Impact of Fasting and Postprandial Glycemia on Overall Glycemic Control in Type 2 Diabetes: Importance of Postprandial Glycemia to Achieve Target Hba1c Levels

Woerle HJ, Neumann C, Zschau S, Tenner S, Irsigler A, Schirra J, Gerich JE, Goke B. Diabetes Res Clin Pract. 2007;77:280-285.

Several clinical trials have demonstrated that decreasing A1C levels can reduce the risk of patients with type 2 diabetes mellitus (T2DM) developing diabetic complications. Because A1C levels represent overall glycemic exposure over a period of 2 to 3 months, both fasting and postprandial plasma glucose (FPG and PPG) contribute to A1C. Current recommendations for glycemic control include the American Diabetes Association (ADA) goal of A1C ≤ 7%, and the International Diabetes Federation (IDF) and American Association of Clinical Endocrinologists (AACE) goal of ≤ 6.5% based on evidence that more strict glycemic control may prevent macrovascular complications. This is a prospective study designed to assess the relative contribution of controlling fasting and postprandial hyperglycemia in achieving the A1C goals recommended by IDF and AACE.

Subjects with suboptimal glycemic control, defined as A1C levels > 7.5% (N = 164), 90 of whom were male and 74 female, were enrolled in this trial. During their first clinic visit, venous blood samples were obtained from patients to determine A1C levels, and they were trained to self-monitor their blood glucose (BG) values for the duration of the study. From then on, each individual participated in a 1-week structured diabetes training program that included 7 sessions of 90 minutes each. The sessions focused on lifestyle interventions, including reduced caloric intake, avoidance of rapidly absorbed carbohydrates, and reduced consumption of high fat and high protein foods. Follow-up sessions included special attention to the therapy for each individual, which focused on optimal timing and techniques for drug administration, the effects of specific medications on plasma glucose regulation, and their potential for causing hypoglycemia. During the first week, each patient obtained daily BG profiles and was seen by a physician ≥ 3 to 4 times in order to assess the need for altering and/or adjusting treatment regimens. Therapeutic targets for FPG (< 100) and PPG (< 140) treatment were taken from the IDF clinical guidelines. All major modifications of therapy took place within the first 2 weeks. Once their goals of therapy were achieved, patients were seen ≥ 1 time per month until the end of the study. Patients were advised not to eat > 3 carbohydrate-containing meals per day; they were also asked to measure a 7-point diurnal BG profile before any treatment modifications were initiated. Preprandial glucose measurements were taken at ~ 7 am, 1 pm, and 7 pm; postprandial measurements at 90 minutes after completion of each meal; and a bedtime measurement at ~ 11 pm.

The initial NPH insulin dosage was determined based on the FPG, body mass index (BMI), and A1C of each participant. The primary goal of therapy intensification was achieving FPG < 100 mg/dL. Patients who had A1C > 7.5% were treated for 3 months with individualized forced titration regimens designed to decrease FPG to ≤ 100 mg/dL and 90-minute postmeal plasma glucose to ≤ 140 mg/dL. If their initial FPG was > 100 but < 140 mg/dL when receiving diet intervention alone, patients were given metformin (MET). MET was also added to the treatment regimen of patients not controlled with a sulfonylurea (SU). If FPG < 100 mg/dL was not achieved when patients were receiving MET (with or without an SU), then NPH insulin at bedtime was initiated, doses were titrated based on FPG levels, and SU use was discontinued. Among patients whose FPG values were > 140 mg/dL, MET and NPH insulin were initiated and SU use was discontinued. Among patients > 65 years of age with BMI < 23 kg/m², as well as those with any conditions that contraindicated the use of MET, NPH insulin was given as monotherapy. Patients determined 3 am glucose values periodically (initially ≥ 1/wk) to detect any cases of nocturnal hypoglycemia. If their bedtime glucose concentrations were < 80 mg/dL, patients were advised to have a bedtime snack rather than receive bedtime insulin. Repaglinide was administered prior to meals among patients who met the FPG goal of < 100 mg/dL but had PPG values > 140 mg/dL. If they did not achieve postmeal goals with repaglinide, it was halted, and a short-acting insulin was given before meals. Dose adjustments of short-acting insulins were based on premeal and bedtime glucose concentrations. Insulin doses were not increased if glucose concentrations were < 100 mg/dL prior to the next meal but > 140 mg/dL 90 minutes postmeal.

At the beginning of this study, 26% of the patients were being managed by diet alone, but this decreased to 4% following the initiation of the intensified treatment program. During that same period, the percentage of patients treated with oral agents alone declined from 44% to 26%, whereas the percentage of patients treated with insulin alone or in combination with oral agents increased from 31% to 70%. Average A1C levels decreased from 8.7 ± 0.1 to 6.5 ± 0.1% (P < .001), FPG concentrations from 174 ± 4 to 117 ± 2 mg/dL (P < .001), and PPG concentrations from 224 ± 4 to 159 ± 3 mg/dL (P < .001). The patients also had significantly greater decreases in postprandial than fasting hyperglycemia (P < .05), and their daylong levels of glycemia decreased from 199 ± 4 to 141 ± 2 mg/dL (P < .001). Almost three-fourths (73%) of patients achieved A1C ≤ 7%, and among those who reached that goal, average levels were 6.2 ± 0.04% compared with 7.6 ± 0.1% for patients with A1C > 7% (P < .001). Individuals with A1C ≤ 7% also had significantly lower postprandial (153 ± 3 mg/dL vs 180 ± 5 mg/dL) and daylong (135 ± 2 mg/dL vs 159 ± 4 mg/dL) glycemic levels than those who did not (both P < .001). However, regardless of their A1C levels, patients had almost identical FPG concentrations (≥ 7% group: 117 ± 2 mg/dL, < 7% group: 119 ± 3 mg/dL; P = .63).

In order to determine the relative contributions of FPG and daylong glycemic exposure to A1C, multiple regressions were conducted with FPG and daylong glycemia as the predictors and A1C as the dependent variable. Daylong glycemic reductions explained approximately twice as much of the A1C reduction as did FPG. Among those who achieved the goal of PPG ≤ 140 mg/dL, 94% achieved an A1C ≤ 7%. By comparison, only 64% of patients who met the FPG target also achieved the A1C target. Further analyses revealed postprandial hyperglycemia accounted for ~ 90% of A1C values if they were < 6.2% but only ~ 40% if A1C was > 8.9%. The body weight of participants did not significantly change, from 84 ± 1.4 kg at baseline to 82.9 ± 1.5 kg at the end of the trial, nor did their incidence of severe hypoglycemia, as defined by Diabetes Control and Complications Trial (DCCT) criteria (0 before and after treatment). There were 5 cases of plasma glucose < 70 mg/dL before and 12 cases after intensification of therapy (P < .05), and no cases of plasma glucose < 50 mg/dL before the change of treatment followed by 1 after its initiation.

The main goal of this study was to determine the importance of improvements in fasting compared with postprandial hyperglycemia for achieving optimal glycemic control among patients with T2DM. The results indicate that PPG has a greater role than FPG in A1C levels, and that postprandial control of glycemia is essential for patients to obtain A1C goals of < 7 or even ≤ 6.5%. In addition, the data obtained reveal that such tight glycemic control can be achieved among patients with T2DM without weight gain or severe hypoglycemia. The authors of this paper concluded that among patients who cannot reach A1C goals despite optimal control of FPG, treating postprandial hyperglycemia is essential for optimizing glycemic control.