Previous studies had “been divided as to [the receptor's] presence in the artery wall,” although they did show that it existed in other types of tissue, Dr. Law said.

By binding to the artery receptors, the medication may lower diabetics’ risk of clogged arteries, including restenosis (when an artery is blocked again after angioplasty), the team reports. Rosiglitazone treats type 2 diabetes, which begins in adulthood, and not type 1, which usually begins in childhood.

If an artery is damaged even slightly, such as from atherosclerosis or after angioplasty, the tissue increases production of growth factors that cause cells in the area to multiply and migrate. Such cell activity is dangerous, because it can lead to artery walls getting thicker. However, when the researchers exposed artery smooth muscle cells to the diabetes medication, the cells failed to multiply or migrate, the team reports. The drugs may slow the build-up of fatty substances along the artery wall.

What the PPAR gamma receptor normally does other than bind with diabetes drugs is unclear, Dr. Law told Mediconsult. “We don’t really understand what normally turns these receptors on, or what their role is in tissue other than…to make more fat cells, he said.

The team also tested another diabetes drug, troglitazone (Rezulin), but it was taken off the market in March 2000, because of possible dangerous side effects. Both drugs are part of the thiazolidinedione (TZD) class of drugs that control blood sugar levels in people with type 2 diabetes.

Commenting on the study, Dr. Andrew P. Levy, M.D., Ph.D, at the Technion Faculty of Medicine, and Medical Advisor for HeartInfo, says that, “The new TZD drugs described above will help patients with type 2 control their glucose levels. The precise mechanism as to how these drugs achieve their effect is not entirely clear. More research is required to fully understand their mode of action, but their efficacy is indisputable.”

Study Design

This was a multicentre, randomised, double-blind study of the safety and efficacy of a combination of 30 or 45 mg of pioglitazone (Actos) and insulin when given to patients with type 2 diabetes mellitus whose glucose levels were poorly controlled by their current insulin therapy. Patients who participated in this study were at least 18 years of age, had an HbA1c value greater than or equal to 8.0%, and were on a stable, fixed dose (at least 30 units/day) of insulin for at least 30 days before the study.

The primary efficacy variable was HbA1c. The secondary efficacy variables were HbA1c responder rate defined as a percentage of patients meeting a clinically relevant target value, fasting plasma glucose (FPG), FPG responder rate, and serum lipids (ie, triglycerides, total cholesterol, high density lipoprotein (HDL) cholesterol, low density lipoprotein (LDL) cholesterol, and very low density lipoprotein (VLDL) cholesterol, and free fatty acids (FFA). A total of 345 patients were randomly assigned to each treatment arm, for a total of 690 patients in the intent-to-treat (ITT) population. The mean age for patients was 56.5 years, and mean BMI was 33.19 kg/m2. Approximately two thirds (63.3%) of the patients were Caucasian, and slightly more than half (54.6%) were male. The mean insulin dose (all forms) at Baseline for ITT patients was 69.2 units/day, and 27.1% of the patients reported use of antidiabetes therapy in addition to insulin. There were no major differences between the treatment groups with regard to any of the baseline variables.

Results

The improvements in glycaemic control observed in this study occurred in concert with overall reductions in insulin use by both treatment groups. Statistically significant difference from Baseline in insulin use were first observed at Week 4 for the 45 mg treatment group and at Week 8 for the 30 mg treatment group. The reductions were maintained throughout the remainder of the study, and there was a 4.5 and 7.3 U/d reduction with 30 mg and 45 mg of pioglitazone (Actos), respectively, at Endpoint. The reduction in insulin dose was statistically significantly greater in the 45 mg treatment group at all time points.

Introduction

Actos (pioglitazone HCl), a member of the thiazolidinediene (TZD) insulin-sensitizing class of drugs, was recently approved by the FDA for marketing in the US. Actos, developed by Takeda America Research and Development Center, Inc., is indicated for glycemic control in people with type 2 diabetes. It can be used alone or in combination with sulfonylurea, metformin, or insulin when these three agents prove to be ineffective on their own. Whether used as monotherapy or as a component of combination therapy, treatment should also include proper diet and exercise.

Clinical Study Results

Three randomized, double-blinded, placebo-controlled clinical trials were conducted in the United States to determine the safety and efficacy of Actos monotherapy. The first study lasted 26 weeks and included 408 patients with type 2 diabetes. They were randomized to receive 7.5 mg, 15, mg, 30 mg, 45 mg, or placebo once daily. Statistically significant differences were noted in the HbA1c and in the fasting blood glucose levels at endpoint in the patients who received 15, mg, 30 mg, and 45 mg compared to placebo. There was a one percentage point difference in HbA1c between both the 15 mg and 30 mg Actos patients and the control patients, and a 1.6 percentage point difference between the 45 mg patients and the control group (p < 0.05). After treatment, FBG increased by 9 mg/dL in placebo patients and decreased by 30, 32, and 56 mg/dL in patients who received 15, 30, and 45 mg of Actos, respectively (p < 0.05). A total of 260 patients participated in the second 24-week study. Patients were randomized to receive one of two forced-Actos titration regimens or placebo titration. The first Actos titration group received 7.5 mg of Actos for four weeks, with doses increasing to 15 mg and then 30 mg in four-week intervals. The second group followed a similar pattern of dosage increases, but began with 15 mg/day and went up to 45 mg/day. HbA1c levels were significantly lower in both treatment groups compared to the control group (1.5 percentage point difference for both, p < 0.05 for both).

