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 Associate Clinical Professor, School of Pharmacy, University of California, San Francisco.

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

The FDA has approved a fixed-ratio, once-daily, insulin glargine and the glucagon-like peptide-1 (GLP-1) receptor agonist, lixisenatide combination (iGlarLixi) for the treatment of type 2 diabetics. The new combination is marketed as Soliqua.

INDICATIONS

iGlarLixi is indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus inadequately controlled on basal insulin (< 60 units/day) or lixisenatide.1

DOSAGE

The recommended dose for patients inadequately controlled on < 30 units of basal insulin or on lixisenatide is 15 units of insulin glargine and 5 mcg of lixisenatide administered subcutaneously once daily within the hour prior to the first meal of the day.1 For those inadequately controlled on 30-60 units of basal insulin, the dose is 30 units of insulin glargine and 10 mcg of lixisenatide. The dosage may be titrated up or down by two to four units every week based on response and until patient achieves desired fasting plasma glucose. The maximum dose is 60 units of insulin glargine and 20 mcg of lixisenatide. iGlarLixi is available as a single-patient use 3 mL pen containing 100 units of insulin glargine and 33 mcg of lixisenatide per mL.

POTENTIAL ADVANTAGES

iGlarLixi provides another option for patients inadequately controlled on basal insulin or lixisenatide. The number of documented hypoglycemic events (FPG < 70 mg/dL) was higher with insulin glargine than iGlarLixi at 3.0 events vs. 4.2 events per patient-year.3

POTENTIAL DISADVANTAGES

Acute pancreatitis, including fatal and non-fatal hemorrhagic or necrotizing pancreatitis, has been reported with GLP-1 receptor agonists. In clinical trials, the incidence rate for lixisenatide was 21 per 10,000 patient-years compared to 17 for comparators.1 Diarrhea and nausea were more frequent with iGlarLixi than with insulin glargine. Lixisenatide delays gastric emptying and may reduce the rate of absorption of other drugs.1 For drugs that should be taken with food, it is recommended that they be taken when lixisenatide is not administered. Antidrug antibodies may develop to glargine and lixisenatide. High levels of antibodies can attenuate the glycemic affect (seen with 2.4% of patients). Antibody-positive patients also are more likely to experience allergic reactions and injection-site reactions.

COMMENTS

The efficacy and safety of iGlarLixi was primarily based on demonstrating superiority to insulin glargine in type 2 diabetic subjects inadequately controlled on basal insulin with or without up to two oral agents.1,2,3 Subjects had baseline HbA1c of 8.1%. During a run-in period, insulin glargine was introduced and/or titrated, and oral agents other than metformin were discontinued. Subjects were then randomized to iGlarLixi (n = 365) or insulin glargine (n = 365). The primary endpoint was change in HbA1c at week 30. The secondary endpoint was the proportion of responders with HbA1c < 7%. At week 30, iGlarLixi reduced HbA1c to 6.9% compared to 7.5% with a least square mean difference of -0.5 (95% confidence interval, -0.6 to -0.4; P < 0.0001). Fifty-five percent of iGlarLixi patients reached HbA1c of 7% compared to 30% for insulin glargine. iGlarLixi produced minimal effect on fasting plasma glucose, since the dose was titrated to fasting plasma levels, but significantly improved postprandial glucose excursion compared to insulin glargine.3 There is minimal weight reduction with iGlarLixi, as the weight gain caused by insulin glargine is mitigated by weight reduction of lixisenatide.

CLINICAL IMPLICATIONS

iGlarLixi provides a fixed-ratio basal insulin and GLP-1 agonist for patients inadequately controlled on separate agents. Lixisenatide has demonstrated neutrality in terms of cardiovascular events compared to placebo in type 2 diabetics with a recent acute coronary syndrome.4 The wholesale cost of iGlarLixi is $127 per 3 mL pen.

REFERENCES

  1. Soliqua Prescribing Information. Sanofi. November 2016.
  2. Aroda VR, et al. Efficacy and safety of LixiLan, a titratable fixed-ratio combination of insulin glargine plus lixisenatide in type 2 diabetes inadequately controlled on basal insulin and metformin: The LixiLan-L Randomized Trial. Diabetes Care 2016;39:1972-1980.
  3. FDA Briefing Document. Endocrinologic and Metabolic Drugs Advisory Committee Meeting, May 25, 2016. Available at: http://bit.ly/2igCdx8. Accessed Dec. 9, 2016.
  4. Pfeffer MA, et al. Lixisenatide in patients with type 2 diabetes and acute coronary syndrome. N Engl J Med 2015;373:2247-2257.