Role of Metformin for Treatment of Type Ii Diabetes Mellitus

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The role of metformin in the treatment of type II Diabetes Mellitus

Introduction:

Diabetes mellitus is a sever inherited or acquired disease which occurs when either pancreas does not produce enough insulin, which characterises type I diabetes and it is most commonly diagnosed in children, or the insulin that has been produced does not get used by the body effectively, type II diabetes and therefore patients will have abnormally high level of glucose. Type II diabetes was previously called non-insulin-dependent or adult-onset diabetes (World Health Organisation, WHO website).

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The latest estimate of the number of diabetics worldwide in 2001 by the World health Organisation (WHO) is 171 million and this figure is likely to be doubled by 2030 (WHO website). A recent study conducted in the UK using the General Practice Research Database (GPRD) illustrate that the mortality rate is twice as high for patients with diabetes type II than those without it (Mulnier et al, 2006).

The prevalence of type II diabetes is increasing rapidly both in the UK and worldwide. It has increased by 54% (from 2.8% to 4.3%) and the incidence has increased by 63% over the past decade (Gonzalez, 2009). In most of the cases Type II diabetes is associated with another disorder, obesity, (Krentz et al, 2008). Hence such high increase in the incidence rate for type II diabetes could be due to the increased rate of obesity over past few years as the life style of the population is generally getting poorer and 20% of the population is now obese (UK Obesity Statistics).

Understanding and treatment of diabetes has advanced throughout the twentieth century and since insulin has been discovered, many antidiabetic therapies and oral agents such as, Sulphonylureas and Biguanides have been developed to improve glycaemia. Sulphonylurea was the first oral therapy to be discovered for diabetes. It is insulin secretagogues and hence it combats the abnormally high level of blood glucose but it also causes hypoglycaemia and weight gain as it can prolong insulin secretion (Warrell et al, 2006). Biguanides is a class of drugs that are considered antihyperglycemic agents. Metformin is a primary member of this class and it has surpassed sulfonylureas as the most prescribed oral antidiabetic drug in the UK and most parts of the world (Filion, 2009). Metformin is now the most popular treatment for diabetes type II as a study carried out using The Health Improvement database from 1966 to 2005 in the UK shows that only a small number of patients were treated with insulin and its use did not change significantly over the time of study period, in 1966 Sulphonylurea was the most common drug and metformin was relatively less common but by 2005 the use of Sulphonylurea had decreased remarkably and there had been a parallel increase in the use of metformin as a therapy for diabetes (Gonzalez, 2009). In 2006 the American Diabetes Association recommended it as the first drug of choice for patients. In the 15th edition of the Model list of Essential Medicine by WHO, metformin is one of the only two antidebetic oral drug agents (the other is glibenclamide) stated there (WHO, 2007).

The other members of biguanides drug class are phenformin and buformin however these two drugs are no longer used in many countries because it carries a very high risk of lactic acidosis.

Historical development:

In medieval times, French lilac or Goat’s rue known as Galega officinalis was used as a remedy for intense urination associated with the disease that is now known as diabetes mellitus and the active ingredient in the French lilac that had blood glucose lowering properties was discovered as galegine or isomyleneguanidine, but later on it was discovered that this ingredient was toxic in the plant that caused death of grazing animals (Witters, 2001). In 1918, guanidine was discovered to be blood glucose lowering agent but then it was also found that it is too toxic to be used as a therapy (Foye, 2007). Whilst guanidine itself and some of its other derivatives were considered to be too toxic to be used for diabetes mellitus treatment, the biguanides, two linked guanidine, proved to be safe and effective for the treatment of diabetes (Witters, 2001).

In the 1920s, in a search for these guanidine-containing compounds with antidiabetic activities, phenformin, buformin and metformin were discovered. Although they were known to have glucose lowering properties it was not until 1957 when these biguanides were tried on man and introduced clinically in Europe (Gottlieb & Auld, 1962, Reitman & Schadt, 2007). For the first time in a medical literature by Ungar et al (1957, as cited by Oubre et al 1997) biguanides were described as an efficacious new class of oral drug for the treatment of diabetes. Phenformin which is similar to metformin in structure was very popular in 1960s but in early 1970s it was found to be associated with lactic acidosis and by 1976 clinical studies proved that the hazards of phenformin treatment outweighed its benefits and therefore, phenformin and all the products containing phenformin were withdrawn by the Ministry of Health and buformin was also withdrawn from many countries for the same reason (WHO, 2003). However, metformin was proved to be safer and did not have same risk of lactic acidosis if appropriately prescribed, and it took another twenty years after a safe and effective use in the Europe until United States Food and Drug Administration (FDA) approved it for use in the United States (Reitman & Schadt, 2007). Glucophage the trade name of metformin, formulated by a drug company called Bristol-Myers Squibb, was the first brand to be marketed in the United States (U.S. FDA).

Metformin used to be only prescribed for diabetes but then studies published in European journal of clinical investigation 1998 proved that metformin can have a significant effect on reducing weight as well (Paolisso et al, 1998).

Meformin has now been used for over 50 years and it has established to be first-line drug of choice for the treatment of diabetes type II, but to get its maximum effect in the anticipation to reduce insulin resistance, weight loss and also to contribute in the improvement of cardiovascular diseases,the American Diabetes Association and the European Association for the Study of Diabetes strongly recommend to use metformin along with lifestyle intervention (Papanas & Maltezos, 2009).

Mode of Action/ Physiological Effects:

Metformin is an antidiabetic oral drug that belongs to a class of drugs called biguanides. It acts by lowering the amount of glucose that liver makes on its own in the body hence it has antihyperglycaemic effects. It was licensed as antihyperglycaemic medication in Europe in 1970s, at that time there was only little known about the mode of action and its physiological effects on body.

Despite metformin being in use since 1950s, its cellular mechanism of action is not definite. It primarily acts by inhibiting gluconeogenesis in the liver and hence it reduces the hepatic glucose output; it has also been shown to enhance glucose uptake in the muscles and improve peripheral insulin sensitivity (Ronco et al, 2008).

Insulin is a very powerful anabolic hormone and it is involved in the synthesis and storage of glucose, lipid, and amino acid/protein. When blood glucose level rises, insulin is produced by the beta cells of the pancreas. As described by Gropper et al (2008) in their book, it stimulates the uptake of glucose by muscle cells and adipocytes, it also inhibits the gluconeogenesis by the liver to bring about an overall decrease in plasma glucose level. Insulin binds to a specific receptor on the plasma membrane of muscle cells and adipocytes which initiates a cascade of second messenger system that stimulates the tubulovesicle-enclosed GLUT4 glucose transporters to be translocated to the plasma membrane. Insulin also activates the enzyme glycogen synthase and inhibits glycogen phosphorylase and together they help store glucose in the form of glycogen. Hence this way glucose is removed from the blood circulation and is brought to normal level (Gropper et al, 2008).

