DXR MEX 60 1000 Launch Handbook-

Launch Handbook



Content • Diamicron XR MEX 60/1000 mg • Power of CONTROL • Power of CARE • Power of FLEXIBILITY • Diamicron XR MEX 60/1000 mg • Product essentials



Power of CONTROL What to refer to ? • GUIDE study • EASY 2 study • New 2021 Diamicron XR MEX study



Head-to-head double blind randomised controlled trial of Diamicron XR* vs Glimepiride Schernthaner G et al. - European Journal of Clinical Investigation 2004;34: 535–542 845 patients with type 2 diabetes HbA1c: 6.9% - 11.5% Newly diagnosed or Uncontrolled on metformin (469 patients) or Uncontrolled on AGIs Diamicron XR * 30 mg 60 mg 90 mg 120 mg Duration = 27 weeks 1 mg 2 mg 3 mg 4-6mg Glimepiride In patients uncontrolled on metofmin (n = 469) HbA1c decreased significantly in both groups (p < 0.001 vs baseline) At Baseline At Baseline 8.4 % 8.3 % - 1% - 0.9% At 27 weeks At 27 weeks 7.4% 7.4% Diamciron XR*+ Metformin Glimepiride + Metformin HbA1C: Glycated hemoglobin; AGI: Alpha-glucosidase inhibitor * The study was conducted with Diamicron MR (modified release) from Servier. In Servier India (Serdia), the brand available is Diamicron XR 60 mg and in combination with metformin is Diamicron XR MEX.

Treatment of Indian patients with type 2 diabetes with once-daily Diamicron XR 60 mg or combination of Diamicron XR 60 mg + Metformin Wangnoo S K - International Journal of Diabetes in Developing Countries 2005;25:50-54 162 patients with type 2 diabetes Uncontrolled patients (fasting plasma glucose > 150mg/dL) Patients treated with twice daily gliclazide 80mg as monotherapy or in combination with metformin (62 patients) Morning Afternoon Evening Gliclazide 80 mg + - Gliclazide 80 mg + Metformin Metformin Switch to ONCE-DAILY Gliclazide extended - - release 60 mg + Metformin extended release The metformin immediate release is switched to metformin extended-release at the same total daily dose e.g., Patients on twice daily combination of Gliclazide 80 mg + Metformin 500 mg will be shifted to once-daily FDC of Gliclazide extended release 60 mg + Metformin 1000 mg Duration = 14 weeks Reduction in FPG in mg/dL In patients uncontrolled on 197 twice daily combination of Gliclazide 80 mg + metofmin - 25 mg/dL (n = 62) : 122 -25 mg/dL reductioni Gliclazide 80 mg + Metformin (Twice Daily) in FPG with switch Gliclazide XR 60 mg + Metformin (once-daily) to once-daily combination of Gliclazide extended release 60 mg + Metformin Patient adherance improved to 97%

Names of the Investigators who participated in the study Wangnoo S K - International Journal of Diabetes in Developing Countries 2005;25:50-54 Dr A Kulshrestha (Agra); Dr D Dantara (Ahmedabad); Dr V Agrawal, Dr A Mathur (Allahabad);Dr V Jain (Ambala); Dr V Apte, Dr R K Shah (Aurangabad); Dr L Krishnamurthy, Dr H N Seshadri, Dr S Subramanyam (Bangalore); Dr R S Meena, Dr A Shukla (Bhopal); Dr V K Chhabra, Dr A Pahwa (Chandigarh); Dr V T Bhaskaran, Dr M Chandrasekar, Dr S Chandrasekar, Dr M V Mohan, Dr S Nallaperumal, Dr V Parthasarathy, Dr D S Victor (Chennai); Dr. N Senthil Vel (Coimbatore); Dr J K Panda (Cuttack); Dr P N Daiv (Dahanu); Dr R Bansal, Dr A Bhatia, Dr D S Chadha, Dr A R Choudhary, Dr M K Daga, Dr M L Goglani, Dr S K Gupta, Dr U Kansra, Dr A K Manchanda, Dr R Manocha, Dr V K Rastogi, Dr B K Tripathi (Delhi); Dr H Mehta (Ghaziabad); Dr M Abubaker, Dr M Idrees, Dr P Raghuramulu, Dr J Ramesh, Dr V Rao, Dr L Rodrigues, Dr B Rojanandam, Dr M Siraj (Hyderabad); Dr N Batra, Dr G Devpura, Dr D K Jain, Dr P Saxena (Jaipur); Dr C P Mathur (Jodhpur); Dr V Kalyanarayanswamy (Karaikudi); Dr S Kalra (Karnal); Dr D P Banerjee, Dr G Banerjee, Dr P K Das, Dr S K Das, Dr N Mallik, Dr D Saha, Dr K N Sen, Dr U K Sengupta (Kolkata); Dr V Balachandran (Kollam); Dr A Agarwal, Dr A Sharma (Lucknow); Dr P Khanna (Ludhiana); Dr B D Rai, Dr A P Rao (Mangalore); Dr E D’Mello (Margao); Dr A Gautam, Dr N K Sharma (Meerut); Dr V I Agera, Dr P Bhatia,Dr A Doshi, Dr SJ Doshi, Dr A Ghongane, Dr A C Hattangadi, Dr H K Kundalia, Dr V Parvatkar, Dr D Patil, Dr S Pawar, Dr S Sahasrabudhe, Dr R S Tungare (Mumbai); Dr N Furtado (Panaji); Dr N Parameswaran (Perambur); Dr L Gunalan (Pondicherry) ; Dr V N Tiwari (Ranchi); Dr M G Uvaraj (Salem); Dr J J Rao (Secunderabad); Dr J Antao (Taleigao); Dr T Palanichamy (Trichy); Dr R Nair (Trivandrum); Dr D P Singh (Udaipur); Dr D T Gaikwad (Ulhasnagar); Dr W A Ansari, Dr M K Jaiswal (Varanasi); Dr V Phadke (Vasai); Dr D Prabhu (Vasco da Gama); Dr K Annamalai (Vellore); Dr M Kumar, Dr Y Sivakumar (Vijayawada); Dr N Sivaprakash, Dr K A V Subramanyam (Vizag)

Real-world experience of treatment individualization based on a FDC of Diamicron XR MEX 60/500 + metformin extended-release in Indian patients with type 2 diabetes Sanjay Kalra, Deepak Khandelwal, Aravinda Jagadeesha, Kirti Samudra, Sharvil Gadve, Supratik Bhattacharyya - Clinical Diabetology 2021;10(4):337-341 455 patients with type 2 diabetes Newly diagnosed with HbA1c >9% (122 patients) or Uncontrolled on metformin (197 patients) or Uncontrolled on conventional Gliclazide + Metformin 60/500 mg FDC of Diamicron XR MEX 500 + Duration = 90 Days Metformin extended release 500 mg ( as per the patient need) In Newly diagnosed patients with HbA1c >9% (122 patients) HbA1c decreased significantly by 2.09 % (p < 0.001) 267 -98 mg/dL 182 -73 mg/dL p < 0.001 p < 0.001 169 109 FPG in mg/dL PPG in mg/dL HbA1C: Glycated hemoglobin; FDC = Fixed Dose Combination, FPG = Fasting Plasma Glucose , PPG = Post-Prandial Glucose

Real-world experience of treatment individualization based on a FDC of Diamicron XR MEX 60/500 + metformin extended-release in Indian patients with type 2 diabetes Sanjay Kalra, Deepak Khandelwal, Aravinda Jagadeesha, Kirti Samudra, Sharvil Gadve, Supratik Bhattacharyya - Clinical Diabetology 2021;10(4):337-341 455 patients with type 2 diabetes Newly diagnosed with HbA1c >9% (122 patients) or Uncontrolled on metformin (197 patients) or Uncontrolled on conventional Gliclazide + Metformin 60/500 mg FDC of Diamicron XR MEX 500 + Duration = 90 Days Metformin extended release 500 mg ( as per the patient need) In patients ucontrolled on metformin (197 patients) HbA1c decreased significantly by 0.8 % (p < 0.001) 231 -69 mg/dL p < 0.001 160 -55 mg/dL 162 p < 0.001 109 FPG in mg/dL PPG in mg/dL HbA1C: Glycated hemoglobin; FDC = Fixed Dose Combination, FPG = Fasting Plasma Glucose , PPG = Post-Prandial Glucose



