The Effect of Glucagon-like-peptide 1 (GLP-1) Receptor Agonism on Diabetic Kidney Disease

Diabetic Kidney Disease Clinical Trial

Official title:

Phase 3 Study of the Effect of Glucagon-like-peptide 1 (GLP-1) Receptor Agonism on Renal Outcomes in Humans With Diabetic Kidney Disease

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT01847313
• Other study ID #: GLP-1-2012-01
• Status: Completed
• Phase: Phase 3
• Start date: April 2013
• Est. completion date: November 2015

Study information

• Verified date: September 2018
• Source: University College Dublin
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

Diabetic kidney disease (DKD) is a devastating complication of diabetes, that in it's worst form, can lead to early cardiovascular death or kidney failure. A group of medicines used to treat diabetes, glucagon-like-peptide-1 analogues (GLP-1), may be able to protect people with diabetes from DKD by reducing inflammation in the kidney. This study aims to test this theory by studying the effect of GLP-1 on kidney function in people with diabetes.

To understand how GLP-1 can affect inflammation, the investigators will give a GLP-1 treatment (Liraglutide) to people with DKD and monitor the effect on inflammation and kidney function using blood and urine tests. The investigators will compare these results to patients with DKD who do not receive GLP-1 treatment.

If GLP-1 proves to be effective in reducing inflammation and improving kidney function, then it could be developed as a viable new treatment for people with DKD, and may significantly reduce the disease burden, or the risk of DKD, in people with diabetes. This would be a major advance in the treatment of DKD.

Description:

A randomised controlled trial for patients with microalbuminuria and type 2 diabetes. Treatment is 0.6mg of liraglutide and is compared to standard care. Treatment duration is 6 months.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 20
• Est. completion date: November 2015
• Est. primary completion date: November 2015
• Accepts healthy volunteers: No
• Gender: All
• Age group: 30 Years to 75 Years

Eligibility

Inclusion Criteria:

• Type 2 diabetes with a HbA1c of 42-75mmol/mol (6-9%DCCT)

• Male or female aged above 30 years

• Have a negative pregnancy test at screening (women of child bearing potential only)

• Body mass index (BMI) of 25kg/m2 or greater

• On a renin-angiotensin system antagonist, at a stable dose, for at least 8 weeks before inclusion into the study

• Established microalbuminuria

• Estimated glomerular filtration rate (eGFR) 30ml/min/1.73m2 or above by Modification of Diet in Renal Disease (MDRD) formula

Exclusion Criteria:

• Patients with any cognitive impediment that preclude the patient from giving free and informed consent

• Patients on dipeptidyl peptidase 4 inhibitors or thiazolidinedione treatment

• Patients with stage 4-5 renal disease, defined as an eGFR of 30ml/min/1.73m2 or less

• Patients who have used a GLP-1 agent in the last 6 months

• Female patients of child bearing potential who are pregnant, breastfeeding, or unwilling to practice an acceptable barrier and/or hormonal method of contraception or abstinence during participation in the study

• Previous pancreatitis

• Hypersensitivity to GLP-1 analogues

• Proliferative diabetic retinopathy

• Any other contraindications, as per the SmPC for liraglutide

• Patients with any other clinical condition or prior therapy that, in the opinion of the investigator, would make the patient unsuitable for the study or unable to comply with the dosing requirements

• Concurrent treatment with an investigational drug or participation in another clinical trial

• Use of an investigational drug within 4 weeks or 5 half-lives, whichever is longer, preceding the first dose of investigational medicinal product

Related Conditions & MeSH terms

• Diabetic Kidney Disease
• Diabetic Nephropathies
• Kidney Diseases

Intervention

Drug:
• Liraglutide
Daily administration of liraglutide for 6 months

Locations

Country	Name	City	State
Ireland	St Vincent's Healthcare Group	Dublin

Sponsors (2)

Lead Sponsor	Collaborator
Karl Neff	University College Dublin

Country where clinical trial is conducted

Ireland, 

References & Publications (24)

Ahern T, Tobin AM, Corrigan M, Hogan A, Sweeney C, Kirby B, O'Shea D. Glucagon-like peptide-1 analogue therapy for psoriasis patients with obesity and type 2 diabetes: a prospective cohort study. J Eur Acad Dermatol Venereol. 2013 Nov;27(11):1440-3. doi: 10.1111/j.1468-3083.2012.04609.x. Epub 2012 Jun 13. — View Citation

