Type 2 DiabetesNCT04485871
Targeting Risk Factors for Diabetes in Subjects With Normal Blood Cholesterol Using Omega-3 Fatty Acids
A study testing Omega-3 fatty acids in people with Type 2 Diabetes and Inflammation, run by Institut de Recherches Cliniques de Montreal at 1 site in Canada.
Trial summary
Every 3 minutes a new case of diabetes is diagnosed in Canada, mostly type 2 diabetes (T2D) increasing the risk for heart disease. T2D and heart disease share many common risk factors such as aging, obesity and unhealthy lifestyle. Read more about this study
- Who is it for?
- Ages 45 to 74 yearsHealthy volunteers can take part
- Conditions the study is for
- Type 2 Diabetes, Inflammation, Insulin Sensitivity/Resistance
- What is being tested?
- Omega-3 fatty acids
- Type of treatment
- Pill or oral medicine
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 48 participants
- Where
- 1 siteCanada
- Study dates
- 19 Dec 2019to 31 May 2027
- Phase
- Interventional
- Are there results?
- Not yet: the study is under way
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 45 to 74 years
- All sexes
- Healthy volunteers accepted
- Adult, Older adult
Who may be able to join
- Men and post-menopausal women:
- Having a body mass index (BMI= 25-40 kg/m2)
- Aged between 45 and 74 years
- Having confirmed menopausal status (FSH ≥ 30 U/l)
- Non-smoker
- Sedentary (less than 2 hours of structured physical exercise (ex: sports club) per week)
- Low alcohol consumption: less than 2 alcoholic drinks/day
Who cannot join
- Plasma LDL cholesterol > 3.5 mmol/L (i.e. > 75th percentile in a Canadian population).
- Elevated risk of cardiovascular disease (≥ 20% of calculated Framingham Risk Score) who would require immediate medical intervention by lipid-lowering agents.
- Prior history of cardiovascular events (like stroke, transient ischemic attack, myocardial infarction, angina, heart failure…)
- Systolic blood pressure > 140 mmHg or diastolic blood pressure > 90 mmHg
- Type 1 or 2 diabetes or fasting glucose > 7.0 mmol/L
- Prior history of cancer within the last 3 years
Show all 25Show fewer
- Thyroid disease - untreated or unstable
- Anemia - Hb < 120 g/L
- Renal dysfunction or plasma creatinine > 100 µmol/L
- Hepatic dysfunction - AST/ALT > 3 times normal limit
- Blood coagulation problems (i.e. bleeding predisposition)
- Autoimmune and chronic inflammatory disease (i.e. celiac, inflammatory bowel, Graves, multiple sclerosis, psoriasis, rheumatoid arthritis, and lupus).Known history of difficulties accessing a vein
- Claustrophobia
- Sleep apnea
- Seizures
- Concomitant medications: Hormone replacement therapy (except thyroid hormone at a stable dose), systemic corticosteroids, anti-psychotic medications and psycho-active medication, anticoagulant or anti-aggregates treatment (Aspirin, NSAIDs, warfarin, coumadin..), adrenergic agonist, anti-hypertensive drugs, weight-loss medication, lipid lowering medication
- Known substance abuse
- Already taking more than 250 mg of omega-3 supplements (EPA/DHA) per day
- Allergy to seafood or fish
- Allergy to Xylocaine
- Unable to eat the components of the high fat meal (croissant, cheese, bacon, brownies)
- None compliance to the study requirements (i.e. not being fasting) or cancellation of the same scheduled testing visit more than once.
- Lack of time to participate in the full length of the study (33 weeks)
- Have exceeded the annual total allowed radiation dose (like X-ray scans and/or tomography in the previous year or in the year to come) according to the physician's judgement.
- All other medical or psychological conditions deemed inappropriate according to the physician
Trial locations and contacts
1 site in 1 country. Contact the study team or a site near you to ask about taking part.
Canada1 site, 1 recruiting
- Recruiting
Montreal Clinical Research Institute
Montreal, Quebec, H2W 1R7
Justine Fricher, MSc, 514-987-5500 ext. 3260, justine.fricher@ircm.qc.ca
May Faraj, PDt, PhD
About this study
Official title: White Adipose Tissue LDL Receptors and Omega-3 as Modulators of the Risk for Type 2 Diabetes in Subjects With Normal Plasma LDL Cholesterol
Every 3 minutes a new case of diabetes is diagnosed in Canada, mostly type 2 diabetes (T2D) increasing the risk for heart disease. T2D and heart disease share many common risk factors such as aging, obesity and unhealthy lifestyle.
Paradoxically however, while lowering blood LDL, commonly known as "bad cholesterol", is protective against heart disease, research over the past 10 years have shown that the lower is blood LDL, the higher is the chance of developing T2D. This phenomena is happening whether blood LDL is lowered by a common drug against heart disease called Statins, or by being born with certain variations in genes, some of which are very common (~80% of people have them).
Read more
To date, it is unclear why lowering blood LDL is associated with higher risk for diabetes, and whether this can be treated naturally with certain nutrients.
Investigators believe that lowering blood LDL by forcing LDL entry into the body tissue through their receptors promotes T2D. This is because investigators have shown that LDL entry into human fat tissue induces fat tissue dysfunction, which would promote T2D especially in subjects with excess weight.
On the other hand, investigators have shown that omega-3 fatty acids (omega-3) can directly treat the same defects induced by LDL entry into fat tissue. Omega-3 is a unique type of fat that is found mostly in fish oil.
