Liver and Metabolic Effects of Insulin Pump Therapy in Diabetics Type 2 With Non-alcoholic Hepatic Steatosis (STEATO-POMPE)

Liver and Metabolic Effects of Insulin Pump Therapy in a Population of Type 2 Diabetics With Non-alcoholic Hepatic Steatosis

The prevalence of fatty liver disease (NAFLD: Non-Alcoholic Fatty Liver Disease or to a more severe degree NASH: Non-Alcoholic SteatoHepatitis) reached 40-70% in subjects with type 2 diabetes (T2D). NAFLD can be easily detected by performing a hepatic ultrasonography. The presence of a NAFLD is positively correlated with the severity of insulin resistance and dysglycemia in this population. The presence of NAFLD worsens the prognosis of T2D with an increased cardiovascular risk. This hepatic impairment would also increase the risk of microvascular complications, especially nephropathy. Conversely, T2D increases the risk of transition from NAFLD to NASH and then to hepatic fibrosis and its related complications (cirrhosis, hepatocellular carcinoma). The risk of progression of liver steatosis to fibrosis is also more important as diabetes and insulin resistance are more severe.

In addition to diabetes and insulin resistance, other risk factors are associated with more severe liver damage such as changes in microbiota. Indeed, it has already been described a smaller amount of bacteroides in the microbiota of subjects with T2D and the most severe hepatic impairment. The treatment of NAFLD/NASH is poorly codified without approved drugs in this indication, while many phase 3 trials with candidate drugs are undergoing. Life-style measures (physical activity and low carbohydrate/calorie diet) can limit the progression from NAFLD to more severe liver fibrosis. Some bariatric surgery studies have also shown good results in this situation. Pharmacological interventions are also reported with proven efficacy of pioglitazone, vitamin E and orlistat.

The OPT2MISE study has recently shown the superiority of insulin pump (or continuous sub-cutaneous insulin infusion: CSII) compared to multiple daily insulin injections (MDI) to improve glycemic control in a population of patients with T2D in failure of well-titrated MDI. In addition, treatment with CSII showed a 45% decrease in insulin resistance (assessed by HOMA-IR) in a population of newly diagnosed T2D.

In light of these data, investigators hypothesize that the introduction of insulin pump treatment in a population of subjects with T2D and NAFLD, by improving insulin sensitivity, could reduce fatty liver content compared to standard MDI treatment.

Study Overview

• Status: Recruiting
• Conditions: Type 2 Diabetes (T2D)
• Intervention / Treatment: Procedure: Insulin pump therapy; Procedure: Multi-injection treatment ( MDI ).

• Study Type: Interventional
• Enrollment (Anticipated): 52
• Phase: Not Applicable

Contacts and Locations

• Study Contact: Name: Matthieu Pichelin; Phone Number: 02.53.48.27.06; Email: matthieu.pichelin@chu-nantes.fr

Study Locations

• France
  • Angers, France, 49933
    • Recruiting
    • CHU
    • Contact: Claire BRIET
    • Principal Investigator: Claire BRIET
  • Caen, France, 14033
    • Not yet recruiting
    • CHU
    • Contact: Michaël JOUBERT, MD; Email: joubert-m@chu-caen.fr
    • Principal Investigator: Michaël JOUBERT, MD
  • Dijon, France, 21000
    • Not yet recruiting
    • CHU
    • Principal Investigator: Jean-Michel PETIT
    • Contact: Jean-Michel Petit, MD; Phone Number: 05.46.45.51.31
  • La Rochette, France, 17019
    • Recruiting
    • CHU
    • Contact: Didier GOUET, MD
    • Principal Investigator: Didier GOUET, MD
  • Lyon, France, 69495
    • Recruiting
    • Hospices Civils
    • Contact: Cyrielle CAUSSY, MD; Phone Number: 04 78 86 14 89
    • Principal Investigator: Cyrielle CAUSSY, MD
  • Nantes, France, 44093
    • Recruiting
    • Nantes UH
    • Contact: Matthieu Pichelin; Email: matthieu.pichelin@chu-nantes.fr
    • Principal Investigator: Bertrand Cariou, MD
  • Poitiers, France, 86000
    • Recruiting
    • CHU
    • Contact: Xavier PIGUEL, MD; Phone Number: 05.49.44.40.34
    • Principal Investigator: Xavier PIGUEL
  • Rennes, France, 35203
    • Not yet recruiting
    • CHU de Rennes
    • Contact: Isabelle GUILHEM, MD
    • Principal Investigator: Isabelle GUILHEM, MD
  • Toulouse, France, 31059
    • Recruiting
    • CHU
    • Contact: Pierre Gourdy, MD
    • Principal Investigator: Pierre GOURDY, MD

