Weekly Insulin is Just Around the Corner

A once-weekly basal insulin injection for type 2 diabetes could be available as soon as next year.

One shot instead of seven shots — it seems like a no-brainer, right? Experts definitely agree. At a symposium at the recent American Diabetes Association (ADA) Scientific Sessions conference, multiple panelists used that very phrase to describe the appeal of the single weekly basal insulin shot.

Two new types of once-weekly basal insulin — Lilly’s efsitora alfa and Novo Nordisk’s icodec —are now wrapping up their last pivotal trials, and will soon apply for FDA approval. Eventually, these medicines could even become the standard of care for people with type 2 diabetes that use basal insulin.

What are the major benefits of a once-weekly basal insulin shot?

Above all, convenience. Administering one injection is far easier than seven injections.

That may initially sound like a minor advantage, but the experts at the ADA panel think that it can have big ripple effects that really help people with diabetes improve their long-term outcomes.

A once-weekly insulin could address some of the barriers to insulin introduction and use, helping patients address hyperglycemia more effectively. It could reduce treatment burden (for both patients and healthcare providers) and improve quality of life.

Juan Pablo Frias, M.D., a principal investigator at Velocity clinical research, explained that many studies of many health conditions have shown that “less frequent dosing can improve treatment adherence.” Unfortunately, many people with diabetes do not consistently take the medicines they’ve been prescribed, with predictably negative effects on glycemic control and patient outcomes.

Patients are also often reluctant to use insulin due both to the inconvenience and to discomfort with or fear of needle injections, according to a 2021 study. Knowing that their patients can be doubtful about the drug, doctors can also be reluctant to prescribe insulin when it is first medically indicated.

Both patient satisfaction surveys and anecdotal evidence seem to confirm that many people with diabetes prefer the switch to weekly injections. Chantal Mathieu, M.D., Ph.D., a Professor of Medicine at Belgium’s Katholieke Universiteit, shared that one of her patients “was extremely angry with me that she could not continue her once-weekly insulin” after a clinical trial ended.

How does weekly insulin work?

Weekly insulin has been formulated in a new way to dramatically increase its half-life, or the length of time that it is active in the body. Today’s most popular basal insulins have half-lives of around 12 hours, but the new weekly insulins will have half-lives from 8 to 17 days.

The result is actually a much smoother and more consistent activity profile. Dr. Frias demonstrated that insulin glargine (Lantus), when dosed once per day, has a peak-to-trough ratio of 1.8, meaning that at its most powerful the insulin can be about 80 percent stronger than at its least powerful. But weekly insulin provides steady glucose-lowering action for days at a time, with few significant peaks or troughs. Its peak-to-trough ratio is only 1.1.

Some patients with diabetes split their long-acting dose into two or three daily injections in order to achieve this effect, a practice that weekly insulin renders unnecessary.

Is that too much to inject at once?

If you’re struggling to imagine how you’ll comfortably inject 100 or more units of insulin at once, you should know that weekly insulin is highly concentrated. One “unit” of weekly insulin has the same glucose-lowering power as one unit of daily insulin, but it packs its medicine into significantly less volume. So, even if you inject the same number of units, you’re putting much less liquid into your body.

Is weekly insulin good for blood sugar control? 

Weekly insulin only needs to be “non-inferior” to daily insulin in order to be worthwhile, given the convenience factor. But the evidence suggests that weekly basal insulin might actually be better for blood sugar control in type 2 diabetes.

Some studies have shown that switching from daily to weekly insulin results in a modest but narrowly significant improvement in both A1C and time-in-range. Others have found that the blood sugar results were comparable. The important thing is that experts seem convinced that weekly basal insulin works.

Is once-weekly insulin riskier than daily insulin?

It seems like there might be an inherent risk to weekly insulin, given the large size of each dose, which can understandably lead to concerns about hypoglycemia.

Surveying all of the published literature, Ildiko Lingvay, MD, MPH, MSCS, concluded that there is a slightly enhanced risk of hypoglycemia, “but in absolute terms, the numbers are extremely small. The excess risk is tiny.” These hypoglycemic events are neither longer nor more severe than the hypos caused by daily basal insulin.

But what happens if you forget whether or not you’ve given yourself your weekly injection? What if you inject twice?

The developers are worried about the same thing, and they put it to the test. Lingvay, a professor at UT Southwestern Medical Center, shared the results of a trial in which investigators intentionally administered double and triple doses of insulin. This was a carefully controlled experiment in a lab; clinicians stood by ready to help anyone experiencing hypoglycemia.

Amazingly, the double and triple doses of weekly insulin were not any more dangerous than double and triple doses of daily insulin. Lingvay called the results “very reassuring.”

“You might get a low, but it’s not going to be any worse than [daily insulin].”

Does once-weekly insulin cause weight gain?

Yes, it does, but it’s not any better or worse than the insulin currently on the market. Insulin leads to weight gain.

While no study has been designed specifically to answer this question, Lingvay took it upon herself to do an unofficial review of the data from all of the phase 3 studies.

“I took every study out there and I plotted the change in A1C vs the change in weight for each individual group in these 11 studies.” What she found was that “the greater the insulin lowered A1C, the greater the gain in weight.” But the type of insulin didn’t matter — the control groups using daily insulin gained just as much weight as those using weekly insulin.

Will once-weekly insulin be available for people with type 1 diabetes?

 Not anytime soon. The experts agreed that weekly basal insulin is somewhat more problematic in the setting of type 1 diabetes, a condition in which basal insulin requirements can vary wildly throughout the day and week. A single weekly basal insulin injection would reduce a patient’s ability to make fine adjustments when exercise, stress, illness, menstruation, and other factors change insulin sensitivity levels.

If there’s potential, it’s probably for patients that have difficulty using basal insulin therapy consistently. Mathieu said, “I would give money to have a once-weekly insulin for many of my [type 1] patients, so I know that they have at least some insulin in their bodies.”

“There will be people with type 1 benefiting from weekly insulin, but we’ll have to decide in whom this may have an advantage.”

It will be years before weekly insulin receives official approval for use in type 1 diabetes. Of the eleven phase 3 trials planned for efsitora alfa and icodec, nine are examining the new drugs in type 2 diabetes, and only two are devoted to type 1. The panelists all agree that far more study will be needed to assess how to use weekly basal insulin safely and effectively in type 1.

Remaining Questions

There are many details that clinicians still need to sort out. How does weekly insulin impact exercise habits? What happens if illness or hormones cause your insulin sensitivity to change rapidly? Is weekly insulin safe in children, the elderly, or pregnant women?

As with other diabetes medications, cost may also be an issue. That’s in the hands of the pharmaceutical companies. At the moment, we can probably assume that weekly insulin will be more expensive than daily insulin, though we can’t guess as to the difference, or how insurers will categorize the new drug on their formularies.

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