Targeting Beta-cell Failure in Lean Patients With Type 2 Diabetes

NCT04657939 | Completed Phase 4

• 3 other identifiers: 26520818/000590819/WM/0365
• Study Type: interventional
• Target: 57
• Locations: 1 country
• Sites: 1

Brief Summary

The majority of people with type 2 diabetes (T2D) are overweight, and while weight gain is a major contributor to diabetes, a minority of patients with T2D are not overweight or obese. The reasons why lean or normal body weight individuals develop T2D (lean-T2D) are not yet understood. T2D occurs when the body does not produce enough insulin, or becomes less sensitive to its effects. Insulin acts like a key to allow sugar into cells and if someone is overweight that key works less well. Recent research suggests that T2D in lean people should be considered a different disease from the diabetes associated with obesity and the main problem in lean-T2D patients may be a reduced capacity of insulin secretion. However, some researchers argue that many seemingly thin people carry more fat than muscle, making them trim on the outside, but fat on the inside, and they are in fact not truly lean. This implies that just like overweight diabetics, lean diabetics also have high resistance to insulin. The main aim of this research is to better understand the main driver of T2D in lean individuals, as this will determine how best to treat these individuals. There are many different types of drugs for treating T2D. Liraglutide improves insulin secretion capacity of the pancreas. Pioglitazone reduces resistance to insulin action. The investigators will compare the actions of these diabetes drugs on the blood supply and the heart's energy levels in lean-T2D and obese-T2D patients. This will allow the investigators to determine the ideal treatment strategies for improving cardiovascular health in lean-T2D patients, and better understand the role of impaired insulin secretory capacity, insulin resistance and excess fat deposition specifically in this group.

Conditions

Diabetes Mellitus, Type 2

Outcome Measures

Primary Outcomes (1)

• Change in myocardial perfusion after treatment

  Measured changes in myocardial perfusion by Magnetic Resonance Imaging (MRI) after treatment with liraglutide and pioglitazone.

  40 weeks

Secondary Outcomes (7)

• Myocardial energetics (PCr/ATP ratio)

  40 weeks

• Myocardial steatosis (myocardial triglyceride content)

  40 weeks

• Myocardial function

  40 weeks

• Insulin resistance (HOMA-IR)

  40 weeks

• Physical performance

  40 weeks

Study Arms (2)

Liraglutide-Pioglitazone

ACTIVE COMPARATOR

Participants randomised to receive liraglutide treatment for 16 weeks, followed by an 8 week washout then commencing 16 weeks of treatment with pioglitazone.

Drug: Liraglutide; Drug: Pioglitazone

Pioglitazone-Liraglutide

ACTIVE COMPARATOR

Participants randomised to receive pioglitazone treatment for 16 weeks, followed by an 8 week washout then commencing 16 weeks of treatment with liraglutide.

Drug: Liraglutide; Drug: Pioglitazone

Interventions

Liraglutide DRUG

Liraglutide 0.6mg once daily by subcutaneous injection escalated to 1.2mg after 2 weeks.

Liraglutide-Pioglitazone; Pioglitazone-Liraglutide

Pioglitazone DRUG

Pioglitazone 15mg once daily tablets taken orally escalated to 30mg after 2 weeks then escalated to 45mg after another 2 weeks.

Liraglutide-Pioglitazone; Pioglitazone-Liraglutide

Eligibility Criteria

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

You may qualify if:

• Lean cohort
• Men and women\>18 years of age;
• Normal body weight (18.5 ≤ BMI ≤25 kg/m2);
• T2D patients can be on treatment with oral glucose lowering therapies, and if they are, they must have been on these treatments for at least 12 weeks prior to screening;
• ≤HBA1c≤10% at screening;
• Agreement to maintain prior diet and exercise habits for the duration of the study.
• Overweight cohort
• Men and women\>18 years of age;
• Increased body weight (BMI \>27 kg/m2);
• T2D patients can be on treatment with oral glucose lowering therapies, and must have been on these treatments for at least 12 weeks prior to screening;
• ≤HBA1c≤10% at screening;
• Agreement to maintain prior diet and exercise habits for the duration of the study.

You may not qualify if:

• Any type of diabetes other than T2D;
• Past history of significant CAD;
• Known HF;
• Significant renal impairment (eGFR\<30ml/min/m2);
• Participation in a clinical trial of an investigational medicinal product (CTIMP) in the preceding 12 weeks;
• Known hypersensitivity to dobutamine or gadolinium or any other contra-indications to MRI;
• Participants with obesity where their girth exceeds the scanner bore;
• History of pancreatitis;
• Any history of liver disease;
• Patients with Multiple Endocrine Neoplasia syndrome type 2 (MEN 2);
• Prior or current use of thiazolidinediones (aka PPAR-γ agonists), fibrates, GLP-1RA or insulin;
• Patients that are pregnant (female participants only);
• Inflammatory bowel disease
• Diabetic gastroparesis

Sponsors & Collaborators

• University of Leeds: lead

Study Sites (1)

Leeds Teaching Hospitals Trust

Leeds, West Yorkshire, LS1 3EX, United Kingdom

Location

Related Publications (1)

• Chowdhary A, Thirunavukarasu S, Joseph T, Jex N, Kotha S, Giannoudi M, Procter H, Cash L, Akkaya S, Broadbent D, Xue H, Swoboda P, Valkovic L, Kellman P, Plein S, Rider OJ, Neubauer S, Greenwood JP, Levelt E. Liraglutide Improves Myocardial Perfusion and Energetics and Exercise Tolerance in Patients With Type 2 Diabetes. J Am Coll Cardiol. 2024 Aug 6;84(6):540-557. doi: 10.1016/j.jacc.2024.04.064.

  PMID: 39084829 DERIVED

MeSH Terms

Conditions

Diabetes Mellitus, Type 2

Interventions

Liraglutide; Pioglitazone

Condition Hierarchy (Ancestors)

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

Intervention Hierarchy (Ancestors)

Glucagon-Like Peptide 1; Glucagon-Like Peptides; Proglucagon; Gastrointestinal Hormones; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Thiazolidinediones; Thiazoles; Sulfur Compounds; Organic Chemicals; Azoles; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds

Study Design

• Study Type: interventional
• Phase: phase 4
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: CROSSOVER
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Principal Investigator

Study Record Dates

• First Submitted: December 1, 2020
• First Posted: December 8, 2020
• Study Start: December 1, 2020
• Primary Completion: October 31, 2022
• Study Completion: October 31, 2022
• Last Updated: February 27, 2023

Record last verified: 2023-02

Locations

GB (1)