The majority of individuals with type II diabetes are insulin resistant. They have plenty of insulin circulating but their body is not able to respond to it either by having defective or insufficient number of insulin receptors therefore, glucose cannot enter the cells resulting in increased level of plasma glucose. Pancreas continues to produce more insulin in an effort to lower the increased level of glucose and eventually when an individual can no longer produce enough insulin to compensate for the rise, type 2 diabetes develops (Kaufman, 2008).

Figure 1shows an overview of antihyoerglycaemic effect of metformin in type II diabetes mellitus. Metformin has various metabolic effects on lowering the hyperglycaemia. It partially acts by improving insulin action and partially by non-directly insulin dependent effects (Krentz & Bailey, 2005). Metformin suppresses the hepatic glucose output by decreasing gluconeogenesis, glycogenolysis and fatty acid oxidation and this is the most evident principal blood glucose lowering mechanism and it does so by mainly increasing insulin sensitivity (Krentz & Bailey, 2005).

In the skeletal muscles metformin increases the insulin mediated glucose uptake and glycogen formation (glycogenesis), it also reduces the fatty acid oxidation. These changes in the muscle cells increase glucose transporters to move to the plasma membrane surface so that glucose can enter the cells (Krentz & Bailey, 2005).

Another way in which metformin lowers hyperglycaemia is via increasing the anaerobic metabolism of glucose which produces lactate as a by-product and this contributes in lowering the amount of glucose available to move to the serosal side from the lumen, lactate is taken to the liver via portal system (Bailey et al, 2008). Another way in which metformin works independent of insulin action to lower glucose is via increasing the splancchic glucose turn over (Krentz & Bailey, 2005).

The effect of metformin on skeletal muscles and adipose tissues in improving glucose utilisation in them appears to work through improved binding of insulin to its receptors on the plasma membranes of these cells and therefore, metformin seems to be ineffective without some residual functioning islet cells (Porte et al, 2002). Metformin has no direct effect on insulin secretion in contrast to other antidiabetic drugs such as sulfonylureas, therefore it does not cause hypoglycaemia rather in clinical practice it shows anti-hyperglycaemic actions (Porte et al, 2002).

The level of glucose throughout the day changes, it is typically higher after eating and lower in the fasting state. The fasting plasma glucose concentration is measured by the HbA1c test, HbA1c is a glycosylates haemologlibin that is glucose attached with hamemoglobin so the higher the concentration of glucose the higher the level of HbA1c ( Medline Encyclopaedia, 2009). A fasting glucose level lower than 6mmol/l or 7% is normal in non-pregnant individuals and an elevated level shows that either the patient is diabetic or the patient has impaired fasting glucose/impaired glucose tolerance (Bupa’s health information factsheet, 2008; American diabetes association, 2009).

It is important for type II diabetes patients to achieve normal or near-normal glycaemic control with their oral anti hyperglycaemic medications. There are numerous studies that show the effect of metformin decreasing the fasting plasma glucose level. Such as a study by Lozzo (2003), done on type II diabetes patients over 26 weeks with metformin increased the whole-body insulin sensitivity and that was likely to be determined by the reduction in HbA1c and body weight. A similar study done on patients with newly diagnosed Type II diabetes mellitus showed that adding metformin to insulin therapy effectively decreased the HbA1c level from 10.8 to 5.9% and 100% patients achieved an HbA1c less than 7% (Lingvay, 2007).

Metformin has also been suggested to work by a biochemical pathway through activation of a protein kinase enzyme 5′ adenosine monophosphate-activated protein kinase (AMPK). Its activity is regulated by the depletion in ATP (Adenosin tri-phosphate) and raised level of AMP when energy demand increases, such as in a exercising muscle, thus it is a “metabolic stress-sensing enzyme” that regulates the energy demand and energy production balance by modulating various metabolic pathways that bring about glucose, protein and fatty acid metabolism homeostasis (Hawley & Zierath, 2008). In order for metformin to be effective in the inhibition of the production of glucose, activation of AMPK is required (Zhou, 2001). Kim et al (2008) published a study in 2008 that further described the mechanism of metformin through the activation of AMPK. This study was done on hepatocytes and it showed that through AMPK-dependant pathway metformin increased the gene expression of small heterodimer partner, (SHP), SHP protein represses the transcriptional activity of a number of nuclear reptors including hepatocyte nuclear factor, and that in turn inhibits the expression of the hepatic gluconeogenic genes PEPCK and Glc-6-pase, these are the two enzymes that perform a key role in the homeostatic regulation of blood glucose levels and inhibition of these enzyme gene expression lead to the hepatic glucose production in vivo.

Metformin has advantageous effects on atherosclerosis by decreasing Low Density Lipoprotein levels by about 0.26 mmol/L (10 mg/dL), whereas other oral agents appear to have no obvious effects on LDL cholesterol levels (Bolen et al, 2007). Recent prospective and retrospective studies confirm this drug not only being safe for its glucose lowering effects but also indicate its potential anti-atherosclerotic and cardioprotective effects (Scarpello & Howlett, 2008). In the UKPD (United Kingdom Prospective Diabetes Study) a randomised trial on obese and overweight patients with initial metformin monotherapy showed a significant reduction in myocardial infarction and diabetes related deaths, it showed 39% decrease in heart attacks and 36% decrease overall mortality rate; metformin was found to be more effective than any other medication with regards to the strokes and overall mortality rate in overweight patients (Krentz & Bailey 2005). Kooy et al (2009) investigated whether metformin had sustained beneficial effects on metabolic control and risk of cardiovascular disease. After a follow-up period of 4.3 years it was found that metformin added to insulin in type II diabetic patients improved body weight, glycaemic control and it reduced the risk of macravascular disease.

A 2007 systematic review evaluating antidiabetic agents and outcomes in patients with both diabetes and heart failure showed that metformin is the only antidiabetic agent that is not associated with harm in patients with heart failure and diabetes. In this systematic review and meta-analysis of controlled studies, two of three studies showed association of metformin with reduced all cause mortality and no association with increased hospital admissions. (Eurich et al, 2007)

Pharmacokinetics

The chemical name of biguanide is 1-(Diaminomethylidene)guanidine (chemical formula C2H7N5) and it includes compounds that have biguanide structure. Figure 2 shows the molecular structure of metformin that has biguanide structure with two methyl groups added on the amine group of the first carbon atom therefore its chemical name being 1,1-dimethylbiguanide and chemical formula C4H11N5 (Porte et al, 2002).

