FDA approves lixisenatide for type 2 diabetes

December 19, 2016

New drug review

In July, the FDA approved lixisenatide (Adlyxin; Sanofi-Aventis), for the treatment of type 2 diabetes in combination with diet and exercise. It is estimated that 29.1 million people in the U.S. have received a diagnosis of type 2 diabetes.

Lisa M. HolleVarious therapies exist to treat hyperglycemia associated with diabetes. Lixisenatide is a glucagon-like-peptide-1 receptor agonist (GLP-1 RA): these agents are associated with improved glycemic control, reduced weight, and a limited risk for hypoglycemia. However, lixisenatide significantly decreases postprandial glucose compared with other GLP-1 RAs.1

Efficacy

The approval of lixisenatide was based on the GetGoal clinical program, composed of 13 multinational clinical trials that evaluated lixisenatide against placebo as monotherapy and as adjunct therapy to both oral antidiabetics (OADs) and insulin. More than 5,000 adults were evaluated worldwide.2  GetGoal-Mono Japan3 evaluated lixisenatide in 361 and 69 patients, respectively, as monotherapy. Lixisenatide was evaluated in GetGoal-F1, GetGoal-M, GetGoal-M-Asia, GetGoal-S, and GetGoal-P for combination therapy with OADs.4-8 All studies evaluated patients whose diabetes was inadequately controlled on OADs. GetGoal-F1 and GetGoal-M evaluated 484 and 680 patients, respectively, who were receiving ≥1500 mg/d of metformin. GetGoal-M-Asia evaluated 391 patients receiving between 1000-1500 mg/d of metformin and/or sulfonylurea at a maximum effective dose. GetGoal-S evaluated 859 patients using sulfonylureas, and GetGoal-P evaluated 484 patients receiving pioglitazone, with or without metformin.

GetGoal-Duo 19 evaluated patients previously on OADs who had started taking insulin glargine for 12 weeks but who still had an A1c 7% but <9%. GetGoal-L10 evaluated uncontrolled patients on a stable dose of basal insulin with or without metformin ≥1500 mg/d. GetGoal-L-Asia11 evaluated uncontrolledAsian patients on a stable dose of basal insulin with or without a stable dose of a sulfonylurea. GetGoal-X12 compared lixisenatide once daily to exenatide twice daily, another GLP-1 RA, in 634 patients who were previously receiving metformin ≥1500 mg/d. GetGoal-Duo 213 compared lixisenatide to insulin glulisine, a rapid acting prandial insulin, in 894 patients receiving basal insulin with or without OADs where patients had a run-in phase resulting in the discontinuation of all oral agents other than metformin and optimization of insulin glargine.

In GetGoal-Mono, GetGoal-Mono Japan, and GetGoal-F1, patients were randomized into four groups: lixisenatide 10 mcg daily for 1 week, then 15 mcg daily for 1 week, then 20 mcg daily thereafter (2-step); lixisenatide 10 mcg daily for 2 weeks, then 20 mcg daily thereafter (1-step); placebo (2-step); or placebo (1-step). In GetGoal M, GetGoal-M-Asia, GetGoal-S, GetGoal-P, GetGoal-Duo 1, and GetGoal-L, patients were randomized to receive either lixisenatide 20 mcg daily or placebo. GetGoal-M further stratified patients to receive lixisenatide in the morning or evening. GetGoal-L-Asia randomized patients to receive a stepwise dose increase to 20 mcg daily of lixisenatide or placebo. GetGoal-X randomized patients to lixisenatide 20 mcg daily or exenatide 10 mcg twice daily. GetGoal-Duo 2 randomized patients to either lixisenatide 20 mcg daily (after a titration of 10 mcg daily x 2 weeks) or insulin glulisine daily or three times daily.

The primary endpoint for all studies was HbA1c reduction at 12 or 24 weeks. The GetGoal phase III clinical trial program showed that lixisenatide effectively reduced A1c (range: -0.7 to -1.0%), weight (range: -0.2 to -2.96 kg), and 2-hour postprandial glucose of the immediate meal following its administration (range: -3.1 to -7.96 mmol/L).

Safety

Lixisenatide is generally well tolerated. The most common adverse events (>  5%of patients) reported in the studies were nausea (25%), vomiting (10%), headache (9%), diarrhea (8%), dizziness (7%), and hypoglycemia (2% as monotherapy, 3% to 47% with combination therapy; more so in combination with basal insulin than OADs). Neither a one-step versus a two-step titration or morning versus evening administration appeared to have a significant impact on the rates of adverse events.

 

In GetGoal-X, patients reported fewer episodes of nausea compared to exenatide twice daily (24.5% vs. 35.1%, p<0.05) and hypoglycemia (2.5% vs. 7.9%, p<0.05). Data from the ELIXA14 study demonstrated no increase incidence in pancreatitis or cancers and a neutral effect on risk of cardiovascular problems. Lixisenatide is contraindicated in patients who have a hypersensitivity to lixisenatide or any product components.

Dosing

Lixisenatide is supplied as a disposable pre-filled pen for a single dose of 10 mcg (50 mcg/mL) or 20 mcg (100 mcg/mL) for subcutaneous administration to the abdomen, thigh, or upper arm. Recommended starting dose is 10 mcg/d for 14 days. On day 15, the dosage is increased to 20 mcg/d. Use is not recommended in patients with a CrCl <15 ml/min, because the drug was not well studied in this   population.

