Guidelines

4. Glycemic Control and A1c Goals

Supplemental Information

For patients with T2DM, an A1c goal of less than 8% may be more appropriate than an A1c goal of less than 7%, when including the following factors:

• Known cardiovascular disease or high cardiovascular risk, and may be determined by the Framingham or ACC/AHA Cardiovascular Risk Calculator, or alternatively as having two or more cardiovascular risks (BMI > 30, hypertension, dyslipidemia, smoking and microalbuminuria)
• Inability to recognize and treat hypoglycemia, including a history of severe hypoglycemia requiring assistance
• Inability to comply with standard goals, such as polypharmacy issues
• Limited life expectancy or estimated survival of less than 10 years.
• Cognitive impairment.
• Extensive comorbid conditions such as renal failure, liver failure and end-stage disease complications.

A multifactorial approach to diabetes care that includes emphasis on blood pressure, lipids, glucose, aspirin use and non-use of tobacco will maximize health outcomes far more than a strategy that is limited to just one or two of these clinical domains (American Diabetes Association, 2014; Duckworth, 2009; Gaede, 2008; Holman, 2008a).

Multifactorial approach

The benefits of a multifactorial approach to diabetes care are supported by the results of the Steno-2 Study of 160 patients with T2DM and microalbuminuria. Multifactorial interventions achieved a 50% reduction in mortality and significant reduction in microvascular complications five years after ending a 7.8-year multifactorial intervention that achieved A1c of 7.8%, low-density lipoprotein 83 mg/dL, blood pressure 131/73, compared to a conventional group that achieved A1c 9%, low-density lipoprotein 126 mg/ dL and blood pressure 146/78 (Gaede, 2008). Results of this study are consistent with the need for reasonable blood glucose control with emphasis on blood pressure and lipid management.

Microvascular/macrovascular complications

Follow-up data from the United Kingdom Prospective Diabetes Study of newly diagnosed patients with T2DM confirm major macrovascular and microvascular benefits of achieving A1c in the 7.1 to 7.3% range, versus A1c of about 8% in the comparison groups (Holman, 2008a). The United Kingdom Prospective Diabetes Study main trial included 3,867 newly diagnosed T2DM patients and showed over a 10-year period a 25% decrease in microvascular outcomes with a policy using insulin and sulfonylureas that achieved a median A1c of 7.1%, compared to 7.9%. A subgroup of obese patients (n=1,704) treated with metformin and achieving a median A1c of 7.3% showed greater advantages over conventional treatment: a 32% reduction of diabetes-related end points (P=0.002), a 42% reduction of diabetes-related deaths (P=0.017), and a 36% reduction of all-cause mortality (P=0.011) (UK Prospective Diabetes Study Group, 1998b).

Several reported clinical trials have evaluated the impact of A1c less than 7% on macrovascular and micro- vascular complications of T2DM. These studies – the Action to Control Cardiovascular Risk in Diabetes (ACCORD), the Action in Diabetes and Vascular Disease: Preferax and Diamcron Modified Release Controlled Evaluation (ADVANCE), and VADT Trials – are the first that have ever achieved and maintained A1c less than 7% in his/her intensive treatment patients.

Cardiovascular risk

In the ACCORD Trial, excess mortality in the intensive group (A1c mean 6.4% vs. standard group A1c 7.5%) forced the safety board to discontinue the intensive treatment arm earlier than planned (ACCORD Study Group, The, 2008). There was one excess death for every 90 patients in the intensive group over a 3.5-year period of time. In the ADVANCE trial, intensive group patients achieved A1c 6.5% (vs. 7.5% in standard group) but had no reduction in cardiovascular complications or events. In the VADT trial, intensive group patients achieved A1c of 6.9% but had no significant reduction in cardiovascular events or microvascular complications compared to standard group patients who achieved A1c of 8.4%. However, the VADT Trial was underpowered for its main hypothesis tests (Duckworth, 2009). In the ADVANCE trial, intensive group patients had less progression to proteinuria (one less patient advancing to proteinuria for every 100 people in the intensive group over a five-year period of time), but no fewer eye complications in the intensive group than in the standard group. ACCORD analysis showed lower rates of early stage microvascular complications in the intensively treated group. Some patients, especially those with little comorbidity and long life expectancy, may benefit from more intensive glycemic goals as long as hypoglycemia does not become a barrier. However, the risk of lower glycemic targets may outweigh the potential benefits on microvascular complications for many patients (Ismail-Beigi, 2010; ACCORD Study Group, The, 2008).

