Why Are Physicians Still Prescribing Sulfonylureas as First Choice for Older Diabetic Adults?

Many of us from the older generation of physicians recall how apparently miraculous the introduction of sulfonylureas were to the treatment of diabetes mellitus—which before the introduction of this class of drugs had only dietary methods and insulin as therapy. The clinical introduction of the class of drugs in the late 1950s and 1960s by Upjohn in the United States with Orinase® (generic term tolbutamide), changed the practice of diabetic management. The longer acting Diabinese® chlorpropamide was released soon after. Both seemed to offer part of a spectrum of treatment that altered the options in diabetes therapy. However, in the early 1970s the first reports and then studies came out suggesting that this class of medications might be implicated in premature cardiovascular disease. Over time as new iterations of the class of medications have been produced with modifications in the pharmacology and apparent diminution of some of the more concerning short-term side effects, the issue of long-term negative effects became more apparent.

How Did Metformin Fare?

In more recent years there has been a modification of recommendations from the National Diabetes Associations to shift from sulfonylureas to biguanides especially metformin (Glcophage®) as the medication of first choice for type 2 diabetics. However, the terrible clinical experience with its drug classmate phenformin marketed as (DBI®) by Ciba-Geigy drew metformin in the vortex of withdrawal from the American market in the late 1970s due to a high risk of lactic acidosis, with phenformin which was fatal in 50% of cases. Unfortunately, in the United States because of the class association with phenformin, metformin was not re-released for use until 1995 by which time Canada, the United Kingdom, the Commonwealth and Western Europe had all benefitted from its long-time availability and accumulated clinical knowledge as to its benefits and safety. In that American therapeutic vacuum sulfonylureas ruled as the most used class of oral agent.

Utilization of Sulfonylureas

The use of the sulfonylureas continues at a hefty pace as better tolerated products are produced. Clearly there is motivation for the manufacturers of original medications and of generic forms as the population at risk and potentially benefitting from pharmacological intervention is enormous. In 2003, it was estimated that 13.8 million people in the U.S. had established type 2 diabetes; of these, 7.8 million people used at least one oral anti-diabetes medication. Glyburide, available as a generic, is relatively inexpensive and widely used from within the sulfonylurea class.  In Canada, 2,671,060 or 10.5 % of the population carry the diabetes label of which only 10% of have type 1 diabetes. From a large data base in Ontario spanning from 1995 to 2001 three-quarters of older patients receiving medications through the government supported medication program were receiving a sulfonylurea either as the primary medication or as one of a combination of medication. On the more positive side, the initiation of biguanides tripled during this period.

The number of people with type 2 diabetes is increasing dramatically due to a number of factors: the population is aging; obesity rates are rising; lifestyles are increasingly sedentary; and aboriginal people are three to five times more likely than the general population to develop type 2-diabetes. In Canada and also likely in the United States, almost 80% of immigrants come from populations that are at higher risk for type 2 diabetes. These include people of Aboriginal, Hispanic, Asian, South Asian or African descent.

New European Study

Recently a presentation in Europe appears to have demonstrated without doubt that there is an increase in excessive deaths linked to the first-line use of this class of medications. As the summary of the paper notes, “First-line treatment with sulfonylureas instead of metformin in people with type 2 diabetes is associated with a significantly elevated risk for death. Examining data from the U.K.'s Clinical Practice Research Datalink, researchers found that between 2000 and 2012, 76,811 patients with type 2 diabetes began glucose-lowering treatment with metformin, while 15,687 began sulfonylureas (which include glipizide, glyburide, and glimepiride). After adjustment for baseline differences, mortality was 58% higher in the sulfonylurea group (44.6 deaths per 1000 patient-years with sulfonylureas versus 13.6 with metformin).

The researchers acknowledge that while "residual confounding and confounding by indication may remain; this study indicates that treatment with first-line mono-therapy with sulfonylureas should be reconsidered."

This is not the first call for the reduction of if not the elimination of the use of this class of medication as first-line mono-therapy in especially the older adult and yet their use continues. The well-known Beers Criteria for medication use in older adults in its 2012 update recommends against the use of the most currently most commonly used sulfonylurea, glyburide, in older individuals. In a 2007 study from McMaster University in Ontario it was concluded that, “The main findings of this meta-analysis are that glyburide caused more hypoglycemia than other secretagogues and more hypoglycemia than other sulfonylureas. In the meta-analysis of the two studies that reported major hypoglycemia, there was a trend toward a greater number of events in patients treated with glyburide than with other sulfonylureas.

Of special concern is the continued and frequent use of sulfonylureas in the frail elderly nursing home populations. The prevalence of type 2 diabetes in this population varies but is probably in the range of 25% with a wide variation. Fom a Canadian study in 2009 the use of sulfonylureas ranged from 24% as monotherapy and 30% as combined therapy.

The message seems to be clear. Despite their relative low cost, the health status implications of the use of sulfonylureas in older adults in particular as first-line therapy, especially the frail elderly in institutional care should be curtailed. This is an excellent quality assurance program for the administrative and medical leadership in the long-term care industry in North America as well as elsewhere in the western world.