• Consider evaluating 24-hour variability in glucose levels with patients’ self-monitoring glucose meters (in addition to monitoring glycosylated hemoglobin [HbA1c] levels at regular intervals). C
• If glycemic goals are unmet 2 to 3 months after initiating treatment with exercise and diet or with oral agent monotherapy, consider starting insulin therapy. C
Strength of recommendation (SOR)
A Good-quality patient-oriented evidence
B Inconsistent or limited-quality patient-oriented evidence
C Consensus, usual practice, opinion, disease-oriented evidence, case series
Though we have the knowledge and the means to reduce complications of type 2 diabetes mellitus (T2DM), most patients may not be reaching all the glycemic goals necessary to achieve optimal risk reduction.1 Maintaining an acceptable level of glycosylated hemoglobin (HbA1c) is one of the important glycemic goals. But that measurement is an average of glucose levels occurring over the prior 3 months. Regardless of a given HbA1c measurement, an emerging body of evidence supports the presumption that glycemic variability over each 24-hour cycle is an independent risk factor for vascular complications.2-15
In this article, I review the literature pertaining to the risk associated with glycemic variability and to the benefit in correcting it. I also review the comparative outcomes achievable with normal human insulin and insulin analogs, as well as the advisability of starting insulin earlier in the management process.
Glycemic variability increases vascular risk independently
HbA1c, considered the gold standard for monitoring glycemic control in patients with T2DM, is an average of the full range of glucose values in the preceding 3 months, including fasting plasma glucose (FPG) and 2-hour postprandial glucose (PPG) levels. Studies have linked lowering HbA1c to reducing the risk and progression of micro- and macrovascular complications associated with diabetes.16,17 But evidence shows that other glycemic values are also important.
The Diabetes Control and Complications Trial (DCCT) was a landmark study in which patients with type 1 diabetes mellitus who received targeted intensive insulin therapy experienced delayed onset and slowed progression of micro-vascular complications compared with those who received conventional insulin treatment.16 Interestingly, this study also reported that patients randomized to receive conventional insulin treatment did not exhibit a reduction in the risk of progression of microvascular disease despite having HbA1c values comparable to those in the intensive-treatment group. One hypothesis is that glucose excursions occurred more frequently in the conventionally treated group, which received fewer daily insulin injections.5
Acute glucose fluctuations during the postprandial period trigger oxidative stress and are more predictive of atherosclerosis development than are FPG or HbA1c6,7 (see “Implications of glycemic variability” below). This suggests that therapy for patients with T2DM should not only target HbA1c as a long-term goal, but also aim to avoid acute glucose fluctuations as an immediate goal. Several studies have shown that postprandial hyperglycemia is an independent risk factor for vascular complications in patients with T2DM.2,7-9,12,14,15
Evidence of increased vascular risk with glycemic variability. The Diabetes Epidemiology: COllaborative analysis of Diagnostic criteria in Europe study (DECODE) followed more than 25,000 patients for more than 7 years and found that increased mortality was more closely associated with increased 2-hour PPG levels than with FPG.14 In the Framingham Offspring Study, Meigs et al9 reported that, in nondiabetic subjects, an elevated glucose level 2 hours after an oral challenge increased the relative risk for cardiovascular disease by up to 40%, independent of fasting hyperglycemia.
Mixed outcomes with Hba1c reduction only. Macrovascular risk reduction with intensive HbA1c management was not apparent in 3 recent studies—Action to Control Cardiovascular Risk in Diabetes (ACCORD),18 Action in Diabetes and Vascular Disease: Preterax and Diamicron MR Controlled Evaluation (ADVANCE),19 and Veterans Affairs Diabetes Trial (VADT).20 The ACCORD study, in fact, showed an increase in cardiovascular events in the intensively managed group (HbA1c target <6.0%). Indeed, previous studies had suggested an association between fasting hypoglycemia and poor cardiovascular outcomes.3,4 Retrospective subanalysis of the ACCORD study suggested that patients with poorer glycemic control had a greater risk of hypoglycemia independent of HbA1c values, and that patients who had difficulty reaching lower HbA1c levels may have had poorer cardiovascular outcomes.21
The apparent absence of a reduction in macrovascular events in the ACCORD, ADVANCE, and VADT studies also suggests an additive effect of nonglycemic risk factors that frequently accompany diabetes—ie, hypertension, hyperlipidemia, and hypercoagulability/pro-inflammatory states.