Abstract

Metformin is the most common prescribed oral antidiabetic drug in the world .It shall continue to maintain itsposition despite of several other classes of oral agents have been recently introduced both as initial therapyand in combination with these newer drugs for prevention and treatment of type 2 diabetes mellitus (DM).The current review focuses on novel mechanism of action, efficacy, toxicity, administration of newer metforminformulation and technology of metformin. Metformin is a hepato-selective insulin sensitizer. It has beneficialproperties of metformin including weight loss, lipid reduction and modulator of endothelial function. It is anatherostatic agent and also improves ovarian function in some insulin-resistant women. It does not causehyperinsulinaemia or hypoglycaemia. Metformin is effective as monotherapy and, in combination with bothinsulin secretagogues and thiazolidinediones (TZDs) and may obviate the need for insulin treatment. Severalfixed-dose combination pills containing metformin and other agents are available. Metformin remains a safeand effective agent for the therapy of patients with type 2 DM. It is still in most circumstances the agent ofchoice for first line initial therapy of the typical obese patient with type 2 DM and mild to moderatehyperglycaemia. With the current sustained release (XL) formulation of metformin, metformin therapy hasnow upgraded itself from the Gold Standard to Platinum. These unique XL bioequivalent metforminpreparations will become the platinum standards in modern diabetes management. ©

HISTORY

Guanidine was recognized as the active glucose-lowering constituent of French lilac (Gallegaofficinalis), which had been employed in continentalEurope as a traditional remedy for DM for centuries.1The use of guanidine and guanidine derivatives(Phenformin, Buformin, Metformin) as therapeuticagents for diabetes mellitus (DM) dates from the early1900s.2,3 Phenformin (phenylethylbiguanide), the firstbiguanide, was introduced in the late 1950s, but due toits association with lactic acidosis4,5 was withdrawnfrom across the globe in the late 1970s, in India onlyrecently.6 Metformin is substantially different fromphenformin structurally, the latter possessing a phenyl-ethyl ring on a guanidine side chain, thus rendering itless polar and more lipid soluble. In clinical use, itappears that secondary failure to metformin therapyoccurs with approximately the same frequency (about5–10% per year) as to sulfonylureas,7-9 which is likely toreflect the progressive nature of type 2 DM. Trials showthat metformin monotherapy in patients with type 2 DMreduces fasting plasma glucose by 50-70 mg% (3–4mmol/l) and glycosylated haemoglobin A1c (HbA1c) by 1.5–2%.10-12 While metformin was not licensed for use inthe US until 1995, it remained in widespread usethroughout Canada, Europe and much of the worldincluding India for the period from 1978 through1995.13–16 In India, Metformin was available since 1980sas traditional agent (Glyciphage) and since last 5 yearsseveral newer sustained release formulations have alsobecome available (like Glyciphage SR, Metaday, etc).

MECHANISM OF ACTION OF METFORMIN

Despite decades of clinical use, the molecularmechanisms by which metformin acts still have not beendefinitively determined and many more mechanisms willbe elucidated. Unlike secretagogues, metformin has noeffect on plasma insulin concentration increase, and dueto reduction in glucotoxicity it has an indirect effect onbeta cell secretory function (marginal, secondary effect).When administered to non-diabetic subjects, metformindoes not induce hypoglycaemia, even in considerabledoses.7,17 In contrast to phenformin, metformin alsoappears to have little or no effect on gastrointestinalglucose absorption.18-20

Hepato-Selective Effect : The principalglucoregulatory actions of metformin occur primarily atthe liver to reduce glucose output and secondarily at theperipheral tissues (muscle, adipose tissue) to augmentglucose uptake. Metformin has shown a reduction in fasting hepatic glucose by inhibiting gluconeogenesis.A variety of possible mechanisms has been nowdemonstrated, including phosphorylation of the insulinreceptor and insulin receptor substrate-2, inhibition ofkey enzymes in the gluconeogenic pathway (e.g.phosphoenolpyruvate carboxykinase, fructose-1,6-bisphosphatase and glucose-6-phosphatase) andactivation of pyruvate kinase.21–24 Reduction in hepaticuptake of gluconeogenic substrates (lactate and alanine),possibly by depolarization of the hepatocyte membrane,has also been postulated.25-27 Studies have alsodemonstrated inhibition of mitochondrial respiration bymetformin, which may reduce the energy supply requiredto execute gluconeogenesis.28,29

