It is safe to say that following the 2008 ACCORD study, there is quite a bit of confusion about appropriate glycemic targets. For the three major intervention studies published that year (ACCORD, ADVANCE, and the VADT), not one trial showed a benefit of tight control for the primary cardiovascular endpoints. In fact, ACCORD made national headlines when it was stopped prematurely due to an increase in mortality in the group randomized to intensive therapy—an HbA1c of 6.4% (compared to 7.5% with standard therapy). Since then, further analyses have tried to explain the results of that study. While there was greater mortality in the intensive therapy group, it was those patients with HbA1c levels above 7% that had the increased mortality. The relationship between HbA1c and mortality was virtually a straight line with the lowest mortality associated with an HbA1c of 6% and the highest at 9%. For standard therapy, the relationship was a “U” shaped curve, with the bottom of the “U” at an HbA1c of 7.5%. The reasons for these different relationships are not known.

 

How does that impact our patient presented here? The answer is, it really doesn’t. The ACCORD Trial, and for that matter the other two intervention trials, were studying the effect of intensive therapy on an older population of patients (generally above 60 years) with roughly a decade duration of diabetes and either known or relatively high risk of cardiovascular disease. Our patient, on the other hand, is 55 years old with newly diagnosed diabetes. She has no known cardiovascular disease (CVD), well controlled hypertension, and her LDL-C is within target. She has no albuminuria, and although she needs a formal dilated retinal exam, no apparent retinopathy. The fundamental point is, the ACCORD trial cannot be extrapolated to her as she would not have been included in this trial. Rather, her clinical profile is similar to patients studied in the United Kingdom Prospective Diabetes Study (UKPDS).

 

In this latter trial, newly diagnosed patients with type 2 diabetes were randomized to an “intensive” or “standard” policy of glucose control. The difference in HbA1c between the two groups was 0.9% (7.0 vs. 7.9%). The results showed a dramatic reduction in microvascular disease, but no significant change in the primary macrovascular endpoint, myocardial infarction (MI). Although there was a 16% reduction in MI, it was not statistically significant (p=0.052). Importantly, ten-year follow-up of these patients showed that despite similar HbA1c levels immediately following the formal trial, there continued to be a reduction in microvascular disease. Furthermore, despite similar glycemic control between the two groups for a decade, those randomized to the “intensive policy” had a significant reduction not only of MI, but also all-cause mortality. These investigators termed this long-term benefit of early glycemic control the “legacy effect,” but it has also been called “metabolic memory” in the landmark study of people with type 1 diabetes, the Diabetes Control and Complications Trial (DCCT), which reported a similarly beneficial impact of early control on disease progression. Although specific cellular mechanisms for this phenomenon are not clear, it is now appreciated that glycemic control tends to have greater impact shortly after the diagnosis of diabetes.

 

While considering the three studies assessing CVD in patients with more long-standing type 2 diabetes, it is thus important to note the concept of individualization of glycemic targets. Our newly-diagnosed 55-year-old is not similar to the patients in the three studies but rather more like the population studied in the UKPDS. Therefore, a HbA1c target of < 7.0% is reasonable for her, and, in fact, some would suggest an even lower target, particularly if this patient can achieve it without high risks for hypoglycemia.

 

From my point of view, having a single HbA1c target for all patients is too simplistic and does not reflect the literature. Clinicians need to address many factors when developing HbA1c targets: age, duration of diabetes, presence of both diabetes-related complications and non-diabetes-related co-morbidities, and certainly socioeconomic factors. It is a complex process, one of which not all of us will agree for an individual patient. It is my hope that we will eventually use the data published to develop a scoring system that will better allow us to categorize patients to achieve the best target glycemic control possible for any single patient.