Power of CARE What to refer to ? • GUIDE study • SCHRAMM study

Head-to-head double blind randomised controlled trial of Diamicron XR* vs Glimepiride Schernthaner G et al. - European Journal of Clinical Investigation 2004;34: 535–542 845 patients with type 2 diabetes, HbA1c: 6.9% - 11.5% Newly diagnosed or Uncontrolled on metformin (469 patients) or Uncontrolled on AGIs Patients able to perform home blood glucose monitoring [1 day per week, three times per day (before breakfast, lunch, and dinner) and at occurrence of symptoms of hypoglycemia]# 30 mg Diamicron XR * 120 mg 1 mg 60 mg 90 mg 4-6mg 2 mg 3 mg Duration = 27 weeks Glimepiride In patients uncontrolled on metofmin (n = 469) % of patients with Hypoglycemia ( blood glucose level < 54 mg/dL) 8.6% -70% less no.of patients with hypoglycemia p  0.02 2.6% HbA1C: Glycated hemoglobin; AGI: Alpha-glucosidase inhibitor *The study was conducted with Diamicron MR (modified release) from Servier. In Servier India (Serdia), the brand available is Diamicron XR 60 mg and in combination with metformin is Diamicron XR MEX. # All patients were provided with the same blood glucose monitoring device and were trained to recognize symptoms suggestive of hypoglycemia. Patients systematically measured blood glucose 1 day per week (three times daily: before breakfast, lunch, and dinner). At any occurrence of symptoms they were instructed to measure their blood glucose level, to record the event in a diary, which was reviewed by the investigator at each visit

Mortality and cardiovascular risk associated with different insulin secretagogues compared with metformin in type 2 diabetes Schramm t. k. et al. - European Heart Journal (2011) 32, 1900–1908 1,07,806 patients with type 2 diabetes (National wide study in Denmark*) 9607 patients had previous MI  20 years, initiated with single-agent insulin secretagogue or metformin between 1997 and 2006 Gliclazide Duration = 9 years follow-up Glimepiride Other insulin secretagogues: Glibenclamide, Glipizide, Tolbutamide & Repaglinide Analysis of 9,607 patients with previous MI, • 29% significant (p <0.001) increase in the risk of MI, stroke and cardiovascular death with Glimepiride as compared to the reference treatment - metformin • Risk of MI, stroke and cardiovascular death for Gliclazide is - 14% as compared to the reference treatment of metformin + 29% RISK -14% MI = Myocardial Infarction , Prior MI was identified as a hospitalization with MI as the primary or secondary diagnosis * The study was conducted as a nationwide study in Denmark and included analysis of the data from The Danish National Prescription Registry ( data avaible since 1995) and National Patient Registry ( hospitalization data avaible since 1978)



Power of FLEXIBILITY What to refer to ? • ANALYSIS OF DIAMICRON XR MEX 60/1000 mg • PRESCRIBING INFORMATION OF DIAMICRON XR MEX 60/1000 mg

Each uncoated bi-layered scored tablet contains gliclazide extended release 60 mg and metformin extended release 1000 mg as a fixed dose combination DIAMICRON® XR MEX 60/1000 is a scored tablet and can be broken for sequential increase or decrease in the dose to achieve the desired glycemic control. - DIAMICRON® XR MEX 60/1000 Package insert PI version 1.0, Oct. 2021

Analysis of the scored tablets of Diamicron XR MEX 60/1000 mg DATA ON FILE – Analysis conducted by third party on sample code – CAL/21/2240 The dissolution profile of Diamicron XR MEX 60/1000 mg confirms that the efficacy of the tablet is not affected on breaking the tablet into half i.e. dosage adjustment as per the patient need is possible with this scored FDC % Drug release – Gliclazide XR 60 mg: Full tablet versus half tablet Full tablet Half tablet 100 88 % Drug Release 80 86 60 41 40 19 44 20 19 0 0 2 4 6 8 10 12 14 Time Point (Hours) % Drug release – Metformin Hydrochloride 1000 mg: Full tablet versus half tablet Full tablet Half tablet 97 100 96 80 72 60 52 71 % Drug 40 29 51 Release 28 20 0 0 2 4 6 8 10 12 14 Time Point (Hours) CONFIDENTIAL – Analysis of the scored tablet Diamicron XR MEX 60 / 1000 mg , 08/01/2022. FDC = Fixed Dose Combination

References • GUIDE study • EASY 2 study • New 2021 Diamicron XR MEX study • SCHRAMM study • PRESCRIBING INFORMATION OF DIAMICRON XR MEX 60/1000 mg

European Journal of Clinical Investigation (2004) 34, 535– 542 GUIDEBlackwellPublishing,Ltd. study: double-blind comparison of once-daily gliclazide MR and glimepiride in type 2 diabetic patients G. Schernthaner*, A. Grimaldi†, U. Di Mario‡, J. Drzewoski§, P. Kempler¶, M. Kvapil**, A. Novials††, R. Rottiers‡‡, G. E. H. M. Rutten§§ and K. M. Shaw¶¶ *Rudolfstiftung Hospital, Vienna, Austria; †Pitié Salpétrière Hospital, Paris, France, ‡Policlinico Umberto I, Rome, Italy, §Medical University of Lodz, Lodz, Poland, ¶Semmelweis University, Budapest, Hungary, **Faculty Hospital Motol, Prague, Czech Republic, ††Fundació Sardà Farriol, Barcelona, Spain, ‡‡University Hospital, Gent, Belgium, §§Utrecht University, Utrecht, the Netherlands, ¶¶Queen Alexandra Hospital, Portsmouth, UK Abstract Background Progressive β-cell failure is a characteristic feature of type 2 diabetes; consequently, β-cell secretagogues are useful for achieving sufficient glycaemic control. The European GUIDE study is the first large-scale head-to-head comparison of two sulphonylureas designed for once-daily administration used under conditions of everyday clinical practice. Design Eight hundred and forty-five type 2 diabetic patients were randomized to either gliclazide modified release (MR) 30–120 mg daily or glimepiride 1–6 mg daily as monotherapy or in combination with their current treatment (metformin or an α-glucosidase inhibitor) according to a double-blind, 27-week, parallel-group design. Efficacy was evaluated by HbA1c and safety by hypoglycaemic episodes using the European Agency definition. Results HbA1c decreased similarly in both groups from 8·4% to 7·2% on gliclazide MR and from 8·2% to 7·2% on glimepiride. Approximately 50% of the patients achieved HbA1c levels less than 7%, and 25% less than 6·5%. The mean difference between groups of the final HbA1c was −0·06% (noninferiority test P < 0·0001). No hypoglycaemia requiring external assistance occurred. Hypoglycaemia with blood glucose level < 3 mmol L−1 occurred significantly less frequently (P = 0·003) with gliclazide MR (3·7% of patients) compared with glimepiride (8·9% of patients). The distribution of the sulphonylurea doses was similar in both groups. Conclusions This study provides new insights into therapeutic strategies using sulphonylureas. It shows that gliclazide MR is at least as effective as glimepiride, either as monotherapy or in combination. The safety of gliclazide MR was significantly better, demonstrating approximately 50% fewer confirmed hypoglycaemic episodes in comparison with glimepiride. Keywords Glucose control, HbA1c, hypoglycaemia, sulphonylureas, type 2 diabetes. Eur J Clin Invest 2004; 34 (0): 000–000 Department of Medicine I, Rudolfstiftung Hospital, Vienna, Austria (G. Schernthaner); Pitié Salpétrière Hospital, Paris, France (A. Grimaldi); Policlinico Umberto I, Rome, Italy (U. Di Mario); Medical University of Lodz, Lodz, Poland ( J. Drzewoski); Semmelweis University, Budapest, Hungary (P. Kempler); Faculty Hospital Motol, Prague, Czech Republic (M. Kvapil); Fundació Sardà Farriol, Barcelona, Spain (A. Novials); University Hospital, Gent, Belgium (G. E. H. M. Rutten); Utrecht University, Utrecht, the Netherlands; Queen Alexandra Hospital, Portsmouth, UK (K. M. Shaw). Correspondence to: Professor Guntram Schernthaner, Rudolfstiftung Hospital, Department of Medicine I, Juchgasse 25, A-1030 Vienna, Austria. Tel.: +43 1711 65 21 07; fax: +43 1711 65 21 09, e-mail: [email protected] Received 19 April 2004; accepted 24 June 2004 © 2004 Blackwell Publishing Ltd

