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Home , Biguanide, Buformin, Metformin

Glucophage® ( Hydrochloride), the Wonder Drug: A Class Treatment of Type 2

Gabrielle Wentling

Faculty Sponsor: Dr. Eun Hoo Kim eartment of hemistr an Phsial iene

Abstract

iabetes is a isease that has been aroun for a er long time—from as far bak as the anient gtians. he isease oes not hae ust one straightforar etiolog, sine there are seeral ifferent tes of iabetes. e iabetes affets at least erent of the nite tates oulation, an one of the most reommene rugs in treating te iabetes is metformin. nthesie from a naturall ourring floer that ha been use in the ast to treat the smtoms of iabetes, metformin has man ositie effets, inluing loere hemoglobin leels b, eight reution, an a loere risk of heart attak. Metformin an also be use in treating other onitions, suh as olsti oarian snrome an aner. urrent researh is even exploring metformin’s ability to counteract aging. he eat mehanism of metformin is still being researched, but it is believed that the center of metformin’s action is an alteration of the energ metabolism of the ell.

Introduction

Metformin is a member of the biguanie lass of rugs an is use in treating a number of iseases an onitions, of hih te iabetes is most realent. e iabetes is haraterie b abnormall high leels of gluose in the bloo ue to either resistane of the ells or too muh gluose roution in the lier or a ombination of both. Metformin’s is related to increasing the activity of energy sensor aenosinemonohoshateatiate rotein kinases, hih inreases gluose utake in arious tissues, inreases lii metabolism, an ereases gluose roution in the lier.,, hus metformin loers bloo gluose onentrations but also inreasingl seems to roue a host of other benefiial effets in both iabetis an noniabetis.

112 History and Epidemiology

iabetes is an old disease, and can be found recorded as far bac as by gyptian physicians. ntil the s, hen anting and est discovered ho to extract and purify insulin, there as no efficacious treatment for diabetes. he different manifestations of diabetes include type diabetes mellitus , type diabetes , mellitus, maturityonset diabetes of the young, endocrinopathies, and diseases of the such as pancreatic or . hey all have differences in underlying pathogenesis, but the unifying theme is that hen untreated they all result in chronic . rom to , the rate of diabetes increased from . to . in men, and from . to . in omen, to affect a total of million people around the orld., n the nited tates, affects . million people or . of the total population, according to the enters for isease ontrol and revention. actors contributing to this rising epidemic include aging, population groth, increasing urbaniation, increasing incidence of obesity, and more inactive lifestyles., oever, is only one classification of the many maladies that fall under the umbrella of diabetes. accounts for approximately of all diabetic cases and is a condition in hich the blood is hyperglycemic. atients ith do not need insulin to survive but may present ith varying severity of pathophysiologies ranging from predominantly insulin resistant ith relative insulin deficiency to predominantly insulin secretory defect ith some . etter and fello researchers described as “characteried by three pathophysiologic abnormalities relative insulin deficiency, insulin resistance involving myocytes and adipocytes, and hepatic insulin resistance” which result in increased and impaired glycogen synthesis. he ris of developing this form of diabetes increases ith old age, obesity, and inactivity. t has ties ith different ethnic groups and is also presumed to have a stronger association to genetics than the autoimmune form of diabetes, . ntreated chronic hyperglycemia that results from can result in severely detrimental side effects. hese include nephropathy, neuropathy, retinopathy, and macrovascular complications. f all deaths in patients ith , involve or stroe, reflecting the macrovascular complications of the disease. ardiovascular abnormalities can be a result of other factors, including obesity, abnormalities, hypertension, hypercoagulation, platelet dysfunction, and endothelial dysfunction. europathy can potentially result in limb amputation retinopathy can lead to blindness and nephropathy leads to endstage renal disease and the need for renal dialysis or transplants. elaying or preventing these complications are primary goals in treating diabetes. n arold imsorth differentiated beteen insulinsensitive and insulin resistant types of diabetes. his discovery opened the door for the array of or insulinresistant diabetic treatments. rugs currently on the maret for treating include, but are not limited to, , thiaolidinediones, , incretin mimetics, peroxisome proliferatoractivated receptor gamma , and α glucosidase inhibitors. he oldest of these drugs are the sulfonylureas, hich ere the primary treatment for before metformin. he merican iabetesƔ ssociation

113 recommends treating a patient with y starting with liestyle modiications such as diet and eercise lthough these modiications are important, they are rarely completely eicacious in treating hyperglycemia is a progressively degenerative disease that worsens with age and involves progressive etacell unctional decline t is important to reassess patients every ew months, whatever s they may e on

