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Adding GLP-1 to Insulin

Patients with type 2 diabetes not responding to basal insulin therapy alone may see glycemic improvement with a GLP-1 receptor agonist.

Usually with diabetes management, adding on prandial or rapid-acting insulin to the basal insulin regimen is the go-to algorithm. However, research has shown that adding a GLP-1 receptor agonist to basal insulin therapy can be just as effective as prandial insulin.

The Harmony 6 study, a randomized, open-label, active-controlled trial, tested once-weekly albiglutide versus thrice-daily prandial insulin lispro as an add-on to titrated once-daily insulin glargine. The primary endpoint was the difference in the HbA1c change from baseline at week 26. The study found the HbA1c decreased from baseline by -0.82 ± SE 0.06% (9.0 mmol/mol) with albiglutide and -0.66 ± 0.06% (7.2 mmol/mol) with lispro. They also saw a decrease in weight with albiglutide but an increase in weight with lispro, -0.73 ± 0.19 kg vs. +0.81 ± 0.19 kg respectively. The weekly albiglutide was a simpler therapeutic option compared to the three-times daily lispro with reductions in HbA1c and weight loss. However, there were more gastrointestinal adverse events in the albiglutide group.

Another study had a 30-week, open-label, multicenter, randomized, non-inferiority trial with 12 weeks prior insulin optimization with 627 patients who had insufficient HbA1c and were all randomized to exenatide therapy or thrice-daily lispro. The study compared the efficacy of exenatide to insulin lispro in patients who had inadequate glycemic control with insulin glargine and metformin. The results of the study revealed that the HbA1c and fasting glucose were 8.3% and 7.1 mmol/L for exenatide and 8.2% and 7.1 mmol/L for lispro. After 30 weeks, the mean HbA1c changes were non-inferior for exenatide compared with lispro. Weight decreased in the exenatide group and increased in the lispro group with -2.5 kg vs. +2.1 kg respectively. They also had more patients report treatment satisfaction and better quality of life on exenatide over lispro even though a larger portion of the patients on exenatide experienced gastrointestinal side effects. They concluded that adding exenatide to glargine with metformin had a similar glycemic control to lispro therapy.

Similarly, another systematic review and meta-analysis compared the combination treatment of type 2 diabetes with a GLP-1 receptor agonist and basal insulin. The researchers found that, compared with other diabetic treatments, GLP-1 agonist and basal insulin combination had an improved mean reduction in HbA1c of -0.44%. There was no increased risk of hypoglycemia and the mean weight loss was -3.22 kg, compared with basal-bolus insulin regimens, which yielded a mean reduction of HbA1c of -0.1%, and reduction of mean weight of -5.66 kg. The conclusion was that a combination of GLP-1 receptor agonist and basal insulin could be an ideal diabetic treatment with no increased hypoglycemia or weight gain.

In a review of clinical trials, there were 10 trials identified from 2011 to July 2017 that combined basal insulin therapy with an add-on of GLP-1 receptor agonists that included: exenatide (Byetta), lixisenatide (Adlyxin) and a fixed-ratio treatment of insulin glargine and lixisenatide (Soliqua). The trials were identified and reviewed in PubMed, the Cochrane Central Register of Clinical Trials and clinicaltrials.gov. Many of the studies in this review showed that adding a prandial GLP-1 receptor agonist to basal insulin had equal or slightly superior efficacy compared to the addition of prandial insulin, as well as experiencing weight loss and less hypoglycemia. The combination was found to be a safe and effective treatment option.

Since GLP-1 receptor agonists do have gastrointestinal side effects, there is the possibility of patients having low adherence or discontinuing therapy, but the weight loss and less hypoglycemia might have more benefits than risks for type 2 diabetes patients. Another advantage is the lower treatment burden for patients because of fewer required injections.

It was noted by the researchers in the review of clinical trials that using a fixed-ratio combination of insulin glargine and lixisenatide may help with patient adherence and can improve glycemic control without the risks of weight gain in patients who have poor glycemic control on basal insulin.

Practice Pearls:

  • GLP-1 receptor agonists can help with weight loss and have less hypoglycemia when used in combination with insulin.
  • Using a fixed-ratio treatment of insulin glargine and lixisenatide can increase patient use and help improve glycemic control.
  • GLP-1 receptor agonists are a safe and effective addition to type 2 diabetes therapies but still have side effects such as nausea, vomiting and diarrhea.

References:

Rosenstock J, Fonseca VA, Gross JL, et al.; Harmony 6 Study Group. Advancing basal insulin replacement in type 2 diabetes inadequately controlled with insulin glargine plus oral agents: a comparison of adding albiglutide, a weekly GLP-1 receptor agonist, versus thrice-daily prandial insulin lispro. Diabetes Care 2014; 37:2317–2325.

Diamont M, Nauck MA, Shaginian R, et al.; 4B Study Group. Glucagon-like peptide 1 receptor agonist or bolus insulin with optimized basal insulin in type 2 diabetes. Diabetes Care 2014; 37:2763–2773

Eng C, Kramer CK, Zinman B, Retnakaran R. Glucagon-like peptide-1 receptor agonist and basal insulin combination treatment for management of type 2 diabetes: a systematic review and meta-analysis. Lancet. 2014 Dec 20; 384 (9961): 2228-34. doi: 10.1016/S0140-6736(14)61335-0.

Goldenberg, RM, Berard, L. (2017). Adding Prandial GLP-1 receptor agonists to basal insulin: a promising option for type 2 diabetes therapy. Curr Med Res Opin. 2017 Sep 28:1-10. doi: 10.1080/03007995.2017.1372118.

 

Jessica Quach, Doctor of Pharmacy Candidate, Class of 2018, GA-PCOM School of Pharmacy