Shifting the Disease Management Paradigm From Glucose: What are the cons?

As shown in numerous prospective studies, the deleterious effects of dysglycemia—fasting and postprandial hyperglycemia—develop before diabetes is diagnosed. In the Glucose Abnormalities in Patients with Myocardial Infarction (GAMI) study of patients with acute coronary syndrome, abnormal glucose tolerance was the strongest independent predictor of subsequent cardiovascular complications and death (12). In the Asian Pacific Study, fasting plasma glucose was shown to be an independent predictor of cardiovascular events up to a level of ∼5.2 mmol/l (13). The authors calculated that a difference of 1 mmol/l in fasting plasma glucose may be related to reduction of cardiovascular disease by 23%. The importance of postprandial hyperglycemia is supported by rich evidence from prospective studies (14).

It was extrapolated from the Diabetes Epidemiology: Collaborative Analysis of Diagnostic Criteria in Europe (DECODE) study that a reduction of 2-h postchallenge hyperglycemia by 2 mmol/l may be associated with a decrease in all-cause mortality by 28.8% (15). Based on the results of epidemiological reports, a near to normal control of fasting, as well as postprandial hyperglycemia, should be achieved, since risk of vascular disease starts before diabetes is diagnosed (13,16,–18). A fresh look at old facts—importance of peaks and valleys, or in scientific terms, of quality of glucohomeostasis—was possible when reliable and precise continuous glucose measurement systems became available for clinical use. As shown by Monnier et al. (19), glucose fluctuations measured as mean average glycemic excursions were closely associated with oxidative stress generation, whereas average glycemic level was not. Today we have consistent data from pathophysiological investigations that glucose fluctuations may be a vascular risk factor in its own right (Fig. 1). Glucose fluctuations and hyperglycemia are triggers for inflammatory responses via increased mitochondrial superoxide production (20) and endoplasmic reticulum stress (21). Inflammation leads to insulin resistance (22) and β-cell dysfunction, which further aggravates hyperglycemia. The molecular pathways that integrate hyperglycemia, oxidative stress, and diabetic vascular complications have been most clearly described in the pathogenesis of endothelial dysfunction (23). According to the response to injury hypothesis, endothelial dysfunction represents the first step of atherogenesis (24).

The results of these molecular investigations were confirmed by studies in patients. Acute hyperglycemia rapidly attenuated endothelium-dependent vasodilation (25,26) and reduced myocardial perfusion (27). Thus, direct effects of glucotoxicity, oxidative stress and low grade inflammation act in a vicious circle that impairs insulin sensitivity, accelerates and escalates loss of β-cells, impairs endothelial function and leads to microvascular and macrovascular disease (Fig. 2). The best way to prevent chronic progression of type 2 diabetes is to keep the glucotriad in a normal range as shown in primary prevention trials with lifestyle (28,29) or drug intervention (28,30,31), respectively.

As previously discussed, endothelial dysfunction and the risk of vascular disease develops along a continuum starting at a level of fasting hyperglycemia below 5.6 mmol/l and of postmeal glucose below 7.8 mmol/l. For fluctuations, we have no data from prospective studies related to MAGE or standard deviation. There are, however, hints that indicate that valleys with glucose levels below 2.2 mmol/l are associated with an increased risk of cardiovascular mortality (32). Possible harmful effects of strict control of hyperglycemia obviously depend on the stage of diabetes and time of intervention. Thus, there may be a distinct improvement if hyperglycemia is controlled in the stage of pre-diabetes, or early diabetes when A1C is still below 8 or 7%, as shown in A Diabetes Outcome Progression Trial (ADOPT) and the UKPDS (31). In the ADOPT study, control of hyperglycemia was associated with improved β-cell function without an excessive risk of hypoglycemia (31). In the UKPDS, intensified glucose control was achieved with a significantly lower incidence of diabetes-related complications, as was the case in the Kumamoto (33) and DCCT studies (5). Even more important, intensive glucose control in those with newly diagnosed type 2 diabetes in the Diabetes Intervention Study (DIS) (34) and a post-trial legacy analysis of the UKPDS (35) was associated with significantly lower all-cause mortality. Conversely, aggressive treatment of long-term diabetes is associated with weight gain and high risk of hypoglycemia and may be associated with excessive mortality as indicated by the ACCORD study (9).

Recent evidence from pathophysiology, extensive clinical experience, and a number of well-controlled prospective studies clearly prove that hyperglycemia is a key risk factor for diabetes-related complications and a driving force for deterioration of β-cell function and cardiovascular disease resulting in a significant reduction of life expectancy. Therefore, early intervention to keep the glucotriad and A1C in a near-normal range should remain a high priority to protect our patients, together with integrated treatment of comorbidities, such as hypertension, dyslipidemia, and hypercoagulation. Shifting to a better form of individualized disease management does not imply that diabetologists should not maintain confidence in their well-established treatment strategies based on sound evidence and good clinical practice.

No potential conflicts of interest relevant to this article were reported.