Could Combos Replace Basal-Bolus Insulin in Type 2 Diabetes?

Miriam E. Tucker

May 06, 2021

For patients with type 2 diabetes who are taking multiple daily insulin injections, switching to combination treatment with basal insulin plus an agent from one of two newer glucose-lowering drug classes may offer a more convenient and safer alternative, a new randomized study indicates.

The study shows that switching patients from basal-bolus insulin (BBI) regimens (four injections per day) to either a once-daily fixed combination of basal insulin plus either a glucagon-like peptide 1 receptor agonist (GLP-1 agonist) or a daily oral sodium-glucose cotransporter 2 inhibitor (SGLT2 inhibitor) produced comparable glycemic control but with lower insulin doses, fewer injections, and less hypoglycemia.

Because of progressive loss of beta cell function among patients with type 2 diabetes, use of insulin is often required. About one quarter of people with type 2 diabetes are currently receiving insulin therapy, yet only 50% of those individuals achieve a target A1c level of <7%. The American Diabetes Association advises considering intensification of injectable insulin therapy when the basal dose is >0.5 units/kg/d and A1c remains above target.

However, the new data "seem to confute the dogma about the untouchability of BBI regimen in type 2 diabetes by providing evidence that it is possible and safe to switch from a BBI regimen to either a once-daily fixed-combo injection or once-daily gliflozin pill added to basal insulin," say Dario Giugliano, MD, PhD, of the University of Campania, Naples, Italy, and colleagues in their article, which was published online April 21 in Diabetes Care.

"This simplification strategy may work, in terms of significant and clinically relevant reduction of A1c, in many patients who maintain their results for at least 6 months," they note, and "the addition of a drug with proven cardiorenal benefits may be seen as a further potential merit of the combination strategy."

If the results continue beyond the trial's 6-month period, Giugliano and colleagues say, "they will facilitate the role of the physician, will be appreciated by the patient, and hopefully will provide better guidance to practitioners in the choice of medications."

"Really Important Work": Approach Could Combat "Overbasalization"

Asked to comment, Rozalina G. McCoy, MD, an endocrinologist and primary care clinician at the Mayo Clinic, Rochester, Minnesota, called the study "really important work."

She told Medscape Medical News that she often sees patients who are recieving basal insulin but instead of premeal insulin, their basal dose has been continually raised to the point of "overbasalization," which doesn't cover the food consumed but at the same time can lead to hypoglycemia.

"So, if we keep ramping up the basal, it's a problem, but it's either too much basal or they end up on a complex regimen with four injections a day," she said.

In contrast, she said, "I think what this study really shows is that if we use either GLP-1 agonists or SGLT2 inhibitors together with basal insulin, we can effectively cover some of their mealtime needs without having the hypoglycemia, the weight gain, and the treatment burden of MDI [multiple daily injection] therapy."

However, she noted, "This is a short study, only 6 months. The big question is, how much time do we buy? Many patients with type 2 diabetes will ultimately require multiple daily insulin injection therapy, but the hope, and where I think this study comes in, is to delay that as much as possible."

Equivalent Glucose-Lowering, Fewer Injections, Less Hypoglycemia

The study included 305 adults older than 35 years with type 2 diabetes whose A1c levels were >7.5% with basal-bolus multiple daily injection therapy (four injections per day).

They were randomly assigned to receive either intensification of their current basal-bolus regimen, a fixed combination of basal insulin plus a GLP-1 agonist (IDegLira or IGlarLixi), or basal insulin plus an SGLT2 inhibitor (either canagliflozin, dapagliflozin, or empagliflozin). Of the 305 patients, 100%, 88%, and 91%, respectively, completed the study.

The primary outcome, changes in A1c from baseline at 6 months, were -0.6, -0.6, and -0.7 percentage points, respectively (P = .356) for BBI, the GLP-1 agonist combination, and the SGLT2 inhibitor combo. The proportion of patients who achieved A1c levels of ≤7.0%, ≤7.5%, and ≤8.0% didn't differ significantly among the three groups (P = .189), with noninferiority for both combinations compared to basal-bolus (P < .001 for both).

Total daily insulin doses increased in the basal-bolus group and decreased in both the combination groups (superiority, P < .01 for both). Patients in the fixed GLP-1 agonist combination group experienced significant weight loss compared to the other two groups (-1.9 kg vs -0.6 kg for the SGLT2 inhibitor combination and a gain of 0.3 kg with BBI; P < .001, P = .855, and P = .159, respectively).

The proportions who experienced at least one episode of level 1 hypoglycemia (<70 mg/dL with symptoms/signs) was 17.8%, 7.8% and 5.9% for basal-bolus, fixed GLP-1 agonist combo, and SGLT2 inhibitor combo, respectively (P = .015). Less than 5% of patients in any group experienced hypoglycemia of level 2 (<54 mg/dL) or level 3 (<50 mg/dL or needing assistance).

Approach Could Help Avoid Therapeutic Inertia in Primary Care

McCoy said she doesn't typically use the fixed-dose basal insulin–GLP-1 agonist combination products because they don't allow as much flexibility as does giving the agents separately. "With fixed combos, you're not getting as much benefit as you can, because you're limited in how much you can give," she said.

However, she said, "the principle of basal insulin plus GLP-1 agonist or SGLT2 inhibitor is really important because, if anything, it will help avoid this dead end of basal insulin therapy in primary care.

"It's really hard for the primary care provider to start MDI therapy. It requires a lot of patient education and close monitoring.... Hopefully, this will help with some of that therapeutic inertia."

The study was funded in part by the Associazione "Salute con Stile," Naples, Italy. Giugliano received honoraria for speaking at meetings from Novartis, Sanofi, Eli Lilly and Company, AstraZeneca, and Novo Nordisk. McCoy is funded by the National Institutes of Health.

Diabetes Care. Published online April 21, 2021. Abstract

Miriam E. Tucker is a freelance journalist based in the Washington, DC, area. She is a regular contributor to Medscape. Other work of hers has appeared in the Washington Post, NPR's Shots blog, and Diabetes Forecast magazine. She can be found on Twitter @MiriamETucker.

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