Risk of Hypoglycemia in the Transition From Inpatient to Outpatient Setting. Comparative Study of Basal-bolus Insulin Versus Basal Insulin Plus GLP-1 Analogue

The association of insulin degludec with liraglutide in the same device (IDegLira) is a potent but at the same time safe drug that reduces the risk of hypoglycemia when compared to a basal or basal-bolus insulin schedule.

The DUAL (Dual Action of Liraglutide and Insulin Degludec) studies are the pivotal studies of this combination. Specifically, the DUAL VII study has demonstrated that ideglira is a non-inferior drug in terms of glycemic control versus a basal-bolus schedule in patients in the outpatient setting who have failed basal insulin.

Although the basal-bolus insulin plus correction schedule is frequently used in hospitalized patients with hyperglycemia, outpatient management with a complex insulin schedule creates challenges that are difficult to mitigate due to limited time for patient education during an acute illness and limited access to the physician responsible for post-discharge diabetes management.

The use of IDegLira has not been evaluated in clinical studies in the hospital discharge setting where the authors believe it has great potential because it offers similar potency to the basal-bolus scheme but with greater safety with respect to hypoglycemia and less complexity for the patient because it is associated with fewer applications and less need for capillary self-monitoring.

For this reason, in the hospital-home transition scenario, ideglira therapy in patients with poor metabolic control and requiring intensification therapy is proposed as an alternative to the basal-bolus scheme.

Study Overview

• Status: Recruiting
• Conditions: Diabetes Mellitus, Type 2 Treated With Insulin
• Intervention / Treatment: Drug: Insulin Glargine - Insulin Aspart; Drug: insulin degludec + liraglutide

Detailed Description

Type 2 diabetes mellitus (DM 2) is a chronic non-communicable metabolic disease characterized by progressive deterioration of beta cell functionality, which associated with the presence of insulin resistance results in persistent elevations of plasma glucose or hyperglycemia. The objectives of its treatment are to prevent or delay complications and optimize quality of life.

The American Diabetes Association (ADA) consensus report "Standards of Medical Care in Diabetes-2021" recommends a patient-centered approach to choosing appropriate pharmacologic treatment of glycemia. This includes consideration of key patient factors: 1) important comorbidities, such as atherosclerotic cardiovascular disease, high-risk indicators of cardiovascular, chronic kidney disease, and heart failure, 2) risk of hypoglycemia, 3) effects on body weight, 4) side effects, 5) cost, and 6) patient preferences.

With these considerations in mind, drug therapy should be initiated in conjunction with a lifestyle modification consultation focused on diet and physical activity. Considering the progressive nature of the disease, monotherapy only achieves glycemic control for a few years and treatment intensification is required as the disease progresses, however, therapeutic inertia leads to delayed intensification in diabetic patients who are not at glycemic control goals, mainly when it comes to the use of injectable therapies such as insulins.

In recent years, two combinations of basal insulin with GLP-1 analog received regulatory approval from the European Medicines Agency and the U.S. Food and Drug Administration Agency. These therapeutic strategies are fixed ratio combinations of insulin degludec U100 and liraglutide (IDegLira); and insulin glargine U100 and lixisenatide (IGlarLixi). Both options demonstrated non-inferiority or superiority in reducing (Hb1Ac) levels in terms of glycemic control compared to their individual components in monotherapy, in the DUAL I study for IDegLira and in the LixiLan-O study for IGlarLixi .

Clinical trials supporting the efficacy and safety of IDegLira in the outpatient setting include DUAL (Dual Action of Liraglutide and Insulin Degludec in Type 2 Diabetes. On the other hand, there are authors who propose considering the use of IDegLira as the first injectable therapy in type 2 diabetic patients and as a therapeutic alternative in those who do not reach glycemic control goals with pharmacological treatment including monotherapy with GLP1 analogues, basal insulin or therapy with multiple doses of insulin in patients with recurrent hypoglycemia.

Considering the above, injectable therapy combined with IDegLira is proposed as an alternative for therapeutic intensification in patients with uncontrolled DM 2, since it has demonstrated efficacy and safety in the management of this pathology, achieving adequate glycemic control while leading to weight loss, lower rates of hypoglycemia and savings in insulin doses, in addition to providing a simple application scheme compared to the basal-bolus scheme.

In patients with DM 2, hospitalization represents an important change in medication: most consensus and guidelines propose the use of insulin therapy for glycemic control during hospital stay.

However, therapy at the time of hospital discharge should be adjusted and reconciled with the use of other non-insulin diabetes medications.

