Exciting Recommendation from FDA Panel to Approve Basal Insulin/GLP-1 Combinations

Why Novo Nordisk and Sanofi’s combination drugs are potential gamechangers for type 2 diabetes. 

In a major win for people with type 2 diabetes, an advisory panel recently recommended that the FDA approve Novo Nordisk’s and Sanofi’s basal insulin/GLP-1 agonist combination drugs. The positive votes make it far more likely that the FDA will approve the once-daily injectable drugs this year.

The drugs discussed in the back-to-back advisory committee meetings were Novo Nordisk’s insulin degludec/liraglutide (called Xultophy outside the US) and Sanofi’s insulin glargine/lixisenatide (“LixiLan”). Based on tremendously stirring clinical trial results, Xultophy and LixiLan offer the potential for larger A1c reductions (nearly 2.0%) less negative side effects from insulin (hypoglycemia, weight gain), and less nausea from GLP-1 agonists. For patients, these drugs will come in a single injection and require only one co-pay, which should make them easier to access and take.

The meeting for Novo Nordisk’s Xultophy ended with a 16-0 vote in favor of approval of the drug, and Sanofi’s meeting ended with a 12-2 vote in favor of approval of LixiLan. While an FDA advisory panel does not approve drugs itself, it is common for the FDA to follow the recommendation of its advisory panels, meaning approval of both drugs could come later this year. diaTribe’s Editor in Chief, Kelly Close, spoke at the open hearing portions of the meetings in support of these drugs; read a summary of her comments at the end of this article! 

Based on their existing clinical trial results, Xultophy and LixiLan have clinical benefits of a reduced A1c (up to almost 2.0%), less weight gain, and less hypoglycemia than basal insulin:

Based on these clinical trials, Xultophy does better against Lantus than LixiLan in terms of A1c reduction and weight, but one of the main differences between the two drugs is that the GLP-1 agonist in LixiLan is short-acting; short-acting GLP-1 agonists generally have stronger effects on post-meal glucose for the first meal taken after the injection, which could provide an advantage for some patients with lower A1cs wishing to control blood sugars after meals. Xultophy has already been on the market in Europe for about a year, and LixiLan was just submitted in Europe earlier this year. It's important to keep in mind that these studies aren't directly comparable to each other as they were designed and conducted differently, and that they are designed to stand alone in their comparisons to just basal insulin.

What were the main points discussed at the advisory committee meetings?

While the panel voted in favor of recommending approval of these drugs, there were a few points of discussion. For Novo Nordisk’s Xultophy, these points mostly centered on dosing considerations and the target patient population for this combination. For Sanofi’s LixiLan, the panel’s main concerns were regarding its packaging and delivery.

Xultophy

The FDA raised concerns about whether people with low insulin-requirements – and therefore taking low doses of Xultophy – would experience the side effects of liraglutide without the glycemic benefits. Many panelists felt that the combination should only be used in patients already on a GLP-1 agonist, a basal insulin, or both.

LixiLan

LixiLan differs from Xultophy in that it has two dose options, differentiated by two delivery pens. Panelists raised concerns regarding the potential for patients to confuse the two pens, leading to potential dosing errors, though the pens are colored differently. Additionally, while the pens accurately label the number of insulin units in a given injection, the number of units of lixisenatide is not labeled. Panelists worried that this could also lead to dosing errors.

Despite these concerns, panelists acknowledged that the single injection aspect of the combination is significant and could encourage greater patient acceptance than attempting to start two separate injections. The vote bodes well for patients, especially if FDA approves these drugs for all people with type 2 diabetes (and not just those already taking either basal insulin or a GLP-1 agonist). If these drugs are also approved as a first injectable treatment (like insulin or GLP-1 are today), earlier use of a combination product represents a more aggressive approach that could potentially slow down the overall progression of diabetes .

Open Public Hearing Commentary

The presentations at the Open Public Hearing emphatically endorsed these combination drugs. Patients, providers, and patient advocates discussed the challenges of daily diabetes management and the insulin/GLP-1 combination drugs’ potential to improve outcomes by reducing the number of missed shots. diaTribe founder and Editor in Chief Kelly Close provided compelling commentary on the potential for Xultophy and LixiLan to improve the lives of people with diabetes and their healthcare providers through its simple, patient-centered design. 

Kelly emphasized the value of drugs that fit into patients’ lives and providers’ workflow, emphasizing her belief that these drugs have a better chance than the current options. She also urged panelists to consider the impact of drugs on quality of life  - “Randomized controlled trials are so valuable, but from a patient perspective we want to know what real life will be like.” She noted that these drugs’ promise of less hypoglycemia, less worry about hypoglycemia, and less weight gain can improve quality of life and make it easier for patients to take the next step in their diabetes management successfully. In addition, Kelly expressed the importance of access, stating that although access is not exactly the realm of the FDA, if drugs are approved but not covered, they might as well not be approved. She said that even savings from two co-pays to one could make a meaningful difference for some patients. If Xultophy and LixiLan are approved and affordable, it can help achieve what we all want for patients: better health and a better quality of life.

We’ll report back with the FDA’s decision on these combination drugs later this year!

Appendix: What are basal insulin/GLP-1 agonist fixed-dose combination drugs?

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 higher risk of weight gain and hypoglycemia.

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 while maintaining reductions in A1c – so treatment can be a little more aggressive. 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 than normal. Finally, a combination product offers the convenience of one daily injection rather than two. Read our previous coverage of these drugs here. –NK/ER