Effects of Sequential Treatment Based on Lina/MET After Short-term Intensive Insulin in Newly Diagnosed Type 2 Diabetes

Effects of Linagliptin and Metformin Monotherapy or Combined Sequential Treatment After Early Short-term Intensive Insulin Treatment on Long-term Blood Glucose Control and Function of β Cells in Patients With Type 2 Diabetes

Short-term intensive insulin therapy(SIIT) is able to reverse β cell dysfunction and induce glycemic remission in patients with newly diagnosed type 2 diabetes. However, proportion of patients with response gradually decreases over time. There is no consensus on which treatment should be given in order to maintain the benefit in glycemic control and β cell recovery. In this multi-center, randomized, controlled study, effects of various sequential treatments ( metformin, linagliptin and combined with both drugs) on long-term blood glucose control as well as preservation of β cell function after SIIT were investigated.

In total, 448 patients with newly diagnosed type 2 diabetes who meet the inclusive criteria will be enrolled in eight centers in China. After baseline assessments, all patients will be treated with insulin pump to achieve and maintain euglycemia for 2 weeks. After completion of intensive treatment, insulin pump will be stopped. Different treatments will be applied to patients for 48 weeks according to randomization: Group A: Linagliptin 5 mg Qd + Metformin 0.5 g bid; Group B: Linagliptin 5 mg Qd; Group C: Metformin 0.5 g bid; Group D: No oral drugs. Primary endpoint is proportion of patients achieving glycosylated hemoglobin A1C <7% at the end of the study. Secondary endpoints include proportion of patients achieving glycosylated hemoglobin A1C <6.5% at the end of study; differences in β-cell function , insulin sensitivity, GLP-1 and glucagon secretion among treatment groups, and differences in adverse events among treatment groups.

Study Overview

• Status: Recruiting
• Conditions: Type 2 Diabetes Mellitus
• Intervention / Treatment: Drug: CSII followed by Lina+MET; Drug: CSII followed by Lina; Drug: CSII followed by MET; Drug: CSII alone

• Study Type: Interventional
• Enrollment (Anticipated): 448
• Phase: Phase 4

Contacts and Locations

Study Locations

• China
  • Guangdong
    • Guangzhou, Guangdong, China, 510080
      • Recruiting
      • endocrinology department of the first affiliated hospital of Sun Yat-sen University

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 25 years to 65 years (ADULT, OLDER_ADULT)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

1. Patients with type 2 diabetes who have never received any hypoglycemic treatment, or patients with type 2 diabetes <1 year from diagnosis who have used no more than 1 type of hypoglycemic drug for no more than 1 week and discontinued for more than 4 weeks before enrollment;
2. Fasting plasma glucose (FPG) between 7.0 mmol/l (126 mg/dl) and 16.7 mmol/l (300 mg/dl); glycosylated hemoglobin A1C>8.5%;
3. Aged between 25 and 65 years, body mass index (BMI) 22-35 kg/m2.

Exclusion Criteria:

1. Type 1 diabetes or special type of diabetes;
2. Acute complications of diabetes (including DKA, HHS and lactic acidosis)
3. Serious microvascular complications: proliferative stage of retinopathy; urine AER >300 mg/g or urine protein positive, quantification >0.5 g/d; uncontrolled painful diabetic neuropathy and significant diabetic autonomic neuropathy;
4. Severe macrovascular complications: acute cerebrovascular accident, acute coronary syndrome, vascular intervention for peripheral arterial disease or amputation requiring hospitalization within 12 months prior to enrollment;
5. Persistently increased blood pressure >180/110 mmHg;
6. Blood creatinine clearance less than 50 ml/min, alanine aminotransferase ≥2.5×upper limit of normal, total bilirubin ≥1.5×upper limit of normal;
7. Hemoglobin <100 g/L or need regular blood transfusion;
8. Use of drugs that may influence blood glucose within 12 weeks;
9. Systemic infection or serious concomitant disease; patients with malignancy or chronic diarrhea;
10. Uncontrolled endocrine gland dysfunction;
11. Patients with mental or communication disorders;
12. Chronic cardiac insufficiency, heart function class III and above;
13. Pregnant women, lactating women and women of child bearing age who are not willing to take contraception during the study;
14. Subjects who don't cooperate, cannot be followed up or have difficulty in completing the study considered by the investigator.

Study Plan

How is the study designed?

Design Details

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

Number of Arms

4

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
ACTIVE_COMPARATOR: Linagliptin plus metformin; CSII followed by Linagliptin 5 mg Qd + Metformin 0.5 g bid for 48 weeks	Drug: CSII followed by Lina+MET; short-term intensive CSII followed by Linagliptin 5mg qd and Metformin 0.5g bid for 48 weeks; Other Names: CSII+Lina+Met
ACTIVE_COMPARATOR: Linagliptin; CSII followed by Linagliptin 5mg Qd for 48 weeks	Drug: CSII followed by Lina; short-term intensive CSII followed by Linagliptin 5mg qd for 48 weeks; Other Names: CSII+Lina
ACTIVE_COMPARATOR: Metformin; CSII followed by Metformin 0.5 bid for 48 weeks	Drug: CSII followed by MET; short-term intensive CSII followed by Metformin 0.5g bid for 48 weeks; Other Names: CSII+Met
ACTIVE_COMPARATOR: Lifestyle alone; No OHA is given after CSII	Drug: CSII alone; No OHA is given after short-term intensive CSII; Other Names: CSII

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
proportion of subjects with optimal glycemic control	proportion of patients achieving glycosylated hemoglobin A1C <7% at the end of sequential treatment in each treatment group.	48 weeks

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
proportion of subjects with excellent glycemic control	proportion of patients achieving glycosylated hemoglobin A1C <6.5% at the end of sequential treatment in each treatment group.	48 weeks
Change of β cell function	Differences in β-cell indicators among treatment arms at the end of study.	48 weeks
Change of insulin sensitivity	Differences in insulin sensitivity indicators among treatment arms at the end of study.	48 weeks
Incidence of adverse events	Differences in incidence of adverse events among treatment arms at the end of study.	48 weeks

Collaborators and Investigators

• Sponsor: Sun Yat-sen University
• Collaborators: Guangdong Provincial Hospital of Traditional Chinese Medicine; The Third Affiliated Hospital of Guangzhou Medical University; Guangzhou First People's Hospital; Nanfang Hospital of Southern Medical University; The Third Affiliated Hospital of Southern Medical University; Sun Yat-Sen Memorial Hospital of Sun Yat-Sen University; Guangdong Provincial People's Hospital; Zhujiang Hospital

Study record dates

Study Major Dates

• Study Start (ACTUAL): November 1, 2017
• Primary Completion (ANTICIPATED): December 31, 2022
• Study Completion (ANTICIPATED): December 31, 2022

Study Registration Dates

• First Submitted: June 19, 2017
• First Submitted That Met QC Criteria: June 19, 2017
• First Posted (ACTUAL): June 21, 2017

Study Record Updates

• Last Update Posted (ACTUAL): April 29, 2021
• Last Update Submitted That Met QC Criteria: April 28, 2021
• Last Verified: April 1, 2021

More Information

Terms related to this study

• Keywords: Metformin; Type 2 diabetes mellitus; Linagliptin; Continuous subcutaneous insulin infusion
• Additional Relevant MeSH Terms: Glucose Metabolism Disorders; Metabolic Diseases; Endocrine System Diseases; Diabetes Mellitus; Diabetes Mellitus, Type 2
• Other Study ID Numbers: 2016146

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: UNDECIDED

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