Sulfonylureas ulonylureas were the primary treatment or eore metormin and now are sometimes used in comination with metormin arutamide was a irstgeneration memer o the sulonylurea amily and was discovered in to e eective in treating hyperglycemia owever, carutamide had adverse eects on one marrow and so was withdrawn rom the maret n the s, later generations o sulonylureas were shown to e no more eective in treating than diet and eercise, and thus were recommended as a irst line o treatment in newly diagnosed patients econd generation sulonylureas with no adverse eects on the heart or one are now on the maret and possess eective mechanisms o lowering lood glucose concentrations ulonylureas wor as channel locers and result in an increase o insulin secreted from the pancreatic β cells into the plasma, regardless of the concentration of lood glucose In addition to their effects on pancreatic β cells, sulfonylureas increase receptors or insulin on monocytes, adipocytes, and erythrocytes when the patient receives chronic treatment epending on the generation, sulonylureas are usually taen once a day with increasing dosages as needed and have an active duration o rom hours he maor limitation o sulonylureas, especially with the longeracting agents such as glyuride and , is their high ris or ecause they increase insulin secretion regardless o how much insulin is already in the lood

Metformin etormin is in the class o iguanides and is currently a irstline treatment or ,,, t is not insulin ut is considered an insulin sensitier, t is in the iguanide amily, isolated rom the lower , commonly known as goat’s rue, and was used to treat diaetes in the medieval period ecause it relieved the intense urination n was ound to e the active ingredient in Galega officinalis that lowered lood glucose levels henormin and uormin were synthesied as part o the iguanide class in the s, ut were withdrawn in the s ecause o increased incidences o death due to and cardiac dysunctions resulting rom use o phenormin in treating those with , etormin was part o the net generation o iguanides, and in , ater years on the maret in the nited ingdom , it was approved or use in the nited tates ecause it did not have the same toic eects as phenormin, he guanidine structure o metormin is a nitrogenous analog o caronic acid, and includes two methyl groups, whereas phenormin and uormin have apparently toic aromatic rings or alyl chains n igure , the dierences etween phenormin and metormin can e oserved

114 etormin has a greater association with reductions in weight and lowdensity lipoprotein cholesterol, and a much lower ris o hypoglycemia when compared with sulonylureas and with thiaolidinediones, a newer option in treating ,

Figure 1. ierences in structure etween phenormin, metormin, and uormin etormin carries a low ris o hypoglycemia ecause its primary action is inhiition o gluconeogenesis, the ’s production of glucose rom noncarohydrates such as proteins or ats n contrast, the eect o most other drugs is to stimulate insulin secretion. Metformin’s eneicial eect on diaetes is dependent on there eing circulating insulin in the lood hus it cannot e a sustitute or insulin or the only treatment in insulindependent diaetes such as etormin is indicated in treating insulinresistant classes o diaetes, such as or gestational diaetes hen compared against placeo eect or insulin, metormin also decreases cardiovascular mortality rates, long with these eects, metormin provides protection against nephropathy, heart disease, and polycystic ovarian syndrome, and a signiicant reduction in cancer ris

Development of Metformin

he otanical Galega officinalis, as previously mentioned, was given to diaetic patients ecause it relieved the ecessive urination symptom he plant is also nown as rench lilac or talian itch, and was given to patients during plague epidemics to promote perspiration urther research showed that the active ingredient in rench lilac that resulted in lowering o lood glucose was galegine, or isoamylene guanidine etormin is a sustituted iguanide synthesied rom the guanidine active principle and is shown in igure a and igure Metformin’s oicial chemical name is , dimethylimidodicaronimidic diamide also called ,dimethyliguanide, and its ormula is

Figure 2a. olecular structure o metormin

115 Figure 2b. llndstic model of metformin.

Metformin s first descried in erner nd ell nd it inoled simple precipittion rection of dimetlmine drocloride nd cnogunidine oer et. is sntesis cn e seen in igure . More rections to produce metformin e een descried nd ptented. Metformin drocloride te slt ersion of te drug is sntesied i te rection of euimolr mounts of dimetlmine nd cnogunidine dissoled in it cooling to me concentrted solution it euimolr mounts of drogen cloride slol dded. e miture oils nd ten fter cooling metformin drocloride is ielded in precipitte it ield.

