(British Approved Name Modified, US Adopted Name, rINN)

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

Hidrocloruro de metformina; LA-6023 (metformin or metformin hydrochloride); Metformiinihydrokloridi; Metformin Hidroklorur; Metformin hydrochlorid; Metformine, chlorhydrate de; Metformin-hidroklorid; Metforminhydroklorid; Metformini hydrochloridum; Metformino hidrochloridas.

C₄H₁₁N₅,HCI = 165,6.

CAS — 657-24-9 (metformin); 1115-70-4 (metformin hydrochloride).

ATC — A10BA02.

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

European Pharmacopoeia, 6th ed. (Metformin Hydrochlonde). White or almost white crystals. Freely soluble in water slightly soluble in alcohol practically insoluble in acetone and in dichloromethane.

The United States Pharmacopeia 31, 2008 (Metformin Hydrochloride). A white crystalline powder. Freely soluble in water slightly soluble in alcohol practically insoluble in acetone and in dichloromethane.

Adverse Effects, Treatment, and Precautions

As for biguanides in general.

Breast feeding. Based on animal studies the UK and US licensed product information warns that metformin may be distributed into breast milk, and that the possible effects on the infant should be considered if women wish to breast feed while receiving the drug. However, a study in 7 breast-feeding women receiving metformin at a median dose of 1.5 g daily found the concentrations in milk to be about a third of those in maternal plasma, resulting in a mean calculated dose to the infants of 40 micrograms/kg daily. Blood samples were taken from 4 of the infants: metformin concentrations were undetectable in 2, and were very low (10 to 15% of maternal values) in the others. Given these results the authors considered that women receiving metformin need not be discouraged from breast feeding. Similar results from 3 other studies’ that included 13 women have provided further evidence that metformin is distributed into breast milk, that concentrations in milk are less than those in maternal plasma, and that breast-fed infants would be exposed to a very small percentage of the maternal dose. Six infants were breastfed with no adverse effects that could be attributed to metformin. A prospective study of weight, height, and motor-social development over 6 months, in infants of women taking metformin (1.5 to 2.55 g daily) for poly cystic ovary syndrome, found no difference between 61 infants who were breast-fed and 50 who were formula-fed.

Fasting. For the view that metformin could be used with little risk of hypoglycaemia in fasting Muslim patients during Ramadan, and suggestions for modifying the timing of doses, see under Precautions of Insulin.

Pregnancy. Insulin is generally preferred for treatment of diabetes during pregnancy. However, there are limited data to suggest that metformin does not increase the risk of congenital abnormalities and does not adversely affect pregnancy outcome in diabetic women. A controlled study comparing insulin with metformin in gestational diabetes is underway.The use of metformin to improve ovulation in polycystic ovary syndrome (PCOS) is increasing. There is growing evidence to suggest that metformin used before and during pregnancy in these women does not increase the risk of congenital abnormalities, and may reduce first trimester spontaneous abortion,’which is common in women with PCOS.

Interactions

As for biguanides in general.

Pharmacokinetics

Metformin hydrochloride is slowly and incompletely absorbed from the gastrointestinal tract the absolute bioavailability of a single 500-mg dose is reported to be about 50 to 60%, although this is reduced somewhat if taken with food. Once absorbed, protein binding in plasma is negligible the drug is excreted unchanged in the urine. The plasma elimination half-life is reported to range from about 2 to 6 hours after oral doses. Metformin crosses the placenta and is distributed into breast milk in small amounts.

Uses and Administration

Metformin hydrochloride is a biguanide antidiabetic. It is given orally in the treatment of type 2 diabetes mellitus, and is the drug of first choice in overweight patients. Initial dosage is 500 mg two or three times daily or 850 mg once or twice daily with or after meals, gradually increased if necessary, at intervals of at least 1 week, to 2 to 3 g daily doses of 3 g daily are associated with an increased incidence of gastrointestinal adverse effects. Gastrointestinal effects are also common on beginning therapy, and the BNF recommends starting therapy more gradually with 500 mg at breakfast for at least 1 week, then increasing to 500 mg twice daily for at least 1 week, with further increases as required, up to a usual maximum of 2 g daily in 3 divided doses with meals. A modified-re-lease preparation is also available, which is given in an initial dose of 500 mg once daily and may be increased in increments of 500 mg, at intervals of at least 1 week, to a maximum of 2 g once daily with the evening meal. If glycaemic control is not adequate the dose may be divided to give 1 g twice daily with meals. If doses above 2 g daily are required, they should be given as the standard preparation. For doses used in children and adolescents, see below.