There was a 68 mg/dL difference between patients in the higher dose Actos regimen and those in the placebo group, and a 62 mg/dL difference between those in the lower dose Actos regimen and patients in the placebo group (p < 0.05). Lastly, in a 16-week study with 197 participants, 30 mg Actos was compared to placebo. A 1.4 percentage point difference in HbA1c from placebo and a 58 mg/dL difference in FBG from placebo were observed.

Three 16-week, randomized, double-blind, placebo-controlled studies were conducted to evaluate the effects of Actos on glycemic control in type 2 diabetes patients as part of combination therapy. The addition of Actos to a treatment regimen consisting of sulfonylurea significantly reduced the mean HbA1c by 0.9% and 1.3%, with 15 mg and 30 mg of Actos, respectively. Treatment with metformin also benefited from the addition of Actos to the regimen, with a 0.8% reduction in HbA1c and a 38 mg/dL decrease in FBG. Patients with unsuccessful glycemic control with insulin alone experienced a 0.7 percentage point and 1.0 percentage point decrease in HbA1c with 15 mg Actos and 30 mg Actos, respectively. FBG levels decreased as well by 35mg/dL and 49 mg/dL with the addition of 15 mg Actos and 30 mg Actos to the insulin regimen.

What the Patient Should Know

Some of the patients in the clinical trials experienced upper respiratory tract infection, headache, sinusitis, muscle pain, and sore throat. Patients should also be aware of the possibility of moderate to mild edema and anemia. Using Actos in combination with insulin and sulfonylurea is associated with a greater risk for hypoglycemia. As a result, lowering the doses of insulin or sulfonylurea may be necessary.

(US Adopted Name, rINN)

Drug Nomenclature

Profile

Buformin is a biguanide antidiabetic. It has been given orally in the treatment of type 2 diabetes mellitus in doses of up to 300 mg daily. Buformin is also used as the hydrochloride.

Proprietary Preparations

Czech Republic: Adebit † Silubin- †

Hungary: Adebit

Spain: Silubin †

Switzerland: Silubin †

Carbutamide

Drug Approvals

(British Approved Name, rINN)

International Nonproprietary Names (INNs) in main languages (French, Latin, Spanish):

Profile

Carbutamide is a sulfonylurea antidiabetic. It is given orally in the treatment of type 2 diabetes mellitus in single daily doses of 0.5 to 1 g, but is more toxic than chlorpropamide.

Proprietary Preparations

France: Glucidoral

Epalrestat

(rINN)

Drug Nomenclature

Profile

Epalrestat inhibits the enzyme aldose reductase which catalyses the conversion of glucose to sorbitol. It has been suggested that accumulation of sorbitol in certain cells, occurring only in conditions of hyperglycaemia and resulting in a hyperosmotic effect, may be involved in the pathogenesis of some diabetic complications. Aldose reductase inhibitors have no influence on blood-glucose concentrations. Epalrestat is given orally for the treatment of diabetic complications including neuropathy, in a usual dose of 50 mg three times daily before meals.

Proprietary Preparations

Japan: Kinedak

Glibornuride

Drug Approvals

(British Approved Name, US Adopted Name, rINN)

INNs in other languages (French, Latin, and Spanish):

Note. The name glibornuride has frequently but erroneously been applied to glibenclamide.

Profile

Glibornuride is a sulfonylurea antidiabetic. It is given orally in the treatment of type 2 diabetes mellitus in doses of 12.5 to 75 mg daily. Daily doses of 50 mg or more are given in 2 divided doses.

Proprietary Preparations

Austria: Glutril

France: Glutril

Germany: Gluborid Glutril

Switzerland: Gluborid Glutril

Turkey: Glutril

Glisentide

Drug Nomenclature

Profile

Glisentide is a sulfonylurea antidiabetic. It is given orally in the treatment of type 2 diabetes mellitus in doses of 2.5 to 20 mg daily.

Proprietary Preparations

Spain: Staticum

Glisolamide

Drug Nomenclature

Profile

Glisolamide is a sulfonylurea antidiabetic. It has been given in the treatment of type 2 diabetes mellitus.

Proprietary Preparations

Italy: Diabenor

Glisoxepide

Drug Nomenclature

Profile

Glisoxepide is a sulfonylurea antidiabetic. It has been given in the treatment of type 2 diabetes mellitus.

Proprietary Preparations

Austria: Pro-Diaban

Glybuzole

Drug Nomenclature

Profile

Glybuzole is an oral antidiabetic with a structure distinct from that of the sulfonylureas, biguanides, or sulfonamidopyrimidines.

Proprietary Preparations

Japan: Gludiase

Glycyclamide

Drug Nomenclature

Profile

Glycyclamide is a sulfonylurea antidiabetic. It is given by mouth in the treatment of type 2 diabetes mellitus.

