7th March 2022, Dr Chee L Khoo
We are all familiar with various fixed dose combination of glucose lowering agents. We have DDP4 inhibitors + metformin, SGLT2 inhibitors + Metformin and SGLT2 inhibitors + DPP4 inhibitors. We also have combination insulins for some time – rapid acting insulin + long acting insulin (so-called pre-mix or co-formulations). Pharmacologically, they make sense as these combined agents either work via different mechanisms or have different pharmacokinetics. They are also convenient in administration and cheaper for patients. Daily or twice daily GLP1 agonists seems to have given way to the more convenient weekly GLP1 agonists but the daily GLP1 agonists have fought back. Basal insulin + daily GLP1 agonists have been approved by the US FDA for the management of patients with type 2 diabetes (T2D). We might see these agents coming our way.
LixiLan-L trial ()
Patients with T2D who, despite being on a basal insulin (glargine U100, NPH or determir insulins), continued to have fasting glucose >10 mmol/L were randomised to either continued basal insulin (glargine U100) or LixiLan (2U glargine + 1 µg lixisenatide or 3U glargine + 1 µg lixisenatide). HbA1c at baseline was 8.5% +/- 0.7.
After 30 weeks, LixiLan was more effective in achieving meaningful improvements in glycaemic control than glargine U100 alone, reaching a final mean HbA1c of 6.9% (52 mmol/mol) for iGlarLixi, with beneficial effects on body weight and without increasing hypoglycemia risk.
DUAL V & DUAL VII ()
What about IDegLira? In DUAL V, patients with T2D who were inadequately managed on basal insulin (glargine U100) were randomised to either continued uptitration with basal insulin or transition to IDegLira (starting dose of 16U Degludec/0.58 mg Liraglutide). Both groups were titrated twice weekly in 2 unit increments. In DUAL VII, patients who were inadequately controlled on basal insulin (glargine U100) were uptitrated to either a basal-bolus regimen (glargine U100 + insulin aspart) or transition to IDegLira with a similar starting dose.
In both trials, IDegLira participants experienced weight loss vs. weight gain, lower rates of hypoglycaemia and a lower mean end of trial total daily insulin dose.
The above trial results were not surprising. Patients who are initiated on basal insulin eventually will need treatment of their prandial hyperglycaemia. Continued uptitration with more basal insulins will not get the patient to glycaemic target. At some point in time, we will need to manage the prandial hyperglycaemia.
You can either add a rapid acting prandial insulin to the basal insulin (basal-bolus regimen) which is the traditional way of getting patients to target. But you can add a GLP1 agonist to the basal insulin regimen. Under the PBS, you could add a short acting GLP1 agonist like exenatide or a weekly GLP1 agonist like dulaglutide or semaglutide).
The many ways of using insulin
International and Australian guidelines for the management of hyperglycaemia suggest that we should consider a GLP1 agonist if we are thinking about initiating insulin in patients who has not achieve their glycaemic targets. It is not a matter of one or the other agent. Not uncommonly, we may need to commence insulin if GLP1 agonist doesn’t get the patient to target.
For patients who are already on a basal (or mix) insulin, it is not uncommon that we have to add a GLP1 agonist to assist these patients in getting to glycaemic target. Adding a GLP1 agonist to insulin instead of a prandial (rapid) insulin helps to reduce the incidence of hypoglycaemia and negate the potential weight gain from insulin therapy.
The addition of a GLP1 agonist not only helps patients to target, it also address the insulin resistance and sometimes, get patients off their insulin. At the very least, an addition of a GLP1 agonist often reduce the patients’ insulin dose.
Thus, you can see that insulin and GLP1 agonists work well together. It then make sense to combine them in one device. Titratable fixed-ratio combinations (FRCs) of a basal insulin and a glucagon-like peptide-1 (GLP-1) receptor agonist are new therapeutic options for people with type 2 diabetes. Two FRCs— insulin glargine/lixisenatide (iGlarLixi) and insulin degludec/liraglutide (IDegLira) — are approved for use in the United States. iGlarLixi, a once-daily titratable FRC of basal insulin glargine 100 U/mL (iGlar) plus lixisenatide (Lixi) and IDegLira, a once-daily titratable FRC of insulin degludec (IDeg) plus liraglutide (Lira).
In the meantime…
Unfortunately, we don’t have lixisenatide nor insulin degludec in Australia. (Insulin degludec is approved for use in Australia as a co-formulation with insulin aspart, Ryzodeg). When we do, it would make sense to combine both agents (insulin + GLP1 agonist) in one pen and get our patients to glycaemic target with less weight gain (maybe even weight loss) using a lower dose of insulin without an increase in hypoglycaemia.
In the meantime, adding a weekly GLP1 agonist to your patient on insulin is recommended. Of course, both the weekly GLP1 agonist have cardiovascular and renal benefits.
Vanita R. Aroda, Julio Rosenstock, Carol Wysham, 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 1 November 2016; 39 (11): 1972–1980. https://doi.org/10.2337/dc16-1495
DUAL: Meneghini L, Doshi A, Gouet D, Vilsbøll T, Begtrup K, Őrsy P, Ranthe MF, Lingvay I. Insulin degludec/liraglutide (IDegLira) maintains glycaemic control and improves clinical outcomes, regardless of pre-trial insulin dose, in people with type 2 diabetes that is uncontrolled on basal insulin. Diabet Med. 2020 Feb;37(2):267-276. doi: 10.1111/dme.14178.