Metformin is also used as the chlorophenoxyacetate and as the embonate.

Action. A review of the action of metformin considered that although a number of possible mechanisms have been suggested, the major action of metformin lay in increasing glucose transport across the cell membrane in skeletal muscle. There is also some evidence in vitro that it can inhibit the formation of advanced glycosylation end-products.

Administration in children. In children aged 10 years and older with type 2 diabetes mellitus, oral metformin hydrochloride may be used in a starting dose of 500 mg or 850 mg once daily, or 500 mg twice daily, given with or after a meal. It may be gradually increased if needed, at intervals of at least 1 week, to a maximum of 2 g daily given in 2 or 3 divided doses. Modified-release preparations are generally not licensed for use in children.

Although rare, the incidence of type 2 diabetes is increasing in children and adolescents, related in part to the increase in obesity occurring particularly in westernised countries. A small placebo-controlled study of patients aged 10 to 17 years with type 2 diabetes found that metformin improved glycaemic control and that adverse effects were similar to those in adults. In obese children and adolescents with hyperinsulinaemia, who are at risk of developing type 2 diabetes, small studies of metformin use have reported improvements in body composition and fasting insulin concentrations. There has also been some interest in the use of metformin as an adjunct to insulin in adolescents with type 1 diabetes improvements in glycaemic control and reductions in insulin doses have been reported.

Diabetes mellitus. Results of the United Kingdom Prospective Diabetes Study (UKPDS) showed that intensive blood glucose control with metformin reduces the risk of diabetic complications and death in overweight patients with type 2 diabetes.The study also generated some concern regarding intensive therapy with metformin plus a sulfonylurea (see under Interactions) but this was not borne out on further analysis and such combinations are widely used. Metformin is also used with the thiazolidinediones, or with insulin in patients requiring combined or more intensive therapy. Metformin has also been investigated for the prevention of type 2 diabetes in patients at high risk. Although metformin treatment for an average 2.8 years reduced the incidence of type 2 diabetes by 31% in a study of patients with impaired glucose tolerance, intensive lifestyle modification was actually more effective (58% reduction). Lifestyle modification was also more effective than metformin in reducing cardiovascular risk factors and the development of the metabolic syndrome. The durability of these effects is unknown but follow-up of this study is ongoing.

There is some interest in using oral hypoglycaemics as adjuncts to insulin therapy in patients with type 1 diabetes. Short-term results from small studies have suggested that metformin may be beneficial, in this context, in adolescents with pubertal insulin resistance (see also Administration in Children, above) and perhaps in adults who are overweight or otherwise at risk of reduced insulin sensitivity.

Polycystic ovary syndrome. It has been suggested that hyper -insulinism may play a pathogenetic role in stimulating the abnormal androgen production from the ovary seen in women with polycystic ovary syndrome (PCOS). Most early studies ofmetformin in PCOS were small, observational, and of short duration, with mixed results. Although there were reports of reduced insulin levels, increased insulin sensitivity, and improved androgen concentrations, other studies failed to confirm these effects. Later randomised studies were also small, but some were of longer duration. These reported weight reductions of obese patients, reductions in insulin levels and increased sensitivity, improved androgen and other hormonal measures, improved menstrual patterns, and reduced hirsutism, but again, not consistently. Metformin has also been reported to increase the rate of spontaneous ovulation, and may improve the outcome of IVF procedures. Combination ofmetformin with clo-mifene appeared to improve ovulatory response, compared with clomifene alone, in studies of women with PCOS, though there is also a report of no apparent benefit. Furthermore, 2 large, placebo-controlled studies have found that metformin, either alone or with clomifene, did not improve the rate of ovulation, pregnancy, or live births in women with polycystic ovary syndrome.

Some consider that current evidence supports a trial ofmetformin in patients with anovulation, androgen excess, and vascular risk factors, but because of the lack of data on long-term safety such use should be supervised by an endocrinologist or a physician with suitable expertise.

Preparations

British Pharmacopoeia 2008: Metformin Tablets

The United States Pharmacopeia 31, 2008: Glipizide and Metformin Hydrochloride Tablets; Glyburide and Metformin Hydrochloride Tablets; Metformin Hydrochloride Extended-Release Tablets; Metformin Hydrochloride Tablets.

