The Copenhagen Insulin and Metformin Therapy Trial (CIMT)

The Effect of Metformin Versus Placebo, Including Three Insulin-Analogue Regimens With Variating Postprandial Glucose Regulation, on CIMT in T2DM Patients - A Randomized, Multicenter Trial

Type 2 Diabetes Mellitus patients (T2DM) have an increased mortality rate due to macrovascular disease. The primary objective of the study is to evaluate the effect of an 18-month treatment with metformin versus placebo in combination with one of three insulin analogue regimens following a treat-to-target principle. The primary outcome measure is change in wall thickness of the carotic arteries(CIMT)measured by ultrasound. A total of 900 patients with T2DM and HbA1c above 7.5% will be included.

Study Overview

• Status: Completed
• Conditions: Arteriosclerosis; Atherosclerosis; Type 2 Diabetes
• Intervention / Treatment: Drug: metformin; Drug: insulin detemir; Drug: insulin aspart + insulin aspart protamin; Drug: Insulin aspart

• Study Type: Interventional
• Enrollment (Actual): 415
• Phase: Phase 4

Contacts and Locations

Study Locations

• Denmark
  • Copenhagen, Denmark, 2100
    • Rigshospitalet
  • Copenhagen, Denmark, 2400
    • Bispebjerg Hospital
  • Frederiksberg, Denmark, 2000
    • Frederiksberg Hospital
  • Gentofte, Denmark, 2820
    • Steno Diabetes Center
  • Gentofte, Denmark, 2820
    • Gentofte Sygehus
  • Herlev, Denmark, 2830
    • Herlev Hospital
  • Hillerod, Denmark, 3400
    • Hillerod Sygehus
  • Hvidovre, Denmark, 2650
    • Hvidovre Hospital
  • Koge, Denmark, 4600
    • Køge Sygehus

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 30 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Males and females over 30 years of age
• Type 2 diabetes
• Body mass index (BMI): 25.0-39.9 kg/m2
• HbA1c above 7.5 %
• Antidiabetic tablet-treatment during 1 year minimum AND / OR
• Insulin treatment during a minimum of 3 months
• Negative pregnancy test
• Signed, informed consent

Exclusion Criteria:

• MI, coronary revascularization, TCI,or apoplexy within the last 3 months
• TCI with verified stenosis of above 70%
• Heart failure (NYHA class III or IV)
• Former cancer patient, unless disease-free period of more than 5 years
• estimated creatinine clearance < 60 ml/min Liver disease
• Alcohol abuse
• Drug abuse
• Retinopathy with on-going laser treatment at start of study
• Other acute or chronic serious disease leading to hypoxia
• Pregnant or breastfeeding women
• Women of child-bearing potential, not using contraceptives
• Allergy to medication used in the study
• Incapable of understanding the nature of the informed consent

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Factorial Assignment
• Masking: Triple

Number of Arms

6

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: 1M; Metformin + Levemir x1	Drug: metformin; metformin tablets 2 g x 2; Other Names: glucophage; Drug: insulin detemir; insulin as requested; Other Names: Levemir
Placebo Comparator: 1P; Placebo + Levemir x1	Drug: insulin detemir; insulin as requested; Other Names: Levemir
Experimental: 2M; metformin + NovoMix	Drug: metformin; metformin tablets 2 g x 2; Other Names: glucophage; Drug: insulin aspart + insulin aspart protamin; insulin as requested; Other Names: novomix
Placebo Comparator: 2P; Placebo + NovoMix	Drug: insulin aspart + insulin aspart protamin; insulin as requested; Other Names: novomix
Experimental: 3M; Metformin + 4x therapy	Drug: metformin; metformin tablets 2 g x 2; Other Names: glucophage; Drug: insulin detemir; insulin as requested; Other Names: Levemir; Drug: Insulin aspart; insulin as requested; Other Names: NovoRapid
Placebo Comparator: 3P; Placebo + 4x therapy	Drug: insulin detemir; insulin as requested; Other Names: Levemir; Drug: Insulin aspart; insulin as requested; Other Names: NovoRapid

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
Carotid intima media thickness	18 months

Secondary Outcome Measures

Outcome Measure	Time Frame
adverse events	18 months

Collaborators and Investigators

• Sponsor: Steno Diabetes Center Copenhagen
• Collaborators: Zealand University Hospital; Novo Nordisk A/S; Rigshospitalet, Denmark; Hvidovre University Hospital; Bispebjerg Hospital; Herlev Hospital; Hillerod Hospital, Denmark; Frederiksberg University Hospital; University Hospital, Gentofte, Copenhagen; Copenhagen Trial Unit, Center for Clinical Intervention Research
• Investigators: Principal Investigator: Thomas Almdal, MD DMSc, Hvidovre University Hospital

