Brief history of diabetes
The history of diabetes dates back to several millennia. Recognized as a condition marked by the presence of increased urination, the term diabetes, a Greek word (meaning siphon) came into existence in the first century AD. Despite the disease having an identity to the presence of sweet urine, it was only in 17th century AD the term mellitus, a Latin word (meaning sweet like honey) came into use.The later centuries saw significant discoveries with regard to the pathophysiology and treatment of diabetes. The liver and pancreas gained recognition as sites for glycogenolysis and insulin production. Also, the pancreas was established as one of the key sites for the development of diabetes. The 20th century witnessed breakthrough with the discovery of insulin and oral diabetic medications. Despite remarkable advancements with treatment and management strategies, diabetes has reached the status of a global pandemic.
The herbal factor
On a historical perspective, the ancestry of metformin is linked to an herb called Galega officinalis. This is a perineal herb (plant that lives for more than two years) bearing vibrant colored flowers thus making it suitable for ornamental purposes. Also by-named as goat’s rue, French lilac, Italian fitch, Spanish sainfoin, Professor weed, this herb had a conventional foothold in medieval Europe. The period between 17th and 18th century saw this herb as an effective remedy against intestinal parasites, fever, epilepsy, snake bites, tuberculosis, plague as well as symptoms of thirst and frequent urination (symptoms related to increased blood sugar). The herb was also fed to the farm animals to increase milk production. This effect saw its extended use as a galactagogue (an agent that increases breast milk production) in humans. Despite the herb finding its use as a galactagogue in humans for centuries, the scientific evidence behind this is limited. By the beginning of the 19th century Galega was extensively used as a forage crop in the US. However due to the observed toxic effects in sheep, it was classified as a noxious weed in most of the US. In spite of this, the herb has found its place in the treatment of diabetes in many countries. The suggested dose in humans as per the Pharmacognosy by Youngken is 4g/day which is considered a safer limit.
The rise and fall of Guanidine
In the late 19th century, research on the plant chemistry revealed the presence of a substance called guanidine. Studies conducted on this compound in the early part of the 20th century revealed its effectiveness in lowering the blood sugar in animals. But due to safety concerns guanidine did not gain prominence in the treatment of diabetes. In the immediate years that followed, two guanidine extracts namely gelagine and synthalin gained attention. These were considered to have a better safety profile than guanidine. Gelagine had a short stint as a diabetic remedy. But synthalin which was considered to be more effective than gelagine in terms of tolerance and safety gained better recognition as an anti-diabetic agent. The use of guanidine extracts took a downhill course with the discovery of insulin. The increased availability of insulin as well as better insights regarding the harmful effects of guanidine extracts led to its discontinuation as an anti-diabetic agent.
The Biguanides
The quest for safer guanidine extracts continued into the 20th century. Despite the initial setback of the guanidine extracts, continued research work on the chemical structure of guanidine bought into light a compound called biguanide. As the name suggests, this compound was formed by combining two guanidine molecules. This breakthrough scientific work saw the emergence of many biguanides. Among them dimethylbiguanide became the key driving factor behind the development of metformin. Further research into the biguanides revealed them as an efficient blood glucose lowering agents with a better safety profile. The most significant development was that dimethylbiguanide (metformin) was found to be less toxic compared to the other biguanides. But these studies were conducted only on animals. However, these scientific advances failed to gain recognition as higher doses were needed to bring about the desired effects. So, the biguanides lost their prospective as anti-diabetic agents.
The comeback
The middle of the 20th century was marked by the return of dimethylbiguanide from a different stand point. The development of therapeutic strategies against malaria saw the evolution of a guanidine based anti-malarial drug proguanil. This was later followed by the development of an influenza drug called flumamine, which had dimethylbiguanide as its component. A notable observation with both these drugs was their ability to lower the blood glucose levels. With studies on humans missing in the previous analyses, malaria and influenza not only provided new insights about dimethylbiguanide (metformin), but also paved way for further research.