Proprietary Preparations

Argentina: Baligluc DBI AP Diab Dos Glucaminol Glucogood Glucophage Islotin Mectin Medobis Metforal Metfori † Oxemet Redugluc

Australia: Diabex Diaformin Glucohexal Glucomet Glucophage Novomet

Austria: Clonarol Desugar Diabetex Glucomin Glucophage Meglucon Orabet †

Belgium: Glucophage Metformax

Brazil: Diaformin Dimefor Formetf Formyn Glicefor Glifage Glucoformin Metfordin † Metformed Teutoformin

Canada: Glucophage Glumetza Glycon †

Chile: Diaglitab Fintaxim Glafornil Glicenex Glidanil Glifortex Glucophage Hipoglucin Menarini-Metforal †

Czech Republic: Adimet Diaphage Glucomerck Glucophage Gluformin Glumetsan Langerin Metfirex Metfogamma Siofor Stadamet

Denmark: Glucophage Orabet

Finland: Diformin Glucophage Metforem Oramet

France: Diabamyl † Glucophage Stagid

Germany: Biocos Diabesin Diabetase † Espaformin † Glucobon Glucophage Juformin Mediabet Meglucon Mescorit Met Metfodoc Metfogamma Metfor † Metform † MetSurrir Siofor Thiabet

Greece: Glucofree Glucophage Metforil Sukontrol

Hong Kong: CP-Metform Diabetmin Diaformin Glucomet Glucophage Glumet Guamet Melbin

Hungary: Adimet Gluformin Maformin † Meforal Meglucon Merckformin Metfogamma Metrivin † Stadamet

India: Bigomet † Emfor Emnorm Exermet Formin † Glumet Glyciphage Glyree M Insumet Metlong Walaphage X-Met

Indonesia: Benofomin Diabex Eraphage Forbetes Formell Gliformin Glucofor Glucophage Glucotika Gludepatic Glufor Glumin Gradiab Methormyl Methpica Metphar Regius Tudiab Zumamet

Ireland: Glucophage

Israel: Apophage Glucomin Glucophage Glufor

Italy: Glucophage Metbay Metfonorm Metforal Metiguanide

Japan: Glycoran Melbin

Malaysia: Diabemet † Diabetmin Glucomet Glucophage Glumet Riomet Xmet

Mexico: Aglumet Anglucid Apozemia Dabex Debeone Dimefor Dinamel Ficonax Forlucyl Glucophage Glunovag Harbamind Ifor Meglubet Melbexa Mifelar Pharmafet Pre-Dial

The Netherlands: Diabex Dianorm † Finormet † Glucophage Glumeff Niformina

Norway: Glucophage

New Zealand: Glucomet Glucophage † Metomin

Philippines: Diafat Diazen Euform Fornidd Glucare Glucoform Glucomed Glucophage Glumet Glyformin Horsulin Humamet L-Max Insunex Neoform Nidcor Sucranorm Vimetrol Xmet

Poland: Glucophage † Gluformin Metfogamma Metformax Metifor Siofor

Portugal: Diabex Glucophage Mekoll Risidon Stagid

Russia: Bagomet Formin Gliformin Glucophage Metfogamma Siofor

South Africa: Glucophage Metforal

Singapore: Diabetmin Diamin † Glucophage Glycomet Glycoran † Metforal

Spain: Dianben

Sweden: Glucophage

Switzerland: Gluconormine Glucophage Metfin

Thailand: Ammiformin Deson Diamet Formin Gluco Glucoles-500 Glucolyte Glucomet † Glucono Glucophage Gluformin Glustress † Glutabloc Gluzolyte Macromin † Maformin ME-F † Meformed Metfor Metfron Miformin Pocophage Poli-Formin Prophage Serformin Siamformet

Turkey: Glifor Glucophage Gluformin Glukofen

UAE: Dialon

UK: Glucophage Metsol

USA: Fortamet Glucophage Glumetza Riomet

Venezuela: Diaformina DimeforF Glafornil Glucaminol Glucofage

Multi-ingredient

Argentina: Avandamet DBI Duo Glucovance Gludex Plus Isloglib Medobis G Metformin Duo Rosiglit-Met

Australia: Avandamet Glucovance

Belgium: Avandamet Glucovance

Brazil: Glucovance Starform

Canada: Avandamet

Chile: Avandamet Bi-Euglucon M Diaglitab Plus Glifortex-G Glimet Glucovance Glukaut Hipoglucin DA

