By Gary M. Pepper, M.D

Diabetes Treatment

Introduction

Metformin has been used throughout the world for treating type 2 diabetes for over 50 years. It remains one of the most potent oral medications for reducing elevated blood sugar in type 2 diabetes, is among the least expensive anti-diabetes medication and continues to be the most prescribed pill for diabetes management .Add to all of these impressive facts about metformin, is a growing list of potential benefits that are truly mind blowing, including reducing the risk of dementia and certain cancers and even possibly slowing the aging process itself. So why is metformin the Cinderella of the medical world, with a growing undercurrent in the media that there is something not quite right with this drug?  Let’s take a closer look and see what is going on here.

Metformin regulates blood glucose levels by three mechanisms:

● Decreased hepatic glucose output.

● Reduced absorption of glucose via the gut

● Increased insulin sensitivity

Despite years of extensive study the exact mechanism of how this unique medication works is only partially understood.

Metformin’s Unique Effectiveness

An extensive review of multiple studies compared metformin to other anti-diabetic treatments was published in the British Medical Journal in 2007. This analysis found that when compared to other anti-diabetic medications including insulin, metformin was associated with considerably lower all-cause mortality.

The therapeutic efficacy of metformin was also clearly demonstrated in 2011 by a Korean-based study. Newly diagnosed type 2 diabetics receiving this medication were observed to have their HgA1c levels decrease from 7.9% to 7.0% coupled with a decrease in body weight while developing very few side-effects, in this one year study.

A wonder drug not only an anti-diabetic

Metformin-related harm, if any, is generally thought to be minimal. It does not contribute to weight gain, and it has the advantage of being the most reasonably priced diabetic care available. Non-glucose related benefits on the brain, heart, inflammation, ovarian function are becoming increasingly observed. Despite all this, due to the narrow profit margin in today’s market, metformin is fighting a public relations crisis. When it comes to metformin’s cost, safety, availability, and additional health benefits, our belief is that patients are receiving the utmost benefit.

Development and approval history

As mentioned, the voyage of metformin to its current position began in medieval Europe in the 1800s when it was first discovered in the light of herbal medicine ‘Galega officinais, a guanidine-rich plant commonly known as French lilac which was used to treat increased urination.

Previously considered an injurious weed in numerous states of the U.S., this plant was officially reported to decrease blood glucose levels in animals in the 1920’s leading to its use for diabetes. However, the side effects of the naturally occurring herb hampered its transition into clinical use.

Ultimately, Jean Sterne pioneered metformin’s ability to treat hyperglycemia into a therapeutic reality. Through a series of trials and research programs with Lipha pharmaceuticals metformin found its role as a unique medicine in the diabetic world. Ultimately, the FDA-approved metformin in December of 1994.

Soon after its launch, Bristol Myers acquired its marketing rights and initiated the safe introduction of the drug in the U.S. market beginning after the failure of  phenformin, a similar biguanide medication with lethal side effects related to lactic acidosis.

Why metformin remains superior to other anti-diabetic medicines

Many clinical trials have demonstrated the superiority of metformin in terms of its ability to lower elevated glucose levels. One such study comparing the clinical effects of metformin versus sulfonylurea mono-therapy in diabetic individuals appeared in the Diabetes Journal of the American Diabetes Association. The results showed that patients receiving sulfonylurea medication had a death rate of 24.7%, while those receiving solely metformin therapy had a mortality rate of 13.8%.

Another analysis compared several anti-diabetic treatments, published in The British Medical Journal. This study found that when compared to other anti-diabetic medications including insulin, metformin was associated with considerably lower all-cause mortality. The therapeutic efficacy of metformin was demonstrated by a separate 48-week Korean-based study. Throughout the study period, it was observed that Hba1c levels decreased from 7.9% to 7.0% (p< 0.001) coupled with a decrease in body weight.

Most endocrinologists actively support metformin use, and prescriptions have almost doubled within the last two decades for metformin. In 2004, metformin was prescribed for type 2 diabetes more than 40 million times, while in 2020 the number rose to over 90 million times.

Number of prescriptions per year of Metformin

 

 

Figure 1: Graph showing the number of prescriptions in millions from 2004 to 2020.

Source: Statista

The off-label use of metformin

Doctors also prescribe metformin for prediabetes, polycystic ovarian syndrome, and metabolic syndrome due to its ability to reduce insulin resistance.  Oluwaranti Akiyode, PharmD, RPh, BCPS, CDE  a professor and clinical pharmacist at Howard University states, “‘no one exactly knows the full extent of how metformin works” while acknowledging the potential benefits of metformin’s off-label use. One particular potential off-label benefit she points out is for the treatment of ‘HIV-related muscle wasting Also mentioned in this interview are potential benefits of metformin in the treatment of dementia and non-alcoholic fatty liver disease.

Metformin and cancer

A review of the literature conducted in 2019, found that metformin has anti-cancer properties via its interaction with enzymes in the liver. 12 studies were included in the review, all reporting indications of metformin’s anti-cancer properties due to its anti-proliferative nature.

Andrew Chan MD, MPH and a Harvard professor also appreciated the anti-cancer role of metformin. He stated that ‘”individuals taking metformin have a low risk of cancer, as metformin stops the growth of tumor through reducing cell growth, invasion, motility and spread’.

