Efficacy and Tolerance of Liraglutide for Weight Loss in Obese Type 2 Diabetic Hemodialysis Patients

Diabetes Mellitus, Type 2 Clinical Trial

— LIRADIAL  

Official title:

Efficacy and Tolerance of Liraglutide for Weight Loss in Obese Type 2 Diabetic Hemodialysis Patients

Clinical Trial Details — Status: Active, not recruiting

Administrative data

• NCT number: NCT04529278
• Other study ID #: LIRADIAL
• Status: Active, not recruiting
• Phase: Phase 2
• Start date: January 18, 2021
• Est. completion date: December 31, 2023

Study information

• Verified date: April 2023
• Source: Groupe Hospitalier Paris Saint Joseph
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

Diabetes is the second leading cause of end stage renal disease in France (22% in the 2016 REIN register). In hemodialysis, its prevalence is higher, between 30-40% depending on the study. Associated with type 2 diabetes, a large number of patients present with overweight (body mass index or BMI> 25 kg / m2) which can lead to a temporary contraindication to kidney transplant by the surgeon, or even definitive once BMI is over 30 kg / m2. Indeed, above this threshold, patients are exposed to an increased risk of surgical complications (wall infections, suture release), hospitalizations and potentially transplant failure. A recent study based on the Kidney Registry showed that patients with a BMI> 31 kg / m2 were more likely to stay on dialysis than to benefit from a transplant whereas for each decrease of 1 kg / m2 of BMI, there is a 9-11% increase in the likelihood of being transplanted. The management of obesity in dialysis patients is important for reducing cardiovascular risks but also because it increases the chances of access to transplantation. However, current weight loss programs are disappointing. The changes in hygiene and diet rules integrated into a specialized monitoring program only allow a weight loss of 2 to 8% in 24 months for half of the patients. Bariatric surgery is, of course, a more effective alternative, but with a 10% risk of postoperative complications. Glucagon-Like Peptide 1 (aGLP1) analogues are a new class of antidiabetic drugs that have revolutionized the management of type 2 diabetes. In fact, they combine efficacy on glycemic control but also on weight loss. They are used in obese non-diabetic people in some countries, with a reduction in weight of up to 10 to 15% with certain molecules. In addition, they have shown an effect on reducing cardiovascular events in diabetics including with Chronic Kidney Disease CKD 3-4. AGPL1 are well tolerated with side effects mainly of digestive tropism such as nausea or vomiting. Exceptionally, these effects can occur from the first injection requiring permanent discontinuation of treatment. In 20% of cases, these side effects can appear in the first weeks. They gradually fade, spontaneously or after symptomatic treatment and allow titration of the drug. AGLP1 is currently contraindicated in patients with reduced renal function, that is, when the glomerular filtration rate (GFR) is <15 ml / min (MRC stage 5-5D), because this population specific was excluded from the originator studies. However, aGLP1 are small peptides that are not eliminated by the kidneys. Their elimination takes place through the general catabolism of proteins. To date, 2 publications have evaluated the safety profile and efficacy of an aGLP1, liraglutide (Victoza®), in diabetic dialysis patients. These studies showed that the 24 hour plasma concentration of liraglutide increased by 50% over the long term. The safety profile was acceptable with, as expected, a predominance of gastrointestinal effects in the first weeks of treatment such as nausea, vomiting. The authors suggest an adjustment of the dosages and a longer titration period to limit side effects. However, treatment with aGPL1 is effective with better glycemic control and an average weight loss of 2.6 kg over a period of 3 months. Studies show that weight loss under liraglutide continues beyond 3 months with possible losses between 4 and 8 kg at 6 months and 12 months of treatment followed 12. Liraglutide (Victoza®) is the analogue of GPL1 for which we have a sufficiently long follow-up (> 10 years) on its effectiveness and its short and long-term side effects. The main objective of this project, in type 2 diabetic patients on dialysis, as a temporary contraindication for transplant due to overweight, is on the one hand to study the effect of liraglutide on weight loss and control of diabetes, and on the other hand to assess its tolerance in this population. The expected benefit is to be able to facilitate registration on the waiting list and access to renal transplantation of these overweight patients, without having to resort to more invasive methods such as bariatric surgery.