Czech Republic: Avandamet Competact Eucreas Glibomet Glubrava Glucovance

Denmark: Avandamet

Finland: Avandamet

France: Avandamet Competact Eucreas Glucovance

Germany: Avandamet

Greece: Avandamet Normell

Hong Kong: Avandamet Glucovance

Hungary: Avandamet

India: Betaglim M † Diaforte Diaglip M Exermet GM Exermet GZ Exermet P Gliclamet Glimiprex MF Glimulin-MF † Glinil M Glizid-M Glycigon-M Glycinorm M Glygard M Metaglez P-Glitz M Piomed M Piosafe MF Roglin-M Rosicon MF

Indonesia: Avandamet Glucovance

Ireland: Avandamet

Israel: Avandamet

Italy: Avandamet Bi-Euglucon M Glibomet Gliconorm Glicorest Glucomide Pleiamide Suguan M

Malaysia: Avandamet Glucovance

Mexico: Apometglu Avandamet Bi-Dizalon Bi-Euglucon M Bi-Pradia Duo-Anglucid Glimetal Glucotec Glucovance Imalet Insogen Plus Insusym-Forte Maviglin Mellitron Midaphar-ma Mifelar-C Nadib-M Norfaben M Obinese Sibet-C Sil-Norboral Wadil

The Netherlands: Avandamet Glucovance

Norway: Avandamet

Philippines: Avandamet Euglo Plus Glucovance

Poland: Avandamet

Portugal: Avandamet Competact Glucovance

Russia: Glibomet Glucovance

South Africa: Glucovance

Singapore: Avandamet Glucovance

Spain: Avandamet

Sweden: Avandamet

Switzerland: Avandamet Diabiformine Glucovance

Thailand: Avandamet

UK* Avandamet Competact Eucreas

USA: Actoplus Met Avandamet Diofen Glucovance Glybofen Janumet Metaglip

Venezuela: Avandamet Bi-Euglucon Diaformina Plus Glucovance Starform

The symbol † denotes a preparation no longer actively marketed.

(British Approved Name, rINN)

International Nonproprietary Names (INNs) in main languages (French, Latin, and Spanish): Glibenclamida; Glibenclamidum; Glibenklamid; Glibenklamidas; Glibenklamidi; Glybenclamide; Glybenzcyclamide; Glyburide (US-AN); HB-419; U-26452

C₂₃H₂₈CIN₃0₅S = 494.0.

CAS — 10238-21-8.

ATC — A10BB01.

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

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

European Pharmacopoeia, 6th ed. (Glibenclamide). A white or almost white, crystalline powder. Practically insoluble in water slightly soluble in alcohol and in methyl alcohol sparingly soluble in dichloromethane.

The United States Pharmacopeia 31, 2008 (Glyburide). Store in airtight containers.

Adverse Effects, Treatment, and Precautions

As for sulfonylureas in general.

For a suggestion that the failure rate in type 2 diabetics treated with glibenclamide may be higher than that for those treated with chlorpropamide, see Diabetes Mellitus under Uses and Administration of Chlorpropamide.

Hypoglycaemia. Severe hypoglycaemia may occur in any patient given any sulfonylurea glibenclamide which has a relatively prolonged duration of action, may cause severe hypoglycaemia more often than shorter-acting sulfonylureas. In a 1983 review of 57 instances of hypoglycaemia associated with glibenclamide the median age of patients affected was 70 years only one was less than 60 years old. Median daily dosage was 10 mg. Coma or disturbed consciousness was seen in 46 patients. Ten of these remained comatose despite alleviation of their hypoglycaemia and died up to 20 days after presentation. The authors noted that, including their series of 57 cases, there had been published reports on 101 cases of severe hypoglycaemia with glibenclamide, 14 with a fatal outcome. There has been a report of hypoglycaemic coma associated with the inhalation of glibenclamide by a worker at a pharmaceutical plant.

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

Interactions

As for sulfonylureas in general.

Pharmacokinetics

Glibenclamide is readily absorbed from the gastrointestinal tract, peak plasma concentrations usually occurring within 2 to 4 hours, and is extensively bound to plasma proteins. Absorption may be slower in hyper-glycaemic patients and may differ according to the particle size of the preparation used. It is metabolised, almost completely, in the liver, the principal metabolite being only very weakly active. About 50% of a dose is excreted in the urine and 50% via the bile into the faeces.

Uses and Administration

Glibenclamide is a sulfonylurea antidiabetic. It is given orally in the treatment of type 2 diabetes mellitus and has a duration of action of up to 24 hours.

