This year the pharmaceutical drug metformin celebrates the 50^th anniversary since its introduction into clinical research and subsequent marketing as an oral antidiabetic medicine.¹ Metformin, also known as Glucophage®, lowers blood glucose concentrations in diabetics. The development of metformin, which is now reportedly the most widely prescribed agent for the treatment of diabetes, stemme from the study of goat’s rue (Galega officinalis, Fabaceae), a plant used medicinally in medieval Europe.^2,3 Metformin’s 50-year history of safe and effective use reflects its importance as an effective treatment for diabetes and attests to the value of investigating traditional herbs for the development of modern pharmaceuticals, as well as the potential benefits that chemically-complex preparations from such plants may bring as phytomedicines and dietary supplements.

Diabetes and its Prevalence

Diabetes is a group of diseases characterized by high blood glucose levels due to defects in insulin production, insulin action, or both, which can lead to serious health complications. The two most common forms of diabetes are type 1 (often referred to as juvenile onset diabetes), which is characterized by an absolute insulin deficiency, and type 2 (formerly known as non-insulin dependent diabetes), which typically results from insulin resistance and relative insulin deficiency.⁴ Type 1 diabetes, which accounts for 5-10% of all diagnosed diabetes cases, requires that patients receive insulin by injection, inhalation, or pump. Type 2 diabetes, which accounts for 90-95% of all diagnosed cases, can often initially be managed through such treatments as diet (including the judicious use of dietary supplements), exercise, and oral medications, but many patients eventually require insulin. Diabetes, as a general condition, has been ranked the 5^th deadliest disease in the United States according to the American Diabetes Association.⁵ Moreover, the death rate from diabetes has increased 45% over the past 20 years, whereas the death rates from heart disease, stroke, and cancer have all declined. The latest National Diabetes Fact Sheet, published in 2005, notes that 20.8 million Americans, or 7% of the US population, have diabetes.⁴ Data released by the International Diabetes Federation in 2006 show that 246 million people suffer from the disease worldwide, and the majority of cases are type 2 diabetes.⁶ In light of such statistics, the importance of effective treatments for diabetes cannot be understated. In the United States, 57% of adults diagnosed with diabetes treat their condition solely with oral medication, 12% employ a combination of oral medication and insulin, and 16% use insulin alone.⁴ Prior to the development of insulin and modern pharmaceutical drugs, many civilizations employed herbal remedies or dietary modifications to treat symptoms of conditions that are today referred to as diabetes. Perhaps the first known text to provide information and list therapies for diabetes-like symptoms was the Ebers Papyrus of ancient Egypt, written around 1552 BCE.^2,7 Medical texts from ancient India and China also made note of diabetes-like conditions and mentioned therapies for their treatment.⁷ Hundreds of plants have been traditionally used in various cultures for the treatment of diabetes, some of which include garlic (Allium sativum, Alliaceae), karela or bitter melon (Momordica charantia, Cucurbitaceae), banyan (Ficus spp., Moraceae), guar, aka cluster bean (Cyamopsis tetragonoloba, Fabaceae), blueberry (Vaccinium spp., Ericaceae), and a South American species of holly (Ilex guayusa, Aquifoliaceae).¹

The Study of Goat’s Rue and Development of Metformin

Goat’s rue, a perennial herb used medicinally in medieval Europe, would eventually spur major developments in the treatment of diabetes. Also known as French lilac, Italian fitch, false indigo, and Spanish sainfoin, goat’s rue grows in temperate regions, reaches approximately 1 meter in height, and is characterized by white, blue, and purple flowers. The Latin name for the genus of the plant is said to come from the Greek words gala (milk) and aigos (goat), due to the plant’s reputation in the 19^th century for increasing the milk production of goats that grazed upon it.¹ The plant was used to treat plague, worms, snake bites, miasma (the theory that a poisonous, foul-smelling atmosphere generated by swamps or putrid matter could cause disease), dysuria, and St. Vitus dance (aka sydenham chorea—a disorder associated with rheumatic fever that affects children and causes involuntary movements) by early European societies.³ The first known reference to its use was by Italian botanist and physician Pietro Andrea Mattioli, who noted in the 1500s that some farmers in Tuscany used it as a soap.¹ Some versions of Nicholas Culpeper’s herbal treatise, first published in 1652, suggested that the plant had antidiabetic properties.³ Culpeper also noted that the plant could be used to prepare a bath for washing achy feet and that it was used for making cheeses in some areas.⁸ Thomas Green’s Universal Herbal of 1832 noted that an infusion made of dried goat’s rue leaves and boiling water would incite sweating and alleviate fevers. The plant was considered useful for treating symptoms of diabetes in early France, according to French texts published in the 1920s and 1930s.^9,10 In the late 1800s, researchers discovered that goat’s rue was rich in the strongly alkaline crystalline compound guanidine,* and this compound was soon found to generate hypoglycemic activity in animals.³ Guanidine was considered too toxic for clinical use, and in the late 1920s, researchers began to study a less toxic component of goat’s rue called galegine. Galegine was the first example of a botanical alkaloid of known composition that could trigger hypoglycemia.¹ Even though it too could be highly toxic in large doses—generating convulsions, vomiting, diarrhea, paralysis, asphyxia, or possibly even hyperglycemia in animal studies—human clinical studies showed that a low dose could generate a sharp, temporary drop in blood glucose. These results initiated further study of goat’s rue extract and various synthetic guanidine derivatives (including biguanides) for the possible treatment of diabetes.^1,3 Enthusiasm for research into insulin during the early to mid-1920s largely led to the discontinuation of studies into goat’s rue and biguanides for several years.