Thus the objectives of this clinical trial to be conducted in 48 subjects with normal blood LDL are to explore if:
- Subjects with higher LDL receptors and LDL entry into fat tissue have higher risk factors for T2D compared to subjects with lower LDL receptors and LDL entry into fat tissue
- 6-month supplementation of omega-3 from fish oil can treat subjects with higher LDL receptors and LDL entry into fat tissue reducing their risk for T2D.
This study will thus explore and attempt to treat a new risk factor for T2D using an inexpensive and widely accessible nutraceutical, which would aid in preventing T2D in humans.
Read the detailed description
Type 2 (T2D) and cardiovascular disease (CVD) share many risk factors, whose accumulation over years lead to disease onset. However, while lowering plasma low-density lipoprotein cholesterol (LDLC) is cardio-protective, novel evidence over the past 10 years established a role for common LDLC-lowering variants and widely used hypocholesterolemic Statins in higher risk for T2D. This diminishes the cardio-protective role of low plasma LDLC. As these conditions decrease plasma LDLC by increasing tissue-uptake of LDL, a role for LDL receptor (LDLR) pathway was proposed. However underlying mechanisms fueling higher risk for T2D with upregulated LDLR pathway, and nutritional approaches to treat them are unclear.
The central hypothesis examined in this trial is that upregulating receptor-mediated uptake of LDL on white adipose tissue provokes the activation of an innate immunity pathway (the Nucleotide-binding domain and Leucine-rich repeat Receptor, containing a Pyrin domain 3 (NLRP3) inflammasome) leading to the accumulation of risk factors for T2D in subjects with normal plasma LDLC. This can be treated by 6-month supplementation of omega-3 fatty acids (omega-3).
To examine this hypothesis in vivo, ex vivo and in vitro, a clinical trial in conjunction with mechanistic basic research studies have been initiated at the Montreal Clinical Research Institute (IRCM). Forty eight volunteers will be recruited through advertisements in French/English newspapers and online (e.g. Google, Facebook) and placed on a 6-month supplementation of 3.6 g omega-3 per day. Participants will be stratified into 2 groups (N=24/group) with higher and lower white adipose tissue surface-expression LDL receptors (LDLR and CD36) using median plasma PCSK9 (Proprotein Convertase Subtilisin/Kexin type 9) per sex. Plasma PSCK9 will be used as investigators have shown that it is negatively associated with white adipose tissue surface-expression of LDLR and CD36.
The duration of this study is about 8 months (33 weeks) divided into 5 parts:
- Screening and evaluation of eligibility for the study
- Weight stabilisation (+/- 2 kg change over 4 weeks) and confirmation of eligibility after a medical examination by IRCM physician collaborators.
- Baseline testing over 2 days (1- 4 weeks apart) to assess participants risk factors for T2D: white adipose tissue NLRP3 inflammasome activity, white adipose tissue physiology and function (ex vivo after a subcutaneous needle biopsy), systemic inflammation, dietary fat clearance (after a high fat meal), and insulin secretion and sensitivity (by gold-standard Botnia clamp technique). Participants will also be phenotyped for body composition (by dual energy x-ray absorptiometry), resting energy expenditure (by indirect calorimetry), dietary intake (by 3-day dietary journals) and physical activity level (by a questionnaire).
- 24-week intervention with omega-3 fatty acid supplementation (3.6 g eicosapentaenoic acid (EPA) and docosahexaenoic (DHA), 2:1)
- Post intervention testing starting over 2 days (1- 4 weeks apart) to assess risk factors for T2D that were measured at baseline.
Investigators hypothesize that subjects with low plasma PCSK9 (i.e. with higher white adipose tissue LDLR and CD36) will have higher risk factors for T2D at baseline and that the omega-3 intervention will eliminate group-differences in these risk factors.
- Being tested
- Omega-3 fatty acids
- Keywords
- Proprotein Convertase Subtilisin / kexin Type 9 (PCSK9), NLRP3 inflammasome, Eicosapentaenoic acid (EPA), Docosahexaenoic acid (DHA), White adipose tissue, Fat metabolism, ApoB-lipoproteins, LDL receptors (LDLR), Cluster of differentiation 36 (CD36)
- Medical subject headings
- Diabetes Mellitus, Type 2, Inflammation, Insulin Resistance, Hypercholesterolemia, Autosomal Dominant, 3, Hyperlipoproteinemia Type II
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
Omega-3 fatty acidsDietary supplement
Also called Triple Strength Omega-3 from Webber Naturals
Triple Strength Omega-3 from Webber Naturals; 4 oral softgels (600 mg EPA and 300 mg DHA / softgel)
| Study group | Role | What they receive |
|---|---|---|
| Omega-3 fatty acids | Experimental | 3.6 g EPA:DHA / day (2:1) Receives: Dietary Supplement: Omega-3 fatty acids |
What is being measured
The primary outcome is the main question the study is designed to answer.
