ORAL AGENT CLASSES Sulfonylureas
Sulfonylureas are indicated when hyperglycemia cannot be controlled with exercise, diet, and therapeutic lifestyle changes. They bind to a specific receptor on the pancreatic P-cells that enhances the effect on glucose lowering resulting from a closure of the potassium-dependent adenosine triphosphate (K-ATP) channel. Glimepiride (Amaryl) binds to a different protein than the other sulfonylureas, but on the same site as the potassium channel. The subsequent reduction in plasma glucose results in secondary improvement in insulin action. Some concern has been raised recently with regard to the closure of the potassium channel because this channel may play a role in cardiac tissue in coronary artery vasodilatation.
The closing of the potassium pump enhances calcium influx into the myocardial cell, thus enhancing coronary artery vasodilatation. Some argue that this impairment of the potassium pump also impairs coronary artery vasodilatation during acute ischemic events. Thus, recent studies have raised the question about the prognosis of patients who
Table 1
Mechanism of Action of Oral Agents
Class Mechanism of action Agents
Table 1
Mechanism of Action of Oral Agents
Class Mechanism of action Agents
|
Secretagogues |
• Sulfonylureas Increase insulin secretion • Stimulate pancreatic P-cell |
Glipizide, glyburide, glimepiride |
|
Meglitinides |
Repaglinide | |
|
Phenylalanines |
Nateglinide | |
|
Biguanides |
• Decrease hepatic glucose production • Decrease intestinal glucose absorption • Increase peripheral glucose uptake • Increase insulin sensitivity |
Metformin |
|
a-Glucosidase inhibitors |
• Delay carbohydrate digestion |
Acarbose, miglitol |
|
Thiazolidinediones |
• Increase insulin sensitivity • Preserve P-cell function • May regenerate P-cells |
Pioglitazone Rosiglitazone |
present with acute myocardial ischemia and/or infarction while taking sulfonylureas. Concern about the first-generation sulfonylureas was originally raised as early as the 1970s, with the University Group Diabetes Study casting aspersions on tolbutamide use and its worsening prognosis in macrovascular disease.
In general, all sulfonylureas are equally effective in terms of their hypoglycemic potency, although a recent trial has indicated that glimepiride (Amaryl) may be slightly more efficacious than the others. One can expect a 1.5-2% drop in hemoglobin A1-C with entry A1-C greater than 9% in most patients. Generally, the greater the fasting plasma glucose on initiation of therapy, the greater the benefit (3).
Sulfonylureas depend on good P-cell function and the absence of antibodies to glutamic acid decarboxylase or islet-cell for their efficacy. Many patients, particularly those with an entry hemoglobin A1-C greater than 8%, will require the addition of a second oral agent, usually a sensitizer or insulin. Disappointingly, patients on oral agents, although achieving an initial drop in A1-C, experience progressive A1-C and fasting glucose elevations caused by progressive P-cell deterioration over a period of 2-4 years.
Despite their efficacy in causing insulin release from the pancreas, sulfonylureas have not been shown to preserve P-cell function. Weight gain, lack of exercise, and dietary indiscretion are also associated with failures on sulfonylureas. Side effects with these medications are generally mild and reversible with discontinuation of therapy, with less than 2% of patients discontinuing therapy because of adverse affects. The major problem is hypoglycemia, which is more common in agents with longer duration, such as glyburide and chlorpropamide (4).
Sulfonylureas are metabolized hepatically and excreted renally; therefore, any patients with renal insufficiency may have trouble with hypoglycemia with all sulfonylureas (except for glipizide, whose hepatic metabolites are not active, thus there is no dosage decrease necessary in patients with renal insufficiency and taking glipizide).
In some studies, glyburide has been shown to cause increased amounts of hypoglycemia because of its significant suppression of hepatic gluconeogenesis and its long duration of action. The frequency of hypoglycemia requiring hospital admission is 0.20.4 cases per 1000 treatment years for sulfonylurea therapy, although there were somewhat higher levels in the recently completed United Kingdom Respective Diabetes Study (UKPDS) (5) trial.
