Many commonly prescribed medications for patients with diabetes type 2 may be much less effective at preventing cardiovascular disease and death than oral metformin, Danish researchers revealed in the European Heart Journal this week. Diabetes drugs, such as glimepiride, glibenclamide (USA, Canada: glyburide), known as ISs (insulin secretagogues) have been commonly prescribed for many decades.

The authors explain that the long term risks linked to ISs have not been clearly studied. Neither has metformin been compared to ISs for long-term risk and comparative efficacy. Metformin is the first drug of choice for type 2 diabetes.

Dr. Tina Ken Schramm, Heart Centre at the Rigshospitalet Copenhagen University Hospital, and team tracked a large, unselected group of 107,806 people living in Denmark aged 20+ years, who had received either an IS or just metformin between 1997 and 2006.

They found that ISs monotherapy was linked to a higher risk of death from any cause, as well as a considerably greater risk of stroke, heart attack, and death from cardiovascular disease compared to metformin monotherapy. Examples of ISs included glimepiride, glibenclamide, glipizide and tolbutamide.

Monotherapy means treatment of an illness or disorder with just one drug.

They found the greater risk for those on ISs was for individuals who had already had a heart attack as well as those who hadn’t. They added that “Two other ISs, gliclazide and repaglinide, showed no significant difference to metformin in their effectiveness in patients with and without a history of heart attacks.”

Those on an IS had a fifth to one third greater risk of death from any cause than those on metformin. Among individuals who had already had a heart attack, the risk was about one third to one half greater.

The authors stress that their findings do not show that ISs cause harm. All they demonstrate is that metformin appears to be more effective.

Dr Schramm said:

“Previous studies have shown that ISs, in particular sulphonylureas, are associated with a reduction in long-term risk. Therefore, the increased risk from ISs shown in our study presumably has more to do with the beneficial effects of metformin, gliclazide and repaglinide, than the detrimental effect of the other ISs. This is the first study to compare all ISs with metformin despite a wide debate on the possible cardiovascular risk associated with ISs for about three decades. Our findings emphasise how important it is to conduct long-term follow up studies of glucose-lowering medications.”

University of Texas Southwestern Medical Center researchers, Drs Odette Gore and Darren McGuire wrote about these findings:

“It is of key importance to note that the observation of less benefit with most sulphonylureas [ISs] in the study compared with metformin should not be interpreted as causing harm.

Patients taking metformin had the best outcomes, supporting prior evidence of metformin benefit and making it the first-line drug recommended for almost all patients with type 2 diabetes. Compared against this beneficial drug, most of the ISs were associated with worse outcomes, but they would almost certainly be similar to, or better, had the comparison been made against placebo treatment, with the added benefit on kidney, eye, and nerve disease of the glucose control they yield. So patients should not stop their medications based on this study, but certainly should discuss any concerns with their doctor.

It’s important to remember that these are observational analyses and not randomised comparisons, so it is impossible to tease out what if any of the difference in outcomes is due to the drugs compared versus differences in the patients – those taking ISs might have an increased risk to begin with.”

Schramm and team say that further research is required to determine what the mechanisms underlying the effects of ISs and metformin are.

Schramm concluded:

“Our study supports previous studies demonstrating that metformin may be less hazardous or more beneficial than most ISs. This suggests that metformin should be the first drug of choice in type 2 diabetes in most patients. The study shows there are important differences in the risk associated with different ISs, suggesting that gliclazide and maybe repaglinide are preferable, although in patients who have had a previous heart attack the most beneficial agents are metformin and gliclazide. As a result of our findings it is important now that there should be randomised studies focusing on patients at low and high cardiovascular risk.”

“Mortality and cardiovascular risk associated with different insulin secretagogues compared with metformin in type 2 diabetes, with or without a previous myocardial infarction: a nationwide study”
Tina Ken Schramm, Gunnar Hilmar Gislason, Allan Vaag, Jeppe Nørgaard Rasmussen, Fredrik Folke, Morten Lock Hansen, Emil Loldrup Fosbøl, Lars Køber, Mette Lykke Norgaard, Mette Madsen, Peter Riis Hansen and Christian Torp-Pedersen
Eur Heart J (2011) doi: 10.1093/eurheartj/ehr077 First published online: April 6, 2011

Written by Christian Nordqvist