Muscle Effect : Metformin augments peripheralinsulin-mediated glucose uptake, chiefly into muscle.Metformin therapy may restore the activity of enzymesystems involved in the intracellular insulin-signallingcascade.30 Enhanced muscle uptake of insulin,31increased insulin receptor tyrosine kinase activity,32 aswell as increased glucose transporter-4 translocation andtransport activity10,25,33 may account for improvedperipheral glucose utilization in response to metformin.As expected, augmented glucose uptake is achieved byan increase in glucose transport across the cellmembrane, although the precise cellular action ofmetformin remains to be elucidated.34,35

AMPK Activator : Recently, metformin it has beenobserved stimulates adenosine monophosphate-activated protein kinase (AMPK) AMPK inhibits hepaticglucose production, stimulates muscle glucose uptakeand suppresses lipogenesis, making it potentially anideal mediator of metformin’s action.36,37 A recent report,however, demonstrated AMPK activation by Glitazoneas well as by metformin, raising the possibility thatAMPK activation is a non-specific consequence ofinsulin sensitization.38

Other Effects : In addition to its actions on glucosemetabolism, several other metabolic effects have beenascribed to metformin (Table 1), of which a number arebeneficial to the cardiovascular risk profile.

Weight : Best documented and least controversial ofthese is its effect on body weight.11,39–41 Most studies havereported either modest weight reduction in patientstaking metformin,11 protocol II,39–43 or stability of weight,11protocol I,12 in contrast to the weight gain often observedin patients taking sulfonylurea, thiazolidinedione (TZD)or insulin therapy.12,43,44 However in absence of insulinresistance or diabetes it cannot be used as an weightloss agent. Its anorectic property also contributes toweight loss.

Lipids : Several studies have reported a beneficial effecton lipid parameters, including a lowering of totalcholesterol,11,40,45-47 low-density lipoprotein (LDL)-cholesterol11,48 and triglycerides.11,45,47,49 An increase inplasma high-density lipoprotein (HDL) concentrations has also been reported,45,47,50 although others have foundno alteration in this fraction.11,48,51 The observed increasein HDL-cholesterol may be predominantly related to anincrease in the HDL-2 subfraction.52 A few reports havealso found no alteration in any lipid parameter withmetformin therapy.12,15,53,54

Blood Pressure : A number of reports havedocumented a reduction in blood pressure duringtherapy with metformin, either in systolic55 or diastolicpressure alone,39 or in both phases.43,47,49,56 It has beensuggested that lowering of blood pressure may beconsequent upon the attendant weight reductionassociated with administration of metformin; however,significant reductions in blood pressure have beenobserved in studies where no change of weight wasreported to occur.47,56 Overall, metformin has no effect orpossibly (in isolated studies cited above) a small effecton blood pressure. However, a lack of effect of metforminon blood pressure has been reported with equalfrequency.11,12,15,54,57

Endothelial Function : Additional possibly beneficialeffects of metformin include improvement inendothelium-dependent vasodilation,58 a reduction infibrinogen levels47 and increased activity of thefibrinolytic system,59 as well as diminished plateletaggregation60 and plasminogen activator inhibitor-1activity.57 Reductions in both fasting and postprandialinsulin concentrations have been reported.47,61 Metformintherapy is also associated with reduced levels of C-reactive protein.54,62 All of the above factors may havecontributed to the fact that metformin use in obesesubjects with type 2 DM in the UK Prospective DiabetesStudy (UKPDS) study was associated with a reductionin stroke, all-cause mortality and total DM endpointscompared to insulin or sulfonylurea, despite a similardegree of improvement in glycaemia.63 In the DiabetesPrevention Program (DPP), the use of metformin (850 mg twice daily) in subjects with impaired glucosetolerance reduced the incidence of type 2 DM by 31%(from 11% per year to 7.8% per year); this protection wasmost effective in younger, more obese subjects. Subjectsover 60 years of age or with body mass index less than30 kg/m2 did not benefit from metformin.64