 

Metformin is taken orally so it has to pass through the digestive system in order to get into the systemic circulation. It is absorbed from the small intestine and does not get metabolised, under fasting conditions the Bioavailability of metformin ranges between 40%-60% (Foye, 2007). From the gastrointestine it gets completely absorbed after 6 hours of oral administration and after absorption it is rapidly distributed and in the plasma it is completely undetectable after 24 hours; the plasma concentration of metformin reaches its peak value within three hours of its oral administration (Papanas & maltedoz, 2009).

Unlike other biguanides such as phenformin the binding of metformin to plasma protein is negligible and therefore it does not seem to interact with highly plasma protein bound drugs such as sulphonamides and is excreted unchanged (Foye, 2007). Metformin does not get metabolised by the liver and therefore is excreted in the urine from the body as unmetabolised drug through the active tubular excretion and about 30% of an oral dose is excreted through faeces that may be unabsorbed metformin and that retain in the gastrointestinal tract (Porte et al, 2002). It has plasma half life of about 2 to 5 hours in patients with normal renal function but and renal function impairments may lead to retention of metformin in the blood plasma (Foye, 2007).

According to Diabetes UK the daily dosage of metformin should be started from 500mg and then gradually increased to a maximum of 2550mg per day but it is entirely individualistic that it depends on the health of individual to consider what dosage is required.

Generic metformin is sold in the form of tablets. A slow or extended release preparation of metformin (Glucophage XR®), introduced in 2004 can act over 24 hours, it has been designed to release metformin slowly over a longer period of time than standard metformin (acts over 8-12 hours) and so its half life is increased to four to eight hours. Timmins et al (2005), in their study on 16 volunteers with 1000mg standard metformin dose twice a day or 2000mg Glucophage XR® once a day, found out that the pharmacokinetics parameters are similar in Glucophage XR® to standard metformin, but Glucophage XR® it is evident to report fewer gastrointestinal side effects than standard metformin so patients who cannot tolerate standard metformin can switch to Glucophage XR® (Feher et al, 2007).

Side effects and contradictions

When prescribed appropriately the most common adverse side effects of metformin include a change in taste, nausea or vomiting, abdominal distension or gas, loss of appetite, diarrhea, skin rashes or urticaria, rare – Lactic acidosis (Warrell et al, 2006). These problems are usually mild and occur in the first few weeks for taking the medication but it may discourage the patient from taking the drug, starting the medication in low dosage and increasing it slowly help reduce these side effects (Warrell et al, 2006).

In clinical trial done on a total of 286 subjects, 141 were given metformin and the rest were put on placebo. This trial found that 53.2% of subjects who were given Metformin reported diarrhea in comparison with 11.7% for those on placebo, and 25.5% subjects on metformin reported nausea/vomiting compared with 8.3% for those on placebo (Drug Facts and Comparisons, 2005). Compared with any other antidiabetic oral drug metformin is most associated with gastrointestinal distress (Bolen et al, 2007).

Phenformin was withdrawn from its theraputical use because of its association with lactic acidosis. Metformin which is similar in structure to phenformin has also been associated with lactic acidosis; however the risk associated with metformin is ten times lower than phenformin (Warrell et al, 2006).

A case control analysis on the study population of 50,048 type 2 diabetic subjects using the U.K – based General Practice Research Database found out that the rate of incidence of lactic acidosis per 100,000 person-years is 3.3 cases amongst metformin users (Bodmer et al. 2008).

Lactic acid is a by-product of metabolism and it becomes toxic if it is not neutralised fast enough. Lactic acidosis associated with metformin is a very severe and potentially fatal condition that can be avoided easily if the drug is prescribed carefully (Fitzgerald et al, 2009). It arises by the mode of action of metformin, that is the inhibition of hepatic gluconeogensis- a process that consumes lactate, produced by glycolysis, continuously to produce glucose (Warrell et al, 2006).

Adopted from Fitzgerald et al. BMJ 2009

In normal conditions during respiration glucose is broken down into two pyruvate molecules in the first step (glycolysis), in the presence of enough oxygen mitochondria oxidises the pyruvate into CO2 and H2O through Kreb cycle by the use of pyruvate dehydrogenase enzyme. But if there is not enough oxygen present, the mitochondria cannot oxidise all of pyruvate so this excess amount of pyruvate is converted into lactate by the lactate dehydrogenase and this lactate is then used in the process of gluconeogenses in the liver. (Fitzgerald et al, 2009; Nicks A, 2009)

As shown in figure 3, at site A metformin decreases the activity of pyruvate dehydrogenase and the conversion of pyruvate into CO2 and H2O, therefore at site B it enhancing the anaerobic metabolism even in the presence of enough oxygen and resulting in the increased production of lactate and as metformin inhibits the process of gluconeogenses in the liver, the lactate is not used up and is built up to the toxic extent. Lactic acidosis is the built up of lactate level in the blood (usually >5 mMol/L). (Nicks A, 2009; Fitzgerald et al, 2009)

As indicated in figure 3, lactate is excreted 70% by liver, 5% by kidneys therefore liver or renal dysfunctions lead to the retention of lactate and hence to a severe form of lactic acidoses even in the absence of metformin and because metformin is excreted by kidneys if kidneys do not function properly then metformin builds up and hence the severity of lactic acidosis is even greater (Misbin, 2004).

The most common contraindications to the use of metformin in people with type II diabetes are renal and liver dysfunctions, congestive heart failure and advanced age, ≥ 80 years, and the mortality rate of lactic acidosis is close to 50% (McCormack et al, 2005). But although heart failure has long been known as a contraindication for metformin use a systemic review 2007 showed that metformin is the only anti-diabetic drug that is not associated with any harm in patients withheart failure Eurich et al, 2007).

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A Medline searched review on the evidence for the use of metformin in the presence of these contradictions concludes that metformin treatment alone does not result in lactic acidosis unless other contributing factors exist as well (Tahrani et al, 2007). However if ingested in toxic doses or in the presence of renal elimination impairment, lactic acidosis does occur (Fitzgerald et al, 2009).