Preparations

Proprietary Preparations

Italy: Diaborale

Mitiglinide

Profile

Mitiglinide is a meglitinide antidiabetic that is under investiga tion in the treatment of type 2 diabetes mellitus.

Muraglitazar

Profile

Muraglitazar is a dual alfa/gamma peroxisome proliferator-activated receptor (PPAR) activator. It has been investigated in the treatment of type 2 diabetes mellitus.

Adverse effects. A review of data from 5 studies suggested that muraglitazar may be associated with an increased risk of adverse cardiovascular events and heart failure.

Phenformin Hydrochloride

Pharmacopoeias. In China

Profile

Phenformin hydrochloride is a biguanide antidiabetic. Although it is generally considered to be associated with an unacceptably high incidence of lactic acidosis, often fatal, it is still available in some countries for the treatment of type 2 diabetes mellitus.

Phenformin was implicated in the controversial reports of excess cardiovascular mortality associated with oral hypoglycaemic therapy (see under Sulfonylureas, Effects on the Cardiovascular System).

Proprietary Preparations

Greece: Informin

India: DBI

Portugal: Debeina

Multi-ingredient

Greece: Daopar †

India: Chlorformin †

Italy: Bi-Euglucon Bidiabe Gliben  † Gliformin Suguan

Pimagedine

Pimagedine Hydrochloride

Drug Approvals

(US Adopted Name, rINNM)

INNs in main languages (French, Latin, and Spanish):

Profile

Pimagedine reportedly inhibits the formation of glycosylated proteins (advanced glycosylation end-products) and has other actions including inhibition of aldose reductase. It has been investigated for the prevention of diabetic complications.

Ruboxistaurin

Profile

Ruboxistaurin is an oral inhibitor of the p-isoform of the enzyme protein kinase C, which is thought to play a role in the development of diabetic microvascular complications. It is under investigation as an adjunct in the treatment of diabetic retinopathy.

Voglibose

Pharmacopoeias. In Japan.

Profile

Voglibose is an alpha-glue osidase inhibitor with general properties similar to those of acarbose. It is used in the treatment of diabetes mellitus in oral doses of 200 to 300 micrograms three times daily before meals.

Hepatic encephalopathy. Vbglibose has been investigated in the management of hepatic encephalopathy.

Proprietary Preparations

Japan: Basen

Philippines: Basen

Thailand: Basen.

Drug Nomenclature

International Nonproprietary Names (INNs) in main languages (French, Latin, Russian, and Spanish):

Adverse Effects and Precautions

As for alpha-glucosidase inhibitors in general (see Acarbose). Skin rash may occur. Miglitol should be used with caution in patients with renal impairment.

Interactions

As for alpha-glucosidase inhibitors in general (see Acarbose). Miglitol may reduce the bioavailability of propranolol and ranitidine.

Pharmacokinetics

Miglitol is completely absorbed at a dose of 25 mg, but only 50 to 70% is absorbed at a dose of 100 mg. It is not metabolised, and is excreted unchanged in the urine with a plasma elimination half-life of about 2 hours.

Uses and Administration

Miglitol is an alpha-glucosidase inhibitor similar in action to acarbose. It is given orally in the management of type 2 diabetes mellitus, alone or with a sulfonylurea. Usual initial doses are 25 mg three times daily with meals, increased if necessary to a maximum of 100 mg three times daily.

Proprietary Preparations

Austria: Diastabol

Czech Republic: Diastabol

France: Diastabol

Germany: Diastabol

Hungary: Diastabol

India: Diamig Mignar †

Mexico: Diastabol

Poland: Diastabol

Portugal: Diastabol Limarcan

Spain: Diastabol Plumarol

Sweden: Diastabol

Switzerland: Diastabol

USA: Glyset

Adverse Effects

Gastrointestinal disturbances such as nausea, vomiting, heartburn, anorexia, diarrhoea, and a metallic taste may occur with sulfonylureas and are usually mild and dose-dependent increased appetite and weight gain may occur. Skin rashes and pruritus may occur and photosensitivity has been reported. Rashes are usually hyper sensitivity reactions and may progress to more serious disorders (see below). Facial flushing may develop in patients receiving sulfonylureas, particularly chlorpropamide, when alcohol is consumed (see under Interactions, below).

Mild hypoglycaemia may occur severe hypoglycaemia is usually an indication of overdosage and is relatively uncommon. Hypoglycaemia is more likely with long-acting sulfonylureas such as chlorpropamide and glibenclamide, which have been associated with severe, prolonged, and sometimes fatal hypoglycaemia. Other severe effects may be manifestations of a hypersensitivity reaction. They include altered liver enzyme values, hepatitis and cholestatic jaundice, leucopenia, thrombocytopenia, aplastic anaemia, agranulocytosis, haemolytic anaemia, erythema multiforme or the Stevens-Johnson syndrome, exfoliative dermatitis, and erythema nodosum.

The sulfonylureas, particularly chlorpropamide, occasionally induce a syndrome of inappropriate secretion of antidiuretic hormone (SIADH) characterised by water retention, hyponatraemia, and CNS effects. However, some sulfonylureas, such as glibenclamide, glipizide, and tolazamide are also stated to have mild diuretic actions.

