Is Metformin the cure for everything?

Yes, but no

Julia Korowski, XX2 century
For links, see the original article

Here, in the editorial office of the XX2 century, we love metformin very much and talk about it at any opportunity. Today it suppresses the growth of cancer cells, tomorrow it fights inflammation, the day after tomorrow it helps to lose weight, and next week it prolongs life altogether. Readers might have the impression that this medicine overcomes any diseases. Unfortunately, this is not quite true and almost every good news is accompanied by a "yes, but". So we decided to write about metformin again – this time a big text that will explain to those who missed everything, where this drug came from, what they treat and how successfully.

History

It all started with grass. Medicinal goat, aka goat rue, aka Italian ferret, aka, scientifically, Galega officinalis is a perennial herbaceous plant. In medieval Europe, they were treated for frequent urination – one of the symptoms of diabetes – and some other diseases. It is difficult to say how long the goat's nest has been used in folk medicine, but it is known that the famous English aesculapius Nicholas Culpeper mentioned it back in 1652 in the book "The English Doctor".

Galega officinalis is the grandfather of the most popular antidiabetic drug

At the end of the XIX century, scientists closely engaged in goat meat and found out that it contains large amounts of guanidine (this colorless crystalline substance was first synthesized in 1861). In 1918, during experiments on rabbits, scientists showed that guanidine reduces blood glucose levels. But the compound turned out to be too toxic, and it was impossible to treat people with it, so scientists began experimenting with guanidine derivatives. In 1922, Emil Alphonse Werner and James Bell obtained dimethylbiguanidine, known to us as metformin, during the synthesis of N, N-dimethylguanidine, and seven years later, the German scientist Karl Slotta tested it on animals. There were other drugs based on guanidine – galegin (isoamylene-diguanidine), biguanides Synthalin A and B. Synthalines were even used in clinical practice for some time, but after the industrial production of insulin began (in 1923, Eli Lilly and Company began selling it under the name "Iletin"), guanidine derivatives were forgotten.

In 1949, metformin fell into the hands of Filipino infectious disease specialist Eusebio Garcia. He called the substance "flumamine" (flumamine) and treated flu and malaria with it. A year later, in the article Fluamine, a new synthetic analgesic and antiflu drug (Flumamine: a new synthetic analgesic and antipruritic drug) Garcia said that a single injection of the drug relieved the headache of thirty patients and completely cured them in 24 hours. The doctor did not know the exact mechanism of action, and suggested that flumamine reduces the concentration of sugar in the blood, but did not provide any evidence.

These speculations were enough to interest another physician, the Frenchman Jean Sterne, a specialist in diabetology. He conducted experiments on dogs, rats and rabbits and found that six months of treatment did not affect either their development or liver function. Even the autopsy failed to detect any anomalies. Stern conducted clinical trials on humans, called the drug a "glucophagus" ("sugar eater") and began treating diabetics with it.

Metformin almost immediately had competitors – the more powerful phenoformin and buformin. But these drugs caused lactic acidosis – a dangerous condition that is accompanied by central nervous system depression, respiratory disorders, cardiovascular system functions and urinary excretion. Therefore, by the end of the 70s, they were no longer used in most countries. And that's when metformin became the main alternative to insulin. In the late 50s, it was sold in France and in Great Britain, in the 70s – in Canada, and it entered the American market only after approval by the Food and Drug Administration (FDA) in 1994. There he quickly became a "bestseller"

What we know about metformin

Now metformin is considered a "first-line drug" for the treatment of type 2 diabetes. Its main advantage is that it practically does not cause hypoglycemia, which distinguishes it from insulin and another class of hypoglycemic agents – sulfonylurea derivatives. Metformin reduces the concentration of glucose in the blood by inhibiting its formation in the liver, while sulfonylureas increase the release of insulin from beta cells in the pancreas. In addition, it does not contribute to weight gain. Of course, it also has side effects, unpleasant, but not fatal: the most common are gastrointestinal disorders, in particular nausea, vomiting, flatulence and diarrhea. And a decrease in appetite is even useful.

Much of what we know about the effects of metformin on health, we know thanks to clinical studies. This drug was originally developed to reduce blood sugar, and it was studied, of course, primarily in the context of diabetes. In order to talk about the advantages and disadvantages of metformin, you need to tell at least a little about how doctors extracted this information – otherwise the story will turn into "scientists have proved". Here are some of the most significant clinical trials on type 2 diabetes:

• The University Group Diabetes Program, UGDP (Diabetic program of the university group)
• United Kingdom Prospective Diabetes Study, UKPDS (UK Prospective Diabetes Study)
• Diabetes Prevention Program, DPP (Diabetes Prevention Program)

UGDP was the first randomized clinical trial dedicated to diabetes. 1,027 people took part in it, the study lasted 21 years, from 1960 to 1981, and the first results were published in 1970. Scientists wanted to find out which medicine most effectively prevents the development of cardiovascular complications. The clinical trial has been fiercely criticized, including due to errors in randomization. However, the FDA found no reason not to trust his findings. The participants did not take Metformin, but UGDP declared ineffective another drug of the same class – phenformin, and as a result, the drug "by analogy" was not approved for use in the United States. It was thanks to UGDP that the drug's entry into the market of this country was postponed for many years.

UKPDS was the largest clinical trial at that time – it included 5,102 patients with type 2 diabetes. The trial lasted 20 years, from 1977 to 1997. UKPDS was supposed to answer the question: can intensive control of blood glucose levels prevent the development of complications, and which medicine is best suited for this? Participants took first-generation sulfonylureas, insulin, or followed a diet. After the publication of the results, doctors began to recommend metformin more often.

3,234 people took part in the DPP. The aim of the study was to find the most effective way to prevent type 2 diabetes in people with prediabetes. To do this, one group was offered a diet, exercise and lifestyle changes, another was offered metformin, and the third was offered a placebo. After the clinical trial, another one was conducted – Diabetes Prevention Program Outcomes Study, DPPOS or, in Russian, "Diabetes Prevention Program: a study of the consequences". Doctors studied the health status of DPP participants after 15 years.

Only overweight patients received metformin during UKPDS. The results showed that the drug reduces the risk of death from complications of diabetes by 42% and mortality from all causes by 36%. A good result, but it is not so impressive when you consider that the medicine was compared with an ordinary diet. The risk of cardiovascular complications in patients on metformin, insulin and sulfonylureas was practically the same. Paired with urea derivatives, the drug even increased mortality. But, unlike other drugs, metformin did not contribute to weight gain and caused hypoglycemia less often. Therefore, scientists have proposed nothing less than prescribing metformin as a first-line drug in the treatment of obese patients. This marked the beginning of his popularity.

DPP/DPPOS have shown that taking metformin can reduce the risk of diabetes in people with prediabetes by 31%. But it is still better to change the lifestyle - in this case, the incidence is reduced by 58%. The good old physical education and diet turned out to be almost 2 times more effective. But the drug had another advantage – metformin helped to lose weight. People with prediabetes who took the drug lost about two kilograms on average. The effect persisted all the time while the study participants drank pills, while the medicine was well tolerated.

Of course, there have been other metformin studies and even meta-analyses of these studies. However, we don't know everything about the advantages and disadvantages of this drug yet. For example, scientists are still trying to figure out how metformin affects the development of cardiovascular diseases and mortality - the data on this are contradictory. A review of 30 papers from 2011 showed that the diabetes medication does not bring any significant harm or significant benefit to the heart, and looks good only in comparison with a placebo or a complete lack of treatment. An article from 2016, in which 300 studies were analyzed, says that there is no difference at all between the nine classes of hypoglycemic agents in terms of mortality and cardiovascular diseases. However, the authors of the analysis admit that there was a high risk of bias in the selected articles – more than half of the publications provided information selectively, and sponsors participated in the work on them. On the other hand, a recent study based on 17 publications shows that metformin still reduces mortality in patients with chronic kidney disease, congestive heart failure and chronic liver failure.

New application

In Russia and the USA, metformin is approved only for the treatment of type 2 diabetes, but they are trying to treat other diseases with it. And the more it becomes known about the mechanisms of action and the effect of the drug on the body, the more actively it is sought for a new application.

The fact that taking metformin is accompanied by weight loss has been known for a long time. DDP and DDPOS did not open the eyes of doctors, but only confirmed previous observations. Therefore, doctors tried to treat healthy obese people with metformin. One of the first such studies was published in 1970 in the Lancet journal. Scientists compared the effectiveness of metformin and fenfluramine on the example of 34 women aged 22-59 years. After 8 weeks of therapy, they came to the conclusion that fenfluramine works better, and it has fewer side effects.

Works from 1998 and 2001 rehabilitated the hypoglycemic drug and showed that it reduces weight in non-diabetics, but later a meta-analysis came out that called these results into question. Scientists selected 57 studies and excluded 48 of them because they did not meet the standards of clinical trials. There are only 9 left – and after the analysis it became clear that there is not enough data on the effectiveness of metformin. 3 years later, another review was released and confirmed the results of the previous one. Metformin seemed to reduce weight by 3-9 kilograms, but the sample of such studies was small, the duration was short, and the design was "weak". In addition, the participants, in addition to taking medication, were engaged in physical education – try to figure out what exactly helped them lose weight. Several longer trials, devoid of these drawbacks, showed only a slight weight loss.

Four years ago, the results of perhaps the largest clinical study devoted to the treatment of obesity in non-diabetics were published. If in previous works it was about three or four dozen people, now there were 200 volunteers. 20% could not lose weight at all, and 9 people gained it. The remaining study participants lost, on average, 5% of their body weight, and most of all the drug helped people with impaired insulin susceptibility. But a methodological catch crept into this study as well: there was no randomization of the control group.

Overweight children and adolescents are also treated with metformin, but not particularly successfully. In 2016, Cochrane, an international NGO that studies the effectiveness of healthcare technologies, presented a systematic review and showed that not only metformin, but also other drugs in this category of the population are ineffective. And the quality of the available data expects much to be desired. In general, doctors recognize that it is too early to recommend a diabetic drug for the treatment of obesity to both children and adults. The problem is still solved mainly by diet and physical education.

Another use of metformin is the treatment of polycystic ovary syndrome (PCOS). PCOS is a condition in which women's levels of male hormones (androgens) increase, ovarian function is disrupted and the menstrual cycle is disrupted. As a result, ovulation does not occur, and it becomes difficult to get pregnant (although not always impossible). Many patients begin to have excessive hair growth on their face and body, acne appears, and about half gain excess weight. It was not possible to fully understand the causes of PCOS, and it is impossible to cure it once and for all. But it is already known that the disease is associated with insensitivity of tissues to insulin, and women with this syndrome have an increased risk of developing type 2 diabetes. Metformin, which fights insulin resistance, seems to come in handy here.

But not everything is so simple. In 1994, the drug proved itself well – then Venezuelan scientists conducted a study involving 29 women, 7 of whom recovered their menstrual cycle, and three spontaneously became pregnant. "With the help of metformin, many, if not all, metabolic disorders of PCOS can be reversed," the authors wrote. However, it was immediately stipulated that they did not randomize and did not use a placebo for comparison. However, larger and more thoughtful clinical trials in 2006-2007 did not confirm the optimistic assumptions. Metformin stimulated ovulation not particularly effectively and was inferior to clomiphene (trade name – Klostylbegit).