In patients with a risk for hypoglycemia, the shorter-acting agents, such as the shorter-acting glipizide, may be more efficacious, particularly as glomerular filtration rates begin to decline and in elderly patients.
Most instances of hypoglycemia with sulfonylureas occur because of variations in patients' diet and progressive renal insufficiencies. When taking oral agents, patients must be cautioned about avoiding alcohol ingestion, which may promote an antabuse-like reaction, and irregular eating habits, which can cause havoc with glycemic consistency.
Ischemic preconditioning (as shown in animal models) indicates that brief periods of ischemia with intermittent perfusion may protect the myocardium from the effect of a major ischemic episode. Some sulfonylureas used in the treatment of type 2 diabetes may have adverse effects on cardiovascular outcomes, because sulfonylureas close the potassium channels that are necessary for ischemic preconditioning protection. Glimepiride seems to have less of an effect on the potassium channel than other sulfonylureas.
Despite the concerns about potassium channel interference with sulfonylureas, their benefit in achieving tighter glycemic control is important in reducing microvascu-lar complications of the disease, but not in statistically reducing the risks of macrovas-cular disease (particularly myocardial infarction). Subsequent long-term trials covering over 10 years of therapy did not show an increased incidence of cardiovascular complications with the use of sulfonylureas.
The DIGAMI trial showed a significant difference in mortality between the sulfony-lurea-treated group and the insulin-treated group in terms of sudden death and fatal reinfarction. This may be partially related to the beneficial effects of insulin in these acute settings (6). The UKPDS trial did not include patients with significant coronary artery disease, thus the issue of postinfarction prognosis in these patients was not evaluated (7).
Although glimepiride, in general, has less effects on the cardiac potassium channel, no head-to-head trials have confirmed a cardiovascular benefit with glimepiride over other sulfonylureas. These secretogogues have been reported to cause rash, nausea, and abnormalities in liver enzymes, with a pattern most consistent with cholestatic injury.
Chlorpropamide can cause significant hyponatremia, particularly in elderly patients, as a result of increased sensitivity of the renal tubule to endogenously produced antidiuretic hormone. Although some weight gain can occur with the sulfonylureas, this is not as prominent as the weight gain we see with the TZDs. Sulfonylureas are sulfa drugs and are contraindicated in patients with allergies to sulfa products (8).
Drugs that undergo protein binding, such as the ^-blockers, warfarin, and nonsteroidal anti-inflammatory drugs, may compete with sulfonylureas, thus exacerbating hypoglycemia. However, the second-generation sulfonylureas are nonionically bound to plasma proteins and therefore, there is less of a risk of this potential drug interaction when compared with the first-generation agents.
First-generation sulfonylureas include the following:
1. Acetohexamide (Dymelor), which has a duration of action of 12-18 hours.
2. Chlorpropamide (Diabinese), which has a duration of action of more than 48 hours.
3. Tolazimide (Tolinase), which has a duration of action of 12-24 hours.
4. Tolbutamide (Orinase), which has a duration of action of 6-12 hours.
Second-generation sulfonylureas include the following:
1. Glyburide (Micronase, Glynase, or Diabeta), which has a duration of action of 12-24 hours.
2. Glipizide (Glucotrol or Glucotrol XL), which has a duration of action of 12-18 hours, and up to 24 hours with Glucotrol XL.
3. Glimepiride (Amaryl), which has a duration of action of 24 hours.
Sulfonylureas should be taken approximately 15-30 minutes before meals, except for Glucotrol XL. Therapy should begin with the lowest effective dose and the should be titrated up slowly every 3-4 weeks. Only acetohexamide and tolbutamide are primarily renally cleared; the rest of the sulfonylureas are metabolized hepatically and cleared renally.
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