Figure 3. ntesis of metformin first performed erner nd ell.

n metformin s son to loer lood glucose concentrtions in rits nd s te most efficcious out of ll te igunides studied simultneousl ut tis discoer s oersdoed te retroug of etrcting nd purifing insulin round te sme time. Metformin s pproed for te prmceuticl mret in fter recognition of te cidosis ris of penformin noter memer of te igunide fmil. e dosge of metformin is usull pills per d t different sies of mg mg or mg ten it mels in order to reduce derse gstrointestinl side effects. e dosge is usull cnged en ten in comintion it oter drugs. Metformin cn e used concomitntl it oter drugs suc s glipiide gluride rosiglitone pioglitone repglinide sitgliptin nd insulin to crete eneficil glucose loering effects.

116 Testing and Clinical Trials

Organic Cation Transporter u nd collegues performed testing on eptic tissues in vitro nd in mice in vivo soing tt te orgnic ction trnsporter is importnt in metformin ctiit. e resercers determined tt in primr cultures of mouse eptoctes elimintion of Oct1 gene reduced te response to metformin. nd in vivo testing in mice soed tt s reuired for metformin to loer lood glucose leels. e lso osered in umns tt polmorpisms modulted cellulr nd clinicl responses to metformin nd concluded tt medites te first step in te response pt of metformin. us cnges in Oct1 epression or prelence m cnge te effectieness of metformin in umns.

Type 2 Diabetes rious clinicl trils e son tt metformin s mn more positie effects tn simpl loering c leels ic it s originll used to do. Metformin s lso een son to decrese colesterol leels reduce eigt nd preent det due to crdiosculr disese . Metformin’s glucoseloering cpilit is relted to its ilit to perform long list of functions. Metformin improes glucose metolism nd insulin ction ing positie effect on insulin receptor epression s ell s trosineinse ctiit. Metformin’s binding interactions result in increased denosine monopospte M ctited protein inse M ctiit ic increses denosine tripospte generting pts nd decreses te consuming pts. M nd re inoled in regulting certin iocemicl cellulr processes suc s lipid metolism memrne trnsport nd cell prolifertion. e inding interctions increse mitocondril iogenesis nd lipid oidtion s ell s insulin sensitiit. AMPK is activated by metformin’s binding to the respiratory chain comple. lMir ogueir nd ontine (2000) discovered “te tretment dimetligunide in vivo or in vitro in intct isolted eptoctes ffects te mitocondrial respiratory chain specifically at the complex I site,” and isolation of the oter protein complees in te respirtor cin did not proe effectie. e lso concluded testing in vitro eptoctes tt rectie ogen species scengers d no effect on metformin nor on its ction. esting lso soed tt metformin increses plsm leels of glucgonlie peptide ic elps it insulin signling. is secreted from te gut in response to ingestion of food. n people not suffering from dietes stimultes insulin secretion ile in ptients ctiit is not efficient or it is suppressed. olett nd ile ssert tt metformin s een son not onl to loer lood glucose concentrtions ut lso to positiel impct nd triglceride leels in te lood in ptients it . t cn produce to percent reduction in plsm triglceride leels in nonpertriglceridemic ptients nd up to percent triglceride reduction in pertriglceridemic ptients percent decrese in totl colesterol leels n increse of percent in igdensit lipoprotein leels nd percent decrese in lodensit lipoprotein leels.

117 Metformin is beneficial in reducing cholesterol not only in diabetic patients but nondiabetics as ell arlsen and colleagues () noticed a 2 percent decrease in lipid levels over a 2ee period and reported that “metformin, given for 2 ees as a supplement to lovastatin, diet and lifestyle advice to nondiabetic male patients ith coronary heart disease, further improves the lipid pattern in normal eight patients, and reduces eight in the overeight patients” Iamanna and fello researchers (20) concluded that, in reducing ris, metformin as more beneficial in its effects on cardiovascular events in trials that had longer lengths ith younger participants, and that the greatest benefit of metformin in reducing and allcause mortality derives from its glucose and lipiddecreasing factors0 According to ristolMyers uibb, the company that marets lucophage, other studies have shon more concrete evidence that metformin significantly decreases mortality ris According to afieianKopaei and aradaran (20), metformin may have renoprotective ualities as ell0 lycosuria, a condition characteried by high levels of glucose in the urine is harmful to the renal tubules because it can disrupt the filtering capabilities of the glomeruli and lead to idney damage Metformin decreases incidences of glycosuria and also possesses antioxidant effects, hich contribute to less damage in the idneys As of 202, metformin is not indicated as a eightloss drug, even though studies have shon that metformin reduces eight and can prevent the development of 22, he iabetes Prevention Program esearch roup (202) administered a study on approximately ,200 participants ho ere classified as prediabetic, hich means that they had impaired glucose tolerance of 0 mgd and impaired glucose of 2 mgd he participants also had to meet certain MI and age criteria he researchers randomly separated participants into to groups, one receiving metformin and the other a placebo hose in the metformin group sa a percent eight reduction and lost at least 2 cm from their aist circumference over a period of 2 years2