The usual initial dose of conventional formulations in type 2 diabetes mellitus is 2.5 to 5 mg daily with breakfast, adjusted every 7 days in steps of 2.5 or 5 mg daily up to 15 mg daily. Although increasing the dose above 15 mg is unlikely to produce further benefit, doses of up to 20 mg daily have been given. Doses greater than 10 mg daily may be given in 2 divided doses. Because of the relatively long duration of action of glibenclamide, it is best avoided in the elderly. In some countries micronised preparations of glibenclamide are available, in which the drug is formulated with a smaller particle size, and which have enhanced bioavailability. The usual initial dose of one such preparation (Glynase PresTab; Pharmacia Upjohn, USA) is 1.5 to 3 mg daily, adjusted every 7 days in steps of 1.5 mg, up to a usual maximum of 12 mg daily. Doses greater than 6 mg daily may be given in 2 divided doses.

Action. Proceedings of a symposium on the mechanism of action of glibenclamide.

EFFECTS ON THE HEART. A reduced incidence of ventricular fibrillation has been reported in diabetics treated with glibenclamide who develop myocardial infarction, compared with those receiving other treatments or with nondiabetic patients with myocardial infarction. However, some evidence has also suggested that sulfonylureas may impair the adaptive responses of the heart to ischaemia.

Preparations

British Pharmacopoeia 2008: Glibenclamide Tablets

The United States Pharmacopeia 31, 2008: Glyburide and Metformin Hydrochloride Tablets Glyburide Tablet.

Proprietary Preparations

Argentina: Agobilina Benclamid Daonil Diabe Pass Diabemin Euglucon Gardoton Glentor Glibediab † Glibemida Glidanil Gliptid Glitral GON Pira Siruc

Australia: Daonil Glimel Semi-Daonil

Austria: Daonil Dia-Eptal Euglucon Gilemal Glucobene Glucostad Normoglucon Semi-Euglucon

Belgium: Bevoren Daonil Euglucon

Brazil: Aglucil Benclamin Clamiben Daonil Diaben Diabetty’s † Diabexil Euglucon Gliben † Glibenclamon Glibendiab Glibexil † Glicamin Glionil Lisaglucon Uni Gliben †

Canada: DiaBeta Euglucon Gen-Glybe

Chile: Daonil Euglusid Mezalit

Czech Republic: Betan-ase † Glibenhexal † Glucobene Humedia † Maninil

Denmark: Daonil Hexaglucon Regulin †

Finland: Daonil † Euglamin Euglucon Origlucon Semi-Euglucon

France: Daonil Euglucan Hemi-Daonil Miglucan

Germany: Azuglucon † Bastiverit † duraglucon N Euglucon N Glib Glib-ratiopharm Gliben Glib-en-Azu † Gliben-Puren N † Glibenbeta Glibendoc Glibenhexal Glimidstada † Glucoremed † Glukoreduct † Glukovital glycolande N † Humedia Jutaglucon † Maninil Praeciglucon † Semi-Euglucon N

Greece: Daonil Deroctyl Diabefar †

Hong Kong: Calabren † Clamide Daonil Euglucon Gliben Gliboral Glimel Glitisol Marglucon Semi-Daonil † Semi-Euglucon Xeltic

Hungary: Gilemal Glucobene Maninil

India: Daonil Euglucon Glinil Glybovin Semi-Daonil Semi-Euglucon

Indonesia: Condiabet Daonil Glidanil Glimel Gluconic Glulo Glyamid Libronil Prodiabet Prodiamel Renabetic Semi-Daonil Tiabet Trodeb

Ireland: Daonil Semi-Daonil

Israel: Daonil † Glibetic Gluben

Italy: Daonil Euglucon Gliben Gliboral

Japan: Euglucon

Malaysia: Claben † Daonil Debtan † Dibelet Gliben Glibesyn Glimide

Mexico: Abuglib Apogly Biostin Daonil Dibetid Diglexol Euglucon Gadinor Glemicid Glibenil Glibenval Glicavin Glicoxem Glifarcal Glihexal Glikeyer † Glipar Glucal Glucoven Insusym Mibeclag Nadib † Norboral Ocrix Reglusan

The Netherlands: Daonil Hemi-Daonil †

Norway: Daonil †

New Zealand: Gliben

Philippines: Ameciadin Daonil Diabitor Euglucon Eundin Gluban Glymod Insol Loduice Orabetic Semi-Euglucon Sentionyi Sucron