Fasting white adipose tissue NLRP3 inflammasome activation
White adipose tissue medium accumulation of interleukin 1 beta (IL-1β) ex vivo over 4 hours (pg/mg tissue by AlphaLISA)
Measured: Baseline
Fasting white adipose tissue NLRP3 inflammasome activation
White adipose tissue medium accumulation of interleukin 1 beta (IL-1β) ex vivo over 4 hours (pg/mg tissue by AlphaLISA)
Measured: At 24 weeks
Secondary outcomes (22)
Fasting plasma PCSK9 concentration
Plasma PCSK9 (g/L by ElISA kit)
Measured: Baseline
Fasting plasma PCSK9 concentration
Plasma PCSK9 (g/L by ElISA kit)
Measured: At 24 weeks
White adipose tissue receptors for apoB-lipoproteins
Fasting and 4 hour-postprandial change in white adipose tissue surface-expression LDLR and CD36 (% of control by immunohistochemistry in white adipose tissue slides)
Measured: Baseline
White adipose tissue receptors for apoB-lipoproteins
Fasting and 4 hour-postprandial change in white adipose tissue surface-expression LDLR and CD36 (% of control by immunohistochemistry in white adipose tissue slides)
Measured: At 24 weeks
White adipose tissue inflammation profile
Fasting and 4 hour-postprandial change in NLRP3 inflammasome related inflammatory parameters; including gene expression of IL1B, NLRP3 and ADGRE1 (by RT-PCR) and secretion of IL-1β and IL-1Ra (per mg tissue by AlphaLISA)
Measured: Baseline
White adipose tissue inflammation profile
Fasting and 4 hour-postprandial change in NLRP3 inflammasome related inflammatory parameters; including gene expression of IL1B, NLRP3 and ADGRE1 (by RT-PCR) and secretion of IL-1β and IL-1Ra (per mg tissue by AlphaLISA)
Measured: At 24 weeks
White adipose tissue function ex vivo
Fasting and 4 hour postprandial change in situ lipoprotein lipase activity (nmol 3H-triglyceride/mg tissue)
Measured: Baseline
White adipose tissue function ex vivo
Fasting and 4 hour postprandial change in situ lipoprotein lipase activity (nmol 3H-triglyceride/mg tissue)
Measured: At 24 weeks
Postprandial fat metabolism
Area under the 6 hour time curve of plasma triglycerides (mmol/hour) after a high-fat meal (66% fat)
Measured: Baseline
Postprandial fat metabolism
Area under the 6 hour time curve of plasma triglycerides (mmol/hour) after a high-fat meal (66% fat)
Measured: At 24 week
Systemic inflammation
Fasting and 4 hour postprandial change in plasma inflammatory parameters including IL-1Ra and IL-1β (pg/mL by AlphaLISA)
Measured: Baseline
Systemic inflammation
Fasting and 4 hour postprandial change in plasma inflammatory parameters including IL-1Ra and IL-1β (pg/mL by AlphaLISA)
Measured: At 24 weeks
Disposition index
Calculated as glucose-induced insulin secretion (uU/mL/min) multiplied by insulin sensitivity (glucose infusion rate mg/kg/min) measured by Botnia clamp
Measured: Baseline
Disposition index
Calculated as glucose-induced insulin secretion (uU/mL/min) multiplied by insulin sensitivity (glucose infusion rate mg/kg/min) measured by Botnia clamp
Measured: At 24 weeks
Fatty acid profile in red blood cell phospholipid fraction
(As μmol/L by gas chromatography mass spectrometry)
Measured: Baseline
Fatty acid profile in red blood cell phospholipid fraction
(As μmol/L by gas chromatography mass spectrometry)
Measured: At 24 weeks
Body composition
Fat and lean body mass (as kg by dual energy x-ray absorptiometry)
Measured: Baseline
Body composition
Fat and lean body mass (as kg by dual energy x-ray absorptiometry)
Measured: At 24 weeks
Energy intake
(Average of 3 day energy intake as kcal/day collected by 3-day dietary records)
Measured: Baseline
Energy intake
(Average of 3 day energy intake as kcal/day collected by 3-day dietary records)
Measured: At 24 weeks
Physical activity
(using Godin Leisure Time Exercise Questionnaire)
Measured: Baseline
Physical activity
(using Godin Leisure Time Exercise Questionnaire)
Measured: At 24 weeks
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted24 Jul 2020
- Study start19 Dec 2019
- Primary completion31 May 2027 (estimated)
- Study completion31 May 2027 (estimated)
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (12)Papers the sponsor has linked to this study.
- Other trials for Type 2 DiabetesStudies of the same condition, open and under way.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase N/A
- Primary purpose
- Prevention
- Allocation
- Not applicable
- Intervention model
- Single group
- Model description
- Subjects (N=48) will be recruited with the same inclusion/exclusion criteria and will received the same omega-3 intervention. After completion of recruitment, subjects will be stratified into 2 groups (24/group) based on a baseline plasma PCSK9 for group characterisation and comparison.
- Masking
- None (open label)
- Enrolment
- 48 participants (estimated)
Sponsor and investigators
- Lead sponsor
- Institut de Recherches Cliniques de Montreal
- Sponsor type
- University, hospital or other
- Collaborators
- Canadian Institutes of Health Research (CIHR)
- Responsible party
- Principal investigator, May Faraj, PDt, PhD, Institut de Recherches Cliniques de Montreal
- Investigators
- May Faraj, PDt, PhD, Principal investigator, Montreal Clinical Research Institute/ University of Montreal
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT04485871
- Sponsor's protocol ID
- 2020-1035
- Other IDs
- NUT407816
- Status last verified
- Mar 2026
- First submitted
- 16 Jul 2020
- Last updated
- 12 Mar 2026
- Results posted
- No
- Data monitoring committee
- No
- FDA-regulated drug
- No
- FDA-regulated device
- No
- Individual data sharing
- No: Frozen plasma and white adipose tissue samples (when sufficient) can be made available for analysis by other investigators. However data statistical analyses incorporating complete IPD must be conducted by the research team of Dr May Faraj as per subject consent form.