Type 1 Diabetes According to und and colleagues (200), patients ith that have poor glycemic control have ust as much ris for cardiovascular disease and dyslipidemia, thus they benefit eually from metformin therapy In a randomied controlled study of one year length, 00 subects ith and poor glycemic control ere given adunct metformin therapy in combination ith insulin or other drugs verall, the subects involved in the study had a decrease of 0 mmol in both total and cholesterol he results in cholesterol ere not significant, hoever ther studies sho similar results Abdelghaffar and Attia (200) observe that “studies done in demonstrated different combinations of the following: reduction of glycosylated hemoglobin Ac, increased insulin sensitivity, decreased dosage of insulin, decreased , and improvement of lipid profile.” he safety of metformin in may be uestionable because the drug comes ith a higher ris for lactic acidosis and hypoglycemia than hen used as treatment in patients ith 2 he main effect of metformin in is most liely due to its insulinsensitiing effect, in contrast to metformin’s effect in 2 in contributing to decreased hepatic glucose output

118 Contraindications and Side Effects he main concerns with any available treatment for diabetes include hypoglycemia and diabetic etoacidosis. iabetic etoacidosis as a result of prolonged elevation of glucose in the blood is a very serious state. t includes severe dehydration from a combination of loss of electrolytes, sweating, hyperventilation, and fever, as well as includes cardiac and seletal muscle toxicity. can be easily avoided with close monitoring of blood glucose levels. ne out of , patients taing lucophage reports incidences of in a year. ccording to usi and efrono 1, “Unlike (a precursor to metformin of the biguanide family), metformin does not adversely affect mitochondrial lactate oxidation and therefore does not cause lactic acidosis unless plasma concentrations of metformin are excessive.”

Adverse Reaction GLUCOPHAGE Placebo Monotherapy (n = 141) (n=145)

Diarrhea¶ 53.2 11.7

Nausea/Vomiting 25.5 8.3

Flatulence 12.1 5.5

Asthenia 9.2 5.5

Indigestion 7.1 4.1

Abdominal Discomfort 6.4 4.8

Headache 5.7 4.8

Table 1. ost common adverse reactions . percent in a placebo controlled clinical study. umbers listed as percentages of patients that experienced symptoms. iarrhea led to a discontinuation of the study in of patients receiving the lucophage monotherapy.

119 etformin does not cause hypoglycemia by itself, but hen used in combination ith other diabetic treatments, there is potential for hypoglycemia. ypoglycemia can be avoided by careful monitoring of blood glucose levels. astrointestinal effects occur in up to of patients using metformin. hey include bloating, , , abdominal pain, , anorexia, and dyspepsia, but these symptoms are almost alays transient and resolve ithin a fe days, especially hen metformin is taken ith food or in a gradual titration., ommon side effects can be seen in able . he maor route of elimination of metformin is via the renal tubules, so any knon compromised kidney function is a contraindication for the drug because it increases the risk of . etformin is also contraindicated in hypoxic conditions such as cardiovascular collapse, acute , congestive that reuires pharmacological treatment, and acute or chronic . oever, recent research has shon the positive effects of metformin on cardiovascular events, leading to an indication that it may be beneficial to use in patients ith cardiovascular disease histories and may even help prevent cardiovascular events., astly, metformin is contraindicated in patients ith severe liver dysfunction and severe chronic obstructive pulmonary disease because these disorders increase the acidic state of the patient, hich could potentially lead to .

