Similar HbA1c Reduction Seen with Exenatide vs Lispro Added to Basal Insulin


Intensify treatment and minimize weight gain/hypoglycemia? It's possible, say results of the first study to compare a GLP-1 agonist with titrated lispro on a background of optimized basal insulin.

Intensifying treatment for patients with type 2 diabetes who are not optimized on basal insulin traditionally is accomplished by adding bolus insulin 3 times daily at mealtimes to control post-prandial glucose excursions. The treatment is effective but often leads to weight gain and increases the risk for hypoglycemia.

While there is some evidence that using a short-acting GLP-1 receptor agonist (GLP-1RA) in place of prandial insulin is a viable alternative, a new study published in the October issue of Diabetes Care is the first to directly compare the safety and efficacy of a GLP-1RA (exenatide) with mealtime insulin in patients receiving optimized basal insulin.

“Addition of exenatide twice-daily to basal insulin glargine achieves the same glycaemic effect [in terms of reductions in HbA1c] as titrated insulin lispro before meals, but with less hypoglycaemia, and with weight loss instead of weight gain,” commented Bruce H.R. Wolffenbuttel, MD, PhD, professor of endocrinology and metabolism at the University Medical Center Groningen in the Netherlands.  “In addition, there is a cardiovascular benefit, and the participants reported higher treatment satisfaction with exenatide.”

The open-label, randomized trial took place at 108 health centers in 17 countries from September 2009 to August 2012. At enrollment, patients were being treated with insulin glargine and metformin with or without a sulfonylurea. At study entry, patients continued metformin and discontinued the sulfonylurea.  

“Patients were treated to the best results, aiming to normalize fasting blood glucose, with long-acting insulin glargine before randomization,” Wolffenbuttel explained. “Other studies have not been so rigorous in pretreatment before randomization.” Basal insulin was optimized for 12 weeks.

Researchers then randomized 627 participants whose HbA1c remained above 7.0% despite optimization, to exenatide (10 to 20 µg/day) or three-times daily prandial insulin lispro titrated to a premeal glucose of 5.6 to 6.0 mmol/L. At randomization, glargine was titrated down according to predefined algorithms, based on blood glucose self-monitoring in the lispro group, and on package insert and past research evidence in the exenatide group.  Participants were followed for 30 weeks.

Randomized patients had a mean age of 59.8 years, median diabetes duration of 12 years, mean HbA1c of 8.2%, mean BMI of 35 kg/m2 and 88% were white. Key results included:

  - Change in mean A1c from randomization: Similar with exenatide (-1.13) and lispro (-1.10%), (p=.627).

  - Treatment differences: per protocol (n=150), -0.04 (95% CI -0.18, 0.11); intention-to-treat (n=627), -0.03 (95% CI -0.16, 0.11), meeting noninferiority criteria of <0.4 and <0.3%.

  - A1c ≤7% at study completion: 49.6% in exenatide group; 49% in lispro group  

  - Fasting glucose: Lower with exenatide (6.5 mmol/L) vs lispro (7.2 mmol/L), (p=.002).

  - Weight loss: Greater with exenatide (2.5 kg) vs lispro (2.1 kg) (p<.001). 

  - Systolic blood pressure: exenatide, 4.1 mm Hg decrease vs lispro, 0.4 mm Hg increase (p<.001)

  - Adverse events (AEs): More common with exenatide, especially gastrointestinal side effects (47% with exenatide vs. 13% with lispro).

  - Hypoglycemia: More common with lispro vs exenatide (34% and 15%, respectively)

  - Nocturnal hypoglycemia: Similar for exenatide and lispro (25% vs 27%, respectively)

  - Serious AEs: Similar with exenatide and lispro (5.7% and 7.4%, respectively)

  - Self-reported satisfaction/quality of life: Improved in both groups, but more so with exenatide (p=.003).

“GLP1 agonists have been associated with increased risk of pancreatitis, but the last two years, with critical appraisal of all available data, this increase risk appears very limited,” Wolffenbuttel commented.  “We did not see any single case of pancreatitis in our study.”

During the first weeks after starting treatment, more patients experienced nausea and upper gastrointestinal side-effects with exenatide. This appears to be consistent with earlier studies and is likely related to the mechanism of action of the GLP-1RAs, Wolffenbuttel explained.

“These complaints are known to diminish" Wolfenbuttel added, "and usually disappear with prolonged use.”


The study was part of the Eli Lilly and Company/Amylin Pharmaceuticals Alliance and the Bristol-Myers Squibb/AstraZeneca Alliance.


Diamant M, Nauck MA, Shaginian R, et al.  Glucagon-like peptide 1 receptor agonist or bolus insulin with optimized basal insulin in type 2 diabetes. Diabetes Care 2014; 37:2763-2773.  doi: 10.2337/dc14-0876

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