According to the clinical recommendations of the International Society of Endocrinologists (Endocrine Society), the diabetic drug helps with metabolic disorders and irregular menstruation, but is limited or ineffective in the treatment of infertility, acne and excessive hair growth. A similar conclusion was reached by the participants of a seminar organized by the American Society for Reproductive Medicine. They recommended metformin only to women with impaired glucose tolerance. But the Cochrane review from 2014 says that the drug is more effective than a placebo and increases the chance of getting pregnant. However, the quality of the evidence base of the research was recognized as low, and the probability of error was high.

And metformin, theoretically, can help in the fight against cancer. But to what extent these hopes are justified, it is still unknown. They began to seriously look at the medicine from this side only 12 years ago – an insignificant period, if you remember how long it lasted, for example, UKPDS. In 2005, Josie Evans and her colleagues from the University of Dundee reported that taking metformin reduces the incidence of cancer among diabetics by 23%. They came to such conclusions after analyzing the data of the electronic medical database DARTS.

The publication inspired the other doctors, and they began to double-check the conclusions of colleagues with the help of other medical registries. Gradually, the benefits of metformin were confirmed by more and more studies. There were reviews of scientific papers that showed a decrease in morbidity at the level of 31-34%. Then – experiments on cell cultures and mice. It turned out that in rodents, under the influence of a diabetic drug, tumor growth slows down by as much as 50% – however, the medicine was fed to them in doses exceeding human ones.

Why can't we please the readers and say that we have finally found a new effective remedy for cancer? For two reasons. Firstly, there is no abstract "cancer" - it is a combination of different oncological diseases. How effectively metformin fights each of them needs to be tested during clinical trials, and this process is still far from complete. Secondly, the reliability of the data that aroused enthusiasm at an early stage was questioned. In two dozen papers, errors were found that could distort the results. And where they did not find, they did not find a link between metformin and the incidence of cancer. In general, more time is needed, more research is needed.

Metformin and aging

If metformin is mentioned in the media, the article is probably about prolonging life. Gerontologists look at the old medicine with hope, and they have good reasons for this. Firstly, in recent years, scientists have begun to actively investigate the molecular and genetic mechanisms of aging. Studies show that limiting calorie intake increases the lifespan of mice and rats by about 30-40%. According to an article published this year, such "therapeutic fasting" prolongs the life of primates. "What does metformin have to do with it?" you may ask. According to some scientists, metformin causes approximately the same changes in the body as calorie restriction: increases insulin sensitivity, lowers cholesterol, improves physical condition. And the expression of genes in rodents fed with metformin resembles that of animals on a low-calorie diet.

So scientists undertook to test the effect of the drug on model organisms. Caenorhabditis elegans worms treated with metformin lived 18-36% longer (depending on the dose) than their relatives from the control group. Mice – by 5%. By the way, similar experiments were carried out in Russia, at the N. N. Petrov Research Institute of Oncology. Scientists fed metformin not to ordinary rats, but to a breed created specifically for the study of hypertension and cardiovascular diseases. In such animals, the average life expectancy increased by 37.8%. Gerontologists even got to crickets: in the Acheta domesticus species, after treatment with an antidiabetic drug, the maximum life expectancy was 138% compared to the control group.

The next logical step would be to conduct human trials. The results of one such study have already been published. Scientists analyzed data from 180,000 people: 78,000 had diabetes and took metformin, 12,000 drank sulfonylureas and 90,500 were healthy. This information was obtained not during a double-blind placebo-controlled trial, but from the Clinical Practice Research Datalink database of medical documentation. The results showed that diabetics on metformin live 15% longer than healthy people. The media wrote about a drug that can prolong life, but some scientists were not impressed by the work entitled "Can people with type 2 diabetes live longer than healthy people?" Here's what Kevin McConway, Professor of applied statistics at The British Open University, said about her:

"The title of the article is misleading, because whoever reads it may misunderstand it – in fact, this study cannot answer the question asked for the reasons I will give below, and it seems as if doctors have reason to recommend metformin to healthy people. But that's not what the study is about.

In a press release, Craig Curry says "After a person develops diabetes, his life expectancy is reduced, on average, by 8 years" and further explains why.

If the lives of diabetics are so much shorter than those of healthy people, how can they "live longer than those who do not have diabetes," as the headlines of the article and press release say?

The fact is that the study is devoted to the period of time when diabetic patients received metformin as first-line therapy (this group is also compared with those who received sulfonylureas as first-line therapy). At some point, many patients will be transferred to second-line therapy due to the fact that diabetes or its symptoms have worsened. But at this point, the study simply ends.

So in the quote about reducing life expectancy in patients with type 2 diabetes by 8 years, we are talking about the patient's entire life after diagnosis, including the period when he is on more aggressive second-line therapy. But the study only takes into account the time interval before the change in the treatment regimen. It won't fit into a capacious title, but it's important to note that not everything is so simple here.

But if the survival rate of diabetics taking metformin is significantly higher than that of healthy people, even for a limited period of time, does this not mean that people who do not have diabetes should take metformin to live longer? No, it doesn't. Such a clear difference may not be due to metformin, but to something else. […]

The difference in survival between diabetics on metformin and the control group was statistically significant, but, in fact, quite small and probably within the limits that can be explained by residual distortion (the influence of other variables that are not taken into account during the analysis)."

In addition, it would be unfair not to mention that the research was funded by pharmaceutical companies AstraZeneca and Bristol-Myers Squibb. Employees of these firms had access to the research data, although the article states that they could not influence the analysis, review or publication process. And the scientists themselves are quite familiar with the pharmaceutical industry. Five of them worked for the research consulting company Pharmatelligence, which receives grants from drug manufacturers. Another was an employee of Bristol-Myers Squibb. By itself, this does not make the results unreliable, but, you must agree, it is somewhat alarming. Especially considering the fact that both sponsor companies produce metformin.

So it is impossible to understand this issue without full-fledged clinical trials. One of the first studies on the relationship between metformin and aging was supposed to be the "Study of the effect of metformin on life expectancy" (Metformin in Longevity Study). But since its launch in 2014, no information has appeared about it. Preliminary results were supposed to be obtained two years ago, but since then not a single publication has been published.

Another clinical trial is on the way – "Fighting aging with Metformin" (Targeting age with Metformin, TAME). This double-blind, randomized, placebo–controlled trial is the gold standard, just the way we like it. It will be attended by 3,000 people aged 65 to 79 years. TAME is quite unusual for several reasons. Firstly, it is aimed at studying what does not seem to exist. Aging, from a medical point of view, is not a disease. There is also no universally recognized biomarker by which it would be possible to understand whether this process is slowing down or not. Therefore, the purpose of the study is to determine whether metformin can slow down the development of age–related diseases: cardiovascular, neurological, oncological, and so on.

Scientists hope that they will be able to set a precedent, and in the future the FDA will recognize aging as an "indication", a condition that can be treated.

"I think the FDA would rather accept what is called "concomitant diseases" than something called "aging," says the head of the scientific group Nir Barzilai. – Even in our... in my opinion, old age is not a disease. This is, you know, human nature! We are born, we die, and in between we grow old… I mean, 'I don't care what you call it, as long as I can delay it.'"

Another unusual detail is that neither pharmaceutical companies nor the state sponsor the study. Funds are collected by the American Federation for the Study of Aging (American Federation for Aging Research), a donation can be made by anyone. According to Barzilai, conducting clinical trials will cost "50 million dollars, plus or minus 20 million." The results will not be available soon: it will take some time to collect money, the study itself will last 3-4.5 years, plus time for processing and publishing data. But when it comes to prolonging life, you can wait.

Portal "Eternal youth" http://vechnayamolodost.ru  03.04.2017