Glipizide

Glipizide is a sulfonylurea-type oral hypoglycaemic agent. Its main action is to stimulate insulin secretion by the beta cells of the pancreatic islets, so its effect depends on there being functional beta cells. Effects outside the pancreas, such as potentiation of insulin action, also contribute.

Mechanism of Action

• Insulin secretion: glipizide binds to the sulfonylurea receptor on the pancreatic beta-cell membrane and closes ATP-sensitive potassium channels. The cell depolarises, voltage-gated calcium channels open, and the influx of calcium triggers the release of insulin granules.
• Response to meals: insulin release is stimulated in response to food. Fasting insulin levels are not raised, even during long-term treatment, but the insulin response after a meal remains enhanced after six months. In patients with diabetes the response occurs about 30 minutes after a dose, and the raised insulin levels do not last beyond the stimulation by food.
• Duration of effect: blood glucose control lasts up to 24 hours after a single dose, even though plasma concentrations have by then fallen to a small fraction of their peak.
• Extrapancreatic effects: the SmPC describes potentiation of insulin action. DrugBank adds that glipizide may act on pancreatic alpha and delta cells, suppressing glucagon and stimulating somatostatin secretion.
• Variable response: some patients do not respond at first, or lose their response to sulfonylureas over time. Glipizide may be effective in some patients who did not respond, or stopped responding, to another sulfonylurea.

Pharmacokinetics

• Absorption: uniform, rapid and complete from the gut, with minimal first-pass metabolism; 80–100% of a dose is bioavailable. Peak concentrations are reached 1 to 3 hours after a single oral dose. Food does not change total absorption but delays it by about 40 minutes, which is why glipizide works best when taken 30 minutes before a meal.
• Distribution: about 98–99% bound to plasma proteins. The apparent volume of distribution after intravenous dosing is about 11 litres, indicating the extracellular compartment. Glipizide does not accumulate in plasma with repeated oral doses.
• Metabolism: extensive, mainly in the liver. The main metabolites are inactive hydroxylated products and polar conjugates.
• Elimination: half-life 2–4 hours in healthy subjects after oral or intravenous dosing. The metabolites are excreted mainly in urine; less than 10% of the dose appears unchanged in urine.
• Special populations: hepatic or renal impairment can lengthen the time the drug stays in the body and reduce gluconeogenic capacity, which raises the risk of severe hypoglycaemia.

• Type 2 diabetes mellitus: treatment in adults when diet and physical exercise are not adequate to improve glycaemic control.
• Use: alone, or together with other oral antidiabetic medicines or with insulin, after diet and exercise have failed. Diet and exercise must be continued during treatment.
• Short courses: in patients whose diet normally controls blood glucose, short periods of glipizide may be enough to cover a temporary loss of control.

• Hypersensitivity to glipizide or to any of the excipients.
• Type 1 diabetes mellitus.
• Diabetic ketoacidosis.
• Diabetic coma.

The reactions listed in the SmPC are mainly hypoglycaemia and gastrointestinal effects; most of the others have an unknown frequency. No reaction is listed as very common, rare or very rare.

Common (≥1/100 to <1/10): hypoglycaemia; nausea, diarrhoea, upper abdominal pain and abdominal pain (the gastrointestinal effects appear to be dose-related and usually go away when the dose is divided or reduced).

Uncommon (≥1/1,000 to <1/100): dizziness, drowsiness and tremor (usually transient, and can be a symptom of hypoglycaemia); blurred vision; vomiting; cholestatic jaundice; eczema (usually goes away with continued treatment).

Not known: agranulocytosis, leucopenia, thrombocytopenia, haemolytic anaemia and pancytopenia; hyponatraemia; confusion, headache and malaise; double vision, visual disturbances and decreased visual acuity; constipation; abnormal liver function and hepatitis; allergic dermatitis, erythema, morbilliform and maculopapular rash, urticaria, itching and photosensitivity reactions; non-acute porphyria; raised blood levels of AST, lactate dehydrogenase, alkaline phosphatase, urea and creatinine (the link with glipizide is unclear and these rarely cause symptoms).