Recruitment information / eligibility

• Status: Active, not recruiting
• Enrollment: 18
• Est. completion date: December 31, 2023
• Est. primary completion date: January 17, 2023
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years to 70 Years

Eligibility

Inclusion Criteria:

• Patient aged = 18 and <70
• Patient on hemodialysis for more than 6 months
• Type 2 diabetic patient
• Patient with a BMI> 30 kg / m2 with a Temporary Contraindication for kidney transplant for renal transplant due to overweight by his graft center
• Patient affiliated to a health insurance plan
• French speaking patient
• Patient having given free, informed and written consent

Exclusion Criteria:

• Patient with a Temporary Contraindication for kidney transplant for a cause other than overweight
• Patient with personal or family history of thyroid medullary cancer
• Patient with a history of acute or chronic pancreatitis
• Patient who has already had hypersensitivity to liraglutide (or to any other component of the product)
• Patient who has already had a severe digestive intolerance to taking GLP-1 receptor agonists (such as exenatide or lixisenatide)
• Patient already included in an interventional risk research protocol (RIPH1)
• Pregnant or lactating woman
• Patient under guardianship or curatorship
• Patient deprived of liberty

Related Conditions & MeSH terms

• Diabetes Mellitus, Type 2
• Hemodialysis
• Obese
• Weight Loss

Intervention

Drug:
• Liraglutide
Liraglutide is initiated at 0.6 mg / day during week S1 (initiation D1) during weekly hospitalization in the diabetology department. Then the dose of liraglutide is increased to 1.2 mg / day on week S2 (increase in dose on D8) then to 1.8 mg / day on week S3 (increase in dose on D15). The daily dose is then 1.8 mg until week W26.

Locations

Country	Name	City	State
France	AURA Paris Plaisance	Paris	Groupe Hospitalier Paris Saint-Joseph
France	Groupe Hospitalier Paris Saint-Joseph	Paris
France	Hôpital Bichat	Paris
France	AURA Paris Site de Saint Ouen	Saint-Ouen

Sponsors (1)

Lead Sponsor	Collaborator
Groupe Hospitalier Paris Saint Joseph

Country where clinical trial is conducted

France, 

References & Publications (12)

Astrup A, Rossner S, Van Gaal L, Rissanen A, Niskanen L, Al Hakim M, Madsen J, Rasmussen MF, Lean ME; NN8022-1807 Study Group. Effects of liraglutide in the treatment of obesity: a randomised, double-blind, placebo-controlled study. Lancet. 2009 Nov 7;374 — View Citation

Gill JS, Hendren E, Dong J, Johnston O, Gill J. Differential association of body mass index with access to kidney transplantation in men and women. Clin J Am Soc Nephrol. 2014 May;9(5):951-9. doi: 10.2215/CJN.08310813. Epub 2014 Apr 17. — View Citation

Idorn T, Knop FK, Jorgensen MB, Jensen T, Resuli M, Hansen PM, Christensen KB, Holst JJ, Hornum M, Feldt-Rasmussen B. Safety and Efficacy of Liraglutide in Patients With Type 2 Diabetes and End-Stage Renal Disease: An Investigator-Initiated, Placebo-Contr — View Citation

Lassalle M, Fezeu LK, Couchoud C, Hannedouche T, Massy ZA, Czernichow S. Obesity and access to kidney transplantation in patients starting dialysis: A prospective cohort study. PLoS One. 2017 May 11;12(5):e0176616. doi: 10.1371/journal.pone.0176616. eColl — View Citation

