Stepwise insulin intensification non-inferior to basal-bolus regimen

Stepwise prandial insulin intensification provided glycemic control that was non-inferior to a full basal-bolus regimen after 32 weeks, with significantly lower hypoglycemia risk and better patient satisfaction, an industry-funded study found.

Researchers conducted a 32-week, randomized, treat-to-target trial at 150 sites in 7 countries from Oct. 27, 2010 to April 25, 2012. The study was funded by Novo Nordisk. Results appeared online in The Lancet Diabetes & Endocrinology on Sept. 25.

In this trial, 401 patients (mean age 59.8 years; mean diabetes duration 12.6 years; mean hemoglobin A1c [HbA1c] 7.9%) were randomized to either stepwise intensification or full basal-bolus treatment. Patients in the basal-bolus group received insulin aspart before every meal, while patients in the stepwise group received one bolus dose with the largest meal and added doses before the next largest meal at 11 weeks and again at 22 weeks if their HbA1c remained at 7% or above.

During the 32-week treatment, the proportion of participants who withdrew was significantly higher in the basal-bolus group (52 [26%]) than in the stepwise group (28 [14%]; P=0.002). After 32 weeks, HbA1c change from baseline was −0.98% (95% CI, −1.09 to −0.87) for the stepwise group and −1.12% (95% CI, −1.23 to −1.00) for the basal-bolus group (mean treatment difference, 0.14; 95% CI, −0.02 to 0.30; P=0.0876). Significantly more patients in the basal-bolus group reached their target HbA1c at the end of the first treatment period (odds ratio [OR], 6.85; 95% CI, 4.12 to 11.39; P<0.0001) and second treatment period (OR, 2.38; 95% CI, 1.56 to 3.64; P<0.0001), but this difference was not significant by the end of the trial (OR, 1.36; 95% CI, 0.90 to 2.07; P=0.15). Finally, patients were significantly more satisfied with the stepwise approach than with the basal-bolus approach (P=0.0072).

In the basal-bolus group, hypoglycemia rates increased rapidly between weeks 0 and 10, and seemed to decline slightly during the remainder of the trial, the authors noted. In the stepwise treatment group, the rate of hypoglycemia increased slightly over the first 10 weeks, fell during weeks 10 through 21, and then remained at around the same level through the end of the trial. Patients in the stepwise group had fewer overall hypoglycemic episodes than did those in the basal-bolus treatment group (rate ratio, 0.58; 95% CI, 0.45 to 0.75; P<0.0001). Adverse events did not differ between the two groups, and the most common were nasopharyngitis, influenza, diarrhea, headache, peripheral edema and wrong drug given.

Researchers wrote, “This regimen is an attractive alternative to initiation of full basal-bolus insulin replacement involving four injections per day. The stepwise approach consists of fewer injections, fewer associated glucose measurements, less burden on the patient in terms of titrating insulin doses, lower risk of hypoglycemia, less weight gain, and better adherence than the basal-bolus approach.”

An editorialist outlined how starting prandial insulin in a stepwise manner can be done in a practical way. The patient identifies which meal has the most carbohydrates, and takes 4 to 6 units of a rapid-acting insulin analogue, ideally 10 to 15 minutes before eating. The dose is then adjusted once or twice a week so that the next prandial or bedtime glucose reading is at target (less than 130 mg/dL). If the HbA1c remains above target, a second and third dose can be added if needed. The editorialist wrote, “Clinicians should be aware that every addition of a prandial dose of insulin to a patient's daily regimen increases the risk of hypoglycemia, and therefore should be weighed against potential benefits of intensifying therapy.”