Publications
Bissonnette S, Salem H, Wassef H, Saint-Pierre N, Tardif A, Baass A, Dufour R, Faraj M. Low density lipoprotein delays clearance of triglyceride-rich lipoprotein by human subcutaneous adipose tissue. J Lipid Res. 2013 May;54(5):1466-76. doi: 10.1194/jlr.P023176. Epub 2013 Feb 17.
PubMed 23417739Wassef H, Bissonnette S, Saint-Pierre N, Lamantia V, Cyr Y, Chretien M, Faraj M. The apoB-to-PCSK9 ratio: A new index for metabolic risk in humans. J Clin Lipidol. 2015 Sep-Oct;9(5):664-75. doi: 10.1016/j.jacl.2015.06.012. Epub 2015 Jul 2.
PubMed 26350813Lamantia V, Bissonnette S, Wassef H, Cyr Y, Baass A, Dufour R, Rabasa-Lhoret R, Faraj M. ApoB-lipoproteins and dysfunctional white adipose tissue: Relation to risk factors for type 2 diabetes in humans. J Clin Lipidol. 2017 Jan-Feb;11(1):34-45.e2. doi: 10.1016/j.jacl.2016.09.013. Epub 2016 Oct 3.
PubMed 28391908Skeldon AM, Faraj M, Saleh M. Caspases and inflammasomes in metabolic inflammation. Immunol Cell Biol. 2014 Apr;92(4):304-13. doi: 10.1038/icb.2014.5. Epub 2014 Feb 11.
PubMed 24518981Sattar N, Preiss D, Murray HM, Welsh P, Buckley BM, de Craen AJ, Seshasai SR, McMurray JJ, Freeman DJ, Jukema JW, Macfarlane PW, Packard CJ, Stott DJ, Westendorp RG, Shepherd J, Davis BR, Pressel SL, Marchioli R, Marfisi RM, Maggioni AP, Tavazzi L, Tognoni G, Kjekshus J, Pedersen TR, Cook TJ, Gotto AM, Clearfield MB, Downs JR, Nakamura H, Ohashi Y, Mizuno K, Ray KK, Ford I. Statins and risk of incident diabetes: a collaborative meta-analysis of randomised statin trials. Lancet. 2010 Feb 27;375(9716):735-42. doi: 10.1016/S0140-6736(09)61965-6. Epub 2010 Feb 16.
PubMed 20167359Ridker PM, Pradhan A, MacFadyen JG, Libby P, Glynn RJ. Cardiovascular benefits and diabetes risks of statin therapy in primary prevention: an analysis from the JUPITER trial. Lancet. 2012 Aug 11;380(9841):565-71. doi: 10.1016/S0140-6736(12)61190-8.
PubMed 22883507Lotta LA, Sharp SJ, Burgess S, Perry JRB, Stewart ID, Willems SM, Luan J, Ardanaz E, Arriola L, Balkau B, Boeing H, Deloukas P, Forouhi NG, Franks PW, Grioni S, Kaaks R, Key TJ, Navarro C, Nilsson PM, Overvad K, Palli D, Panico S, Quiros JR, Riboli E, Rolandsson O, Sacerdote C, Salamanca EC, Slimani N, Spijkerman AM, Tjonneland A, Tumino R, van der A DL, van der Schouw YT, McCarthy MI, Barroso I, O'Rahilly S, Savage DB, Sattar N, Langenberg C, Scott RA, Wareham NJ. Association Between Low-Density Lipoprotein Cholesterol-Lowering Genetic Variants and Risk of Type 2 Diabetes: A Meta-analysis. JAMA. 2016 Oct 4;316(13):1383-1391. doi: 10.1001/jama.2016.14568.
PubMed 27701660Schmidt AF, Swerdlow DI, Holmes MV, Patel RS, Fairhurst-Hunter Z, Lyall DM, Hartwig FP, Horta BL, Hypponen E, Power C, Moldovan M, van Iperen E, Hovingh GK, Demuth I, Norman K, Steinhagen-Thiessen E, Demuth J, Bertram L, Liu T, Coassin S, Willeit J, Kiechl S, Willeit K, Mason D, Wright J, Morris R, Wanamethee G, Whincup P, Ben-Shlomo Y, McLachlan S, Price JF, Kivimaki M, Welch C, Sanchez-Galvez A, Marques-Vidal P, Nicolaides A, Panayiotou AG, Onland-Moret NC, van der Schouw YT, Matullo G, Fiorito G, Guarrera S, Sacerdote C, Wareham NJ, Langenberg C, Scott R, Luan J, Bobak M, Malyutina S, Pajak A, Kubinova R, Tamosiunas A, Pikhart H, Husemoen LL, Grarup N, Pedersen O, Hansen T, Linneberg A, Simonsen KS, Cooper J, Humphries SE, Brilliant M, Kitchner T, Hakonarson H, Carrell DS, McCarty CA, Kirchner HL, Larson EB, Crosslin DR, de Andrade M, Roden DM, Denny JC, Carty C, Hancock S, Attia J, Holliday E, O'Donnell M, Yusuf S, Chong M, Pare G, van der Harst P, Said MA, Eppinga RN, Verweij N, Snieder H; LifeLines Cohort study group; Christen T, Mook-Kanamori DO, Gustafsson S, Lind L, Ingelsson E, Pazoki R, Franco O, Hofman A, Uitterlinden A, Dehghan A, Teumer A, Baumeister S, Dorr M, Lerch MM, Volker U, Volzke H, Ward J, Pell JP, Smith DJ, Meade T, Maitland-van der Zee AH, Baranova EV, Young R, Ford I, Campbell A, Padmanabhan S, Bots ML, Grobbee DE, Froguel P, Thuillier D, Balkau B, Bonnefond A, Cariou B, Smart M, Bao Y, Kumari M, Mahajan A, Ridker PM, Chasman DI, Reiner AP, Lange LA, Ritchie MD, Asselbergs FW, Casas JP, Keating BJ, Preiss D, Hingorani AD; UCLEB consortium; Sattar N. PCSK9 genetic variants and risk of type 2 diabetes: a mendelian randomisation study. Lancet Diabetes Endocrinol. 2017 Feb;5(2):97-105. doi: 10.1016/S2213-8587(16)30396-5. Epub 2016 Nov 29.