Important serious reactions are severe hypoglycaemia, which can progress to coma and need hospital care; blood disorders such as agranulocytosis, pancytopenia and haemolytic anaemia; and cholestatic jaundice, in which case treatment should be stopped. With other sulfonylureas, aplastic anaemia and disulfiram-like reactions have been reported.

Several medicines change the blood glucose-lowering effect of glipizide. When one of the medicines below is started or stopped in a patient taking glipizide, the patient should be watched for symptoms of hypoglycaemia (for medicines that increase the effect) or of lost glycaemic control (for medicines that reduce it).

• Alcohol: can potentiate a hypoglycaemic reaction, which may lead to hypoglycaemic coma. Excessive or chronic alcohol use should be avoided.
• Azole antifungals: miconazole potentiates the effect, up to coma; fluconazole has been followed by hypoglycaemia, possibly because it lengthens the half-life of glipizide; voriconazole has not been studied but may raise sulfonylurea concentrations. Blood glucose should be monitored closely with each.
• NSAIDs (for example phenylbutazone): increase the effect by displacing sulfonylureas from plasma proteins and/or reducing their elimination.
• Salicylates: high doses of acetylsalicylic acid increase the effect, as at such doses it lowers blood glucose itself.
• Beta-blockers: mask symptoms of hypoglycaemia such as palpitations and a fast heart rate; most non-cardioselective beta-blockers also increase the incidence and severity of hypoglycaemia.
• ACE inhibitors: may increase the glucose-lowering effect in diabetic patients on sulfonylureas, so the glipizide dose may need to be reduced.
• H2-receptor antagonists (for example cimetidine): can potentiate the effect.
• Antacids: magnesium hydroxide and sodium bicarbonate increased the rate, though not the total amount, of glipizide absorption; aluminium hydroxide did not.
• MAO inhibitors, quinolones and highly protein-bound medicines such as chloramphenicol, sulfonamides, probenecid or coumarin derivatives: may potentiate sulfonylureas.
• Medicines that reduce the effect and cause hyperglycaemia: phenothiazines (for example chlorpromazine above 100 mg a day), corticosteroids, sympathomimetics (for example ritodrine, salbutamol, terbutaline), thiazide and other diuretics, medicines for thyroid function, oral contraceptives, oestrogens and progestogens, phenytoin, nicotinic acid, isoniazid and calcium channel blockers.

The dose is set individually by the treating doctor from tolerability and blood glucose results. The tablets are swallowed with enough water. In general, Minodiab is taken in the 30 minutes before a meal to give the best control of the rise in glucose after eating. Diet and exercise must be continued alongside any oral antidiabetic medicine, glipizide included.

Recommended Dose

• Starting dose: 5 mg a day, taken before breakfast or lunch.
• Titration: increase gradually in steps of 2.5 to 5 mg, at intervals of at least several days (usually 3 to 7 days), according to glycaemic control.
• Maintenance: some patients are controlled on a single daily dose, up to a maximum of 15 mg a day as one dose. If that is not enough, the dose can be divided into two. Doses above 15 mg should be split into at least two doses taken before meals. Total daily doses above 30 mg (in two doses) have been given safely over the long term. Patients can usually be controlled on 2.5–30 mg a day, and the maximum recommended dose is 40 mg a day.

Switching and Combination Treatment

• From insulin: patients with type 2 diabetes controlled on insulin may be switched. If the insulin requirement is 20 units a day or less, insulin can be stopped and glipizide started at the usual recommended dose, leaving several days before the next increase. For higher insulin requirements, the insulin is reduced by about 50% and glipizide started at the usual dose (see the SmPC for the exact insulin-dose threshold). Further insulin reductions follow the patient’s response; the patient should check blood glucose and contact the doctor if readings are abnormal. Hospitalisation during the transition may be advisable, especially for patients on more than 40 units of insulin a day.
• From another oral antidiabetic: no transition period is needed, and the previous medicine can be stopped abruptly. With long half-life medicines such as chlorpropamide, closer monitoring during the first 1–2 weeks is advisable because the effects may add up.
• With insulin: combining oral antidiabetic medicines with insulin seems to improve glycaemic control with lower insulin doses than insulin alone. It may be useful in some patients but increases the risk of hypoglycaemia.
• With other glucose-lowering medicines: when another one is added to glipizide, it is started at its lowest recommended dose with monitoring for hypoglycaemia. When glipizide is added to other glucose-lowering medicines, it is started at 5 mg; patients who are more sensitive can start lower, and the dose is then raised according to clinical judgement.

