Charles R. McClave II MD FACP
Saint Vincent Healthcare Diabetes Center
This 55-year-old woman has had documented type 2 diabetes for 18 months but already has early diabetic retinopathy, indicating she has had metabolic issues for a much longer time and is likely to develop further complications if her control is not improved. At this stage of her disease, she is clearly still secreting insulin, but not enough to maintain euglycemia by meeting insulin demands. By stimulating her endogenous insulin secretion, sulfonylureas will likely provide enough additional circulating insulin to control her glucose levels, at least for a period of time. The average decrease in hemoglobin A1c that can be expected from these medications is 1-2%, which should be enough to lower below 7%, the current ADA recommended target.
Glucose Lowering Effects of Sulfonylureas
Sulfonylureas work by binding to the sulfonylurea binding site (sulfonylurea receptor, or SUR) on the β-cell wall, triggering the closure of potassium channels and consequent membrane depolarization, calcium channel opening, and calcium influx. The resultant increase in intracellular calcium triggers insulin release. Sulfonylureas in current common use include glyburide, glimeparide and glipizide. Of these, glyburide has the strongest receptor affinity, with glimeparide and glipizide following in that order.
Table 1 summarizes the characteristics of these drugs, but a few points are worth additional emphasis. First, comparing the half-lives of these drugs is somewhat misleading due to the formation of inactive metabolites. The hypoglycemic effects of both glyburide and glimeparide can be observed for more than 24 hours. In addition, the clinical frequency of hypoglycemia is highest with glyburide, with glimeparide and glipizide following. Because of their long durations of effect, glyburide and glimeparide are most effective in lowering fasting plasma glucose. This potential benefit has to be weighed against the increased risk of hypoglycemia.
Table 1 Characteristics of “second generation” sulfonylureas
For the patient under discussion, any of these medications could be used. Since her fasting glucose is significantly elevated, one of the longer acting, more potent medications might be most appropriate. Due to the relatively high incidence of hypoglycemia associated with glyburide, I would probably choose glimeparide, beginning with a dose of 1 mg each morning. My own preference when adjusting diabetic medication is to have the patient measure fingerstick glucose four times daily, before each meal and at bedtime. We have the patient provide us glucose records on a weekly basis, titrating the drug upward at weekly intervals until control is reached. The frequent glucose monitoring provides a measure of protection against hypoglycemia, and also frequently provides the patient with useful information about the glycemic effect of meal and snacking habits. As control tightens, it is often useful to have the patient check during the night as well to detect any nocturnal hypoglycemia. Typically, control is likely to be achieved with no more than 4 mg glimeparide as a daily dose, unless there is marked insulin resistance. If glipizide is chosen, I typically start with 2.5 -5 mg in the morning, increasing to twice daily dosing when the dose exceeds 10 mg. Doses above 20 mg per day, particularly if the XL preparation is used, rarely add much more effect in my experience.
Sulfonylurea Therapy as a Stopgap Measure
There may be two immediate problems with sulfonylurea therapy in this patient, regardless of the agent chosen. The first, already touched on, is the potential for hypoglycemia. One of the reasons I have patients test four times daily is that it helps to predict when hypoglycemia is most likely to occur, so that the patient can be properly educated. In my experience, individuals with type 2 diabetes fall into one of three categories. Many have sustained hypoglycemia throughout the day and night, but some have relatively good fasting sugars with deterioration when they eat, and a smaller number will have their biggest problem with high fasting sugars, which actually improve with the ingestion of food and increased activity during the day. Those with good fasting sugars will be most prone to nocturnal hypoglycemia with sulfonylureas. These patients have their greatest difficulty processing ingested carbohydrate, as opposed to controlling nighttime hepatic glucose production. If they have severe nocturnal hypoglycemia on sulfonylureas, an alternative choice might be repaglinide or nateglinide—short acting, non-sulfonylurea insulin secretagogues. Patients with high fasting sugars and improved daytime sugars will be most prone to hypoglycemia during the day, particularly with exercise, and should be cautioned accordingly.
A second immediate problem with sulfonylurea therapy in this patient will be the tendency to gain weight. There may be several reasons for this. With fasting sugars in the 160 range, it is likely that postprandial sugars will exceed 200 mg/dl which will result in some degree of glycosuria. To consider net 24-hour caloric intake, calories lost in the urine must be subtracted from total dietary intake. If the net caloric intake results in a stable weight prior to treatment, lowering the glucose and eliminating urinary loss with medication (regardless of type) will result in a net increase in 24-hour calorie consumption. If the patient does not restrict her intake when the sulfonylurea is started, successful glucose control will result in further weight gain. If hypoglycemia is occurring due to therapy, moreover, forcing the patient to eat additional food compounds the problem.
A long-term problem associated with sulfonylurea use is the loss of effectiveness with time. The UKDPS study demonstrated that insulin production progressively declines over a period of years, regardless of the type of therapy, in fact. We now know this problem of durability occurs because of progressive loss of β-cell mass, for reasons that are not entirely clear. Sulfonylureas, while effective in the short run, do nothing to address this problem.
Given these challenges, sulfonylurea therapy in this patient should be regarded as a stopgap measure to control glucose for the next year or two. If coupled with aggressive emphasis on caloric restriction and increasing daily exercise it may be successful for a substantially longer period. When using these drugs, I also believe it is essential to emphasize to this patient the need for lifestyle changes, warning her that she may well require insulin or other medications in the near future if no changes are made. I would also recommend follow-up at least four times per year for monitoring, encouragement, and A1c determinations. The more attention we as physicians pay to our patients’ diabetes, the more likely they are to modify behavior.
Tight control of glucose has been shown to reduce microvascular complications of diabetes; the current American Diabetes Association recommended target is <7%. Given this patient’s history and clinical findings, sulfonylurea, a highly cost-effective class of drugs, could be used as a second-line therapy to improve glucose control in light of their known ability to reduce hemoglobin A1c levels 1-2%. Because sulfonylureas do not address the underlying problem of β-cell loss, however, they will probably only serve as a stopgap therapy. In addition, any clinician prescribing these drugs must consider the hypoglycemia and weight gain associated with the sulfonylureas and arrange for frequent office followup, including A1c determinations and aggressive attempts to encourage lifestyle modifications and weight loss.
See below for References and Disclosures.