PubMed 27908689Ference BA, Robinson JG, Brook RD, Catapano AL, Chapman MJ, Neff DR, Voros S, Giugliano RP, Davey Smith G, Fazio S, Sabatine MS. Variation in PCSK9 and HMGCR and Risk of Cardiovascular Disease and Diabetes. N Engl J Med. 2016 Dec 1;375(22):2144-2153. doi: 10.1056/NEJMoa1604304.
PubMed 27959767Faraj M. LDL, LDL receptors, and PCSK9 as modulators of the risk for type 2 diabetes: a focus on white adipose tissue. J Biomed Res. 2020 Mar 12;34(4):251-259. doi: 10.7555/JBR.34.20190124.
PubMed 32701068Cyr Y, Bissonnette S, Lamantia V, Wassef H, Loizon E, Ngo Sock ET, Vidal H, Mayer G, Chretien M, Faraj M. White Adipose Tissue Surface Expression of LDLR and CD36 is Associated with Risk Factors for Type 2 Diabetes in Adults with Obesity. Obesity (Silver Spring). 2020 Dec;28(12):2357-2367. doi: 10.1002/oby.22985. Epub 2020 Oct 11.
PubMed 33043593Cyr Y, Lamantia V, Bissonnette S, Burnette M, Besse-Patin A, Demers A, Wabitsch M, Chretien M, Mayer G, Estall JL, Saleh M, Faraj M. Lower plasma PCSK9 in normocholesterolemic subjects is associated with upregulated adipose tissue surface-expression of LDLR and CD36 and NLRP3 inflammasome. Physiol Rep. 2021 Feb;9(3):e14721. doi: 10.14814/phy2.14721.
PubMed 33527668
Study at a glance
From the registry record, last updated by the sponsor on 12 Mar 2026. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- White Adipose Tissue LDL Receptors and Omega-3 as Modulators of the Risk for Type 2 Diabetes in Subjects With Normal Plasma LDL Cholesterol
- ClinicalTrials.gov ID
- NCT04485871
- Acronym / sponsor ID
- 2020-1035
- Keywords
- Proprotein Convertase Subtilisin / kexin Type 9 (PCSK9), NLRP3 inflammasome, Eicosapentaenoic acid (EPA), Docosahexaenoic acid (DHA), White adipose tissue, Fat metabolism, ApoB-lipoproteins, LDL receptors (LDLR)
- Study type
- Interventional
- Recruitment status
- Recruiting
- Enrolment
- 48 participants (estimated)
- Lead sponsor
- Institut de Recherches Cliniques de MontrealUniversity, hospital or other
- Collaborators
- Canadian Institutes of Health Research (CIHR)
- Study start
- 19 Dec 2019 (actual)
- Primary completion
- 31 May 2027 (estimated)
- Study completion
- 31 May 2027 (estimated)
- First posted
- 24 Jul 2020 (actual)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
Every 3 minutes a new case of diabetes is diagnosed in Canada, mostly type 2 diabetes (T2D) increasing the risk for heart disease. T2D and heart disease share many common risk factors such as aging, obesity and unhealthy lifestyle.
Paradoxically however, while lowering blood LDL, commonly known as "bad cholesterol", is protective against heart disease, research over the past 10 years have shown that the lower is blood LDL, the higher is the chance of developing T2D. This phenomena is happening whether blood LDL is lowered by a common drug against heart disease called Statins, or by being born with certain variations in genes, some of which are very common (~80% of people have them).
To date, it is unclear why lowering blood LDL is associated with higher risk for diabetes, and whether this can be treated naturally with certain nutrients.
Investigators believe that lowering blood LDL by forcing LDL entry into the body tissue through their receptors promotes T2D. This is because investigators have shown that LDL entry into human fat tissue induces fat tissue dysfunction, which would promote T2D especially in subjects with excess weight.
On the other hand, investigators have shown that omega-3 fatty acids (omega-3) can directly treat the same defects induced by LDL entry into fat tissue. Omega-3 is a unique type of fat that is found mostly in fish oil.
Thus the objectives of this clinical trial to be conducted in 48 subjects with normal blood LDL are to explore if:
- Subjects with higher LDL receptors and LDL entry into fat tissue have higher risk factors for T2D compared to subjects with lower LDL receptors and LDL entry into fat tissue
- 6-month supplementation of omega-3 from fish oil can treat subjects with higher LDL receptors and LDL entry into fat tissue reducing their risk for T2D.