A meta-analysis analyzed five randomized controlled trials (UKPDS, PROactive, ADVANCE, VADT and ACCORD) for the effect of intensive glucose control on cardiovascular outcomes. Overall, this meta-analysis concluded that more intensive glucose control significantly reduced non-fatal myocardial infarct events and coronary heart disease events (non-fatal myocardial infarct and all-cardiac mortality) with no evidence of either a benefit or adverse effect on all-cause mortality. Heterogeneity among studies was noted with regard to all-cause mortality, suggesting that the impact of glycemic reduction on all-cause mortality may differ among different populations (Ray, 2009). A subset analysis from ACCORD, ADVANCE and VADT suggested that intensive glucose lowering has a modest (9%) but statistically significant reduction in major CVD outcomes, primarily non-fatal MI, with no significant effect on mortality. However, a pre-specified subgroup analysis suggested that major cardiovascular disease outcome reduction occurred in patients without known cardiovascular disease at baseline (Turnbull, 2009).

Glycosylated hemoglobin assays

Glycosylated hemoglobin assays provide an accurate indication of long-term glycemic control. Glycated hemoglobin is formed by the continuous non-enzymatic glycosylation of hemoglobin throughout the lifespan of an erythrocyte. The A1c assay yields an accurate measure of time-averaged blood glucose during the previous six to eight weeks. Clinically, it can assist in determining duration and severity of hyperglycemia and can help guide treatment.

Eating, physical activity or acute metabolic stress does not influence the A1c test. The test can be done at any time of day and does not require fasting.

Self-monitoring blood glucose (SMBG)

Self-monitoring blood glucose (SMBG) allows patients to evaluate his/her individual response to therapy and assess whether glucose targets are being achieved. Results of SMBG can be useful in preventing hypo- glycemia and adjusting medications, medical nutrition therapy and physical activity (American Diabetes Association, 1994).

Major clinical trials assessing the impact of glycemic control on diabetes complications have included self-monitoring blood glucose testing (SMBG) as part of multifactorial interventions, suggesting that self-monitoring blood glucose is a component of effective therapy (American Diabetes Association, 2014). Several diabetes management strategies reliant on SMBG testing have demonstrated improved glucose control in patients (Polonsky, 2011; Weinger, 2011).

Table 1 gives ranges of self-monitored glucose readings that would be expected as goals for patients with the corresponding A1c level goals.

Table 1. Ranges of self-monitored blood glucose values for various A1c goals

Table 1 was developed by the diabetes work group based on data currently available from studies of frequently monitored glucose values and will be modified if necessary as further studies become available.

The frequency and timing of SMBG should be dictated by the particular needs and goals of the individual patient. Bedtime glucose goals vary dependent on the patient’s treatment program, risks for hypoglycemia and time after last meal. Patients with T2DM on insulin typically need to perform self-monitoring blood glucose more frequently than those not using insulin, particularly if using glucose readings to guide mealtime insulin dosing. It is recommended that patients using multiple insulin injections perform SMBG prior to meals, snack or exercise or when low blood glucose is questioned (American Diabetes Association, 2014). The optimal frequency and timing of SMBG for patients with T2DM on oral or non-insulin injectable therapy are not known but should be sufficient to facilitate reaching glucose goals. SMBG should be performed more frequently when adding or modifying therapy; two-hour post-prandial glucose testing is useful in some patients. The role of SMBG in stable diet-treated patients with T2DM is not known.

Because the accuracy of SMBG is instrumental and user dependent, it is important for health care clinicians to evaluate each patient’s monitoring technique and accuracy of equipment. In addition, optimal use of SMBG requires proper interpretation of the data. When appropriate, patients can be taught how to use the data to adjust food intake, exercise or pharmacological therapy to achieve specific glycemic goals.