Counteracting Deleterious Metabolic Glucocorticoid Effects With Metformin

NCT04659915 | Completed Phase 4

• 1 other identifier: EKNZ 2020-01233
• Study Type: interventional
• Target: 19
• Locations: 1 country
• Sites: 1

Brief Summary

Supraphysiological doses of glucocorticoids (GCs) are widely prescribed as immunosuppressants and metabolic side effects such as obesity and diabetes are extremely common. Efforts to investigate and prevent these side effects are lacking. The antidiabetic drug metformin was shown in previous studies to prevent deterioration of glucose homeostasis during GC therapy in patients. However, mechanisms of metformin counteracting GC-induced side effects remain poorly understood. In a randomized, placebo-controlled, cross-over study, 18 healthy volunteers will receive a 7-day course of prednisone with metformin or placebo. Established methods will be used to assess systemic changes in energy homeostasis and novel techniques such as metabolomics will identify underlying pathways. This will advance the understanding of energy homeostasis during GC excess, may prevent thousands of patients from GC-induced side effects and also offers a model for targeting disrupted endogenous GCs secretion.

Conditions

Glucocorticoid Effect

Outcome Measures

Primary Outcomes (1)

• Insulin sensitivity

  Change in insulin sensitivity (HOMA-Index) assessed with a mixed meal tolerance test.

  Two 1-week intervention periods

Secondary Outcomes (16)

• Lipids (mmol/l)

  Two 1-week intervention periods

• Cortisol (nmol/l)

  Two 1-week intervention periods

• GLP-1 (nmol/l)

  Two 1-week intervention periods

• GIP (nmol/l)

  Two 1-week intervention periods

• PYY (pg/ml)

  Two 1-week intervention periods

Other Outcomes (2)

• Metabolomics

  Two 1-week intervention periods

• Gene expression analysis

  Two 1-week intervention periods

Study Arms (2)

Metformin + Prednison

EXPERIMENTAL

During one of the study periods, subjects receive Metformin 500 mg tablets p.o. for seven days (starting with a dose of 500 mg /d, then the dose will be increased by 500 mg the next days until 2000 mg /d is achieved). Subjects also receive Prednisone 20 mg 1.5x/d tablets p.o. for seven days.

Drug: Metformin 500 mg Oral Tablets + Prednisone 20mg Tablets

Placebo + Prednison

PLACEBO COMPARATOR

During the other study period, subjects receive the same dose of placebo tablets p.o instead of metformin. Subjects also receive Prednisone 20 mg 1.5x/d tablets p.o. for seven days.

Drug: Placebo 500 mg Tablets + Prednisone 20mg Tablets

Interventions

Metformin 500 mg Oral Tablets + Prednisone 20mg Tablets DRUG

During one phase of the study: Metformin 500mg Day 1 1-0-0 Day 2 1-0-0 Day 3 1-0-1 Day 4 1-0-1 Day 5 2-0-1 Day 6 2-0-1 Day 7 4-0-0 In combination with prednisone 20mg: day 1 to day 7 1.5-0-0.

Metformin + Prednison

Placebo 500 mg Tablets + Prednisone 20mg Tablets DRUG

During another phase of the study: identical looking placebo pills starting day 1 500mg 1-0-0, day 2 500mg 1-0-0, day 3 500mg 1-0-1, day 4 500mg 1-0-1, day 5 500mg 2-0-1. day 6 2-0-1, day 7 4-0-0. In combination with prednisone 20mg: day 1 to day 7 1.5-0-0.

Placebo + Prednison

Eligibility Criteria

• Age: 18 Years - 40 Years
• Gender Eligibility Details: Since hormone fluctuations associated with the menstrual cycle may alter cortisol levels, women will not be included in the study. Although diversity will be reduced and the statements of the study cannot be applied to the female sex, these strict inclusion criteria allow an optimal homogeneity and increase statistical power.
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64)

You may qualify if:

• BMI 18.5 - 25 kg/m2

You may not qualify if:

• Any current significant disease,
• Any medication
• Regular alcohol intake (\>30g/d),
• Regular physical activity (\>4hrs per week),
• Known allergy to metformin,
• Inability or unwillingness to provide informed consent.

Sponsors & Collaborators

• Eleonora Seelig: lead

Study Sites (1)

University Hospital Basel

Basel, Canton of Basel-City, 4031, Switzerland

Location

Related Publications (7)

