IDegLira HIGH Trial

Extensive literature has shown that persistent hyperglycemia is associated with short- and
long-term complications. Sustained hyperglycemia, also known as glucotoxicity, leads to
progressive loss of beta-cell function and is considered a key pathophysiological process in
the development of type 2 diabetes (T2D). Patients with severe hyperglycemia may respond
poorly to oral anti-diabetic agents (OAD) alone initially and frequently require insulin to
achieve glycemic targets. Current guidelines recommend to initiate therapy with basal insulin
and progressively step up to basal-bolus insulin in patients with high HbA1c >9%,
particularly if symptomatic or with catabolic symptoms.

A basal-bolus insulin regimen increases the risk of hypoglycemia, weight gain and glycemic
variability, which are limiting factors in achieving glycemic targets. A basal-bolus insulin
regimen is also labor intensive and often requires multiple daily injections, further
increasing the burden of diabetes care and decreasing patient adherence. In contrast,
simplified treatment plans may improve adherence, leading to glycemic targets achievement.
Thus, there is a critical need for simpler regimens that could overcome clinical inertia,
improve patient adherence, and decrease glycemic variability in patients with poorly
controlled type 2 diabetes. This prospective randomized control trial will compare IDegLira
to basal-bolus insulin regimen in achieving glycemic control, while reducing hypoglycemia,
glycemic variability, and weight gain in patients with uncontrolled T2D and HbA1c ≥9%.

Inclusion Criteria:

- Type 2 diabetes, diagnosed for ≥ 6 months

- HBA1c ≥ 9% - 12%

- Previously treated with oral antidiabetic agents, including metformin, sulfonylurea,
repaglinide/nateglinide, pioglitazone, dipeptidyl peptidase-4 (DPP4), inhibitors,
SGLT2 inhibitors, (monotherapy + basal insulin) or in combination therapy (2-3
agents), and/or on basal insulin (neutral protamine hagedorn (NPH), detemir or
glargine U100) at a total daily dose (TDD) 20-50 units (stable doses of metformin and
basal insulin for at least 90 days, defined as up to ±10% variability)

- Body mass index (BMI) ≥ 25 Kg/m2 and ≤ 40 Kg/m2

Exclusion Criteria:

- Subjects with type 1 diabetes or latent autoimmune diabetes of adults (LADA) (positive
glutamic acid decarboxylase (GAD-65) antibody and/or ketones)

- Subjects with a BG > 400 mg/dL during the screening visit and laboratory evidence of
diabetic ketoacidosis

- Previous treatment with glucagon-like peptide-1 (GLP-1) agonists (during prior 3
months)

- Previous treatment with basal-bolus insulin or mixed insulin (within prior 3 months)

- Recurrent severe hypoglycemia or known hypoglycemia unawareness.

- Personal or family history of medullary thyroid cancer or multiple endocrine neoplasia
2

- Patients with acute or chronic pancreatitis, pancreatic cancer

- Patients with clinically significant hepatic disease (cirrhosis, jaundice, end-stage
liver disease) or significantly impaired renal function (GFR < 30 ml/min).

- Treatment with oral or injectable corticosteroid (equivalent or higher than prednisone
5 mg/day), parenteral nutrition and immunosuppressive treatment.

- Mental condition rendering the subject unable to understand the nature, scope, and
possible consequences of the study

- Hypersensitivity to study drugs

- Participating in another investigational drug trial

- The receipt of any investigational drug (within 3 months) prior to this trial.

- Previously randomized in this trial

- Heart Failure New York Heart Association (NYHA) class 4 or uncontrolled hypertension
(blood pressure > 180/110 mmHg)

- Female subjects who are pregnant or breast-feeding at time of enrollment into the
study

- Females of childbearing potential who are not using adequate contraceptive methods (as
required by local law or practice)

- Known or suspected allergy to trial medications (degludec, liraglutide, aspart),
excipients, or related products.

- Subjects could be excluded based on PI's discretion

- Unable to comply with trial protocol, and/or at investigator discretion

- Patients receiving treatment for active diabetic retinopathy or with proliferative
retinopathy