The renal function of patients using metfomin should be regularly monitored. It showed be withdrawn if there is any disturbance in the renal function found. Figure 4 shows the current recommendations on contraindications and guidelines for the withdrawal of metformin. Metformin dose should be reviewed if serum creatinine level is greater than 130 µmol/l and a cut-off serum creatinine level above which metformin should be stopped is 150µmol/l (Fitzgerald et al, 2009). It should be withdrawn during suspected tissue hypoxia that is a condition in which body tissues are deprived of adequate oxygen so cells are forced to respire anaerobically. Patients aged greater than 80 years are at greater risk because they are more likely to have heart problems and kidney or hepatic dysfunctions and patients should be more careful about their alcohol intake while they are on metformin because alcohol can seriously harm liver and that can lead to lactic acidosis (Tahrani et al. BMJ 2007). Metformin should be withdrawn before any radiographical procedures involving iodinated contrast and should remain discontinued until after three days as this contrast dye may temporarily impair kidney function and cause the retention of metformin indirectly leading to lactic acidosis (Thomsen andMorcos, 2003)

 

“Review dose of metformin

* If serum creatinine is >130 µmol/l or estimated glomerular filtration rate is <45 ml/min/1.73 m2

Stop metformin

* If serum creatinine is >150 µmol/l or estimated glomerular filtration rate is <30 ml/min/1.73 m2

Withdraw metformin*

* During periods of suspected tissue hypoxia (such as myocardial infarction, sepsis)

* For three days after use of contrast medium that contains iodine

* Two days before general anaesthesia

*Reinstate when renal function stabilises

Contraindications

* Renal dysfunction

* Congestive cardiac failure needing drug treatment

* Hypersensitivity to metformin

* Acute or chronic metabolic acidosis

* Impaired hepatic function

Precautions

* Age >80 years until renal dysfunction ruled out

* Acute myocardial infarction

* Radiological studies involving iodinated contrast

* Surgical procedures

* Alcohol intake ”

Salpeter et al (2003), in a system review considered 194 studies published between 1, 1959, and March 31, 2002 that evaluated metformin mono therapy or in combination with other treatments for at least one month, in data from these 194 studies there were no fatal or nonfatal lactic acidosis cases found in 36,893 patient-years in the metformin group or in 30,109 patients-years in the nonmetformin or placebo group. It also did not find any difference in lactate levels in metformin therapy and placebo or other non-biguanide therapies. This systemic review concluded that there is no evidence to support association of metformin therapy with increased risk of lactic acidosis or increased lactate level compared with other antihyperglycemic treatments provided that the drugs are prescribed in a suitable dose and all the contraindications are taken into account.

Another side effect to the use of metformin is that when it is used in long term it is associated with malabsorption of vitamin B12 (Ting et al, 2006).

Combination with other antidiabetic drugs

Metformin monotherapy works well with life style interventions in type II diabetic patients but when Type II Diabetes is not controlled with Metformin monotherapy adequately it is often combined with other antidiabetic drugs to maximise its effect.

The combination of metformin with rosiglitazone as a single product is known as Avandame, itwas approved by the FDA in October 2002 for the treatment of diabetes and although it has not been appraised by the National Institute for Clinical Excellence (NICE) yet it is often prescribed to patients with type II diabetes who fail to control their glycaemia despite the maximum dose of metformin (Diabetes UK, 2009). The active constituent of Avandamet, metformin and rosiglitazone,have different mechanism of action complementing the action of each other. The tolerability profile of Avandamet is similar to that of metformin, it is more effective in terms of lowering the HbA1c level than metformin or rosiglitazone (Wellington, 2005).

Pooled data from two double-blind studies that involved 550 patients randomised to be given metformin with rosiglitazone or placebo patients were divided into obese, overweight or non-overweight. Patients from all groups improved their level of HbA1c and fasting plasma glucose (FPG) to a clinically important extent but the greatest improvement was found in the obese group, these patients improved their glycaemic control, beta cell function and insulin sensitivity with the addition of rosiglitazone to metformin than those who received placebo/metformin (Jones et al, 2003).

Metformin can be combined with glyburide which is a member of sulphonylureas and it acts by enhancing insulin release from the cell of pancrease. The combination of these two drugs is proves to be successful in improving the glycaemic control in patients with type II diabetes Studies, such as sixteen week multicenter, randomized, double-blind, 4-arm and parallel clinical trial study (Chien et al, 2007) that involved a total of 100 Chinese patients with type II diabetes and out of which 76 were randomly given metformin 500mg, glyburide 5mg, glyburide/metformin 2.5 mg/500 mg or glyburide/metformin 5.0mg/500mg. After 16 weeks, those who received a combination of both drugs had a greater decrease in both fasting plasma glucose and HbA1c compared with those who received either metformin or glyburide.

Insulin therapy alone sometimes fails in patients for the treatment of type II diabetes so metformin can be added to improve the sensitivity of insulin and this combination of two drugs results in superior glycaemic control compared with metformin or insulin alone and it also minimizes the weight gain in insulin therapy ( Wulffele et al, 2002). Continued use of metformin after insulin introduction patients with type II diabetes not only reduce weight and improve glycaemic control but have beneficial effect on cardiovascular outcomes (Kooy, 2009).

Addition of pioglitazone to metformin is another combination for the treatment of type II diabetes, this is shown in double-blind, placebo-controlled, clinical trial done by Kaku (2009), compared with metformin monotherapy patients who received pioglitazone plus metformin improved their HbA1C by mean 0.67% and they significantly improved their fasting glucose level and other important markers such as free fatty acids, adiponectin and HDL, that are linked with increased insulin resistance and cardiovascular risks.

Metformin can also be combined with other antidiabetic oral agents as a triple therapy for diabetes type II. In a study which was supported by Bristol-Myers Squibb Pharmaceutical Research Institute, 365 patients who were given metformin/glyburide treatment prior to a 24-week double-blind treatment were either assigned to rosiglitazone or placebo while carrying on with metformin, 40% of those patients who received rosiglitazone in addition to metformin/glyburide were able to achieve final HbA1c less than 7.0% and this study concluded that combination of rosiglitazone to metformin/glyburide is “an effective therapeutic strategy” for those who are unable to control their glycaemia and this treatment is beneficial for lowering HbA1C and fasting plasma glucose levels (Dailey et al, 2004).

Who should be treated?

Metformin is a very effective antihyperglaecamic drug for patients with diabetes type II and the American Diabetes Association (2006) recommended it as the first drug of choice for patients.

Metformin is a preferred treatment for obese diabetics. In most of the cases Type II diabetes is associated with another disorder, obesity (Krentz et al, 2008). Obesity increases the risk of developing type II diabetes and many antidiabetic drugs increase body weight whereas, metformin demonstrates a significant weight loss in type II diabetic patients, Golay (2007) in his review on summarising the effect of metformin on body weight confirms that metformin has been shown to induce weight loss in nondiabetic obese patients, although long term studies on these patients are very rare. Therefore patients with obesity and on the risk of developing diabetes type II should start on metformin.