The big leap
The continuing scientific research into the second half of the 20th century proved to be a crucial turning point in the history of metformin. The pioneering work of Jean Sterne was a huge step forward in demonstrating the therapeutic potential of metformin for clinical application. Jean Sterne was a physician at the Aron Laboratories in France. After his initial evaluation of the data centered around flumamine, he teamed up with Denise Duval, a pharmacist attached to the same lab. This pair conducted studies on a number of biguanides and reciprocated the findings from the earlier studies regarding their safety and efficiency. After evaluating many biguanides, it was found that metformin performed better in terms of dosage, safety and efficiency. So, combining the evidence from the studies on flumamine, further analysis was done with metformin on animals. These studies were extended to humans wherein Sterne began to test metformin on his patients. His groups of patients included those who had juvenile-onset and maturity-onset diabetes who were treated with insulin. It was found that metformin was efficient in either reducing the insulin dose or totally cutting down on insulin in patients who had maturity-onset diabetes. On the contrary, in those with juvenile diabetes metformin was not effective in replacing the need for insulin. In addition to these findings, it was observed that metformin did not cause hypoglycemia. These findings were first published in a Moroccan medical journal by Sterne in 1957. This publication was considered an important milestone as it brought into light the application of metformin in the treatment of diabetes. Sterne also recommended the name ‘Glucophage’ (meaning glucose eater) and this name was used to market metformin. His work not only laid the foundation for future research, but also in initiating the clinical use of metformin in Europe.
Exploring other Biguanides
In the timeline that followed the groundbreaking work of Jean Sterne, other biguanides were looked into by different researchers. In the same year of publication of Sterne’s findings, Ungar and his team also published their work on Phenformin. In 1958 Beringer revealed the glucose lowering potential of another biguanide called Buformin. These discoveries further paved way into introducing more biguanides. However, the studies conducted on them revealed disappointing results.Meanwhile phenformin and buformin gained greater acceptance owing to their better effectiveness in reducing the blood glucose levels. But phenformin gained greater recognition compared to Buformin and ultimately both these Biguanides overshadowed Metformin.
The threat
The biguanides phenformin and buformin enjoyed the status of potent anti-diabetic medications following their introduction in the late 1950’s. However, their popularity took a downhill course due to the increasing concerns about lactic acidosis. This is a condition characterized by the accumulation of excessive amounts of lactic acid in the blood stream. Some of the symptoms include abdominal discomfort, reduced appetite, intense fatigue, muscle pain, diarrhoea, increased heart rate, rapid and shallow breathing and confusion. The increase in the blood lactate levels was an observation that was made at the time when phenformin made its entry as an anti-diabetic drug. But in the next two decades that followed, increased case reports on phenformin related lactic acidosis led to growing concerns about its safety. Hence this drug was pulled off the markets in most countries by the late 1970’s. On the other hand, though the evidence behind the association of lactic acidosis with buformin was not as firm as it was with phenformin, available reports pointed to its risky profile. As a consequence, buformin also met with a similar fate. Contrary to the above disqualifications of these two biguanides, there are some reports stating their availability in some countries.
The Hopeful future
The discovery of biguanides in the 20th century provided new insights to the treatment of diabetes. But the risk of lactic acidosis associated with their use proved to be a real black mark to their popularity. The very fact that metformin also belonged to biguanides, affected its status despite having a better safety profile compared to phenformin, even though the evidence behind this was lean in the initial stages. But the studies conducted in the last two decades of the 20th century not only widened the knowledge base on metformin, but also demonstrated its safety and efficiency. Concomitant to the changing perspective on diabetes as a condition associated with insulin resistance and beta cell dysfunction, numerous studies revealed the ability of metformin to decrease insulin resistance, reduce hepatic glucose output, enhance the glucose uptake in the peripheral tissues without bringing on hypoglycemia or increase in weight. In continuum with the earlier data on the safety profile, more trials not only pointed to its reduced probability of lactic acidosis, but also proved the point of its efficiency without potential harm.