536 G. Schernthaner et al. Introduction Study design Sulphonylureas are widely used in the management of type After confirmation of eligibility, patients were randomized 2 diabetes, as impaired insulin secretion plays an important to either gliclazide MR or glimepiride either as monotherapy role in the pathophysiology of hyperglycaemia [1]. Tight in patients previously treated with diet alone or in combi- glycaemic control is essential in order to prevent or delay nation with their current treatment (metformin or an α- diabetes complications [2,3]. One deterrent to tight gly- glucosidase inhibitor maintained at stable dosage) for a caemic control is the risk of hypoglycaemia [2]. Moderate 27-week double-blind treatment period that comprised a hypoglycaemia induces cognitive impairment [4] and 9-week dose titration period followed by an 18-week many complex attention tasks relevant to everyday life maintenance period. The randomization of treatments was may be impaired [5]. Recurrent severe hypoglycaemia may balanced, using permutation blocks of four and stratified on induce impaired awareness of hypoglycaemia and possibly the centres. long-term sequelae in the form of cumulative cognitive impairment [6,7]. Intensive therapy frequently means The four dosages of gliclazide MR, from 30 to 120 mg multiple medications, negatively impacting treatment adher- daily, and the five dosages of glimepiride, from 1 to 6 mg ence. Studies have demonstrated that adherence depends daily, currently recommended in European countries were on the frequency of doses: fewer intakes lead to higher used. Tablets were masked in capsules. It was checked that compliance [8]. Gliclazide modified release (MR) and the blinding method using capsules did not modify the dis- glimepiride are the two once-daily sulphonylureas used solution kinetics of the tablets. Capsules were taken once most frequently in type 2 diabetes treatment in many daily, just before or during breakfast as follows (gliclazide European countries [9]. Gliclazide MR has demonstrated MR /glimepiride): dose 1 (30 mg or 1 mg); dose 2 (60 mg efficacy and safety [10 – 12]; a smaller incidence of hypogly- or 2 mg); dose 3 (90 mg or 3 mg); dose 4 (120 mg or 4 mg); caemia has been reported with gliclazide than with other and dose 5 (120 mg or 6 mg). Patients started double-blind sulphonylureas in several studies [13–15]. Glimepiride medication with the lowest dose of gliclazide MR 30 mg or demonstrated equivalent efficacy to glibenclamide, with a glimepiride 1 mg. During the titration period, the dose of lower incidence of hypoglycaemia during the first weeks study medication could be increased every 3 weeks up to of treatment [16,17]. Despite sulphonylureas being a dose 4 until metabolic control was achieved [therapeutic widely used class of oral antidiabetics [9], few direct goal defined as fasting plasma glucose (FPG) between 5 and comparisons have been performed. GUIDE (GlUcose 7·8 mmol L−1]. Visits were then scheduled every 9 weeks control in type 2 diabetes: Diamicron MR vs. glimEpiride) (W).The product monograph for glimepiride states that the is a large scale prospective double-blind, randomized usual maintenance dose is 1–4 mg and the maximal dose study comparing gliclazide MR and glimepiride, over of 6 mg allowed in most European countries improves blood 27 weeks in type 2 diabetic patients. The study was glucose control only in exceptional cases. However, designed first to assess the efficacy of these sulphonylureas, glimepiride 6 mg (dose 5) could be prescribed at visit W18 following current recommendations for dose adapta- based on HbA1c and the investigator’s judgement. Dose 5 tion and second to obtain reliable information on for gliclazide MR corresponded like dose 4–120 mg. sulphonylurea-related hypoglycaemia when glycaemic control Throughout the study, the dose could be decreased in case is improved. of hypoglycaemia according to the investigator’s judgement or more than 3 episodes within 1 month. Methods The trial was approved by the Medical Ethical Review Subjects Committees of participating centres and conducted in accordance with the revised Declaration of Helsinki Inclusion criteria were: type 2 diabetic patients (accord- (Edinburgh revision, 2000). All patients gave their written ing to World Health Organization criteria), >35 years informed consent to participate in the study. One hundred old, treated for at least 3 months with diet alone or in and fifty-four clinical centres in Austria, Belgium, the Czech combination with metformin or an α-glucosidase inhibitor Republic, France, Germany, Hungary, Italy, the Nether- (acarbose or miglitol), with glycated haemoglobin lands, Poland, Slovakia, Spain, and the United Kingdom (HbA1c) between 6·9% to 11·5%, and able to perform were involved. home blood glucose monitoring. Exclusion criteria were: currently treatment with insulin-secreting agents All fasting blood samples were analyzed in a central or thiazolidinediones, contraindication to study drugs, laboratory (MDS-Pharma Services, France), except for FPG no effective contraception in women with child-bearing during the titration period, which was analyzed in local potential, elevated transaminases more than threefold laboratories ( W3, W6, and W9). the upper normal range or calculated creatinine clearance (CCl) using the Cockroft formula: CCl < Central HbA1c and FPG were assessed at baseline ( W0), 20 mL min−1. at the end of the titration period ( W9), and during the main- tenance period ( W18 andW27). HbA1c was assayed with the high-performance liquid chromatography (HPLC) Biorad Variant. The lipid profile [including total cholesterol, high- density lipoprotein (HDL) cholesterol, calculated low- density lipoprotein (LDL) cholesterol, and triglycerides, using an enzymatic method] and biochemical safety screen © 2004 Blackwell Publishing Ltd, European Journal of Clinical Investigation, 34, 000–000

GUIDE study: gliclazide MR vs. glimepiride 537 (serum creatinine, transaminases, alkaline phosphatase) Changes from baseline to last value were analyzed in each were assessed at W0 and at the last visit. treatment group using a paired Student’s t-test. Changes from baseline were tested in each treatment group using one-way Adverse events were recorded at each visit after examina- analysis of variance for repeated measures on time factor tion and questioning of patients. and completed by a Dunnett t-test (baseline as reference). All patients were provided with the same blood glucose For hypoglycaemic episodes, the percentage of patients monitoring device with a memory (Glucotrend, Roche reporting at least one episode and the distribution of the Diagnostics) and were trained to recognize symptoms sug- number of episodes were compared between treatment gestive of hypoglycaemia. Patients systematically measured groups using Fisher’s exact test. The time of occurrence of capillary blood glucose 1 day per week (three times daily: the first event was compared between the two treatment before breakfast, lunch, and dinner). At any occurrence of groups using a model for survival curves (Kaplan–Meier symptoms they were instructed to measure their blood glucose estimator) and Wilcoxon test. level (BGL) and to record the event in a diary, which was reviewed by the investigator at each visit. Analyses were also performed on prespecified subgroups according to concomitant antidiabetic treatment, age The definitions used to classify suspected hypoglycaemia (≤ 65, and > 65 years, > 75 years), CCl < 50, 50–80, were those recommended by the European Agency for the and > 80 mL min−1, and body mass index (BMI) (≤ and Evaluation of Medicinal Products (EMEA) [18]: (i) severe > 30 kg m−2). hypoglycaemia, defined as symptomatic episodes requiring external assistance owing to severe impairment in con- All statistical analyses were performed using SAS soft- sciousness or behaviour, with BGL < 3 mmol L−1; (ii) ware (Statistical Analysis System, version 8·2, SAS Institute, hypoglycaemia with BGL < 3 mmol L−1 being either symp- Cary, NC). Data management and statistical analysis were tomatic with no need for external assistance, or asympto- performed by a professional institute independent from the matic; and (iii) episodes suggestive of hypoglycaemia, where sponsor (UMANIS, Levallois-Perret, France). blood glucose measurements are not available. Additionally the blood glucose threshold of less than 4 mmol L−1 was also Results used to describe hypoglycaemia, following the Canadian guidelines [19]. Statistical analysis Demographic and baseline characteristics The primary efficacy endpoint was HbA1c. Secondary A total of 845 patients were randomized in the study. The endpoints included FPG, lipid levels, and hypoglycaemic two groups were comparable for all baseline characteristics episodes. (Table 1). Of the 845 patients, 842 were exposed to at least one dose of study medication corresponding to the safety Sample size was estimated based on the final value of population. Of them, 815 had at least one HbA1c value on HbA1c, using the one-sided Student’s t-test at 2·5% type I study medication corresponding to the intention-to-treat error (noninferiority limit set at 0·5%); 400 patients per population. group were needed to conclude noninferiority of gliclazide MR compared with glimepiride with a SD of 1·5% and a Overall, 778 of 845 patients (92%) completed the study. power greater than 90%. This figure was also appropriate Thus, 67 patients withdrew from the study (35 gliclazide to evaluate differences in the incidence of hypoglycaemic MR/32 glimepiride): 23 owing to adverse events other than episodes. hypoglycaemia (12 gliclazide MR/11 glimepiride), 10 owing to hypoglycaemia (1 gliclazide MR/9 glimepiride), two All efficacy analyses were performed on the intention-to- owing to lack of efficacy (one in each treatment group), 25 treat population, defined as all patients exposed to study for a nonmedical reason (16 gliclazide MR/9 glimepiride), medication with one baseline and at least one postbaseline and seven because of a protocol deviation (five gliclazide efficacy evaluation on treatment, and the per-protocol pop- MR/2 glimepiride). ulation defined as completed patients without deviation interfering with primary efficacy criterion. Safety analyses Efficacy were performed on all patients who were exposed to at least one dose of study medication. Final values for withdrawn Over the 27 weeks of treatment, improvement in blood patients corresponded to the final values on treatment (final glucose control was statistically significant in both groups observation on treatment carried forward). Data are expressed with decreases in HbA1c of 1·1 – 1% (Table 2) and in FPG as mean ± SD. of 1·4 – 1·3 mmol L−1 in the gliclazide MR and glimepiride groups, respectively. Mean adjusted differences between For efficacy analyses, covariance analysis on the last value groups were – 0·06% (95% CI –0·19 to 0·07) for HbA1c including the baseline value as covariate and country and and – 0·05 mmol L−1 (95% CI –0·33 to 0·23) for FPG with concomitant antidiabetic treatment as factors was used. A noninferiority tests, both P < 0·0001.The time course of the 95% confidence interval (CI) for differences between the changes in mean HbA1c and FPG in each treatment group least-squares means (gliclazide MR – glimepiride) obtained were similar with an early decrease at 9 weeks (Fig. 1). from the covariance analysis were calculated as well as an exact P-value (using a noncentred Student’s t-test). © 2004 Blackwell Publishing Ltd, European Journal of Clinical Investigation, 34, 000 –000