Poland: Euclamin

Portugal: Daonil Euglucon Semi-Daonil Semi-Euglucon †

Russia: Betanase Glibamide Glibex Glidanil Maninil

South Africa: Daonil Diacare Euglucon † Glycomin

Singapore: Clamide Daonil Dibelet GBN † Glibemid † Glibesyn Glimel Glimide

Spain: Daonil Euglucon Glucolon Norglicem

Sweden: Daonil Euglucon

Switzerland: Daonil Euglucon Glibasan Glibenorme Glibesifar Melix Semi-Daonil Semi-Euglucon †

Thailand: Benclamin BNIL Cytagon † Daonil Daono Debtan Diabenol Dibelet Diclanil Euglucon Glencamide † Gliben † Glibetic Glibic Gluconil Gluzo Locose Manoglucon Med-Glionil † Semi-Euglucon † Sugril Unil Xeltic

Turkey: Dianorm Diyalen Gliben

United Arab Emirates: Glynase Mini-Glynase

UK: Daonil Diabetamide † Euglucon † Semi-Daonil †

USA: DiaBeta Glynase Micronase

Venezuela: Daonil Euglucon Gliciron.

Multi-ingredient

Argentina: DBI Duo Glucovance Isloglib Medobis G Metformin Duo

Australia: Glucovance

Belgium: Glucovance

Brazil: Glucovance

Chile: Bi-Euglucon M Diaglitab Plus Glifortex-G Glimet Glucovance Glukaut Hipoglucin DA

Czech Republic: Glibomet Glucovance

France: Glucovance

Greece: Daopar † Normell

Hong Kong: Glucovance

India: Diaforte Glinil M

Indonesia: Glucovance

Italy: Bi-Euglucon M Bi-Euglucon † Gliben  † Glibomet Gliconorm Glicorest Gliformin Glucomide Suguan M Suguan †

Malaysia: Glucovance

Mexico: Apometglu Bi-Dizalon Bi-Euglucon M Bi-Pradia Duo-Anglucid Glinorboral Glucotec Glucovance Imalet Insusym-Forte Maviglin Midapharma Mifelar-C Nadib-M Norfaben M Sibet-C Sil-Norboral Wadil

The Netherlands: Glucovance

Philippines: Euglo Plus Glucovance

Portugal: Glucovance

Russia: Glibomet Glucovance

South Africa: Glucovance

Singapore: Glucovance

Switzerland: Glucovance

USA: Diofen Glucovance Glybofen

Venezuela: Bi-Euglucon Diaformina Plus Glucovance.

Oral antidiabetic drugs fall into several classes (Table 5). Of particular interest are the insulin sensitizers because they specifically target insulin resistance. Other agents address different aspects of glycemic control.

Insulin secretion stimulators (secretagogues)

For more than 40 years, sulfonylureas have been the first line of therapy for individuals with type 2 diabetes. These agents directly stimulate pancreatic b-cells to produce insulin by increasing the influx of calcium. Sulfonylureas increase circulating insulin and reduce both fasting and postprandial glucose, but they are not insulin sensitizers and therefore do not address the problem of insulin resistance. Sulfonylureas lower A1C an average of 1% to 2% and offer effective glycemic control in up to 75% of patients; however, efficacy lapses over time, with about 5-10% of patients per year failing to maintain the initial glycemic control. Primary adverse effects include hypoglycemia and weight gain (typically 2-5 kg). Glimepiride (Amaryl) is emerging as the sulfonylurea of choice due to its once-a-day dosing, extrapancreatic effect, and the fact that it causes less weight gain and hypoglycemia and is priced as low as generic glyburide.

Another class of secretagogues, derivatives of meglitinide or phenylalanine, also stimulate insulin but act at a different site on pancreatic beta-cells than the sulfonylureas. Because these agents have a very short onset of action and short half-life, they must be taken immediately before every meal (compared to once-daily dosing for sulfonylureas), so treatment adherence may be an issue for some patients. They have a side effect profile similar to the sulfonylureas; however, because meglitinides are shorter-acting agents, they carry a lower risk of sustained hypoglycemia. Efficacy is similar to that of sulfonylureas. The two products currently available are nateglinide (Starlix) and repaglinide (Prandin).

