Very High HbA1c Falls Most With GLP-1 Agonist Plus Basal Insulin

Marlene Busko

July 04, 2018

ORLANDO — Among patients with uncontrolled type 2 diabetes with very high HbA1c, two treatment regimens led to "dramatic improvements" in glycemic control at 6 months, but one strategy stood out, researchers report.

That is, initiating a treatment regimen of basal insulin plus the glucagon-like peptide-1 (GLP-1) receptor agonist liraglutide (Victoza, Novo Nordisk) was more effective at lowering HbA1c than a regimen of basal plus bolus insulin in the randomized SIMPLE study, which was sponsored by Novo Nordisk.

Marconi Abreu, MD, from the UT Southwestern Medical Center, Dallas, Texas, presented these findings here at the American Diabetes Association (ADA) 2018 Scientific Sessions.

"In summary, this is the first and only trial that compares two strategies suggested by the ADA for patients with HbA1c above 10%," he said. "It showed that a strategy based on [basal insulin plus a GLP-1 receptor agonist] was superior to a strategy of basal-bolus insulin, with an estimated treatment difference [in attained HbA1c] of -1.1%."

Importantly, he noted, more patients in the group that received basal insulin plus the GLP-1 receptor agonist achieved a target HbA1c below 7% at 6 months, and this group of patients also attained "a better weight profile, less hypoglycemia, and improvement in quality of life — all that with fewer insulin injections."

Two things about the trial stood out for session chair Tricia Santos Cavaiola, MD, an endocrinologist at UC San Diego Health, in California.

First, "I think it is an unmet need," she told Medscape Medical News. "More trials are needed in that patient population because we certainly do see [patients with type 2 diabetes with very elevated HbA1c levels], and the guidelines are not as clear in terms of what to do."

Second, "the patients that were started on basal-bolus therapy were started on...four injections a day," whereas "most often when we start patients on combination basal-bolus therapy they're usually already on basal insulin...and typically we add one dose of bolus insulin with the largest meal and progress as needed."

She wondered if part of the lower compliance in that group was related to the four injections a day, which those patients may have found were "too much or too complicated a regimen,” as compared with the once-a-day injections of the other group.

Patients With Very High HbA1c a Neglected Population

Basal-bolus insulin is the most established treatment strategy for patients with very high HbA1c (> 10%), especially if they have symptoms, Abreu told delegates.

And metformin plus a GLP-1 receptor agonist plus basal insulin has been shown to be effective in lowering glucose.

But "to date, there has been no single randomized controlled trial properly designed to evaluate a population of patients with HbA1c above 10%," Abreu said. 

Researchers randomized 120 adults with type 2 diabetes and HbA1c above 10% who were seen at their center.

Patients were a mean age of 47 years and mainly African American (42%) or Hispanic (40%), and less often non-Hispanic White (18%). Close to three quarters (71%) were women.

Participants were obese with a mean weight of 102 kg (approximately 225 Ibs) and mean body mass index of 37 kg/m2.

On average, patients had had diabetes for 10.5 years and a high HbA1c of 12.1%. Three quarters of the patients were already on insulin.

Patients received the study drugs free of cost.   

All patients continued to receive, or were started on, metformin, which was titrated to 2000 mg/day or maximum tolerated dose (at least 1000 mg/day).

All patients continued on the same dose or were initiated on a dose of 0.3 units/kg of basal insulin detemir.  

Patients in the liraglutide group received an initial dose of 0.6 mg/day, titrated to 1.8 mg/day or maximum tolerated dose (at least 1.2 mg/day).

Patients in the bolus insulin group were initiated with meal-time insulin aspart at 0.1 units/kg/meal times three meals a day.

The investigators hypothesized that at 6 months a similar percentage of patients in both groups would reach HbA1c < 7.0%, and second, more patients in the group that received a GLP-1 receptor agonist plus basal insulin would achieve these levels without severe hypoglycemia or significant weight gain.

Newer Strategy Topped Established Strategy

Mean HbA1c dropped from 11.8% to 8.8% in the basal-bolus insulin group and from 12.2% to 8.1% in the group that received basal insulin plus the GLP-1 receptor agonist, a significant difference of -1.1% (P = .03).

"More importantly," Abreu stressed, twice as many patients in the group that received basal insulin plus a GLP-1 receptor agonist reached the HbA1c target of 7% or lower, and roughly twice as many achieved an HbA1c of 8% or lower with no hypoglycemia or weight gain.

Patients on basal-bolus insulin gained weight, whereas patients on basal insulin plus the GLP-1 receptor agonist had a modest weight loss, for a treatment difference of -3.7 kg (-8.2 Ib) (P = .001).

Almost twice as many patients in the basal-bolus insulin group than the other group had moderate or severe hypoglycemia.  

And not only did patients in the group taking basal insulin plus a GLP-1 receptor agonist achieve better HbA1c, they achieved it with 32% less insulin use, Abreu pointed out.

Patients in both groups reported better quality of life, with the greatest improvement in patients treated with basal insulin plus the GLP-1 receptor agonist. Those in the latter group were also more compliant with their treatment regimen.

An audience member asked, "Did you start the insulin and liraglutide at the same time or did you do that sequentially?" Abreu replied all drugs were started at the same time.

The study was supported by Novo Nordisk. Abreu and Santos Cavaiola have reported no relevant financial relationships.

American Diabetes Association 2018 Scientific Sessions. June 25, 2018; Orlando, Florida. Abstract 124-OR.

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