538 G. Schernthaner et al. Table 1 Baseline characteristics in the randomized population Age (years) Gliclazide MR 405 patients Glimepiride 440 patients Sex (M/F) (%) Body weight (kg) 60·5 ± 9·9 60·6 ± 10·5 Body mass index (kg m−2) 51/49 52/48 Blood pressure (mmHg) 83·1 ± 14·3 83·8 ± 16·0 Known duration of diabetes (years) 30·5 ± 4·8 30·6 ± 4·9 HbA1c (%) 136 ± 13/81 ± 8 137 ± 14/81 ± 8 Fasting plasma glucose (mmol L−1) Hypertension (%) 5·6 ± 5·9 5·8 ± 5·8 Dyslipidemia (%) 8·4 ± 1·1 8·2 ± 1·0 Macrovascular complications (%) 10·2 ± 2·6 10·1 ± 2·6 Microvascular complications (%) 61 64 Antihypertensive agents (%) 49 49 Lipid-lowering agents (%) 22 21 Anti-platelet agents (%) 10 11 60 62 30 33 21 21 Data are mean ±SD. Table 2 Change in glycated haemoglobin (%) in the intention-to-treat population Whole population Gliclazide MR Final Change Glimepiride Final Change 7·2 ± 1·1 −1·1 ± 1·1* 7·2 ± 1·1 −1·0 ± 1·1* Subgroups n Baseline n Baseline 388 8·4 ± 1·1 7·0 ± 0·9 −1·3 ± 1·1* 427 8·2 ± 1·0 6·9 ± 0·9 −1·2 ± 1·0* Treatment regimen 129 8·3 ± 1·1 7·4 ± 1·2 −1·0 ± 1·1* 150 8·1 ± 1·0 7·4 ± 1·2 −0·9 ± 1·1* Monotherapy 7·3 ± 1·1 −1·1 ± 1·2* 7·3 ± 1·1 −0·9 ± 1·2* 219 8·4 ± 1·1 250 8·3 ± 1·0 Combination therapy 40 8·4 ± 1·0 7·3 ± 1·2 −1·2 ± 1·1* 27 8·2 ± 1·1 7·2 ± 1·1 −1·1 ± 1·1* 7·2 ± 1·0 −1·1 ± 1·2* 7·2 ± 1·1 −0·9 ± 1·0* Metformin 253 8·4 ± 1·1 276 8·3 ± 1·0 α-glucosidase inhibitor 135 8·4 ± 1·1 7·2 ± 1·1 −1·2 ± 1·1* 151 8·1 ± 0·9 7·2 ± 1·1 −1·1 ± 1·1* Age 7·3 ± 1·1 −1·0 ± 1·1* 7·3 ± 1·1 −0·9 ± 1·1* ≤ 65 years 218 8·4 ± 1·1 7·0 ± 1·0 −1·4 ± 1·6† 229 8·3 ± 1·1 7·0 ± 1·3 −1·0 ± 1·0* > 65 years 151 8·4 ± 1·1 176 8·2 ± 0·9 7·3 ± 1·1 −1·2 ± 1·2* 7·3 ± 1·1 −1·0 ± 1·2* Creatinine clearance‡ 16 8·4 ± 1·2 7·2 ± 1·0 −1·1 ± 1·1* 22 8·1 ± 0·9 7·2 ± 1·0 −1·0 ± 1·0* > 80 mL min−1 50–80 mL min−1 201 8·4 ± 1·2 216 8·2 ± 1·0 < 50 mL min−1 187 8·4 ± 1·1 211 8·4 ± 1·1 BMI ≤ 30 kg m−2 > 30 kg m−2 Data are mean ± SD. *P < 0·001; †P < 0·01. ‡Calculated using the Cockroft formula; missing data for three patients. Improvement of blood glucose control was observed as early (32%/32·8%); dose 2 (18%/19·2%); dose 3 (14·2%/16·9%); as W9 with HbA1c of 7·5 (1·1%) and 7·4 (1·0%) at W9 and 7·3 (1·1%) and 7·2 (1·1%) at W18 in the gliclazide MR and dose 4 (15·5%/14·3%), and dose 5 (20·3%/16·8%). Mean glimepiride groups, respectively, and a mean FPG of 8·6 (± SD) final daily dosages were 76·2 (38·1) mg for gliclazide (2·3) mmol L−1 at W9 and 8·7 (2·3) mmol L−1 at W18 in both MR and 2·9 (1·8) mg for glimepiride. In patients in whom groups.The evolution of HbA1c was similar in all subgroups according to concomitant antidiabetic treatment, age, renal the glimepiride dose was increased from 4 to 6 mg at W18, function and BMI (Table 2). In both treatment groups, the mean HbA1c (± SD) remained stable at 8·5 (1·4)% at approximately 50% of patients achieved HbA1c levels W18 and 8·4 (1·2)% at W27. HbA1c values were 8·4 (1·2)% less than 7%, and 25% less than 6·5% by the end of study and 8·2 (1·2)%, respectively, over the same period in treatment. patients receiving dose 5 of gliclazide MR (same dosage as The method in which the final doses were distributed was similar in the gliclazide MR/glimepiride groups: dose 1 dose 4, i.e. 120 mg). Lipid parameters remained stable throughout the study, with minimal changes in LDL-cholesterol from 3·3 to 3·2 mmol L−1 and from 3·2 to 3·2 mmol L−1 and of © 2004 Blackwell Publishing Ltd, European Journal of Clinical Investigation, 34, 000–000

GUIDE study: gliclazide MR vs. glimepiride 539 triglycerides from 2·2 to 2·1 mmol L−1 and from 2·3 to 2·2 mmol L−1 in the gliclazide MR and glimepiride groups, respectively. Identical results were observed in the per-protocol population for all efficacy criteria. Safety and tolerability Figure 1 Changes in HbA1c (a) and fasting plasma glucose Overall, 66% and 69% of symptoms of hypoglycaemia were (b). Data are means ± SEM. ᭡: gliclazide MR; ᭿: glimepiride. documented with blood glucose measured before sugar intake on gliclazide MR and glimepiride, respectively. non-inferiority test, P < 0·0001. Hypoglycaemia with BGL < 3 mmol L−1 occurred signif- icantly less frequently (P = 0·003) in the gliclazide MR group (3·7%) compared with the glimepiride group (8·9%) with an odds ratio of 2·5 (95% CI, 1·4–4·7) (Table 3). Epi- sodes suggestive of hypoglycaemia (symptoms with no blood glucose measurement) also occurred less frequently on gli- clazide MR [34 patients (8·4%) experienced 45 episodes in total] compared with glimepiride [52 patients (11·8%) experienced 82 episodes in total]. The occurrence of hypoglycaemic episodes was evenly distributed during the 27-week study (Fig. 2). No episodes requiring external assistance or nocturnal symptomatic epi- sodes occurred. On both drugs, most of the hypoglycaemic episodes occurred in the late morning (58% between 11:00 and 13:00) and early afternoon (17% between 13:00 and 15:00) (Fig. 3). Hypoglycaemic symptoms led to nine patients on glimepiride withdrawing from the study vs. Table 3 Hypoglycaemia with blood glucose level < 3 mmol L−1 in the safety population Whole population Gliclazide MR n (%) Patients Episodes Glimepiride (%) Patients (n) Episodes Patients exposed (n) 15 (3·7)* 22† Patients exposed (n) 39 (8·9)* 56† Subgroups 403 439 10 (3·8)* 12 25 (8·8)* 39 Age 264 5 (3·6)‡ 10 284 14 (9·0)‡ 17 ≤ 65 years 139 155 > 65 years 10 (4·4)‡ 12 13 (5·6)‡ 23 226 5 (3·2)* 10 232 23 (12·6)* 27 Creatinine clearance§ 157 0 (0)‡ 182 > 80 mL min−1 0 3 (12·0)‡ 6 50–80 mL min−1 17 7 (5·3)‡ 25 < 50 mL min−1 8 15 (9·6)‡ 19 133 6 (2·6)* 156 Treatment details 2 (4·9)‡ 12 22 (8·6)* 35 229 2 255 2 (7·1)‡ 2 Treatment regimen 41 2 (2·1) 28 6 (6·6) 2 20 (17·5) 24 Monotherapy 97 3 (3·7) 11 114 7 (6·5) 10 91 1 (2·1) 108 8 (10·0) 14 Combination therapy 81 3 (4·2) 4 3 (6·0) 48 1 80 0 6 Metformin 71 4 50 0 α-glucosidase inhibitor 75 Final HbA1c (%)¶ ≤ 6·5 6·5–7 7–7·5 7·5–8 >8 Between-group comparisons: *P ≤ 0·02, †P = 0·007, ‡non-significant, §calculated using the Cockroft formula; the three patients with missing creatinine clearance did not experience hypoglycaemia with a blood glucose level < 3 mmol L−1. ¶Data on safety population except for final HbA1c (intention-to-treat population; final HbA1c missing in 15 patients on gliclazide MR and 12 patients on glimepiride, one patient reported two hypoglycaemic episodes in the glimepiride group). © 2004 Blackwell Publishing Ltd, European Journal of Clinical Investigation, 34, 000 –000

540 G. Schernthaner et al. At least one adverse event other than hypoglycaemia was reported in 40·9% and 40·1% of patients in the gliclazide MR and glimepiride groups, respectively. Fifty-six serious adverse events occurred: 28 in each group. The most fre- quent were cardiovascular events at similar frequencies and judged to be nonrelated to the treatment by the investigator. There were no significant changes in the biochemical safety screen. Body weight was stable during the study with mean changes from 83·1 to 83·6 kg and 83·7 to 84·3 kg on gliclazide MR and glimepiride, respectively. Figure 2 Kaplan–Meier curves for time to appearance of the Discussion first hypoglycaemia with blood glucose level < 3 mmol L−1. ––: gliclazide MR; - -: glimepiride. Wilcoxon test, P = 0·004. Significant improvements in blood glucose control were obtained in this study, with sulphonylureas used as first-line one patient on gliclazide MR. Study-treatment dose was therapy or in combination with metformin or α-glucosidase decreased for one patient only, who experienced one episode inhibitors. From a mean baseline value of 8·3%, half the with no blood glucose measurement. population attained a final HbA1c value less than 7%, and 25% less than 6·5%. Gliclazide MR and glimepiride, used The 3 mmol L−1 threshold for BGL complies with the under identical glucose level target titration, were similarly EMEA recommendation of having a high level of specificity effective in improving blood glucose control with early in the diagnosis of hypoglycaemia in clinical trials. When decreases after 9 weeks of treatment. Sulphonylureas pro- considering patients with symptoms and a BGL between 3 vide long-lasting improvement in blood glucose control and 4 mmol L−1 (hypoglycaemia in clinical practice), there [20], but this entails a risk of hypoglycaemia. This study was also a 50% difference between gliclazide MR and provides detailed data on hypoglycaemia in well-trained glimepiride [for gliclazide MR, 31 patients (7·7%) experi- patients performing home blood glucose monitoring on a enced 45 episodes in total; for glimepiride, 63 patients regular basis. The confirmation of hypoglycaemic episodes (14·4%) experienced 108 episodes in total; P = 0·002]. by capillary blood glucose enhances the value of the data. The safety of gliclazide MR was significantly better, Table 3 displays hypoglycaemia with BGL < 3 mmol L−1 demonstrating approximately 50% fewer hypoglycaemic epi- according to age, renal function, concomitant antidiabetic sodes in comparison with glimepiride. It is worth noting that treatment, and final HbA1c achieved. Among the 75 patients the incidence of hypoglycaemia was particularly low in the with baseline HbA1c ≤ 7%, 2·3% and 12·5% of patients in gliclazide MR-treated patients whose HbA1c was either the gliclazide MR and glimepiride groups, respectively, moderately elevated at baseline (≤ 7%) and /or decreased experienced hypoglycaemia with BGL < 3 mmol L−1 (data less than 6·5% on treatment and who were at higher risk not shown). In patients > 75 years (23 on gliclazide MR and for hypoglycaemia [21]. This shows that gliclazide MR can 30 on glimepiride), 0 and 3 reported hypoglycaemia with be used following current recommendations of aggressive BGL < 3 mmol L−1, respectively. Most episodes occurred treatment to obtain HbA1c targets between 6·5% and 7% at the lowest treatment doses, 13 and two out of 22 episodes [19,22,23]. Data suggest that even mild impairment of on 30 mg and 60 mg gliclazide MR, respectively, and 21 and 27 out of 56 episodes on glimepiride 1 and 2 mg. No hypoglycaemia was observed on glimepiride 6 mg. Figure 3 Time of occurrence of hypoglycaemia with blood glucose level < 3 mmol L−1. ᮀ: gliclazide MR; ᭿: glimepiride. © 2004 Blackwell Publishing Ltd, European Journal of Clinical Investigation, 34, 000–000

GUIDE study: gliclazide MR vs. glimepiride 541 renal function increases the incidence of hypoglycaemia on This study was supported by a grant from the Institut de glimepiride and not on gliclazide MR.This might contribute Recherches Internationales Servier, Courbevoie, France. to the difference between the drugs considering the high prevalence of patients with creatinine clearance less than References 80 mL min−1. 1 Kahn SE. The relative contribution of insulin resistance and No episodes of severe hypoglycaemia were reported during beta-cell dysfunction to the pathophysiology of type 2 diabetes. the study in patients carefully trained in the management Diabetes 2003;46:3–19. of hypoglycaemia. However, in routine practice severe hypoglycaemia is encountered in patients with type 2 diabetes. 2 UK Prospective Diabetes Study (UKPDS) group. Intensive It should be noted that risk factors for severe hypoglycaemia blood glucose control with sulphonylureas or insulin compared recorded in a recent survey in acute care units are consistent with conventional treatment and risk of complications in with the nonsevere hypoglycaemia in this study, in particular patients with type 2 diabetes (UKPDS 33). Lancet low HbA1c and renal impairment for glimepiride [21]. 1998;352:837 – 53. The observed difference in hypoglycaemic risk between 3 Gaede P, Vedel P, Larsen N, Jensen GVH, Parving HH, the two sulphonylureas may be explained by the pharma- Pedersen O. Multifactorial intervention and cardiovascular cokinetic and pharmacodynamic properties of gliclazide disease in patients with type 2 diabetes. N Engl J Med MR and glimepiride. First, the two drugs show different 2003;348:383 – 93. pharmacokinetic profiles with the occurrence of an active metabolite eliminated by the kidney for glimepiride [16] and 4 Cryer PE, Davis SN, Shamoo H. Hypoglycemia in diabetes. no circulating active metabolite for gliclazide MR [10], Diabetes 2003;26:1902–12. consistent with the higher incidence of hypoglycaemia in patients with impaired renal function. Moreover, the course 5 McAulay V, Deary IJ, Ferguson SC, Frier BM. Acute of the drug concentration profile over time is different, with hypoglycemia in humans causes attentional dysfunction while a progressive increase in gliclazide plasma concentrations nonverbal intelligence is preserved. Diabetes Care over 6 h after drug administration [10,24] contrasting with 2001;24:1745 – 50. a broad and sharp increase to maximal concentration for glimepiride [16,25]. The time to reach peak plasma con- 6 Smith D, Amiel SA. Hypoglycaemia unawareness and the centration (tmax) of glimepiride, by 2 – 4 h, is also consistent brain. Diabetologia 2002;45:949–58. with the peak of appearance of hypoglycaemia in the late morning [16]. The same time of appearance was reported 7 Frier BM. Hypoglycaemia and cognitive function in diabetes. for severe episodes on glimepiride [21]. Second, these agents Int J Clin Pract Suppl 2001;123:30 – 7. show different binding behaviour to the sulphonylurea receptor of the pancreatic β cell with a rapidly reversible 8 Paes AH, Bakker A, Soe-Agnie CJ. Impact of dosage frequency interaction for gliclazide [26] and prolonged binding for on patient compliance. Diabetes Care 1997;20:1512–7. glimepiride, with prolonged cell stimulation [27].Third, the two drugs induce a different insulin secretion profile. In the 9 IMS Health, IMS MIDAS (2003). Data for 2003 in a panel of classic model of isolated rat pancreas, perfused with glucose 15 European countries (Database). Extracted June 2004. 5 or 8·3 mmol L−1 and exposed to therapeutic concentra- tions of sulphonylureas, glimepiride produces a prolonged 10 McGavin JK, Perry CM, Goa KL. Gliclazide modified release. second phase of insulin secretion [28,29], whereas it returns Drugs 2002;62:1357–64. more quickly to basal values with gliclazide [30]. 11 Drouin P, Diamicron® MR Study Group. Diamicron® MR In conclusion, using a current therapeutic strategy, gli- once-daily is effective and well tolerated in type 2 diabetes. A clazide MR and glimepiride have been shown to be effective double-blind, randomized, multinational study. J Diabetes alone or in combination with metformin or α-glucosidase Complicat 2000;14:185–91. inhibitors, with a better safety profile for gliclazide MR. In the context of recommended early intensive therapy in type 12 Schernthaner G. Gliclazide modified release: a critical review 2 diabetes [3,19,22,23], the availability of a once-daily effec- of pharmacodynamic, metabolic, and vasoprotective effects. tive sulphonylurea with a good safety profile is of relevant Metabolism 2003;52:29–34. clinical interest. 13 Jennings AM, Wilson RM, Ward JD. Symptomatic Acknowledgements hypoglycemia in NIDDM patients treated with oral hypoglycemic agents. Diabetes Care 1989;12:203–8. We would like to thank all the investigators of the GUIDE study. 14 Tessier D, Dawson K, Tétrault JP, Bravo G, Meneilly GS. Glibenclamide versus gliclazide in type 2 diabetes of the elderly. The National coordinator for Italy was Pr Di Mario, Diabet Med 1994;11:974–80. whose recent death on 16 February 2004 has greatly saddened us. 15 Van Staa T, Abenhaim L, Monette J. Pharmacoepidemiology report. Rates of hypoglycaemia in users of sulfonylureas. J Clin Epidemiol 1997;50:735–41. 16 Langtry HD, Balfour JA. Glimepiride, a review of its use in the management of type 2 diabetes mellitus. Drugs 1998;55:563– 84. 17 Dills DG. Clinical evaluation of glimepiride versus glyburide in NIDDM in a double-blind comparative study. Horm Metab Res 1996;28:426–9. 18 EMEA. Note for guidance on clinical investigation of medicinal products in the treatment of diabetes mellitus. London, UK: CPMP/ EWP/1080/00, 2002. 19 Canadian Diabetes Association Clinical Practice Guidelines Expert Committee 2003. Clinical practice guidelines for the prevention and management of diabetes in Canada. Can J Diabetes 2003;27:S1–S140. © 2004 Blackwell Publishing Ltd, European Journal of Clinical Investigation, 34, 000 –000

542 G. Schernthaner et al. 20 Turner RC, Cull CA, Frighi V, Holman RR. Glycemic clinically effective doses in diabetic patients with renal control with diet, sulfonylurea, metformin, or insulin in impairment. Diabetologia 1996;39:1617–24. patients with type 2 diabetes mellitus. Progressive requirement 26 Gribble FM, Ashcroft FM. Differential sensitivity of beta-cell for multiple therapies (UKPDS 49). JAMA 1999;281:2005– and extrapancreatic KATP channels to gliclazide. Diabetologia 12. 1999;42:845–8. 27 Song DK, Ashcroft FM. Glimepiride block of cloned beta-cell, 21 Holstein A, Plaschke A, Hammer C, Egberts EH. cardiac and smooth muscle KATP channels. Br J Pharmacol Characteristics and time course of severe glimepiride- versus 2001;133:193 – 9. glibenclamide-induced hypoglycaemia. Eur J Clin Pharmacol 28 Gregorio F, Ambrosi F, Cristallini S, Filipponi P, Santeusanio 2003;59:91–7. F. Effects of glimepiride on insulin and glucagon release from isolated rat pancreas at different glucose concentrations. Acta 22 International Diabetes Federation. A desktop guide to type 2 Diabetol 1996;33:25 – 9. diabetes mellitus. European Diabetes Policy Group 1999. 29 Leclercq-Meyer V, Akkan AG, Marchand J, Malaisse WJ. Diabet Med 1999;6:716 – 30. Effects of glimepiride and glibenclamide on insulin and glucagon secretion by the perfused rat pancreas. Biochem 23 American Diabetes Association (ADA). Standards of medical Pharmacol 1991;42:1634–7. care for patients with diabetes mellitus. Diabetes Care 30 Gregorio F, Ambrosi F, Cristallini S, Pedetti M, Filipponi P, 2004;27:S15 –S35. Santeusanio F. Therapeutical concentrations of tolbutamide, glibenclamide, gliclazide and gliquidone at different glucose 24 Francillard M, Frey N, Paraire M, Laveille C, Jochemsen R. levels: in vitro effects on pancreatic A- and B-cell function. Pharmacokinetics of Diamicron® modified release (MR) in Diabetes Res Clin Pract 1992;18:197–206. 1007 type 2 diabetic patients (Abstract). J Nutr Health Aging 2001;5:A14. 25 Rosenkranz B, Profozic V, Metelko Z, Mrzljak V, Lange C, Malerczyk V. Pharmacokinetics and safety of glimepiride at © 2004 Blackwell Publishing Ltd, European Journal of Clinical Investigation, 34, 000–000

TREATMENT OF TYPE 2 DIABETES WITH GLICLAZIDE MODIFIED RELEASE 60MG IN THE PRIMARY CARE SETTING OF INDIA S K Wangnoo ABSTRACT The majority are treated by physicians in the setting of primary care, with a strategy that includes diet, exercise, The majority of Indian type 2 diabetic patients are and blood sugar monitoring, with control of blood sugar, treated in the primary care setting, and not more than blood pressure and dyslipidemia. Surveys indicate that one quarter attain recommended glycemic control this strategy is effective in maintaining American Diabetes targets. This study examines whether substituting twice Association control targets in about 27% of patients in daily gliclazide 80mg with once daily gliclazide modified the community (3). Among the several reasons for this release (MR) 60mg achieves better control of type 2 low rate of glycemic control are an inadequate compliance diabetes in the primary care setting. with oral antidiabetic drugs due to multiple dosage frequency, and side effects such as hypoglycemia. It In a prospective multicentre study, medication with has been reported that type 2 patients on monotherapy twice daily gliclazide 80mg in the treatment regimen of who convert from a multiple dose regimen to a once uncontrolled type 2 diabetic patients was substituted daily formulation increase their adherence to medication with once daily gliclazide MR 60mg, without changing by 23%, and that this is reflected in lower HbA1c levels any other antidiabetic drugs or their doses for 14 weeks. (4). There is therefore a need for once daily oral The primary outcome was the number of patients antidiabetic drugs that are clinically effective and achieving glycemic control. acceptable to patients. 101 investigators recruited 162 patients distributed Gliclazide is one of the most frequently used throughout India. On intention to treat analysis, 64.8% sulphonylureas for the treatment of type 2 diabetes. The (57.4 to 72.2%) of patients achieved fasting blood glucose original formulation required twice daily administration. of less than 130 mg/dl, and there were 4.3% fewer A new once daily gliclazide modified release (MR) hypoglycaemic episodes. Mean (95% confidence interval) formulation has been recently introduced (Diamicron MR fasting plasma glucose decreased by 73.3 (69.5 to 87.1, 60, Serdia, India). In a large randomised study on type 2 P< 0.01) mg/dl, total cholesterol by 20.2 (13.4 to 27.0, diabetic patients, once daily gliclazide MR 30-120mg P< 0.01) mg/dl; low density lipoprotein cholesterol by was as effective as twice daily gliclazide 80-320mg in 13.2 (7.8 to 18.6, P< 0.01) mg/dl; and total triglycerides reducing HbA1c, with fewer side effects and less risk of by 21.5 (10.7 to 32.3, P< 0.01) mg/dl. Mean compliance hypoglycemia (5). However, it is not clear from these was 96.9% with gliclazide MR 60mg. results, based on a strict adherence to the randomised protocol, whether the expected improvement in Once daily gliclazide MR 60mg is more effective than compliance and less hypoglycemia with once daily twice daily gliclazide 80mg in glycemic control and gliclazide MR, translates into more effective glycemic causes less hypoglycemia, both in monotherapy and in control under conditions of primary care practice. Such combination with other agents. Gliclazide MR is a useful information could be useful to physicians in selecting a once daily sulphonylurea formulation for the management gliclazide formulation and help increase glycemic control of type 2 diabetes in primary care. rates in the community. KEYWORDS: Type 2 diabetes, Gliclazide modified The objectives of this study were to examine the release, Glycemic control; Primary care clinical, biochemical, and adverse effects of substituting twice daily gliclazide 80mg with once daily gliclazide INTRODUCTION MR 60mg in the treatment regimen of patients with type 2 diabetes, under the primary care conditions of The prevalence of type 2 diabetes is about 12% in India. urban India (1), and it is estimated that the country has the largest number of these patients in the world (2). Consultant Endocrinologist, Indraprastha Apollo Hospitals, Department of Endocrinology, New Delhi – 110 044, Tel: 011-26914811, Email: [email protected] INT. J. DIAB. DEV. COUNTRIES (2005), VOL. 25 50

MATERIALS AND METHODS RESULTS The Research Society for the study of Diabetes in The 101 investigators recruited 162 uncontrolled India had 3304 members in 2003. A simple 4% random type 2 diabetic patients distributed throughout urban sample of these physicians identified 132 potential India who were undergoing treatment that included investigators distributed throughout urban India, who twice daily gliclazide 80mg, and which could be were invited to participate in the study. Of these, 101 substituted with once daily gliclazide MR 60mg, with physicians accepted the study protocol for no other change in the antidiabetic treatment regimen. implementation. Each investigator identified At baseline (Table 1), patients were of either sex, and consecutive type 2 diabetic outpatients of any age most were middle aged, hypertensive, not obese, and and either sex, who were receiving twice a day under treatment for type 2 diabetes for about 7 years. gliclazide 80mg as monotherapy or in combination More than 70% were receiving antidiabetic treatment with other antidiabetic drugs. Of these, patients with with twice daily gliclazide 80mg as monotherapy or a fasting plasma glucose (FPG) of more than 150mg/ in combination with metformin, 11.1% complained of dL (6), in whom the twice daily gliclazide could be hypoglycemic symptoms, and compliance with the replaced with the equivalent once daily gliclazide MR twice daily gliclazide medication was 89.3%. During 60mg, without changing other antidiabetic drugs or the 14 weeks of study, 12(7.4%) were lost follow up. their dose in the treatment regimen for the next 14 No patients withdrew because of side effects. weeks, were selected for the study. Table 1: Baseline Characteristics of Uncontrolled* After giving their written informed consent, patients Type 2 Diabetic Patients Receiving Treatment that were assessed at baseline for demographic, clinical, included Twice Daily Gliclazide 80mg. treatment and biochemical characteristics shown in Table 1. They were then instructed to discontinue twice Patient Characteristics N=162 daily gliclazide 80mg, and prescribed gliclazide MR 60mg to be taken once a day after breakfast with no Age (years) 52.7 ± 10.9 other change in their treatment regimen. Treatment Males 83(51.2) of associated disease was allowed at the discretion Females 79(48.8) of the physician. All medications were purchased by Duration of diabetes (years) 7.0 ± 4.5 patients from the market. Patients were followed up Treatment and reassessed after 2, 6, 10, and 14 weeks of 56(34.6) treatment. At each follow-up visit, FPG, weight and Gliclazide monotherapy 62(38.3) blood pressure were measured, and patients were Gliclazide + metformin 4(2.5) asked about the frequency of hypoglycemic episodes Gliclazide + glitazones 4(2.5) and side effects since the previous visit. Compliance Gliclazide + acarbose 2(1.2) with gliclazide MR 60mg was assessed by tablet Gliclazide + insulin 34(21.0) count (proportion of tablets ingested out of those Gliclazide + more than one agent prescribed). Biochemical tests done at baseline were Side effects 18(11.1) repeated at the end of the study at 14 weeks. Hypoglycemia 1(0.6) Weight gain 89.3 ± 8.3 Statistical Analysis: The primary outcomes were the Compliance with treatment number of patients achieving glycemic control (FPG Associated disease 108(66.7) < 130mg/dL) on an intention to treat basis, and mean Hypertension 3(1.8) change in FPG from baseline after substituting twice Dyslipidemia 26.9 ± 4.4 daily gliclazide 80mg with once daily gliclazide MR Body mass index (kg/m²) 150.7 ± 82.8 60mg for 14 weeks. Other outcomes were the mean Systolic blood pressure (mmHg) 89.5 ± 11.5 change in weight, plasma lipids, frequency of Diastolic blood pressure (mmHg) 201.9 ± 52.5 hypoglycemic episodes, and compliance with Fasting plasma glucose (mg/dL) gliclazide MR 60mg medication. Changes in Plasma lipids (mg/dL) 219.1 ± 33.6 continuous variables were tested for significance by Total cholesterol 179.9 ± 57.6 the standard error of difference in means. Categorical Total triglycerides 129.8 ± 26.3 data were expressed as percentages with their 95% Low density lipoprotein 48.3 ± 42.2 confidence intervals (CI). Significance was defined as High density lipoprotein 1.0 ± 0.7 a P value of less than 0.05. Serum creatinine (mg/dL) *FPG >150mg/dL. Plus minus values are means ± standard deviation, all other values are numbers of patients followed in parentheses by percentages of the group. 51 INT. J. DIAB. DEV. COUNTRIES (2005), VOL. 25

The number (%, 95% confidence interval(CI)) of Figure 2: Change in Mean Fasting Plasma patients achieving a FPG of less than 130mg/dL after Glucose after Substitution of Twice Daily substitution of twice daily gliclazide 80mg with once Gliclazide 80mg with Once Daily Gliclazide MR daily gliclazide MR 60mg for 14 weeks was, in all 60 in Type 2 Diabetic Patients. patients, 105 (64.8, 57.4 to 72.2); in the subgroups receiving gliclazide monotherapy, 41 (73.2, 61.6 to 84.8); receiving gliclazide plus metformin 40 (65.5, 53.7 to 77.3); and receiving gliclazide plus one or more of glitazones, acarbose, and insulin, 24(54.6, 25.8 to 83.4) (Fig. 1). Mean (95% CI) FPG decreased among all patients by 78.3 (69.5 to 87.1, P<0.01) mg/dL; in the subgroups receiving gliclazide monotherapy by 80.6 (66.0 to 95.2, P<0.01) mg/dL; receiving gliclazide plus metformin by 74.9 (61.6 to 88.2, P<0.01) mg/ dL; and receiving gliclazide plus one or more of glitazones, acarbose and insulin by 80.1 (60.9 to 87.1, P<0.01) mg/dL (Fig. 2). Figure 1: Patients Achieving Glycemic Control* DISCUSSION after Substitution of Twice Daily gliclazide 80mg with Once Daily Gliclazide Modified Release In the setting of primary care, the replacement of 60mg. twice daily gliclazide 80mg with once daily gliclazide MR 60mg in uncontrolled type 2 diabetic patients, without any other change in the treatment regimen for 14 weeks, resulted in substantial benefits. About 70% of patients were able to achieve glycemic control in monotherapy and 60% in combination with other antidiabetic agents, average FPG decreased significantly, and the frequency of patients complaining of hypoglycemia decreased by more than half. The number (%) of patients complaining of In a previous prospective observational study on hypoglycemic episodes decreased from 18(11.1) at 151 uncontrolled type 2 patients under treatment with baseline to 11(6.8) among all patients and to 3(1.9) diet and gliclazide 80mg, switching to the equivalent in those achieving glycemic control (FPG<130mg/dL) gliclazide MR 30mg/day significantly reduced HbA1c after substitution of twice daily gliclazide 80mg with by nearly 10% after 27 weeks (7). However, the effect once daily gliclazide MR 60mg. Other adverse effects of such action on FPG, the proportion of patients reported by patients with twice daily gliclazide at achieving glycemic control, and the benefits of baseline, (nausea in 3, giddiness in 2 and vertigo in switching to the more usual dose of twice a day 1) did not occur with once daily GMR 60mg. Mean gliclazide 80mg with once a day gliclazide MR 60mg (95% CI) total cholesterol decreased by 20.9(13.4 to has not been reported. Although a 4 month double 27.0, P<0.01) mg/dL; low density lipoprotein blind randomised study comparing the two cholesterol by 13.2(7.8 to 18.6, P<0.01) mg/dL; and formulations reported equivalent efficacy (5), the likely total triglycerides by 21.5(10.7 to 32.3, P<0.01) mg/ influence of differences in patient compliance under dL. The increase of 2.0mg/dL in high density conditions of day to day primary care practice on efficacy lipoprotein was not significant. Body weight, blood is not known. The low frequency of hypoglycemic pressure, and serum creatinine showed no significant episodes with once daily gliclazide MR observed in this change. Mean compliance with the once daily study is consistent with earlier reports (5). medication of gliclazide MR 60mg was 96.9%. The once daily gliclazide MR formulation is based on a specially developed hydrophilic polymer matrix tablet that has gastric dissolution characteristics, INT. J. DIAB. DEV. COUNTRIES (2005), VOL. 25 52