Heart Failure : Recently in the a new study suggeststhat the diabetes drug metformin, may improve survivaland clinical outcome in diabetic patients with heartfailure, even though US FDA labeling recommendsagainst using the drug in these patients. “Stable heartfailure and diabetes I think can be safely treated withmetformin,” Said Johnson et al of the University of Albertain Edmonton & his team in the October 2005 issue ofDiabetes Care.65 Warnings against using metformin arebased on past experience with phenformin — a similardrug that was taken off the market in the 1970s afterbeing linked to hundreds of cases of lactic acidosis, apotentially life-threatening build-up of lactic acid in theblood that can damage vital organs. However, there is ascarcity of information metformin to this side effect, andrecent studies suggest metformin may actually be moreeffective than so-called sulfonylurea drugs in reducingdeath from cardiac causes. According to Johnson et al,as many as 10 to 15 percent of diabetic patients withheart failure are prescribed metformin despite thelabeling, largely due to the scarcity of other treatmentoptions. To investigate whether contraindications arewarranted, the researchers identified 12,272 new usersof oral antidiabetic drugs, 1833 of whom developed heartfailure, and classified them based on the type of drugthey were taking. Compared to treatment with asulfonylurea, treatment with metformin was associatedwith reduced hospitalization and death among patientswith heart failure, the team reports in the October issueof Diabetes Care. One third of patients on metformindied, compared with 52 percent of patients onsulfonylureas only. Seventy-seven percent of patients onmetformin died or were hospitalized, compared with 85percent of patients on sulfonylurea alone. Given thatthis is a comparative study, Johnson notes, it’s notpossible to say whether metformin improved outcomesor sulfonylureas worsened them.

Pregnancy : Metformin has recently used to treatpregnant women with type 2 diabetes or gestationaldiabetes, although several studies suggest this issafe.66–69 One small study suggested that metformin usein pregnancy increased rates of preeclampsia andperinatal mortality;70 however, because metformin waspreferentially used in obese women, among whom ratesof preeclampsia and perinatal mortality are known tobe higher,73 the results are most likely related tocharacteristics of the treated women, rather thanmetformin itself.

PCOS/NASH : Recently, beneficial effects ofmetformin on reducing androgen levels and restoring ovulation in women with polycystic ovary syndrome(PCOS) have been published.55,72,73 In addition,preliminary studies of metformin use during pregnancyin PCOS have shown normalization of the often highrates of gestational DM and first trimester fetal loss inthese women.74–76 Given the importance of insulinresistance as a predictor of diabetes, hypertension andcoronary artery disease, metformin is increasinglyprescribed to insulin-resistant women with PCOS.77Studies on NASH are ongoing.

ADVERSE EFFECTS OF CONVENTIONALMETFORMIN THERAPY

These are summarized in Table 2. The most widelypublicized adverse effect of biguanide therapy is lacticacidosis.4–6 This is due to stimulatory action ofbiguanides on non-oxidative glucose metabolism, whichresults in accelerated conversion of pyruvate to bothlactate and acetyl CoA.78 In settings of increased lactateproduction or reduced lactate clearance, like hepatic orrenal dysfunction (including acute renal failure relatedto administration of radiocontrast dye) or other illnesscausing tissue hypoxia, especially cardiac or respiratorydysfunction, this action of the biguanides may provokelactic acidosis, which has a high mortality.79 However,the incidence of lactic acidosis is clearly much greaterwith phenformin than with metformin, being about 10–15 times higher,4,80–83 and metformin causes little or norise in plasma lactate levels.11,12,15,40 In addition, data onthe incidence of lactic acidosis in diabetic patients notreceiving biguanide therapy are lacking. The overallincidence of lactic acidosis with metformin has beenestimated at one case per 30 000 patient-years.84 MALAStudy: The MALA (Metformin Associated LacticAcidosis) study showed that except elderly and withrenal insufficiency (creatinine above >3mg%) it was safe.

The most frequently encountered adverse effects ofmetformin therapy are gastrointestinal namely,abdominal discomfort, anorexia or diarrhoea initiallyaffects about one-fifth of patients (468 to 50%31).7Fortunately, these effects are minimized whenadministered with meals and with gradual dosagetitration,15 and generally necessitate discontinuation ofthe drug in less than 5% of patients.15,47,56,79,82Hypoglycaemia is very uncommon with metforminmonotherapy11,47 but has been reported in combinationregimens,12,53,61 presumably as a function of potentiation by metformin of the other therapeutic agent or agents.

Drug Interaction : Clinically significant druginteractions involving metformin are rare. The a-glucosidase inhibitor acarbose has been reported to causea significant reduction in bioavailability and peakplasma levels of metformin when co-administered;89however, this did not prevent improvement in HbA1c by0.65% when acarbose was added to the treatment ofpatients inadequately controlled on diet plusmetformin.90 Cimetidine reduces renal clearance ofmetformin.91

Contraindications

Contraindications are shown in table 3.

*Creatinine >135 mmol/l in men or >110 mmol/l in women;verify normal renal function by calculating creatinine clearancein older patients.

