By William Elliott, MD, FACP, and James Chan, PharmD, PhD

Dr. Elliott is Medical Director, Pharmacy, Northern California Kaiser Permanente, and Assistant Clinical Professor of Medicine, University of California, San Francisco. Dr. Chan is Pharmacy Quality and Outcomes Manager, Kaiser Permanente, Oakland, CA.

Drs. Elliott and Chan report no financial relationships relevant to this field of study.

The FDA has approved the fifth glucagon-like peptide-1 (GLP-1) receptor agonist. Lixisenatide is injected once-daily and is marketed as Adlyxin.

INDICATIONS

Lixisenatide is indicated as an adjunct to diet and exercise to improve glycemic control in adults suffering from type 2 diabetes mellitus (T2DM).1

DOSAGE

The initial dose is 10 mcg once daily for 14 days. On day 15, increase the dose to 20 mcg once daily. Inject lixisenatide within one hour before the first meal of the day.1 Lixisenatide is available as 50 mcg and 100 mcg prefilled pens, which provide 14 pre-set doses of 10 mcg and 20 mcg, respectively.

POTENTIAL ADVANTAGES

Lixisenatide provides another GLP-1 receptor agonist.

POTENTIAL DISADVANTAGES

Lixisenatide may be less effective than exenatide. Lixisenatide requires daily dosing one hour before the first meal. There are several medications in the same therapeutic class that are dosed once weekly.

COMMENTS

The safety and efficacy of lixisenatide was evaluated in 10 clinical trials that enrolled 5,400 patients. As with other antidiabetic drugs, its efficacy was evaluated as monotherapy and as an add-on to metformin.1 As monotherapy, lixisenatide (n = 119) was compared to placebo (n = 122) in a 12-week, double-blind study in subjects suffering from T2DM with a mean baseline HbA1c of 8.07% and a mean fasting plasma glucose (FPG) of 160.4 mg/dL. At week 12, mean change in HbA1c from baseline was -0.83% for lixisenatide 20 mcg daily compared to -0.18% for placebo. Mean changes in FPG from baseline were -15.8 mg/dL and +1.46 mg/dL, respectively. Forty-four percent of subjects achieved HbA1c < 7% for lixisenatide compared to 24% for placebo. Lixisenatide is significantly more effective than placebo when added on to metformin, metformin with or without a sulfonylurea, sulfonylurea with or without metformin, pioglitazone with or without metformin, basal insulin with or without metformin, and insulin glargine with or without metformin. However, lixisenatide was statistically less effective in lowering HbA1c than exenatide administered twice daily and insulin glulisine administered three times daily. Mean differences (i.e., greater reduction with lixisenatide) were 0.17% and 0.23%. Noninferiority was claimed since the differences did not meet the prespecified margin of 0.4%.1 The most common adverse events (vs. placebo) were nausea (25% vs. 6%), vomiting (10% vs. 2%), and headache (9% vs. 6%). In a randomized, placebo-controlled trial, lixisenatide was compared to placebo in T2DM subjects who experienced an acute coronary event within 180 days (n = 6,008).2 The primary endpoint was time to the first occurrence of a cardiovascular event (death from cardiovascular cause, nonfatal myocardial infarction, nonfatal stroke, or hospitalization for unstable angina). After a median follow-up of 25 months, lixisenatide was found to be noninferior to placebo but not superior.

CLINICAL IMPLICATIONS

Lixisenatide is the fifth approved GLP-1 receptor agonist. It appears to have a neutral effect on patients who experienced a recent cardiovascular event. In contrast, in a longer study (3.8 years) in T2DM patients with at least one cardiovascular coexisting condition, liraglutide showed a reduction in a composite first cardiovascular event (death from cardiovascular event, nonfatal myocardial infarction, or nonfatal stroke).3

It is not clear if lixisenatide offers any clear clinical advantage over existing GLP-1 receptor agonists. The cost of lixisenatide was not available at the time of this review. The makers of lixisenatide hope to gain FDA approval for a fixed-ratio combination of basal insulin glargine 100 units/mL and lixisenatide in the near future.

REFERENCES

  1. Adlyxin Prescribing Information. Sanofi-Aventis. July 2016.
  2. Pfeffer MA, Claggett B, Diaz R, et al. Lixisenatide in patients with type 2 diabetes and acute coronary syndrome. N Engl J Med 2015;373:2247-2257.
  3. Marso SP, Daniels GH, Brown-Frandsen K, et al. Liraglutide and cardiovascular outcomes in type 2 diabetes. N Engl J Med 2016375:311-322.