Glycemic Variability: Can We Bridge the Divide Between Controversies?

What does it take to put glucose variability into or out the heart of glycemic disorders in type 2 diabetes? By analyzing the database of the Hyperglycemia and Its Effect After Acute Myocardial Infarction on Cardiovascular Outcomes in Patients With Type 2 Diabetes Mellitus) HEART2D trial, a premonitory acronym, Siegelaar et al. (1) have reported in this issue of Diabetes Care that glycemic variability cannot be placed at the heart of the risk factors implicated in the progression of cardiovascular diseases in people with type 2 diabetes. The HEART2D trial (2) was initially designed to know whether control of basal hyperglycemia or postprandial hyperglycemia is best for reducing cardiovascular outcomes in patients with type 2 diabetes who had a history of myocardial infarction. In order to answer this question, the investigators of the HEART2D trial have enrolled poorly controlled type 2 diabetic patients who had experienced acute myocardial infarction. Patients were further assigned to either a basal insulin strategy that targeted fasting and interprandial glycemia or an insulin regimen with three daily injections of a rapid insulin analog at premeal times in order to target postprandial glucose excursions. A similar lowering effect on ambient (sustained chronic) hyperglycemia assessed by HbA1c levels was observed with the two insulin regimens. No difference in the incidence of cardiovascular events was detected between the two regimens despite that the prandial group had lower postprandial glycemia compared with the basal group at interim analysis, when the study was halted after a mean follow-up of 2.7 years. Even though the authors of theHEART2D trial did not perform any specific assessment of glycemic variability, a rapid glance at the 7-point glycemic profile seems to indicate that the range of glycemic variability was different between the prandial and basal insulin regimens at study end. The analysis by Siegelaar et al. (1) was designed for quantifying these differences. Unfortunately, the results indicate that glycemic variability did not differ between the two groups when classical well-recognized markers of within-day glycemic variability—SD around the mean glucose value and the mean amplitude of glycemic excursions (MAGE) (3)—were used. Significant differences were only observed when using a new marker, the mean absolute glucose (MAG) change, which calculates the slopes of the absolute increments and decrements from peaks to nadirs (1). However, it should be noted that this marker, which includes time as x-axis coordinate, is more a reflection of the kinetics of glycemic changes per unit of time than a true assessment of the magnitude of absolute glucose fluctuations. In addition, it should be noted that this marker was never validated elsewhere. Therefore, before detailing the pros and cons arguments for the possible impact of glycemic variability on the development or progression of microor macrovascular complications in type 2 diabetes, we are left with a mixed impression that the analysis by Siegelaar et al. (1) is not appropriately designed for drawing any firm conclusion and for permitting to gain further insight into the debate whether glycemic variability is an important risk factor of diabetes complications. Therefore, such results should be discussed and integrated in a broader context. Consider that glycemic disorders can be separated into two independent components: the sustained chronic or ambient hyperglycemia and the glycemic variability characterized by acute glucose swings from peaks to nadirs. At present, there is cogent evidence for the deleterious effect of the former glycemic disorder (4–6). As a consequence, the pathogenesis of vascular complications in type 2 diabetes can be depicted by a very simple “catenary model,” in which cardiovascular outcomes result from an excess of glycation caused by a sustained glucose exposure that in turn can be assessed and quantified by using quarterly determinations of HbA1c levels (7,8). Ambient glucose exposure results not only from basal hyperglycemia but also from postprandial hyperglycemia. The latter parameter can participate in the development of diabetes complications at least because its absolute impact on HbA1c, expressed as percentage points of HbA1c, is constant at approximately 1% across the HbA1c continuum in non–insulin-treated diabetic patients who have an HbA1c level .6.5% (9,10). Postprandial glucose excursions can exert deleterious pathophysiological effects through other mechanisms. For instance, besides their role in glycation, postprandial glucose excursions can be a cause for vascular diseases through the activation of oxidative stress (11). More generally, in people with type 2 diabetes, it has been demonstrated that the oxidative stress is activated by acute glucose fluctuations (12,13). According to these observations, the pathophysiology of diabetes complications can be extended from a simple catenary model to a “parallel catenary model,” in which the two parallel arms correspond to the sustained chronic hyperglycemia and the glycemic variability with their two subsequent consequences: the excess of glycation and the activation of oxidative stress, respectively. Unfortunately, the data of the HEART2D trial (1,2) do not seem to support such a model since the apparent improvement in glycemic variability as observed in the prandial group has no significant impact on the progression of macrovascular complications. These results are in agreement with those reported in two retrospective analyses of the Diabetes Control and Complications Trial (DCCT) datasets (14,15). These reports concluded that glucose variability has only a minor contribution to microvascular complications of type 1 diabetes. The data obtained by the HEART2D trial investigators extend this concept to macrovascular complications of type 2 diabetes treated with insulin. Such results raise new questions. A few years ago, we have shown that glycemic variability exerts a strong trigger effect on oxidative stress in type 2 diabetic patients who were treated with oral hypoglycemic agents alone (12). In addition, several studies seem to indicate that activation of oxidative stress is probably one of the key factors in the pathogenesis of diabetes complications (6). As the results of the HEART2D trial suggest that glucose variability is not a risk factor for cardiovascular diseases in patients with type 2 diabetes treated with insulin (1,2), several “burning” questions can be raised, why could glucose variability be a risk factor for cardiovascular diseases in patients