Publications and helpful links

General Publications

• Hansen CS, Lundby-Christiansen L, Tarnow L, Gluud C, Hedetoft C, Thorsteinsson B, Hemmingsen B, Wiinberg N, Sneppen SB, Lund SS, Krarup T, Madsbad S, Almdal T, Carstensen B, Jorgensen ME; CIMT study group. Metformin may adversely affect orthostatic blood pressure recovery in patients with type 2 diabetes: substudy from the placebo-controlled Copenhagen Insulin and Metformin Therapy (CIMT) trial. Cardiovasc Diabetol. 2020 Sep 26;19(1):150. doi: 10.1186/s12933-020-01131-3.
• Nordklint AK, Almdal TP, Vestergaard P, Lundby-Christensen L, Boesgaard TW, Breum L, Gade-Rasmussen B, Sneppen SB, Gluud C, Hemmingsen B, Jensen T, Krarup T, Madsbad S, Mathiesen ER, Perrild H, Tarnow L, Thorsteinsson B, Vestergaard H, Lund SS, Eiken P. The effect of metformin versus placebo in combination with insulin analogues on bone mineral density and trabecular bone score in patients with type 2 diabetes mellitus: a randomized placebo-controlled trial. Osteoporos Int. 2018 Nov;29(11):2517-2526. doi: 10.1007/s00198-018-4637-z. Epub 2018 Jul 19.
• Lundby-Christensen L, Vaag A, Tarnow L, Almdal TP, Lund SS, Wetterslev J, Gluud C, Boesgaard TW, Wiinberg N, Perrild H, Krarup T, Snorgaard O, Gade-Rasmussen B, Thorsteinsson B, Roder M, Mathiesen ER, Jensen T, Vestergaard H, Hedetoft C, Breum L, Duun E, Sneppen SB, Pedersen O, Hemmingsen B, Carstensen B, Madsbad S. Effects of biphasic, basal-bolus or basal insulin analogue treatments on carotid intima-media thickness in patients with type 2 diabetes mellitus: the randomised Copenhagen Insulin and Metformin Therapy (CIMT) trial. BMJ Open. 2016 Feb 25;6(2):e008377. doi: 10.1136/bmjopen-2015-008377.
• Lundby-Christensen L, Tarnow L, Boesgaard TW, Lund SS, Wiinberg N, Perrild H, Krarup T, Snorgaard O, Gade-Rasmussen B, Thorsteinsson B, Roder M, Mathiesen ER, Jensen T, Vestergaard H, Hedetoft C, Breum L, Duun E, Sneppen SB, Pedersen O, Hemmingsen B, Carstensen B, Madsbad S, Gluud C, Wetterslev J, Vaag A, Almdal TP. Metformin versus placebo in combination with insulin analogues in patients with type 2 diabetes mellitus-the randomised, blinded Copenhagen Insulin and Metformin Therapy (CIMT) trial. BMJ Open. 2016 Feb 25;6(2):e008376. doi: 10.1136/bmjopen-2015-008376.

Study record dates

Study Major Dates

• Study Start: April 1, 2008
• Primary Completion (Actual): December 1, 2012
• Study Completion (Actual): December 1, 2012

Study Registration Dates

• First Submitted: April 8, 2008
• First Submitted That Met QC Criteria: April 11, 2008
• First Posted (Estimate): April 14, 2008

Study Record Updates

• Last Update Posted (Estimate): February 4, 2014
• Last Update Submitted That Met QC Criteria: February 2, 2014
• Last Verified: February 1, 2014

More Information

Terms related to this study

• Keywords: insulin; metformin; media; carotid; thickness; intima
• Additional Relevant MeSH Terms: Cardiovascular Diseases; Vascular Diseases; Arterial Occlusive Diseases; Arteriosclerosis; Atherosclerosis; Hypoglycemic Agents; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Coagulants; Heparin Antagonists; Insulin; Insulin, Globin Zinc; Insulin Aspart; Insulin, Long-Acting; Insulin degludec, insulin aspart drug combination; Metformin; Insulin Detemir; Protamines
• Other Study ID Numbers: EudraCT 2007-006665-33