Shifting the Disease Management Paradigm From Glucose

V ascular comorbidities and complications are the major causes of excessive mortality and costs in patients with diabetes (1,2). For more than half a century, overwhelming evidence has been accumulating that demonstrates significant harmful effects of hyperglycemia. As shown in the Multiple Risk Factor Intervention Trial (MRFIT) study, at any given level of major cardiovascular risk factors, diabetes is associated with an odds ratio of 2–4 for cardiovascular mortality, in comparison with subjects without diabetes (3). In a recently published 18-year follow-up study on the impact of type 1 and type 2 diabetes on cardiovascular mortality in middle-aged subjects from Finland, the adjusted hazard ratio for patients with type 1 diabetes versus no diabetes was 3.6 in men and 13.3 in women (4). The corresponding hazard ratios for type 2 diabetes were 3.3 and 10.1, respectively. This study confirms harmful effects of hyperglycemia shown in high-level controlled trials, such as the Diabetes Control and Complications Trial (DCCT) for type 1 diabetes (5) and the U.K. Prospective Diabetes Study (UKPDS) for type 2 diabetes (6). For 25 years, the Joslin Clinic conducted the Diabetes Natural History Study that followed up diabetic patients diagnosed between 1939 and 1959. The lifetime was 5 years less for men and 12 years less for women than for those in the general population (7). A unique 29-year complete follow-up study was conducted on 166 patients (mean age 63 years) with newly diagnosed type 2 diabetes. These subjects were from a district outpatient department in East Germany. The study revealed a reduction in life expectancy by 5.3 and 6.4 years in men and women, respectively (8). Thus, today, immense evidence exists on long-term follow-up, populationbased studies in patients with types 1 and 2 diabetes. This evidence convincingly suggests that hyperglycemia or diabetes itself is a key risk factor not only for diabetes-related diseases, but also for cardiovascular and all-cause mortality. Based on their long-term population observational study, Juutilainen et al. (4) calculated an increment of cardiovascular mortality per increase of 1 unit (%) A1C of 52.5% in type 1 diabetes and of 7.5% in type 2 diabetes, respectively. Recently, an interim analysis of the Action to Control Cardiovascular Risk in Diabetes (ACCORD) study indicated that aggressive reduction of A1C to 6.4% in elderly patients with long-term type 2 diabetes and a baseline level of A1C of 8.1% was associated with a 22% higher mortality rate compared with the standard care group with a level of 7.5% A1C (9). Therefore, the intensified polypharmacy treatment of hyperglycemia was stopped prematurely and a treatment target of A1C between 7.0 and 7.9% was recommended. This surprising outcome of intensified treatment of hyperglycemia could not be confirmed in the Action in Diabetes and Vascular Disease: Preterax and Diamicron Modified Release Controlled Evaluation (ADVANCE) study, another large prospective trial for improved diabetes control in patients with type 2 diabetes, which showed a 10% relative reduction in the combined outcome of microand macrovascular events in the group with more intensive A1C control (A1C 6.5%) compared with the standard control group (A1C 7.3%) (10). At the same time, the 13.3-year follow-up data of the Danish multifactorial intervention study in type 2 diabetes (STENO-2) were published on 160 patients randomly assigned to receive either intensive or conventional multimodal therapy with tight glucose control, use of renin-angiotensin system blockers, aspirin, and lipidlowering agents (11). At the end of the intervention after 7.8 years, A1C was 7.9% for intensive therapy and 9% for conventional therapy. At the end of follow-up, A1C was 7.7 and 8.0%, respectively (difference not significant). Only a minority of patients reached the target A1C of 6.5% (after 7.8 years, 16 vs. 4%, and after 13.3 years, 18 vs. 11% for intensified versus standard treatment, respectively). By contrast, the majority of intensified treated patients reached targets of blood pressure and cholesterol levels. During the follow-up, 40 patients died in the standard treatment group versus 24 (30%) in the intervention arm (P 0.02). Diabetes-related microvascular diseases were also impressively reduced. By extrapolation of ACCORD interim results, and the convincing outcomes of better treatment of blood pressure and lipids with multiple drug combinations including aspirin, as was the case in the STENO-2 study, one could argue that it may be beneficial to shift diabetes management to control of major cardiovascular risk factors, e.g., hypertension, dyslipidemia, and increased procoagulatory activity. However, despite intensified treatment of blood pressure and dyslipidemia in STENO-2 in patients at the age of 54.9 years at entry, 30% died after 13.3 years when they averaged 66 years of age (11). This mortality rate of 2% per year is comparable with the mortality rate of diabetic patients in the observational study of Juutilainen et al. (4) and is about fourfold higher than the rate of nondia● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ●