Accepted Article

Original Article

METFORMIN POWDER FORMULATION COMPARED TO METFORMIN TABLETS ON GLYCEMIC CONTROL AND ON TREATMENT SATISFACTION IN SUBJECTS † WITH TYPE 2 DIABETES MELLITUS 1,2

Giuseppe Derosa MD, PhD, 1Davide Romano MD, 1Lucio Bianchi MD, 1Angela D’Angelo BD, 1,3 Pamela Maffioli MD 1

Department of Internal Medicine and Therapeutics, University of Pavia, and Fondazione IRCCS Policlinico S. Matteo, PAVIA, Italy 2 Center for the Study of Endocrine-Metabolic Pathophysiology and Clinical Research, University of Pavia, PAVIA, Italy 3 PhD in Experimental Medicine, University of Pavia, PAVIA, Italy Address for Correspondence: Giuseppe Derosa, MD, PhD, Department of Internal Medicine and Therapeutics, University of Pavia and Fondazione IRCCS Policlinico S. Matteo, PAVIA, P.le C. Golgi, 2 - 27100 PAVIA, Italy. Tel: +39-0382 526217, fax: +39-0382 526259. E-mail: [email protected] Keywords: metformin powder, new formulation, metformin tablets.

List of abbreviations: BMI: body mass index; WC: waist circumference; HbA1c: glycated hemoglobin; FPG: fasting plasma glucose, PPG: post-prandial plasma glucose, FPI: fasting plasma insulin, HOMA-IR: homeostasis model assessment insulin resistance index. Running head: metformin powder on glycemic control



This article has been accepted for publication and undergone full peer review but has not been through the copyediting, typesetting, pagination and proofreading process, which may lead to differences between this version and the Version of Record. Please cite this article as doi: [10.1002/jcph.415]

Received 20 August 2014; Revised 14 October 2014; Accepted 15 October 2014 The Journal of Clinical Pharmacology © 2014, The American College of Clinical Pharmacology DOI: 10.1002/jcph.415 1

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Abstract The aim of this study was to evaluate if the new metformin powder formulation improves the treatment satisfaction in patients with type 2 diabetes, in a case-control clinical trial. We enrolled 602 subjects in therapy with metformin in tablets formulation and instructed them to take the same dose of metformin in the new powder formulation. At baseline, and after 6 months since the assumption of metformin powder, each patient answered the following questionnaires: the SF-36 Health Survey, the Diabetes Quality Of Life questionnaire Modified (DQOL/Mod) and the Diabetes Treatment Satisfaction Questionnaire (DTSQ). We also assessed at baseline, at 3 and 6 months: fasting plasma glucose (FPG) and post-prandial glucose (PPG), glycated hemoglobin (HbA1c), fasting plasma insulin (FPI), and homeostasis model assessment index of insulin resistance (HOMA -IR). We observed a statistically significant reduction in HbA1c, FPG, PPG, FPI and HOMA-IR (p < 0.05 for all) with metformin powder. The DTSQ questionnaire showed a higher level of satisfaction linked to the assumption of metformin powder compared to the tablets formulation. In conclusion, metformin powder formulation seems to be more appropriate for the treatment of diabetic patients. The improvement of glycemic control suggests a better adherence to the powder formulation.

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Introduction Data collected from electronic archives of general practitioners and some studies about the consumption of anti-diabetic drugs show that the prevalence of type 2 diabetes mellitus in Italy has reached 5%.1 On a national basis, this indicates that people diagnosed with type 2 diabetes in Italy are about 3 million. Despite the wide range of blood glucose lowering drugs available on the market, there are still many people with type 2 diabetes mellitus whose blood glucose is not adequately controlled and consequently at risk of experiencing dangerous complications such as heart attack, stroke, kidney failure, lower limb amputations, visual impairment, or even death. In Italy, according to the Annals of AMD 2010,2 the value of glycated hemoglobin (HbA1c) is lower

than 7% in just a quarter of people with type 1 diabetes and in less than half (44%) of those with type 2 diabetes mellitus. According to the American Diabetes Association guidelines for the treatment of type 2 diabetes mellitus,3 a low glycemic index diet and aerobical physical activity should be the first line therapy for the treatment of type 2 diabetes mellitus. When they are not enough to reach an adequate glycemic control, we should consider pharmacological treatment. In the absence of contraindications (diabetic ketoacidosis, severe renal failure, shock, heart, respiratory or liver failure), the first line anti-diabetic drug should be metformin. Metformin gives a reduction of glucose plasma level, reducing hepatic glucose production through inhibition of gluconeogenesis and reducing glycogenolysis in the musculature. Metformin also increases insulin sensitivity by enhancing the uptake and utilization of peripheral glucose; moreover, metformin retards intestinal glucose absorption.4 Due to its mechanism of action, metformin reduces insulin resistance without increasing the risk of hypoglycemia.5 Metformin is effective both as monotherapy and in combination with other oral hypoglycemic agents such as insulin secretagogues,6 glitazones,7,8

dipeptidyl peptidase-4 inhibitors,9-11 GLP-1 receptor agonists12 and insulin. The choice of the most suitable drug to use should be made on the basis of the patient’s characteristics. Compliance to treatment is a critical aspect in the management of chronic diseases, especially in some particular patient populations, such as elderly or patients taking multiple therapies. Proper adherence to oral 3

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anti-diabetic treatment is crucial, but difficult to obtain, and there is a clinical need to adopt strategies that increase patient’s adherence to anti-diabetic therapy. It has been proven that the factors that negatively influence patient adherence to drug therapy are: the complexity of the treatment, the possible side effects of various medications, such as weight gain or hypoglycemia, and dysphagia, a disease whose prevalence increases with age. The problem of dysphagia becomes predominant when the tablets are quite large, as in the case of metformin tablets which have sizes of 19x10 mm. To overcome, at least in part, this problem, a new powder formulation of metformin has been recently made available in Italy by Bruno Pharmaceutics. Italian National Health System makes metformin powder available for free at the dosage of 850 mg in order to improve patients’ compliance. The new formulation powder is unflavored and dissolves completely and quickly in water, without the need to shake, to form a crystalline solution and it has the purpose to increase patient adherence to therapy. In available literature, there are no studies to verify if this new formulation is effective in improving patient adherence to therapy. For this reason, we designed a study to assess whether the new powder formulation of metformin improves patient satisfaction for diabetic treatment and whether this formulation is effective in improving the degree of glycemic control.

Material and methods Study design This case-control study was conducted at the Department of Internal Medicine and Therapeutics, University of Pavia (Pavia, Italy). The study protocol was approved by institutional review board

and was conducted in accordance with the Declaration of Helsinki and its amendments. Suitable patients, identified from review of case notes and/or computerized clinic registers, were contacted by the investigators in person or by telephone. All patients provided written informed consent to participate. 4

Accepted Article Patients

We enrolled 602 Caucasian type 2 diabetic patients, not well controlled, HbA1c >7.5% (58 mmol/mol) and ≤9.0% (75 mmol/mol), aged ≥ 18 of either sex (Table 1) according to the ESC (European Society of Cardiology) and EASD (European Association for the Study of Diabetes) Guidelines criteria,13 taking metformin in tablets formulation at the dosage of 850 mg two or three

times a day. Patients were excluded if they had a history of ketoacidosis or had unstable or rapidly progressive diabetic retinopathy, nephropathy, or neuropathy; impaired hepatic function (defined as plasma aminotransferase and/or gamma-glutamyltransferase level higher than the upper limit of normal [ULN] for age and sex), impaired renal function (defined as serum creatinine level higher than the ULN for age and sex), or severe anemia. Patients with serious cardiovascular disease (CVD) (eg,

New York Heart Association class I-IV congestive heart failure or a history of myocardial infarction or stroke) or cerebrovascular conditions within 6 months before study enrolment also were excluded. Patients with a history of pancreatitis were excluded. Women who were pregnant or breastfeeding or of childbearing potential and not taking adequate contraceptive precautions were also excluded. Treatments All patients enrolled were on stable dosage of metformin in tablets formulation, at the dosage of 850 mg two or three times a day, since at least 6 months. At baseline patients were instructed to take the same dosage of metformin, but in powder formulation. Medication compliance was assessed by counting the number of envelopes returned at the time of specified clinic visits. Throughout the study, we instructed patients to take their first dose of new medication on the day after they were given the study medication. At the same time, all unused medication was retrieved for inventory. All medications were provided free of charge.

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Assessments Before starting the study, all patients underwent an initial screening assessment that included a medical history, physical examination, vital signs, and a 12-lead electrocardiogram. We evaluated at the baseline, and after 3, and 6 months these parameters: body mass index (BMI), waist circumference (WC), abdominal circumference, and hip circumference, HbA1c, fasting plasma glucose (FPG), post-prandial plasma glucose (PPG), fasting plasma insulin (FPI), homeostasis model assessment insulin resistance index (HOMA-IR). At the baseline, and after 6 months, we administered patients the following questionnaires: the SF-36 Health Survey, the Diabetes Quality Of Life Modified Questionnaire (DQOL/Mod) and the Diabetes Treatment Satisfaction Questionnaire (DTSQ). All questionnaires were validated in Italian. All plasma parameters were determined after a 12-h overnight fast, with the exception of PPG, determined 2 hours after a standardized meal. Venous blood samples were taken for all patients between 08.00 and 09.00. We used plasma obtained by addition of Na2-EDTA, 1 mg/ml, and

centrifuged at 3000 g for 15 minutes at 4°C. Immediately after centrifugation, the plasma samples were frozen and stored at -80°C for no more than 3 months. All measurements were performed in a central laboratory. Body mass index was calculated as weight in kilograms divided by the square of height in meters. Glycated hemoglobin level was measured by a high-performance liquid chromatography (HPLC) method (DIAMAT, Bio-Rad, Hercules, CA, USA; normal values 4.2-6.2%), with intra- and

interassay coefficients of variation (CsV) of < 2%.14 Plasma glucose was assayed by glucoseoxidase method (GOD/PAP, Roche Diagnostics, Mannheim, Germany) with intra- and interassay CsV of < 2%.15 Plasma insulin was assayed with Phadiaseph Insulin radioimmunoassay (RIA) (Pharmacia, Uppsala, Sweden) by using a second antibody to separate the free and antibody-bound

125 I-insulin (intra- and interassay CsV: 4.6 and 7.3%, respectively).16 The HOMA-IR was calculated as the product of basal glucose (mmol/l) and insulin levels (μU/ml)

divided by 22.5.17 6

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2.6 Questionnaires SF-36 Health Survey The SF-36 is a multi-purpose, short-form health survey with 36 questions. It yields eight scaled scores, which are the weighted sums of the questions in their section. Each scale is directly

transformed into a 0-100 scale on the assumption that each question carries equal weight. The lower the score the more is disability; the higher the score the less is disability. The eight sections include: vitality, physical functioning, bodily pain, general health perceptions, physical role functioning, emotional role functioning, social role functioning, mental health profile of functional health and well-being scores as well as psychometrically-based physical and mental health. It is a generic measure, as opposed to one that targets a specific age, disease, or treatment group.18 Diabetes Quality Of Life Modified Questionnaire (DQOL/Mod) The modified DQOL/Mod questionnaire included 39 items. The “Satisfaction” section included 14 items and explored the patients’ psychological well-being. The 20-item “Impact” test primarily assessed the practical consequences of diabetes on everyday life. Finally, the 5-item “Worry: Social/Vocational” section investigated diabetes-related anxiety, with special reference to clinical conditions.19 Diabetes Treatment Satisfaction Questionnaire (DTSQ) The DTSQ is designed to measure satisfaction with diabetes treatment regimens in people with

diabetes. The questionnaire consists of eight items: six concerning various aspects of treatment satisfaction and two items regarding the perceived frequency of hyper- and hypoglycemia during the previous few weeks. The score for each item ranges from 1 to 6, where 1 stay for “very unsatisfied” and 6 stay for “very satisfied” (Table 2).20 Statistical Analysis Data are presented as mean ± standard deviation (SD). A Student’s t test for independent data was used to compare quantitative variables between the two groups. A two-tailed t test was used to determine if there was a significant difference between the two groups regarding the questionnaires 7

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scores. Continuous variables were compared by analysis of variance (ANOVA). Intervention effects were adjusted for additional potential confounders using analysis of covariance (ANCOVA). ANOVA was also used to assess the significance within and between groups. The statistical significance of the independent effects of treatments on the other variables was determined using ANCOVA. The questionnaires were included in the analysis if ≥ 80% of questions had been processed. Statistical analysis of data was performed using the Statistical Package for Social Sciences software version 14.0 (SPSS Inc., Chicago, Illinois, USA). For all statistical analyses, p < 0.05 was considered statistically significant.21

Results

Study sample Of the 602 patients enrolled, 596 completed the study; six patients (three males and three females) did not complete the study, in particular four subjects (three males and one female) were lost to follow-up, and two females reported a bad taste of metformin powder and stopped taking it. Body weight and glycol-metabolic parameters We did not record any significant differences in anthropometric parameters between metformin powder and tablets, while we observed a statistically significant reduction of HbA1c, FPG, PPG, FPI, and HOMA-IR (p < 0.05 for all) after 6 months of taking metformin powder compared to tablets (Table 1). Questionnaires Regarding the SF-36 Health Survey questionnaire, there was an increase in the score of the two questions related to general health perception (Question 1: “In general, would you say your health is” and question 2 “Compared to one year ago, how would you rate your health in general now?”), with a higher scores, meaning a better health perception, after the introduction of metformin powder compared to metformin in tablets. No other significant differences were recorded for the other questions. At the DQOL/Mod questionnaire, instead, after six months of metformin powder there 8

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were lower scores, meaning a minor impact of diabetes in the patient life, in questions: 1 (“How much was the quality of your life affected by your diabetes medication schedule?”), 4 (“How much was the quality of your life affected by following your doctor prescribed treatment plan for diabetes?”), 31 (“How much was the quality of your life affected by having your schedule center around diabetes?”), 38 (“How much was the quality of your life affected by having diabetes interfere with your family life?”), 39 (“How much was the quality of your life affected by diabetes in general?”). Moreover, there was a greater degree of satisfaction for the metformin powder according to the DTSQ; in particular there was a higher score in the fields 1 (“How much satisfied are you of your current treatment?”), 4 (“How much did you find easy to take/comfortable your treatment, in the last period?”), 5 (“How did you feel flexible your treatment in the last period?”), 7 (“Would you recommend your treatment to someone else?”), 8 (“How much would you be satisfied to continue with the current treatment?”) (Figure 1). No differences were observed with regard to the fields regarding the perception of hypo- and hyperglycemia.

Discussion Type 2 diabetes mellitus is associated with increasing levels of morbidity and mortality. Full adherence to treatment recommendations such as pharmacological agents, dietary changes, physical activity and regular self-monitoring of blood glucose is essential to achieve good metabolic control.22 Non-adherence to treatment leads to a worsening of glycemic control, resulting in a significant impact on the cost of the diabetic disease.23 The American Diabetes Association

estimated that $ 174 billion are lost because of diabetes, with $ 116 billion due to health care costs and $ 58 billion to lost productivity.24 The high cost of diabetes is mainly due to the high incidence of complications, linked to a not well controlled type 2 diabetes mellitus. For this reason, compliance to medications has become a topic of a lot of studies involving various pathologies, and various interventions have been proposed to improve patients’ compliance. For example, Leifeld et

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al. conducted a study about a comparison between mesalazine granules and mesalazine tablets, with

granules being superior to tablets in inducing remission in distal ulcerative colitis.25 Data presented in our study suggest that the metformin powder has a better effect than tablets in improving glycemic control and insulin resistance. These data could be explained considering that one of the factors that affects glycemic control is patients’ compliance to therapy. Compliance is correlated to the complexity of the treatment, to the total number of tablets taken daily, to the size of the tablets, to the difficulty in swallowing, to the side effects, and to the cost of therapy.26 The formulation of metformin powder allows solving many of these problems: it simplifies the complexity of the treatment and at the same time reduces the total number of tablets taken daily. Moreover, the powder formulation solves the problem of the size of the pills and the consequent difficulty in swallowing. Of course our study has some limitations: ideally, the study could have used a cross-over design to strengthen its validity and statistical power. However, we think that the familiarity of the patients with the standard preparation and the high sample size mitigates against this necessity. Moreover, despite the design of the study does not allow to quantify the degree of patient compliance to metformin tablets, the improvement of glycemic control suggests a better adherence to the powder formulation, probably secondary to a better acceptance of the treatment by the patient. This seems to be confirmed by the best score at the DTSQ and DQOL/Mod questionnaire after taking the powder formulation.

Conclusions Metformin in powder formulation seems to be more appropriate for the treatment of patients with type 2 diabetes mellitus. The improvement of glycemic control suggests a better adherence to the powder formulation, probably secondary to a better acceptance of the treatment by the patient.

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Acknowledgements Prof. Giuseppe Derosa and Dr. Pamela Maffioli designed the study, researched data, conducted statistical analysis and wrote the manuscript; Dr. Angela D’Angelo processed and analyzed collected samples; Dr. Davide Romano, and Dr. Lucio Bianchi researched data. The authors certify that have no affiliation with, or financial involvement in, any organization or entity with a direct financial interest in the subject matter or materials discussed in the manuscript. No potential conflicts of interest relevant to this article were reported.

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Derosa G, Maffioli P. Patient considerations and clinical utility of a fixed dose combination of saxagliptin/metformin in the treatment of type 2 diabetes. Diabetes Metab Syndr Obes 2011; 4: 263-271.

10. Derosa G, Maffioli P. Dipeptidyl peptidase-4 inhibitors: 3 years of experience. Diabetes Technol Ther 2012; 14(4): 350-364.

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12. Derosa G, Maffioli P. GLP-1 agonists exenatide and liraglutide: a review about their safety and efficacy. Curr Clin Pharmacol 2012; 7(3): 214-228.

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16. Heding LG. Determination of total serum insulin (IRI) in insulin-treated diabetic patients. Diabetologia 1972; 8: 260-266.

17. Matthews DR, Hosker JP, Rudenski AS, Naylor BA, Treacher DF, Turner RC. Homeostasis model assessment: insulin resistance and beta-cell function from fasting plasma glucose and insulin concentrations in man. Diabetologia 1985; 28: 412-419.

18. Ware JE, Jr, Gandek B. Overview of the SF-36 Health Survey and the International Quality of Life Assessment (IQOLA) Project. J Clin Epidemiol 1998; 51: 903-912. 12

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19. Trento M, Passera P, Tomalino M, et al. Group visits improve metabolic control in type 2 diabetes. A 2-year follow-up. Diabetes Care 2001; 24: 995-1000.

20. Nicolucci A, Giorgino R, Cucinotta D, et al. Validation of the Italian version of the WHOWell-Being Questionnaire (WHO-WBQ) and the WHO-Diabetes Treatment Satisfaction Questionnaire (WHO-DTSQ). Diabetes Nutr Metab 2004; 17(4): 235-243.

21. Winer BJ. Statistical Principles in Experimental Design. 2nd ed, McGraw-Hill, New York, 1971.

22. Asante E. Interventions to promote treatment adherence in type 2 diabetes mellitus. Br J Community Nurs 2013; 18(6): 267-274.

23. Hughes DA, Bagust A, Haycox A, Walley T. The impact of non-compliance on the costeffectiveness of pharmaceuticals: a review of the literature. Health Econ 2001;10: 601-615.

24. American Diabetes Association. Economic costs of diabetes in the U.S. in 2007. Diabetes Care 2008; 31: 596-615.

25. Leifeld L, Pfützer R, Morgenstern J, Gibson PR, Marakhouski Y, Greinwald R, Mueller R, Kruis W. Mesalazine granules are superior to Eudragit-L-coated mesalazine tablets for induction of remission in distal ulcerative colitis - a pooled analysis. Aliment Pharmacol Ther 2011; 34(9): 1115-1122.

26. Melikian C, White TJ, Vanderplas A, Dezii CM, Chang E. Adherence to oral antidiabetic therapy in a managed care organization: a comparison of monotherapy, combination therapy, and fixed-dose combination therapy. Clin Ther 2002; 24(3): 460-467.

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Figure 1: comparison of Diabetes Treatment Satisfaction Questionnaire score with metformin in

tablets and in powder.

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Score

6

*

*

*

*

*

Metformin powder

4

Metformin tablets

2

0

1

2

3

4

5

6

7

8

DTSQ items

*p < 0.05 vs metformin tablets DTSQ: Diabetes Treatment Satisfaction Questionnaire

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Table 1: variations of glyco-metabolic control and insulin resistance at baseline and after 6 months of metformin powder.

N Sex (M/F) Age (years) Height (m) Weight (Kg) BMI (Kg/m2) Abdominal Circ. (cm) Waist Circ. (cm) Hip Circ. (cm) HbA1c (%) HbA1c (mmol/mol) FPG (mmol/l) PPG (mmol/l) FPI (U/mL) HOMA-IR

Tablets Baseline 602 299/303 62.5 ± 10.2 1.68 ± 0.03 83.2 ± 9.4 29.5 ± 2.5 95.2 ± 3.3 91.3 ± 2.6 99.6 ± 4.1 8.1 ± 0.9 65 ± 14 7.4 ± 1.1 8.9  1.6 19.7  5.1 6.5  2.3

Powder 3 months 600 298/302 82.5 ± 8.6 29.2 ± 2.3 94.9 ± 3.1 90.8 ± 2.1 99.1 ± 3.7 7.7 ± 0.7 61 ± 16 6.9 ± 0.7 8.1  1.3 18.9  4.6 5.8  1.8

6 months 596 296/300 81.4 ± 7.8 28.9 ± 1.8 94.7 ± 2.9 90.1 ± 1.8 98.6 ± 3.3 7.1 ± 0.6* 54 ± 17* 6.1 ± 0.5* 7.5  1.1* 17.0  3.8* 5.6  1.6*

Data are expressed as mean ± standard deviation *p < 0.05 vs baseline (metformin powder)

BMI: body mass index; HbA1c: glycated hemoglobin; FPG: fasting plasma glucose, PPG: postprandial plasma glucose, FPI: fasting plasma insulin, HOMA-IR: homeostasis model assessment insulin resistance index.

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Table 2: Diabetes Treatment Satisfaction Questionnaire (DTSQ). The following questions relate to the treatment of diabetes (including insulin, tablets and/or diet) and your experience in the latest 2 weeks. Please answer each question by circling one of the numbers in each scale 1. How much satisfied are you of your current anti-diabetic treatment? 6 5 4 3 2 1 Very satisfied Very dissatisfied 2. Recently, how often did you feel that your blood sugar was too high? 6 5 4 3 2 1 Most of the time

Never

3. Recently, how often did you feel that your blood sugar was too low? 6 5 4 3 2 1 Most of the time

Never

4. How much did you find easy to take/comfortable your anti-diabetic treatment, in the latest period? Very easy/ 6 5 4 3 2 1 Very uneasy / comfortable uncomfortable 5. How much did you feel your treatment being flexible in the latest period? 6 5 4 3 2 1 Very flexible Very inflexible 6. How much satisfied are you of your knowledge of diabetes? 6 5 4 3 2 Very satisfied

1

Very dissatisfied

7. Would you recommend your treatment to someone else? Definitely 6 5 4 3 2 1 Definitely do not recommend recommend 8. How much would you be satisfied to continue with the current treatment? 6 5 4 3 2 1 Very satisfied Very dissatisfied

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Metformin powder formulation compared to metformin tablets on glycemic control and on treatment satisfaction in subjects with type 2 diabetes mellitus.

The aim of this study was to evaluate if the new metformin powder formulation improves the treatment satisfaction in patients with type 2 diabetes, in...
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