Interest in the study of biguanides for treatment of diabetes was revived by physician and clinical pharmacologist Jean Sterne in 1956.¹ Sterne and his colleague Denise Duval initiated trials to study the anti-hyperglycemic action (suppression of excessive hepatic glucose production) and toxicity of the biguanide compound dimethyl-biguanide (metformin). Their studies confirmed the powerful anti-hyperglycemic properties observed in earlier research, and they further disproved the chronic toxicity that earlier researchers attributed to the compound. In 1957, Sterne introduced metformin, called “Glucophage” (glucose eater), into hospital care in France and published the results of the first clinical trials, which demonstrated metformin’s efficacy and safety. Hospitals in several other countries soon expressed interest in the treatment, and numerous follow-up studies were conducted using thousands of patients.

The Use of Metformin as a Diabetes Treatment

Metformin was officially launched on the market in 1959 in France, Great Britain, and several countries with English affinities, including Sweden, South Africa, and Malaysia.¹ By 1968, the drug was being used in about 40 countries worldwide with the exception of eastern European countries and the North American continent. The pharmaceutical product entered North America in 1972 via Canada. Other biguanides, specifically phenformin and buformin, initially garnered greater success and acclaim than metformin because they were more potent.³ However, these products were later associated with lactic acidosis (a sometimes fatal condition in which lactic acid builds up in the blood stream faster than it can be removed). Because of this, both phenformin and buformin were removed from the market in most countries by the end of the 1970s. Metformin’s reputation may have temporarily suffered from its relationship to phenformin and buformin. However, increasing evidence of the drug’s effectiveness in preventing hyperglycemia and countering insulin resistance, as well as evidence that the risk of lactic acidosis from use of metformin was considerably smaller than that with its counterparts, led to continued and renewed confidence in the drug.^3,11 Metformin finally entered the United States’ market (with a warning concerning lactic acidosis risk) in 1995, under franchise to Bristol Myers Squibb.³ It remains the only biguanide available in the United States,¹¹ and it is the country’s leading diabetes medication, with 34.8 million prescriptions in 2006.¹²

Many studies have been conducted that support metformin’s efficacy in lowering blood glucose and providing additional benefits to diabetics. An important government-sponsored trial, the United Kingdom Prospective Diabetes Study, published in Lancet in 1998, found that early use of metformin in obese patients with type 2 diabetes mellitus led to a reduction in stroke, all-cause mortality, and total diabetes endpoints compared to insulin and sulfonylurea.¹³ More recently, a review article published in 2005 re-evaluated the drug’s usefulness in light of new oral antidiabetic agents that have entered the market over the years.¹⁴ According to this review, most studies have shown that metformin causes a reduction in fasting hepatic glucose output and several have found that metformin augments peripheral insulin-mediated glucose uptake. Most studies have reported that participants achieved either modest weight reduction or stability of weight while taking the medication. This is in contrast to the weight gain usually associated with other diabetes treatments. Some studies have reported a beneficial effect on lipid parameters and blood pressure, while other studies have found no change to such parameters. The authors concluded that metformin has been a valuable and safe treatment option for patients with type 2 diabetes, both in monotherapy and combination therapy, and that it can be used as a “therapeutic agent of first choice” despite the appearance of new oral therapy options.

Recent safety concerns regarding the newer antidiabetic drug rosiglitazone (Avandia®, GlaxoSmithKline) could even reinforce the value of metformin, in light of its longevity and safety record. Avandia, which entered the market in 1999, is the second most commonly prescribed oral medication for diabetes in the United States (following metformin), with 11.3 million prescriptions in 2006.¹² In May of 2007, a meta-analysis published online by the New England Journal of Medicine, based on 42 trials, found that rosiglitazone was associated with a significantly increased risk of myocardial infarction and of death from cardiovascular causes as compared to placebo and comparative drugs (including metformin).¹⁵ The meta-analysis did have several limitations, as it was based on relatively short trials, a small number of events, and used publicly available trial data and not original source data. Another major limitation was the use of cardiovascular event data from trials that were not designed or powered to study those events. The US Food and Drug Administration (FDA) issued a public safety alert after the study was published, urging users to consult their doctors about possible cardiovascular risks.¹²

Current Uses and Reputation of Goat’s Rue

As for metformin’s original source, goat’s rue, it was recently observed that the plant is increasingly prevalent within the United Kingdom.² The plant was introduced into cultivation in England in 1568 and first recorded in the wild in 1640, but its distribution was not mapped for many years. The New Atlas of British and Irish Flora of 2002 noted that goat’s rue is now found within 75% of the mapped area of London and that it is widely distributed in various counties. The spread of goat’s rue currently does not seem to be considered problematic within the United Kingdom.

