A Decrease in Glucose Variability Does Not Reduce Cardiovascular Event Rates in Type 2 Diabetic Patients After Acute Myocardial Infarction: A reanalysis of the HEART2D study

The HEART2D study included 1,115 type 2 diabetic patients who had had a recent myocardial infarction; patients well-controlled with diet or treated with intensive insulin therapy were excluded. It was designed to investigate possible differences between two insulin treatment strategies on time until first combined cardiovascular event (a composite of cardiovascular death, nonfatal myocardial infarction, nonfatal stroke, coronary revascularization, or hospitalization for acute coronary syndrome) (9). Within 21 days after admission for acute myocardial infarction, patients were randomized to one of two insulin treatment strategies: one targeted postprandial hyperglycemia with thrice-daily premeal insulin lispro (PRANDIAL; n = 557), and the other targeted fasting/interprandial hyperglycemia with once-daily insulin glargine or twice-daily NPH (BASAL; n = 558). The study succeeded in achieving similar HbA_1c levels in both strategies, which allowed the authors to look at effects of targeting postprandial glucose values independent from glycemic control. There was no significant difference between groups in time to first combined cardiovascular event (hazard ratio 0.98 [95% CI 0.8–1.21]). Though the PRANDIAL group achieved significantly lower mean postprandial blood glucose values, the between-group difference was less than expected. The trial was halted early due to futility with a lower than expected overall number of cardiovascular events. We evaluated the effect of glycemic variability to help further the interpretation of HEART2D results.

In the present analysis we calculated mean GV in both strategies from 7-point self-measured BG profiles collected prior to study visits during the study period, obtained over 24 h from breakfast to breakfast the next morning. This adds to the original analysis since postprandial excursions contribute to GV, but GV encompasses more than postprandial excursions alone. Because no gold standard for quantifying GV exists (7), we calculated mean absolute glucose (MAG) change, mean amplitude of glycemic excursions (MAGE), and SD. MAG is the summated change in glucose per unit of time (MAG = |ΔGlucose|/ΔTime) (Fig. 1), which showed in the intensive care unit a stronger association with mortality than SD (10). This is the first time MAG is used in a diabetic population. MAGE is the average of all BG increases or decreases that are >1 SD of all BG measures (11). Differences between regimens and those experiencing versus those not experiencing a cardiovascular event were assessed using a pattern mixed-model repeated-measurement analysis. The model included strategy, baseline GV, randomization factors, and an additional factor for study duration (defined as ≤30, >30 and ≤42, and >42 months) (9).

The original HEART2D study analysis showed that HbA_1c did not differ between groups during the study (mean [SEM] PRANDIAL 7.7 [0.1] %, BASAL 7.8 [0.1] %, P = 0.4). We found that the PRANDIAL strategy resulted in a significantly lower MAG compared with the BASAL strategy (mean [SEM] PRANDIAL 0.40 [0.03] mmol/L/h, BASAL 0.49 [0.02] mmol/L/h, difference 0.09 [0.04] mmol/L/h, P = 0.02). Also MAGE and SD were lower in the PRANDIAL group, however, not significantly (MAGE PRANDIAL 3.14 [0.22] mmol/L, BASAL 3.32 [0.17] mmol/L, difference 0.18 [0.27] mmol/L, P = 0.50; SD PRANDIAL 1.42 [0.09] mmol/L, BASAL 1.58 [0.07] mmol/L, difference 0.16 [0.11] mmol/L, P = 0.15). Additionally, taking the two randomization groups together, there was no difference in GV between those experiencing versus those not experiencing a cardiovascular event (mean [SEM] MAG 0.47 [0.03] mmol/L/h vs. 0.44 [0.02] mmol/L/h, P = 0.57; MAGE 3.35 [0.23] mmol/L vs. 3.16 [0.16] mmol/L, P = 0.49; SD 1.56 [0.10] mmol/L vs. 1.48 [0.07] mmol/L, P = 0.52).

We found that in type 2 diabetic patients after acute myocardial infarction an insulin regimen targeting postprandial hyperglycemia lowered intraday GV compared with a basal insulin strategy, with similar overall glycemic control. However, GV decreases shown in the PRANDIAL strategy did not translate into a reduction in cardiovascular outcomes compared with treatment with BASAL strategy.

It might be possible that these negative results are explained by the patient group studied, i.e., type 2 diabetic patients with advanced atherosclerosis. Another possibility is that patients with diabetes, in contrast with critically ill patients without previously diagnosed diabetes (10), are not affected by GV because of the ability of cells to adapt to the harmful effects of changing ambient glucose.

A strong point of the current study is the assessment of GV by MAG. MAG takes GV into account to its fullest extent as opposed to MAGE, which neglects glycemic swings smaller than 1 SD and assesses only the increases or decreases of the glucose profile (11). Furthermore, MAG calculates glucose change over time, whereas SD does not take time into account (Fig. 1).

In conclusion, the results of the present analysis showed that targeting postprandial glucose decreased intraday GV by 18% without a corresponding reduction in subsequent secondary cardiovascular events at least in this population. Further studies looking at different groups of patients are needed to investigate whether reducing GV will reduce cardiovascular risk independently from HbA_1c.

L.K. and S.J.J. are employed by Eli Lilly and Company, sponsors of the HEART2D study, and own stock in Eli Lilly and Company. No other potential conflicts of interest relevant to this article were reported.

S.E.S. contributed to discussion and wrote the manuscript. L.K. and S.J.J. researched data, contributed to discussion, and reviewed and edited the manuscript. J.H.D. contributed to discussion and reviewed and edited the manuscript.