CGM is currently recommended and reimbursed by the Italian National Health Service for the management of patients with T1DM and T2DM treated with multiple daily insulin injections (16). However, a growing need is felt by Italian experts to extend its use to patients with T2DM, regardless diabetes treatment, with special needs or at high risk of complications. Indeed, quantifying the duration and magnitude of glycaemic excursions provides another means of assessing glucose control, which is perceived by the panel as complementary and more complete than SMBG and HbA1c (10). Blood glucose is a vital parameter that in physiology changes in relation to meals, physical activity and all conditions that generate stress; in pathological conditions, such as in people with diabetes, glycaemia also changes with therapies, particularly those that can lead to severe reductions such as insulin. GV is a process characterized by amplitude, frequency, and duration of the fluctuations. Consequently, GV is directly related to hypoglycaemic and hyperglycaemic episodes, as well as their duration and TIR (21). It is well known that GV is an independent risk factor for diabetes complications, including cardiovascular diseases, acting through the oxidative stress pathway (22–26), and has effects on cognitive function and quality of life (27). Moreover, increased GV is strongly associated with mortality in the intensive care setting (28, 29). Furthermore, the objective of diabetes control is to keep blood glucose levels into an accepted range, since deviations from the range in both directions are harmful, increasing the risk of complications with the amplitude of the deviations. Two large randomized controlled trials have demonstrated a significant reduction of hypoglycaemic events and GV, as well as increase in TIR and patients’ satisfaction in subjects with T1DM (30) and insulin treated T2DM (31) managed with FGM, as compared to SMBG. In addition, real-world studies showed greater reductions in HbA1c levels using FGM compared to SMBG (32, 33), also showing that the number of glucose scans is inversely associated with time spent in hypoglycaemia or hyperglycaemia and is positively correlated with TIR (34). Consequently, besides hypoglycaemic, and hyperglycaemic episodes, according to the panel, also GV and TIR should now be assessed as part of the routine management of diabetes (10). In this regard, given the evidence reported above, the experts believed that CGM can have a prognostic role in patients for whom it is recommended by guidelines and reimbursed by the Italian NHS, but also to other to whom the recommendation may be extended.
Diabetes is a traditional risk factor for CV disease, carrying a higher risk for sudden cardiac death, accelerated atherosclerosis, ischaemic heart disease, cardiomyopathy, and HF (35). In addition, oscillating glucose is considered to have more deleterious effects than constant high glucose levels on endothelial function (36) and postprandial glycaemic spikes may be a more robust determinant of CV disease risk than average glucose levels (37). This is explained by the hyperglycaemia-induced activation of oxidative stress pathways and inflammation as well as by the rapid formation of advanced glycosylated end-products (AGEs) (38). However, a doubtful reduction of coronary artery disease by glucose-lowering treatment was found in large meta-analyses (39, 40), possibly because the benefits were partly counterweighed by an increased occurrence of severe hypoglycaemic episodes, associated with the intensive insulin therapy. In fact, hypoglycaemia can be associated with the development of adverse CV outcomes by means of several mechanisms, including blood coagulation abnormalities, inflammation, endothelial dysfunction, and sympathetic responses (35, 41). Accordingly, the panel agreed that CGM with the new glucometrics may have a prognostic role in patients with ischaemic heart disease. Notably, although to a lesser extent than hypoglycaemia, also hyperglycaemic episodes are perceived as prognostically deleterious by the panel.
Diabetes is also a risk factor for HF (42) and left ventricular dysfunction can be found in up to 40% of diabetic people (43). The link between the two conditions goes beyond ischemic heart disease, but also involves several other mechanisms, including micro-circulatory dysfunction, metabolic derangements with lipotoxicity, cytokine and renin–angiotensin–aldosterone system activation, altered calcium handling, and endothelial dysfunction (44, 45). Oxidative stress and inflammation seem to be at the basis of the phenomenon and are also the hallmark of HF with preserved ejection fraction, as currently hypothesized (46, 47). Finally, also diabetic neuropathy and consequently cardiac autonym dysfunction can play a role in this context (48). The interest about the link between HF and diabetes is recently growing in the cardiologic scenario after the publication of SGLT2 inhibitors trials, which demonstrated beneficial effects of these drugs in HF patients, which was in fact independent from diabetes itself (49, 50). The panel agreed in considering hypoglycaemic events, TIR and GV as having a prognostic role in HF patients with diabetes, even if dedicated studies are still lacking. This perception should prompt future research in this field.
Mortality in acute myocardial infarction and other acute CV events is also increased in patients with diabetes (51, 52). This may occur independently from the extent of myocardial infarct size, because of various negative effects, including increased inflammation, endothelial dysfunction, pro-thrombotic state and oxidative stress (52). Acute hyperglycaemia characterizes up to 50% of patients admitted for myocardial infarction (53), and for every 18 mg/dL (1 mmol/L) increase in glucose level above 200 mg/dL, it has been reported a 4% and a 5% increase in hospital mortality risk in patients without and with diabetes, respectively (54). In addition, impaired control of glycemia in this setting has been associated with severe coronary flow impairment, increased left ventricular dysfunction, larger infarct size, and higher risk of acute HF, cardiogenic shock, and acute kidney injury (53). On the other hand, also acute myocardial infarction patients with hypoglycaemia appear to have worse outcomes (55, 56), including myocardial ischaemia and arrhythmias (57). Furthermore, both hypoglycaemia and hyperglycaemia are associated with a three-fold increased risk of 30-day mortality when compared with euglycaemic patients, thus determining a U-shaped relationship between blood glucose levels and adverse outcomes (56). Consequently, the consensus is that both hyperglycaemia and hypoglycaemia should be avoided in critically ill patients (58). In fact, acute variability of glucose values negatively correlates with the proportion of reversibly injured myocardial tissue that does not progress to infarction (59). GV > 49 mg/dL was demonstrated to be the strongest independent predictor of mid-term major adverse cardiac events (death for cardiac cause, new-onset myocardial infarction, acute HF) (60). Finally, the experts agreed that the CGM can be useful in intensive care unit as it carries prognostic information at short-term (e.g., in-hospital mortality). In addition, the improvement in TIR, GV and time spent in hypoglycaemia is perceived to also improve the long-term prognosis of an acute CV event, even if specific data are lacking.
CGM use was demonstrated to improve patients’ quality of life, with a greater satisfaction than SMBG (30, 31, 61). In fact, according to the expert panel, the system has an educational aspect, helping patients’ perception of their own disease and increasing the adherence and the confidence to treatment. Notably, CGM reduces hypoglycaemic episodes, which are most feared therapy complication (30, 31), particularly by the activation of dedicated alarms in the more recent systems, which can help preventing them.