Alpha-glucosidase inhibitors

Drugs in this group produce mild reductions in postprandial hyperglycemia by inhibiting the enzyme responsible for metabolizing complex carbohydrates in the small intestine. Taken right before a meal, these agents reduce glucose levels by slowing absorption of carbohydrates and delaying entry of glucose into liver and muscle tissue. Gastrointestinal side effects (ie, abdominal pain, diarrhea, and flatulence) are the most common reactions to alpha-glucosidase inhibitors (reported in up to 75% of patients), leading some patients to discontinue therapy with these drugs. Available agents include acarbose (Precose) and miglitol (Glyset). Gastrointestinal side effects can be greatly reduced if low doses are started and then gradually titrated over 10-12 weeks to the maximum and effective doses. At present, these agents are seldom used in the United States.

Thiazolidinediones

The thiazolidinediones (TZDs or glitazones) are a relatively new class of agents that reduce insulin resistance. TZDs do not stimulate the secretion of insulin but rather enhance the effects of circulating insulin by improving insulin sensitivity in muscle and adipose tissue and by inhibiting hepatic gluconeogenesis. TZDs work by stimulating certain receptors (peroxisome proliferator-activated receptor gamma, or PPAR-gamma) in the nucleus of the cells. Activation of PPAR-gamma modulates the transcription of a number of insulin-responsive genes involved in the control of glucose and lipid metabolism. In response to thiazolidinediones stimulation, the genes produce a protein called GLUT-4. Insulin works by recruiting GLUT-4 to the cell’s outer membrane. This partnership, in turn, promotes transport of glucose across the membrane and into the cell’s interior.

Examples of insulin sensitizers include pioglitazone hydrochloride (Actos) and rosiglitazone maleate (Avandia). Another drug in this class, troglitazone (Rezulin), was removed from the market because it was linked to idiosyncratic cases of hepatotoxicity. In clinical trials, there has been no evidence of drug-induced hepatotoxicity with pioglitazone or rosiglitazone, but there have been rare postmarketing case reports of liver damage in patients receiving rosiglitazone and pioglitazone (causality not established). The safe use of these agents, therefore, requires careful monitoring of liver function: ALT enzyme levels should be measured at baseline and monitored every 2 months for 1 year and periodically thereafter. Patients with hepatic impairment should not be treated with thiazolidinediones.

In large placebo-controlled trials lasting up to 26 weeks, monotherapy with pioglitazone or rosiglitazoneproduced significant improvements in A1C and fasting blood glucose concentrations (Table 6). Pioglitazone also led to significant improvements in A1C and improvements in FPG when combined with a sulfonylurea, metformin, or insulin. Rosiglitazone resulted in significant decreases in A1C and FPG levels when combined with metformin or a sulfonylurea.

In addition to reducing insulin resistance, thiazolidinediones also have effects on lipids (Table 6). In a 26-week placebo-controlled study, pioglitazone was associated with decreases in triglycerides of 9.0%, 9.6%, and 9.3% in patients treated with 15-, 30-, and 45-mg, respectively, compared with baseline. HDL (“good”) cholesterol increased by 14%, 12%, and 19% in the 15-, 30-, and 45-mg groups, respectively. No consistent differences were reported for LDL (“bad”) cholesterol and total cholesterol in patients treated with pioglitazone versus placebo.

In a similar 26-week pla-cebo-controlled study, rosiglitazone raised HDL cholesterol by 11.4% and 14.2% in doses of 4- and 8-mg per day, respectively, compared to baseline, but the drug also raised LDL cholesterol by 14.1% and 18.6%, respectively. Changes in triglycerides were variable and generally not statistically significant compared to placebo controls. A recent retrospective review of type 2 diabetes patients treated with either pioglitazone (n=525) or rosiglitazone (n=590) suggested that pioglitazone provides a greater benefit in terms of blood lipid profile than does rosiglitazone.

Because TZDs do not affect insulin secretion, they do not induce hypoglycemia. Dose-related weight gain is seen with both pioglitazone (average increase 0.5 kg to 2.8 kg) and rosiglitazone (median increase 1.0 kg to 3.1 kg). Also, a small number of patients experience mild to moderate edema and anemia. TZDs can cause fluid retention, which may lead to or exacerbate heart failure; thus, patients should be observed for signs and symptoms of congestive heart failure, and TZDs should not be used in patients with class III or IV cardiac status. Studies are currently underway to determine whether thiazolidinediones may be effective in preventing progression of insulin resistance to full-blown type 2 diabetes.

Introduction

The drugs metformin and glyburide are commonly used by people with type 2 diabetes to control blood glucose levels. Individually the agents may or may not be effective. But together they pack a synergistic punch. A new combination of metformin and glyburide in a single tablet (250 mg metformin and 1.25 mg glyburide), manufactured by Bristol-Myers Squibb under the trade name Glucovance, helped people with type 2 diabetes achieve greater blood glucose control than either pill alone, reported investigators at the 60th annual meeting of the American Diabetes Association in June 2000. Glucovance is currently under review by the FDA.

