In an analysis of the datasets collected in the Diabetes Control and Complications Trial, Kilpatrick et al. (1) reported that mean blood glucose was predictive of microvascular complications in patients with type 1 diabetes, while glucose variability did not appear to be a factor in their development. We question their methodology and thereby also the conclusions. They calculated the variability of within-day blood glucose as the SD around the mean of a seven-point glycemic profile measured at each patient’s quarterly visit. With such a methodology, they have probably not selected major glucose fluctuations, but rather a composite of both major and minor fluctuations, and most of them were likely to be minor. Furthermore, they have probably blunted the contribution of major glucose fluctuations, as it is not likely that the four pre- and interprandial and three postprandial glucose values included in the seven-point profile were in perfect coincidence with the nadirs and peaks of glucose, respectively. In contrast, the mean amplitude of glycemic excursions (MAGE) described by Service et al. (2) are designed to quantify major swings of glycemia and to exclude minor ones, since its measurement is obtained by calculating the differences between consecutive peaks or nadirs and includes only those greater than the SD of mean glycemic values. Indirect evidence for this is given by observations from the study of Monnier et al. (3). By further analyzing their data, they first found that the MAGE value in 21 patients with type 2 diabetes was much greater (75 mg/dl) than the SDs of within-day blood glucose calculated from seven-point glycemic profiles (37 mg/dl). Second, the activation of oxidative stress, as estimated from urinary excretion rates of isoprostanes, was highly correlated with MAGE calculated from continuous monitoring of glucose in the interstitial fluid (r = 0.85; P < 0.0001) (3). A deterioration of this relationship (r = 0.43; P = 0.05) was observed when SDs of seven-point glycemic profiles were substituted for MAGE values.
Even though the MAGE determination requires continuous glucose monitoring, we believe that this parameter should be the “gold standard” for assessing glucose fluctuations in all prospective interventional studies designed to estimate glucose variability. We therefore believe that additional studies are required to definitively determine the role of glycemic variability in the pathogenesis of the micro- and macrovascular complications of diabetes. Even though the technology of continuous measurements of glucose in interstitial fluid remains a subject of debate, the use of continuous glucose sensors might be useful for conducting such trials.
L.L. has received research funding from, has provided CME on behalf of, and has acted as a consultant to Eli Lilly, GlaxoSmithKline, Novartis, Pfizer, and sanofi-aventis. M. H. has served on the boards of the following studies: GlaxoSmithKline RECORD, GlaxoSmithKline-DREAM, sanofi-aventis ORIGIN, and Novartis NAVIGATOR and has received honoraria for lectures from Takeda, Sanyko, Bayer, GlaxoSmithKline, sanofi-aventis, and Merck Sharp & Dohme. J.D. has taken part in research studies with Eli Lilly, sanofi-aventis, Novartis, SmithKline Beecham, and Novo Nordisk and has been a consultant and/or speaker for Kos, Bristol Myer Quibb, Eli Lilly, sanofi-aventis, Pfizer, SmithKline Beecham, Takeda, Novartis, and Roche.