Work on tolbutamide has suggested that the sulfonylureas might be associated with an increase in cardiovascular mortality this has been the subject of considerable debate (see Effects on the Cardiovascular System, below).

Effects on the cardiovascular system. A multicentre study carried out under the University Group Diabetes Program (UGDP) reported an increased incidence in mortality from cardiovascular complications in diabetic patients given tolbutamide as compared with those treated with diet alone or insulin a similar increase was also noted in patients given phenformin. The reports from the UGDP aroused prolonged controversy which was not entirely settled by detailed reassessment of relevant studies. Eventually in 1984 the FDA made it a requirement that sulfonylurea oral antidiabetics be labelled with a specific warning about the possibility of increased cardiovascular mortality associated with the use of these drugs Subsequently the cardiovascular effects of the sulfonylureas were reviewed. It has been hypothesised that the action of the sulfonylureas in preventing the opening of ATP-sensitive potassium channels in the myocardium may abolish adaptive changes (ischaemic preconditioning) that protect the heart against ischaemic insult. A recent retrospective cohort study has also found that, among patients newly treated for type 2 diabetes, sulfonylurea monotherapy was associated with an increased mortality compared with metformin therapy. However, results from the UK Prospective Diabetes Study did not demonstrate any adverse cardiovascular effects associated with sulfonylurea therapy.

Effects on the eyes. When a diabetic patient who had experienced bilateral visual loss for several months and who had been taking chlorpropamide for one year stopped treatment, visual acuity improved and colour vision rapidly returned. A 5-day challenge with chlorpropamide resulted in a mild decrease in acuity followed by return to baseline values when treatment was again stopped. Drug-induced optic neuropathy was considered to have occurred. There is also a report of a patient with type 2 diabetes mellitus who developed myopia two days after starting treatment with glibenclamide 10 mg daily. Visual difficulties resolved a few days after stopping glibenclamide.

Effects on the kidneys. The nephrotic syndrome has been reported in a patient treated with chlorpropamide. Serological testing and renal biopsy showed that the glomerular lesions were of an immune-complex nature. Both the nephrotic syndrome and the glomerulonephritis resolved after treatment was stopped. The patient also developed a skin eruption, hepatitis, and eosino-philia.

Effects on the liver. Chlorpropamide was implicated in 8 of 53 cases of drug-induced acute liver disease admitted to a hospital in Jamaica over the years 1973 to 1988. Hepatocanalicular cholestasis occurred in 5 cases and diffuse necrosis in 3. One patient with massive hepatic necrosis died. Intrahepatic cholestasis, an acute hepatitis-like syndrome, and a combination of both have been described in patients receiving glibenclamide.

Effects on the thyroid. See under Precautions, below.

Hypoglycaemia. Severe hypoglycaemia may occur in any patient treated with any sulfonylurea this potentially life-threatening complication requires prolonged and energetic treatment.Sulfonylureas with a prolonged duration of action such as chlorpropamide and glibenclamide appear to cause severe hypoglycaemia more often than shorteracting drugs such as tolbutamide. Experience with newer drugs is limited.

A review of 1418 cases of drug-induced hypoglycaemia reported since 1940 showed that sulfonylureas (especially chlorpropamide and glibenclamide), either alone or with a second antidiabetic or potentiating agent, accounted for 63% of all cases. A study of sulfonylurea use in nearly 14,000 patients aged 65 years or older confirmed that chlorpropamide and glibenclamide were associated with hypoglycaemia. However, glipizide caused significantly fewer cases than glibenclamide.

An analysis, of 185 children reported to 10 regional poison centres in the USA after ingesting sulfonylureas found that hypoglycaemia developed only in 56. A lack of hypoglycaemia during the first 8 hours after ingestion was predictive of a benign outcome, and it was recommended that suspected cases be observed for 8 hours with frequent blood glucose monitoring. Children who developed signs of hypoglycaemia, or in whom blood glucose fell below 3.3 mmol/litre could be given intravenous glucose if necessary.

Treatment of Adverse Effects

In acute poisoning with sulfonylureas, if the patient is conscious and presents within 1 hour of ingestion, the stomach should be emptied and/or activated charcoal given. Hypoglycaemia should be treated with urgency the general management of hypoglycaemia is described under insulin. The patient should be observed over several days in case hypoglycaemia recurs. Octreotide has been used in the treatment of severe refractory cases of sulfonylurea-induced hypoglycaemia.

Precautions

Sulfonylureas should not be used in type 1 diabetes mellitus. Use in type 2 diabetes mellitus is contra-indicated in patients with ketoacidosis and in those with severe infection, trauma, or other severe conditions where the sulfonylurea is unlikely to control the hyperglycaemia insulin should be used in such situations.

Insulin is also preferred for therapy during pregnancy.

