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Written by Stephanie Cloutier, PharmD - Pharmacy Resident at Western New England University College of Pharmacy / Reviewed by Kam Capoccia, PharmD, BCPS, CDE - Clinical Associate Professor at Western New England University College of Pharmacy

In November 2016, the FDA approved a new combination drug for type 2 diabetes mellitus, Soliqua®. Soliqua® 100/33 injection is a combination of insulin glargine (100 units/mL) and glucagon-like peptide-1 (GLP-1) receptor agonist, lixisenatide (33 mcg/mL). Based on the mechanisms of the two drugs individually, Soliqua® works by stimulating peripheral glucose uptake and inhibits hepatic glucose production, lipolysis, and proteolysis (insulin glargine), and it decreases glucagon secretion, increases release of glucose-dependent insulin, and slows gastric emptying (lixisenatide). Overall, insulin glargine improves fasting blood glucose, and lixisenatide improves postprandial blood glucose. By administering both medications simultaneously at a gradual dose titration, it may decrease the risk of hypoglycemia, mitigate weight gain, and decrease gastrointestinal adverse effects that these agents cause individually.^{1, 2}

The LixiLan-O study was an open-label, randomized, parallel-group, multinational, multicenter phase III clinical trial. It was conducted to evaluate the safety and efficacy of LixiLan (iGlarLixi), the combination of insulin glargine and lixisenatide, compared to each individual component (iGlar and Lixi) in patients with type 2 diabetes mellitus inadequately controlled on metformin with or without a second glucose-lowering drug. The primary outcome was hemoglobin A1C change at 30 weeks. The mean hemoglobin A1C levels at 30 weeks were as follows: 6.5% for iGlarLixi, 6.8% for iGlar, and 7.3% for Lixi. Mean changes in hemoglobin A1C from baseline were -1.63% for iGlarLixi, -1.34% for iGlar, and -0.85% for Lixi. In regards to secondary outcomes, a significantly higher proportion of patients in the iGlarLixi group reached hemoglobin A1C target of <7%, and there was a significant difference in weight loss from baseline between iGlarLixi and iGlar groups (see table 1). A higher proportion of patients in the iGlarLixi group also reached the composite end points of hemoglobin A1C <7% with no body weight gain, hemoglobin A1C <7% with no documented symptomatic hypoglycemia, and hemoglobin A1C <7% with no body weight gain and no documented symptomatic hypoglycemia (see table 1). In regards to safety profile, the incidence of hypoglycemia (≤70 mg/dL) was similar between iGlarLixi and iGlar (26% and 24% respectively), and iGlarLixi showed considerably fewer GI adverse effects compared with Lixi (see table 2). In conclusion, iGlarLixi was found to be more effective improving glycemic control compared to iGlar or Lixi alone, without increased weight gain and risk of hypoglycemia, and fewer GI adverse effects.²

There are currently no studies directly comparing the efficacy of Soliqua® as one injection with basal insulin-GLP-1 receptor agonist therapy administered simultaneously as two separate injections. This would be needed in order to determine additional benefits of fixed ratio combination therapy. However, an indirect comparison to the GetGoal-Duo 1 study, which studied the efficacy of the initiation of insulin glargine first then adding lixisenatide 3-months later, suggests that more patients reached hemoglobin A1C goal of <7% when insulin glargine and lixisenatide were administered as one injection .²

Prior to initiating Soliqua®, the basal insulin and/or lixisenatide therapy should be discontinued. It is a subcutaneous injection that should be given in the abdominal area, thigh, or upper arm. For patients who are inadequately controlled on less than 30 units of basal insulin or on lixisenatide, the initial dosing is 15 units of Soliqua® (15 units insulin glargine/5 mcg lixisenatide) subcutaneously once daily within the hour prior to the first meal. For patients who are inadequately controlled on 30 to 60 units of basal insulin, the initial dose is 30 units (30 units insulin glargine/10 mcg lixisenatide) subcutaneously once daily within the hour prior to the first meal. The dose should be titrated by 2 to 4 units each week until desired fasting plasma glucose is achieved. The maximum dose of Soliqua® is 60 units (60 units insulin glargine/20 mcg lixisenatide) per dose. If a dose is missed, resume the once-daily regimen with the next scheduled dose; do not administer an extra or increased dose.¹

Soliqua® use is contraindicated during episodes of hypoglycemia and in patients with a hypersensitivity to insulin glargine, lixisenatide, or any component of the product. No dose adjustments are required for patients with mild to moderate renal impairment, but use is not recommended in patients with an eGFR < 15 mL/min/1.73 m². Use is also not recommended in patients with severe gastroparesis, and Soliqua® should be dosed conservatively in geriatric patients to avoid hypoglycemia. Common side effects of Soliqua® include hypoglycemia (26-40%), nausea (10%), diarrhea (7%), nasopharyngitis (7%), upper respiratory infection (5.5%), and headache (5.4%).¹

Patients and doctors can be hesitant to starting insulin therapy due to the risks of weight gain and hypoglycemia despite poor glycemic control. Soliqua® has shown to achieve glycemic control without increasing body weight and without increasing the risk of hypoglycemia compared to insulin glargine alone. Due to the slow titration dosing, Soliqua® has also shown lower rates of nausea and vomiting compared to lixisenatide alone. The convenience of two glucose-lowering medications in a once-daily injection is great for patients, but unfortunately, it comes at a cost. Many insurance plans do not currently cover Soliqua® and do not have it on their formularies, requiring a prior authorization. There is a coupon card that is available on the Soliqua® website (https://www.soliqua100-33.com/), where patients can sign up and get up to $700 off per pack of every Soliqua® prescription for the first 12 months. This offer is for commercially insured patients and is not valid for patients whose prescriptions are covered through Medicare, Medicaid, VA, DOD, or TRICARE, or similar federal or state programs including any state pharmaceutical program. Hopefully, Soliqua® will be covered on more insurances in the future in order for patients taking a basal insulin and a GLP-1 receptor agonist to improve their medication regimen and blood sugars by only having to inject once a day.³

References:

1) Soliqua. Micromedex Solutions. Truven Health Analytics, Inc. Ann Arbor, MI. Available at: http://www.micromedexsolutions.com. Accessed May 8^th, 2017.

2) Rosenstock J, Aronson R, Grunberger G, 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

3) The official site for SOLIQUA® 100/33 (insulin glargine & lixisenatide injection) 100 Units/mL & 33 mcgmL. SOLIQUA® 100/33. https://www.soliqua100-33.com/. Published May 2017. Accessed May 13, 2017.

Table 1:

Table 2: