Metformin - a cure for everything? Yes but no
We here, in the XX2 Century edition, love Metformin very much and tell about it at any opportunity. Today it inhibits 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 disease. Unfortunately, this is not entirely true and almost yes to every good news is attached. So we decided to write again about metformin - this time a big text that will explain to those who missed everything, where did this drug come from, what treatment was it and how successful.
It all started with grass. Kozlyatnik medicinal, he is goat ruta, he is an Italian polecad, he, in a scientific way, Galéga officinális is a perennial herb. In medieval Europe, they were treated with frequent urination — one of the symptoms of diabetes — and some other diseases. It is difficult to say how long the goatling is used in traditional medicine, but it is known that the famous English doctor Nicholas Culpeper mentioned it in 1652 in the book The English Doctor.
At the end of the 19th century, scientists took a close look at the goatling and found out that it contained large amounts of guanidine (this colorless crystalline substance was first synthesized in 1861). In 1918, during experiments on rabbits, scientists have shown that guanidine reduces the level of glucose in the blood. But the compound was too toxic, and they could not treat people, so scientists began experimenting with guanidine derivatives. In 1922, Emil Alphonse Werner and James Bell, during the synthesis of N, N-dimethylguanidine, received dimethyl biguanidine, known to us as Metformin, and seven years later the German scientist Karl Slotta tested it on animals . There were other guanidine-based drugs — galegin (isoamylene-diguanidine), the biguanides Sintalin A and B. Syntalines were even used in clinical practice for some time, but after the industrial production of insulin began (in 1923, Eli Lilly and Company started selling it under the name "Iletin"), forgotten about guanidine derivatives.
In 1949, Metformin fell into the hands of the Philippine infectiologist Eusebio García (Eusebio Garcia). He called the substance "flumamine" (flumamine) and treated them for influenza and malaria. A year later, in the article Fluamine, a new synthetic analgesic and antiflu drug (Flumamine: a new synthetic anesthetic and anti-cold medicine), Garcia said that a single injection of the drug alleviated 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 medic - Frenchman Jean Sterne, a specialist in diabetology. He conducted experiments on dogs, rats and rabbits and found that the semi-annual treatment did not affect either their development or the function of the liver. Even during the autopsy, no anomalies were found. Stern conducted clinical trials in humans, called the drug "glucophage" ("sugar eater", by analogy with the bacteriophage) and began treating diabetics with it.
At metformin almost immediately appeared competitors - more powerful fenoformin and buformin. But these drugs caused lactic acidosis - a dangerous condition that is accompanied by depression of the central nervous system, respiratory failure, cardiovascular and urinary functions. Therefore, by the end of the 70s, they were no longer used in most countries. And then metformin became the main alternative to insulin. In the late 1950s, it was sold in France and the UK, in the 1970s in Canada, and it entered the American market only after it was approved by the Food and Drug Administration in 1994. year There he quickly became a "bestseller".
What do we know about metformin
Metformin is now considered a "first line drug" for the treatment of type 2 diabetes. Its main advantage is that it almost does not cause hypoglycemia, it distinguishes it from insulin and another class of sugar-lowering drugs - sulfonylurea derivatives. Metformin reduces the concentration of glucose in the blood by inhibiting its formation in the liver, while sulfonylurea drugs increase insulin secretion from beta cells in the pancreas. In addition, it does not contribute to weight gain. The side effects of him, of course, also exist, unpleasant, but not fatal: the most common are gastrointestinal disorders, in particular, nausea, vomiting, flatulence and diarrhea. A decrease in appetite is even useful.
Much of what we know about the effects of metformin on health, we know from clinical studies. This drug was originally developed to reduce blood sugar, and studied it, of course, primarily in the context of diabetes. In order to talk about the advantages and disadvantages of metformin, you need at least a little to tell about how physicians extracted this information - otherwise the story will turn into "scientists proved". Here are some of the most significant clinical trials on type 2 diabetes:
- The University Group Diabetes Program, UGDP (University Diabetes Program)
- United Kingdom Prospective Diabetes Study, UKPDS (British Prospective Diabetes Study)
- Diabetes Prevention Program, DPP (Diabetes Prevention Program)
The UGDP was the first randomized diabetes clinical trial. 1027 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 know which medicine most effectively prevents the development of cardiovascular complications. The clinical trial was subjected to fierce criticism, including due to errors in randomization. However, the FDA found no reason not to trust its findings. The participants did not take metformin, but the UGDP declared another drug of the same class, phenformin, ineffective, and as a result, the drug "by analogy" was not approved for use in the United States. It is thanks to the UGDP that the entry of drugs into the market of this country has been postponed for many years.
The UKPDS was the largest clinical study at that time - it included 5,102 people with type 2 diabetes. The test lasted 20 years, from 1977 to 1997. The UKPDS had to answer the question: can intensive control of blood glucose level prevent the development of complications, and which medicine is best suited for this? Participants took first-generation sulfonylurea drugs, insulin, or followed a diet. After the results were published, doctors began to recommend metformin more often.
3 234 people took part in the DPP. The goal of the study was to find the most effective way to prevent type 2 diabetes in people with pre-diabetes. For this, one group was offered diet, exercise and lifestyle changes, the other - metformin, and the third - a placebo. After a clinical trial, another study was conducted - the Diabetes Prevention Program Outcomes Study, DPPOS or, in Russian, the "Program for the Prevention of Diabetes: A Study of the Impact". Doctors studied the health of the DPP participants 15 years later.
During UKPDS, only overweight patients received metformin. The results showed that the drug reduces the risk of death from diabetes complications by 42% and all-cause mortality 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 sulfonylurea preparations was almost the same. Coupled with urea derivatives, the drug even increased mortality. But, unlike other means, metformin did not contribute to weight gain and less often caused hypoglycemia. Therefore, scientists have suggested no less than to appoint metformin first-line drug in the treatment of patients with obesity. This marked the beginning of his popularity.
DPP / DPPOS have shown that taking metformin can reduce the risk of developing diabetes in people with pre-diabetes by 31%. But it is better to change the lifestyle - in this case, the incidence is reduced by 58%. The good old physical culture and diet were almost 2 times more effective. But the drug found another advantage - Metformin helped to lose weight. People with prediabetes who took the drug, on average, lost about two kilograms. The effect persisted as long as the study participants drank the pills, while the medicine was well tolerated.
Of course, there were other studies of metformin and even meta-analyzes of these studies. However, we do not yet know everything about the advantages and disadvantages of this drug. For example, scientists are still trying to figure out how metformin affects the development of cardiovascular diseases and mortality - the data on this account are contradictory. A review of 30 papers from 2011 showed that the cure for diabetes does not cause the heart any substantial harm or significant benefit, and it looks like a good man only in comparison with placebo or the complete absence of treatment. An article from 2016, which analyzed 300 studies, says that there is no difference between mortality and cardiovascular diseases between the nine classes of sugar-reducing drugs. 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 submitted information selectively, and sponsors participated in the work on them. On the other hand, a recent study based on 17 publications shows that in patients with chronic kidney disease, congestive heart failure and chronic liver failure, metformin still reduces mortality.
In Russia and the United States, metformin is approved only for the treatment of type 2 diabetes, but other diseases are also being tried. And the more it becomes aware of the mechanisms of action and the effect of the drug on the body, the more actively they are looking for a new use.
The fact that the intake of metformin is accompanied by weight loss has been known for a long time. DDP and DDPOS did not open their eyes to doctors, but only confirmed previous observations. Therefore, doctors tried to treat healthy people with obesity with metformin. One of the first such studies was published in 1970 in the journal Lancet. Scientists compared the efficacy of metformin and fenfluramine on the example of 34 women aged 22–59 years. After 8 weeks of therapy, they concluded that fenfluramine works better and has fewer side effects.
The 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, which put these results into question. Scientists selected 57 studies and 48 of them were excluded because they did not meet the standards for conducting clinical trials. There are only 9 left - and after the analysis it became clear that the data on the effectiveness of metformin is not enough. After 3 years, another review came out and confirmed the results of the previous one. Metformin, it seems, reduced the weight by 3–9 kilograms, but the sample of such studies was small, the duration was short, and the design was "weak." In addition, participants in addition to taking medication were engaged in physical exercise - try to figure out what exactly helped them lose weight. Several longer trials lacking these deficiencies showed only a slight weight loss.
Four years ago, they published the results of perhaps the most extensive clinical study on the treatment of obesity in non-diabetics. 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 participants in the study lost, on average, 5% of body weight, and most of all the drug helped people with impaired insulin susceptibility. But a methodological trick also crept into this study: there was no randomization of the control group.
Children and adolescents with overweight metformin are also treated, but not particularly successfully. In 2016, Cochrane (an international NGO that studies the effectiveness of health technologies) presented a systematic review and showed that not only metformin, but other drugs in this category of the population are ineffective. And the quality of the available data expects to be desired. In general, doctors recognize that it is too early to recommend a diabetic drug for the treatment of obesity in both children and adults. The problem is still solved, mainly with diet and physical education.
Another use of metformin is the treatment of polycystic ovary syndrome (PCOS). PCOS is a condition in which women increase the level of male hormones (androgens), disrupt ovarian function, and lose the menstrual cycle. As a result of ovulation does not occur, and it becomes difficult to get pregnant (although it is not always impossible). In many patients, excessive growth of facial and body hair begins, acne appears, and about half gain weight. Until the end, it was not possible to 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 in women with this syndrome there is an increased risk of developing type 2 diabetes. Metformin, which fights insulin resistance, seems to be the way here.
But not everything is so simple. In 1994, the drug proved to be good - then Venezuelan scientists conducted a study involving 29 women, 7 of whom restored the menstrual cycle, and three of them spontaneously became pregnant. "With the help of metformin, you can reverse many, if not all, metabolic disorders of PCOS," the authors wrote. True, they immediately made a reservation that they did not carry out randomization and did not use placebo for comparison. However, larger and more sophisticated clinical trials of 2006–2007 did not confirm optimistic assumptions. Metformin stimulated ovulation is not particularly effective and inferior to clomiphene (trade name - Klostilbegit).
According to the clinical guidelines of the International Society of Endocrinologists (Endocrine Society), the diabetic drug helps with metabolic disorders and irregular menstruation, but is limited or not effective in the treatment of infertility, acne and excessive hair growth. A similar conclusion was reached by participants in a seminar organized by the American Society for Reproductive Medicine (American Society for Reproductive Medicine). They recommended metformin only to women with impaired glucose tolerance. But the Cockrane Review from 2014 says that the medicine is more effective than placebo and increases the chance of getting pregnant. True, the quality of the evidence base of research was recognized low, and the probability of error was high.
And metformin, theoretically, can help fight cancer. But how far these hopes are justified is not yet known. From this side, only 12 years ago began to seriously look at the medicine - an insignificant period, if you remember how long the UKPDS lasted. In 2005, Josie Evans and her colleagues at the University of Dundee (University of Dundee) reported that taking metformin by 23% reduces the incidence of cancer among diabetics. They came to such conclusions after analyzing the data of the electronic medical database DARTS.
The publication inspired the rest of the medical profession, and they began to double-check the findings of their colleagues with the help of other medical registries. Gradually, the benefit of metformin was confirmed by more and more studies. There were reviews of scientific works, which showed a decrease in the incidence 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 is it impossible to please the readers and say that we have finally found a new effective cancer medicine? For two reasons. First, the abstract "cancer" does not exist - it is a combination of various oncological diseases. How effectively metformin fights with each of them needs to be tested during clinical trials, and this process is far from complete. Secondly, the credibility of the data that aroused enthusiasm at an early stage was called into question. In two dozen papers found errors that could distort the results. And where they didn’t find, they didn’t find any connection between metformin and cancer incidence. In general, you need more time, you need more research.
Metformin and aging
If the media mention metformin, the article in the article is probably about life extension. Gerontologists look at the old medicine with hope, and they have good reasons for this. First, in recent years, scientists have begun to actively explore the molecular and genetic mechanisms of aging. Studies show that restricting calorie intake increases the lifespan of mice and rats by about 30-40%. If you believe the article published this year, this "therapeutic fasting" prolongs life and primates. "What does metformin have to do with this?", You ask. According to some scientists, metformin causes approximately the same changes in the body as calorie restriction: it increases insulin sensitivity, lowers cholesterol, and improves physical condition. And the expression of genes in rodents fed with metformin resembles that of animals sitting on a low-calorie diet.
So scientists took to test the effect of the drug on model organisms. Worms of Caenorhabditis elegans, treated with metformin, lived 18–36% (depending on the dose) longer than their relatives in the control group. Mice - 5%. By the way, similar experiments were conducted in Russia, at the Oncology Research Institute. N. N. Petrova. Scientists fed metformin not ordinary rats, but a breed created specifically to study hypertension and cardiovascular diseases. In such animals, the average life expectancy increased by 37.8%. Gerontologists even reached the crickets: in the species Acheta domesticus, after treatment with an antidiabetic drug, the maximum life expectancy was 138% compared with the control group.
The next logical step would be to conduct a human trial. The results of one such study have already been published. Scientists analyzed the data of 180,000 people: 78,000 had diabetes and took metformin, 12,000 drank sulfonylureas, and 90,500 were healthy. This information was not obtained in a double-blind, placebo-controlled trial, but from the Clinical Practice Research Datalink medical documentation database. The results showed that diabetics on metformin live 15% longer than healthy people. The media has written about a drug that can prolong life, but some scientists have not been impressed by the work entitled "Can people with type 2 diabetes live longer than healthy people?" This is what Kevin McConway, professor of applied statistics of the British Open University (The Open University), said about it:
"The title of the article is misleading, because the one who reads it may misunderstand it - in fact, this study cannot answer the question asked for reasons that I will give below, and it seems as if the doctors have a reason to recommend metformin healthy people. But the study is not about this.
In a press release, Craig Curry says, "After a person develops diabetes, his life span is reduced by an average of 8 years," and then he explains why. If the life of diabetics is so shorter than that of healthy people, how can they "live longer than those who do not have diabetes," as stated in the headlines of the article and the press release?
The fact is that the study is devoted to the period when diabetic patients received metformin as a first-line therapy (this group is also compared to those who received sulfonylurea as a first-line therapy). At some point, many patients will be transferred to second-line therapy because diabetes or its symptoms have worsened. But at this point the research simply ends.
So the quote about reducing the life expectancy of patients with type 2 diabetes for 8 years is about the patient's entire life after a diagnosis, including the period when he is on more aggressive second-line therapy. But the study takes into account only the time before the change in treatment regimen. It will not fit in a capacious title, but it is important to note that not everything is so simple here.
But if the survival of diabetics taking metformin is significantly higher than the survival of healthy people, even for a limited period of time, does this mean that people who do not have diabetes should take metformin to live longer? No, does not mean. This apparent 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 in the analysis). "
In addition, it would be dishonest not to mention that the research was financed by the pharmaceutical companies AstraZeneca and Bristol-Myers Squibb. The 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 pretty familiar with the pharmaceutical industry. Five worked in the Pharmatelligence research consulting company, which receives grants from drug manufacturers. Another was an employee of Bristol-Myers Squibb. In itself, this does not make the results unreliable, but, you see, it is somewhat alarming. Especially considering the fact that both sponsoring companies produce metformin.
So without a full clinical trial in this matter can not figure out. One of the first studies on the relationship between metformin and aging was to study the effect of metformin on life expectancy (Metformin in Longevity Study). But since the start in 2014, no information appeared about him. The 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 - Anti-aging with Metformin (Targeting age with Metformin, TAME). This double-blind, randomized, placebo-controlled trial is the gold standard, everything we love. It will be attended by 3,000 people aged 65 to 79 years. TAME is rather unusual for several reasons. Firstly, it is aimed at studying what does not exist. Aging from a medical point of view is not a disease. There is no generally accepted biomarker, which can be used to determine if 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 recognizes aging as an "indication", a condition that can be treated. "I think that the FDA will rather perceive what is called" comorbidities "than something called" aging, "says the head of the research group Nir Barzilai. "Even in our ... in my opinion, old age is not a disease." This, you know, human nature! We are born, we die, and in the interval we grow old ... I mean: "I do not care how to call it if I can delay it."
Another unusual detail is that the research is not sponsored by either pharmaceutical companies or the state. The funds are collected by the American Federation for the Study of Aging (American Federation for Aging Research), anyone can make a donation. According to Barzilya, conducting clinical trials will cost "$ 50 million, plus or minus 20 million." The results will not be soon: some time will be spent on collecting money, the research itself will last 3-4.5 years, plus the time for processing and publishing data. But when it comes to prolonging life, you can wait.