A Potential Game-Changer in Type 2 Diabetes: GLP-1 Agonist/ Basal Insulin Combinations?
By Emily Regier
Twitter summary: The scoop on GLP-1 agonist/basal insulin combos – how they work, why we’re so excited about them, and what’s on the horizon
Short summary: GLP-1 agonist/basal insulin combinations are some of the most exciting new treatments in development for type 2 diabetes. We discuss why these two drug classes are such a good match, what we’ve learned from clinical trials so far, and when the combination should be available for patients.
What are GLP-1 agonist/basal insulin fixed-dose combinations?
GLP-1 agonist/basal insulin combinations bring two drug classes together into a single injection device for people with type 2 diabetes. On their own, GLP-1 agonists like Victoza (liraglutide), Byetta/Bydureon (exenatide), Trulicity (dulaglutide), and Tanzeum (albiglutide) are effective at lowering blood sugar (average drop in A1c of ~1%) and often lead to weight loss. They also pose a low risk of hypoglycemia. The main downside is that nausea is a common side effect, especially at the beginning of treatment. On the other hand, long acting (basal) insulins are the most effective at lowering blood glucose, but they carry a much higher risk of weight gain and hypoglycemia.
Why combine them?
The goal of combining the two drugs is to maximize the benefits and minimize the side effects of each. Both GLP-1 agonists and basal insulin lead to impressive A1c reductions on their own, but they each have their limits. In particular, injecting insulin can come with the accompanied risk of hypoglycemia. But combining basal insulin with a GLP-1 agonist leads to less hypoglycemia and therefore the opportunity for larger improvements in glucose control with less fear of hypoglycemia.
In addition, with GLP-1 agonist/basal insulin combinations, the weight loss seen with GLP-1 agonists should offset the weight gain that is common with basal insulin. Meanwhile, patients typically experience less nausea with the combination, since the GLP-1 dose can be lower. Finally, a combination product offers the convenience of one daily injection rather than two.
To help explain the benefits and drawbacks of combining these two drugs, we’ve created the following table:
When will they be available?
Novo Nordisk’s Xultophy (insulin degludec/liraglutide; previously known as IDegLira) was approved in Europe in September 2014 and is launching there in the first half of this year (starting with Switzerland). Xultophy’s progress in the US is significantly delayed because the Food and Drug Administration (FDA) asked for more safety data on its basal insulin component, Tresiba (insulin degludec). Xultophy cannot be submitted to the FDA until Tresiba is resubmitted – this could potentially happen in mid-2015.
The other product on the horizon is Sanofi’s LixiLan, a combination of Lyxumia (lixisenatide) and Lantus (insulin glargine), which should be submitted for approval by the end of 2015. If the FDA review process takes about one year, both drugs (Xultophy and LixiLan) would be available in the US in mid-to-late 2016 at the earliest.
Will they live up to the hype?
There has been a lot of excitement about these combinations – one attendee at this fall’s European Association of the Study of Diabetes conference even described them as “miraculous.” Xultophy has had impressive clinical trial results: in one recent phase 3 study, the combination led to an average A1c drop of 1.8% after one year vs. 1.4% with Tresiba alone (the insulin component) and 1.2% with Victoza alone (the GLP-1 component). Xultophy was also associated with a 37% reduction in hypoglycemia compared to Tresiba despite the fact that the A1c was substantially lower. Additionally, Xultophy led to a mean weight loss of 0.4 kg (about one pound), compared to an average weight gain of 2.3 kg (about five pounds) with Tresiba. Xultophy also led to significantly lower rates of nausea and other gastrointestinal side effects compared to Victoza. Tresiba and Victoza are strong therapies in their own right, but combining them appears to have clear benefits.
LixiLan has also looked promising in phase 2 trials: in one recent study, the drug led to an average A1c reduction of 1.8% (slightly greater than the 1.6% seen with Lantus alone) along with reductions in post-meal blood sugars, no increase in hypoglycemia, and low rates of gastrointestinal side effects. Results from two ongoing major for LixiLan are expected this year.
How much will they cost?
At the moment, it is not clear how expensive these combinations will be. If they are priced according to the sum of their parts (adding the cost of the GLP-1 agonist to the cost of the basal insulin), the cost could be high, although in the US, people who would otherwise be taking both drugs separately could save money by only having to pay only one co-pay. A lot will depend on how well the products are covered by insurance and whether the companies will offer savings programs similar to those for other recently approved drugs (including all three available SGLT-2 inhibitors and Lilly’s new GLP-1 agonist Trulicity [dulaglutide]). But given the very strong trial data, it seems likely that insurance coverage will be favorable.
Who might benefit from GLP-1 agonist/basal insulin combinations?
These drugs are intended for type 2 patients who are not reaching their A1c goals. The combination of a GLP-1 and a basal insulin brings strong efficacy and more mild side effects than the individual components. And let’s not forget that they avoid the weight gain of insulin. That should make it an appealing option for a wide range of people with type 2 diabetes.