METFORMIN: THE NEED FOR SUSTAINEDRELEASE (XL) FORMULATIONS
Metformin is usually marketed in the form of itshydrochloride salt. Metformin hydrochloride hasintrinsically poor permeability in the lower portion ofthe gastrointestinal tract leading to absorption almostexclusively in the upper part of the gastrointestinal tract.Its oral bioavailability is in the range of 40 to 60%decreasing with increasing dosage, which suggests somekind of saturable absorption process, or permeability/transit time limited absorption. It also has a very highwater solubility (>300 mg/ml at 25° C). This can lead todifficulty in providing a slow release rate from aformulation and problems in controlling the initial burstof drug from such a formulation. These two difficultiesare further compounded by the high unit dose, 500 mgper tablet, usually required for metformin hydrochloride.Drugs that have absorption limited to the uppergastrointestinal tract coupled with poor absorption inthe distal small intestine, large intestine and colon areusually regarded as inappropriate candidates forformulation into oral controlled delivery systems. Thislimitation on absorption (for example, in the uppergastrointestinal tract) is referred to as the “absorptionwindow”.

The gastrointestinal tract functions to propel ingestedmaterial from the stomach (where digestion takes place) into the small intestine (where absorption principallyoccurs) and on to the large intestine (where water isabsorbed/secreted as part of body fluid regulationprocesses). Residence time for non-digestible materialsin the stomach depends on whether one is dealing witha fed or a fasted subject. Typical gastric emptying timesfor particulate material (greater than a few millimetersin diameter) varies from a few tens of minutes in thefasted state to a few hours in the fed state. Transit timesthrough the small intestine are consistently of the orderof 3 to 4 hours.

Oral controlled release delivery systems function byreleasing their payload of drug over an extended periodof time following administration. Thus, controlled releasedosage forms may only spend a relatively short periodin the regions of the gastrointestinal tract where goodabsorption of certain drugs can occur. The dosage formwill pass on to regions of the intestine where absorptionof certain drugs is poor or non-existent, still releasing itscontained drug albeit with a significant percentage ofits payload still to be delivered. Drug when released fromthe dosage form in the circumstances described will notbe absorbed. Thus, administration of a drug subject to awindow of absorption in a conventional controlledrelease delivery system can lead to subtherapeutic bloodlevels and ineffective treatment of the disease state forwhich the drug was intended.

Drugs with very high solubility in water (for example,greater than 100 mg/ml) can be difficult to formulateinto a controlled release oral dosage form. Solubility is adriving force for a drug substance to dissolve in water;the greater the solubility the greater the rate of dissolutionwhen all other factors are maintained constant.

n a controlled release dosage form, the formulatortries to reduce the rate of dissolution by, for example,embedding the drug in a polymeric matrix orsurrounding it with a polymeric barrier membranethrough which drug must diffuse to be released forabsorption. To reduce the rate of release of drug from thedosage form to an appropriate level consistent with theblood level profile desired for a drug possessing veryhigh water solubility, very large amounts of polymerwould be required for the matrix or barrier membrane. Ifthe total daily dose of drug to be delivered is of the orderof only a few milligrams this may be feasible, but manydrugs having the solubility properties described requiretotal daily doses of the order of many hundreds ofmilligrams. Whilst it is possible to create oral controlledrelease dosage forms for such products by use of largeamounts of polymer, an unacceptably large dosage formmay result.

A further problem with highly water soluble drugsformulated into a controlled release dosage form is thata significant and variable “burst” of drug can occur fromthese systems. The burst of highly water soluble drug isthe initial rapid release of drug that occurs from oral controlled release dosage forms when first contactingfluid, such as gastric fluids, prior to release controllingmechanisms of the dosage form establishing themselvesand a stable release rate being provided. Hydration ofany polymer matrix used to formulate the dosage formis a pre-requirement of establishing a stable release rate.Thus, a readily hydrating polymer is required toestablish the desired stable release rate. However, if thepolymer used is slow to hydrate, then an undesirablevariable burst can occur.

Studies by Vidon strongly suggest that there ispermeability limited absorption of metformin. Drug willtransit down the small intestine following dissolutionfrom an ingested dosage form and, if absorption rate isslow, it is possible that drug can reach regions of poorpermeability before absorption of a given dose iscomplete. In such a case, increasing the given dose maybe predicted to result in a reduction in the percentage ofadministered dose absorbed.