The Approval
The publication of Jean Sterne’s work on metformin in 1957 led to the accessibility to this drug in Europe though not to a significant extent. In USA phenformin was dominating the picture. The withdrawal of this drug from USA in the late 1970’s owing to its safety issues and the continuing research that followed in the decade and a half, gave a strong foothold to metformin in many countries. However, the US Food and Drug Administration (FDA) was skeptical of metformin. The hard work of Dr. Gerard Daniel and his team of Lipha Pharmaceuticals and the extensive research conducted for FDA, were able to provide clarity to a number of questions raised by FDA. Finally, metformin gained the trust of FDA in the year 1994 for clinical application and by 1995 it gained wide popularity as the most prescribed anti-diabetic agent. With the efficient marketing strategy by Bristol Myers Squibb, metformin scaled the heights of success. In the later years metformin underwent modifications with the introduction of extended release and fixed dose combination tablets for more therapeutic efficiency.
Moving forward
The recognition of metformin continued to bloom as the world stepped into the 21st century. The United Kingdom Prospective Diabetes Study (UKPDS), one of the most sizeable and longest leading studies conducted on individuals with type 2 diabetes, in the year 1998, with a follow-up period of 10 years, brought new objectives to the treatment of type 2 diabetes. This study reported the beneficial effects of metformin in reducing the cardiovascular risk and improving survival. In the years that followed the UKPDS report, many studies have come up with differing opinions in contrast with the UKPDS findings. Despite the introduction of new anti-diabetic drugs which have been shown to fare better compared to metformin with respect to the cardiovascular risk and survival, metformin still holds a prominent position as the evidence that has accumulated post UKPDS has supported metformin.The studies of metformin benefits have been extended to individuals with prediabetes and those with established cardiovascular ailments for which the reports are still awaited. The year 2002 was marked with metformin achieving the label of most frequently prescribed oral anti-diabetic drug. The International Diabetes Foundation issued recommendations for metformin as the first-line drug for diabetes in 2005. Metformin was included to the list of essential medicines by WHO in 2011. Many studies conducted on metformin related lactic acidosis have convincing evidence regarding its safety. The limitations to the use of metformin in the context of reduced kidney function has undergone recent modifications in favor of the drug.
Action sequence
The drug metformin stands out in being the natures precious medicine for the treatment of diabetes. In contrast to the current medicines, metformin has not been formulated for specified actions due to its herbal origin. Even before the scientific advancements, metformin secured its place in the treatment of diabetes in terms of safety and efficiency. In spite of being in the picture for more than six decades, the evidence base pertaining to its in-depth actions is yet to see a clarity in some areas. However, the available data in humans have tracked the actions of metformin on the liver, kidney and the intestines. Several lines of evidence have pointed to reduction in the hepatic glucose production (gluconeogenesis) by metformin. At the molecular level, the mechanism of metformin action on the liver involving the activation of AMP-activated protein kinase (AMPK) has been known for two decades. AMPK is an enzyme considered as an energy sensor that gets turned on in instances of excessive energy usage in the cells. In the context of metformin, activation of this enzyme results in the reduction of the liver gluconeogenesis.The production of glucose by the liver is a laborious task requiring enormous amounts of energy. The mitochondria also known as ‘power house of the cell’ produces a compound called Adenosine triphosphate (ATP) which is the main source of energy for the cellular activities. According to recent studies, metformin has been postulated to concentrate in the mitochondria of the liver cells and suppress ATP production by acting as a block to the many stages of the respiratory chain involved in the process of producing ATP. On the other hand, the effect of metformin on the intestines has been doing rounds since long. Some studies even point out the significance of intestinal action over the liver. Metformin has been found to exert its intestinal action by increasing the glucose absorption in the gut in addition to bringing about changes in the gut microorganisms and increasing the production of glucagon-like peptide (GLP-1) which is an intestinal hormone known to increase insulin secretion. But still no clarity exists regarding the relationship between the changes in the intestinal bacteria and blood glucose reducing effect of metformin. On a final note, studies have suggested that the increase in the muscle glucose uptake by metformin is the consequence of improved glucose control rather than its direct effects on the muscle.