Sulfonylureas with a long half-life such as chlorpropamide or glibenclamide are associated with an increased risk of hypoglycaemia. They should therefore be avoided in patients with impairment of renal or hepatic function, and a similar precaution would tend to apply in other groups with an increased susceptibility to this effect, such as the elderly, debilitated or malnourished patients, and those with adrenal or pituitary insufficiency. Irregular mealtimes, missed meals, changes in diet, or prolonged exercise may also provoke hypoglycaemia. Where a sulfonylurea needs to be used in patients at increased risk of hypoglycaemia, a short-acting drug such as tolbutamide or gliclazide may be preferred these 2 sulfonylureas, being principally inactivated in the liver, are perhaps particularly suitable in renal impairment, although careful monitoring of blood-glucose concentration is essential.

Abuse. Severe hypoglycaemia, at first thought to be due to insulinoma but later found to be due to nesidioblastosis [proliferation of the islet cells], was reported in a woman covertly taking chlorpropamide.

Administration. It has been suggested that continuously high plasma concentrations of sulfonylureas may lead to the development of tolerance, and that therefore the maximum recommended doses should be reduced.

Breast feeding. Some sulfonylureas are distributed into breast milk and the class of drugs should be avoided during breast feeding.

Driving. In the UK, patients with diabetes mellitus treated with insulin or oral hypoglycaemics are required to notify their condition to the Driver and Vehicle Licensing Agency, who then assess their fitness to drive. Patients treated with oral hypoglycaemics are generally allowed to retain standard driving licences those treated with insulin receive restricted licences which must be renewed (with appropriate checks) every 1 to 3 years. Patients should be warned of the dangers of hypoglycaemic attacks while driving, and should be counselled in appropriate management of the situation (stopping driving as soon as it is safe to do so, taking carbohydrate immediately, and quitting the driving seat and removing the ignition key from the car) should such an event occur. Patients who have lost hypoglycaemic awareness, or have frequent hypoglycaemic episodes, should not drive. In addition, eyesight must be adequate (field of vision of at least 120°) for a licence to be valid. Patients treated with diet or oral hypoglycaemics are normally allowed to hold vocational driving licences for heavy goods vehicles or passenger carrying vehicles those treated with insulin may not drive such vehicles, and are restricted in driving some other vehicles such as small lorries and minibuses. References.

Fasting. For the suggestion that sulfonylureas should be used with caution in fasting Muslim patients during Ramadan, and that chlorpropamide is contra-indicated in this group, see under Precautions of Insulin.

Porphyria. Sulfonylureas have been associated with acute attacks of porphyria and are considered unsafe in porphyric patients.

Thyroid disorders. There are conflicting reports concerning the effects of sulfonylureas on thyroid function, with some studies suggesting an increased incidence of thyroid dysfunction in patients treated with tolbutamide or chlorpropamide, while other suggest no antithyroid action. Some licensed product information consequently recommends that chlorpropamide should be avoided in patients with impaired thyroid function. Changes in thyroid function may conversely affect glycaemic control — for mention of the possible effects of thyroid hormones on anti-diabetic drug requirements see under Interactions, below.

Interactions

Many interactions have been reported with the sulfonylureas, largely representing either pharmacokinetic interactions (due to the displacement of the antidiabetic from plasma proteins or alteration in its metabolism or excretion) or pharmacological interactions with drugs having an independent effect on blood glucose. In the former class most reports concern older sulfonylureas such as chlorpropamide and tolbutamide, although the possibility of such reactions with newer drugs should be borne in mind.

A diminished hypoglycaemic effect, possibly requiring an increased dose of sulfonylurea, has been seen or might be expected on theoretical grounds with adrenaline, aminoglutethimide, chlorpromazine, corticosteroids, diazoxide, oral contraceptives, rifamycins, thiazide diuretics, and thyroid hormones.

An increased hypoglycaemic effect has occurred or might be expected with ACE inhibitors, alcohol, allopurinol, some analgesics (notably azapropazone, phenylbutazone, and the salicylates), azole antifungals (fluconazole, ketoconazole, and miconazole), chloramphenicol, cimetidine, clofibrate and related compounds, coumarin anticoagulants, fluoroquinolones, heparin, MAOIs, octreotide (although this may also produce hyperglycaemia), ranitidine, sulfinpyrazone, sulfonamides (including cotrimoxazole), tetracyclines, and tricyclic antidepressants.

Beta blockers have been reported both to increase hypoglycaemia and to mask the typical sympathetic warning signs. There are sporadic and conflicting reports of a possible interaction with calcium-channel blockers, but overall any effect seems to be of little clinical significance.

In addition to producing hypoglycaemia alcohol can interact with chlorpropamide to produce an unpleasant flushing reaction. Such an effect is rare with other sulfonylureas and alcohol.

ACE inhibitors. There are sporadic reports of marked hypoglycaemia developing in patients taking a sulfonylurea who are given an ACE inhibitor (mainly captopril or enalapril) and 2 case-control studies have indicated that the combination is associated with an increased risk of developing severe hypoglycaemia. However, other studies have failed to find much evidence of a problem.

