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

Durability of Combination of Insulin and GLP-1 Receptor Agonist or SGLT-2 Inhibitors Versus Basal Bolus Insulin Regimen in Type 2 Diabetes: a Randomized Controlled Trial

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.

Study Overview

• Status: Completed
• Conditions: Type 2 Diabetes
• Intervention / Treatment: Drug: IDegLira; Drug: IGlarLixi; Drug: Insulin/Canaglifozin; Drug: Insulin/Dapaglifozin; Drug: Insulin/Empaglifozin; Drug: Basal Bolus

• Study Type: Interventional
• Enrollment (Actual): 258
• Phase: Phase 4

Contacts and Locations

Study Locations

• Italy
  • Naples, Italy, 80138
    • Unit of Endocrinology and Metabolic Diseases

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 35 years to 75 years (ADULT, OLDER_ADULT)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

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

Exclusion Criteria:

• 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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: RANDOMIZED
• Interventional Model: PARALLEL
• Masking: NONE

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
ACTIVE_COMPARATOR: FR insulin/GLP-1RA; 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; 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).; Drug: IGlarLixi; 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).
ACTIVE_COMPARATOR: Insulin/SGLT-2i; 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; 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).; Drug: Insulin/Dapaglifozin; 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; Drug: Insulin/Empaglifozin; 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).
ACTIVE_COMPARATOR: Basal Bolus; 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; 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.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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 Outcome Measures

Outcome Measure	Measure Description	Time Frame
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
Post-prandial glycemia change		Baseline, 6 months, 18 months
C-peptide change		Baseline, 6 months, 18 months
Change in total daily insulin dose		Baseline, 6 months, 18 months
Change in lipide profile	Difference between groups in total cholesterol, LDL-cholesterol, HDL-cholesterol, triglycerides	Baseline, 6 months, 18 months
Change in eGFR		Baseline, 6 months, 18 months
Diabetes treatment satisfaction	In order to measure satisfaction with diabetes treatment regimens, we used the self-reported Diabetes Treatment Satisfaction Questionnaire. This instrument aims to assess levels of satisfaction in subjects using different treatment strategies. The questionnaire consists of eight questions: six questions addresses general satisfaction with a score from 0 to 6 for each question (0 = worst), that has to be computed in a total score ranging from 0 (=worst) to 36 (=best); among the remaining two questions, which has to be computed separately as two subscales, one concerns the perception of hyperglycemic events and another the perception of hypoglycemic events, both with a score from 0 (none of the time) to 6 (most of the time).	Baseline, 6 months, 18 months

Collaborators and Investigators

• Sponsor: University of Campania "Luigi Vanvitelli"
• Investigators: Principal Investigator: 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; Study Chair: 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

Publications and helpful links

General Publications

• 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.
• 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.

Study record dates

Study Major Dates

• Study Start (ACTUAL): November 27, 2019
• Primary Completion (ACTUAL): September 30, 2020
• Study Completion (ACTUAL): October 20, 2020

Study Registration Dates

• First Submitted: December 6, 2019
• First Submitted That Met QC Criteria: December 11, 2019
• First Posted (ACTUAL): December 12, 2019

Study Record Updates

• Last Update Posted (ACTUAL): October 22, 2020
• Last Update Submitted That Met QC Criteria: October 20, 2020
• Last Verified: October 1, 2020

More Information

Terms related to this study

• Keywords: type 2 diabetes; glycemic control; basal insulin; GLP-1RA; SGLT-2i; basal bolus
• Additional Relevant MeSH Terms: Glucose Metabolism Disorders; Metabolic Diseases; Endocrine System Diseases; Diabetes Mellitus; Diabetes Mellitus, Type 2; Hypoglycemic Agents; Physiological Effects of Drugs; Insulin; Insulin, Globin Zinc
• Other Study ID Numbers: BEYOND Protocol

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

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