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Combination of Insulin Glargine and Lixisenatide = LixiLan

A single, once-daily injection to lower both fasting and postprandial blood glucose

LixiLan is an investigational injectable glucose-lowering agent that combines insulin glargine and the GLP-1 lixisenatide in a fixed ratio. In an open-label, randomized, parallel-group, phase III clinical trial by J. Rosenstock, et al., the combination of insulin glargine and lixisenatide (IG+L) was compared to insulin glargine alone and lixisenatide alone over 30 weeks in patients with type 2 diabetes mellitus who were inadequately controlled on metformin. The primary objective was to assess the HbA1c-lowering capabilities of LixiLan versus its individual components when used as an add-on agent to metformin monotherapy.

Eligible patients had to be at least 18 years old and have inadequate glycemic control after at least 3 months of treatment with metformin +/- a second oral glucose-lowering agent.  Patients were excluded if they received treatment with glucose-lowering agents other than a sulfonylurea, glinide, sodium glucose cotransporter 2, or dipeptidyl  peptidase 4 inhibitor in the 3 months preceding screening or if they previously used insulin, had discontinued a GLP-1RA due to safety, tolerability or lack of efficacy, had an elevated amylase or lipase level, or elevated calcitonin level. During a 4-week run-in phase, eligible patients discontinued glucose-lowering agents other than metformin, and the dose of metformin was titrated to a minimum of 1,500 mg per day, or 2000 mg daily if tolerated. At the end of the run-in phase, patients with a fasting plasma glucose of ≤250 mg/dL and HbA1c ≥7.0% and ≤10.0% were randomized to receive either IG+L, glargine alone or lixisenatide alone in a 2:2:1 ratio. The primary endpoint was the change in HbA1c between baseline and week 30.

A total of 1,170 patients were randomized to the 3 treatment arms.  Baseline characteristics were similar across groups, most patients were overweight or obese, and most patients were Caucasian.  The mean age was 58 years, mean baseline HbA1c was 8.1, and the mean duration of diabetes was 9 years. At week 30, the mean HbA1c was 6.5% for the IG+L group, compared with 6.8% for insulin glargine alone and 7.3% for lixisenatide alone.  With regard to reduction in HbA1c, the combination of IG+L was statistically non-inferior compared with insulin glargine alone, and was statistically superior compared with lixisenatide alone. However, statistically significantly more patients in the IG+L arm were able to achieve a target HbA1c of less than 7% than those in the insulin glargine alone arm (74% vs 59% respectively, p<0.0001).

Reductions in HbA1c were achieved in the IG+L group without significantly increasing the risk of hypoglycemia or other adverse events. Symptomatic hypoglycemia was not significantly different between IG+L and insulin glargine alone. Treatment with IG+L was also associated with weight loss, while glargine alone was associated with weight gain for a statistically significant difference of 1.4 Kg from baseline to week 30 between the two groups. There was also a significant decrease in incidence of nausea and vomiting in the IG+L group compared to lixisenatide alone.  Fasting blood glucose was similar between groups, however IG+L significantly reduced postprandial blood glucose by ~38 mg/dL more than insulin glargine alone (p<0.001).

For patients with type 2 diabetes who are not adequately controlled on metformin or other oral antidiabetic agents, fixed-ratio combination insulin glargine/lixisenatide is at least as effective as insulin glargine and superior to lixisenatide at lowering HbA1c levels, with similar rates of hypoglycemia, reduced weight gain, and less nausea compared with its individual components.  In addition to decreased adverse effects, IG+L may also increase patient adherence by combining two glucose-lowering agents into a single, once-daily injection.  The fixed ratio of IG+L in this study was delivered via a pen device with a maximum daily dose of 60 units insulin glargine and 20 mcg lixisenatide, and therefore, may not be appropriate for patients who require larger doses of basal insulin to achieve glycemic control. Combination insulin glargine/lixisenatide may be an appropriate option for patients on metformin or other agents who are not at goal, those patients on basal insulin and a GLP-1RA looking to decrease their number of daily injections or patients on metformin and basal insulin with inadequate postprandial blood glucose control.

Practice Pearls:

  • When used in addition to metformin, fixed-ratio combination insulin glargine/lixisenatide demonstrates HbA1c  lowering similar to insulin glargine alone, and superior to lixisenatide alone.
  • Treatment with insulin glargine/lixisenatide was also associated with weight loss, while glargine alone was associated with weight gain for a statistically significant difference of 1.4 Kg.
  • Near normal glycemic levels can be achieved through treatment with combination insulin glargine/lixisenatide without an increased risk of hypoglycemia, weight gain, or gastrointestinal effects commonly seen with insulin or GLP-1 receptor antagonists alone.

References:

Rosenstock J, Aronson R, Grunberger G, Hanefeld M, Piatti P et al. Benefits of LixiLan, a titratable fixed-ratio combination of insulin glargine plus lixisenatide, versus insulin glargine and lixisenatide monocomponents in type 2 diabetes inadequately controlled with oral agents: the lixilan-o randomized trial. Diabetes Care. 2016 Aug 15.

Researched and prepared by Emily McDonnell, URI College of Pharmacy Pharm.D. Candidate, Class of 2017. Reviewed by Michelle Caetano, Pharm.D, BCPS, BCACP, CDOE, CVDOE.