Diabetes Forecast

Pros and Cons of Type 2 Combination Injectable Drugs

By Allison Tsai , , ,

Illustration by Haleigh Eason/Mittera

In the spring of 2017, Gregory French, 53, was at a crossroads with his diabetes management. Oral medication was no longer enough to curb his daily blood glucose highs, and his A1C was creeping up. Typically, the next step would be to add long-acting insulin or a glucagon-like peptide-1 (GLP-1) receptor agonist to the regimen, but French was struggling with high blood glucose in the morning and after meals. To address both of these concerns at once, his doctor made an unexpected choice: He prescribed a combination pen.

Such medications bring together a long-acting insulin and a GLP-1 receptor agonist in a single injectable pen. They include Xultophy, a mix of insulin degludec and liraglutide, and Soliqua, a mix of insulin glargine and lixisenatide.

For French, who has type 2 diabetes, the combination helped address his fasting glucose and his post-meal highs. “I’ve seen my blood glucose drop 50 or 60 points on average,” he says.

While the combination pen is working for French, these drugs are expensive and may not be the right choice for everyone. Here’s what you need to know about combination injectables in order to make the best decision for your diabetes management.

The Players

Separately, insulin and GLP-1s are effective treatments for type 2 diabetes. “Individually, [they] are arguably the two most powerful classes of diabetes drugs that we have,” says John Buse, MD, professor of medicine and chief of the Division of Endocrinology at the University of North Carolina School of Medicine. He’s an investigative consultant for Novo Nordisk (which produces Xultophy) and Sanofi (which makes Soliqua).

But research suggests the drugs might be at their best when working together. For starters, using the combo drug cuts down on the number of injections you need to take. But more important, each may limit the side effects of the other because each drug can be used at lower doses than if used alone, says Anne Peters, MD, director of the Clinical Diabetes Program at the Keck School of Medicine of the University of Southern California and a consultant for the combination drugs’ manufacturers.

Separate Action

Insulin and GLP-1 receptor agonists work in different ways to lower blood glucose. Long-acting insulin is the best drug for lowering fasting glucose levels. But any injected insulin comes with a risk for low blood glucose (hypoglycemia) and weight gain. And sometimes basal insulin alone may not be enough to manage high blood glucose. In that case, GLP-1 may be added to the diabetes treatment plan.

GLP-1 is secreted from the intestine and works in several ways:

  • It stimulates the pancreas to make more insulin.
  • It signals the pancreas to decrease the production of glucagon, a hormone that causes the liver to release stored glucose into the bloodstream.
  • It slows the progress of food in the gastrointestinal tract, which curbs the post-meal rise in blood glucose.
  • It may decrease appetite and promote weight loss.

In people with type 2 diabetes, however, this GLP-1 secretion is blunted. Which is where GLP-1 receptor agonists come in. “[Scientists] were able to identify these substances and then re-create them so that they could be a useful treatment for diabetes,” says Evan Sisson, PharmD, MSHA, CDE, FAADE, an associate professor at Virginia Commonwealth University School of Pharmacy and a spokesperson for the American Association of Diabetes Educators.

A major benefit of GLP-1s is that they stimulate insulin production only in the presence of higher-than-normal blood glucose levels. When blood glucose falls into the normal or low range, they stop telling the body to make insulin, which means they are unlikely to cause hypoglycemia. 

The benefits come with some side effects, though: Because they slow stomach emptying, the medications can lead to nausea and upset stomach. These side effects are usually short-lived, and only a small percentage of people need to stop taking the medication because of them.

Team Effort

Clinical trials have shown that when people take both basal insulin and a GLP-1, their A1C is better than when either drug is taken alone. Study participants who used both drugs experienced less hypoglycemia and weight gain than those on only basal insulin, and they had fewer gastrointestinal side effects than their peers injecting only a GLP-1 receptor agonist. “When you’re [taking] the two together, you tend to go up more slowly on the dose,” says Peters. Those smaller, gradual increases in dose minimize side effects, including stomach issues.

If you are already taking basal insulin but your after-meal glucose levels are too high, you have several options, including: Add mealtime (rapid-acting) insulin or add a GLP-1. Sisson says adding a GLP-1 may be the better option. “A GLP-1 will help the pancreas make more insulin around mealtime and bring down those post-meal sugars,” he says. This simplifies treatment for people who may have trouble counting carbohydrates to match fast-acting insulin at meals.

Serious Snags

The benefits of long-acting insulin and GLP-1s may lessen when both drugs are combined into a single injection pen. “Insulin plus a GLP-1 receptor agonist can be a very effective combination,” says Paris Roach, MD, associate professor of clinical medicine in the Division of Endocrinology and Metabolism at Indiana University School of Medicine in Indianapolis and editor in chief of Diabetes Forecast. But if you’re talking about a two-in-one pen, Roach says the simplicity of a single injection may be the only plus among several major drawbacks.

One big concern is in the fixed ratio of the combination. That means the amount of insulin to GLP-1 is set—you can’t increase one without the other. “Most prescribers are going to want to use the maximum dose of the GLP-1, but because of the fixed-ratio combination, the maximum dose for GLP-1 is only going to be delivered when the maximum dose of insulin, 50 units for either product, is selected,” Roach says. “If a person takes less than 50 units of insulin, they’re taking less than the optimal dose of the GLP-1.” Using separate insulin and GLP-1 injections, you can better fine-tune your dose of each medication.

The GLP-1 liraglutide can benefit heart health in people with cardiovascular disease, but studies on this looked at only higher doses of the GLP-1. It’s unclear whether lower doses would be effective. Because of that, dosing the drugs individually may be better for your heart. “It may be ideal to take as much GLP-1 receptor agonist as you can tolerate and then as little insulin as you need to get to your target,” says Buse.

Unexpected highs may also be a problem. To begin the combination medication, you’ll start at a low dose and gradually increase, which seems to minimize the gastrointestinal effects of the GLP-1 receptor agonist, says Sisson. If you now take a high dose of long-acting insulin, the starting dose of the combo will not be enough insulin for you, and you may see your blood glucose increase for a period of time. Adjustments to the dose of the combo can take up to a few months.

The Bottom Line

Whether you’re intrigued by the convenience of taking two diabetes drugs with one injection or concerned that these pens don’t offer enough precision for your blood glucose management, it warrants a discussion with your doctor. On the other hand, if your A1C is in target range and you’re doing well with your medications, Peters says, “Don’t mess with success.”

Cost Consideration

While your insurance may cover these combo injectables, retail costs are high. According to a search on GoodRx, a website and app that gathers drug prices from local pharmacies, per box of five (3-milliliter) pens, Soliqua costs about $700 and Xultophy runs about $1,000. Boxes typically last about a month (for a 50-unit daily dose).

Call your insurance company prior to filling your prescription to see if you have coverage for and can afford these drugs, says Anne Peters, MD, director of the Clinical Diabetes Program at the Keck School of Medicine of the University of Southern California. There are discount cards and assistance programs available through Novo Nordisk, which makes Xultophy, and Sanofi, which makes Soliqua. Your pharmacist or diabetes educator can help you navigate those options.



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