Clinical Study on the Improvement of Diabetic Neuropathic Pain by Liraglutide

October 23, 2019 updated by: Bin Lu, Fudan University
Diabetic neuropathic pain is a common clinical manifestation of diabetic neuropathy, which seriously affects the quality of life of patients. The clinical treatment is limited and the curative effect is not good. In the previous animal studies, investigators found that the change of pain threshold in diabetic rats showed a staged change, and was significantly related to the change of brain microglia activity. It was confirmed that liraglutide could regulate the activation of microglia in vitro. Then investigators found that it could intervene diabetic neuropathic pain through the intervention of liraglutide in diabetic rats. In the early stage of clinical observation, the investigators also preliminarily observed that liraglutide can intervene diabetic neuropathic pain. At present, liraglutide is a commonly used hypoglycemic drug in clinic. Therefore, on the basis of previous studies, this study intends to select diabetic neuropathic pain patients whose blood sugar is not up to the standard, and give Mecobalamin to treat diabetic neuropathy. In addition, on the basis of the original hypoglycemic treatment, participants are randomly divided into one group to give liraglutide, one group to increase or adjust insulin, with similar blood glucose level. The improvement of diabetic neuropathic pain was observed. The aim of this study was to evaluate the safety and efficacy of liraglutide in improving diabetic neuropathic pain.

Study Overview

Status

Unknown

Conditions

Intervention / Treatment

Detailed Description

1. Diabetic neuropathic pain seriously affects the quality of life, clinical problems are difficult, and new treatment methods are urgently needed.

Diabetic neuropathy is one of the most common complications of diabetes mellitus. The study of investigators shows that the prevalence rate of diabetic neuropathy diagnosed in downtown Shanghai is as high as 61.8%. The most common type of diabetic peripheral neuropathy is distal symmetric polyneuropathy, which is the main cause of diabetic neuropathic pain (DNP). Diabetic neuropathic pain can affect about one fifth of diabetic patients, which can lead to the decrease of daily activities, even the loss of work, severe depression, and quality of life. The pathogenesis of diabetic neuropathic pain is complex and not yet fully clear, so there is a lack of available and effective treatment. At present, the first-line clinical treatment drugs include pregabalin, duloxetine, amitriptyline, gabapentin and venlafaxine, etc., and these drugs sometimes relieve the symptoms of diabetic neuropathic pain not obvious, and have more side effects, which has become a difficult problem in clinical treatment. Therefore, it is urgent to explore effective drugs for diabetic neuropathic pain.

2. The clinical observation and animal study of the investigators show that the GLP-1 receptor agonist (liraglutide) can improve diabetic neuropathic pain.

  1. Diabetic neuropathic pain is related to brain microglia. In the animal model of diabetes mellitus, investigators found the phenomenon of abnormal activation of microglia. Previous studies showed that the abnormal activation of microglia at the level of spinal cord was closely related to diabetic neuropathic pain, and microglia at the level of spinal cord played an important role in the transmission of pain. As the center of pain loop, the activity of microglia in cerebral cortex and thalamus is less related to diabetic neuropathic pain.

    Therefore, investigators used STZ induced diabetic neuropathy model of SD rats. Before STZ injection (0 week), at the 2nd, 4th, 6th and 12th week after STZ induced hyperglycemia. The investigators monitored the changes of body weight, blood glucose level and pain threshold of mechanical pain and thermal pain in rats. The investigators used [18F] dpa714 specific marker transfer protein TSPO to carry out PET / CT scan of brain to reflect microglia in each brain area. After PET / CT scan, EMG was used to evaluate the degree of peripheral nerve injury. The results showed that after STZ injection, compared with the control group, the blood glucose of STZ group increased gradually, and with the increase of blood glucose, the nerve conduction velocity of diabetic rats decreased gradually. Mechanical pain decreased significantly in 4-6 weeks, thermal pain threshold decreased significantly in 4 weeks, and mechanical pain and thermal pain sensitivity disappeared in 12 weeks. The results of PET / CT showed that in cortex, hippocampus, thalamus, hypothalamus and pituitary, dpa714 standard uptake value was significantly higher than other time points in the fourth week, and significantly higher than that in the control group. The correlation analysis indicated that the pain threshold of thermal pain was significantly related to the activity of microglia in thalamus and hypothalamus. Previous studies have shown that hyperglycemia can induce neuropathic pain. Thermal hyperalgesia occurs 4 weeks after hyperglycemia, while mechanical hyperalgesia occurs 4-6 weeks. PET / CT study showed that the activity of microglia in the brain of diabetic rats increased in the fourth week, and the activity of microglia was significantly related to the occurrence of heat pain. It has not been reported that the relationship between the activity of microglia and diabetic neuropathic pain was directly observed by PET / CT.