Conventional extended release formulations havebeen demonstrated to invariably compromise theavailability of metformin. This is probably because thedosage form carries a significant proportion of the drugcontent remaining to be released, as the dosage form iscarried to regions of the gastrointestinal tract with verypoor permeability to the drug. To reduce dosing frequency,the rate of release from the dosage form must be such asto extend effective plasma levels, but the potential foreffective delivery at this rate is compromised by thecombined influences of the significant reduction inpermeability to the drug in passing from the proximalsmall intestine down to the colon and the limitedresidence time in the regions of the gastrointestinal tractwhere the drug is well absorbed. That transit time downthe “useful” region of the gastrointestinal tract is onlylikely to be of the order of a few hours.

Maintained or even improved bioavailability from anextended release dosage form that releases metformin ata rate likely to provide the desired plasma levels of drugfor an extended time period might, however, be possiblefrom a dosage form that has extended residence time inthe upper gastrointestinal tract, resisting mechanismsthat promote normal transit time for solid materials. Thatthis principle might work in practice was demonstratedin an in-house study where metformin was co-administered with propantheline, an agent that reducesgastrointestinal motility. Compared with givingmetformin alone, the combination provided an increasedAUC, a delayed tmax and an extended time period overwhich therapeutically beneficial plasma levels of drugwere maintained.

Giving a drug such as metformin for the treatment ofdiabetes with a further drug, such as propantheline, notused for the treatment of diabetes and where the soleintent of using the second agent is to achieve extendedresidence time in the upper GI tract, has many disadvantages although it is likely to allow effectiveextended delivery of metformin to an optimal absorptionsite. The co-administered drug may have otherundesirable pharmacological effects or side effectsdeleterious to the patients well being and detract fromthe improved quality of life offered by the treatment fortheir diabetes. Furthermore, it may be difficult orimpossible to appropriately co-formulate the two agentsdue to chemical compatibility issues or solubilitydifferences, the latter preventing the required release rateof agent influencing residence time in the upper GI tract.Thus, the patient could be required to take separate,multiple medications to achieve the desired effect. Thetiming of taking the two medications would be criticalto effective delivery of the drug with the limited windowof absorption and many patients may thus fail to taketheir medication correctly resulting in ineffectivetreatment of their diabetes.

It would be desirable to provide a dosage form thatinherently has the property of extended gastric residence,possessing some resistance to the pattern of waves ofmotility present in the gastrointestinal tract that serve topropel material through it. There have been manyattempts to provide for this, with varying degrees ofsuccess.

Technologies employed in formulation of controlledrelease metformin XL none tablets are Wax Matrix,Monolithic devices Gastro retentive Systems: SwellableMatrix devices (soluble & insoluble), and GITS –LaserBased Technology. The wax matrix system has waxgranules and beads with coating with hot melt, hardgelatin capsules filled with waxes and change in drugproperty like polymorphism/recrystalization. Thechannelizing agents concentration is critical for properrelease pH may alter the release pattern of drug. Ghostmatrix which passes through feaces. These are notrecommended for tropical countries like India thoughfew Indian preparation exist like Glycomet SR wherethe wax melt can get erratic. The monolithic devices aremonolithic systems viz. the bio active agent isincorporated in the polymer phase either in dissolvedor in dispersed form. Release is achieved by simplediffusion through the polymer. This is the most commonof the devices for controlling the release of drugs, theyare relatively easy to fabricate, and there is no danger ofan accidental high dosage that caused result from therupture of the membrane of a reservoir device. Thegastroretentives (GRT, GRDF) are based on gastricemptying is naturally phenomenon and can be modifiedfor the sake of drug delivery. The retention in gastricmedium can be achieved by modifying drug deliverysystems. These are swellable matrix tablets activated bywater and drug release control depending on theinteractions between water, polymer and drug. Thepresence of water decreases the glassy-rubberytemperature (glass transition temperature) giving rise tothe transformation of glassy polymer in gel phase. These are mucoadhesive involving alginic acid, sodium CMC,sodium alginate, polycarbophil, polyacrylic acids andneed adequate quantity of media required to float thetablets like metaday. These can be packaged as verysmall size pills. The SR technology is an hydrophilicmatrix systems like HPMC based which is GRASexcipient in USA a swellable and erodable matrix andpH independent.

The different drug delivery systems are:

(1) Floating or buoyant systems

These are designed to have a low density and thusshould float on gastric contents after administrationuntil the system either disintegrates or the device absorbsfluid to the point where its density is such that it losesbuoyancy and can pass more easily from the stomachwith a wave of motility responsible for gastric emptying.