Metformin is also effective with regards to strokes in obese/overweight patients i.e. those on the risk of developing diabetes. UKPD showed a significant reduction in myocardial

The role of metformin in the treatment of type II Diabetes Mellitus

Introduction:

Diabetes mellitus is a sever inherited or acquired disease which occurs when either pancreas does not produce enough insulin, which characterises type I diabetes and it is most commonly diagnosed in children, or the insulin that has been produced does not get used by the body effectively, type II diabetes and therefore patients will have abnormally high level of glucose. Type II diabetes was previously called non-insulin-dependent or adult-onset diabetes (World Health Organisation, WHO website).

The latest estimate of the number of diabetics worldwide in 2001 by the World health Organisation (WHO) is 171 million and this figure is likely to be doubled by 2030 (WHO website). A recent study conducted in the UK using the General Practice Research Database (GPRD) illustrate that the mortality rate is twice as high for patients with diabetes type II than those without it (Mulnier et al, 2006).

The prevalence of type II diabetes is increasing rapidly both in the UK and worldwide. It has increased by 54% (from 2.8% to 4.3%) and the incidence has increased by 63% over the past decade (Gonzalez, 2009). In most of the cases Type II diabetes is associated with another disorder, obesity, (Krentz et al, 2008). Hence such high increase in the incidence rate for type II diabetes could be due to the increased rate of obesity over past few years as the life style of the population is generally getting poorer and 20% of the population is now obese (UK Obesity Statistics).

Understanding and treatment of diabetes has advanced throughout the twentieth century and since insulin has been discovered, many antidiabetic therapies and oral agents such as, Sulphonylureas and Biguanides have been developed to improve glycaemia. Sulphonylurea was the first oral therapy to be discovered for diabetes. It is insulin secretagogues and hence it combats the abnormally high level of blood glucose but it also causes hypoglycaemia and weight gain as it can prolong insulin secretion (Warrell et al, 2006). Biguanides is a class of drugs that are considered antihyperglycemic agents. Metformin is a primary member of this class and it has surpassed sulfonylureas as the most prescribed oral antidiabetic drug in the UK and most parts of the world (Filion, 2009). Metformin is now the most popular treatment for diabetes type II as a study carried out using The Health Improvement database from 1966 to 2005 in the UK shows that only a small number of patients were treated with insulin and its use did not change significantly over the time of study period, in 1966 Sulphonylurea was the most common drug and metformin was relatively less common but by 2005 the use of Sulphonylurea had decreased remarkably and there had been a parallel increase in the use of metformin as a therapy for diabetes (Gonzalez, 2009). In 2006 the American Diabetes Association recommended it as the first drug of choice for patients. In the 15th edition of the Model list of Essential Medicine by WHO, metformin is one of the only two antidebetic oral drug agents (the other is glibenclamide) stated there (WHO, 2007).

The other members of biguanides drug class are phenformin and buformin however these two drugs are no longer used in many countries because it carries a very high risk of lactic acidosis.

Historical development:

In medieval times, French lilac or Goat’s rue known as Galega officinalis was used as a remedy for intense urination associated with the disease that is now known as diabetes mellitus and the active ingredient in the French lilac that had blood glucose lowering properties was discovered as galegine or isomyleneguanidine, but later on it was discovered that this ingredient was toxic in the plant that caused death of grazing animals (Witters, 2001). In 1918, guanidine was discovered to be blood glucose lowering agent but then it was also found that it is too toxic to be used as a therapy (Foye, 2007). Whilst guanidine itself and some of its other derivatives were considered to be too toxic to be used for diabetes mellitus treatment, the biguanides, two linked guanidine, proved to be safe and effective for the treatment of diabetes (Witters, 2001).

In the 1920s, in a search for these guanidine-containing compounds with antidiabetic activities, phenformin, buformin and metformin were discovered. Although they were known to have glucose lowering properties it was not until 1957 when these biguanides were tried on man and introduced clinically in Europe (Gottlieb & Auld, 1962, Reitman & Schadt, 2007). For the first time in a medical literature by Ungar et al (1957, as cited by Oubre et al 1997) biguanides were described as an efficacious new class of oral drug for the treatment of diabetes. Phenformin which is similar to metformin in structure was very popular in 1960s but in early 1970s it was found to be associated with lactic acidosis and by 1976 clinical studies proved that the hazards of phenformin treatment outweighed its benefits and therefore, phenformin and all the products containing phenformin were withdrawn by the Ministry of Health and buformin was also withdrawn from many countries for the same reason (WHO, 2003). However, metformin was proved to be safer and did not have same risk of lactic acidosis if appropriately prescribed, and it took another twenty years after a safe and effective use in the Europe until United States Food and Drug Administration (FDA) approved it for use in the United States (Reitman & Schadt, 2007). Glucophage the trade name of metformin, formulated by a drug company called Bristol-Myers Squibb, was the first brand to be marketed in the United States (U.S. FDA).

Metformin used to be only prescribed for diabetes but then studies published in European journal of clinical investigation 1998 proved that metformin can have a significant effect on reducing weight as well (Paolisso et al, 1998).

Meformin has now been used for over 50 years and it has established to be first-line drug of choice for the treatment of diabetes type II, but to get its maximum effect in the anticipation to reduce insulin resistance, weight loss and also to contribute in the improvement of cardiovascular diseases,the American Diabetes Association and the European Association for the Study of Diabetes strongly recommend to use metformin along with lifestyle intervention (Papanas & Maltezos, 2009).

Mode of Action/ Physiological Effects:

Metformin is an antidiabetic oral drug that belongs to a class of drugs called biguanides. It acts by lowering the amount of glucose that liver makes on its own in the body hence it has antihyperglycaemic effects. It was licensed as antihyperglycaemic medication in Europe in 1970s, at that time there was only little known about the mode of action and its physiological effects on body.

Despite metformin being in use since 1950s, its cellular mechanism of action is not definite. It primarily acts by inhibiting gluconeogenesis in the liver and hence it reduces the hepatic glucose output; it has also been shown to enhance glucose uptake in the muscles and improve peripheral insulin sensitivity (Ronco et al, 2008).

Insulin is a very powerful anabolic hormone and it is involved in the synthesis and storage of glucose, lipid, and amino acid/protein. When blood glucose level rises, insulin is produced by the beta cells of the pancreas. As described by Gropper et al (2008) in their book, it stimulates the uptake of glucose by muscle cells and adipocytes, it also inhibits the gluconeogenesis by the liver to bring about an overall decrease in plasma glucose level. Insulin binds to a specific receptor on the plasma membrane of muscle cells and adipocytes which initiates a cascade of second messenger system that stimulates the tubulovesicle-enclosed GLUT4 glucose transporters to be translocated to the plasma membrane. Insulin also activates the enzyme glycogen synthase and inhibits glycogen phosphorylase and together they help store glucose in the form of glycogen. Hence this way glucose is removed from the blood circulation and is brought to normal level (Gropper et al, 2008).