The nasty side
Metformin holds the tag being a safe anti-diabetic drug since its introduction more than six decades back. Generally speaking, the drug shows good levels of acceptance by majority of the individuals. However, it does cause unwanted side effects in some.
Digestive system: About 20-30% of the individuals taking metformin face nausea, vomiting, diarrhoea, abdominal discomfort and metallic taste in the mouth. These effects are perhaps attributed to its increased presence in the digestive tract and also changes in the gut bacteria. Hence it is advisable to slowly increase the dosage and also take it with food. The other option is to switch over to extended-release tablets.
Lactic acidosis: Metformin holds the black box warning (a strict warning issued by FDA) for this side effect even though it is a rare happening. Roughly 1 in 30,000 experience this side effect which can be fatal. It is thought to occur in patients with severe kidney or liver disease, heart failure, recent heart attack, elderly and alcoholics. However recent studies have put forward the fact that the occurrence of lactic acidosis is very infrequent even in the presence of risk factors.
Vitamin B12 insufficiency: Prolonged use of metformin could result in low B12 levels. There is possible association between metformin and reduced absorption of B12 in the intestine. The initial symptoms include numbness and paresthesia (pins and needles) of the feet. This stage is correctable with B12 supplementation. As the deficiency progresses,the main risk is the occurrence of neurological damage that cannot be reversed. Hence it is advisable to periodically check B12 levels and give supplements to those with low levels.
Low blood sugar and allergic reaction: Metformin intake does not lead to low blood sugar. However, the possibility of hypoglycemia occurs if metformin is taken in combination with other anti-diabetic medications known to cause hypoglycemia. There have been some reports of metformin allergy although it is very rare.
Pediatric application
Childhood obesity has risen to the status of a public health burden on a global scale. The increase in the incidence of type 2 diabetes in children can be attributed to this. The drug metformin having established a strong foothold in adult population, has now stepped into the pediatric population and holds the banner for the only FDA approved oral anti-diabetic drug for use in children over the age of 10 years. This green signal was given by FDA in the year 2000. The American Diabetes Association (ADA) recommends metformin as the first choice in children and adolescents in whom the diagnosis of diabetes is made incidentally with no symptoms together with dietary and life style modifications.However, in the presence of very high blood sugar and ketoacidosis insulin should be added. The degree of safety and efficiency of metformin in children has been proven to be similar to that of adult population though children carry a small risk of hypoglycemia and lactic acidosis with metformin. Recent studies that have analyzed the role of metformin in obese adolescents with prediabetes and insulin resistance have reported its beneficial effects. Similarly in children and adolescents with non-alcoholic fatty liver disease (NAFLD), a condition wherein there is increased fat deposition in the liver occurring as a consequence of obesity, metformin has been shown to offer beneficial effects in addition to diet and life-style. But metformin has not been included in ADA recommendations with respect to NAFLD treatment as more studies are warranted. Also, the use of metformin as an add on to insulin in adolescents with type 1 diabetes has been investigated. Children are prone to insulin resistance during puberty as a result of hormonal changes. But due to the varying opinions expressed, its use in type 1 diabetes has not been recommended. Adolescent girls with obesity are at increased risk for polycystic ovarian syndrome (PCOs). This can have a series of adverse consequences hormonally and metabolically. Despite studies pointing out to the possible benefits of metformin in PCOs, stronger evidence is awaited to ascertain its advantages in adolescent girls with PCOs. On a final note, the future of metformin though looks promising with regard to the pediatric population, long term studies are needed in all the above-mentioned areas to define its full potential.
Amazing facts
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