(2) Bioadhesive systems

These are designed to imbibe fluid followingadministration such that the outer layer becomes aviscous, tacky material that adheres to the gastricmucosa/mucus layer.

(3) Swelling and expanding systems

These are designed to be sufficiently small onadministration so as not to make ingestion of the dosageform difficult (for example, less than approximately 23mm long and less than 11 mm wide for an oval orcapsule-shaped tablet). On ingestion they rapidly swellor unfold to a size that precludes passage through thepylorus until after drug release has progressed to arequired degree.

The distinct advantages of Metformin XL are itreduces the number of daily doses and increases patientcompliance. Metformin XL, being a modified releasepreparation can also avoid “dose-loading”. Thiscommonly occurs with conventional oral formulationswhen large doses are given which may cause suddenrelease and absorption of a large amount of drug.Metformin XL is released in smaller doses in upper partof the small intestine, and hence ensures increasedbioavailability and decreased side effects. In contrast,conventional Metformin has lesser bioavailability sinceits absorption decreases as it passes through the lowerpart of small intestine. Conventional Metformin has anoral bioavailability of 40 to 60 % and gastrointestinalabsorption is apparently complete within 6 hours ofingestion. Plasma t ½ is 2 to 6 hours. Hence it has to begiven 2 to 3 times a day, whereas Metformin XL being acontrolled release “gastro-retentive” formulation, isreleased in small quantities in upper part of smallintestine where the drug is better absorbed and has aprolonged duration of action (24 hours). Metformin XL-the absorption is more dependable and complete as thedrug is released gradually mainly in the upper part ofsmall intestine, whereas in Metformin plain theabsorption is erratic as Metformin is also absorbed in the latter part of small intestine where absorption iserratic and “non-dependable”. Since Metformin XL isreleased slowly, side effects like flatulence, abdominaldiscomfort, diarrhoea and lactic acidosis are less unlikeplain Metformin. An inverse relationship was observedbetween the dose ingested and relative absorption withtherapeutic doses ranging from 0.5 to 1.5 gms suggestingthe involvement of an active, saturable absorptionprocess. Thus an extended release formulation ofMetformin can not only optimizes the daily requirementof Metformin, but can also reduce the need of a higherdose. The bioequivalence study as per US FDA arerequired to be compared with Glucophage and Metaday(Fig. 1) while the plain and ‘XL’ comparisons are madein Fig. 2 and Fig. 3.

Metformin XL is a modified release gastro-retentiveformulation. By virtue of its gastro-retentive property itreleases Metformin gradually in small amounts, whichis well absorbed in the upper part of the small intestineand duodenum. Metformin incorporated into the gastro-retentive formulation is released slowly over a prolongedperiod of 24 hours; hence given once a day. Other thenrelease technology which improves availability of activedrug, what is important is also size of the tablet.Currently there are some brands that are large in sizemaking it difficult for the patient to swallow while thenewer ones like MetadayTM, the size of the tablet is verysmall making it the more patient friendly.

METFORMIN MONOTHERAPY IN CLINICALPRACTICE: WHEN TO START?

In head-to-head clinical trials, metformin and TZD

Fig 1 : Bioequivalence of metformin hydrochloride Xl 500 mg tabletswith International Formulations.(Courtesy: Dr. R. Jha with permission).

Fig. 2 : Bioequivalence of plain and metformin XL.(Adapted from Joshi SR. Type 2 Diabetes Management Fixed DoseCombination – The Indian Consensus. Ind J Clin Pharm & Therap2002; 19(4):33-65 with permission).

Fig. 3 Bioequivalence of plain and metformin XL.(Adapted from Joshi SR. Type 2 Diabetes Management Fixed DoseCombination – The Indian Consensus. Ind J Clin Pharm & Therap2002; 19(4):33-65 with permission).

monotherapy as oral agent naive subjects achievedcomparable benefits in glycaemic control and hepaticglucose uptake, both improved indices of peripheralinsulin sensitivity, consistent with their differingmechanism of action.42,43,92 But in these trials, metforminuse was associated with weight loss while the TZDswere associated with mild weight gain42,43 or stableweight.92 Another factor to consider in choosing a TZDvs. metformin is the need to regularly monitor liver-function tests. The majority of patients with type 2 DMare >190% of ideal body weight and exhibit a fastingglucose less than 250 mg% (14 mmol/l) when drugtherapy is initiated, and metformin is currently the drugof choice for this group, for considerations of efficacy,cost, frequency of monitoring for adverse effects, andassociated beneficial metabolic actions; if notcontraindicated. If a patient is to receive radiocontrastdye, metformin should be discontinued prior to theprocedure and not restarted until laboratory evidence ofnormal renal function is obtained 48 h late, often N-acetyl cysteine may co-administered.