Alcohol. Sulfonylurea-induced alcohol intolerance is seen mainly but not exclusively with chlorpropamide this is similar to the disulfiram-alcohol interaction, although it is not clear whether the mechanism is the same. Since the main symptom of the reaction (facial flushing) appears to occur more commonly in diabetic than non-diabetic subj ects, it has been proposed that this symptom could be used as a diagnostic test for a certain subset of patients with type 2 diabetes mellitus. However, some have not considered the test to be sufficiently specific and despite a great deal having been published on the chlorpropamide-alcohol flushing test (CPAF), its value remains poorly defined. Alcohol, as well as provoking a flushing reaction with chlorpropamide, has been reported both to increase and to decrease the half-life of tolbutamide depending on whether the alcohol administration was acute or chronic. Alcohol may also have a variable effect of its own on blood-glucose concentrations there is a general tendency to increased hypoglycaemia when alcohol and sulfonylureas are taken concurrently.

Analgesics. Phenylbutazone and related drugs such as azapropazone have been associated with acute hypoglycaemic episodes when given to patients receiving sulfonylureas (in most reports, tolbutamide). Other analgesics may enhance the hypoglycaemic effect of sulfonylureas, including indobufen fenclofenac and the salicylates. Although a study in healthy subjects found no interaction, there has been a report of hypoglycaemia with ibuprofen in a diabetic patient who had been stabilised on glibenclamide.

Antibacterials. Chloramphenicol markedly inhibits the metabolism of tolbutamide and increases its half-life, which can result in hypoglycaemia. Sulfonamides, including cotrimoxazole may also enhance the hypoglycaemic effects of the sulfonylureas. There have been rare reports of elevated glibenclamide concentrations and hypoglycaemia when ciprofloxacin was given to patients who were on stable glibenclamide therapy. For reports of hypoglycaemia when gatifloxacin was given to patients already receiving a sulfonylurea (glimepiride in one case, and glibenclamide plus pioglitazone in another). There have also been a few cases of severe hypoglycaemia when clarithromycin was added to glibenclamide or glipizide renal impairment may have played a role in these cases. Rifampicin (and probably other rifamycins) can enhance the metabolism and decrease the effect of tolbutamide, chlorpropamide, and glibenclamide and dosage of the hypoglycaemic drug may need to be increased. The effects on glipizide and glimepirideappear to be less pronounced.

Anticoagulants. Dicoumarol increases serum concentrations and therefore the hypoglycaemic effects of tolbutamide, and possibly chlorpropamide. In addition, sulfonylureas may affect anticoagulant function.

Antiepileptics. For references to phenytoin toxicity when tolbutamide or tolazamide was given, see under Phenytoin.

Antifungals. Increased plasma concentrations of tolbutamide have been reported when fluconazole was given, but there was no evidence of hypoglycaemia, and no hypoglycaemic symptoms were seen in 29 women receiving gliclazide or glibenclamide who were given fluconazole or clotrimazole for vulvovaginitis. A study in healthy subjects found that fluconazole increased plasma concentrations of glimepiride, but again there was no significant effect on glucose concentrations. However, there are reports of hypoglycaemia in a patient who took fluconazole with glipizide, and another who took fluconazole and cotrimoxazole with gliclazide. Similar interactions have been reported for ketoconazole (with tolbutamide, in healthy subjects)and miconazole (with tolbutamide, in a diabetic), suggesting that such combinations should be regarded with caution.

Ciclosporin. For the effect of glibenclamide on blood concentrations of ciclosporin see Hypoglycaemic Drugs.

Metformin. Results apparently suggesting increased mortality in patients who received intensive drug therapy with metformin and a sulfonylurea were reported by the UK Prospective Diabetes Study. This was considered to be artefactual, since it was not confirmed by epidemiological analysis, and such combinations are widely used in practice, but some concern remains and further study is needed.

Thyroid hormones. It has been suggested that starting thyroid replacement therapy may increase the requirement for insulin or oral antidiabetic drugs in diabetic patients, which would not seem unreasonable given the stimulant effects of thyroid hormones on metabolic function. For a discussion of the mooted effects of sulfonylureas on thyroid function, see under Precautions, above.

Uses and Administration

The sulfonylurea antidiabetics are a class of oral antidiabetic drugs used in the treatment of type 2 diabetes mellitus. They are given to supplement treatment by diet modification when such modification has not proved effective on its own, although metformin is preferred in patients who are obese. Sulfonylureas appear to have several modes of action, apparently mediated by inhibition of ATP-sensitive potassium channels. Initially, secretion of insulin by functioning islet beta cells is increased. However, insulin secretion subsequently falls again but the hypoglycaemic effect persists and may be due to inhibition of hepatic glucose production and increased sensitivity to any available insulin this may explain the observed clinical improvement in glycaemic control. The duration of action of sulfonylureas is variable drugs such as tolbutamide are relatively short-acting (about 6 to 12 hours) while chlorpropamide has a prolonged action (over 24 hours).

Sulfonylurea therapy may be combined with metformin or other oral hypoglycaemics in patients who fail to respond to a single type of drug such combination therapy is usually tried (in the absence of contraindications) before considering the addition of, or transfer to, insulin therapy.

(British Approved Name, US Adopted Name, rINN)

Pharmacopoeias. In British, Japan, and US.