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 35 years to 68 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Male / female 35/70 years (including ranges) with T2D ≥ 1 year
• Benefiting from the indication of use of the free Freestyle glucose meter
• Treatment with multi-injection insulin therapy comprising a daily injection of basal insulin (Glargine U100, Glargine U300, Degludec) and at least 2 daily injections of an insulin analogue (lispro, aspart or glulisine) +/- metformin, dipeptidyl peptidase-4 (DPP4) and/or sodium-glucose cotransporter type 2 (SGLT2) at a dose stable for at least 3 months.
• For women of childbearing age, oestro-progestative pill, IUD, implant.
• 11% ≥ HbA1c ≥ 6.5%
• Presence of hepatic steatosis according to the ultrasonography
• Absence of chronic alcoholic intoxication
• Absence of chronic viral hepatitis or other chronic liver diseases (eg hemochromatosis ...)

Exclusion Criteria:

• Type 1 diabetes
• Contraindication to pump treatment
• Treatment with anti-diabetics or other than metformin, dipeptidyl peptidase-4 (DPP4) and/or sodium-glucose cotransporter type 2 (SGLT2)
• Treatment with basal inulin of Levemir
• Contraindication to performing MRI
• Chronic alcohol abuse (after alcohol consumption> 20g / day in men and> 10g / day in women) according to the medical examination
• Chronic viral hepatitis based on HBV and HCV serology results
• Hemochromatosis according to the martial assessment
• Other toxic or drug hepatitis
• Severe hepatic pathology: hepatic cirrhosis, hepatocellular carcinoma
• Severe renal insufficiency (MDRD <30 ml / min)
• Severe and progressive cardiovascular pathology
• Treatment (permanent or intermittent) with glucocorticoids
• Treatment known to improve hepatic steatosis (glitazone, vitamin E, orlistat)
• history or bariatric surgery project for the duration of the study
• Drug treatment likely to cause hepatic steatosis (amiodarone, carbamazepine, tamoxifen, valproate, clozapine, anti-retroviral drugs) unless the dose has been stable for ≥ 3 months
• Guardianship, curatorship or safeguard of justice

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Other
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Insulin pump therapy	Procedure: Insulin pump therapy; 5-day hospitalization in case of randomization in the insulin pump group (insulin pump establishing in according to the recommendations of the HAS)
Active Comparator: Multi-injection treatment ( MDI ).	Procedure: Multi-injection treatment ( MDI ).; Corresponds to an outpatient visit if the patient is randomized into the multi-injection group