Special Populations

• Elderly and high-risk patients: the dose is raised in steps of 2.5 or 5 mg according to the glucose response, with several days between steps.
• Renal or hepatic impairment: these can lengthen the time the drug stays in the body and reduce gluconeogenic capacity, so starting and maintenance doses should be adjusted. Treatment may start at 2.5 mg a day.
• Children and adolescents: safety and efficacy in children have not been established.

Hypoglycaemia

Like all sulfonylureas, glipizide can cause severe hypoglycaemia that may progress to coma and need hospital treatment. This calls for appropriate glucose therapy and monitoring for 24 to 48 hours. Hypoglycaemia is more frequent with a low calorie intake, after prolonged exercise, with alcohol, or when several antidiabetic medicines are combined. Hepatic or renal impairment raises the risk of severe episodes. Elderly, debilitated or malnourished patients, and those with adrenal or pituitary insufficiency, are particularly sensitive. Symptoms can be hard to recognise in elderly patients and in those taking beta-blockers. Patients and their families should be told about the risk of hypoglycaemia, its causes, symptoms and treatment. Particular caution is advised when an antifungal medicine is needed together with glipizide.

Stress, Loss of Effect and Monitoring

• Stress situations: in trauma, surgery, or infectious and feverish illness, temporary insulin therapy may be needed to keep metabolic control.
• Secondary failure: the effect of glucose-lowering medicines, glipizide included, often declines over time, through progression of the disease or a weaker response. Before calling this secondary failure, check that the dose and adherence to diet and exercise are adequate. Primary failure means the medicine is ineffective from the first use.
• Monitoring: blood glucose is checked regularly, and glycated haemoglobin is measured and acted on according to current treatment targets.

Glucose-6-Phosphate Dehydrogenase Deficiency

Sulfonylureas can cause haemolytic anaemia in patients with glucose-6-phosphate dehydrogenase deficiency. Glipizide should be given with caution to these patients, and a non-sulfonylurea alternative should be considered.

Pregnancy and Breastfeeding

• Pregnancy: glipizide should be given only when the potential benefit justifies the risk to the foetus. Abnormally high blood glucose in pregnancy is associated with more congenital anomalies, so specialists recommend insulin during pregnancy to keep blood glucose close to normal. Severe and prolonged hypoglycaemia (4 to 10 days) has been reported in newborns whose mothers were taking sulfonylureas at delivery. If glipizide is used in pregnancy, it should be stopped at least one month before delivery and other treatment used to keep blood glucose close to normal.
• Breastfeeding: it is not known whether glipizide passes into breast milk, although some sulfonylureas do. Because the infant could develop hypoglycaemia, stopping breastfeeding or stopping the medicine should be considered, depending on how important the treatment is for the mother. If treatment is stopped and diet alone is not enough, insulin should be considered.

Lactose

Each 5 mg tablet contains 153 mg of lactose monohydrate. Patients with rare hereditary galactose intolerance, total lactase deficiency or glucose-galactose malabsorption should not take this medicine.

Effect on Driving

Concentration and reaction time can be impaired by hypoglycaemia, hyperglycaemia or reduced vision, which is a risk when driving or operating machinery. Patients should watch for symptoms of low and high blood glucose and take care when driving or using machines.

Minodiab tablets need no special storage conditions. They are supplied in PVC/PVC-aluminium blisters (the Spanish SmPC lists a pack of 100 tablets). Keep out of the sight and reach of children.

5 years. Do not use after the expiry date on the pack.

Prescription only (Rx), on the prescription of a doctor who manages the patient’s diabetes. Glipizide tablets are taken at home, so they are supplied to the patient or to the treating clinic on prescription. They need no cold chain.