It is important to initiate metformin therapy slowly,as this may markedly improve patient acceptability andminimize gastrointestinal side effects.14,15 A dose–response study showed that 2000 mg daily is the mosteffective dose of metformin (HbA1c lowered 2% comparedto placebo), best given as 1000 mg with breakfast and dinner to facilitate compliance with therapy.95 Thecurrent XL formulations of 500 mg, 1000 mg haveobviated this need with better bioequivalence.

For this reason, sulfonylureas be administered withmetformin when immediate high-dose oral agent therapyis required in symptomatic patients with markedhyperglycaemia. Additionally, in this setting, avoidanceof sulfonylurea-induced hypoglycaemia is a lessimmediate concern, and the short-term potential formetabolic decompensation to hyperosmolar non-ketoticsyndrome is greater.

PLACE OF METFORMIN IN COMBINATIONTHERAPY

With Sulfonylurea (SU): Hitherto, when employedas part of a combined therapeutic regimen, metforminhas been most frequently used in combination withsulfonylureas.14,11,12,49,97 In patients already on maximalsulfonylurea dosage in whom glycaemic control remainsunsatisfactory, metformin therapy can be initiated in thesame manner as for monotherapy. Dosage titrationshould be gradual, because the tendency ofsulfonylureas to cause hypoglycaemia may re-emergewhen metformin is added.11,12 Combination of metforminwith sulfonylureas does not generally result in weightgain,53,77,97 Conversely, sulfonylureas may be added whenglycaemic control is suboptimal with metformin alone.Most patients remain on maximal dosage of sulfonylureawhen metformin is added,16,49,98,99 or vice versa. The idealtime is to add is when 50 mg% of the pharmacologicaldoes not combined metformin and repaglinide therapyhas been shown to produce superior glycaemic controlto monotherapy with metformin or repaglinide insubjects with poorly controlled type 2 DM (1.4% HbA1cvs. no significant change on monotherapy).100 An open-label, randomized, multicentre trial found significantlygreater reductions in HbA1c and fasting glucose withrepaglinide plus metformin (1.28% and 2.2 mmol/l) thanwith nateglinide plus metformin (0.67% and 1.2 mmol/l).101 Combination therapy may allow a number ofpatients to avoid the need to switch from oral agent toinsulin therapy.

With TZD : Because metformin’s insulin-sensitizingeffect occurs mainly at the liver, combination with TZDs,which mainly sensitize muscle to insulin-mediatedglucose uptake, is a rational therapeutic strategy. The first study to address this showed that metformin andthe TZD troglitazone had an additive effect on glycaemiccontrol in subjects with type 2 DM;102 however,troglitazone is no longer available. More recently,patients poorly controlled on metformin monotherapywere randomized to metformin plus placebo or metforminplus pioglitazone 30 mg daily; patients in the latter groupattained greater reduction in fasting plasma glucose 40mg% (2.1 mmol/l) and HbA1c levels (0.83%), as well asgreater improvements in triglycerides (18.2%) and HDL-cholesterol (8.7%).103 Several randomized, placebo-controlled, double-blind trials of the addition of glitazoneto the regimen of patients poorly controlled on metforminmonotherapy consistently demonstrated improvedglycaemic control on the combination therapy (0.7–1.2%reduction in HbA1c), as well as improvements in insulinsensitivity and beta-cell function.50,104,105 Thus, combinedmetformin and TZD therapy is a safe and efficaciousmethod of improving glycaemic control, withouthyperinsulinaemia or significant hypoglycaemia. Asmonotherapy metformin is associated with weight lossand TZDs with weight gain, in combination, no changeor slight weight gain (3 kg) was observed in clinical trials.Nevertheless, some experts favour a combination ofinsulin sensitizer plus insulin secretagogue to addressboth the fundamental metabolic defects present in type2 DM.106