This study will thus explore and attempt to treat a new risk factor for T2D using an inexpensive and widely accessible nutraceutical, which would aid in preventing T2D in humans.
Detailed description
Type 2 (T2D) and cardiovascular disease (CVD) share many risk factors, whose accumulation over years lead to disease onset. However, while lowering plasma low-density lipoprotein cholesterol (LDLC) is cardio-protective, novel evidence over the past 10 years established a role for common LDLC-lowering variants and widely used hypocholesterolemic Statins in higher risk for T2D. This diminishes the cardio-protective role of low plasma LDLC. As these conditions decrease plasma LDLC by increasing tissue-uptake of LDL, a role for LDL receptor (LDLR) pathway was proposed. However underlying mechanisms fueling higher risk for T2D with upregulated LDLR pathway, and nutritional approaches to treat them are unclear.
The central hypothesis examined in this trial is that upregulating receptor-mediated uptake of LDL on white adipose tissue provokes the activation of an innate immunity pathway (the Nucleotide-binding domain and Leucine-rich repeat Receptor, containing a Pyrin domain 3 (NLRP3) inflammasome) leading to the accumulation of risk factors for T2D in subjects with normal plasma LDLC. This can be treated by 6-month supplementation of omega-3 fatty acids (omega-3).
To examine this hypothesis in vivo, ex vivo and in vitro, a clinical trial in conjunction with mechanistic basic research studies have been initiated at the Montreal Clinical Research Institute (IRCM). Forty eight volunteers will be recruited through advertisements in French/English newspapers and online (e.g. Google, Facebook) and placed on a 6-month supplementation of 3.6 g omega-3 per day. Participants will be stratified into 2 groups (N=24/group) with higher and lower white adipose tissue surface-expression LDL receptors (LDLR and CD36) using median plasma PCSK9 (Proprotein Convertase Subtilisin/Kexin type 9) per sex. Plasma PSCK9 will be used as investigators have shown that it is negatively associated with white adipose tissue surface-expression of LDLR and CD36.
The duration of this study is about 8 months (33 weeks) divided into 5 parts:
- Screening and evaluation of eligibility for the study
- Weight stabilisation (+/- 2 kg change over 4 weeks) and confirmation of eligibility after a medical examination by IRCM physician collaborators.
- Baseline testing over 2 days (1- 4 weeks apart) to assess participants risk factors for T2D: white adipose tissue NLRP3 inflammasome activity, white adipose tissue physiology and function (ex vivo after a subcutaneous needle biopsy), systemic inflammation, dietary fat clearance (after a high fat meal), and insulin secretion and sensitivity (by gold-standard Botnia clamp technique). Participants will also be phenotyped for body composition (by dual energy x-ray absorptiometry), resting energy expenditure (by indirect calorimetry), dietary intake (by 3-day dietary journals) and physical activity level (by a questionnaire).
- 24-week intervention with omega-3 fatty acid supplementation (3.6 g eicosapentaenoic acid (EPA) and docosahexaenoic (DHA), 2:1)
- Post intervention testing starting over 2 days (1- 4 weeks apart) to assess risk factors for T2D that were measured at baseline.
Investigators hypothesize that subjects with low plasma PCSK9 (i.e. with higher white adipose tissue LDLR and CD36) will have higher risk factors for T2D at baseline and that the omega-3 intervention will eliminate group-differences in these risk factors.
Study design
- Primary purpose
- Prevention
- Allocation
- Not applicable
- Intervention model
- Single group
- Masking
- None (open label)
- Number of arms
- 1
- Model description
- Subjects (N=48) will be recruited with the same inclusion/exclusion criteria and will received the same omega-3 intervention. After completion of recruitment, subjects will be stratified into 2 groups (24/group) based on a baseline plasma PCSK9 for group characterisation and comparison.
| Arm | Type | Receives |
|---|---|---|
| Omega-3 fatty acids | Experimental | Dietary Supplement: Omega-3 fatty acids3.6 g EPA:DHA / day (2:1) |
Who may qualify
- Ages
- 45 to 74 years
- Sex
- All
- Healthy volunteers
- Accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (7 listed)
- Having a body mass index (BMI= 25-40 kg/m2)
- Aged between 45 and 74 years
- Having confirmed menopausal status (FSH ≥ 30 U/l)
- Non-smoker
- Sedentary (less than 2 hours of structured physical exercise (ex: sports club) per week)
Key exclusion criteria (25 listed)
- Plasma LDL cholesterol > 3.5 mmol/L (i.e. > 75th percentile in a Canadian population).
- Elevated risk of cardiovascular disease (≥ 20% of calculated Framingham Risk Score) who would require immediate medical intervention by lipid-lowering agents.