How It Works

Metformin increases insulin action in peripheral tissues and reduces hepatic glucose output by inhibiting gluconeogenesis. Metformin may also reduce plasma glucose by decreasing the absorption of glucose from the small intestine.

Glyburide is a sulfonylurea that causes hypoglycemia by stimulating insulin release from pancreatic beta cells. Sulfonylureas may also further increase insulin levels by reducing hepatic clearance of the hormone.

Clinical Study Results

A total of 806 people with type 2 diabetes age 60 and older were randomized into multicenter, double-blind, placebo-controlled trials. Patients received either placebo, 2.5 mg glyburide, 500 mg metformin, 250 mg/1.25 mg metformin/glyburide, or 500 mg/2.5 mg metformin/glyburide, and were followed for 20 weeks. At the end of the study period, 66% of the 250 mg/1.25 mg metformin/glyburide group and 72% of the 500 mg/2.5 mg metformin/glyburide group achieved HbA1C levels of less than or equal to 7%, compared to 20% of patients taking placebo, 60% of those on glyburide alone, and 50% of those taking metformin alone.

Subjects in both metformin/glyburide groups also demonstrated significantly larger mean decreases in absolute postprandial glucose (-60.7 mg/dL for the 250mg/1.25 mg group and -58.8 mg/dL for the 500 mg/2.5 mg group) compared to patients taking placebo (+4.5 mg/dL), glyburide (-42.4 mg/dL), or metformin (-40.3 mg/dL) alone. Subjects taking metformin/glyburide also experienced larger mean increases in absolute 2-hour postprandial insulin (29.7 mU/ml for the 250mg/1.25 mg group and 25.0 mU/ml for the 500 mg/2.5 mg group) compared to patients taking placebo (0.9 mU/ml), glyburide (15.1 mU/ml), or metformin (4.0 mU/ml) alone. Finally, subjects in both metformin/glyburide groups also demonstrated significantly larger mean decreases in fasting plasma glucose (-41.5 mg/dL for the 250 mg/1.25 mg group and -40.1 mg/dL for the 500 mg/2.5 mg group) compared to patients taking placebo (+4.6 mg/dL), glyburide (-35.7 mg/dL), or metformin (-21.2 mg/dL) alone.

Adverse Events

Glucovance-related adverse events were minor and included diarrhea, nausea, upset stomach, and hypoglycemia. Patients taking the 250 mg/1.25 mg metformin/glyburide combination had fewer gastrointestinal side effects than patients taking metformin and fewer symptoms of hypoglycemia than those taking glyburide. Patients taking the 500 mg/2.5 mg metformin/glyburide combination reported more symptoms of hypoglycemia than patients taking glyburide, establishing the 250 mg/1.25 mg dosage as the optimal dosage of Glucovance.

A total of 806 people with type 2 diabetes age 60 and older took part in the clinical trials. Patients received either placebo, 2.5 mg glyburide, 500 mg metformin, 250 mg/1.25 mg metformin/glyburide or 500 mg/2.5 mg metformin/glyburide, and were followed for 20 weeks. At the end of the study period, 66 percent of the 250 mg/1.25 mg metformin/glyburide group and 72 percent of the 500 mg/2.5 mg metformin/glyburide group achieved HbA1C levels of less than or equal to seven percent — a measure of adequate blood sugar control — compared to 20 percent of patients taking placebo, 60 percent of those on glyburide alone and 50 percent of those taking metformin alone. Patients taking a metformin/glyburide combination also experienced better control of blood glucose and insulin levels both before and after eating.

“It is quite possible that the results of this study may lead to a new treatment paradigm for patients with type 2 diabetes,” said Dr. Daniel Donovan, assistant clinical professor of medicine, College of Physicians & Surgeons, Columbia University, and one of the study investigators. “None of the currently available oral antidiabetic drugs can, by themselves, address both of the major causes of type 2 diabetes: insulin resistance and insulin deficiency. The results of this study are encouraging because they demonstrate that by prescribing this novel oral antidiabetic, which attacks both major defects of type 2 diabetes, we can help our patients to aggressively control their blood sugar and, most importantly, avoid potentially serious complications.”

Side effects related to Glucovance were minor and included diarrhea, nausea, upset stomach and hypoglycemia.