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Variation of hepatic steatosis, between the insulin pump therapy (CSII) vs Multi injection treatement (MDI) groups.	Change of fatty liver by MRI quantification	6 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
In the CSII group : avantage of an insulin pump treatment on the fatty liver between inclusion and the 6th month,	Variation of hepatic steatosis (MRI quantization by gradient echo sequences & centralized reading	6 months
In the CSII group : avantage of an insulin pump treatment on the fatty liver (quantified by MRI), between inclusion and the 12th month,	Variation of hepatic steatosis (MRI quantization by gradient echo sequences & centralized reading	12 months
Evaluate the effectiveness of a CSII vs MDI treatment, between randomization and 6 months, on hepatic biological parameters and non-invasive biomarkers of fatty liver (FLI) and of fibrosis of the liver (FIB-4 and NAFLD Score),	Liver fonction (AST ; ALAT ; GGT ; PAL ; Ferritin) Test-fibrosis score criteria (FIB- 4 and NAFLD Score) ; FLI	6 months
Evaluate the effectiveness of a CSII vs MDI treatment, between randomization and 6 months on insulin sensitivity	dosage of plasma adiponectin	6 months
Evaluate the effectiveness of a CSII vs MDI treatment, between randomization and 6 months on insulin sensitivity	calculation of the modified HOMA-IR index (peptide C, blood sugar),	6 months
Evaluate the effectiveness of a CSII vs MDI treatment, between randomization and 6 months on glycemic balance	HbA1c dosages	6 months
Evaluate the effectiveness of a CSII vs MDI treatment, between randomization and 6 months on the total daily insulin dose	daily insulin dose record	6 months
Evaluate the effectiveness of a CSII vs MDI treatment, between randomization and 6 months on lipid profile • the inflammatory condition	total cholesterol	6 months
Evaluate the effectiveness of a CSII vs MDI treatment, between randomization and 6 months on lipid profile • the inflammatory condition	LDL-cholesterol	6 months
Evaluate the effectiveness of a CSII vs MDI treatment, between randomization and 6 months on lipid profile • the inflammatory condition	HDL-cholesterol	6 months
Evaluate the effectiveness of a CSII vs MDI treatment, between randomization and 6 months on lipid profile • the inflammatory condition	triglycerides (TG)	6 months
Evaluate the effectiveness of a CSII vs MDI treatment, between randomization and 6 months on lipid profile • the inflammatory condition	fatty-free acids	6 months
Evaluate the effectiveness of a CSII vs MDI treatment, between randomization and 6 months on lipid profile • the inflammatory condition	ApoB,	6 months
Evaluate the effectiveness of a CSII vs MDI treatment, between randomization and 6 months on CRPus	Ultra-sensitive C-reactive protein (CRPus)	6 months
Evaluation of quality of life	DTSQ	6 months
Evaluation of quality of life	SF36	6 months
Safety analysis at 6 months: comparison the first 6 months, in the CSII and MDI groups:	Reporting by patient of all severe hypoglycemia during the study	6 months
Safety analysis at 6 months: comparison the first 6 months, in the CSII and MDI groups:	Reporting by the patient of all episode of ketoacidosis during the study	6 months
Calculation of the sensitivity values of the FLI for the detection of fatty liver in this population,	quantification of hepatic MRI as Gold Standard.	6 months
Calculation of the specificity values of the FLI for the detection of fatty liver in this population, by using the quantification of hepatic MRI as Gold Standard.	quantification of hepatic MRI as Gold Standard.	6 months
Calculation of the positive predictive values of the FLI for the detection of fatty liver in this population, by using the quantification of hepatic MRI as Gold Standard.	quantification of hepatic MRI as Gold Standard.	6 months
Calculation negative predictive values of the FLI for the detection of fatty liver in this population, by using the quantification of hepatic MRI as Gold Standard.	quantification of hepatic MRI as Gold Standard.	6 months

Collaborators and Investigators

• Sponsor: Nantes University Hospital
• Collaborators: University Hospital, Angers

Study record dates

Study Major Dates

• Study Start (Actual): February 5, 2021
• Primary Completion (Anticipated): April 5, 2023
• Study Completion (Anticipated): April 5, 2023

Study Registration Dates

• First Submitted: February 10, 2020
• First Submitted That Met QC Criteria: February 12, 2020
• First Posted (Actual): February 17, 2020

Study Record Updates

• Last Update Posted (Actual): March 23, 2021
• Last Update Submitted That Met QC Criteria: March 22, 2021
• Last Verified: March 1, 2021

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Digestive System Diseases; Liver Diseases; Fatty Liver; Hypoglycemic Agents; Physiological Effects of Drugs; Insulin
• Other Study ID Numbers: RC19_0449

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