• Metformin and pioglitazone in the treatment of diabetes mellitus type 2

    June 22, 2015

    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