The majority of individuals with type II diabetes are insulin resistant. They have plenty of insulin circulating but their body is not able to respond to it either by having defective or insufficient number of insulin receptors therefore, glucose cannot enter the cells resulting in increased level of plasma glucose. Pancreas continues to produce more insulin in an effort to lower the increased level of glucose and eventually when an individual can no longer produce enough insulin to compensate for the rise, type 2 diabetes develops (Kaufman, 2008).

Figure 1shows an overview of antihyoerglycaemic effect of metformin in type II diabetes mellitus. Metformin has various metabolic effects on lowering the hyperglycaemia. It partially acts by improving insulin action and partially by non-directly insulin dependent effects (Krentz & Bailey, 2005). Metformin suppresses the hepatic glucose output by decreasing gluconeogenesis, glycogenolysis and fatty acid oxidation and this is the most evident principal blood glucose lowering mechanism and it does so by mainly increasing insulin sensitivity (Krentz & Bailey, 2005).

In the skeletal muscles metformin increases the insulin mediated glucose uptake and glycogen formation (glycogenesis), it also reduces the fatty acid oxidation. These changes in the muscle cells increase glucose transporters to move to the plasma membrane surface so that glucose can enter the cells (Krentz & Bailey, 2005).

Another way in which metformin lowers hyperglycaemia is via increasing the anaerobic metabolism of glucose which produces lactate as a by-product and this contributes in lowering the amount of glucose available to move to the serosal side from the lumen, lactate is taken to the liver via portal system (Bailey et al, 2008). Another way in which metformin works independent of insulin action to lower glucose is via increasing the splancchic glucose turn over (Krentz & Bailey, 2005).

The effect of metformin on skeletal muscles and adipose tissues in improving glucose utilisation in them appears to work through improved binding of insulin to its receptors on the plasma membranes of these cells and therefore, metformin seems to be ineffective without some residual functioning islet cells (Porte et al, 2002). Metformin has no direct effect on insulin secretion in contrast to other antidiabetic drugs such as sulfonylureas, therefore it does not cause hypoglycaemia rather in clinical practice it shows anti-hyperglycaemic actions (Porte et al, 2002).

The level of glucose throughout the day changes, it is typically higher after eating and lower in the fasting state. The fasting plasma glucose concentration is measured by the HbA1c test, HbA1c is a glycosylates haemologlibin that is glucose attached with hamemoglobin so the higher the concentration of glucose the higher the level of HbA1c ( Medline Encyclopaedia, 2009). A fasting glucose level lower than 6mmol/l or 7% is normal in non-pregnant individuals and an elevated level shows that either the patient is diabetic or the patient has impaired fasting glucose/impaired glucose tolerance (Bupa’s health information factsheet, 2008; American diabetes association, 2009).

It is important for type II diabetes patients to achieve normal or near-normal glycaemic control with their oral anti hyperglycaemic medications. There are numerous studies that show the effect of metformin decreasing the fasting plasma glucose level. Such as a study by Lozzo (2003), done on type II diabetes patients over 26 weeks with metformin increased the whole-body insulin sensitivity and that was likely to be determined by the reduction in HbA1c and body weight. A similar study done on patients with newly diagnosed Type II diabetes mellitus showed that adding metformin to insulin therapy effectively decreased the HbA1c level from 10.8 to 5.9% and 100% patients achieved an HbA1c less than 7% (Lingvay, 2007).

Metformin has also been suggested to work by a biochemical pathway through activation of a protein kinase enzyme 5′ adenosine monophosphate-activated protein kinase (AMPK). Its activity is regulated by the depletion in ATP (Adenosin tri-phosphate) and raised level of AMP when energy demand increases, such as in a exercising muscle, thus it is a “metabolic stress-sensing enzyme” that regulates the energy demand and energy production balance by modulating various metabolic pathways that bring about glucose, protein and fatty acid metabolism homeostasis (Hawley & Zierath, 2008). In order for metformin to be effective in the inhibition of the production of glucose, activation of AMPK is required (Zhou, 2001). Kim et al (2008) published a study in 2008 that further described the mechanism of metformin through the activation of AMPK. This study was done on hepatocytes and it showed that through AMPK-dependant pathway metformin increased the gene expression of small heterodimer partner, (SHP), SHP protein represses the transcriptional activity of a number of nuclear reptors including hepatocyte nuclear factor, and that in turn inhibits the expression of the hepatic gluconeogenic genes PEPCK and Glc-6-pase, these are the two enzymes that perform a key role in the homeostatic regulation of blood glucose levels and inhibition of these enzyme gene expression lead to the hepatic glucose production in vivo.

Metformin has advantageous effects on atherosclerosis by decreasing Low Density Lipoprotein levels by about 0.26 mmol/L (10 mg/dL), whereas other oral agents appear to have no obvious effects on LDL cholesterol levels (Bolen et al, 2007). Recent prospective and retrospective studies confirm this drug not only being safe for its glucose lowering effects but also indicate its potential anti-atherosclerotic and cardioprotective effects (Scarpello & Howlett, 2008). In the UKPD (United Kingdom Prospective Diabetes Study) a randomised trial on obese and overweight patients with initial metformin monotherapy showed a significant reduction in myocardial infarction and diabetes related deaths, it showed 39% decrease in heart attacks and 36% decrease overall mortality rate; metformin was found to be more effective than any other medication with regards to the strokes and overall mortality rate in overweight patients (Krentz & Bailey 2005). Kooy et al (2009) investigated whether metformin had sustained beneficial effects on metabolic control and risk of cardiovascular disease. After a follow-up period of 4.3 years it was found that metformin added to insulin in type II diabetic patients improved body weight, glycaemic control and it reduced the risk of macravascular disease.

A 2007 systematic review evaluating antidiabetic agents and outcomes in patients with both diabetes and heart failure showed that metformin is the only antidiabetic agent that is not associated with harm in patients with heart failure and diabetes. In this systematic review and meta-analysis of controlled studies, two of three studies showed association of metformin with reduced all cause mortality and no association with increased hospital admissions. (Eurich et al, 2007)

Pharmacokinetics

The chemical name of biguanide is 1-(Diaminomethylidene)guanidine (chemical formula C2H7N5) and it includes compounds that have biguanide structure. Figure 2 shows the molecular structure of metformin that has biguanide structure with two methyl groups added on the amine group of the first carbon atom therefore its chemical name being 1,1-dimethylbiguanide and chemical formula C4H11N5 (Porte et al, 2002).

