|Year : 2020 | Volume
| Issue : 3 | Page : 175-182
Evaluation of type 2 diabetes treatment with gliclazide modified release in Azerbaijan (the EdiAzer study): Results from a 16-week observational clinical study
Valeh A Mirzazada1, Ramila A Huseynova1, Sevil A Mustafayeva1, Fidan N Gasimova1, Ulviyya Ahmadova2, Narmin Ismayilova2, Vafa Kerimova2, Hagigat Mehdiyeva3, Rana Suleymanova4, Zahrakhanim Maharramova4, Gulnara Iskandarli5, Ofeliya Gurbanova6, Sariyya Aghayeva2, Sabina Malikova7, Konul Ismayilova8, Khanim Salimkhanova9
1 Azerbaijan State Institute for Physician Postgraduate Education, Baku, Azerbaijan
2 Republic Endocrinology Center, Baku, Azerbaijan
3 City Polyclinic No. 24, Baku, Azerbaijan
4 Central Hospital for Oil Workers, Baku, Azerbaijan
5 Nasraddin Tusi Clinic, Baku, Azerbaijan
6 City Polyclinic No. 34, Baku, Azerbaijan
7 Starlab Private Medical Center, Baku, Azerbaijan
8 Azerbaijani Medical University, Baku, Azerbaijan
9 Baku Private Clinic, Baku, Azerbaijan
|Date of Submission||13-Jan-2020|
|Date of Decision||13-Mar-2020|
|Date of Acceptance||21-Apr-2020|
|Date of Web Publication||1-Sep-2020|
Dr. Valeh A Mirzazada
Azerbaijan State Institute for Physician Postgraduate Education, Baku.
Source of Support: None, Conflict of Interest: None
Introduction: Type 2 diabetes is a major public health problem across all economic regions. This open-label study collected real-world data on patients presenting with type 2 diabetes in Azerbaijan treated with gliclazide modified release (MR). Materials and Methods: Newly-diagnosed patients uncontrolled by diet, and patients uncontrolled by metformin were prescribed gliclazide MR 60mg (30–120mg/day) for 16 weeks. Primary study endpoints were changes in mean glycated hemoglobin A1c (HbA1c) and percentage of participants achieving HbA1c ≤7.0% and/or an HbA1c improvement ≥1.0%. Secondary endpoints included changes in mean fasting plasma glucose (FPG) and weight. Serious adverse events were monitored throughout the study. Results: Data from 105 patients were available for analysis. Mean age was 55.1 ± 10.4 years, 53.3% were female and 82.9% were overweight or obese. Mean duration of diabetes was 2.3 ± 2.6 years. A total of 44 patients were receiving metformin before study entry. At W0, 61 patients (58.1%) were prescribed gliclazide MR monotherapy, and 44 (41.9%) were prescribed gliclazide MR in combination with the metformin. At the end of the study, a statistically significant decrease was observed in mean HbA1c levels from 8.8% ± 1.4% to 7.6% ± 1.0% (P < 0.001). In addition, 30 (28.6%) patients achieved an HbA1c <7.0% (P < 0.0001), and 61 (58.1%) an HbA1c reduction of ≥1.0%. Reductions in FPG levels were statistically significant compared with baseline from week 2 onward. No weight gain was observed, and there were no serious adverse events, including no reports of severe hypoglycemia. Conclusion: Gliclazide MR is an effective and well-tolerated first- or second-line agent in type 2 diabetes and may be particularly valuable in low-to-middle income countries where therapeutic options are limited by accessibility and cost.