On the other hand, goat’s rue is included on a list of poisonous plants for livestock in New Zealand and is distinguished as a Federal Noxious Weed (FNW) in the United States.^16,17 According to its record in the US FNW Database, goat’s rue is classified as a FNW because it competes with and reduces yields of forage plants in moist or irrigated pastures and because it is toxic to livestock.¹⁷ The plant is reportedly unpalatable to cattle and horses and can cause such toxic effects as vomiting and even death in some goats and sheep under certain conditions. The plant was intentionally introduced into the United States in 1891 by researchers at Utah State University, who tested it as a forage crop. The project was soon abandoned due to unsuccessful results, but the experimental stands were not destroyed. In the 1920s, goat’s rue was discovered a mile from its original site, and it eventually spread throughout an area of about 38,000 acres. An eradication program was initiated in 1981, eventually covering all of the infested area plus 1,440 acres of adjacent lands as a buffer against spread of the plant.

Goat’s rue is still used in some medicinal herbal formulas, and the plant’s abilities to stimulate milk production, in particular, seem to have generated renewed interest in recent years. “Goat’s rue use as a galactogogue has increased and has a generally very positive reputation amongst those lactation consultants who recommend it,” said lactation consultant Sheila Humphrey, who recently authored a chapter on lactation-inducing herbs for a forthcoming textbook on lactation (e-mail, August 15, 2007). Humphrey stated that although there have been animal trials regarding goat’s rue’s use as a lactation aid, as well as positive human clinical studies conducted in Germany in the 1960s, no modern human trials provide strong evidence for its safety and efficacy. “It would appear that goat’s rue is one of the most powerful galactogogues, works where the much more familiar fenugreek [Trigonella foenum-graecum¸ Fabaceae] does not, yet scares the heck out of doctors who read the fate of sheep who eat too much too fast,” she explained. In 2005, the herbal company Motherlove (LaPorte, CO) introduced a goat’s rue supplement into its lineup of lactation-assisting products, claiming that the goat’s rue capsules can help develop mammary tissue and stimulate both the flow and production of milk.¹⁸ Humphrey noted that no safety issues have been reported to Motherlove since the company began marketing the supplement.

The plant’s usefulness as a lactation aid for animals has also been the subject of recent research. A New Zealand study in 2004 investigated goat’s rue’s potential for safely increasing the milk production of “Churra” ewes.¹⁶ The authors found that a controlled daily dose of dry matter (2 g, which the researchers wrote is 5 times less than the reported toxic dose for sheep, according to the available literature) significantly increased milk production without toxic effects. According to the authors, the results indicate that goat’s rue could be a useful addition to sheep diet in controlled doses, for the purpose of milk production.

Goat’s rue is not currently used by the various manufacturers of metformin when formulating the diabetes drug. The drug is synthetically manufactured as a hydrochloride compound. Goat’s rue, however, will forever be known as the “natural ancestor”³ or “precursor”² to metformin, which was based on a prototypic molecule found in the plant.⁷

Possible Future Drug Discovery for Diabetes from Medicinal Plants

The development of metformin from goat’s rue provides evidence of the value of studying medicinal plants for the development of pharmaceuticals—and the importance of investigating plants as sources of drugs for treating diabetes, in particular. The authors of an article published in the journal Phytomedicine in 1995 noted that more than 1200 species of plants have been used in the treatment of diabetes mellitus, half as traditional remedies and half as experimental agents studied for their hypoglycemic effects.¹⁹ More than 80% of the traditional remedies studied pharmacologically were demonstrated to have hypoglycemic activity, although the authors noted that the mechanisms of action for these effects in some of the plants would not be therapeutically useful and more than a third of all the plants were reported to be toxic. The authors concluded that carefully planned scientific research into some of the traditionally-used plants could be useful for determining sources for new hypoglycemic agents, and they supplied examples of plants that could provide a starting point for researchers interested in pursuing such research.

An article published in Diabetologia in 1997 similarly used the example of goat’s rue and metformin to support a proposal that more researchers investigate plant-based therapies of traditional healers in their search for new drugs to treat diabetes.⁷ According to the authors, such studies could also benefit patient populations in poorer countries—where botanical medicines are commonly used—by providing clinical evidence to either validate or challenge the effectiveness of their traditional treatments for diabetes. Like goat’s rue, perhaps these other botanicals could also serve as the impetus for important drugs to treat this increasingly prevalent disease.

References

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3. Bailey CJ, Day C. Metformin: its botanical background. Pract Diab Int. 2004;21(3):115-117.
4. National Diabetes Fact Sheet. American Diabetes Association Web site. Available at: http://www.cdc.gov/diabetes/pubs/pdf/ndfs_2005. pdf. Accessed May 17, 2007.
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18. Motherlove Herbal Company introduces goat’s rue vegetarian capsules and a new lactation pack for breastfeeding mothers [press release]. LaPorte, CO: Motherlove Herbal Company; September 2005.
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