Mechanism of Action

or a long time, metformin’s mechanism of action () as unknon.,, ince the drug as first synthesied in , it has taken almost years to start comprehending the cellular and molecular mechanisms. ven though much more is no knon about the multiple effects of metformin, the mechanisms of these pleiotropic effects are still ambiguous. t is believed that, in counteracting hyperglycemia, metformin binds to the protein complex in the respiratory complex chain. n igure this binding is visualied. o get to the protein complex in the mitochondrial membrane, metformin must first be transported inside the cell via organic cation transporter ()., etformin has a pa of ., so it is fully protonated and positively charged at physiologic p thus it does not passively diffuse through the cell. hat is hy is so important in metformin’s action, and deletion of the Oct1 gene can cause metformin to be ineffective. hen metformin binds to protein complex in the mitochondrial membrane it causes inhibition of the electron transport chain, hich leads to decreased levels of cyclic (c) in the cell, hich leads to decreased production. his activates adenosine monophosphate kinase (), hich leads to an increased activity in the generating pathays and decreased activity in consuming pathays to counteract the imbalance. y increasing and decreasing these pathays, metformin helps the patient regulate homeostatic levels, keeping circulating lipids, glucose, and insulin levels lo. decreases glucose levels, ectopic fat deposition, insulin secretion, glucose production, lipid synthesis, lipolysis, and lipogenesis. ncreased activity increases , lipid oxidation, mitochondrial biogenesis, and insulin sensitivity. he systemic effects of activation listed can be seen in igure .

120 Figure 5. Metformin’s mechanism of action in the respiratory chain complex.

Figure 6. stemic effects of metformin

121 olycystic oarian synrome affects approximately percent of omen it is an enocrinopathic conition in hich cysts eelop on the oaries leain to increase anroen proction inslin resistance amenorrhea an anolation. hen aministere to omen ith metformin has een shon to increase olation improe menstral relarity rece serm anroen leels an improe inslin sensitiity. he exact moleclar mechanisms of metformin in these effects remain elsie t it is thoht that they are a reslt of ecrease inslin exposre in the oaries. ih leels of inslin in the oary hae een shon to increase actiity of steroioenic enymes. n clinical trials metformin has also een shon to rece ris of aortion in omen ith y increasin factors sch as an lycoelin leels as ell as increasin terine loo flo hich protect the eelopin emryo an fets. Metformin also ecreases factors sch as enometrial anroen receptor expression an plasmic hich at hih leels increase ris for aortion. ain the mechanisms that case these effects are nnon t the effects may e in part e to metformin’s improvement of inslin sensitiity. eart isease is a maor threat to patients ith in fact it is the leain case of eath in those ith . t metformin can rece iaetesrelate eath an allcase mortality y an percent respectiely as emonstrate in the lonitinal rospectie iaetes ty hich folloe approximately patients for years an as reporte in . he loer eath rates amon those aministere metformin can e attrite to the M actiation an rece amonts of . oroaneh an fello researchers iscoere the enefits of metformin in comatin heart isease in mice an concle that metformin attenates atherosclerosis an asclar senescence in mice fe a hih fat iet an preents the prelation of aniotensin type receptor y a hih fat iet in the aortas of mice. hs consierin the non eleterios effects of aniotensin meiate y aniotensin type receptor the asclar enefits of metformin may e meiate at least in part y aniotensin type receptor onrelation.

Pharmacokinetics

ccorin to ristolMyers i ompany lcophae metformin has an asolte ioaailaility ner fastin conitions of to percent. ince metformin is sally taen ith foo asorption is ecrease an slihtly elaye in relar sae t the clinical relevance of metformin’s potency ecreasin ith foo is nnon. Maximm leels of concentration are achiee ithin a meian ale of hors an a rane of to hors. nterestinly hihfat or lofat meals mae no ifferences in the maximm concentration of lcophae. hereas slfonylreas are on to plasma proteins metformin is neliily on an partitions into erythrocytes as a fnction of time. he apparent olme of istrition aerae in clinical trials. teay state plasma concentrations are reache in to ays.

122 etformin is ecrete nchane in renal tles an oes not nero hepatic metaolism or iliar ecretion as evience the renal of metformin ein times reater than creatinine clearance fter hors approimatel percent of metformin is eliminate via the renal tles

