De-Intensification From Basal Bolus to Subcutaneous Semaglutide and Basal Insulin

When an individual’s Type 2 diabetes (T2D) is well controlled with multiple daily injections of insulin (MDI), also commonly referred to as basal/bolus, the decision to maintain that therapy is often the status quo.

However, as Cleveland Clinic researchers explain, replacing MDI with once-weekly subcutaneous (SC) semaglutide in combination with basal insulin, cannot only maintain or improve glycemic control and reduce weight, it can also reduce the overwhelming burden of diabetes-management that is associated with MDI.

A 26-week study by Cleveland Clinic’s Endocrinology & Metabolism Institute compared outcomes of people who replaced the prandial insulin component of their MDI regimen with SC semaglutide.

Kevin M. Pantalone, DO, Director of Diabetes Initiatives for the Department of Endocrinology and the study’s principal investigator, says the team identified a clear unmet need for a safe and effective strategy to de-intensify T2D treatment from MDI to regimens that were less intense and lower in complexity.

“Despite the well-documented safety and efficacy of glucagon-like peptide-1 receptor agonists (GLP-1RAs) added to basal insulin, there was very limited prospective data on transitioning individuals who had already initiated MDI to a regimen of once-weekly GLP-1RA plus basal insulin,” says Dr. Pantalone.

Ideally, he adds, the use of MDI in individuals T2D should be restricted to those unable to achieve glycemic control with other pharmacological interventions.

“With the advent of newer and more effective non-insulin therapies, we sought to demonstrate that once an individual’s T2D was reasonably well controlled on MDI (glycated hemoglobin, HbA1c ≤ 7.5%), one might not only be able to reduce their burden of disease management (frequency of injections) but also maintain or further improve HbA1c, while assisting with weight loss,” says Dr. Pantalone.

The results support consideration of transitioning therapy for more patients, where appropriate, from MDI to a GLP-1RA plus basal insulin, says researcher and primary author Paloma Rodriguez, MD.

“When people with T2D initiate basal/bolus insulin therapy, they are usually in a later stage of the disease,” says Dr. Rodriguez. “Most of the time, they're taking multiple daily injections because their goals could not be achieved with other regimens. Traditionally, once physicians put their patients on this regimen, it is considered lifelong therapy.”

Although the arrival of GLP-1RAs has dramatically improved the treatment landscape for many with T2D, leveraging the therapy to de-escalate treatment is rather uncommon, Dr. Rodriguez adds.

The study

The researchers randomized 60 adults whose HbA1c was stable ≤7.5% and who were taking MDI ≤120 units a day. Group one (N=40) was given long-acting basal plus 1.0 mg SC semaglutide. Group two (N=20) received long-acting basal insulin plus multiple injections of short-acting insulin with each meal. All patients’ basal insulin was transitioned to degludec, and short-acting insulin to insulin aspart, for the purpose of standardization.

The primary outcome was percentage of subjects maintaining glycated hemoglobin ≤7.5% at week 26.

Results

At week 26, 90% of those on the semaglutide regimen and 75% of MDI subjects maintained glycated hemoglobin ≤7.5%.

At week 26, mean changes for the semaglutide group versus the MDI group were, respectively:

• HbA1c, −0.5% versus 0.0%.
• Body weight, −8.9 kg versus 1.5 kg.
• Percentage of body weight, −8.6% versus 1.4%.

In addition, total daily insulin requirements decreased 56% for the semaglutide patients and increased 6.7% for those on MDI. Among semaglutide subjects, 58% reduced their total daily insulin more than 50%, and 45% lost more than 10% body weight. Patient satisfaction scores trended higher with semaglutide compared to MDI.

Frequency of hypoglycemia was similar between groups. The rate of adverse effects was similarly low in both groups. The differences in the groups’ need for insulin was a notable result, says Dr. Rodriguez.

“In addition to stopping meal time insulin, we found ourselves needing to decrease the basal insulin of the semaglutide patients. A possible explanation for that is that they lost weight and they ate less, so they needed less insulin overall.”

All-at-once transition

Participants allocated to the semaglutide group switched from MDI to basal insulin plus semaglutide on a single day. Their mealtime insulin was stopped on the day of their first dose of semaglutide, which was titrated gradually from 0.25 mg weekly to 1 mg over the following 12 weeks. That made the experience simple and applicable to real-world practice, says Dr. Rodriguez.

“At the time we stopped mealtime insulin, patients were not receiving the full dose of semaglutide,” she says. “We believe this was important to the observed success, because when one is injecting exogenous insulin, the pancreas’s own insulin secretion is suppressed.”

Most people with T2Ds have residual insulin-producing capacity even at later stages of the disease. By ceasing prandial insulin as soon as the semaglutide therapy is initiated, the pancreas is able to secrete insulin more effectively in response to rising glucose levels.

As a precaution, patients on semaglutide performed blood-glucose checks before each meal for the first 12 weeks, and if their glucose was higher than 150 mg/dL before any meal, they took a small correction dose of short-acting insulin to correct the high blood sugar, says Dr. Rodriguez.

“I expected we might see a lot of people needing correction insulin during the transition,” she says. “We did not tabulate that, but we did not see many patients require very frequent correction doses of short-acting insulin.”

It is also important to note that the study population was not comprised of individuals with recently diagnosed T2D; the median (IQR) self-reported duration of T2D for the overall study population was 18.5 (9.2, 25.0) years.

“Providers should not assume individuals with long-standing diabetes cannot respond favorably to newer therapies, such as a very effective GLP-1RA like once-weekly SC semaglutide,” says Dr. Pantalone. “The only way one will know if something it going to work is to try it.”

It is his hope that the study findings will help other providers become more comfortable trying more novel approaches to T2D management even in individuals with long-standing T2D receiving MDI.

“Many individuals may have simply been placed on MDI because these newer and more effective therapies were not available at the time, or because their former provider may not have felt comfortable using them,” he says.

For clinicians

For primary care physicians working with patients for whom T2D is just one among multiple health issues, a steady HbA1c of ≤ 7.5% s on MDI may be acceptable, but Dr. Rodriguez believes it’s worth reconsideration. Because HbA1c is an average, those numbers can mask larger fluctuations in blood sugar.

“Patients can really be harmed by large swings in their blood sugar,” she says. “The down swings and the variability of their control can decrease quality of life, sense of well-being, and some studies have suggested it may even increase their cardiovascular risk.”

For clinicians considering whether to keep a patient with a reasonably well controlled HbA1c on MDI, Dr. Rodriguez emphasizes that HbA1c is just an average, and that even if it’s good now, it is unlikely to be maintained for the long-term on a regimen of MDI.

In addition, the move to semaglutide with basal insulin may well improve their quality of life, thanks to weight loss and dramatically reduced frequency of needle sticks, Dr. Rodriguez says.

“You can improve their quality of life if you do an intervention to simplify their treatment complexity.”

Future research is planned to evaluate if a similar strategy may work in patients with A1C > 7.5%, or requiring > 120 units/day of insulin therapy.