BP 2008 (Tolazamide). A white or almost white, odourless or almost odourless, crystalline powder. Very slightly soluble in water slightly soluble in alcohol soluble in acetone freely soluble in chloroform.

The United States Pharmacopeia 31, 2008 (Tolazamide). A white or off-white crystalline powder, odourless or having a slight odour. Very slightly soluble in water slightly soluble in alcohol soluble in acetone freely soluble in chloroform.

Adverse Effects, Treatment, and Precautions

As for sulfonylureas in general.

Porphyria. Tolazamide has been associated with acute attacks of porphyria and is considered unsafe in porphyric patients.

Interactions

As for sulfonylureas in general.

Pharmacokinetics

Tolazamide is slowly absorbed from the gastrointestinal tract, peak plasma concentrations occurring 4 to 8 hours after a dose by mouth, and is extensively bound to plasma proteins. It has a half-life of about 7 hours. It is metabolised in the liver to metabolites with some hypoglycaemic activity. About 85% of an oral dose is excreted in the urine, chiefly as metabolites.

Uses and Administration

Tolazamide is a sulfonylurea antidiabetic. It is given orally in the treatment of type 2 diabetes mellitus and has a duration of action of at least 10 hours and sometimes up to 20 hours. The usual initial dose is 100 to 250 mg daily given as a single dose with breakfast. Dosage may be increased if necessary at weekly intervals by 100 to 250 mg, usually to a maximum of 1 g daily no further benefit is likely to be gained with higher doses. Doses of more than 500 mg daily may be given in divided doses.

Preparations

British Pharmacopoeia 2008: Tolazamide Tablets

The United States Pharmacopeia 31, 2008: Tolazamide Tablets

Proprietary Preparations

USA: Tolinase

Profile

Vildagliptin is an inhibitor of the enzyme dipeptidylpeptidase-4, an enzyme responsible, among other roles, for the degradation of the incretin hormone glucagon-like peptide-1 (GLP-1 insulinotropin), which plays a role in regulating insulin secretion. Vildagliptin is used in the treatment of type 2 diabetes mellitus it may be added to metformin, a sulfonylurea, or a thiazolidinedione, when monotherapy with these is insufficient. It is given orally in a dose of 50 mg twice daily when given with metformin or a thiazolidinedione, and in a dose of 50 mg once daily in the morning when given with a sulfonylurea. A total daily dose of more than 100 mg of vildagliptin is not recommended, and in patients taking a combination of vildagliptin with a sulfonylurea, a dose of vildagliptin 100 mg daily is no more effective than vildagliptin 50 mg daily. Vildagliptin may be given with or without food.

Adverse effects of vildagliptin may include dizziness, headache, peripheral oedema, constipation, nasopharyngitis, upper respiratory-tract infection, and arthralgia. Rare cases of hepatic dysfunction, including hepatitis, have been reported. Vildagliptin should not be used in patients with hepatic impairment liver function should be tested before starting the drug, and monitored during therapy (every 3 months in the first year and periodically thereafter). Vildagliptin should be stopped if there is a persistent increase of 3 or more times the upper limit of normal in alanine aminotransferase (ALT) or aspartate aminotransferase (AST), or if the patient develops jaundice or other signs of liver dysfunction in such cases, it should not be restarted.

Preparations

Proprietary Preparations

Czech Republic: Galvus

France: Galvus

Portugal: Galvus

United Kingdom: Galvus

Multi-ingredient

Czech Republic: Eucreas

France: Eucreas

United Kingdom: Eucreas

(British Approved Name, US Adopted Name, rINN)

Adverse Effects and Precautions

Troglitazone has been associated with severe hepatic reactions, sometimes fatal, which has led to its withdrawal in most countries. Regular monitoring of liver function during therapy, and withdrawal of the drug in any patient who develops j aundice or signs of liver dysfunction, is required. It should not be given to patients with pre-existing moderate or severe elevations of liver enzyme values, or active liver disease. Increased plasma volume has been reported in healthy subjects given troglitazone: it should be used with caution in patients with heart failure. Other adverse effects reported in patients receiving troglitazone include dizziness, headache, fatigue, musculoskeletal pain, and nausea and vomiting. There is no evidence of hypoglycaemia associated with the use of troglitazone alone.

Effects on the liver. The UK CSM was aware of over 130 cases of hepatic reactions to troglitazone worldwide as of December 1997, although only 1 had been in the UK. There had been 6 deaths. The average time to the onset of the reaction was 3 months, but the frequency of these reactions, and the existence of risk factors predisposing to them, were unclear. The manufacturers had voluntarily withdrawn the drug in the UK. The US manufacturer and the FDA recommended a schedule for routine monitoring of liver function in November 1997 and revised this again in December 1997. It was estimated that 2% of patients treated with troglitazone would have elevated liver enzyme values necessitating discontinuation of the drug. The FDAhad received 560 reports of troglitazone-associated hepatotoxic-ity by June 1998. There were 24 cases of hepatic failure which were likely to have been caused by the drug 21 patients died and 3 patients received transplants. More intensive liver function monitoring recommendations were made by the US manufacturer again in July 1998 and in June 1999. Subsequently the manufacturer withdrew the drug in Australiaia, Japan, and the USA in March 2000. The clinical details of 94 cases of liver failure associated with troglitazone, which were reported to the FDA, have been reviewed.

