5 Benefits of Combining Insulin and GLP-1 Drugs

What if there was a way to get the benefits of both insulin and a GLP-1 receptor agonist without experiencing side effects? 

Basal insulin and GLP-1 combinations, or fixed-ratio combination drugs, promise to do just that: maximize the benefits and minimize the side effects someone might experience taking each drug separately. Currently, there are two options available in the U.S.: 

• Xultophy (iDegLira), a once-daily injection that combines Tresiba (insulin degludec, a basal insulin) with Victoza (liraglutide)
• Soliqua (iGlarLixi), a once-daily injection that combines Lantus (insulin glargine, a basal insulin) with Adlyxin (lixisenatide)

At the 2024 American Diabetes Association conference, Dr. Liana Billings, an endocrinologist at Endeavor Health NorthShore Hospitals in Illinois, highlighted the potential of these drugs for people with type 2 diabetes.

Benefits of combining basal insulin and GLP-1s

Each of these drugs on its own has advantages and limitations. But combined, Billings emphasized that insulin and GLP-1 agonists have complementary effects. 

Basal insulin is highly effective in reducing blood glucose, especially overnight. However, insulin can also cause hypoglycemia (low blood sugar) and often leads to modest weight gain. There are several reasons why insulin can cause you to gain weight: 

• Insulin is a growth hormone. When growth hormones are taken as medication, they tend to make you feel hungry and eat more than your body needs, and this can cause weight gain. 
• When you start taking insulin, your body is able to absorb sugar again. If you consume more food than your body needs, the extra sugar is converted into fat. 
• Before a diabetes diagnosis, many people experience weight loss as a symptom of untreated diabetes. When you start taking insulin, you may regain some of the weight you lost before your diabetes diagnosis. 

Meanwhile, GLP-1s such as Ozempic (semaglutide) and Trulicity (dulaglutide) are very effective at managing post-meal blood sugars, have a low risk of hypoglycemia, and help with weight loss. However, these medications can cause gastrointestinal side effects such as nausea and vomiting. 

When combined into one injection, insulin and a GLP-1 offer a range of benefits while reducing the undesirable side effects of each drug alone. 

1. Less nausea and vomiting 

Nausea is a common side effect of GLP-1s, affecting around 10-25% of participants in clinical trials. Fear of nausea and vomiting is real, Billings said, and can impact how closely people follow their treatment. For instance, Billings cited research on cancer treatments showing that people may consider delaying future treatment or stopping potentially lifesaving treatment due to nausea. 

Fortunately, fixed-ratio combination drugs appear to reduce nausea rates by about 50%. In a large clinical trial for Soliqua, 20% of participants taking Adlyxin alone experienced nausea, compared to 9% of those taking Soliqua. 

Similarly, 8% of participants taking Adlyxin alone experienced vomiting, compared to 4% of those on Soliqua. For these reasons, Billings called fixed ratio combinations “the ideal therapy if you are trying to limit side effects of nausea and vomiting.” 

Starting a GLP-1 tends to cause more nausea and vomiting in the first few weeks. Billings noted that basal insulin and GLP-1 combinations led to low rates of these side effects throughout clinical trials.

2. Lower risk of weight gain

Many people experience weight gain when starting insulin treatment. Taking a fixed-ratio combination drug leads to a lower risk of weight gain, thanks to the action of GLP-1s. 

Generally, Xultophy and Soliqua are considered weight neutral, meaning they cause neither weight loss nor weight gain. The weight gain from the insulin and the weight loss from the GLP-1 essentially cancel each other out. 

In clinical trials, insulin and GLP-1 fixed ratio combinations also showed the potential to reduce a person’s daily insulin dose. In the DUAL I trial, participants taking Xultophy required a lower average of 39 units of insulin per day, compared to 62 units for those on Tresiba alone. 

Taking less insulin also helps prevent weight gain. Insulin tends to cause fluid retention (edema), a type of swelling that occurs when the body is unable to remove extra fluids. In extreme cases, edema can cause considerable weight gain. 