- Prior history of cardiovascular events (like stroke, transient ischemic attack, myocardial infarction, angina, heart failure…)
- Systolic blood pressure > 140 mmHg or diastolic blood pressure > 90 mmHg
- Type 1 or 2 diabetes or fasting glucose > 7.0 mmol/L
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| Omega-3 fatty acidsAlso: Triple Strength Omega-3 from Webber NaturalsTriple Strength Omega-3 from Webber Naturals; 4 oral softgels (600 mg EPA and 300 mg DHA / softgel) | Dietary supplement | Omega-3 fatty acids |
Primary outcome
Fasting white adipose tissue NLRP3 inflammasome activation
Time frame: Baseline
White adipose tissue medium accumulation of interleukin 1 beta (IL-1β) ex vivo over 4 hours (pg/mg tissue by AlphaLISA)
Fasting white adipose tissue NLRP3 inflammasome activation
Time frame: At 24 weeks
White adipose tissue medium accumulation of interleukin 1 beta (IL-1β) ex vivo over 4 hours (pg/mg tissue by AlphaLISA)
22 secondary outcomes
Fasting plasma PCSK9 concentration
Time frame: Baseline
Fasting plasma PCSK9 concentration
Time frame: At 24 weeks
White adipose tissue receptors for apoB-lipoproteins
Time frame: Baseline
White adipose tissue receptors for apoB-lipoproteins
Time frame: At 24 weeks
White adipose tissue inflammation profile
Time frame: Baseline
White adipose tissue inflammation profile
Time frame: At 24 weeks
White adipose tissue function ex vivo
Time frame: Baseline
White adipose tissue function ex vivo
Time frame: At 24 weeks
Postprandial fat metabolism
Time frame: Baseline
Postprandial fat metabolism
Time frame: At 24 week
Systemic inflammation
Time frame: Baseline
Systemic inflammation
Time frame: At 24 weeks
Disposition index
Time frame: Baseline
Disposition index
Time frame: At 24 weeks
Fatty acid profile in red blood cell phospholipid fraction
Time frame: Baseline
Fatty acid profile in red blood cell phospholipid fraction
Time frame: At 24 weeks
Body composition
Time frame: Baseline
Body composition
Time frame: At 24 weeks
Energy intake
Time frame: Baseline
Energy intake
Time frame: At 24 weeks
Physical activity
Time frame: Baseline
Physical activity
Time frame: At 24 weeks
Results and safety
This study is still under way. Results are not available in the source record yet.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 12 Mar 2026.
- Background: PubMed 23417739Bissonnette S, Salem H, Wassef H, Saint-Pierre N, Tardif A, Baass A, Dufour R, Faraj M. Low density lipoprotein delays clearance of triglyceride-rich lipoprotein by human subcutaneous adipose tissue. J Lipid Res. 2013 May;54(5):1466-76. doi: 10.1194/jlr.P023176. Epub 2013 Feb 17.
- Background: PubMed 26350813Wassef H, Bissonnette S, Saint-Pierre N, Lamantia V, Cyr Y, Chretien M, Faraj M. The apoB-to-PCSK9 ratio: A new index for metabolic risk in humans. J Clin Lipidol. 2015 Sep-Oct;9(5):664-75. doi: 10.1016/j.jacl.2015.06.012. Epub 2015 Jul 2.
- Background: PubMed 28391908Lamantia V, Bissonnette S, Wassef H, Cyr Y, Baass A, Dufour R, Rabasa-Lhoret R, Faraj M. ApoB-lipoproteins and dysfunctional white adipose tissue: Relation to risk factors for type 2 diabetes in humans. J Clin Lipidol. 2017 Jan-Feb;11(1):34-45.e2. doi: 10.1016/j.jacl.2016.09.013. Epub 2016 Oct 3.
- Background: PubMed 24518981Skeldon AM, Faraj M, Saleh M. Caspases and inflammasomes in metabolic inflammation. Immunol Cell Biol. 2014 Apr;92(4):304-13. doi: 10.1038/icb.2014.5. Epub 2014 Feb 11.
- Background: PubMed 20167359Sattar N, Preiss D, Murray HM, Welsh P, Buckley BM, de Craen AJ, Seshasai SR, McMurray JJ, Freeman DJ, Jukema JW, Macfarlane PW, Packard CJ, Stott DJ, Westendorp RG, Shepherd J, Davis BR, Pressel SL, Marchioli R, Marfisi RM, Maggioni AP, Tavazzi L, Tognoni G, Kjekshus J, Pedersen TR, Cook TJ, Gotto AM, Clearfield MB, Downs JR, Nakamura H, Ohashi Y, Mizuno K, Ray KK, Ford I. Statins and risk of incident diabetes: a collaborative meta-analysis of randomised statin trials. Lancet. 2010 Feb 27;375(9716):735-42. doi: 10.1016/S0140-6736(09)61965-6. Epub 2010 Feb 16.
- Background: PubMed 22883507Ridker PM, Pradhan A, MacFadyen JG, Libby P, Glynn RJ. Cardiovascular benefits and diabetes risks of statin therapy in primary prevention: an analysis from the JUPITER trial. Lancet. 2012 Aug 11;380(9841):565-71. doi: 10.1016/S0140-6736(12)61190-8.
- Background: PubMed 27701660Lotta LA, Sharp SJ, Burgess S, Perry JRB, Stewart ID, Willems SM, Luan J, Ardanaz E, Arriola L, Balkau B, Boeing H, Deloukas P, Forouhi NG, Franks PW, Grioni S, Kaaks R, Key TJ, Navarro C, Nilsson PM, Overvad K, Palli D, Panico S, Quiros JR, Riboli E, Rolandsson O, Sacerdote C, Salamanca EC, Slimani N, Spijkerman AM, Tjonneland A, Tumino R, van der A DL, van der Schouw YT, McCarthy MI, Barroso I, O'Rahilly S, Savage DB, Sattar N, Langenberg C, Scott RA, Wareham NJ. Association Between Low-Density Lipoprotein Cholesterol-Lowering Genetic Variants and Risk of Type 2 Diabetes: A Meta-analysis. JAMA. 2016 Oct 4;316(13):1383-1391. doi: 10.1001/jama.2016.14568.
