Glipizide

Abstract

Synopsis. Glipizide¹ is a ‘second generation’ oral hypoglycaemic agent similar in potency to glibenclamide. It is completely absorbed after oral administration and has a rapid onset of action, but the duration of its hypoglycaemic effect is shorter than that of glibenclamide. It is rapidly metabolised to inactive metabolites which are excreted in the urine. Therapeutic trials have shown the efficacy of glipizide in maturity onset diabetes mellitus to be comparable with that of glibenclamide and chlorpropamide in newly diagnosed patients unresponsive to diet as well as in patients previously treated with oral hypoglycaemic drugs. Glipizide is well tolerated, but careful adjustment of dosage and attention to diet may be needed to avoid hypoglycaemic symptoms a few hours after a single daily dose. Pharmacology: In animals, as well as in man, glipizide is at least 100 times more potent (weight for weight) than tolbutamide. Glipizide has a more rapid onset of action than glibenclamide when given orally or intravenously, but the duration of action of glipizide is shorter than that of glibenclamide. In healthy subjects and in diabetic patients a single dose of glipizide results in an increase in immunoreactive insulin (IRI) and a decrease in fasting blood glucose levels and similar changes in insulin and glucose after a glucose load or a standard meal. Studies in diabetic patients indicate that a single 5 to 10mg dose of glipizide given before breakfast may often control hyperglycaemia throughout the day. However, better control might be expected in some cases when one dose is given before breakfast and another before supper. Dosages above 10mg may have to be given in divided doses to avoid hypoglycaemic episodes. A more marked decrease in blood glucose occurs when glipizide is given 30 minutes before, rather than with, a meal. Glipizide, like the other sulphonylureas, appears to act principally by stimulating the release of insulin from the pancreatic β-cells. Recent studies suggest that its action may also be associated with some alteration in the pharmacokinetics of endogenous insulin and apparently is glucose dependent. Pharmacokinetics: Glipizide is almost completely absorbed after oral administration. In comparisons with glibenclamide, plasma concentrations of glipizide have been about twice those of glibenclamide, but the preparations compared were not those that are commercially available. Glipizide is extensively bound to plasma albumin and has a relatively low volume of distribution. Glipizide is eliminated by metabolic biotransformation and excretion of the metabolites in the urine. The metabolites are essentially devoid of hypoglycaemic activity. Only about 3 to 9 % of the administered dose is excreted in the urine as unchanged drug over a period of 24 hours. The half-life of glipizide (parent drug and metabolites) is about 3 to 4 hours. In patients with renal impairment (GFR 10 to 30ml/min) the disappearance rate of unchanged glipizide seems to be only slightly decreased, but that of the metabolites is greatly decreased. Moderate renal impairment should not result in a markedly increased hypoglycaemic effect, but hypoglycaemia might be expected where both renal and hepatic impairment are present. Therapeutic Trials: In open studies, treatment with glipizide has resulted in satisfactory control of hyperglycaemia in 81 to 97 % of patients with maturity onset nonketosis-prone diabetes mellitus. Generally, hyperglycaemia has been well controlled in a higher proportion of newly diagnosed patients not controlled on diet alone, than in patients previously treated with other sulphonylurea drugs, particularly when not well controlled on these drugs. In some studies however, the substitution of glipizide for existing sulphonylurea therapy has resulted in improved control of blood glucose in many patients. This trend has been less apparent in controlled studies in which glipizide has been directly compared with previous sulphonylurea therapy. Limited data on the use of oral glipizide in patients who had previously been treated with relatively low dosages of insulin alone, suggest that insulin can be discontinued in some patients and the dosage decreased in others during glipizide. However, controlled studies are lacking. As with other sulphonylureas, glipizide combined with a biguanide is effective in some patients unresponsive to a sulphonylurea alone. Under double-blind trial conditions, glipizide has been shown to be consistently superior to diet alone or placebo. Under the more rigid conditions of the formal controlled studies, the proportion of previously treated patients in whom a fasting blood glucose of less than 130mg/ 100ml (7.2mmol/L) was achieved with glipizide therapy has been somewhat lower than in open studies. Similarly, in controlled studies directly comparing glipizide with previous oral hypoglycaemic drugs, only a small minority of patients poorly controlled with previous therapy have been adequately controlled by glipizide alone. Glipizide has been shown to be comparable with glibenclamide in newly diagnosed maturity onset diabetics as well as in those adequately or inadequately controlled by previous oral hypoglycaemic drugs. In the small numbers of patients’Studied it appears that the efficacy of glipizide is comparable with that of chlorpropamide. In a trial in hospitalised patients, glipizide was statistically significantly superior to tolbutamide, but this degree of superiority was not apparent in another study in outpatients. As far as can be determined from the limited numbers of patients in the controlled studies and considering the shortcomings of open studies, it appears that the frequency with which hyperglycaemia is well controlled by glipizide is influenced by the quality of response to previous oral hypoglycaemic drugs, the duration of the disease, and whether or not patients have been previously treated. It appears that in most instances, patients whose fasting or postprandial blood glucose is not well controlled by a daily dosage of 20 to 25mg of glipizide, will not benefit from an increase in dosage. Side Effects: Glipizide is well tolerated by the great majority of patients. The most frequently reported side effects have been gastrointestinal upset, such as abdominal pain, nausea, vomiting, vertigo, weight gain, skin reactions and symptoms of hypoglycaemia which are indicative of overdosage rather than an adverse effect of the drug. Although hypoglycaemia has been reported by many investigators, blood glucose levels in the hypoglycaemic range have seldom been documented. Contraindications and Precautions: Glipizide, like other oral sulphonylurea drugs is indicated only where diet fails to control hyperglycaemia and glycosuria. It has no place in the treatment of juvenile diabetes or where there is severe metabolic decompensation with acidosis, and should not be used in severe renal impairment, particularly when liver function is also impaired, or in patients with hepatic dysfunction. Dosage: A daily dosage of 2.5 to 15mg daily is adequate in most patients with adult onset nonketosis-prone diabetes mellitus. Maximum recommended daily dosage is 40mg daily. If control cannot be achieved in 4 to 6 weeks at maximum dosage plus strict diet, an oral biguanide may be added provided ketosis has not developed, when insulin must be given.