Fixed-Ratio Combination of Basal Insulin and GLP-1 Receptor Agonist

Ninety percent of diabetes cases are type 2, which is a major cause of morbidity and mortality. Because it is a progressive multi-organ disease, effective therapies

are critical. Current guidelines recommend a patient-centered approach aimed at minimizing adverse effects, such as hypoglycemia and weight gain, while maximizing efficacy.¹ Most patients start with metformin monotherapy. If the condition remains uncontrolled, therapy is intensified with either oral or injectable agents. Patients who are unlikely to achieve a glycated hemoglobin (A1C) goal with 1 agent may be initiated on combination therapy at diagnosis.

The combination of a glucagon-like peptide-1 receptor agonist (GLP-1 RA)^2,3 and basal insulin is increasing in popularity because these pharmacologic actions complement one another. Although a basal and GLP-1 RA regimen requires fewer daily injections, compared with basal and bolus (prandial) insulin therapy, using the 2 agents separately still requires multiple injections.

Fixed-ratio combination products decrease the number of injections to once a day. Both the American Diabetes Association and the American Association of Clinical Endocrinologists support the use of basal insulin plus a GLP-1 RA in combination with metformin.⁴ The 2 components work synergistically to reduce blood sugar and A1C. Insulin stimulates peripheral glucose uptake by muscle and fat cells and inhibits hepatic glucose production. GLP-1 RAs increase glucose-dependent insulin release and, thus, work only in the presence of hyperglycemia,⁵ leading to a low risk of hypoglycemia. The GLP-1 RA component may mitigate weight gain that can occur with basal insulin and may instead cause weight loss. The combination of basal insulin and a GLP-1 RA addresses 7 of the 8 core defects found in advanced type 2 diabetes.

The GLP-1 RA lixisenatide has a more profound effect on postprandial blood glucose levels than liraglutide⁶ does. Postprandial reduction occurs primarily via delayed gastric emptying and reduced glucagon release. Lixisenatide’s half-life is 2 to 4 hours. Hence, this drug is dosed prior to the first meal of the day. With a half-life of 13 hours, liraglutide⁶ can be dosed once a day at any time. It has activity on both postprandial and fasting glucose levels. Insulin glargine has a protracted action through post-injection precipitation, which slows absorption and results in a half-life of about 12 hours, allowing once-daily dosing in most patients. Insulin degludec attains its protracted action through multi-hexamer formation in the subcutaneous injection depot. It has a half-life of about 25 hours, so with once-daily dosing, a steady state is achieved.

To improve glycemic control in adults with type 2 diabetes inadequately controlled on basal insulin (<60 units) or lixisenatide, the FDA approved 2 fixed-ratio combination products in November 2016: Soliqua 100/33^7,8 and Xultophy⁹ 100/3.6. Soliqua^7,8 is a combination of glargine insulin and lixisenatide, and Xultophy⁹ combines degludec insulin and liraglutide. Both combinations are dosed according to the basal insulin.

In the clinical development programs for these combination agents, different titration regimens were used. However, the 2 products are both titrated as a basal insulin. When titrated gradually (table), gastrointestinal adverse effects may be minimized or avoided. No head-to-head trials of these 2 agents have been done, and comparisons between outcomes should not be made because of different study designs, interventions, definitions, and patient populations.

Patients to consider for using one of these combination products to intensify therapy include those who did not reach their A1C target with either component alone. The combination targets both fasting and postprandial blood sugar values and, in clinical trials, led to more patients achieving A1C goals. The fixed-dose combination decreases the number of injections daily; minimizes hypoglycemia risk and weight gain; and, more important, makes pharmacologic sense. This availability may also potentially increase adherence, though insurance coverage is not well known.

Drs. Patel and Goldman are both professors of pharmacy practice at Massachusetts College of Pharmacy and Health Sciences School of Pharmacy, in Boston.

References

• American Diabetes Association. Standards of medical care in diabetes—2017. Diabetes Care. 2017;40(suppl 1):4-5. doi:10.2337/dc17-S003.
• Eng C, Kramer CK, Zinman B, Retnakaran R. Glucagon-like peptide-1 receptor agonist and basal insulin combination treatment for the management of type 2 diabetes: a systematic review and meta-analysis. Lancet. 2014 20;384(9961):2228-2234. doi: 10.1016/S0140-6736(14)61335-0.
• Berlie H, Hurren KM, Pinelli NR. Glucagon-like peptide-1 receptor agonists as add-on therapy to basal insulin in patients with type 2 diabetes: a systematic review. Diabetes Metab Syndr Obes. 2012;5:165-174. doi: 10.2147/DMSO.S27528.
• Garber AJ. Abrahamson MJ, Barzilay JI, et al. Consensus statement by the American Association of Clinical Endocrinologists and American College of Endocrinology on the comprehensive type 2 diabetes management algorithm—2016 executive summary. Endocr Pract. 2016;22(1):84-113. doi: 10.4158/EP151126.CS.
• Inzucchi SE, Bergenstal RM, Buse JB, et al. Management of hyperglycemia in type 2 diabetes, 2015: a patient-centered approach: update to a position statement of the American Diabetes Association and the European Association for the Study of Diabetes. Diabetes Care. 2015;38(1):140-149. doi: 10.2337/dc14-2441.
• Marso SP, Daniels GH, Brown-Frandsen K, et al. Liraglutide and cardiovascular outcomes in type 2 diabetes. N Engl J Med. 2016;375(4):311-322. doi: 10.1056/NEJMoa1603827.
• Soliqua [prescribing information]. Bridgewater, NJ: Sanofi-Aventis U.S. LLC; 2016.
• Sanofi receives FDA approval of Soliqua 100/33 for the treatment of adults with type 2 diabetes. [news release]. Paris, France: Sanofi; November 21, 2016. news.sanofi.us/2016-11-21-Sanofi-Receives-FDA-Approval-of-Soliqua-100-33-for-the-Treatment-of-Adults-with-Type-2-Diabetes. Accessed March 13, 2017.
• Novo Nordisk receives FDA approval for Xultophy 100/3.6 (insulin degludec and liraglutide injection) [news release]. Plainsboro, NJ: Novo Nordisk; November 21, 2016. press.novonordisk-us.com/2016-11-21-Novo-Nordisk-Receives-FDA-Approval-for-Xultophy-100-3-6-insulin-degludec-and-liraglutide-injection. Accessed March 13, 2017.
• Meier JJ, Rosenstock J, Hincelin-Méry A, et al. Contrasting effects of lixisenatide and liraglutide on postprandial glycemic control, gastric emptying, and safety parameters in patients with type 2 diabetes on optimized insulin glargine with or without metformin: a randomized, open-label trial. Diabetes Care. 2015;38(7):1263-1273. doi: 10.2337/dc14-1984.