first study to address this showed that metformin andthe TZD troglitazone had an additive effect on glycaemiccontrol in subjects with type 2 DM;102 however,troglitazone is no longer available. More recently,patients poorly controlled on metformin monotherapywere randomized to metformin plus placebo or metforminplus pioglitazone 30 mg daily; patients in the latter groupattained greater reduction in fasting plasma glucose 40mg% (2.1 mmol/l) and HbA1c levels (0.83%), as well asgreater improvements in triglycerides (18.2%) and HDL-cholesterol (8.7%).103 Several randomized, placebo-controlled, double-blind trials of the addition of glitazoneto the regimen of patients poorly controlled on metforminmonotherapy consistently demonstrated improvedglycaemic control on the combination therapy (0.7–1.2%reduction in HbA1c), as well as improvements in insulinsensitivity and beta-cell function.50,104,105 Thus, combinedmetformin and TZD therapy is a safe and efficaciousmethod of improving glycaemic control, withouthyperinsulinaemia or significant hypoglycaemia. Asmonotherapy metformin is associated with weight lossand TZDs with weight gain, in combination, no changeor slight weight gain (3 kg) was observed in clinical trials.Nevertheless, some experts favour a combination ofinsulin sensitizer plus insulin secretagogue to addressboth the fundamental metabolic defects present in type2 DM.106

Since last decade, preparations of metformin in fixed-dose combination with glibenclamide, glicazide,glimepiride, pioglitazone and rosiglitazone havebecome available in the India. While compliance may beexpected to be greater with a combination preparation,flexibility of dosing the individual components isnecessarily limited. Metformin can be used incombination with insulin, in which case, metformin hasan ‘insulin-sparing’ effect, permitting about a 15–25%reduction in total daily insulin dosage.56,107,108 Thisproperty is of particular usefulness in patients on largedoses of insulin, whose insulin dosage may otherwiseexceed the capacity of a single syringe, necessitating asecond injection at a given time. There is experimentalevidence to suggest that such a reduction in insulindosage may attenuate possible atherogenic effects of highcirculating insulin concentrations.109

The question of which insulin sensitizer (metforminor TZD) to add to patients failing sulfonylurea therapyhas been addressed in many clinical trials. One trialrandomized patients failing sulfonylurea therapy to 4mg rosiglitazone or 1 g metformin and found comparableHbA1c lowering of approximately 1%.110 Two trials havecompared addition of pioglitazone to addition ofmetformin in subjects failing sulfonylurea therapy andalso found comparable effects on HbA1c (1.20 to1.36%).111,112 The longer trial (1 year) demonstratedimprovements in triglycerides, HDL-cholesterol andurinary albumin-to-creatinine ratio with pioglitazone and decreased LDL-cholesterol with metformin.111 Moresuch studies, using currently available TZDs, are neededto address which class of insulin sensitizer, if any, ispreferable in combination therapy with sulfonylureas.In terms of addition to patients failing insulin therapy,in one study, troglitazone addition resulted in betterglycaemic control and lower triglyceride levels whilemetformin addition resulted in less weight gain (0.5 vs.4.4 kg) and less hypoglycaemia.113 This emphasizes theneed to individualize therapy according to each patient’sneeds.

CONCLUSIONS

Metformin has been a ideal therapeutic optionavailable for the patient with type 2 DM. In monotherapy,metformin will often achieve a significant reduction inglycaemia, with ancillary benefits of weight reductionand improvement in the lipid profile, and possiblysecondary markers of atherogenesis and endothelialfunction; without hypoglycaemia. In combinationtherapy, it has an important place in obviating the needfor insulin therapy in patients inadequately controlledon insulin secretagogues or TZDs alone and, in selectedpatients, may be used in combination with insulin forits ‘insulin-sparing’ properties. When usedappropriately and with gradual upward adjustment ofdosage, adverse effects of metformin are rarelytroublesome, nor are they dangerous. Patient compliancewith metformin has increased with the availability oflong acting preparations. Moreover GI side effectsassociated with regular metformin therapy is alsoreduced significantly with metformin long actingpreparations. Small size and improved releasetechnology has evolved the therapy of metformin. Thus,despite the appearance of several new oral agents inrecent years, metformin still is used as a therapeuticagent of first choice for monotherapy of the typicaloverweight patient with type 2 DM and low risk ofmetabolic acidosis who exhibits mild to moderatehyperglycemia, and as adjunctive therapy for patientspoorly controlled on sulfonylureas or TZDs. Newersustained release formulation like ‘XL’ technology haveobviated the need for GE side effects and betterbioequivalence. With the current sustained release (XL)formulation of metformin, metformin therapy has nowupgraded itself from the Gold Standard to Platinum.These unique XL bioequivalent metformin preparationswill become the platinum standards in modern diabetesmanagement.

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