  2. Liraglutide can regulate the activation of microglia Glucagon like peptide 1 (GLP-1) acts by binding to GLP-1 receptor, which is a G protein coupled receptor. A large number of studies have shown that GLP-1 receptor agonists can improve the activation of macrophages, microglia as macrophages in the brain, and GLP-1 receptor agonists can improve the activation of macrophages. However, few studies have shown that in vitro cultured astrocytes and microglia, GLP-1 analogues can change the morphology of glial cells, reduce IL-1 β and increase cAMP level at mRNA level.

    Therefore, liraglutide, the GLP-1 agonist, was selected as the intervention drug . BV2 microglia cell line was used as the following treatment methods: liraglutide was co cultured with LPS or high glucose, and liraglutide was added after LPS and high glucose induced activation. After treatment, the levels of IL-6 and TNF - α in the supernatant of the cells were observed. The results showed that liraglutide was added in advance before induction and activation. Or the level of IL-6 and TNF - α released by BV2 could be significantly reduced by using liraglutide. Therefore, liraglutide can regulate LPS and high glucose induced microglia activation.

  3. Animal experiments show that liraglutide can improve diabetic neuropathic pain. On the basis of previous work, the investigators further studied the effect of liraglutide on diabetic neuropathic pain at the animal level. SD rats were divided into three groups: normal blood glucose group, normal saline control group and 200ug / kg / dliraglutide injection group. The latencies and thresholds of thermal and mechanical pain were monitored weekly. It was observed that for diabetic neuropathic pain rats, the peripheral injection of GLP-1 receptor agonist (liraglutide 200ug / kg / D) significantly increased the thermal pain threshold at 4 weeks, the mechanical pain threshold at 8 weeks, and the pain sensitivity disappeared at 12 weeks in both the normal saline control group and the liraglutide injection group.
  4. Observation of clinical cases In clinical work, the investigators observed some obese patients with neuropathic pain in type 2 diabetes mellitus. In the process of using GLP-1 receptor agonist to control blood glucose, the symptoms of pain were also significantly improved. In addition, a clinical study showed that the use of sitagliptin (DPP-IV inhibitor, which can inhibit the degradation of GLP-1 in vivo) can also improve diabetic neuropathic pain. However, these observations and studies have significant limitations, not excluding the effect of blood glucose lowering itself in the population level, nor exploring the mechanism.

3. The clinical study of liraglutide in improving diabetic neuropathic pain has better clinical value.

The investigators found that liraglutide can improve the activation of microglia, and it can significantly alleviate diabetic neuropathic pain at the animal level and clinical cases. The systematic study of liraglutide used to improve neuropathic pain in diabetic patients has not been reported, and this subject has better clinical value.

Therefore, considering the hypoglycemic effect of liraglutide on the basis of previous studies, the investigators plan to select diabetic neuropathic pain patients whose blood sugar is not up to standard in this study, and give Mecobalamin (one of the commonly used drugs recommended in the guidelines for prevention and treatment of diabetes mellitus to treat neuropathy). At the same time, on the basis of the original hypoglycemic treatment, participants were randomly divided into one group to be given liraglutide and the other group to be increased/adjusted insulin. After 3 months, the improvement of diabetic neuropathic pain in the two groups under the condition of similar blood glucose level were observed. The purpose of this study was to evaluate the safety and efficacy of liraglutide in improving diabetic neuropathic pain.

