The Impact of Liraglutide on Glucose Tolerance and the Risk of Type 2 Diabetes in Women With Previous Pregnancy-induced Diabetes

The Impact of Liraglutide on Glucose Tolerance and the Risk of Type 2 Diabetes in Women With Previous Gestational Diabetes Mellitus

It is well-known that women with previous gestational diabetes mellitus are in risk of developing type 2 diabetes later in life; approximately half of the women develop overt type 2 diabetes within the first 10 years after pregnancy. Knowing this, we want to examine the effect of the type 2 diabetes medicine, liraglutide (Victoza), in women with previous gestational diabetes with the aim of reducing the risk of developing type 2 diabetes.

Study Overview

• Status: Completed
• Conditions: Gestational Diabetes Mellitus
• Intervention / Treatment: Drug: Liraglutide; Drug: Placebo

• Study Type: Interventional
• Enrollment (Actual): 105
• Phase: Phase 4

Contacts and Locations

Study Locations

• Denmark
  • Hellerup, Denmark, 2900
    • Clinical Metabolic Physiology, Steno Diabetes Center Copenhagen

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: Yes
• Genders Eligible for Study: Female

Description

Inclusion Criteria for women with previous GDM:

• Informed oral and written consent
• Previous diagnosis of GDM according to current Danish guidelines (mainly PG concentrationa t 120 min after 75 g OGTT ≥ 9.0 mM) during pregnancy within the last 5 years
• Age >18 years
• 25 kg/m2 < BMI < 45 kg/m2
• NGT, IFG and or IGT
• Safe contraception and negative pregnancy test

Exclusion Criteria for women with previous GDM:

• Patients with diabetes
• HbA1c ≥6.5%
• Patients with previous pancreatitis or previous neoplasia
• Pregnant or breast feeding women
• Anaemia (haemoglobin <7 mM)
• Women planning to become pregnant within the next 5 years
• Women using other contraception than intrauterine device (IUD) or oral contraceptives. Women who do not use safe contraception will be offered application of an IUD.
• Women treated with statins, corticosteroids or other hormone therapy (except estrogens and gestagens)
• Ongoing abuse of alcohol or narcotics
• Impaired hepatic function (liver transaminases >3 times upper normal limit)
• Impaired renal function (se-creatinine >120 μM and/or albuminuria)
• Uncontrolled hypertension (systolic blood pressure >180 mmHg, diastolic blood pressure >100 mmHg)
• Any condition that the investigator feels would interfere with trial participation
• Receiving any investigational drug within the last 3 months

Inclusion criteria for women without previous GDM:

• Informed oral and written consent
• Age >18 years
• 25 kg/m2 < BMI < 45 kg/m2
• NGT
• Safe contraception and negative pregnancy test
• Pregnancy within the last ten years without GDM

Exclusion Criteria for women without previous GDM :

• Pregnant or breast feeding women
• Anaemia (haemoglobin <7 mM)

Inclusion Criteria for women without previous GDM and without NAFLD:

• Informed oral and written consent
• Age >18 years
• 25 kg/m2 < BMI < 45 kg/m2
• NGT
• At least one pregnancy witin the last ten years without GDM

Exclusion Criteria for women without previous GDM and without NAFLD:

• Pregnant or breast feeding women
• Anaemia (haemoglobin <7 mM)
• Steatosis as assessed by ultrasound scanning
• Recieving any investigational drug within the last 3 months
• Any condition that the investigator feels would interfere with the trial participation

Inclusion Criteria for women with biopsi-verified NAFLD:

• Informed oral and written consent
• Women with known NAFLD or NASH
• Age >18 years
• 25 kg/m2 < BMI < 45 kg/m2
• NGT
• At least one prior pregnancy

Exclusion Criteria for women with biopsi-verified NAFLD:

• women with established cirrhosis
• Pregnant or breast feedning women
• Anaemia (haemoglobin <7 mM)
• Women treated with statins, corticosteroids or other hormone therapy ( except oestrogens and gestagens)
• Ongoing abuse of alcohol or narcotics
• Impaired renal function (se-creatinine > 120 μM and/or albuminuria)
• Uncontrolled hypertension (systolic blood pressure > 180 mmHg, diastolic blood presure > 100 mmHg)
• Any condition that the investigator feels would interfere with trial participation

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Prevention
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Triple

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Liraglutide; 1.8 mg liraglutide, subcutaneous, once-daily for five years	Drug: Liraglutide; 1.8 mg liraglutide; Other Names: Victoza; NN2211
Placebo Comparator: Placebo; Placebo, subcutaneous, once-daily for one year	Drug: Placebo; Liraglutide without the GLP-1 analogue
No Intervention: Control; Control without previous GDM.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in glucose tolerance	Changes in glucose is measured by area under the curve for the plasma glucose excursion following a 4-hour 75 g oral glucose tolerance test (OGTT)	from baseline to 52 wks, 53 wks, 260 wks, and 261 wks

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Deterioration in glycaemic status	Percentage of subjects in each treatment arm with normal glucose tolerance (NGT) at inclusion who develop impaired fasting glucose (IFG) and/or impaired glucose tolerance (IGT) or type 2 diabetes; or with IFG or IGT who develop combined IFG/IGT; or with combined IFG/IGT who develop type 2 diabetes	from baseline to 52 wks, 53, wks, 260 wks, and 261 wks

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Changes in glycated hemoglobin	Changes in glycated hemoglobin (HbA1c). From normoglycaemic to prediabetic or type 2 diabetic and from prediabetic to type 2 diabetic or normoglycaemic.	From baseline to 52 wks and 260 wks
Changes in anthropometric measurements	Changes in body mass index (BMI)(kg/m2), absolute body weight (kg), and waist:hip ratio	from baseline to 52 and 260 wks
Changes in beta cell secretory responses	changes in area under the curve during OGTT and isoglycemic intravenous glucose infusion (IIGI), the homeostatic model assessment (HOMA) and pro-insulin ratio	from baseline to 52, 53, 260, and 261 wks
Changes in insulin sensitivity	assessed by HOMA-IR and Matsuda insulin sensitivity index	from baseline to 52, 53, 260, and 261 wks
Changes in incretin hormone secretion	measured as fasting plasma concentrations and plasma responses of GLP-1, GLP2, and GIP and plasma glucagon during OGTT	baseline to 52, 53, 260, and 261 wks
Changes in incretin effect	insulin and c-peptide responses after OGTT vs. IIGI	baseline to 52, 53, 260, and 261 wks
Changes in presence of non-alcoholic fatty liver disease (NAFLD)	gamma-glutamyltranferase (GGT), intra-heptic fat, FGF-21, whole body and visceral fat mass/fat-free mass, circulating lipids, ultrasound scan and fibroscan	baseline to 52 and 260 wks
Changes in cardio-metabolic risk measures	pro-collagen 3, GGT, Intra-hepatic fat, whole body and visceral fat mass/fat-free mass, circulating lipids and cardiovascular biomarkers (highly sensitive c-reactive protein (hs-CRP), N-terminal prohormone of brain natriuretic peptide (NT-proBNP), tumor necrosis factor-alpha (TNF-alpha), adiponectin and plasminogen activator inhibior-1 (PAI-1))	baseline to 52 and 260 wks
Changes in gut microbiota	optional to the main protocol	baseline to 52 and 260 wks
Changes in subjective appetite	visual analogue scale (VAS)	baseline to 52, 53, 260, and 261 wks
Number of participants with treatment-related adverse events (Safety and tolerability)	as assessed by validated questionnaires	baseline to 52 and 260 wks
Change in Quality of life	Assessed by validated questionnaires (SF-36)	Baseline to 52 and 260 wks
Evaluation of alcohol consumption	By validated questionnaires	baseline to 52 and 260 wks
Evaluation of microalbuminuria	Predicitve value of biomarkers for detection of microalbuminuria	baseline to 52 to 260 wks
Evaluation of blindedness of participants and investigators	questionnaire and the end of the blinded trial	baseline to 52 wks
Changes in bonemarkers		baseline to 52 and 260 wks