• Study Type: Interventional
• Enrollment (Anticipated): 66
• Phase: Phase 3

Contacts and Locations

• Study Contact: Name: Ana Maria Gomez, MD; Phone Number: 57(1)5 946161; Email: agomez@husi.org.co
• Study Contact Backup: Name: Yalinne Gómez Quesada, MD; Phone Number: 57(1)5 946161; Email: y.gomezq@javeriana.edu.co

Study Locations

• Colombia
  • Bogotá, Colombia
    • Recruiting
    • Hospital Universitario San Ignacio
    • Contact: Ana Maria Gomez Medina, MD; Phone Number: 2430 +57 (1) 5946161; Email: agomez@husi.org.co
    • Contact: Yalinne Gómez Gómez Quesada, MD; Phone Number: 2430 +57 (1) 5946161; Email: y.gomezq@javeriana.edu.co

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Patients over 18 years of age with a diagnosis of type 2 diabetes mellitus who have received basal-bolus insulin during hospitalization and who, at the time of hospital discharge, are considered necessary to continue this scheme (basal-bolus).

Exclusion Criteria:

• Patient with diagnosis or suspicion of DM1.
• Inability of the patient or family member to continue injectable therapy at home.
• CKD with GFR < 15 ml/minute by CKD EPI.
• History of chronic or acute pancreatitis in the last 3 months.
• History of personal or family history of medullary thyroid cancer.
• History of hypersensitivity to any of the components of the IdegLira combination.
• Women in pregnancy, breastfeeding or absence of hormonal contraception.
• Management for obesity with GLP1 receptor agonist.
• Previous management with basal bolus scheme with total daily dose of insulin (DDT) greater than 70 U/day.
• Patients with hyperglycemia associated with steroids.
• Patients who are insulin users prior to current hospitalization and have an in-hospital HbA1c greater than 11%.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: basal group bolus; Insulin Glargine required on an in-hospital basis; Insulin Aspart required on an in-hospital basis	Drug: Insulin Glargine - Insulin Aspart; The insulin dose of the basal group will be adjusted according to the blood glucose reports presented by the patients.
Experimental: insulin degludec + liraglutide ( ideglira); 16 Units once a day	Drug: insulin degludec + liraglutide; The association of insulin degludec with liraglutide in the same device (IDegLira) is a potent and safe drug that reduces the risk of hypoglycemia.; Other Names: ideglira

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
To compare the percentage of hypoglycemia	To compare the percentage of patients presenting at least one episode of hypoglycemia (defined as one or more episodes of hypoglycemia below 54 mg/ dL for more than 20 minutes by continuous flash glucose monitoring), between the basal bolus group and the degludec/liraglutide (ideglira) group in the first four weeks after hospital discharge.	4 weeks

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Compare episodes of severe hypoglycemia	To compare episodes of severe hypoglycemia between the two groups; defined as episodes with altered state of consciousness or requiring assistance from another person to make corrective decisions.	4 weeks
Compare the metrics of glycemic control	To compare the metrics of glycemic control (time in range 70-180 mg/dL, time above range 180 mg/dL, time above 250 mg/dL , GMI, coefficient of variation ) of the two groups.	4 weeks
Compare the incidence density of hypoglycemia	To compare the incidence density of hypoglycemia defined as the number of hypoglycemia events (readings below 54 mg/ dL for more than 20 minutes by continuous flash glucose monitoring) in each intervention group.	4 weeks
compare the percentage of patients without episodes of hypoglycemia	To compare the percentage of patients achieving a time in range greater than 70% without episodes of hypoglycemia in each intervention group.	4 weeks
HbA1c change	To evaluate the efficacy of the schemes according to Hbac1 metrics before randomization.	4 weeks
To assess whether there is a difference in body weight	To assess whether there is a difference in body weight change according to treatment allocation arm.	4 weeks
Evaluate associated adverse effects	Evaluate and compare associated adverse effects such as: nausea, emesis, abdominal distension, diarrhea, constipation, epigastric pain, early satiety, postprandial fullness, weight gain, acute pancreatitis, symptomatic cholelithiasis, diabetic ketoacidosis, hyperosmolar state (see attached operational definitions).They will be evaluated by means of the CTCAE manual version 5.0.	4 weeks

Collaborators and Investigators

• Sponsor: Hospital Universitario San Ignacio

Study record dates

Study Major Dates

• Study Start (Actual): December 1, 2022
• Primary Completion (Anticipated): August 30, 2023
• Study Completion (Anticipated): August 30, 2023

Study Registration Dates

• First Submitted: February 16, 2023
• First Submitted That Met QC Criteria: March 2, 2023
• First Posted (Actual): March 14, 2023

Study Record Updates

• Last Update Posted (Actual): March 14, 2023
• Last Update Submitted That Met QC Criteria: March 2, 2023
• Last Verified: February 1, 2023

More Information

Terms related to this study

• Keywords: Glycemic; Type 2 diabetes mellitus; IDegLira; Diabetes medications.
• Additional Relevant MeSH Terms: Glucose Metabolism Disorders; Metabolic Diseases; Endocrine System Diseases; Diabetes Mellitus; Diabetes Mellitus, Type 2; Hypoglycemia; Hypoglycemic Agents; Physiological Effects of Drugs; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Incretins; Insulin; Insulin, Globin Zinc; Insulin Aspart; Liraglutide; Insulin Glargine; Xultophy
• Other Study ID Numbers: 2022/145

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO
• IPD Plan Description: There is no plan to make individual participant data (IPD) available to other researchers.

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: Yes