Advise patients to rotate injection sites with each dose, as with other injectables. Patients should administer lixisenatide within one hour before the first meal of the day, preferably the same meal each day. Advise them to protect the pens from light by keeping them in the original packaging and discarding them after 14 days after first use.

Lixisenatide delays gastric emptying and can therefore alter the absorption of oral medications taken concurrently. Medications that depend on threshold concentrations for efficacy should be administered 1 hour before lixisenatide. The same is true when a delay in a medication’s effect is undesirable. Lixisenatide can decrease serum concentrations of progestin and estrogen contraceptives. Oral contraceptives should be taken at least 1 hour before or 11 hours after lixisenatide administration.

Vincent Do, 2017 PharmD Candidate is a 4th year pharmacy student at UConn School of Pharmacy, Storrs, Conn

Lisa M. Holle, PharmD, BCOP, FHOPA is an Associate clinical Professor at UConn School of Pharmacy, Storrs, CT.

References

1. Anderson SL, Trujillo JM. Lixisenatide in type 2 diabetes: latest evidence and clinical usefulness. Ther Adv Chronic Dis. 2016;7:4-17.

2. Fonseca VA, Alvarado-ruiz R, Raccah D, et al. Efficacy and safety of the once-daily GLP-1 receptor agonist lixisenatide in monotherapy: a randomized, double-blind, placebo-controlled trial in patients with type 2 diabetes (GetGoal-Mono). Diabetes Care. 2012;35(6):1225-31.

3. Seino Y, Yabe D, Takami A, et al. Long-term safety of once-daily lixisenatide in Japanese patients with type 2 diabetes mellitus: GetGoal-Mono-Japan. J Diabetes Complicat. 2015;29:1304-1309.

4. Bolli GB, Munteanu M, Dotsenko S, et al. Efficacy and safety of lixisenatide once daily vs. placebo in people with Type 2 diabetes insufficiently controlled on metformin (GetGoal-F1). Diabet Med. 2014;31(2):176-84.

5. Ahrén B, Leguizamo dimas A, Miossec P, Saubadu S, Aronson R. Efficacy and safety of lixisenatide once-daily morning or evening injections in type 2 diabetes inadequately controlled on metformin (GetGoal-M). Diabetes Care. 2013;36:2543-2550.

6. Yu pan C, Han P, Liu X, et al. Lixisenatide treatment improves glycaemic control in Asian patients with type 2 diabetes mellitus inadequately controlled on metformin with or without sulfonylurea: a randomized, double-blind, placebo-controlled, 24-week trial (GetGoal-M-Asia). Diabetes Metab Res Rev. 2014;30:726-735.

7. Rosenstock J, Hanefeld M, Shamanna P, et al. Beneficial effects of once-daily lixisenatide on overall and postprandial glycemic levels without significant excess of hypoglycemia in type 2 diabetes inadequately controlled on a sulfonylurea with or without metformin (GetGoal-S). J Diabetes Complicat. 2014;28:386-392.

8. Pinget M, Goldenberg R, Niemoeller E, et al. Efficacy and safety of lixisenatide once daily versus placebo in type 2 diabetes insufficiently controlled on pioglitazone (GetGoal-P). Diabetes Obes Metab. 2013;15:1000-1007.

9. Riddle MC, Forst T, Aronson R, et al. Adding once-daily lixisenatide for type 2 diabetes inadequately controlled with newly initiated and continuously titrated basal insulin glargine: a 24-week, randomized, placebo-controlled study (GetGoal-Duo 1). Diabetes Care. 2013;36:2497-2503.

10. Riddle MC, Aronson R, Home P, et al. Adding once-daily lixisenatide for type 2 diabetes inadequately controlled by established basal insulin: a 24-week, randomized, placebo-controlled comparison (GetGoal-L). Diabetes Care. 2013;36:2489-2496.

11. Seino Y, Min KW, Niemoeller E, Takami A. Randomized, double-blind, placebo-controlled trial of the once-daily GLP-1 receptor agonist lixisenatide in Asian patients with type 2 diabetes insufficiently controlled on basal insulin with or without a sulfonylurea (GetGoal-L-Asia). Diabetes Obes Metab. 2012;14(10):910-7.

12. Rosenstock J, Raccah D, Korányi L, et al. Efficacy and safety of lixisenatide once daily versus exenatide twice daily in type 2 diabetes inadequately controlled on metformin: a 24-week, randomized, open-label, active-controlled study (GetGoal-X). Diabetes Care. 2013;36:2945-2951.

13. Rosenstock J, Guerci B, Hanefeld M, et al. Prandial options to advance basal insulin glargine therapy: testing lixisenatide plus basal insulin versus insulin glulisine either as basal-plus or basal-bolus in type 2 diabetes: the GetGoal Duo-2 Trial. Diabetes Care. 2016;39(8):1318-28.

14. Pfeffer MA, Claggett B, Diaz R, et al. Lixisenatide in patients with type 2 diabetes and acute coronary syndrome. N Engl J Med. 2015;373:2247-57.