Future Directions

etformin has een shon to rece inflammator marers in oese mice fe a hihfat iet im’s team iscovere that several marers—inclin alpha leptin resistin t an —ere all sinificantl rece in the oese mice hen aministere metformin compare to control rops ince inflammator marers are a part of the metaolic snrome an are relate to evelopin oesit an cancer more research is crrentl elvin into tiliin metformin as an anticancer agent. Metformin’s anticancer effect ma e relate to its antioiant capailities nen an riscoll iscovere that metformin increase the lifespan of ain a irt orm incin a ietar restrictionlie state e report that metformin etens C. elegans meian lifespan via a mechanism that reires the celllar ener sensor its pstream activatin inase an the onstream oiative stress responsive transcription factor t is inepenent of the inslin sinalin patha components that molate lonevit r ata on metformin otcomes are consistent ith the interpretation that metformin acts at least in part as a ietar restriction mimetic in C. elegans an sest that this activit is eecte via a mechanism that is conserve from nematoes to hmans mplications of these finins col inflence evelopment of plasile antiain therapies ase on a r crrentl se in the clinic artinontalvo an fello researchers fon metformin to increase the lifespan in mice mimicin the oil effects of calorie restriction even thoh foo intae as increase he sest that an aaptation to metformin occrs leain to rece oiative stress an increase antioiant efenses hich contrite to loer oiative amae accmlation an inhiition of chronic inflammation he lonitinal st not onl fon a rection in mortalit e to heart isease as state earlier t also fon that metformin increases the lonevit of life in hihris iaetic patients as compare to slfonlreas o assess its antiain properties metformin is crrentl ein aministere in a earlon laele the aretin in ith etformin st ith elerl people ho meet certain hihris characteristics arios esites an maaines have latche onto this st an the tot the claim that metformin col increase the averae epecte lifespan to ears

Developing Drugs

e rs on the maret to treat incle thiaoliineiones s peroisome proliferatoractivate receptor amma melitinies an mil proteinase enmes Ɣ

123 s romote fatt ai tae an storage in aiose tisse aoring to te “fatty acid steal” hypothesis. They “increase adiposetisse mass an sare oter insin sensitie tisses s as seeta mse an te ier an ossi anreati eta es from te armf metaoi effets of ig onentrations of free fatt ais. thus keep fat where it belongs.” it s aiose tisse eression an serm onentrations of aionetin aso inrease. is effet omine it te oering of serm free fatt ai ees ontrites to inrease eati insin sensitiit te oering of eati fat ontent an te iniition of eati gose rotion. s gose onentrations in te oo erease an serm insin onentrations erease as a onseene of enane insin sensitiit an earane. e most serios ontrainiation of s aies to atients it eart faire ease of te otentia to ase eart faire e to satfi retention. so firstgeneration s ase serios ier amage in atients t te neer generations are not as at to ase s arm. Megitinies are simiar to sfonreas in tat te o otassim annes in te eta e t te aso ae te same ogemi effets as sfonreas. e megitinies ae a rai resonse in insin seretion an a sort afife. e neest rgs sti eing researe are rotein an ormonease enmes aagosiase iniitors an ieti etiase . ese are miroteinerie eties fon in fermente air or oter foos ontaining ioatie eties tat ma ae ositie imats on oi fntions or onitions an timate enefit oera eat. e are rrent te set of intensie resear. agosiase iniitors iniit te enme aagosiase i igests arorates at te enteri rsorer. se of tese iniitors rests in an inrease in oera arorate igestion time an ess gose is asore. is a mtifntiona transmemrane rotein tat is ie istrite in ifferent organs an tisses ining te eorine anreas seat gans saiar gans mammar gans tms m noes intestines iiar trat ine ier aenta ters rostate rain oo es an integment. t is non for inatiating te inretin ormones an ia eaage of etie ons after roine or aanine. ine an are ormones tat are reease after eating an enane to of te ostrania insin reease iniition of te enme aos an to ontine enaning insin reease. e rrent eiene sos tat aagosiases an an e fon in e rotein isoates an en aministere in onntion it a mea atients eeriene imroe insin reease. en aministere in isoation mierie eties ae een son to ae etrimenta sie effets. esearers note tat as a onseene tere is an inreasing attention toar natra safe fooerie etie iniitors as tese are itot an sie effets. Mi roteinerie eties it aagosiase an iniitor traits otentia regate te ostrania ergemia in eat an sets iniiting ot te inatiation of te inretin ormones an te arorate roing enmes.

124 Conclusions

espite the wide array of options for treating T etforin reains one of the best antidiabetic drugs on the arket because of its efficiency in lowering blood glucose leels in patients with T and its etreely low risk of side effects such as hypoglyceia and acidosis. nstead of copounding the issue by siply adding ore insulin or stiulating ore insulin secretion as other coon diabetic agents do etforin works with the body to regulate hoeopathic processes. t is currently indicated to treat not only insulinresistant diabetes such as T and gestational diabetes but also polycystic oary syndroe. The full pleiotropic effects of etforin ay not yet be fully discoered and it is currently being researched for anticancer and antiaging treatents. astly etforin is an affordable option due its siple synthesis and cost effectieness.

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