MacLaughlin HL, Cook SA, Kariyawasam D, Roseke M, van Niekerk M, Macdougall IC. Nonrandomized trial of weight loss with orlistat, nutrition education, diet, and exercise in obese patients with CKD: 2-year follow-up. Am J Kidney Dis. 2010 Jan;55(1):69-76. — View Citation

Mann JFE, Orsted DD, Brown-Frandsen K, Marso SP, Poulter NR, Rasmussen S, Tornoe K, Zinman B, Buse JB; LEADER Steering Committee and Investigators. Liraglutide and Renal Outcomes in Type 2 Diabetes. N Engl J Med. 2017 Aug 31;377(9):839-848. doi: 10.1056/N — View Citation

Nauck M, Frid A, Hermansen K, Shah NS, Tankova T, Mitha IH, Zdravkovic M, During M, Matthews DR; LEAD-2 Study Group. Efficacy and safety comparison of liraglutide, glimepiride, and placebo, all in combination with metformin, in type 2 diabetes: the LEAD ( — View Citation

Nicoletto BB, Fonseca NK, Manfro RC, Goncalves LF, Leitao CB, Souza GC. Effects of obesity on kidney transplantation outcomes: a systematic review and meta-analysis. Transplantation. 2014 Jul 27;98(2):167-76. doi: 10.1097/TP.0000000000000028. — View Citation

O'Neil PM, Birkenfeld AL, McGowan B, Mosenzon O, Pedersen SD, Wharton S, Carson CG, Jepsen CH, Kabisch M, Wilding JPH. Efficacy and safety of semaglutide compared with liraglutide and placebo for weight loss in patients with obesity: a randomised, double- — View Citation

Osonoi T, Saito M, Tamasawa A, Ishida H, Tsujino D, Nishimura R, Utsunomiya K. Effect of hemodialysis on plasma glucose profile and plasma level of liraglutide in patients with type 2 diabetes mellitus and end-stage renal disease: a pilot study. PLoS One. — View Citation

Overbeek JA, Heintjes EM, Huisman EL, Tikkanen CK, van Diermen AW, Penning-van Beest FJA, Herings RMC. Clinical effectiveness of liraglutide vs basal insulin in a real-world setting: Evidence of improved glycaemic and weight control in obese people with t — View Citation

Turgeon NA, Perez S, Mondestin M, Davis SS, Lin E, Tata S, Kirk AD, Larsen CP, Pearson TC, Sweeney JF. The impact of renal function on outcomes of bariatric surgery. J Am Soc Nephrol. 2012 May;23(5):885-94. doi: 10.1681/ASN.2011050476. Epub 2012 Mar 1. — View Citation

* Note: There are 12 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Weight Loss at Week 26	This outcome corresponds to Assess weight loss in obese diabetic patients on hemodialysis after 6 months of treatment with liraglutide in order to facilitate access to renal transplants for patients who have been rejected for being overweight.	Week 26
Secondary	Lift of CIT for transplant for obesity	This outcome corresponds to establish the number and percentage of patients whose CIT transplant for obesity will be lifted after 6 months of treatment.	Week 26
Secondary	Tolerance of luraglutide	This outcome corresponds to evaluate the number and percentage of serious and non-serious adverse events in type 2 diabetic patients on hemodialysis.	Week 26
Secondary	Regulation of blood sugar	This ouctome correspond to evaluate the reducing the number / dose of anti-diabetic drugs or the daily dose of insulin.	Week 26
Secondary	Glycemic balance	This ouctome correspond to compare the average variations in glycated hemoglobin (HbA1c) between M0 and M6.	Week 26
Secondary	Hypoglycemia	This ouctome correspond to evaluate the percentage of hypoglycaemia between Week 1 and Week 26.	Week 26
Secondary	Evolution of weight	This ouctome corresponds to evaluate the modifications of the dry mass and the fatty mass between M0 and M6 by bioimpedancemetry.	Week 26
Secondary	Therapeutic monitoring	This ouctome corresponds to evaluateconcentration of liraglutide before and after the dialysis session.	Week 26