Transition From Basal/Bolus to Once-weekly Subcutaneous Semaglutide and Basal Insulin in Patients With T2D

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.

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.

Eligibility Criteria:
Inclusion Criteria:

1. Gender: men and women
2. Ethnicity: all ethnic groups
3. Language: English
4. Age: ≥ 18 to 75 years
5. Type II diabetes

   * Currently treated with MDI (basal/bolus regimen) for at least 6 months
   * MDI must consist of three or more injections of insulin per day, with at least 2 injections being prandial/rapid-acting insulin
   * Prandial insulin restricted to insulin aspart, glulisine, and lispro
   * Basal insulin restricted to long acting once-daily analogues (insulin glargine U- 100, insulin degludec (U-100 or U-200), or insulin glargine U-300)
   * A1C within 30 days of randomization must be ≤ 7.5% on the present therapy
   * Less than or equal to 120 units of total insulin therapy per day
6. Ability to provide informed consent before any trial-related activities. Trial-related activities are any procedure that would not have been performed during normal management of the subject.

Exclusion Criteria:

1. GAD-65 antibody positive
2. Current glucocorticoid therapy greater than 5 mg of daily prednisone (or equivalent dose of other glucocorticoid)
3. Known or suspected allergy to trial medication(s), excipients, or related products, i.e., GLP-1RA therapy or insulin aspart or insulin degludec.
4. The receipt of any investigational drug within 90 days prior to this trial.
5. Previous participation in this trial (Randomized)
6. Mental incapacity or language barrier (non-English speaking)
7. Use of incretin-based therapies \<3 months before inclusion in the study

   * DPP-4 inhibitors sitagliptin, saxagliptin, linagliptin, alogliptin
   * GLP-1RA (exenatide, liraglutide, exenatide LAR, dulaglutide, albiglutide, lixisenatide, semaglutide)
   * GLP-1RA/Basal Insulin combination (IGlarLixi, IDegLira)
8. Present use of oral anti-diabetic agents other than metformin and SGLT-2i. The dose of metformin and/or SGLT-2i must be unchanged and stable for the immediate 3 months prior to baseline.
9. Pregnant, breast-feeding or the intention of becoming pregnant or not using adequate contraceptive measures
10. Personal or family history of medullary thyroid carcinoma
11. Personal or family history of Multiple Endocrine Neoplasia syndrome type 2
12. History of acute or chronic pancreatitis, severe liver disease or LFT's \> 2.5X ULN, or severe disease of digestive tract
13. History of bariatric surgery/procedure (gastric banding, gastric sleeve, or Roux-en-Y)
14. Known elevation of serum calcitonin \> 50 ng/L