated early after a type 2 diabetes diagnosis, those with elevated high-density lipoprotein(HDL) levels, and those without a history of severe hypoglycemic episodes aremost likely to benefit from intensive glucose control, according tosubanalyses of data from the VA Trial of Glycemic Control and Complicationsin Diabetes Mellitus Type 2 (VADT).

This conclusion contrasts with the initial VADT report last yearindicating that there was no benefit in terms of cardiovascular events,including death, with intensive glucose control. Overall, there was anonsignificant 12% reduction in risk for cardiovascular events.

"Treatment before 15 years duration of diabetes has a chance of doinggood, but after that, there are increased risks with intensive glucosecontrol," says William C. Duckworth, MD, cochair of VADT and director ofdiabetes research, Carl T. Hayden VA Medical Center, Phoenix, AZ (pictured left). "We have totreat early and carefully."

The risk of a primary cardiovascular event was reduced by 40% amongpatients receiving intensive glucose control if treatment started 10 to 15years after diagnosis, whether or not patients had been untreated or failedtreatment, Dr. Duckworth says. If diabetes had been presented more than 20years before intensive glucose control was initiated, the risk of acardiovascular event doubled.

Dr. Duckworth says that the impact of diabetes duration on cardiovascularrisk was not affected by age and that outcomes for patients maintained onintensive glucose control for 20 or more years is currently unknown.

HDL protective, hypoglycemia raises risk

"HDL level strongly affected primary outcomes and cardiovascular death,with some individuals benefitting by 90%," Dr, Duckworth says. In VADT,patients experienced an 80% decrease in risk of cardiovascular events withevery 10 mg/dL increase of HDL above baseline. There was a 50% decrease inthe risk of a first primary event for every 10 mg/dL HDL increase and a 55%decrease in all-cause mortality with every 10 mg/dL increase.

There were triple the number of severe hypoglycemic events in theintensive-treatment arm of VADT, with severe defined as loss ofconsciousness or severe change in consciousness. Importantly, the associationbetween hypoglycemia and increased risk was similar in both the standard andintensive control arm.

Overall, patients who had severe hypoglycemia during the trial had an 88%increase in primary cardiovascular events and a 33% increase incardiovascular death. "Multiple hypoglycemic events were strongly related toincreased death," Dr. Duckworth says.

"Type 2 diabetes is an extremely heterogeneous disease, and I stronglyencourage avoiding hypoglycemic events," Dr. Duckworth says. He recommendsthat intensive glucose control be tailored to the patient and that patientsbe encouraged to report all hypoglycemic episodes to their physicians.

The VADT included 1,791 patients from 20 VA medical centers (average age,60 years at study entry). Of these, 97% were men, 16% were African American,16% were Hispanic, and 62% were non-Hispanic whites. At baseline, 40.4% ofpatients had a history of cardiovascular events, primarily MI and stroke.Other prior events included angina, transient ischemic attacks, and bypasssurgery of the carotid artery, coronary artery, or leg arteries. In addition,80% had hypertension, more than half had lipid abnormalities, and a largemajority were obese.

All patients in VADT had already failed initial therapy defined aselevated HbA1c levels while being treated with the maximum dose ofat least one oral antidiabetes agent or insulin. The average baselineHbA1c was 9.5%. The goal was to treat until HbA1clevels were below 7%.

Patients were randomized to either intensive- or standard-treatment arms.By the end of the first year of the 7.5-year study, 90% of theintensive-treatment group was taking insulin versus 74% of thestandard-treatment group. Patients starting insulin during the trial remainedon it throughout the study period. Oral antidiabetic agents were prescribedfor 94% of all VADT patients, with most receiving two or three differentmedications. Average follow-up was 6.25 years.

All patients were also treated with maximum lipid and antihypertensiveagents and diet and lifestyle modification, which included education andcounseling.