 

Metformin is taken orally so it has to pass through the digestive system in order to get into the systemic circulation. It is absorbed from the small intestine and does not get metabolised, under fasting conditions the Bioavailability of metformin ranges between 40%-60% (Foye, 2007). From the gastrointestine it gets completely absorbed after 6 hours of oral administration and after absorption it is rapidly distributed and in the plasma it is completely undetectable after 24 hours; the plasma concentration of metformin reaches its peak value within three hours of its oral administration (Papanas & maltedoz, 2009).

Unlike other biguanides such as phenformin the binding of metformin to plasma protein is negligible and therefore it does not seem to interact with highly plasma protein bound drugs such as sulphonamides and is excreted unchanged (Foye, 2007). Metformin does not get metabolised by the liver and therefore is excreted in the urine from the body as unmetabolised drug through the active tubular excretion and about 30% of an oral dose is excreted through faeces that may be unabsorbed metformin and that retain in the gastrointestinal tract (Porte et al, 2002). It has plasma half life of about 2 to 5 hours in patients with normal renal function but and renal function impairments may lead to retention of metformin in the blood plasma (Foye, 2007).

According to Diabetes UK the daily dosage of metformin should be started from 500mg and then gradually increased to a maximum of 2550mg per day but it is entirely individualistic that it depends on the health of individual to consider what dosage is required.

Generic metformin is sold in the form of tablets. A slow or extended release preparation of metformin (Glucophage XR®), introduced in 2004 can act over 24 hours, it has been designed to release metformin slowly over a longer period of time than standard metformin (acts over 8-12 hours) and so its half life is increased to four to eight hours. Timmins et al (2005), in their study on 16 volunteers with 1000mg standard metformin dose twice a day or 2000mg Glucophage XR® once a day, found out that the pharmacokinetics parameters are similar in Glucophage XR® to standard metformin, but Glucophage XR® it is evident to report fewer gastrointestinal side effects than standard metformin so patients who cannot tolerate standard metformin can switch to Glucophage XR® (Feher et al, 2007).

Side effects and contradictions

When prescribed appropriately the most common adverse side effects of metformin include a change in taste, nausea or vomiting, abdominal distension or gas, loss of appetite, diarrhea, skin rashes or urticaria, rare – Lactic acidosis (Warrell et al, 2006). These problems are usually mild and occur in the first few weeks for taking the medication but it may discourage the patient from taking the drug, starting the medication in low dosage and increasing it slowly help reduce these side effects (Warrell et al, 2006).

In clinical trial done on a total of 286 subjects, 141 were given metformin and the rest were put on placebo. This trial found that 53.2% of subjects who were given Metformin reported diarrhea in comparison with 11.7% for those on placebo, and 25.5% subjects on metformin reported nausea/vomiting compared with 8.3% for those on placebo (Drug Facts and Comparisons, 2005). Compared with any other antidiabetic oral drug metformin is most associated with gastrointestinal distress (Bolen et al, 2007).

Phenformin was withdrawn from its theraputical use because of its association with lactic acidosis. Metformin which is similar in structure to phenformin has also been associated with lactic acidosis; however the risk associated with metformin is ten times lower than phenformin (Warrell et al, 2006).

A case control analysis on the study population of 50,048 type 2 diabetic subjects using the U.K – based General Practice Research Database found out that the rate of incidence of lactic acidosis per 100,000 person-years is 3.3 cases amongst metformin users (Bodmer et al. 2008).

Lactic acid is a by-product of metabolism and it becomes toxic if it is not neutralised fast enough. Lactic acidosis associated with metformin is a very severe and potentially fatal condition that can be avoided easily if the drug is prescribed carefully (Fitzgerald et al, 2009). It arises by the mode of action of metformin, that is the inhibition of hepatic gluconeogensis- a process that consumes lactate, produced by glycolysis, continuously to produce glucose (Warrell et al, 2006).

Adopted from Fitzgerald et al. BMJ 2009

In normal conditions during respiration glucose is broken down into two pyruvate molecules in the first step (glycolysis), in the presence of enough oxygen mitochondria oxidises the pyruvate into CO2 and H2O through Kreb cycle by the use of pyruvate dehydrogenase enzyme. But if there is not enough oxygen present, the mitochondria cannot oxidise all of pyruvate so this excess amount of pyruvate is converted into lactate by the lactate dehydrogenase and this lactate is then used in the process of gluconeogenses in the liver. (Fitzgerald et al, 2009; Nicks A, 2009)

As shown in figure 3, at site A metformin decreases the activity of pyruvate dehydrogenase and the conversion of pyruvate into CO2 and H2O, therefore at site B it enhancing the anaerobic metabolism even in the presence of enough oxygen and resulting in the increased production of lactate and as metformin inhibits the process of gluconeogenses in the liver, the lactate is not used up and is built up to the toxic extent. Lactic acidosis is the built up of lactate level in the blood (usually >5 mMol/L). (Nicks A, 2009; Fitzgerald et al, 2009)

As indicated in figure 3, lactate is excreted 70% by liver, 5% by kidneys therefore liver or renal dysfunctions lead to the retention of lactate and hence to a severe form of lactic acidoses even in the absence of metformin and because metformin is excreted by kidneys if kidneys do not function properly then metformin builds up and hence the severity of lactic acidosis is even greater (Misbin, 2004).

The most common contraindications to the use of metformin in people with type II diabetes are renal and liver dysfunctions, congestive heart failure and advanced age, ≥ 80 years, and the mortality rate of lactic acidosis is close to 50% (McCormack et al, 2005). But although heart failure has long been known as a contraindication for metformin use a systemic review 2007 showed that metformin is the only anti-diabetic drug that is not associated with any harm in patients withheart failure Eurich et al, 2007).

A Medline searched review on the evidence for the use of metformin in the presence of these contradictions concludes that metformin treatment alone does not result in lactic acidosis unless other contributing factors exist as well (Tahrani et al, 2007). However if ingested in toxic doses or in the presence of renal elimination impairment, lactic acidosis does occur (Fitzgerald et al, 2009).