Study Type

Interventional

Enrollment (Anticipated)

60

Phase

  • Not Applicable

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

14 years to 76 years (Adult, Older Adult)

Accepts Healthy Volunteers

No

Genders Eligible for Study

All

Description

Inclusion Criteria:

Age ≥ 18 and ≤ 80; The patients were diagnosed as type 2 diabetic neuropathic pain, and the score of pain digital scoring method was more than 3 points; 7-9% of glycosylated hemoglobin had poor blood glucose control.

Exclusion Criteria:

Non diabetic neuropathic pain; BMI < 20kg / m2; There are serious primary diseases such as cardiovascular, liver, kidney and hematopoietic system; In the past 1 month, there were acute complications such as diabetic ketoacidosis, lactic acidosis and hyperosmotic coma; Over the past five years, there have been alcoholics and / or psychoactive substances, drug abusers and addicts; Pregnant or lactating women; Unwillingness to cooperate or various factors affecting compliance; Psychopaths; Those who have participated in other clinical projects in the past 1 month.

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Treatment
  • Allocation: Randomized
  • Interventional Model: Parallel Assignment
  • Masking: Double

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Experimental: liraglutide group
Mecobalamin tablets (0.5mg/day, oral) and liraglutide (0.6mg/day in the first week, if there is no obvious discomfort, 1.2mg/day in the second week, subcutaneous injection) were used for 3 months.
Drug: Liraglutide
0.6mg/day in the first week, if there is no obvious discomfort, 1.2mg/day in the second week, subcutaneous injection, lasting for 3 months
Other Names:
  • GLP-1RA
Active Comparator: control group
Take Mecobalamin (0.5mg/day, oral), add or adjust insulin (when basic insulin is preferred for those who do not use insulin, if insulin has been used, adjust the dose or program according to the condition, inject subcutaneously) for 3 months.
Drug: insulin
Add or adjust insulin (when basic insulin is preferred for those who do not use insulin, such as those who have already used insulin, adjust the dosage or program according to the condition, inject subcutaneously) for 3 months

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Numerical pain scale (NRS)
Time Frame: 3 months
The number of 0-10 represents the degree of pain of the patient, 0 is no pain, 10 is extreme pain. How to write: circle the number that describes the most severe pain in the last 24 hours.
3 months

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Neurological symptom score (NSS) / neurological deficit score (NDS)
Time Frame: 3 months
Clinical diagnosis criteria of diabetic neuropathy: NDS score ≥ 6 points or NDS score 3-5 points with NSS score ≥ 5 points
3 months
Examination of nerve conduction function
Time Frame: 3 months
The examination of nerve conduction function was completed by professional doctors of EMG room using EMG evoked potential instrument. During the test, the patient was relaxed and lying in a quiet room, and the skin temperature was maintained at 32 ℃ ~ 33 ℃. Motor nerve examination includes: measurement of motor nerve conduction velocity, compound muscle action potential amplitude and distal latency of median nerve, ulnar nerve, common peroneal nerve and tibial nerve; sensory nerve examination includes: measurement of sensory nerve conduction velocity and action potential amplitude of median nerve, ulnar nerve, superficial peroneal nerve and sural nerve.
3 months

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Fudan University

Investigators

  • Study Director: Bin Lu, doctor, Huashan Hospital

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Anticipated)

November 30, 2019

Primary Completion (Anticipated)

November 30, 2022

Study Completion (Anticipated)

November 30, 2022

Study Registration Dates

First Submitted

October 22, 2019

First Submitted That Met QC Criteria

October 22, 2019

First Posted (Actual)

October 24, 2019

Study Record Updates

Last Update Posted (Actual)

October 25, 2019

Last Update Submitted That Met QC Criteria

October 23, 2019

Last Verified

October 1, 2019

More Information

Terms related to this study

Additional Relevant MeSH Terms

Other Study ID Numbers

  • 358106

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

No

IPD Plan Description

we have 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

No

Studies a U.S. FDA-regulated device product

No

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

Clinical Trials on Diabetic Neuropathic Pain

Clinical Trials on Liraglutide

Search Similar Trials

Sponsors and Collaborators

Medical Conditions

Drug Interventions

CROs by country

CROs in Serbia

Conditions

Rare Diseases

Drug Interventions

Dietary Supplements

Sponsor/Collaborators

Locations

Subscribe