VIENNA – Metformin will be tested for its ability to prevent cardiovascular events in the upcoming Glucose Lowering in Non-diabetic Hyperglycemia Trial (GLINT).
The researchers for the U.K.-based trial plan to recruit 11,834 men and women aged 40 years or older who are at increased risk for type 2 diabetes and have a 20% risk of developing CV disease in the next 10 years.
“Metformin is now the most widely prescribed oral antidiabetic drug in the world,” Dr. Rury Holman, director of the University of Oxford Diabetes Trials Unit (DTU) and one of the driving forces behind the new trial, said during a press briefing held at the annual meeting of the European Association for the Study of Diabetes.
This will be “the first large-scale randomized controlled outcome trial of this drug since the UKPDS [United Kingdom Prospective Diabetes Study], and is looking specifically at cardiovascular disease and cancer,” added Dr. Holman, who also is the chief investigator of the landmark UKPDS trial.
Dr. Rury Holman
In the original UKPDS trial (Lancet 1998;352:854–65), there were reductions of 39% in heart attacks and 36% in the risk of death in patients treated with metformin versus conventional therapy, Dr. Holman observed. The effect was sustained, albeit slightly reduced, in the 10-year post-trial follow-up (N. Engl. J. Med. 2008;359:1577-89), but only 753 patients were studied in this analysis.
While there have been plenty of observational data to back up the UKPDS findings, no further randomized controlled trials have been conducted, which is why GLINT is now being conducted to resolve the uncertainty. As to why it is has taken so long to do a second study, Dr. Holman observed that metformin is off patent, and raising the funding to perform the much needed trial has taken time.
GLINT will be a pragmatic, primary prevention study conducted in multiple centers in the United Kingdom and jointly coordinated by Dr. Holman at the DTU and Dr. Nicholas Wareham at the University of Cambridge. A feasibility study is underway, recruiting an expected 500 patients. If it is successful, the study population will be expanded to almost 12,000 U.K. individuals, who will be randomly allocated to double-blind treatment with either an extended-release formulation of metformin (Glucophage, Merck Serono) or placebo. Follow-up will continue for 5 and 7 years, with the results likely to be available in 2022.
While the primary purpose is to look at metformin’s effects on cardiovascular outcome reduction versus placebo, the trial will also look at whether the drug can reduce the risk for cancer. Observational data have suggested that metformin may reduce cancer risk (Diabetes Care 2009;32:1620–5), while meta-analyses of randomized controlled trials have suggested that there is no benefit (Diabetologia 2012;55:2593–603).
Metformin has been used to treat type 2 diabetes for more than 50 years, with the first clinical trial published in 1957 leading to its approval for use in England in 1958. However, it took almost another 20 years for the drug to be licensed in Canada in 1972, with the U.S. Food and Drug Administration approving metformin for the treatment of diabetes only in 1994.
“It’s amazing that, more than five decades after it was introduced in the U.K., we remain unclear about the benefits and risks of the most widely used antidiabetic drug,” Dr. Holman said. “Hopefully, GLINT will bring much needed clarity by providing robust evidence for metformin’s effects.”
GLINT is sponsored by the University of Cambridge and funded by the National Institute for Health Research Health Technology Assessment program. Merck Serono is donating the study drug, Glucophage XR. Dr. Holman has received research funding and honoraria from Bayer, BMS, and MSD, and additional honoraria from Amgen, Elcelyx, Janssen, Novartis, and Novo Nordisk.