The renal function of patients using metfomin should be regularly monitored. It showed be withdrawn if there is any disturbance in the renal function found. Figure 4 shows the current recommendations on contraindications and guidelines for the withdrawal of metformin. Metformin dose should be reviewed if serum creatinine level is greater than 130 µmol/l and a cut-off serum creatinine level above which metformin should be stopped is 150µmol/l (Fitzgerald et al, 2009). It should be withdrawn during suspected tissue hypoxia that is a condition in which body tissues are deprived of adequate oxygen so cells are forced to respire anaerobically. Patients aged greater than 80 years are at greater risk because they are more likely to have heart problems and kidney or hepatic dysfunctions and patients should be more careful about their alcohol intake while they are on metformin because alcohol can seriously harm liver and that can lead to lactic acidosis (Tahrani et al. BMJ 2007). Metformin should be withdrawn before any radiographical procedures involving iodinated contrast and should remain discontinued until after three days as this contrast dye may temporarily impair kidney function and cause the retention of metformin indirectly leading to lactic acidosis (Thomsen andMorcos, 2003)

 

“Review dose of metformin

* If serum creatinine is >130 µmol/l or estimated glomerular filtration rate is <45 ml/min/1.73 m2

Stop metformin

* If serum creatinine is >150 µmol/l or estimated glomerular filtration rate is <30 ml/min/1.73 m2

Withdraw metformin*

* During periods of suspected tissue hypoxia (such as myocardial infarction, sepsis)

* For three days after use of contrast medium that contains iodine

* Two days before general anaesthesia

*Reinstate when renal function stabilises

Contraindications

* Renal dysfunction

* Congestive cardiac failure needing drug treatment

* Hypersensitivity to metformin

* Acute or chronic metabolic acidosis

* Impaired hepatic function

Precautions

* Age >80 years until renal dysfunction ruled out

* Acute myocardial infarction

* Radiological studies involving iodinated contrast

* Surgical procedures

* Alcohol intake ”

Salpeter et al (2003), in a system review considered 194 studies published between 1, 1959, and March 31, 2002 that evaluated metformin mono therapy or in combination with other treatments for at least one month, in data from these 194 studies there were no fatal or nonfatal lactic acidosis cases found in 36,893 patient-years in the metformin group or in 30,109 patients-years in the nonmetformin or placebo group. It also did not find any difference in lactate levels in metformin therapy and placebo or other non-biguanide therapies. This systemic review concluded that there is no evidence to support association of metformin therapy with increased risk of lactic acidosis or increased lactate level compared with other antihyperglycemic treatments provided that the drugs are prescribed in a suitable dose and all the contraindications are taken into account.

Another side effect to the use of metformin is that when it is used in long term it is associated with malabsorption of vitamin B12 (Ting et al, 2006).

Combination with other antidiabetic drugs

Metformin monotherapy works well with life style interventions in type II diabetic patients but when Type II Diabetes is not controlled with Metformin monotherapy adequately it is often combined with other antidiabetic drugs to maximise its effect.

The combination of metformin with rosiglitazone as a single product is known as Avandame, itwas approved by the FDA in October 2002 for the treatment of diabetes and although it has not been appraised by the National Institute for Clinical Excellence (NICE) yet it is often prescribed to patients with type II diabetes who fail to control their glycaemia despite the maximum dose of metformin (Diabetes UK, 2009). The active constituent of Avandamet, metformin and rosiglitazone,have different mechanism of action complementing the action of each other. The tolerability profile of Avandamet is similar to that of metformin, it is more effective in terms of lowering the HbA1c level than metformin or rosiglitazone (Wellington, 2005).

Pooled data from two double-blind studies that involved 550 patients randomised to be given metformin with rosiglitazone or placebo patients were divided into obese, overweight or non-overweight. Patients from all groups improved their level of HbA1c and fasting plasma glucose (FPG) to a clinically important extent but the greatest improvement was found in the obese group, these patients improved their glycaemic control, beta cell function and insulin sensitivity with the addition of rosiglitazone to metformin than those who received placebo/metformin (Jones et al, 2003).

Metformin can be combined with glyburide which is a member of sulphonylureas and it acts by enhancing insulin release from the cell of pancrease. The combination of these two drugs is proves to be successful in improving the glycaemic control in patients with type II diabetes Studies, such as sixteen week multicenter, randomized, double-blind, 4-arm and parallel clinical trial study (Chien et al, 2007) that involved a total of 100 Chinese patients with type II diabetes and out of which 76 were randomly given metformin 500mg, glyburide 5mg, glyburide/metformin 2.5 mg/500 mg or glyburide/metformin 5.0mg/500mg. After 16 weeks, those who received a combination of both drugs had a greater decrease in both fasting plasma glucose and HbA1c compared with those who received either metformin or glyburide.

Insulin therapy alone sometimes fails in patients for the treatment of type II diabetes so metformin can be added to improve the sensitivity of insulin and this combination of two drugs results in superior glycaemic control compared with metformin or insulin alone and it also minimizes the weight gain in insulin therapy ( Wulffele et al, 2002). Continued use of metformin after insulin introduction patients with type II diabetes not only reduce weight and improve glycaemic control but have beneficial effect on cardiovascular outcomes (Kooy, 2009).

Addition of pioglitazone to metformin is another combination for the treatment of type II diabetes, this is shown in double-blind, placebo-controlled, clinical trial done by Kaku (2009), compared with metformin monotherapy patients who received pioglitazone plus metformin improved their HbA1C by mean 0.67% and they significantly improved their fasting glucose level and other important markers such as free fatty acids, adiponectin and HDL, that are linked with increased insulin resistance and cardiovascular risks.

Metformin can also be combined with other antidiabetic oral agents as a triple therapy for diabetes type II. In a study which was supported by Bristol-Myers Squibb Pharmaceutical Research Institute, 365 patients who were given metformin/glyburide treatment prior to a 24-week double-blind treatment were either assigned to rosiglitazone or placebo while carrying on with metformin, 40% of those patients who received rosiglitazone in addition to metformin/glyburide were able to achieve final HbA1c less than 7.0% and this study concluded that combination of rosiglitazone to metformin/glyburide is “an effective therapeutic strategy” for those who are unable to control their glycaemia and this treatment is beneficial for lowering HbA1C and fasting plasma glucose levels (Dailey et al, 2004).

Who should be treated?

Metformin is a very effective antihyperglaecamic drug for patients with diabetes type II and the American Diabetes Association (2006) recommended it as the first drug of choice for patients.

Metformin is a preferred treatment for obese diabetics. In most of the cases Type II diabetes is associated with another disorder, obesity (Krentz et al, 2008). Obesity increases the risk of developing type II diabetes and many antidiabetic drugs increase body weight whereas, metformin demonstrates a significant weight loss in type II diabetic patients, Golay (2007) in his review on summarising the effect of metformin on body weight confirms that metformin has been shown to induce weight loss in nondiabetic obese patients, although long term studies on these patients are very rare. Therefore patients with obesity and on the risk of developing diabetes type II should start on metformin.

Metformin is also effective with regards to strokes in obese/overweight patients i.e. those on the risk of developing diabetes. UKPD showed a significant reduction in myocardial

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