Interactions

Troglitazone may enhance the hypoglycaemic effects of sulfonylureas dosage adjustment may be necessary. There is a possibility that troglitazone may enhance the metabolism of drugs metabolised by cytochrome P450 isoenzyme CYP3A4, including some oral contraceptives and terfenadine.

Ciclosporin. For the effect of troglitazone on blood concentrations of ciclosporin see Hypoglycaemic Drugs.

Colestyramine. Colestyramine markedly impaired the absorption of troglitazone.

Pharmacokinetics

Troglitazone is rapidly absorbed after oral doses, with peak plasma concentrations 1 to 3 hours after a dose. Bioavailability is about 53% absorption is markedly increased in the presence of food. In the body, troglitazone is more than 99% bound to plasma albumin. It is extensively metabolised in the liver and excreted largely in faeces as metabolites small amounts of metabolites are excreted in urine. Plasma elimination half-life ranges from 10 to 39 hours.

Uses and Administration

Troglitazone is a thiazolidinedione oral antidiabetic (see Rosiglitazone Maleate). It has been given orally for the treatment of type 2 diabetes mellitus although as mentioned above it has been withdrawn in most countries owing to hepato-toxicity.

Preparations

The symbol ¤ denotes a preparation which is discontinued or no longer actively marketed.

Australia: Rezulin¤; Japan: Noscal¤; Mexico: Rezulin; United Kingdom: Romozin¤; United States: Rezulin¤

1

(British Approved Name, rINN)

Pharmacopoeias. In China, Europe, International, Japan, and US.

European Pharmacopoeia, 6th ed. (Tolbutamide). A white or almost white, crystalline powder. Practically insoluble in water soluble in alcohol and in acetone. It dissolves in dilute solutions of alkali hydroxides.

The United States Pharmacopeia 31, 2008 (Tolbutamide). A white or practically white, practically odourless, crystalline powder. Practically insoluble in water soluble in alcohol and in chloroform.

Adverse Effects, Treatment, and Precautions

As for sulfonylureas in general. Tolbutamide was implicated in the controversial reports of excess cardiovascular mortality associated with oral hypoglycaemic therapy (see under Sulfonylureas, Effects on the Cardiovascular System).

Thrombophlebitis with thrombosis has occurred after the intravenous injection of tolbutamide sodium, but this is usually painless and the vein gradually recovers. Rapid injection may cause a transient mild pain or sensation of heat in the vein.

The BNFhas suggested that tolbutamide may be suitable for use in patients with renal impairment, but that careful monitoring of blood-glucose concentration is essential. UK licensed product information recommends that it should not be used in patients with severe renal impairment.

Breast feeding. Tolbutamide is distributed into breast milk in relatively low quantities. The American Academy of Pediatricsstates that, although usually compatible with breast feeding, use of tolbutamide by breast-feeding mothers may possibly result in jaundice in the infant.

Porphyria. Tolbutamide has been associated with acute attacks of porphyria and is considered unsafe in porphyric patients.

Interactions

As for sulfonylureas in general.

Pharmacokinetics

Tolbutamide is readily absorbed from the gastrointestinal tract and is extensively bound to plasma proteins the half-life is generally within the range of 4 to 7 hours but may be considerably longer. Tolbutamide is metabolised in the liver by liydroxylation mediated by the cytochrome P450 isoenzyme CYP2C9. It is excreted in the urine chiefly as metabolites with little hypoglycaemic activity. Tolbutamide has been detected in breast milk.

Uses and Administration

Tolbutamide is a sulfonylurea antidiabetic. It is given orally in the treatment of type 2 diabetes mellitus and has a duration of action of about 10 hours.

The usual initial dose in type 2 diabetes mellitus may range from 1 to 2 g daily, given either as a single dose with breakfast or, more usually, in divided doses. Maintenance doses usually range from 0.25 to 2 g daily. Although it is unlikely that the response will be improved by increasing the dose further, daily doses of 3 g have been given.

Tolbutamide sodium (C₁₂H₁₇N₂Na0₃S = 292.3) has sometimes been used in the diagnosis of insulinoma as well as other pancreatic disorders including diabetes mellitus. The equivalent of 1 g of tolbutamide is given by intravenous injection as a 5% solution usually over 2 to 3 minutes. Tolbutamide sodium 1.08 g is equivalent to about 1 g of tolbutamide.

Preparations

British Pharmacopoeia 2008: Tolbutamide Tablets

The United States Pharmacopeia 31, 2008: Tolbutamide for Injection Tolbutamide Tablets.

Proprietary Preparations

Australia: Rastinon

Czech Republic: Dirastan

Denmark: Arcosal

Germany: Orabet Hong Kong Diatol

Israel: Orsinon

Mexico: Artosin Bioglusil Dabetil Diatelan Diaval Flusan Ifumelus Rastinon

New Zealand: Diatol

Poland: Diabetol

South Africa: Tydadex

Singapore: Tolmide

USA: Orinase; Orinase Diagnostic