Metformin and Prevention of Cardiovascular Events in Patients With Acute Myocardial Infarction and Prediabetes (MIMET) (MIMET)

The Myocardial Infarction and New Treatment With Metformin Study (MIMET) - a R-RCT to Study Metformin and the Prevention of Cardiovascular Events in Patients With Acute Myocardial Infarction and Newly Detected Prediabetes

Prediabetes is associated to an increased risk of cardiovascular disease and mortality. Although metformin can delay progression to diabetes there is a lack of RCTs evaluating the effect of metformin on cardiovascular outcomes. MIMET aims to investigate if addition of metformin to standard care has effects on the occurrence of cardiovascular events after acute myocardial infarction in patients with newly detected prediabetes (identified by oral glucose tolerance test, HbA1c or fasting glucose levels).

Study Overview

• Status: Recruiting
• Conditions: ST Elevation Myocardial Infarction; PreDiabetes; Acute Myocardial Infarction; Non ST Elevation Myocardial Infarction
• Intervention / Treatment: Drug: Metformin

Detailed Description

The study is a national multicenter R-RCT associated to the The Swedish Web-system for Enhancement and Development of Evidence-based care in Heart disease Evaluated According to Recommended Therapies (SWEDEHEART registry) where participants, after informed consent, will be randomly assigned to either open treatment with standard care + metformin or standard care alone in a 1:1 ratio. Standard care consists of diet and life-style advice according to national guidelines but does not include metformin. Baseline data for individual patients will be collected from the SWEDEHEART registry. Patients will be followed per routine care at 2 and 12 months post index AMI and in addition at a final study visit at 24 months. Laboratory measurements and collection of SAE will be performed yearly. In total n=5150 patients is expected to be followed for major CV event (all-cause mortality, myocardial infarction, heart failure and stroke) by linkage with SWEDEHEART and national health registries.

• Study Type: Interventional
• Enrollment (Estimated): 5160
• Phase: Phase 3

Contacts and Locations

• Study Contact: Name: Anna Norhammar, MD, Prof.; Phone Number: +46858701568; Email: anna.norhammar@ki.se
• Study Contact Backup: Name: Viveca Ritsinger, MD, PhD; Phone Number: +46372585000; Email: viveca.ritsinger@ki.se

Study Locations

• Sweden
  • Ljungby, Sweden, 341 35
    • Recruiting
    • Medicinkliniken, Ljungby Hospital
    • Principal Investigator: Viveca Ritsinger, MD PhD
    • Contact: Thomas Aronsson, Head of Clinic

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 80 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

I. AMI

II. Swedish citizens with a personal ID number ≥18 years and ≤80 years

III. Newly diagnosed prediabetes:

1. HbA1c 42-47 mmol/mol or
2. Capillary or venous fasting plasma glucose concentration 6.1-6.9 mmol/L or
3. 2-hour post-load capillary glucose concentration 8.9-12.1 mmol/L or
4. 2-h post-load venous plasma glucose concentration 7.8-11.0 mmol/L
5. HbA1c <48 mmol/mol and 2-hour post-load capillary glucose concentration >12.1 mmol/L or 2-h post-load venous plasma glucose concentration >11.0 mmol/L (thus elevated 2-hour glucose levels in the diabetes range but without HbA1c levels diagnostic for diabetes)

IV. Naïve to metformin and other glucose lowering therapy

V. Signed informed consent

Exclusion Criteria:

I. Type 1 diabetes

II. Known type 2 diabetes

III. Indication for glucose lowering treatment

IV. Acute condition with high risk for volume depletion, circulatory shock, hypoxia

V. Serious illness, other than cardiovascular, with short life expectancy

VI. Renal failure (eGFR <60ml/min)

VII. Hepatic failure

VIII. Malignancy within the last year

IX. Contraindication or hypersensitivity to the study drug

X. Alcohol or drug abuse

XI. Pregnancy or breastfeeding

XII. Women of childbearing potential without adequate anticonception during any part of the study period

XIII. Previous hospitalisation for lactic acidosis

XIV. Predicted inability to comply with the study protocol

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Prevention
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Metformin on top of standard care; Metformin will be prescribed by the Investigator at the study site and dispensed at pharmacy of choice by the patient. Metformin will be recommended to be gradually titrated to minimize gastrointestinal side effects with a start dose of 500 mg 1x1 for 1 week and thereafter 500 mg 1x2 with an individualised target dose of 2000 mg daily depending on tolerability. The goal is to a have minimal dose of 500 mg 1x2. Patients will be informed to stop medication in events of sever nausea, vomiting or dehydration according to standard practice. The threshold for metformin titration or adding another drug during follow-up is recommended to be assessed individually by the Investigator at the study site, responsible for the patient. Patients with eGFR <60 cannot be included in the MIMET study. If GFR is between 30-45 ml/min during the study, metformin should be reduced to 1000 mg daily. Metformin is contraindicated if GFR <30 ml/min. Standard care will be the same as in the control arm.	Drug: Metformin; Individualised target dose of 2000 mg daily depending on tolerability.
No Intervention: Standard care alone; Standard care according to national guidelines. In Sweden there is no pharmacological intervention recommended for individuals with prediabetes at present. Standard care includes diet and life-style advice, which will be given to both groups in the same manner according to local routines, based on the present guidelines. Secondary preventive treatment includes physical activity, participating in exercise program, dietary habits, BMI and or waist circumference, smoking and EQ-5D will be followed in accordance with the routinely reported SWEDEHEART-SEPHIA variables.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Time to major CV event	Major CV event; a composite endpoint of first of all-cause death or main diagnosis of MI, heart failure or stroke (reported in SWEDEHEART, the National Patient Register and the Cause of Death Register).	Estimated follow-up for each patient is 1-4 years

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Time to the composite endpoint CV death, main diagnosis of MI, heart failure or stroke.	Time to first event included in the composite endpoint CV death, main diagnosis of MI, heart failure or stroke.	Estimated follow-up for each patient is 1-4 years
Time to the composite endpoint of all-cause death, main diagnosis of MI, stroke and revascularisation (CABG or PCI >4 months after the index AMI).	Time to first event included in the composite endpoint of all-cause death, main diagnosis of MI, stroke and revascularisation (CABG or PCI >4 months after the index AMI).	Estimated follow-up for each patient is 1-4 years
All-cause death	Time to all-cause death	Estimated follow-up for each patient is 1-4 years
CV death	Time to CV death	Estimated follow-up for each patient is 1-4 years
Hospitalisation with MI	Time to readmission for MI. Hospital admission for MI during day 0-30 after index AMI will be excluded	Estimated follow-up for each patient is 1-4 years
Hospitalisation with stroke	Time to hospitalisation for stroke (main diagnosis)	Estimated follow-up for each patient is 1-4 years
Hospitalisation with heart failure	Time to hospitalisation for heart failure (main diagnosis)	Estimated follow-up for each patient is 1-4 years
New cancer diagnosis	Time to new cancer diagnosis defined as the first occurrence of any cancer in the National Patient Register	Estimated follow-up for each patient is 1-4 years
Initiation of any glucose lowering therapy	Time to initiation of any glucose lowering therapy (ATC code A10 in the Prescribed Drug Register, excluding randomisation to metformin)	Estimated follow-up for each patient is 1-4 years
Diabetes diagnosis	Defined as diabetes diagnosis in National Patient Register and/or prescribed glucose lowering treatment in the Prescribed Drug Register excluding randomisation to metformin in the active treatment arm	Estimated follow-up for each patient is 1-4 years

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Serious Adverse Events	Number of Serious Adverse Events with at least a possible relationship to the study medication	Estimated follow-up for each patient is 1-4 years
Lactic acidosis (E11.1D)	Number of events of lactic acidosis	Estimated follow-up for each patient is 1-4 years
Hypoglycaemia	Number of events of hypoglycaemia	Estimated follow-up for each patient is 1-4 years

Collaborators and Investigators

• Sponsor: Karolinska Institutet
• Collaborators: Uppsala University; The Swedish Research Council; Capio Sankt Görans Hospital
• Investigators: Principal Investigator: Anna Norhammar, MD, Prof., Karolinska Institutet

Study record dates

Study Major Dates

• Study Start (Actual): December 2, 2021
• Primary Completion (Estimated): May 1, 2026
• Study Completion (Estimated): May 1, 2026

Study Registration Dates

• First Submitted: December 21, 2021
• First Submitted That Met QC Criteria: December 21, 2021
• First Posted (Actual): January 10, 2022

Study Record Updates

• Last Update Posted (Actual): April 2, 2024
• Last Update Submitted That Met QC Criteria: April 1, 2024
• Last Verified: April 1, 2024

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Ischemia; Pathologic Processes; Necrosis; Myocardial Ischemia; Heart Diseases; Cardiovascular Diseases; Vascular Diseases; Glucose Metabolism Disorders; Metabolic Diseases; Endocrine System Diseases; Diabetes Mellitus; Hyperglycemia; Myocardial Infarction; Infarction; ST Elevation Myocardial Infarction; Prediabetic State; Glucose Intolerance; Non-ST Elevated Myocardial Infarction; Hypoglycemic Agents; Physiological Effects of Drugs; Metformin
• Other Study ID Numbers: 2019-05382

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No