- Background: PubMed 27908689Schmidt AF, Swerdlow DI, Holmes MV, Patel RS, Fairhurst-Hunter Z, Lyall DM, Hartwig FP, Horta BL, Hypponen E, Power C, Moldovan M, van Iperen E, Hovingh GK, Demuth I, Norman K, Steinhagen-Thiessen E, Demuth J, Bertram L, Liu T, Coassin S, Willeit J, Kiechl S, Willeit K, Mason D, Wright J, Morris R, Wanamethee G, Whincup P, Ben-Shlomo Y, McLachlan S, Price JF, Kivimaki M, Welch C, Sanchez-Galvez A, Marques-Vidal P, Nicolaides A, Panayiotou AG, Onland-Moret NC, van der Schouw YT, Matullo G, Fiorito G, Guarrera S, Sacerdote C, Wareham NJ, Langenberg C, Scott R, Luan J, Bobak M, Malyutina S, Pajak A, Kubinova R, Tamosiunas A, Pikhart H, Husemoen LL, Grarup N, Pedersen O, Hansen T, Linneberg A, Simonsen KS, Cooper J, Humphries SE, Brilliant M, Kitchner T, Hakonarson H, Carrell DS, McCarty CA, Kirchner HL, Larson EB, Crosslin DR, de Andrade M, Roden DM, Denny JC, Carty C, Hancock S, Attia J, Holliday E, O'Donnell M, Yusuf S, Chong M, Pare G, van der Harst P, Said MA, Eppinga RN, Verweij N, Snieder H; LifeLines Cohort study group; Christen T, Mook-Kanamori DO, Gustafsson S, Lind L, Ingelsson E, Pazoki R, Franco O, Hofman A, Uitterlinden A, Dehghan A, Teumer A, Baumeister S, Dorr M, Lerch MM, Volker U, Volzke H, Ward J, Pell JP, Smith DJ, Meade T, Maitland-van der Zee AH, Baranova EV, Young R, Ford I, Campbell A, Padmanabhan S, Bots ML, Grobbee DE, Froguel P, Thuillier D, Balkau B, Bonnefond A, Cariou B, Smart M, Bao Y, Kumari M, Mahajan A, Ridker PM, Chasman DI, Reiner AP, Lange LA, Ritchie MD, Asselbergs FW, Casas JP, Keating BJ, Preiss D, Hingorani AD; UCLEB consortium; Sattar N. PCSK9 genetic variants and risk of type 2 diabetes: a mendelian randomisation study. Lancet Diabetes Endocrinol. 2017 Feb;5(2):97-105. doi: 10.1016/S2213-8587(16)30396-5. Epub 2016 Nov 29.
- Background: PubMed 27959767Ference BA, Robinson JG, Brook RD, Catapano AL, Chapman MJ, Neff DR, Voros S, Giugliano RP, Davey Smith G, Fazio S, Sabatine MS. Variation in PCSK9 and HMGCR and Risk of Cardiovascular Disease and Diabetes. N Engl J Med. 2016 Dec 1;375(22):2144-2153. doi: 10.1056/NEJMoa1604304.
- Background: PubMed 32701068Faraj M. LDL, LDL receptors, and PCSK9 as modulators of the risk for type 2 diabetes: a focus on white adipose tissue. J Biomed Res. 2020 Mar 12;34(4):251-259. doi: 10.7555/JBR.34.20190124.
- Background: PubMed 33043593Cyr Y, Bissonnette S, Lamantia V, Wassef H, Loizon E, Ngo Sock ET, Vidal H, Mayer G, Chretien M, Faraj M. White Adipose Tissue Surface Expression of LDLR and CD36 is Associated with Risk Factors for Type 2 Diabetes in Adults with Obesity. Obesity (Silver Spring). 2020 Dec;28(12):2357-2367. doi: 10.1002/oby.22985. Epub 2020 Oct 11.
- Background: PubMed 33527668Cyr Y, Lamantia V, Bissonnette S, Burnette M, Besse-Patin A, Demers A, Wabitsch M, Chretien M, Mayer G, Estall JL, Saleh M, Faraj M. Lower plasma PCSK9 in normocholesterolemic subjects is associated with upregulated adipose tissue surface-expression of LDLR and CD36 and NLRP3 inflammasome. Physiol Rep. 2021 Feb;9(3):e14721. doi: 10.14814/phy2.14721.
- IRCM website for recruitmentLink provided by the sponsor.
- Individual participant dataSharing planned: No. Frozen plasma and white adipose tissue samples (when sufficient) can be made available for analysis by other investigators. However data statistical analyses incorporating complete IPD must be conducted by the research team of Dr May Faraj as per subject consent form.
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part.
May Faraj, PDt, PhD principal investigator
Montreal Clinical Research Institute/ University of Montreal
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A study testing Omega-3 fatty acids in people with Type 2 Diabetes and Inflammation, run by Institut de Recherches Cliniques de Montreal at 1 site in Canada.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 7 inclusion and 25 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: looking for participants now, as of the sponsor's last update on 12 Mar 2026. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in Canada. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
Are results available for this study?
This study is still under way. Results are not available in the source record yet.
How can a doctor refer a patient or contact the research team?
Contact Justine Fricher, MSc (514-987-5500 ext. 3260, justine.fricher@ircm.qc.ca), or a site near the patient. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Fasting white adipose tissue NLRP3 inflammasome activation (time frame: Baseline). The study lists 2 primary outcomes in all. It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT04485871, which also lists 12 linked publications.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 12 Mar 2026.