Clinical Laboratory Strategies: August 28, 2008

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Lowering Glucose Levels in Type 2 Diabetes
ACCORD Study Shows No Reduction in Risk with Intensive Therapy

By John Bell


A central tenet of diabetes screening, diagnosis, and treatment is that every increment of elevation in glycated hemoglobin, or HbA1c, correlates with an increased risk for multiple adverse outcomes, including cardiovascular events and death. However, conventional treatment does not attempt to reduce HbA1c levels to those of nondiabetic persons, and few studies have investigated the effect of targeting treatment to HbA1c levels that are within the nondiabetic reference range. Furthermore, these studies did not report statistically significant cardiovascular outcomes. Now the multi-site ACCORD trial has done both. Yet the investigators found after more than 3 years of follow-up that intensive glucose lowering was associated with an increased rate of death from cardiovascular causes and did nothing to prevent heart disease—and so the trial was halted early. This issue of Strategies investigates its findings.

High levels of HbA1c in patients with type 2 diabetes have been clearly linked to greater risk of neuropathy, organ failure, amputations, stroke, cardiovascular problems, and death. So researchers have long speculated that lowering its level to those of nondiabetic persons might confer lower risk for adverse outcomes.

 A few trials have investigated this question. One, the United Kingdom Prospective Diabetes Study, found statistically insignificant effects on cardiovascular events and mortality. Another study, the Veterans Affairs Diabetes Feasibility Trial, found that intensive lowering posed a non-significant increase in CV events and no effect on mortality. With that history in mind, investigators from institutions across the United States and Canada conducted the Action to Control Cardiovascular Risk in Diabetes (ACCORD) study.

Using intensive therapy to reduce levels of glycated hemoglobin in patients with type 2 diabetes, contrary to expectations, not only failed to reduce the incidence of cardiovascular events but also was associated with increased mortality, according to new findings from the study (NEJM 2008;358:2545-59).

The new data come from 10,251 patients with type 2 diabetes and HbA1c levels of 7.5% or higher who were randomly assigned to receive an intensive intervention that aimed to reduce glycated hemoglobin to a level below 6%, or standard therapy, the goal of which was an HbA1c level of 7.0%–7.9%. Patients fell into one of two groups: those age 40–78 years with cardiovascular disease and those age 55–79 with a major risk factor for CVD, comprising anatomical evidence of significant arteriosclerosis, albuminuria, or left ventricular hypertrophy, or two other risk factors, such as hypertension, obesity, smoking, and dysplidemia. Mean patient age for both groups was 62 years. A total of 5,128 patients were randomly assigned to the intensive therapy, and another 5,123 patients were assigned to standard therapy.

After 4 months, the mean HbA1c level fell from 8.1% to 6.7% in the intensive therapy group and from 8.1% to 7.5% in the standard-therapy group. At the 3.5-year mark, there were 460 total deaths from any cause: 257 among patients given intensive therapy, versus 203 in the group given standard therapy. A similar increase in mortality was seen with deaths from cardiovascular disease; of the 229 total deaths from cardiovascular causes, 135 were in the intensive treatment group and 94 in the standard treatment group. These outcomes led the investigators to halt the trial 17 months early.

William Friedewald, MD, clinical professor of epidemiology and biostatistics at Columbia University’s Mailman School of Public Health in New York, is chair of the ACCORD study group. He said the ACCORD researchers could not suggest any possible cause for the greater rate of deaths in patients on intensive therapy. “We really don’t know. We spent almost a year very carefully going over the data, and we weren’t able to identify any single group or any single combination or single drug that would explain the increased mortality.”

The study did not settle the question of whether there is any benefit to intensive glucose lowering, Friedewald noted, but there are other possibilities for the utility of the research. “There’s still the issue of the microvascular disease,” he said. The ACCORD group will publish results on this at some point, once further data are compiled. Notably, fatal and nonfatal stroke occurred in almost the same percentage of patients in each arm of the trial.

David B. Sacks, MD, medical director of clinical chemistry at Brigham and Women’s Hospital in Boston, noted that the ACCORD findings contrast with those of the Action in Diabetes and Vascular Disease: Preterax and Diamicron MR Controlled Evaluation (ADVANCE) study, which found no increases in mortality with intensive treatment but did find increased risk of severe hypoglycemia among patients with type 2 diabetes. However, that study targeted an HbA1c of 6.5%, Sacks noted. The ACCORD study’s patients were also at high risk of CVD, unlike those of the ADVANCE study. In addition, the overall mortality for both treatment groups in the ACCORD study was lower than the investigators had expected, he said.

“There’s very clear documented evidence that increased HbA1c has adverse cardiovascular risks,”  Sacks explained. “I suspect that eventually, glycated hemoglobin will be included among the cardiovascular risk factors, along with cholesterol and other lipids.” However, the idea that using medications to reduce glycated hemoglobin to the reference range is now in question. “The ACCORD findings have given people pause in terms of saying, ‘Okay, we shouldn’t just keep trying to go as low as we can.’ ” Although elevated HbA1c is associated with adverse cardiovascular outcomes even in nondiabetics, there is no cutpoint at which such outcomes begin. “It’s a continuum,” he said. “I think most people would still recommend targeting 7% or even 6.5%. I think people would, based on at least the initial results of the study, not push to try to get below 6%.”

Fred S. Apple, PhD, medical director of clinical laboratories at Hennepin County Medical Center and professor of laboratory medicine and pathology at the University of Minnesota, Minneapolis, was “astounded by the findings.” He noted that the finding of an increase in hypoglycemia among patients given intensive therapy did not surprise him, however. As far as the future of intensive glucose lowering, “I do not think this will be the last word. I think that because of other outcomes that do improve as you lower HbA1c, people will still continue to study this,” Apple predicted. “I think the long term direction of this is going to be genetics.” He pointed to recent trials showing a better LDL-C response to statins in patients with a KIF-6 polymorphism. “I suspect as we learn more, molecular testing will become more prevalent, along with proteomics.” As far as clinical practice, however, “Clinicians are likely not going to push really low. They’ll keep people in the 7.0% range.”


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