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Mad about "U".

Over the last two decades, “clinical judgment” seems to have taken a back seat to an evidence-based medicine approach to patient care. Clinical practice guidelines, which make recommendations based on systematic reviews or meta-analyses, are transformed into dicta taken literally by the medical community as well as the regulatory and legal communities. In the case of diabetes management, professional organizations have promulgated A1C goals of either 6.5 or 7% (1, 2). A single number is a powerful thing! So despite caveats in the text of these guidelines about how such goals should be individualized, healthcare providers tend to intensify therapy to meet those goals. They do so not only because they believe in the medical benefits that may result but also perhaps because they understand that they are used as metrics to assess their quality of care by healthcare system administrators and/or third-party payers. This is understandable, of course, because it is much easier to determine whether or not a specific number has been achieved (pass or fail) than to account for comorbidities and other factors that may make that goal inappropriate in an individual patient. Fortunately, the pendulum is swinging toward a more nuanced approach to diabetes care. An era of personalized medicine is upon us where a patient’s age, life expectancy, the presence and severity of complications and comorbidities, their personal preferences, psycho-social-educational factors, and costs are among the factors used in selecting the most appropriate antidiabetic medication(s) (3), as well as amending the A1C target from 6.5 or 7% to as high as 8.5–9% (4, 5). There are many reasons for a personalized approach to patient management, but the emerging data that describe U-shaped rather than linear relationships in a variety of clinical situations certainly support this approach (6, 7). Indeed, whereas U-shaped relationships seem to be appearing everywhere, they often defy explanation. Most recently in the diabetes arena, Lipska et al (7) found a U-shaped curve that describes the relationship between hypoglycemia and A1C in elderly patients with type 2 diabetes. What is surprising is that patients with high A1C were just as likely to have hypoglycemia as those with low A1C. In this issue of the JCEM, Schoenaker et al (8) present data from the EURODIAB Prospective Complications Study that demonstrate a U-shaped relationship between A1C and all-cause mortality in patients with type 1 diabetes. This observational study included 2764 European patients ages 15–60 years at enrollment between 1989 and 1991 and documented 101 deaths in 7 years of follow-up. Although it is not surprising that the risk of death (as well as other complications of diabetes) increased as A1C rose, the data show for the first time in type 1 diabetes that there is an increased all-cause mortality risk at low A1Cs. Using a multivariate restricted cubic spline model with fiveknots placed at the fifth, 25th, 50th, 75th, and 95th percentiles, the “sweet spot” for the lowest mortality appears to be in the low 7% range. The Diabetes Control and Complications Trial (DCCT)/Epidemiology of Diabetes Interventions and Complications study (9) showed a decrease in cardiovascular events (including deaths) in the intensively treated group compared with the conventionally treated group over an average of 18 years of followup, but the number of deaths from cardiovascular disease was small (three in the intensive-treatment group and nine in the conventional treatment group). The all-cause mortality rate for the DCCT has not yet been published but should shed additional light on this issue once it is available. The findings of Schoenaker et al (8) are similar to the Uor J-shaped relationship between mortality and A1C that has been described in patients with type 2 diabetes, al-