Blandino-Rosano M, Perez-Arana G, Mellado-Gil JM, Segundo C, Aguilar-Diosdado M. Anti-proliferative effect of pro-inflammatory cytokines in cultured beta cells is associated with extracellular signal-regulated kinase 1/2 pathway inhibition: protective role of glucagon-like peptide -1. J Mol Endocrinol. 2008 Jul;41(1):35-44. doi: 10.1677/JME-07-0154. Epub 2008 May 16. — View Citation

Chow F, Ozols E, Nikolic-Paterson DJ, Atkins RC, Tesch GH. Macrophages in mouse type 2 diabetic nephropathy: correlation with diabetic state and progressive renal injury. Kidney Int. 2004 Jan;65(1):116-28. — View Citation

Chow FY, Nikolic-Paterson DJ, Ozols E, Atkins RC, Rollin BJ, Tesch GH. Monocyte chemoattractant protein-1 promotes the development of diabetic renal injury in streptozotocin-treated mice. Kidney Int. 2006 Jan;69(1):73-80. — View Citation

Cummings BP, Stanhope KL, Graham JL, Baskin DG, Griffen SC, Nilsson C, Sams A, Knudsen LB, Raun K, Havel PJ. Chronic administration of the glucagon-like peptide-1 analog, liraglutide, delays the onset of diabetes and lowers triglycerides in UCD-T2DM rats. Diabetes. 2010 Oct;59(10):2653-61. doi: 10.2337/db09-1564. Epub 2010 Jul 9. — View Citation

Fenske WK, Dubb S, Bueter M, Seyfried F, Patel K, Tam FW, Frankel AH, le Roux CW. Effect of bariatric surgery-induced weight loss on renal and systemic inflammation and blood pressure: a 12-month prospective study. Surg Obes Relat Dis. 2013 Jul-Aug;9(4):559-68. doi: 10.1016/j.soard.2012.03.009. Epub 2012 Apr 10. — View Citation

Hattori S. Sitagliptin reduces albuminuria in patients with type 2 diabetes. Endocr J. 2011;58(1):69-73. Epub 2010 Dec 28. — View Citation

Hogan AE, Tobin AM, Ahern T, Corrigan MA, Gaoatswe G, Jackson R, O'Reilly V, Lynch L, Doherty DG, Moynagh PN, Kirby B, O'Connell J, O'Shea D. Glucagon-like peptide-1 (GLP-1) and the regulation of human invariant natural killer T cells: lessons from obesity, diabetes and psoriasis. Diabetologia. 2011 Nov;54(11):2745-54. doi: 10.1007/s00125-011-2232-3. Epub 2011 Jul 9. — View Citation

Inzucchi SE, Bergenstal RM, Buse JB, Diamant M, Ferrannini E, Nauck M, Peters AL, Tsapas A, Wender R, Matthews DR; American Diabetes Association (ADA); European Association for the Study of Diabetes (EASD). Management of hyperglycemia in type 2 diabetes: a patient-centered approach: position statement of the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD). Diabetes Care. 2012 Jun;35(6):1364-79. doi: 10.2337/dc12-0413. Epub 2012 Apr 19. Review. Erratum in: Diabetes Care. 2013 Feb;36(2):490. — View Citation

Jacobsen LV, Hindsberger C, Robson R, Zdravkovic M. Effect of renal impairment on the pharmacokinetics of the GLP-1 analogue liraglutide. Br J Clin Pharmacol. 2009 Dec;68(6):898-905. doi: 10.1111/j.1365-2125.2009.03536.x. — View Citation

Kanamori H, Matsubara T, Mima A, Sumi E, Nagai K, Takahashi T, Abe H, Iehara N, Fukatsu A, Okamoto H, Kita T, Doi T, Arai H. Inhibition of MCP-1/CCR2 pathway ameliorates the development of diabetic nephropathy. Biochem Biophys Res Commun. 2007 Sep 7;360(4):772-7. Epub 2007 Jul 6. — View Citation

Kodera R, Shikata K, Kataoka HU, Takatsuka T, Miyamoto S, Sasaki M, Kajitani N, Nishishita S, Sarai K, Hirota D, Sato C, Ogawa D, Makino H. Glucagon-like peptide-1 receptor agonist ameliorates renal injury through its anti-inflammatory action without lowering blood glucose level in a rat model of type 1 diabetes. Diabetologia. 2011 Apr;54(4):965-78. doi: 10.1007/s00125-010-2028-x. Epub 2011 Jan 21. — View Citation

Lim AK, Tesch GH. Inflammation in diabetic nephropathy. Mediators Inflamm. 2012;2012:146154. doi: 10.1155/2012/146154. Epub 2012 Aug 21. Review. — View Citation

