Prandial Not Superior to Basal Strategies

Treating diabetic survivors of acute myocardial infarction (AMI) with prandial vs. basal insulin strategies resulted in similar levels of hemoglobin A1c and no difference in the risk for cardiovascular events, according to the results of a multinational, randomized HEART2D controlled trial.

“Among individuals with Type 2 diabetes, those with a previous myocardial infarction have a particularly high risk of additional cardiovascular events,” write Itamar Raz, MD, from the Hadassah Hospital in Jerusalem, Israel, and colleagues from the Hyperglycemia and Its Effect After Acute Myocardial Infarction on Cardiovascular Outcomes in Patients With Type 2 Diabetes Mellitus (HEART2D) trial. “The higher prevalence of classic cardiovascular risk factors in Type 2 diabetes only partly explains the increased cardiovascular risk associated with diabetes. Chronic hyperglycemia increases this risk and postchallenge/postprandial hyperglycemia has been associated with CVD [cardiovascular disease] independent of A1c or fasting blood glucose (FBG).”

The goal of HEART2D was to compare the effects of 2 insulin strategies, one targeting postprandial hyperglycemia and the other targeting fasting and interprandial hyperglycemia, on time until the first combined adjudicated cardiovascular event (primary outcome defined as cardiovascular death, nonfatal MI, nonfatal stroke, coronary revascularization, or hospitalization for acute coronary syndrome).

The study sample consisted of 1115 patients, aged 30 to 75 years, with Type 2 diabetes who were randomly assigned within 21 days after AMI to the prandial strategy or basal strategy. The prandial strategy involved 3 premeal doses of insulin lispro targeting 2-hour postprandial blood glucose levels less than 7.5 mmol/L, whereas the basal strategy involved NPH (neutral protamine hagedorn) insulin twice daily or insulin glargine once daily targeting fasting/premeal blood glucose levels less than 6.7 mmol/L.

After randomization, the mean duration of patient participation was 963 days (range, 1 – 1687 days). Lack of efficacy resulted in early termination of the trial. Both groups had similar risks for first combined adjudicated primary cardiovascular events (prandial: n = 174 [31.2%]; basal: n = 181 [32.4%]; hazard ratio, 0.98; 95% confidence interval [CI], 0.8 – 1.21).
During the study, mean hemoglobin A1c level was similar in both groups (7.7% ± 0.1% vs. 7.8% ± 0.1%; P = .40). Compared with the basal group, the prandial group had a lower daily mean postprandial blood glucose level (7.8 vs. 8.6 mmol/L; P < .01) and 2-hour postprandial blood glucose excursion (0.1 vs. 1.3 mmol/L; P < .001). The basal group showed lower mean fasting blood glucose levels (7.0 vs. 8.1 mmol/L; P < .001). Daily fasting/premeal blood glucose level was similar in both groups (7.7 vs. 7.3 mmol/L; P = .233).

“Treating diabetic survivors of AMI with prandial versus basal strategies achieved differences in fasting blood glucose, less-than-expected differences in postprandial blood glucose, similar levels of A1c, and no difference in risk for future cardiovascular event rates,” the study authors write. “Overall glycemic goals were not fully realized, and a lower A1c level or a much larger sample size may be needed to distinguish between components of the diurnal glucose profile.”

In an accompanying editorial, Antonio Ceriello, MD, from University Hospital of Coventry and Warwickshire, Warwick Medical School, University of Warwick, Coventry, United Kingdom, notes that the HEART2D study has not answered the key question of whether postprandial hyperglycemia is an independent risk factor for cardiovascular complications in diabetes.

“Surely, I wonder whether the results would have been different if the study had used other postprandial drugs in addition to insulin to achieve goal (e.g., acarbose or pramlintide, which are approved with insulin) and whether the study will be repeated with newer drugs that more effectively lower postprandial glucose, such as GLP-1 [glucagon-like peptide 1] agonists or DPP-4 [dipeptidyl peptidase-4] inhibitors,” Dr. Ceriello writes. “Nevertheless, although the key question of whether postprandial hyperglycemia is really a risk factor for cardiovascular disease is still open, I believe that implementing strategies aiming to lower postprandial hyperglycemia in clinical practice remains a good therapeutic choice because it seems the best approach to reach recommended A1c targets. And this is always very good for our patients.”

Eli Lilly and Co sponsored the HEART2D study, employs four of the study authors, and provided funding to all other study authors to conduct the trial, four of whom have disclosed additional financial relationships with Lilly. Some of the study authors have also disclosed various financial relationships with Sanofi-Aventis. Dr. Ceriello has disclosed no relevant financial relationships.

Diabetes Care. March, 2009;32:381-386, 521-522.