Durability of Combination of Insulin and GLP-1 Receptor Agonist or SGLT-2 Inhibitors Versus Basal Bolus Insulin Regimen in Type 2 Diabetes (BEYOND)

NCT04196231 | Completed Phase 4

• 1 other identifier: BEYOND Protocol
• Study Type: interventional
• Target: 258
• Locations: 1 country
• Sites: 1

Brief Summary

BEYOND represents an open-label, parallel, three-arm randomized controlled trial, aimed at evaluating the effects of combination therapy of fixed ratio basal insulin/GLP-1 receptor agonist (GLP-1RA) or basal insulin/SGLT-2 inhibitors (SGLT-2i) on the durability of the glycemic control, as compared with the basal bolus insulin regimen, in people with type 2 diabetes failing to achieve glycemic targets with injective therapy. The potential benefits for participants in the study include the possibility of improving the glyco-metabolic control with drugs that have been evaluated as safe and protective for the heart and the kidneys. The primary outcome of the study is the mean HbA1c change between groups at six months. Participants in the study will be followed for subsequent 18 months in order to evaluate the durability of glycemic control and the chenge of other secondary outcomes.

Conditions

Type 2 Diabetes

Keywords

type 2 diabetes; GLP-1RA; SGLT-2i; basal insulin; basal bolus; glycemic control

Outcome Measures

Primary Outcomes (2)

• Hba1c change

  HbA1c group difference at 6 months

  6 months, 9 months, 12 months

• Proportions of patients with significant HbA1c change

  Proportions of patients undergoing a reduction equal or higher than 0.5% as compared with baseline levels during the follow up

  Baseline, 3 months, 6 months, 9 months, 12 months, 18 months

Secondary Outcomes (11)

• Weight Change

  Baseline, 6 months, 18 months

• BMI Change

  Baseline, 6 months, 18 months

• Waist circumference change

  Baseline, 6 months, 18 months

• Blood pressure change

  Baseline, 6 months, 18 months

• Fasting glycemia change

  Baseline, 6 months, 18 months

Study Arms (3)

FR insulin/GLP-1RA

ACTIVE COMPARATOR

Patients in this arm will receive one of these fixed ratio combo of insulin and GLP-1RAs, according to the current clinical practice and the drugs' data sheet: IDegLira or IGlarLixi

Drug: IDegLira; Drug: IGlarLixi

Insulin/SGLT-2i

ACTIVE COMPARATOR

Patients in this arm will receive the basal insulin used before the randomization and one of these SGLT-2i according to the current clinical practice and the drugs' data sheet: canagliflozin, dapagliflozin or empagliflozin.

Drug: Insulin/Canaglifozin; Drug: Insulin/Dapaglifozin; Drug: Insulin/Empaglifozin

Basal Bolus

ACTIVE COMPARATOR

Patients in this arm will receive a basal insulin (glargine, glargine-300 or degludec) at bed-time plus 3 injections of a short-acting insulin analogue (aspart, lispro or glulisine) before meals

Drug: Basal Bolus

Interventions

IDegLira DRUG

IDegLira will be started at 16 dose steps (16 U insulin degludec plus 0.58 mg liraglutide, once daily). On the basis of prebreakfast self-monitored blood glucose measurements doses of IDegLira will be titrated individually twice per week to achieve a prebreakfast plasma glucose of 80-130 mg/dL by use of an algorithm (adding 2 dose steps for prebreakfast plasma glucose \>130 mg/dL; no dose change for prebreakfast plasma glucose of 80-130 mg/dL; reducing 2 dose steps for prebreakfast plasma glucose \< 80 mg/dL). The daily dose of IDegLira could be titrated to 50 dose steps (50 U insulin degludec plus 1.8 mg liraglutide).

FR insulin/GLP-1RA

IGlarLixi DRUG

IGlarLixi will be started at 10 dose steps (10 U insulin glargine plus 5 mcg lixisenatide, once daily). On the basis of prebreakfast self-monitored blood glucose measurements, doses of IGlarLixi will be titrated individually once per week to achieve a prebreakfast plasma glucose of 80-130 mg/dL by use of an algorithm (adding 2 dose steps for prebreakfast plasma glucose \>130 mg/dL; no dose change for prebreakfast plasma glucose of 80-130 mg/dL; reducing 2 dose steps for prebreakfast plasma glucose \< 80 mg/dL). The daily dose of IGlarLixi could be titrated to 60 dose steps (60 U insulin degludec plus 20 mcg lixisenatide).

FR insulin/GLP-1RA

Insulin/Canaglifozin DRUG

Patients in this arm will continue the basal insulin used before the randomization, with dosage titration on the basis of the following algorithm: adding 2 units for prebreakfast plasma glucose \>130 mg/dL; no dose change for prebreakfast plasma glucose of 80-130 mg/dL; reducing 2 units for prebreakfast plasma glucose \< 80 mg/dL. Moreover, they will be assigned to canaglifozin, according to the current clinical practice and the drugs' data sheet. Canagliflozin will be started at 100 mg daily per oral administration, and augmented to 300 mg/per day if required (HbA1c \>7.5 after 12 weeks).

