Condition category
Nutritional, Metabolic, Endocrine
Date applied
Date assigned
Last edited
Retrospectively registered
Overall trial status
Recruitment status
No longer recruiting
Publication status

Plain English Summary

Not provided at time of registration

Trial website

Contact information



Primary contact

Dr L J Rijzewijk


Contact details

Diabetes Centre/Department of Endocrinology
VU medisch centrum
De Boelelaan 1117
1081 HV

Additional identifiers

EudraCT number number

Protocol/serial number


Study information

Scientific title


The PIRAMID study

Study hypothesis

Patients with type two Diabetes Mellitus (DM2) have a considerably higher risk to develop cardiac disease with a poorer outcome. Ectopic Triglyceride (TG) accumulation underlies diabetic cardiomyopathy. These cardiac abnormalities can be reversed by lowering myocardial TG using a Peroxisome Proliferator-Activated Receptor-g (PPARg) agonist. Metformin, the present gold standard treatment for type two diabetes, might also have cardioprotective properties due to its recently proposed mechanism of action.

Lipotoxicity-related cardiac abnormalities can be reversed by PPAR g agonist therapy in type two diabetes patients.

Ethics approval

Ethics approval received from the local medical ethics committee

Study design

Multicentre, randomised, double blinded, active controlled, parallel group trial

Primary study design


Secondary study design

Randomised controlled trial

Trial setting

Not specified

Trial type


Patient information sheet

Not available in web format, please use the contact details below to request a patient information sheet


Diabetes Mellitus type two (DM2), heart disease


80 subjects on monotherapy sulfanylurea for at least ten weeks will be enrolled. Following this, participants will be randomised to metformin or pioglitazone for 24 weeks. Ten healthy subject will only undergo baseline measurements

Please note that the anticipated end date of this trial has been extended to the 15th January 2007.

Intervention type



Not Specified

Drug names

Metformin or Pioglitazone

Primary outcome measure

Changes in cardiac function and metabolism following treatment with PPARg agonist versus current state of the art therapy, metformin.

Secondary outcome measures

1. Glucose and Free Fatty Acid (FFA) uptake by adipose tissue and skeletal muscle
2. Cardiac High-Energy-Phosphate (HEP) metabolism
3. Haemodynamic and vascular parameters body composition (Body Mass Index [BMI], waist, adipose tissue distribution, including liver fat content, body fat percentage and fluid retention)
4. Plasma parameters of glycemic control and lipoprotein metabolism
5. Circulating levels of markers of inflammation, coagulation activation, fibrinolysis and endothelial functions
6. Whole-body insulin sensitivity (by clamp)

Overall trial start date


Overall trial end date


Reason abandoned (if study stopped)


Participant inclusion criteria

Type two diabetes patients:
1. Type two diabetes diagnosed male patients aged 45 to 65 years (diagnosed according to World Health Organisation [WHO] criteria)
2. Treated by monotherapy of sulfanylurea (i.e. unchanged during more than 30 days prior to inclusion)
3. At least three months stable HbA1c (less than 8.5%) under this therapy
4. Sitting blood pressure less than 150/85 mmHg with or without anti-hypertensive drugs
5. Body Mass Index (BMI) less than 32 kg/m^2

Healthy volunteers:
1. Healthy male subjects, 45 to 65 years
2. Normal sitting blood pressure less than 150/85 mmHg
3. BMI less than 32 kg/m^2
4. Normal glucose tolerance as assessed by 75 g oral glucose tolerance test

Participant type

Healthy volunteer

Age group




Target number of participants


Participant exclusion criteria

Type two diabetes patients:
1. Coronary Artery Disease (CAD)
2. Active malignant disease
3. Impaired renal function (serum creatinine more than 176 mmol/l)
4. Weight greater than or equal to 45 kg (because of 11C-palmitate tracer)
5. Anti-coagulant therapy
6. Severe obstructive lung disease
7. Hereditary lipoprotein disease
8. Impaired hepatic function (defined as Alanine aminotransferase [ALT] more than three Upper Limit of Normal [ULN]) or a history of liver disease
9. Inability to understand study information
10. Inability/unwillingness to sign informed consent
11. Substance abuse
12. Familial polyposis coli
13. Less than three months after participation in other clinical trials or other research projects, whereby radiation is used
14. Haemoglobin less than 8 mmol/l
15. Metal implants and claustrophobia
16. Incompatible with Cardiovascular Magnetic Resonance (CMR)
17. Congestive heart failure (New York Heart Association [NYHA] functional score more than one)
18. Atrial fibrillation or history of sustained ventricular tachycardia
19. Stroke within six months prior to enrolment
20. Microvascular complications including:
a. diabetic nephropathy
b. proliferative retinopathy
c. symptomatic macrovascular complications, and/or
d. (autonomic) neuropathy, except for background diabetic retinopathy, leg ulcers, gangrene, hypersensibility to study medication, current use of Thiazolidinediones (TZD)/fibrates

Healthy volunteers:
1. History or current cardiovascular disease
2. Dyslipidemia, requiring pharmacological treatment according to the Dutch Cholesterol Consensus 1998

Recruitment start date


Recruitment end date



Countries of recruitment


Trial participating centre

Diabetes Centre/Department of Endocrinology
1081 HV

Sponsor information


VU University Medical Centre (Netherlands)

Sponsor details

Van der Boechorststraat 7
1081 BT

Sponsor type




Funder type


Funder name

Eli Lilly Nederland B.V. (Netherlands)

Alternative name(s)

Funding Body Type

Funding Body Subtype


Results and Publications

Publication and dissemination plan

Not provided at time of registration

Intention to publish date

Participant level data

Not provided at time of registration

Basic results (scientific)

Publication list

1. 2009 results in
2. 2010 results in
3. 2011 results in

Publication citations

  1. Results

    van der Meer RW, Rijzewijk LJ, de Jong HW, Lamb HJ, Lubberink M, Romijn JA, Bax JJ, de Roos A, Kamp O, Paulus WJ, Heine RJ, Lammertsma AA, Smit JW, Diamant M, Pioglitazone improves cardiac function and alters myocardial substrate metabolism without affecting cardiac triglyceride accumulation and high-energy phosphate metabolism in patients with well-controlled type 2 diabetes mellitus., Circulation, 2009, 119, 15, 2069-2077, doi: 10.1161/CIRCULATIONAHA.108.803916.

  2. Results

    Jonker JT, Wang Y, de Haan W, Diamant M, Rijzewijk LJ, van der Meer RW, Lamb HJ, Tamsma JT, de Roos A, Romijn JA, Rensen PC, Smit JW, Pioglitazone decreases plasma cholesteryl ester transfer protein mass, associated with a decrease in hepatic triglyceride content, in patients with type 2 diabetes., Diabetes Care, 2010, 33, 7, 1625-1628, doi: 10.2337/dc09-1935.

  3. Results

    Chen WJ, Rijzewijk LJ, van der Meer RW, Heymans MW, van Duinkerken E, Lubberink M, Lammertsma AA, Lamb HJ, de Roos A, Romijn JA, Smit JW, Bax JJ, Bjerre M, Frystyk J, Flyvbjerg A, Diamant M, Association of plasma osteoprotegerin and adiponectin with arterial function, cardiac function and metabolism in asymptomatic type 2 diabetic men., Cardiovasc Diabetol, 2011, 10, 67, doi: 10.1186/1475-2840-10-67.

Additional files

Editorial Notes