Keywords: Azerbaijan, gliclazide modified release, glycemic control, sulfonylurea, type 2 diabetes
|How to cite this article:|
Mirzazada VA, Huseynova RA, Mustafayeva SA, Gasimova FN, Ahmadova U, Ismayilova N, Kerimova V, Mehdiyeva H, Suleymanova R, Maharramova Z, Iskandarli G, Gurbanova O, Aghayeva S, Malikova S, Ismayilova K, Salimkhanova K. Evaluation of type 2 diabetes treatment with gliclazide modified release in Azerbaijan (the EdiAzer study): Results from a 16-week observational clinical study. J Diabetol 2020;11:175-82
|How to cite this URL:|
Mirzazada VA, Huseynova RA, Mustafayeva SA, Gasimova FN, Ahmadova U, Ismayilova N, Kerimova V, Mehdiyeva H, Suleymanova R, Maharramova Z, Iskandarli G, Gurbanova O, Aghayeva S, Malikova S, Ismayilova K, Salimkhanova K. Evaluation of type 2 diabetes treatment with gliclazide modified release in Azerbaijan (the EdiAzer study): Results from a 16-week observational clinical study. J Diabetol [serial online] 2020 [cited 2020 Sep 25];11:175-82. Available from: http://www.journalofdiabetology.org/text.asp?2020/11/3/175/294047
| Introduction|| |
The past few decades have witnessed a dramatic increase in the prevalence of type 2 diabetes. The most recent data from the Global Burden of Disease study estimated that there were over 462 million people with type 2 diabetes worldwide in 2017, four-fifths of whom live in low- to middle-income countries (LMIC). This number is projected to increase to 629 million by 2045, with most of this burden occurring in LMIC. There is therefore an urgent need to develop strategies that prevent the onset of the disease. For those with diagnosed type 2 diabetes, the goals are to prevent or delay the development of diabetes-related complications and to maintain quality of life.
Blood glucose control is an essential component of an integrated approach to diabetes management, along with control of associated risk factors such as hypertension and dyslipidemia.,, According to recent joint recommendations issued by the American Diabetes Association and the European Association for the Study of Diabetes, the management of glycemia involves individualization of treatment goals, the use of metformin as first-line therapy, and the widespread use of glucagon-like peptide 1 receptor agonists (GLP-1 RA) and sodium glucose cotransporter 2 (SGLT-2) inhibitors due to their weight loss promoting actions and proven cardioprotective benefits., Where cost is a major issue, the glucose-lowering algorithm recommends metformin as first-line therapy, with sulfonylureas or thiazolidinediones (TZD) as the next step., Sulfonylureas are also recognized by the World Health Organization (WHO) as an alternative first-line therapy in patients who have contraindications to metformin or in whom metformin does not improve glycemic control.
Type 2 diabetes is a major public health problem not just for its adverse impact on the health of the people affected, but also for the economic burden it places on healthcare systems. According to the World Bank, 34 countries are classified as having low-income economics, 47 lower-middle-income economics, 56 upper-middle-income economics, and 81 high-income economics; Azerbaijan is classed as an upper-middle income country. With the exception of the highest income countries, widespread use of expensive modern glucose-lowering agents such as GLP-1 RA and SGLT-2 inhibitors is not possible, and metformin and the sulfonylureas remain the most widely prescribed first- and second-line agents. In Azerbaijan, national guidelines recommend metformin or sulfonylurea as first-line therapy for type 2 diabetes, and metformin, gliclazide modified release (MR), and glimepiride are included on the state tender list of medicines that are available at no cost to patients.
Since the first sulfonylureas became available, drugs in this class have undergone several stages of development and showed clinically relevant within-class differences in terms of efficacy and side effect profiles.,,,, The EdiAzer observational study was conducted in the outpatient setting to obtain real-world data on people with type 2 diabetes in Azerbaijan treated with gliclazide MR with the aim of determining suitable options for type 2 diabetes pharmacotherapy in LMIC.
| Materials and Methods|| |
EdiAzer was an open-label, non-comparative observational study consisting of a 2-month inclusion period and 4 months of follow-up. The study was conducted according to the standards and principles of the Declaration of Helsinki. Ethical approval was site specific, and written informed consent was obtained from all patients at the inclusion visit. The trial was registered on the ClinicalTrials.gov website with the number NCT03164187.
The study recruited treatment-naïve patients with newly diagnosed type 2 diabetes uncontrolled by diet and patients uncontrolled with metformin monotherapy for whom treating physicians had already decided to prescribe gliclazide MR. Screening took place between September 2016 and April 2017, at nine clinical centers in Baku, Azerbaijan. Patients could be included in the study if they were aged 35 years or older and had a glycated hemoglobin A1c (HbA1c) level >7%. Exclusion criteria included hypersensitivity to sulfonylureas, gliclazide, or any of its excipients, any contraindications to gliclazide, the presence of uncontrolled and clinically significant diseases or known malignancy, severe renal (estimated glomerular filtration rate <45mL/min/1.73 m2) or hepatic insufficiency, women who were pregnant or breastfeeding, inability to attend Week 0 and/or Week 16 examinations, and those likely to be nonadherent to the study expectations. Comorbid conditions present at baseline were determined with the following general definitions, but a uniform approach to their diagnosis was not prespecified: retinopathy (assessed by different ophthalmologists with different qualifications, fundus photography was not performed); nephropathy (no microalbuminuria in all patients); and neuropathy (patients’ complaints were analyzed in all cases, but not all were examined by a neurologist; in most, but not all cases, patients were examined with the use of a monofilament; determination of vibrational, temperature, and pain sensitivity was performed). The flow of participants through the study is shown in [Figure 1].
Subjects were required to make six visits to the center at Weeks 0, 2, 4, 6, 8, and 16. HbA1c levels were measured at Weeks 0 and 16. Fasting plasma glucose (FPG), height, weight, body mass index (BMI), and blood pressure were measured at all visits. Patients meeting the inclusion criteria were prescribed gliclazide MR 60mg either as a first-line therapy, as a switch from previous metformin therapy, or as a second-line therapy to metformin. In both newly diagnosed patients and those uncontrolled with metformin monotherapy, treatment was initiated at a dose of 30mg/day (half tablet). At each subsequent visit, the gliclazide MR dose was increased by half a tablet (30mg) if FPG exceeded 6 mmol/L until the maximum daily dose of gliclazide MR 120mg (two tablets) was reached. Patients on maximal dose gliclazide MR monotherapy with FPG >6 mmol/L received add-on metformin. If FPG remained >6 mmol/L at the next study visit, the dose of metformin was increased. If FPG remained below 6 mmol/L, treatment was continued unchanged. All tablets were taken once daily in the morning before breakfast.
The primary study endpoints were change in mean HbA1c from Week 0 to Week 16 and the percentage of participants achieving an HbA1c ≤7.0% and/or an HbA1c improvement between Week 0 and Week 16 of ≥1.0%. Secondary endpoints included changes in mean FPG, weight, BMI, and blood pressure. Patients were monitored throughout the study for any serious adverse events and for severe hypoglycemic episodes, which were defined according to the American Diabetes Association definition as a hypoglycemic incident in which the patient was unable to treat themselves and required assistance from another person.
Statistical analysis: Quantitative variables were summarized by mean ± standard deviation. Chi-square or Fisher exact tests were used to determine the statistical significance of differences between proportions. Student t tests for paired samples were used to compare mean values over time. A P value <0.05 was considered statistically significant. Statistical analyses were performed using Excel statistical software.
| Results|| |
A total of 13 physicians assessed 121 patients for study eligibility, of whom 110 were included. Eleven patients were excluded because they did not meet the inclusion criteria, and five patients did not attend the visits after Week 0. The final analysis set therefore included 105 patients: 61 were prescribed gliclazide MR monotherapy and 44 were prescribed gliclazide MR in combination with metformin [Figure 1].
Demographics and baseline characteristics
Patient demographics and baseline characteristics are shown in [Table 1]. Mean age was 55.1 ± 10.4 years (range, 25–79 years) with most participants in the age-group of 50–59 years (37.1%), followed by 60–69 years (24.8%), and 40–49 years (23.8%). The proportions of patients younger than 40 and ≥70 years were 6.7% and 7.6%, respectively. There was a slightly higher proportion of women than men (n = 56, 53.3%). Just over half the participants (52.4%) had a duration of diabetes less than 2 years; mean duration was 2.3 ± 2.6 years (range, 0–120 months) [Table 1]. Ten patients were newly diagnosed. Previous treatments for diabetes included diet in 52.4% of patients, physical activity of ≥150min/week (35.2%), and metformin (42.9%) [Table 1]. Mean (standard deviation [SD]) duration of metformin therapy was 32.3 ± 28.8 months with a range of 0.1–120 months. Complications or comorbid conditions were present in 40% of patients, most commonly neuropathy (28.6%), macroangiopathy (10.5%), and microangiopathy (8.6%). In addition, 11 (10.5%) patients had a stroke or myocardial infarction. Over half the study population (52.4%) were overweight (BMI in the range 25.0–29.9kg/m2) and 30.5% were obese (BMI ≥ 30kg/m2). Mean systolic blood pressure (SBP) at Week 0 was 134 ± 19mm Hg, and mean diastolic blood pressure (DBP) was 84 ± 11mm Hg.