Insulin/SGLT-2i

Insulin/Dapaglifozin DRUG

Patients in this arm will continue the basal insulin used before the randomization, with dosage titration on the basis of the following algorithm: adding 2 units for prebreakfast plasma glucose \>130 mg/dL; no dose change for prebreakfast plasma glucose of 80-130 mg/dL; reducing 2 units for prebreakfast plasma glucose \< 80 mg/dL. Moreover, they will be assigned to dapaglifozin, according to the current clinical practice and the drugs' data sheet. Dapagliflozin will be started at 10 mg daily per oral administration

Insulin/SGLT-2i

Insulin/Empaglifozin DRUG

Patients in this arm will continue the basal insulin used before the randomization, with dosage titration on the basis of the following algorithm: adding 2 units for prebreakfast plasma glucose \>130 mg/dL; no dose change for prebreakfast plasma glucose of 80-130 mg/dL; reducing 2 units for prebreakfast plasma glucose \< 80 mg/dL. Moreover, they will be assigned to empaglifozin, according to the current clinical practice and the drugs' data sheet. Empagliflozin will be started at 10 mg daily per oral administration, and augmented to 25 mg/per day if required (HbA1c \>7.5 after 12 weeks).

Insulin/SGLT-2i

Basal Bolus DRUG

Patients in this arm will continue the basal insulin (glargine, degludec or glargine-300) used before the randomization. The insulin titration will be guided by the medical staff, according to the following algorithm: adding 2 units of basal insulin for prebreakfast plasma glucose \>130 mg/dL; no dose change for prebreakfast plasma glucose of 80-130 mg/dL; reducing 2 units of basal insulin for prebreakfast plasma glucose \< 80 mg/dL. The short acting insulin analogue (lispro, aspart or glulisine) will be started at the dosage of 4 units before meals (3 times per day) and will be titrated twice a week until achieving pre-prandial glucose values ranging from 80-130 mg/dL.

Basal Bolus

Eligibility Criteria

• Age: 35 Years - 75 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Poor glycemic control (HbA1c ≥7.5%)
• Stable basal bolus insulin regimen for almost a year, eventually associated with metformin.

You may not qualify if:

• Type 1 diabetes or secondary diabetes;
• Previous treatment for the last three months with GLP-1RA or DPP-4 inhibitors;
• Hypersensitivity towards active substances or other ingredients of the drugs used in the study
• Participation in other trial with experimental drugs within 30 days
• Diseases that represent contraindication to GLP-1RA use (pancreatitis, gallstones)
• Pregnancy or planned pregnancy within the time of the study
• Serum creatinine \> 1,3 mg/dL in women and \>1,4 mg/dL in men
• eGFR \< 30 mL/min
• Previous cancer or antineoplastic therapy for five years before randomization
• Current therapy with glucocorticoid (oral, topic or sistemic administration) or with antypsichotic drugs
• Previous ketoacidosis
• Any clinical, psychologic or psychiatric condition that is incompatible with the study according to the investigator

Sponsors & Collaborators

• University of Campania Luigi Vanvitelli: lead

Study Sites (1)

Unit of Endocrinology and Metabolic Diseases

Naples, 80138, Italy

Location

Related Publications (3)

• Giugliano D, Bellastella G, Maiorino MI, Esposito K. Beyond basal-bolus insulin regimen: Is it still the ultimate chance for therapy in diabetes? Diabetes Res Clin Pract. 2019 Nov;157:107922. doi: 10.1016/j.diabres.2019.107922. Epub 2019 Nov 9. No abstract available.

  PMID: 31715201 BACKGROUND

• Giugliano D, Longo M, Scappaticcio L, Caruso P, Gicchino M, Petrizzo M, Bellastella G, Maiorino MI, Esposito K. BEYOND 2 years: durability of metabolic benefits by simplification of complex insulin regimens in type 2 diabetes. Endocrine. 2024 Feb;83(2):399-404. doi: 10.1007/s12020-023-03547-9. Epub 2023 Oct 3.

  PMID: 37787888 DERIVED

• Giugliano D, Longo M, Caruso P, Di Fraia R, Scappaticcio L, Gicchino M, Petrizzo M, Bellastella G, Maiorino MI, Esposito K. Feasibility of Simplification From a Basal-Bolus Insulin Regimen to a Fixed-Ratio Formulation of Basal Insulin Plus a GLP-1RA or to Basal Insulin Plus an SGLT2 Inhibitor: BEYOND, a Randomized, Pragmatic Trial. Diabetes Care. 2021 Jun;44(6):1353-1360. doi: 10.2337/dc20-2623. Epub 2021 Apr 21.

  PMID: 33883195 DERIVED

MeSH Terms

Conditions

Diabetes Mellitus, Type 2

Interventions

IDegLira; Insulin

Condition Hierarchy (Ancestors)

Diabetes Mellitus; Glucose Metabolism Disorders; Metabolic Diseases; Nutritional and Metabolic Diseases; Endocrine System Diseases

Intervention Hierarchy (Ancestors)

Proinsulin; Insulins; Pancreatic Hormones; Peptide Hormones; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Peptides; Amino Acids, Peptides, and Proteins

Study Officials

• Katherine Esposito, MD, PhD

  Unit of Diabetology University of Campania Luigi Vanvitelli

  PRINCIPAL INVESTIGATOR

• Dario Giugliano, MD

  Unit of Endocrinology and Metabolic Diseases University of Campania Luigi Vanvitelli

  PRINCIPAL INVESTIGATOR

• Giuseppe Bellastella, MD, PhD

  Unit of Endocrinology and Metabolic Diseases University of Campania Luigi Vanvitelli

  STUDY CHAIR

• Maria Ida Maiorino, MD, PhD

  Unit of Diabetology University of Campania Luigi Vanvitelli

  STUDY CHAIR

Study Design

• Study Type: interventional
• Phase: phase 4
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Full Professor of Endocrinology and Metabolic Diseases

Study Record Dates

• First Submitted: December 6, 2019
• First Posted: December 12, 2019
• Study Start: November 27, 2019
• Primary Completion: September 30, 2020
• Study Completion: October 20, 2020
• Last Updated: October 22, 2020

Record last verified: 2020-10

Data Sharing

• IPD Sharing: Will not share

Locations

IT (1)