Clinical Trial Details
— Status: Completed
Administrative data
| NCT number |
NCT04538352 |
| Other study ID # |
20-853 |
| Secondary ID |
|
| Status |
Completed |
| Phase |
Phase 4
|
| First received |
|
| Last updated |
|
| Start date |
January 18, 2021 |
| Est. completion date |
November 1, 2023 |
Study information
| Verified date |
December 2023 |
| Source |
The Cleveland Clinic |
| Contact |
n/a |
| Is FDA regulated |
No |
| Health authority |
|
| Study type |
Interventional
|
Clinical Trial Summary
This study is designed to determine whether therapy with once-weekly sc semaglutide in
combination with once-daily insulin degludec will be capable of maintaining (or improving)
glycemic control, when substituted for multiple daily injections of insulin (MDI), in
patients with T2D with adequate glycemic control (≤ 7.5%) on MDI-based regimens (≤ 80 units
of insulin per day), vs. further titration of insulin therapy in those continuing MDI. Weight
loss, hypoglycemic episodes, and improvement in diabetes-treatment satisfaction will also be
assessed between the two groups.
Description:
Patients with type-2 diabetes mellitus (T2D) are often overweight or obese. In order to
obtain adequate glycemic control, many of these patients require intensive therapy with
multiple daily injections of insulin (referred to as MDI, basal/bolus regimen), using a
rapid-acting/bolus insulin at each meal in combination with a once- or twice-daily long-
acting/basal insulin. Unfortunately, intensive insulin therapy can result in undesired weight
gain, which may, in part, result in further insulin resistance. In addition, weight gain may
adversely affect the control of comorbid health conditions (hypertension, hyperlipidemia,
congestive heart failure, sleep apnea, etc.). The burden of disease management with multiple
daily injections of insulin also serves as a barrier to A1C goal attainment as maintaining
compliance with such complex regimens is often challenging in the real-world setting.
Once patients with T2D require multiple daily injections of insulin to obtain glycemic
control, it is generally considered to be a permanent/life-long therapy. However, reports
have demonstrated the safety and effectiveness of adding once-daily glucagon-like peptide-1
receptor agonist (GLP-1RA) liraglutide to basal insulin therapy in order to obtain glycemic
control (1, 2), and in clinical practice, the addition of liraglutide (or other FDA-approved
GLP-1RAs) to basal insulin often negates or delays the need to initiate prandial insulin.
Subsequently, a newer form of anti-diabetic therapy, a once-daily injectable combination of
GLP-1RA and basal insulin, became available and demonstrated promise that perhaps glycemic
control may even be obtained with less complex regimens (i.e., less daily injections). There
are currently two GLP-1RA/basal insulin combination therapies that are FDA approved:
iGlarLixi (Soliqua®), and iDegLira (Xultophy®) (3, 4). While these observations with
iGlarLixi and iDegLira demonstrating an improvement in A1C while avoiding prandial insulin
injections are very exciting, what remains unclear is if patients with reasonable glycemic
control (A1C ≤ 7.5%) currently receiving MDI (basal/bolus, 3-4 injections per day) could
potentially maintain or even improve glycemic control by switching to a once-daily injectable
product like Xultophy® or Soliqua®. Currently, there are no studies available (or planned)
that have answered this clinical question. One limitation of these combination products in
the clinical setting is the inability to independently titrate the GLP-1RA and basal insulin
components. If a patient begins to experience hypoglycemia, and/or their fasting BG values
are currently within the goal range, the dose of these combination products cannot be further
titrated, limiting one's ability to further improve glycemic control in patients with a
residual A1C elevation.
What also remains unclear is if some of the newer formulations of GLP-1RA may also be able to
reduce the burden of disease management and maintain glycemic control in patients who are
currently well-controlled on a regimen of MDI. Recently, subcutaneous (sc) once-weekly
semaglutide has been demonstrated to be capable of improving glycemic control in patients
with T2D in combination with insulin therapy. In SUSTAIN-5 (5), at week 30, subcutaneous
semaglutide 0.5 and 1.0 mg was demonstrated to reduce A1C by 1.4% and 1.8%, respectively, vs
0.1% with placebo [mean baseline A1C value, 8.4%] in a population of T2D patients receiving
stable therapy with basal insulin with or without metformin. Moreover, mean body weight (kg)
decreased with semaglutide 0.5 and 1.0 mg vs placebo from baseline to end of treatment: 3.7,
6.4, and 1.4 kg, respectively. Premature treatment discontinuation due to adverse events was
higher for semaglutide 0.5 and 1.0 mg vs placebo (4.5%, 6.1%, and 0.8%), mainly due to
gastrointestinal disorders. Even if the transition from MDI to once-daily sc semaglutide in
combination with basal insulin were successful in only a minority of patients, the clinical
advantage and reduction in burden of disease management that would be associated with
transitioning from 3-4 injections of insulin per day to a regimen of once- weekly sc
semaglutide and a once-daily injection of basal insulin would be a rather dramatic and
remarkable transformation for patients, and one that would likely improve patients' diabetes
treatment satisfaction. It would also help to solidify the effectiveness and safety of
semaglutide in yet another population of patients with T2D. What cannot be minimized is the
tremendous impact that a successful transition to once-weekly semaglutide and once-daily
basal insulin could have on patients in terms of reducing their insulin requirements,
assisting with weight loss (or mitigating further weight gain), and reducing the frequency
and burden of hypoglycemia. In my clinical experience, once patients are titrated to full
dose GLP-1RA therapy and attain adequate glycemic control, insulin doses (particularly
prandial insulin) can often be further reduced or eliminated without negatively impacting
glycemic control. Continuing the insulin therapy at higher doses in these patients simply
suppresses the glucose-dependent secretion of endogenous insulin being promoted by the
GLP-1RA therapy. Often, only an abrupt cessation of prandial insulin, or a step-wise
down-titration of insulin therapy in these patients, will reveal that insulin therapy is no
longer required at higher doses to maintain glycemic control. When this does successfully
occur, the impact on patients is transformational.
The purpose of this study is to investigate the ability of once-weekly sc semaglutide (in
combination with once-daily basal insulin) to maintain or improve glycemic control in
patients currently receiving MDI, while providing the patients with a significant reduction
in the burden of disease management. In addition, this approach may also furnish a positive
effect on weight management, a reduction in hypoglycemic episodes, and improvement in
diabetes treatment satisfaction, when substituted for basal/bolus therapy in patients with
T2D who currently have adequate glycemic control (A1C ≤ 7.5%) with a regimen of MDI
(requiring a total of ≤ 80 units of insulin per day). The A1C cut-point of ≤ 7.5% was chosen
because many patients on complex treatment regimens (MDI) with reasonable control, i.e.,
7-7.5%, would be expected to have a realistic chance of success by switching from MDI to sc
semaglutide and basal insulin combination therapy. Also, many patients taking complex insulin
regimens (MDI) fall in the close to A1C goal range of 7-7.5%, so using this cut-point, vs. <
7%, would make recruitment easier. Lastly, patients receiving MDI who are older and/or with
heart disease also have higher individual A1C goal/targets around 7.5%. This study will also
assess the impact that a successful substitution may have on the patients' diabetes treatment
satisfaction, an important, yet under-appreciated aspect of diabetes management.
