Fixed-ratio combination insulin–GLP1 RA products for type 2 diabetes

Many people with type 2 diabetes do not reach their blood glucose targets, leaving them at risk for micro- and macrovascular complications.(1,2) Type 2 diabetes is a progressive disease that requires treatment intensification over time. Clinical inertia is common in people with diabetes.(3) This means that despite clear and evidence-based guidance to aim for achieving a target glycated hemoglobin (A1C) level within three to six months of diagnosis, the target A1C may not be achieved by many people. When A1C is more than 1.5% over the patient’s individualized target, the Diabetes Canada guidelines recommend beginning with metformin and then considering additional agents based on several considerations.(4) Many individuals will eventually require insulin therapy to help achieve and maintain adequate glycemic control and basal insulin is usually the first type of insulin used. Basal insulin, however, is limited in that it doesn’t address postprandial glucose levels and, therefore, preprandial bolus insulin is often required. Intensification with basal–bolus regimens is more complex and requires more injections compared to basal insulin alone. The risk of hypoglycemia and associated weight gain have also often led patients to refuse intensification with basal–bolus regimens.(5) Combining basal insulin with a glucagon-like peptide-1 receptor agonist (GLP1 RA) in a fixed ratio combination (FRC) for the treatment of patients with type 2 diabetes has been demonstrated to be effective and well-tolerated, while mitigating many of the adverse events associated with giving either of these drug classes alone.(6) Which FRC products are currently available in Canada? Table 1 summarizes the current insulin–GLP1 RA combinations marketed in Canada. Some provincial drug plans and several private payers cover the cost of these combination products. What are the current indications for FRC insulin–GLP1 RA products? Xultophy is indicated in Canada for once-daily use, as an adjunct to diet and exercise and in combination with oral medicinal products for the treatment of diabetes, to improve glycemic control in adults with type 2 diabetes.(7) Xultophy can be administered independent of meals, at any time of day, but preferably at the same time each day.(7) Soliqua is indicated in combination with metformin as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes inadequately controlled on: basal insulin (< 60 units daily) alone or in combination with metformin a GLP1 RA in combination with metformin.(8) Soliqua should be administered subcutaneously once daily within one hour before the first meal(8) What are the recommended starting doses for FRC insulin–GLP1 RA products? The starting dose of an FRC is determined by the recommended initiation dose of the GLP1 RA component (0.6 mg/day liraglutide; 5 µg or 10 µg/day lixisenatide) to reduce the incidence of adverse gastrointestinal side effects, particularly nausea. This GLP1 RA starting dose could potentially mean that the patient will receive a lower insulin dose compared to their previous baseline insulin dose. However, various studies have demonstrated that glycemic control does not decline significantly due to the introduction of a GLP1 RA, combined with the prescribed titration of the FRC to fasting glucose targets.(9-11) The recommended starting dose of Xultophy in patients naïve to basal insulin or a GLP1 RA is 10 units (10 units of insulin degludec and 0.36 mg of liraglutide) given subcutaneously once daily.(7) What are the benefits of FRC insulin–GLP1 RA products? The main advantages of FRCs compared to basal–bolus insulin regimens include: improved glycemic control with reduced A1C, as well as reduced hypoglycemia and decreased weight gain (compared to basal insulin or basal–bolus regimens)(12-14) simultaneous administration of two medications in one injection, which simplifies treatment intensification and medication administration, thereby promoting adherence(15) reduced incidence of gastrointestinal side effects, due to a slower titration of the dose, compared to GLP1 RAs alone(16) reduced need for blood glucose monitoring compared to multiple daily injection regimens. What are the limitations of FRC insulin–GLP1 RA products? FRCs may not be suitable for all patients, for example, those who need a different basal insulin to GLP1 RA ratio than what is provided in FRC products. There are limits to the maximum allowable insulin dose (50 units for iDegLira and 60 units for iGlarLixi). To help deal with patients who require a higher insulin dose, there are a few clinical approaches; however, none have been supported with a randomized clinical trial. One option is to abandon the combination and change to separate daily basal insulin and daily or weekly GLP1 RA therapy to increase flexibility. Another option would be to add a separate daily basal insulin to the maximal FRC dose (this would be an off-label use). Another recommendation