Anti-aging properties of metformin

One of the most major risks of diabetes is accelerated aging, which is almost a thousand fold more than normal. Hence, when targeting diabetes, preventing rapid aging always goes hand in hand. Among the first, a  2014 study published in the Journal of Alzheimer’s Disease found that metformin use delayed the decline in cognition. Biological aging markers, some only recently identified, are thought to be influenced by metformin mechanisms. Its effect on gene expression has also been established in the Metformin in Longevity Study (MILES).

Work in this area is accelerating. A collaborative nation wide effort is actively studying the anti-ageing effect of metformin to treat aging as a disease. Almost 3,000 people between the ages of 65 and 79 are expected to be part in the Targeting Aging with Metformin (TAME) Study, This collaboration involves a set of six-year clinical trials being conducted at 14 top research institutes across the United States.

Metformin and arthritis

Metformin has shown benefit in the fight against arthritis. The primary incapacitating elements of arthritis including inflammation, oxidative stress, and pain, are all counteracted by metformin. Thus, it may be used to treat osteoarthritis in the future since it slows down the structural worsening of the syndrome.

A randomized controlled trial conducted in 2021, established metformin as an effective treatment for rheumatoid arthritis. Sixty patients were started on metformin for 6 months, in comparison to a control, and showed decreased levels of CRP and DAS-28-CRP which are both strongly linked with the inflammation and progression of rheumatoid arthritis.

Does metformin come with side effects?

Metformin has been used as the first-line drug for diabetes worldwide for more than 2 decades, and is generally regarded as among the safest diabetic drug available. Intolerance due to gastrointestinal side effects are relatively minor but it is fair to acknowledge that the incidence is high. A major 2021 review of this issue indicated that 20-30% of metformin users develop some gastrointestinal side effects and that 5% stopped metformin use because of this. Almost all patients can tolerate it long-term through dose adjustment or a switch to the extended release version of the drug which is better tolerated, generally.  However, whenever low compliance is seen it is always due to diarrhea or similar gastrointestinal disturbances.

What is Extended-release formulation?

To simplify the daily routine of taking metformin, in 2020 a once daily version of the drug known as Glucophage XR was FDA approved. This version subsequently was found to have a lesser tendency to cause gastrointestinal side-effects such as diarrhea. This provides users the double benefit of convenience and less risk of gastrointestinal issues, although the price is slightly higher than a similar dose of the original twice daily version.

After being diagnosed with diabetes and taking metformin for 20 years, Gretchen Becker the author of The First Year: Type 2 Diabetes: An Essential Guide for the Newly Diagnosed, started developing diarrhea when the doctor accidentally switched her to the immediate release version from the extended release version of metformin. Becher reported, ‘I had very loose bowels for several months until I figured out what the problem was.’

What are some serious complications and contraindications for metformin?

Although rare, one serious side effect of metformin is lactic acidosis, in which the blood acidity is reduced due to increased levels of the metabolite, lactate. This side effect is mostly seen in patients with significant kidney problems dehydration or alcoholic liver disease, hence one of the contraindications of metformin is markedly impaired kidney or liver function. Recent studies have confirmed that this drug, with proper monitoring, exhibits low risk of lactic acidosis even in the face of mild to moderate reduction in kidney function. However, patients on metformin, as are most of those with diabetes, are advised to undergo regular kidney monitoring.

Comparison of metformin with other anti-diabetic medicines

Numerous studies have demonstrated that most of the widely prescribed oral anti-diabetic drugs were essentially similarly effective at suppressing and regulating blood sugar levels. Yet metformin stood out since it provided the same or superior degree of effectiveness at a lower cost without decreasing glucose readings to dangerous levels. Additionally, scientific study points to metformin as a potential inhibitor of atherosclerosis thereby limiting cardiovascular mortality. The estimate of expenditure on insulin and newer anti-diabetic drugs is far more as compared to metformin as noted by the American Diabetes Association. Shari Bolen, a lead study author for diabetic drugs at John Hopkins, said ‘Sometimes newer is not necessarily better.’

Price comparison of metformin to other drugs

As mentioned, metformin is among the least expensive of the anti-diabetic medications as demonstrated in this graphic. Spending hundreds of dollars per month less on medication can influence standards of living. Crucially, spending significantly less on medications enables purchase of healthier and often more expensive foods, gives people access to health sustaining activities and hobbies and generally improves quality of life potentially extending lifespan.

Comparison of the Cost of Diabetes Medications

Figure 2: Price comparison for a month’s supply of diabetic medicines (prices are averages)


Conclusion

Metformin has been called the aspirin of the 21st century and remains undefeated in being the first-line drug for type 2 diabetes. It is cheap, effective, essentially safe and multi-beneficial which makes it stand out. Due to its low profit potential, metformin remains invisible in the mass marketing blitz of newer anti-diabetes medications. Despite its low public profile it is still considered by most experts to be the best first line choice for treating type 2 diabetes with many other non-diabetic related benefits still waiting to be clarified.

Are you or a loved one navigating the complexities of Type 2 diabetes? Dive deeper into the world of metformin and discover how this time-tested medication can be a game-changer in diabetes management. Stay informed, stay healthy.

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