3. Makes dosing easier

Part of taking insulin is adjusting it to meet daily glucose needs. This may involve adjusting both basal insulin and mealtime insulins or taking additional medications like metformin, SGLT-2 inhibitors, or GLP-1s. 

Compared to basal-bolus insulin therapy, insulin/GLP-1 drugs offer a simple and safe approach to managing titration, Billings said. 

In a trial comparing Xultophy to basal-bolus therapy, participants were much more likely to improve glycemic control with Xultophy. For instance, in the DUAL VII study, 35% of those taking Xultophy achieved an A1C below 7% without hypoglycemia or weight gain, compared to only 5% of participants using basal-bolus insulin. 

Billings also noted that taking an insulin/GLP-1 drug may involve just one copay, whereas taking insulin and other diabetes medications separately involves at least two copays. For those on Medicare, Xultophy and Soliqua are included in the $35 per month insulin plan under the Inflation Reduction Act. 

4. Fewer injections 

Compared to basal-bolus therapy, taking an insulin/GLP-1 combination drug substantially reduces the number of daily insulin injections you need. 

Billings calculated that basal-bolus insulin therapy can require up to 1,460 injections per year – four injections per day times 365 days a year. For those who use fingerstick measurements to check blood sugar, the total number of injections could be even higher. Meanwhile, people taking Xultophy or Soliqua would have about 365 injections per year. 

Fewer insulin injections mean greater convenience and less complexity for people with diabetes, healthcare providers, and caregivers. Future research into once-weekly insulins could reduce this number even further. 

5. Heart and kidney protection

While clinical trials have yet to study the long-term benefits of Soliqua and Xultophy, research suggests that GLP-1s on their own can help protect the heart and kidneys. 

In the LEADER trial, Victoza significantly reduced the risk of heart attacks, stroke, or death due to heart problems by 13%. Most recently, results from the FLOW trial found that the GLP-1 Ozempic can slow the progression of kidney disease and reduce the risk of death from kidney or cardiovascular events. 

It’s likely that the benefits of GLP-1s may translate to fixed-ratio combinations. New benefits from GLP-1s continue to be uncovered each day, so it’s also possible that basal insulin/GLP-1 combinations could deliver additional positive effects. 

What’s in development? 

In addition to Xultophy and Soliqua, there is a new fixed-ratio combination drug on the horizon. Novo Nordisk is developing IcoSema as a once-weekly combination of insulin icodec and semaglutide for people with type 2 diabetes. IcoSema could be a true game-changer, as it would further reduce the number of injections to just 52 per year. 

The latest data found that IcoSema led to similar A1C reductions and greater weight loss compared to daily basal-bolus insulin. The one-year trial included 679 people with type 2 diabetes who were unable to achieve glycemic targets on daily basal insulin. IcoSema led to an A1C reduction of 1.47%, while basal-bolus insulin led to a reduction of 1.40%. 

Two additional studies are expected to be completed later this year: one comparing IcoSema to weekly insulin icodec and the other comparing IcoSema to Ozempic (semaglutide 1 mg) – stay tuned. 

The bottom line

Basal insulin and GLP-1 combinations like Xultophy and Soliqua can be a great option for managing type 2 diabetes. These fixed ratio combination drugs allow you to get “the best of both worlds,” Billings said. That is, they are effective at reducing A1C with a low risk of hypoglycemia – and fewer side effects. 

If you are struggling with side effects from GLP-1s or are not able to reach your glycemic goals, you may want to consider speaking with a healthcare provider about a fixed-ratio combination drug like Xultophy or Soliqua and whether it could be a fit for you. 

Learn more about the latest insulins: 

• On the Horizon – a Weekly Insulin, Oral Insulin, Smart Insulin, and Biosimilars
• Does This Insulin Make Me Look Fat?
• What to Know About Shortages for Humalog and Insulin Lispro Injection