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Metformin is the most commonly used anti-diabetic medicine worldwide. It is generally recognized by experts as the first choice diabetic glucose-lowering drug for glycemic diabetes type 2 (DT2) control – the preferred tool for starting pharmacotherapy according to the international guidelines (the European Association for the Study of Diabetes, the American Diabetes Association and the International Diabetes Federation) and the national standards.

Metformin is associated with beneficial effects, including with increasing life expectancy, improving the cardiovascular outcomes or even preventing the onset of certain cancers.

Metformin reduces hyperglycaemia by mainly suppressing hepatic glucose production (hepatic gluconeogenesis), by the activation of the enzyme adenosine monophosphate-activated protein kinase (AMPK).

Other molecular mechanisms that may play a role for the glucose-lowering effect of this drug are: the inhibition of the mitochondrial respiratory chain; the inhibition of the glucagon-induced increase of cyclic adenosine monophosphate (cAMP) and the subsequent activation of protein kinase A (PKA); the activation of the intestinal flora (microbiota) and increased levels of total and intact glucagon-like peptide-1 (GLP-1).
Evidence that metformin is very effective as monotherapy for improving HbA1s dates from 1995. DeFronzo and his colleagues conducted two large randomized, double-blind, parallel group studies in patients with moderate obesity and DT2, who had not achieved good glycemic control with diet alone, and showed that metformin was superior to:

– Placebo, when improving the levels of fasting plasma glucose – FPG (10.6 +/- 0.3, respectively, as compared to 13.7 +/- 0.3 mmol / l) and HbA1c (7.1 +/- 0.1 as compared to 8.6 +/- 0.2%);
– the Sulfonylurea agent glibenclamide, for improving the levels of FPG (10.5 +/- 0.2 as compared to 14.6 +/- 0.2 mmol / l) and HbA1c (7.1 +/- 0.1 as compared to 8.7 +/- 0.1%) but at a low incidence of hypoglycemia.
Moreover, patients treated with metformin demonstrated a statistically significant reduction in the plasma levels of total cholesterol, LDL-cholesterol and triglycerides, while in the other two subgroups no changes were observed.

Metformin maintains lasting control in time, as compared to sulfonylurea agents, applied in both cases as monotherapy (the cumulative rate of depletion of the action for a period of five years – 21% vs. 34%), as the survey data of ADOPT (A Diabetes Outcome Progression Trial), published in 2006 indicated.

Metformin alone can maintain the glycemic control in patients with DT2 at a significantly lower incidence of hypoglycaemia for a long time, as compared to sulfonylurea agents – which is another important conclusion from the study.

The intensive glycemic control with metformin, used as first-line therapy, resulted in a lower incidence of all diabetes-related adverse outcomes, including diabetes-related death in patients with DT2 and obesity, indicated the UKPDS (UK Prospective Diabetes Study) survey data.
Moreover, metformin is associated with a much lower risk for hypoglycemia and has a neutral effect on weight, unlike the sulfonylurea agents CC (+2.3 kg) and insulin (+4.5 kg). The authors of the UKPDS recommend the use metformin as a pharmacological first choice therapy for patients with DT2 and obesity.

There was a decrease of 32% of all diabetes-related outcomes, 42% – of diabetes-related mortality, 36% – of total mortality, 39% – of myocardial infarction and 50% – of deaths from coronary heart disease in patients treated with metformin, as compared to the group on conventional glycemic diet control alone.

In patients on intensive glycemic control, metformin achieved a better effect than the sulfonylurea agents or insulin to lower the incidence of all diabetes-related outcomes, of overall mortality and stroke. In the study HOME, the therapy with metformin resulted in weight loss (-3 kg) and lower insulin needs. The administration of this drug for an average of 4.3 years has led to a reduction in macrovascular events (secondary endpoint) by 39%, confirming the results from the UKPDS.

Retrospective observational studies suggest an increased cardiovascular events and deaths risk associated with sulfonylurea agents, as compared to metformin, used in both cases as an initial monotherapy in patients with DT2. A retrospective analysis of the UK Clinical Practice Research Datalink (CPRD) for the period 2000-2012, compared initial monotherapy with metformin to that with sulfonylurea agents. It indicated that sulfonylurea agents are linked to 1.58 times higher total mortality than biguanide. These data support the idea that metformin should be the first choice for DT2 treatment.

The analysis included the data of 78,241 people treated with metformin, 12 222 patients treated with sulfonylurea agents and 90 463 controls without diabetes, who had similar demographic characteristics, smoking history, health status, and were monitored by the same GP.

A total of 7498 cases were fatal, as the mortality rate reached 14.4 (for those on monotherapy with metformin) and 15.2 (in the corresponding controls) to 50.9 (for those on monotherapy with sulfonylurea agents) and 28.7 (in the corresponding controls) per 1000 patient-years.

Metformin may slow down the development of DT2

The study DPP (Diabetes Prevention Program) found that metformin (850 mg twice daily) as compared to placebo may decrease the risk of the onset of DT2 by 31% over three years in patients with a pre-diabetic condition. The benefits of this preventive intervention are particularly pronounced in younger obese patients.

During the extension phase (the DPPOS- Diabetes Prevention Program Outcomes Study), which lasted for a period of 12 years after the DPP, in the group receiving metformin treatment during the DPP / DPPOS, the risk of DT2 development remained lower by 18% than in the placebo control group during the DPP, although both groups took measures to change their lifestyle.

The authors of the DPPOS drew an important conclusion – that delaying the onset of DT2 via introducing a lifestyle change (the more efficient method) or by taking metformin, or by using both methods, may protect people with pre-diabetes conditions from the onset of DT2 and the related microvascular complications (-28% lower frequency compared to the patients who developed DT2). The results of the DPP / DPPOS show that the treatment with metformin leads to mild, but long-term weight loss, as this seems to be the main factor that slows the development of DT2.

For a period over 15 years biguanidine has demonstrated an excellent safety profile and tolerability. A particularly valuable advantage of metformin is the very low risk of hypoglycaemia. Patients who have suffered through one or more episodes of severe hypoglycemia, associated with glucose-lowering therapy, have a higher likelihood of cardiovascular events (myocardial infarction or ischemic stroke) and increased mortality (cardiovascular and all-cause), showed the results of the studies ADVANCE ( Action in Diabetes and Vascular Disease: Preterax and Diamicron Modified Release Controlled Evaluation) and ORIGIN (Outcomes Reduction with an Initial Glargine Intervention).

Therefore, the prescription of agents that can cause hypoglycemia should be done only when absolutely necessary and after careful consideration. An advantage should be given to antidiabetic drugs that are associated with a minimal risk of hypoglycemia.

Opinion on the control of hyperglycemia in DM type 2

In 2012, the American Diabetes Association and the European Association for the Study of Diabetes produced an Opinion on the control of hyperglycemia in DM type 2, and in 2015 they published a second updated option. According to this opinion, the first step in the treatment of DM type 2 is a change in lifestyle and monotherapy with metformin. If in three months’ time the individual glycemic targets have not been reached, a switch is made to two drugs combination therapy, and upon its failure in another three months – a third medicine is added to the therapy.

Few therapeutic agents intended for the treatment of diabetes type 2 have an effective impact both – insulin resistance, and the function of the beta-cells, when administered as monotherapy. Another drug which enhances insulin sensitivity and improves the function of beta cells apart from metformin is pioglitazone (from the group of the thiazolidinediones). Pioglitazone appears to have an even more pronounced positive effect on beta-cells. These characteristics of both medicines make them suitable combination for initial or additional therapy in patients who cannot achieve good glycemic control.

In comparative/combined studies with metformin, pioglitazone showed equal efficacy in terms of the reduction of glycated hemoglobin and fasting plasma glucose with continuous monitoring. The combination therapy with metformin and pioglitazone had a synergistic effect, leading to significant improvements in glycemic control, as well as an increase in HDL-cholesterol and a decrease in triglycerides, as compared to metformin and placebo.

To sum up:

1. First-line therapy – metformin;
2. Second line therapy – adding sulfonylurea agents to metformin;
3. Third-line therapy – the replacement of sulfonylurea agents/metformin or adding pioglitazone, sitagliptin, vildagliptin, at the choice of the physician. Data from clinical trials showed that the addition of pioglitazone reduced HbA1c to a greater degree than sitagliptin and vildagliptin (Chawla et al., 2013, Liu et al., 2013, Lee et al., 2013, Bolli et al., 2008, Kaur M. et al., 2014, Kaur K. et al., 2014);
4. Fourth-line therapy – exenatide is added to metformin or sulfonylurea agents only when the BMI> 35,0 kg / m².

Tchaikapharma High Quality Medicines Inc. offers the following medicines for the treatment of DM type 2 on the Bulgarian market:

NHIF code – AF 341 – Metformin-Tchaikapharma (metformine)

850 mg x 30 tablets – does not require extra pay

NHIF code – AF 505 – Pizona (pioglitazone)

15 mg x 30 tablets – does not require extra pay

NHIF code –  AF 506 – Pizona (pioglitazone)

30 mg x 30 tablets – does not require extra pay

NHIF code –  AF 507 – Pizona (pioglitazone)

45 mg x 30 tablets – does not require extra pay

Seemingly healthy skin can contain billions of precancerous cells

Mutant cells, capable of causing lethal forms of cancer, hide in the body for years, warn British experts, quoted by the “Daily Express”.

The authors of the study from Cambridge University and the Wellcome Trust Sanger Institute found that seemingly healthy and normal functioning skin can contain billions of precancerous cells. These cells with damaged DNA are in a “dormant” state, in which they can remain for years or even decades before “waking up without warning.”

So far, it has been well documented that excessive exposure to the sun increases the risk of skin cancer, including the deathly cutaneous melanoma. The authors of this study, however, claim that millions of people live in ignorance that their skin can contain lethal mutations as a result of excessive exposure to sunlight years before.

Researchers have found that in healthy people over 55 years, more than a quarter of the cells carry the mutation which may cause cancer, although the skin is seemingly healthy and continues to function normally. Experts believe that this is due to past burns, and each cell has the potential to become dangerous.

Experts remind that in order to be protected, people should avoid excessive exposure to sunlight and reiterate the need to use sunscreen products.

Swiss scientists have developed a tiny implant that warns of a heart attack a few hours before it takes place.

The 14-mm device can be easily implanted under the skin. It regularly measures five indicators, including proteins such as troponin, whose elevated levels signal myocardial injury.

The implant sends information to a smartphone or a computer via the Bluetooth wireless device and gives raise to an alarm when it encounters disturbing results.

Besides being able to recognize the early signs of a heart attack, it can also monitor the level of blood glucose, lactate, and ATP, providing useful physiological information during physical activity or chronic conditions such as diabetes.

The chip is provided with seven biochemical sensors, and should be placed at a depth of about one centimeter under the skin.

Sensors monitor specific molecules such as glucose and cholesterol, depending on what doctors are looking for.

The chip was developed by the Federal Polytechnic Institute in Lausanne by the team of Dr. Giovanni de Micheli.

He points out that except for “early warning”, the implant can be used to monitor patients’ recovery after surgery in real time.

The Health Ministry introduced new specialization rules at the beginning of this year, according to which each clinic is required to conclude an employment contract with the physicians who will work alongside specializing. The aim is to put an end to the free labor of young doctors.

The problem is that most young doctors cannot specialize under the new rules this year, because hospitals have no money with which to pay them salaries. There are no new funds for the recruitment of young doctors and fewer openings are announced for specializing doctors than previous years.

A major problem of the new graduating doctors is the few openings in university hospitals in the country, and there are specialties in those hospitals for which no openings have been announced.

The total number of pediatricians in Bulgaria is 1401. A single pediatrician treats an average of 688 children. Children’s gastroenterologists, however, are a total of 9 specialists for the whole country. There are very few children’s nephrologists and oncologists, but still the medical institutions which will launch a specialization in pediatrics are few and far between. In addition, the appointed according to the new regulation specializing doctors in some hospitals are forced to sign contracts that bind them to remain in the hospital 4-5 years after receiving a specialty. If in this period they decide to leave, they are obliged to return all salaries received over the years.

The regulation also posits some questions that give rise to confusion and uncertainty among specializing doctors in the so-called “specializing doctors status quo”. Most of them want to undergo training according to the new regulation for specializing doctors. Hospitals, however, are not motivated to employ them and for a significant part of them medicine continues to be an expensive hobby – they pay a monthly fee of BGN 180 to work. It is this fee that is one of the main problems among specializing doctors. Most work is at the expense of young doctors, who except working in hospitals often work in another 1-2 places. The reason for this is the low pay and the pursuit of higher incomes. And since quite a lot of them do not receive income from work in clinics, but pay (BGN 180 per month) to treat patients in Bulgaria, this forces them to earn a living by putting in extra work, sometimes unrelated to medicine.

According to Health Ministry’s records hospitals announced 2820 openings for specializing doctors last year, but the actually employed people were 814. The reason was that most of the openings are paid. Among those, the state funded 409 positions, and the major specialties were not sought after by young doctors. For the other openings doctors had to seek education funds on their own, and even for pay for their own work. This year the state will be paying the fee for 415specilizing doctors, but not their salaries. Physicians’ salaries will have to be paid by the hospitals.

Although dozens of young doctors have already begun work under the new Regulation on Specializations, there remain few openings, announced by the largest university hospitals in the country. Many future doctors are considering the question of whether to stay in Bulgaria at all.

Five thousand people less pay contributions to the National Social Security Institute than the people insured in 1993.

Bulgarians have been ill almost two times longer in 2014 than in 2003. This is what the data from the National Social Security Institute budget performance since 2003 has shown.
11 years ago the National Social Security Institute paid an average of five days sick-leave. In 2014 the length of sick-leaves had already become nine days, according to the Institute. Of those nine days, after the changes in 2010, the first 3 are paid for by the employer, while the National Social Security Institute pays only for 6 days.

However, its sickness expenses for paying sick-leave benefits have increased more than 3 times from 2003 to 2014. If 11 years ago BGN 110 million were paid for sick-leaves, during the past year the sum was already BGN 340 million. The reason was the increased amount of pay for sick-leave was due to the higher wages at the time, explained experts from the Institute. The increased illness duration, on the other hand, is due to the changes in the rules for issuing sick-leave – for flu the sick-leave has already become five days, not 3, as it was 3 years ago.

The insured Bulgarians have decreased by 500 000 people from 1993 to 2013, as it becomes clear from the statistics of the Institute. In 1993, 3.030 million working people paid contributions, while in 2013 – the number was 2.4 million people.

The year with the highest number of contributors was 1997, when 3.2 million people paid contributions. The year with the lowest number of contributors was 2002 – only 2 million people paid for health insurance then.

The annual pensions’ payment costs of the Institute in 2003-2014 increased by BGN 5 billion. Eleven years ago BGN 2.8 billion were paid for pensions, while last year a record of BGN 8.1 billion was reached. The NSSI deficit escalated from BGN 500 million to BGN 1.8 billion per year for the same period.

Five times more Bulgarians died before retirement age.

The death benefits of an insured person, who paid the National Social Security Institute, has increased five times for the period of 10 years. In 2003, only BGN 480 thousand were paid for such benefits, while in 2013 – the sum was nearly BGN 2 million. The benefits for a person who died before qualifying for his/her pension rights, were paid to 10 052 heirs.

The amount the National Social Security Institute hands out to the heirs of deceased insured Bulgarians is BGN 540. It is distributed equally among the heirs – spouse or children. According to the Institute, the average amount of compensation received by an heir decreased from BGN 213.20 in 2003 to BGN 193.95 in 2013. An heir received the highest amount in 2007 – BGN 309.17.