Collaborators and Investigators

• Sponsor: Tina Vilsboll
• Collaborators: Novo Nordisk A/S; Aarhus University Hospital; Rigshospitalet, Denmark; University of Copenhagen; Hvidovre University Hospital; Herlev Hospital; Hillerod Hospital, Denmark; The Novo Nordisk Foundation Center for Basic Metabolic Research
• Investigators: Principal Investigator: Tina Vilsbøll, MD, DMSc, University Hospital Gentofte; Principal Investigator: Signe Foghsgaard, MD, PhD, University Hospital Gentofte; Principal Investigator: Emilie Skytte Andersen, MD, PhD-student, Steno Diabetes Center Copenhagen

Publications and helpful links

General Publications

• Flint A, Raben A, Astrup A, Holst JJ. Glucagon-like peptide 1 promotes satiety and suppresses energy intake in humans. J Clin Invest. 1998 Feb 1;101(3):515-20. doi: 10.1172/JCI990.
• Intensive blood-glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33). UK Prospective Diabetes Study (UKPDS) Group. Lancet. 1998 Sep 12;352(9131):837-53. Erratum In: Lancet 1999 Aug 14;354(9178):602.
• Flint A, Raben A, Blundell JE, Astrup A. Reproducibility, power and validity of visual analogue scales in assessment of appetite sensations in single test meal studies. Int J Obes Relat Metab Disord. 2000 Jan;24(1):38-48. doi: 10.1038/sj.ijo.0801083.
• 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(9701):1606-16. doi: 10.1016/S0140-6736(09)61375-1. Epub 2009 Oct 23. Erratum In: Lancet. 2010 Mar 20;375(9719):984.
• Astrup A, Carraro R, Finer N, Harper A, Kunesova M, Lean ME, Niskanen L, Rasmussen MF, Rissanen A, Rossner S, Savolainen MJ, Van Gaal L; NN8022-1807 Investigators. Safety, tolerability and sustained weight loss over 2 years with the once-daily human GLP-1 analog, liraglutide. Int J Obes (Lond). 2012 Jun;36(6):843-54. doi: 10.1038/ijo.2011.158. Epub 2011 Aug 16. Erratum In: Int J Obes (Lond). 2012 Jun;36(6):890. Int J Obes (Lond). 2013 Feb;37(2):322.
• Metzger BE, Coustan DR. Summary and recommendations of the Fourth International Workshop-Conference on Gestational Diabetes Mellitus. The Organizing Committee. Diabetes Care. 1998 Aug;21 Suppl 2:B161-7. No abstract available.
• Holst JJ. The physiology of glucagon-like peptide 1. Physiol Rev. 2007 Oct;87(4):1409-39. doi: 10.1152/physrev.00034.2006.
• Porte D Jr. Mechanisms for hyperglycemia in the metabolic syndrome. The key role of beta-cell dysfunction. Ann N Y Acad Sci. 1999 Nov 18;892:73-83. doi: 10.1111/j.1749-6632.1999.tb07786.x.
• Vilsboll T, Holst JJ. Incretins, insulin secretion and Type 2 diabetes mellitus. Diabetologia. 2004 Mar;47(3):357-366. doi: 10.1007/s00125-004-1342-6. Epub 2004 Feb 13.
• Vilsboll T. On the role of the incretin hormones GIP and GLP-1 in the pathogenesis of Type 2 diabetes mellitus. Dan Med Bull. 2004 Nov;51(4):364-70. No abstract available.
• Damm P, Vestergaard H, Kuhl C, Pedersen O. Impaired insulin-stimulated nonoxidative glucose metabolism in glucose-tolerant women with previous gestational diabetes. Am J Obstet Gynecol. 1996 Feb;174(2):722-9. doi: 10.1016/s0002-9378(96)70456-8.
