New UK Data Support ACCORD Findings, Emphasize Need for Individualization of Blood Glucose Control

February 03, 2010

February 3, 2010 (Cardiff, Wales)— A new retrospective cohort study in patients with type 2 diabetes has found that the lowest and highest glycated hemoglobin A1c (HbA1c) levels were associated with increased all-cause mortality and cardiac events [1]. This U-shaped association showed that the lowest death and lowest event rates were seen at an HbA1c level of 7.5%, say Dr Craig J Currie (Cardiff University, Wales) and colleagues in their paper published online January 27, 2010 in The Lancet.

The results "lend support" to the findings of the Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial, say the British researchers, "and might have important implications for care of people with type 2 diabetes," suggesting that diabetes guidelines "might need revision to include a definition of an HbA1c minimum value," they state.

Coauthor Dr Marc Evans (University Hospital of Wales, Cardiff) told heartwire : "The primary message is that overintensification of blood glucose control, certainly in some patients, may be detrimental in terms of outcome and may be associated with an adverse risk of mortality. That said, poor blood glucose control in the analysis--which is based on real-life data--is also associated with adverse outcomes, so the take-home message is that we should individualize therapy. These results support the current concept, certainly within the UK and increasingly globally, of the importance of individualization of blood glucose control."

The take-home message is that we should individualize therapy.

In an accompanying editorial [2], Drs Beverley Balkau (Université Paris Sud, Villejuif, France) and Dominique Simon (Groupe Hospitalier Pitié Salpetrière, Paris, France) say that more research is needed to establish HbA1c thresholds and the combination of drugs to be recommended for intensive treatment in type 2 diabetes.

However, they agree that individualization of therapy is key, requiring "differing recommendations according to the patient; intensive treatment seems to be more beneficial for cardiovascular outcomes for those who are younger than 60 years, with a short duration of diabetes and absence of microvascular and macrovascular disease."

Some Light Thrown on the Issue

For diabetes doctors, the simple message used to be "the lower, the better" when it comes to HbA1c, but in 2008 the ACCORD trial was halted prematurely--to everyone's surprise--because of an increased risk of death in type 2 diabetes patients who underwent intensive blood glucose lowering compared with conventional therapy. As well as ACCORD, the Action in Diabetes and Vascular Disease (ADVANCE) trial and the Veterans Affairs Diabetes Trial (VADT) showed no significant effect of intensive glucose control on the rates of cardiovascular events.

But long-term follow-up of the United Kingdom Prospective Diabetes Study (UKPDS), in contrast, showed that early intensive glucose lowering had a significant effect on risk of MI or all-cause mortality. Since the release of these conflicting data, diabetes doctors have been debating the issue of the ideal HbA1c level and trying to tease out the best message to convey to primary-care physicians and others who might be treating patients with type 2 diabetes, as discussed in a recent heartwire feature.

In their editorial, Balkau and Simon say: "In the Lancet today, some light is thrown on this issue by Craig Currie and colleagues with data from the large and statistically powerful [UK] General Practice Research Database."

Currie et al studied two cohorts of patients aged 50 years and older with type 2 diabetes in the UK database from 1986 to 2008, identifying 27 965 patients whose treatment had been intensified from oral monotherapy to combination therapy with oral blood glucose lowering agents and 20 005 who had changed to regimens that included insulin. All-cause mortality was the primary outcome, and the findings were adjusted for confounding factors.

Causes of death were not given, and no information was provided about the insulin or drugs used for treatment or about doses.

Hypoglycemia Could Contribute to Increased Mortality

Compared with the HbA1c decile with the lowest hazard (median HbA1c 7.5%), the adjusted hazard ratio for all-cause mortality in the lowest HbA1c decile (median 6.4%) was 1.52 and in the highest HbA1c decile (median 10.5%) was 1.79.

"Results showed a general U-shaped association, with the lowest HR at an HbA1c of about 7.5% for all-cause mortality," Currie et al observe.

The 10% of patients with lowest HbA1c values (<6.7%) had a higher death rate than all but those in the top 10%, who had an HbA1c of 9.9% or higher. Furthermore, cardiovascular disease was more frequent in this low-HbA1c group than in any other decile.

The findings also indicate that premature death might be related to hypoglycemia, because the researchers found that mortality was three times higher in patients in either the conventional- or intensive-treatment groups who had severe hypoglycemia than in those who did not have severe hypoglycemia. "Hypoglycemia is associated with various sequelae that could increase mortality," Currie et al note.

Wide Hba1c Range Okay for Oral Combinations But Not for Insulin-Based Treatment?

In addition, the HR for all-cause mortality in people given insulin-based regimens (2834 deaths) vs those given combination oral agents (n=2035) was 1.49, the researchers note.

"These data imply for oral combination therapy that a wide HbA1c range is safe with respect to all-cause mortality and large-vessel events, but for insulin-based therapy, a more narrow range might be desirable," Currie et al observe.

Balkau and Simon agree: "Priority should be given to insulin sensitizers for as long as possible in patients with type 2 diabetes, because these drugs allow a low HbA1c to be targeted without any risk of hypoglycemia."

And regarding the use of insulin secretagogues or insulin itself, "today's study does provide a rationale for an HbA1c range threshold of 7.5%, corresponding to the lowest death rate and lowest event rate for large-vessel disease," say the French doctors.

Treat the Individual, Not the Population

Evans again emphasized to heartwire what he views as the most important implication of the study: the agreement of a patient-specific HbA1c target with each person. "For example, an HbA1c target of 8% may be appropriate for one person, whereas an HbA1c target of 9% might be more appropriate for someone with lots of comorbidities, living alone, etc, where the adverse risk of hypoglycemia associated with glucose control intensification may offset the relative risk reduction in terms of developing complications.

"Guidelines focus on populations, whereas clinicians don't treat a population, we treat an individual," he concluded.

Evans consults for Abbott, Allergan, Bristol-Myers Squibb, GlaxoSmithKline, Lilly, Novartis, Novo Nordisk, Merck Sharp & Dohme, Roche, Sanofi-Aventis, and Takeda. Disclosures for Currie and other authors are listed in the paper. Balkau has served as a speaker for Sanofi-Aventis and on advisory panels for AstraZeneca, Bristol-Myers Squibb, Lilly, and Sanofi-Aventis. Simon has served as a speaker for GlaxoSmithKline, Sanofi-Aventis and Servier and on advisory panels for AstraZeneca, Bristol-Myers Squibb, GlaxoSmithKline, and Novartis.

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