Gliclazide modified release and metformin doses
The mean dose of gliclazide MR increased over the first 6 weeks of the study from 52.0 ± 21.7mg/day at Week 0 to 83.7 ± 29.0mg/day at Week 6, after which it stabilized [Figure 2]. Mean gliclazide MR dose at the end of the study was 83.4 ± 30.4 mg/day. A total of 45 patients (42.9%) were on metformin before starting the study, the drug was discontinued in four patients and initiated in three patients at inclusion. Consequently, 44 patients were prescribed the drug at Week 0. Metformin was initiated in 16 patients during the study, increasing the number of patients treated to 60 (58.1%) at Week 16. The mean dose remained relatively stable from 1212.5 ± 508.0mg/day at Week 0 to 1254.2 ± 519.7mg/day at Week 16 [Figure 2]. No patients exceeded the maximal permitted daily doses of gliclazide MR and metformin, that is, 120mg and 2000mg, respectively.
|Figure 2: Mean doses (± standard deviation) of metformin and gliclazide modified release prescribed throughout the study|
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Glycated hemoglobin A1c levels
Mean HbA1c levels decreased by 1.2 ± 0.9% from 8.8 ± 1.4% at Week 0 to 7.6 ± 1.0% at Week 16 [Figure 3]. At Week 16, 30 (28.6%) patients had achieved an HbA1c level <7.0% (P < 0.0001), and 61 (58.1%) had achieved an HbA1c reduction ≥1.0%. At baseline, none of the patients had an HbA1c <7% as per the study inclusion criteria. Over two-thirds of patients (73 [69.5%]) achieved either an HbA1c <7.0% or an HbA1c reduction of ≥1.0%. Over half the study population (35 [50.7%]) with an HbA1c level ≥8.0% at Week 0 achieved a level <8.0% at Week 16. When analyzed by level of HbA1c reduction between Week 0 and Week 16, a change of 0.5% was observed in 81%, a change of 1.0% in 58.1%, and a change of ≥1.5% in 24.8% of patients. A reduction in HbA1c levels of ≥2.0% occurred in 18.1% of participants, and a reduction of ≥2.5% in 6.7% of participants.
Fasting plasma glucose levels
FPG levels decreased from 10.9 ± 3.3 mmol/L at Week 0 to 7.1 ± 1.6 mmol/L at Week 16 (P < 0.001) [Figure 4]. Reductions in FPG compared with Week 0 were statistically significant from Week 2 onward. Statistically significant reductions in FPG compared with the previous visit were apparent until Week 6, after which reductions remained at the same level until the end of the study.
Weight and body mass index
Mean body weight was comparable at Weeks 0 and 16 at 80.7 ± 12.1 and 80.3 ± 11.9kg, respectively. Analysis of mean BMI values showed almost no change between Week 0 and Week 16 (29.5 ± 4.8 and 29.4±4.8kg/m2, respectively). A small weight loss was observed between Week 0 and Week 16 in obese (-0.4 ± 3.3kg) and overweight patients (-0.6 ± 1.8kg), whereas a negligible change was observed in patients with normal BMI (+0.1 ± 1.7kg).
Mean blood pressure decreased from 134/84mm Hg at Week 0 to 126/79mm Hg at Week 16 (P < 0.001). The mean decrease was -9 ± 19mm Hg for SBP and -11 ± 22mm Hg for DBP. In the 28 patients with SBP/DBP >140/90mm Hg, the mean decrease was even higher (-26 ± 17mm Hg for SBP, and -17 ± 10 mmHg for DBP). In the majority of patients, SBP and DBP values at the end of the study were either less than or equal to those at Week 0 (87.8% for SBP and 90.8% for DBP).