• Jensen DM, Molsted-Pedersen L, Beck-Nielsen H, Westergaard JG, Ovesen P, Damm P. Screening for gestational diabetes mellitus by a model based on risk indicators: a prospective study. Am J Obstet Gynecol. 2003 Nov;189(5):1383-8. doi: 10.1067/s0002-9378(03)00601-x.
• Lauenborg J, Hansen T, Jensen DM, Vestergaard H, Molsted-Pedersen L, Hornnes P, Locht H, Pedersen O, Damm P. Increasing incidence of diabetes after gestational diabetes: a long-term follow-up in a Danish population. Diabetes Care. 2004 May;27(5):1194-9. doi: 10.2337/diacare.27.5.1194.
• Xiang AH, Kjos SL, Takayanagi M, Trigo E, Buchanan TA. Detailed physiological characterization of the development of type 2 diabetes in Hispanic women with prior gestational diabetes mellitus. Diabetes. 2010 Oct;59(10):2625-30. doi: 10.2337/db10-0521. Epub 2010 Aug 3.
• Hanna FW, Peters JR. Screening for gestational diabetes; past, present and future. Diabet Med. 2002 May;19(5):351-8. doi: 10.1046/j.1464-5491.2002.00684.x.
• Bian X, Gao P, Xiong X, Xu H, Qian M, Liu S. Risk factors for development of diabetes mellitus in women with a history of gestational diabetes mellitus. Chin Med J (Engl). 2000 Aug;113(8):759-62.
• Gerich JE. The genetic basis of type 2 diabetes mellitus: impaired insulin secretion versus impaired insulin sensitivity. Endocr Rev. 1998 Aug;19(4):491-503. doi: 10.1210/edrv.19.4.0338.
• Forbes S, Taylor-Robinson SD, Patel N, Allan P, Walker BR, Johnston DG. Increased prevalence of non-alcoholic fatty liver disease in European women with a history of gestational diabetes. Diabetologia. 2011 Mar;54(3):641-7. doi: 10.1007/s00125-010-2009-0. Epub 2010 Dec 12.
• Foghsgaard S, Vedtofte L, Mathiesen ER, Svare JA, Gluud LL, Holst JJ, Damm P, Knop FK, Vilsboll T. The effect of a glucagon-like peptide-1 receptor agonist on glucose tolerance in women with previous gestational diabetes mellitus: protocol for an investigator-initiated, randomised, placebo-controlled, double-blinded, parallel intervention trial. BMJ Open. 2013 Oct 30;3(10):e003834. doi: 10.1136/bmjopen-2013-003834.

Helpful Links

• Main website for the University Hospital Gentofte

Study record dates

Study Major Dates

• Study Start (Actual): July 1, 2012
• Primary Completion (Actual): September 1, 2019
• Study Completion (Actual): September 1, 2020

Study Registration Dates

• First Submitted: February 18, 2013
• First Submitted That Met QC Criteria: February 18, 2013
• First Posted (Estimate): February 20, 2013

Study Record Updates

• Last Update Posted (Actual): November 4, 2020
• Last Update Submitted That Met QC Criteria: November 3, 2020
• Last Verified: November 1, 2020

More Information

Terms related to this study

• Keywords: GLP-1; type 2 diabetes mellitus; incretin; glucose homeostasis; gestational diabetes mellitus; liraglutide; Victoza
• Additional Relevant MeSH Terms: Glucose Metabolism Disorders; Metabolic Diseases; Endocrine System Diseases; Pregnancy Complications; Diabetes Mellitus; Diabetes Mellitus, Type 2; Diabetes, Gestational; Hypoglycemic Agents; Physiological Effects of Drugs; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Incretins; Liraglutide
• Other Study ID Numbers: GDM-TREAT; 2012-001371-37 (EudraCT Number)