would be to optimize other therapies, including diet, lifestyle and other antihyperglycemic medications. Sick day management poses another challenge as GLP1 RA medications may be recommended to be held when there is a gastrointestinal illness, while insulin may require titration and increased monitoring when oral intake is unpredictable. It is a good idea to recommend that your patients using an FRC have a backup prescription for the corresponding basal insulin in case the FRC is stopped temporarily. There is also a risk of medication errors, as patients may forget to discontinue their previous treatment, which may be duplicated in the combination product. Particular care should be given to counselling patients about stopping any monotherapy duplicate prior to initiating treatment with a combination product. Summary With the increasing use of potent injectable agents, such as insulin and GLP1 RAs, improvements are warranted in the timing and approach of their initiation and intensification to optimize and sustain glycemic control. FRC insulin–GLP1 RA therapies, with their complementary mechanisms of action, provide this opportunity, with the inherent advantage of increased patient adherence and reduced gastrointestinal side effects. Having an open dialogue with those who are not meeting their blood glucose targets may provide important insights into helping them achieve their goals based on a variety of factors that are most important to the patient. Have you had the discussion? Shelley Diamond, BScPhm, is a pharmacist and co-founder of www.diabetescarecommunity.ca an extensive online resource for Canadians living with diabetes, their families and healthcare professionals. References 1. Leiter LA, Berard L, Bowering CK, et al. Type 2 diabetes mellitus management in Canada: is it improving? Can J Diabetes 2013;37:82-9. 2. Nichols GA, Romo-LeTourneau V, Vupputuri S, et al. Delays in anti-hyperglycaemic therapy initiation and intensification are associated with cardiovascular events, hospitalizations for heart failure and all-cause mortality. Diabetes Obes Metab 2019;21:1551-7. 3. Andreozzi F, Candido R, Corrao S, et al. Clinical inertia is the enemy of therapeutic success in the management of diabetes and its complications: a narrative literature review. Diabetol Metab Syndr 2020;12:52. 4. Lipscombe L, Butalia S, Dasgupta K, et al. Diabetes Canada Clinical Practice Guidelines Expert Committee. Pharmacologic glycemic management of type 2 diabetes in adults: 2020 update. Can J Diabetes 2020;44:575-91. 5. Khunti K, Nikolajsen A, Thorsted BL, et al. Clinical inertia with regard to intensifying therapy in people with type 2 diabetes treated with basal insulin. Diabetes Obes Metab 2016;18:401–9. 6. Castellana M, Cignarelli A, Brescia F, et al. GLP-1 receptor agonist added to insulin versus basal-plus or basal-bolus insulin therapy in type 2 diabetes: a systematic review and meta-analysis. Diabetes Metab Res Rev 2019;35(1):e3082. 7. Novo Nordisk Canada Inc. Xultophy (insulin degludec + liraglutide injection) product monograph. Mississauga, ON; November 13, 2020. https://www.novonordisk.ca/content/dam/nncorp/ca/en/products/Xultophy%20PM%20EN_Marketed_13%20November%202020.pdf (accessed June 22, 2021). 8. Sanofi-aventis Canada Inc. Soliqua (insulin glargine and lixisenatide injection) product monograph. Laval, QC; April 30, 2021. https://pdf.hres.ca/dpd_pm/00060752.PDF (accessed June 22, 2021). 9. Price H, Blüher M, Prager R, et al. Use and effectiveness of a fixed-ratio combination of insulin degludec/liraglutide (IDegLira) in a real-world population with type 2 diabetes: Results from a European, multicentre, retrospective chart review study. Diab Obes Metab 2018;20:954-62. 10. 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;39:2026-35. 11. Aroda VR, Rosenstock J, Wysham C, 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;39:2026-35. 12. Balena R, Hensley IE, Miller S, et al. Combination therapy with GLP-1 receptor agonists and basal insulin: a systematic review of the literature. Diabetes Obes Metab 2013;15:485-502. 13. Peng XV, Ayyagari R, Lubwama R, et al. Impact of simultaneous versus sequential initiation of basal insulin and glucagon-like peptide-1 receptor agonists on HbA1C in type 2 diabetes: a retrospective observational study. Diabetes Ther 2020;11:995-1005. 14. Blonde L, Anderson JE, Chava P, et al. Rationale for a titratable fixed-ratio co-formulation of a basal insulin analog and a glucagon-like peptide 1 receptor agonist in patients with type 2 diabetes. Curr Med Res Opin 2019;35:793-804. 15. Hutchins V, Zhang B, Fleurence RL, et al. A systematic review of adherence, treatment satisfaction and costs, in fixed-dose combination regimens in type 2 diabetes. Curr Med Res Opin 2011;27:1157-68. 16. Trujillo JM, Roberts M, Dex T, et al. Low incidence of gastrointestinal adverse events over time with a fixed-ratio combination of insulin glargine and lixisenatide versus lixisenatide alone. Diabetes Obes Metab 2018;20:2690-4.