There were no serious adverse events, and no reports of severe hypoglycemia in the EdiAzer Study. One patient reported an event that he considered to be severe hypoglycemia. However, the patient’s FPG level was normal (5.2 mmol/L), and no outside help was required.
There were no cardiovascular events recorded during the 16-week study, and there were no side effects of treatment that resulted in the withdrawal of either metformin or gliclazide MR.
| Discussion|| |
The EdiAzer study provides valuable data on the characteristics of patients presenting with type 2 diabetes in Azerbaijan and their response to treatment with gliclazide MR as either monotherapy or combination therapy with metformin. According to recent data from the International Diabetes Federation (IDF), there were 484,600 cases of diabetes in Azerbaijan in 2017, of which approximately 436,140 cases (approximately 90%) would be type 2 diabetes. With a total adult population of around 6.9 million, this gives a prevalence rate for diagnosed type 2 diabetes of 6.3%, which is approaching that observed in the United States for the same period (8.5%). The true percentage of individuals with type 2 diabetes may be even higher as these values do not include patients with undiagnosed diabetes.
Major factors influencing the prevalence of type 2 diabetes are overweight and obesity, as a result of unhealthy diets (characterized by low intake of fruit and vegetables and high intake of foods rich in sugars and saturated fats), and limited physical activity. This was reflected in this study where 82.9% of participants were either overweight or obese. Just under half the participants (47.6%) had a duration of diabetes of more than 2 years, yet a quarter had received no previous diabetes management and may therefore already have had long-term exposure to elevated blood glucose levels.
Gliclazide MR was prescribed as either monotherapy or combination therapy with metformin. Over the course of the study, a statistically significant decrease was observed in mean HbA1c levels from Week 0 to Week 16 (P < 0.001). FPG levels were measured at each study visit and also showed statistically significant reductions compared with baseline from Week 2 onward, with maximum reductions observed at Week 6. It should be noted that with an average gliclazide MR dose of 83.4 ± 30.4 mg/day and an average metformin dose of 1254.2 ± 519.71mg/day, HbA1c decreased from 8.8% to 7.6% over the 4-month study. These doses are much lower than the permitted maximum doses, indicating that nonaggressive pharmacotherapy with simultaneous emphasis on the need to change lifestyle habits allows patients to achieve smooth decreases in blood glucose levels without pronounced side effects.
Weight gain is frequently cited as a class effect of the sulfonylureas, with monotherapy reported to induce increases of approximately 1.5–2.5kg. No weight gain was observed in this study, following treatment with gliclazide MR for 16 weeks. These data support findings from the ADVANCE study where overall weight gain was negligible with gliclazide MR intensive therapy with an increase of only 0.1kg over 5 years of follow-up. Furthermore, when analyzed by baseline BMI subgroup, a small mean weight loss of 0.5kg was observed in obese people (BMI ≥30kg/m2).
Over a quarter of participants (27%) had a baseline blood pressure value above the threshold for treatment for patients with diabetes (140/90mm Hg, according to the most recent joint guidelines from the European Society of Cardiology/European Society of Hypertension [ESC/ESH]). Statistically significant reductions in mean blood pressure were observed over the course of the study, which were highest for the patients with SBP/DBP >140/90mm Hg at baseline in whom reductions of -26 ± 17mm Hg for SBP and -17 ± 10mm Hg for DBP were observed. Gliclazide MR itself has no known blood-pressure-lowering effects. Although a number of factors may have been responsible for this reduction, including patient adherence to diet and exercise programs as well as prescription of blood-pressure-lowering medications, any reduction in blood pressure is beneficial in this group of patients at high risk of cardiovascular disease and diabetes-related complications.
Gliclazide MR was well tolerated as monotherapy and in combination with metformin. No cases of severe hypoglycemia and no cardiovascular events were reported. Although the significance of the safety data in the EdiAzer study are limited by the small number of participants, it is consistent with that reported in a previously published meta-analysis.
As an observational study without a control arm and no random treatment allocation, this study does not attempt to make any causal inferences about treatment effect. A further limitation is that self-monitoring of blood glucose was optional, and patients were not required to measure postprandial glucose levels. Nevertheless, observational studies can be more representative of a clinical population and less prone to selection bias than a trial. They can therefore allow investigation of the validity of trial results in more diverse populations, who are often underrepresented in conventional trials. The results of this study add to the body of literature on the use of gliclazide in the management of type 2 diabetes and support the positive results observed in a number of clinical trials in which gliclazide was used as the sulfonylurea, including STENO-2, ADVANCE, Observational Study to analyse titration of Diamicron MR 60 mg in daily clinical practice (EASYDia), and Glucose control in type 2 diabetes: Diamicron MR vs. glimepiride (GUIDE). They also provide important data on the use of two cost-effective medications, metformin and gliclazide MR, in countries such as Azerbaijan that are often underrepresented in clinical trials. The list prices of liraglutide 6mg/3mL, sitagliptin 100mg, and vildagliptin 50mg in Azerbaijan are 233.00 AZN, 72.50 AZN, and 27.23 AZN, respectively, compared with 6.82 AZN for metformin 1000mg and 12.34 for gliclazide MR. Incomes may therefore limit the prescription of more expensive therapies such as the Glucagon-like peptide-1 receptor agonist (GLP-1 RA) and dipeptidyl peptidase-4 (DPP-4) inhibitors.
| Conclusion|| |
In this observational study, statistically significant reductions in HbA1c levels were observed compared with baseline in patients with type 2 diabetes treated with gliclazide MR either alone or in combination with metformin. Weight gain was not observed, and treatment was well tolerated with no reports of severe hypoglycemia. Gliclazide MR may represent a suitable option for initiating pharmacotherapy in people with type 2 diabetes and may be particularly valuable in LMIC where cost and access to therapies are important limiting factors.
Compliance with ethical standards
The study was conducted according to the standards and principles of the Declaration of Helsinki. Ethical approval was site specific, and written informed consent was obtained from all patients at the inclusion visit. The trial was registered on the ClinicalTrials.gov website with the number NCT03164187.
We thank the participants of this study.
Financial support and sponsorship
This study was supported by Servier. Medical writing support was provided by Jenny Grice, a freelance medical writer, and funded by Servier.
Conflicts of interest
The authors have received speaker/consulting honoraria from the following companies: V Mirzazada (Servier, Novo Nordisk, Sanofi, Roche, Lilly, Takeda, Berlin-Chemie, and Novartis); S Mustafayeva (Novo Nordisk, Berlin-Chemie, Sanofi, and Servier); U Ahmadova (Servier, Takeda, Sanofi, Novo Nordisk, Wörwag Pharma, Berlin-Chemie, and Novartis); N Ismayilova (Servier, Takeda, Janssen, Wörwag Pharma, Berlin-Chemie, Sanofi, Novartis, and Novo Nordisk); V Kerimova (Servier, Novo Nordisk, Sanofi, and Berlin-Chemie); H Mehdiyeva (Servier, Takeda, Sanofi, Novo Nordisk, Wörwag Pharma, Berlin-Chemie, and Novartis); R Suleymanova (Wörwag Pharma, Servier, Novo Nordisk, Sanofi, Takeda, Yanssen, and Berlin-Chemie); Z Maharramova (Servier, Berlin-Chemie, Novo Nordisk, Wörwag Pharma, and Novartis); G Iskandarli (Servier, Takeda, Sanofi, Novo Nordisk, Wörwag Pharma, Berlin-Chemie, and Novartis); O Gurbanova (Servier, Novo Nordisk, Sanofi, Wörwag Pharma, Novartis, and Takeda); S Aghayeva (Servier, Novo Nordisk, Sanofi, Wörwag Pharma, Novartis, and Takeda); S Malikova (Servier, Takeda, Berlin-Chemie, Sanofi. Wörwag Pharma, Novartis, and Yanssen); K Ismayilova (Servier, Takeda, Novo Nordisk, Wörwag Pharma, Sanofi, Berlin-Chemie, and Novartis); and K Salimkhanova (Novo Nordisk, Servier, Sanofi, Wörwag Pharma, Takeda, Yanssen, Berlin-Chemie, Acino, Bayer, and Abbott). R Huseynova and F Gasimova declare no conflicts of interest.
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[Figure 1], [Figure 2], [Figure 3], [Figure 4]