Tight Control in Advanced Diabetes Still Risky

At five-year follow-up after an average 3.7 years of intense management targeting a HbA1c below 6%, all-cause mortality remained 19% higher than with standard therapy with a 7% to 7.9% target, Hertzel C. Gerstein, MD, of McMaster University in Hamilton, Ontario, and colleagues found.

The magnitude of the mortality risk stayed essentially unchanged in the post-intervention period when HbA1c rose to 7.2%, similar to the standard therapy group.

"Such a strategy cannot be recommended for high-risk patients with advanced Type 2 diabetes," they urged in the paper.

The Action to Control Cardiovascular Risk in Diabetes (ACCORD)) study turned the tide on tight control when it -- along with the (ADVANCE and VA DIABETES Trials) -- failed to show that targets below the standard 7% had any impact on cardiovascular deaths or events. ACCORD was unique in showing evidence of harm, though. And it has been difficult to explain the 22% excess all-cause mortality risk among patients randomized to intensive management found in an interim analysis that halted the intervention before the five years of planned treatment.

Richard Bergenstal, MD, of the International Diabetes Center at Park Nicollet in Minneapolis, commented that severe hypoglycemia episodes and lower A1c have both been ruled out as the culprit by subsequent analyses. The best guess remains that the intensity of therapy -- pushing too hard in patients who couldn't achieve the low target -- was at fault.

The lack of change in the ACCORD findings with additional follow-up wasn't surprising, noted Bergenstal, who has been an investigator in the trial but was not involved in the latest analysis. For example, the U.K. Prospective Diabetes Study (UKPDS) took a decade to show certain benefits of a 7% goal, he pointed out.

The mortality risk didn't get worse over time in ACCORD, and there's still a chance that the earlier aggressive treatment will turn out to have a significant cardiovascular benefit down the road with further follow-up, he added.

The five-year follow-up of the 10,251 advanced Type 2 diabetes patients at high cardiovascular risk did show a reduced risk of nonfatal myocardial infarction (HR 0.82, 95% CI 0.70 to 0.96).

But the primary composite outcome of nonfatal heart attack, nonfatal stroke, and death from cardiovascular causes remained non-significant throughout the entire five years (HR 0.91, P=0.12).

When the mortality risk became known and the intensive intervention group transitioned to standard therapy, the all-cause mortality risk had been 21% higher with tight control than with standard care (1.42% versus 1.16%, adjusted P=0.036). From the time of transition to the end of five years, that didn't change (P=0.74).

ACCORD also included randomization to intensity of blood pressure and lipid control.

Whereas the lipid arms didn't interact with the glucose control intervention, intensive blood pressure lowering was associated with a marginally higher mortality risk from tight control (HR 1.45, P=0.05) whereas standard blood pressure lowering was not (HR 0.78, P=0.24). The researchers cautioned that this interaction may have been a chance finding.

Moreover, they warned against drawing inferences about between-group differences in the post-transition period, since these may have been driven by differences in who survived and were followed during this period.

Also, the trial included mostly patients middle-age and older who had a long duration of diabetes and a high risk of cardiovascular disease, none of whom had an A1c below 7.5%, so the results might not generalize to those with newly diagnosed diabetes, the investigators added.

For patients with established diabetes, the best goal isn't clear, Bergenstal noted.

The American Diabetes Association, of which he is immediate past president, continues to recommend a 7% goal for A1c as reasonable and doesn't rule out tight glucose control for selected patients working with their physician.

• Explain that five-year follow-up in the ACCORD study showed continued increased all-cause mortality for advanced Type 2 diabetics who received intensive glucose-lowering therapy even though that arm of the study was terminated early.
• Note that glycosylated hemoglobin levels rose in the intensive therapy patients after this therapy stopped, but the higher mortality risk still persisted.

ACCORD Study Group "Long-term effects of intensive glucose lowering on cardiovascular outcomes" N Engl J Med 2011; 364: 818-828.