• GBD 2015 Obesity Collaborators; Afshin A, Forouzanfar MH, Reitsma MB, Sur P, Estep K, Lee A, Marczak L, Mokdad AH, Moradi-Lakeh M, Naghavi M, Salama JS, Vos T, Abate KH, Abbafati C, Ahmed MB, Al-Aly Z, Alkerwi A, Al-Raddadi R, Amare AT, Amberbir A, Amegah AK, Amini E, Amrock SM, Anjana RM, Arnlov J, Asayesh H, Banerjee A, Barac A, Baye E, Bennett DA, Beyene AS, Biadgilign S, Biryukov S, Bjertness E, Boneya DJ, Campos-Nonato I, Carrero JJ, Cecilio P, Cercy K, Ciobanu LG, Cornaby L, Damtew SA, Dandona L, Dandona R, Dharmaratne SD, Duncan BB, Eshrati B, Esteghamati A, Feigin VL, Fernandes JC, Furst T, Gebrehiwot TT, Gold A, Gona PN, Goto A, Habtewold TD, Hadush KT, Hafezi-Nejad N, Hay SI, Horino M, Islami F, Kamal R, Kasaeian A, Katikireddi SV, Kengne AP, Kesavachandran CN, Khader YS, Khang YH, Khubchandani J, Kim D, Kim YJ, Kinfu Y, Kosen S, Ku T, Defo BK, Kumar GA, Larson HJ, Leinsalu M, Liang X, Lim SS, Liu P, Lopez AD, Lozano R, Majeed A, Malekzadeh R, Malta DC, Mazidi M, McAlinden C, McGarvey ST, Mengistu DT, Mensah GA, Mensink GBM, Mezgebe HB, Mirrakhimov EM, Mueller UO, Noubiap JJ, Obermeyer CM, Ogbo FA, Owolabi MO, Patton GC, Pourmalek F, Qorbani M, Rafay A, Rai RK, Ranabhat CL, Reinig N, Safiri S, Salomon JA, Sanabria JR, Santos IS, Sartorius B, Sawhney M, Schmidhuber J, Schutte AE, Schmidt MI, Sepanlou SG, Shamsizadeh M, Sheikhbahaei S, Shin MJ, Shiri R, Shiue I, Roba HS, Silva DAS, Silverberg JI, Singh JA, Stranges S, Swaminathan S, Tabares-Seisdedos R, Tadese F, Tedla BA, Tegegne BS, Terkawi AS, Thakur JS, Tonelli M, Topor-Madry R, Tyrovolas S, Ukwaja KN, Uthman OA, Vaezghasemi M, Vasankari T, Vlassov VV, Vollset SE, Weiderpass E, Werdecker A, Wesana J, Westerman R, Yano Y, Yonemoto N, Yonga G, Zaidi Z, Zenebe ZM, Zipkin B, Murray CJL. Health Effects of Overweight and Obesity in 195 Countries over 25 Years. N Engl J Med. 2017 Jul 6;377(1):13-27. doi: 10.1056/NEJMoa1614362. Epub 2017 Jun 12.

  PMID: 28604169 RESULT

• Prospective Studies Collaboration; Whitlock G, Lewington S, Sherliker P, Clarke R, Emberson J, Halsey J, Qizilbash N, Collins R, Peto R. Body-mass index and cause-specific mortality in 900 000 adults: collaborative analyses of 57 prospective studies. Lancet. 2009 Mar 28;373(9669):1083-96. doi: 10.1016/S0140-6736(09)60318-4. Epub 2009 Mar 18.

  PMID: 19299006 RESULT

• van der Klaauw AA, Farooqi IS. The hunger genes: pathways to obesity. Cell. 2015 Mar 26;161(1):119-132. doi: 10.1016/j.cell.2015.03.008.

  PMID: 25815990 RESULT

• Vgontzas AN, Lin HM, Papaliaga M, Calhoun S, Vela-Bueno A, Chrousos GP, Bixler EO. Short sleep duration and obesity: the role of emotional stress and sleep disturbances. Int J Obes (Lond). 2008 May;32(5):801-9. doi: 10.1038/ijo.2008.4. Epub 2008 Feb 5.

  PMID: 18253159 RESULT

• de Guia RM, Rose AJ, Herzig S. Glucocorticoid hormones and energy homeostasis. Horm Mol Biol Clin Investig. 2014 Aug;19(2):117-28. doi: 10.1515/hmbci-2014-0021.

  PMID: 25390020 RESULT

• Laugesen K, Jorgensen JOL, Sorensen HT, Petersen I. Systemic glucocorticoid use in Denmark: a population-based prevalence study. BMJ Open. 2017 May 29;7(5):e015237. doi: 10.1136/bmjopen-2016-015237.

  PMID: 28554927 RESULT

• McDonough AK, Curtis JR, Saag KG. The epidemiology of glucocorticoid-associated adverse events. Curr Opin Rheumatol. 2008 Mar;20(2):131-7. doi: 10.1097/BOR.0b013e3282f51031.

  PMID: 18349741 RESULT

MeSH Terms

Interventions

Metformin; Prednisone

Intervention Hierarchy (Ancestors)

Biguanides; Guanidines; Amidines; Organic Chemicals; Pregnadienediols; Pregnadienes; Pregnanes; Steroids; Fused-Ring Compounds; Polycyclic Compounds

Study Design

• Study Type: interventional
• Phase: phase 4
• Allocation: RANDOMIZED
• Masking: DOUBLE
• Who Masked: PARTICIPANT, INVESTIGATOR
• Masking Details: Placebo-controlled
• Purpose: PREVENTION
• Intervention Model: CROSSOVER
• Sponsor Type: OTHER
• Responsible Party: SPONSOR INVESTIGATOR
• PI Title: Principal Investigator

Model Details: Double-blind, randomized, placebo-controlled cross-over study

Study Record Dates

• First Submitted: December 1, 2020
• First Posted: December 9, 2020
• Study Start: February 25, 2021
• Primary Completion: August 18, 2021
• Study Completion: August 18, 2021
• Last Updated: September 23, 2021

Record last verified: 2021-09

Data Sharing

• IPD Sharing: Will not share

Locations

CH (1)