Lynch L, O'Shea D, Winter DC, Geoghegan J, Doherty DG, O'Farrelly C. Invariant NKT cells and CD1d(+) cells amass in human omentum and are depleted in patients with cancer and obesity. Eur J Immunol. 2009 Jul;39(7):1893-901. doi: 10.1002/eji.200939349. — View Citation

Lynch LA, O'Connell JM, Kwasnik AK, Cawood TJ, O'Farrelly C, O'Shea DB. Are natural killer cells protecting the metabolically healthy obese patient? Obesity (Silver Spring). 2009 Mar;17(3):601-5. doi: 10.1038/oby.2008.565. Epub 2008 Dec 18. — View Citation

Meguid El Nahas A, Bello AK. Chronic kidney disease: the global challenge. Lancet. 2005 Jan 22-28;365(9456):331-40. Review. — View Citation

Miras AD, Chuah LL, Lascaratos G, Faruq S, Mohite AA, Shah PR, Gill M, Jackson SN, Johnston DG, Olbers T, le Roux CW. Bariatric surgery does not exacerbate and may be beneficial for the microvascular complications of type 2 diabetes. Diabetes Care. 2012 Dec;35(12):e81. doi: 10.2337/dc11-2353. — View Citation

Navarro JF, Milena FJ, Mora C, León C, García J. Renal pro-inflammatory cytokine gene expression in diabetic nephropathy: effect of angiotensin-converting enzyme inhibition and pentoxifylline administration. Am J Nephrol. 2006;26(6):562-70. Epub 2006 Dec 13. — View Citation

Navarro-González JF, Mora-Fernández C, Muros de Fuentes M, García-Pérez J. Inflammatory molecules and pathways in the pathogenesis of diabetic nephropathy. Nat Rev Nephrol. 2011 Jun;7(6):327-40. doi: 10.1038/nrneph.2011.51. Epub 2011 May 3. Review. — View Citation

Pinkney J, Fox T, Ranganath L. Selecting GLP-1 agonists in the management of type 2 diabetes: differential pharmacology and therapeutic benefits of liraglutide and exenatide. Ther Clin Risk Manag. 2010 Sep 7;6:401-11. — View Citation

Shyangdan DS, Royle P, Clar C, Sharma P, Waugh N, Snaith A. Glucagon-like peptide analogues for type 2 diabetes mellitus. Cochrane Database Syst Rev. 2011 Oct 5;(10):CD006423. doi: 10.1002/14651858.CD006423.pub2. Review. — View Citation

Tarabra E, Giunti S, Barutta F, Salvidio G, Burt D, Deferrari G, Gambino R, Vergola D, Pinach S, Perin PC, Camussi G, Gruden G. Effect of the monocyte chemoattractant protein-1/CC chemokine receptor 2 system on nephrin expression in streptozotocin-treated mice and human cultured podocytes. Diabetes. 2009 Sep;58(9):2109-18. doi: 10.2337/db08-0895. Epub 2009 Jul 8. — View Citation

Tone A, Shikata K, Sasaki M, Ohga S, Yozai K, Nishishita S, Usui H, Nagase R, Ogawa D, Okada S, Shikata Y, Wada J, Makino H. Erythromycin ameliorates renal injury via anti-inflammatory effects in experimental diabetic rats. Diabetologia. 2005 Nov;48(11):2402-11. Epub 2005 Oct 18. — View Citation

Yozai K, Shikata K, Sasaki M, Tone A, Ohga S, Usui H, Okada S, Wada J, Nagase R, Ogawa D, Shikata Y, Makino H. Methotrexate prevents renal injury in experimental diabetic rats via anti-inflammatory actions. J Am Soc Nephrol. 2005 Nov;16(11):3326-38. Epub 2005 Sep 21. — View Citation

* Note: There are 24 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	Safety in All Participants as Measured by Adverse Event Rate	Adverse event data collection	Up to 34 weeks
Primary	MCP-1:Creatinine Ratio in Urine	Spot urine sample for MCP-1 and creatinine	Up to 26 weeks
Secondary	Urine Albumin:Creatinine Ratio	Spot urine sample for albumin and creatinine	Up to 26 weeks
Secondary	Urinary Albumin Excretion Rate	Albuminuria as Measured by 24 Hour Albumin Excretion Rate	Up to 26 weeks
Secondary	sCD163 in Serum	Serum sample for sCD163	Up to 26 weeks
Secondary	sCD163:Creatinine Ratio in Urine	Spot urine sample for MCP-1 and creatinine	Up to 26 weeks