which enable controlled release of the embedded consultant epidemiologist; Dr Preeti Modi and Dr Aparna Kalsekar gliclazide in relation to meal timings over 24 hours. for assistance in organising the study, the following doctors When administered at breakfast, plasma who participated in the trial: Dr A Kulshrestha (Agra); Dr D concentration increases and plateaus from the 3rd to Dantara (Ahmedabad); Dr V Agrawal, Dr A Mathur (Allahabad); the 12th hour, which prevents post prandial Dr V Jain (Ambala); Dr V Apte, Dr R K Shah (Aurangabad); Dr hyperglycemia due to meals, and its gradual decrease L Krishnamurthy, Dr H N Seshadri, Dr S Subramanyam thereafter minimizes risk of hypoglycemia during the (Bangalore); Dr R S Meena, Dr A Shukla (Bhopal); Dr V K remainder of the day (7). In a study on type 2 diabetic Chhabra, Dr A Pahwa (Chandigarh); Dr V T Bhaskaran, Dr M patients, plasma glucose was measured at 2 hourly Chandrasekar, Dr S Chandrasekar, Dr M V Mohan, Dr S intervals for 24 hours before and after 10 weeks Nallaperumal, Dr V Parthasarathy, Dr D S Victor (Chennai); Dr treatment with gliclazide MR. After treatment, the N Senthil Vel (Coimbatore); Dr J K Panda (Cuttack); Dr P N mean decrease in plasma glucose from baseline was Daiv (Dahanu); Dr R Bansal, Dr A Bhatia, Dr D S Chadha, Dr A uniform throughout the 24 hours of assessment (8). R Choudhary, Dr M K Daga, Dr M L Goglani, Dr S K Gupta, Dr U Gliclazide MR is therefore suitable for once daily Kansra, Dr A K Manchanda, Dr R Manocha, Dr V K Rastogi, Dr administration. It has a high bioavailability, which B K Tripathi (Delhi); Dr H Mehta (Ghaziabad); Dr M Abubaker, allows an effective dose that is half that of the previous Dr M Idrees, Dr P Raghuramulu, Dr J Ramesh, Dr V Rao, Dr L formulation. These features may translate into better Rodrigues, Dr B Rojanandam, Dr M Siraj (Hyderabad); Dr N patient compliance because of once a day Batra, Dr G Devpura, Dr D K Jain, Dr P Saxena (Jaipur); Dr C P administration, and less hypoglycemia due to a lower Mathur (Jodhpur); Dr V Kalyanarayanswamy (Karaikudi); Dr dose, and serve to explain the useful results of this S Kalra (Karnal); Dr D P Banerjee, Dr G Banerjee, Dr P K Das, study in the primary care setting. Dr S K Das, Dr N Mallik, Dr D Saha, Dr K N Sen, Dr U K Sengupta (Kolkata); Dr V Balachandran (Kollam); Dr A Agarwal, Dr A The study has limitations. The effect of substituting Sharma (Lucknow); Dr P Khanna (Ludhiana); Dr B D Rai, Dr A twice daily gliclazide 80mg with once daily gliclazide P Rao (Mangalore); Dr E D’Mello (Margao); Dr A Gautam, Dr N MR 60mg was not compared with other once daily K Sharma (Meerut); Dr V I Agera, Dr P Bhatia, Dr A Doshi, Dr S sulphonylurea formulations using a randomised J Doshi, Dr A Ghongane, Dr A C Hattangadi, Dr H K Kundalia, Dr protocol. The results are over the short term, and the V Parvatkar, Dr D Patil, Dr S Pawar, Dr S Sahasrabudhe, Dr R S possible benefit of improved compliance due to the Tungare (Mumbai); Dr N Furtado (Panaji); Dr N Parameswaran substitution on glycemic control over a longer period (Perambur); Dr L Gunalan (Pondicherry); Dr V N Tiwari was not assessed. The majority of patients were on (Ranchi); Dr M G Uvaraj (Salem); Dr J J Rao (Secunderabad); gliclazide monotherapy or in combination with Dr J Antao (Taleigao); Dr T Palanichamy (Trichy); Dr R Nair metformin, and the effect of the substitution in patients (Trivandrum); Dr D P Singh (Udaipur); Dr D T Gaikwad on other anti diabetic drug combinations with (Ulhasnagar); Dr W A Ansari, Dr M K Jaiswal (Varanasi); Dr V gliclazide is less clear. However, the patients studied Phadke (Vasai); Dr D Prabhu (Vasco da Gama); Dr K Annamalai were recruited by randomly selected physicians (Vellore); Dr M Kumar, Dr Y Sivakumar (Vijayawada); Dr N distributed throughout urban India, representing type Sivaprakash, Dr K A V Subramanyam (Vizag); and Miss Kinnari 2 diabetic patients seen in primary care, and the Gandhi for secretarial assistance. treatments were administered under conditions of actual clinical practice. REFERENCES The results of this study suggest that in 1. Ramachandran A, Snehlata C, Kapur A et al. High comparison to twice daily gliclazide 80mg, once daily prevalence of diabetes and impaired glucose tolerance gliclazide MR 60mg is more effective in achieving short in India. National Urban Diabetes Survey. Diabetologia term glycemic control with less hypoglycemic 2001; 44: 1094-101. symptoms, both in monotherapy and in combination with other agents. Gliclazide MR is a useful once 2. King H, Rewers M. WHO ad hoc diabetes reporting group, daily sulphonylurea formulation for the management global estimates for prevalence of diabetes and IGT in of type 2 diabetes which will help in reducing the high adults. Diabetes Care 1993; 16: 157-77. frequency of uncontrolled patients in the Indian primary care setting. 3. Lantion-Ang. Epidemiology of diabetes mellitus in Western Pacific region: focus on Philippines. Diab Res ACKNOWLEDGEMENTS: I am indebted to Dr David Park, Clin Pract 2000; 50(Suppl 2): S29-S34. 4. Cramer JA. 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5. Drouin P, Diamicron MR Study Group. J. Diabetes and its 8. Franacillard M, Frey N, Paraire M, Laveille C, Jochemsen complications 2000; 14: 185-91. R. Pharmacokinetics of Diamicron modified release in 1007 type 2 diabetic patients. J Nutr Health Aging 2001; 6. American Diabetes Association. Standards of Medical 5(special issue): 31. Abstract F14. Care for patients with Diabetes Mellitus. Diabetes Care 2002; 25 (Suppl 1): S33-S49. 9. Guillausseau PJ, Greb W. 24 hour glycemic profile in type 2 diabetic patients treated with gliclazide modified 7. Jacek S, Teresa KC, Wladystaw G, Zespot B. release once daily. Diabetes and Metabolism (Paris) Application of gliclazide MR in uncontrolled diabetes 2001; 27: 133-7. type 2 – the treatment phase results of DINAMIC 2 study(V). Diabetologia Praktyczna 2003; 2: 133-6. INT. J. DIAB. DEV. COUNTRIES (2005), VOL. 25 54

ORIGINAL ARTICLE ISSN 2450–7458 e-ISSN 2450–8187 Sanjay Kalra1, Aravinda Jagadeesha2, Deepak Khandelwal3, Kirti Samudra4, Sharvil Gadve5, Supratik Bhattacharyya6 1Bharti Hospital, Karnal, Haryana, India 2Dr. Aravinda’s Diabetes Centre Bengaluru, Karnataka, India 3Consultant Diabetologist and Endocrinologist Clinic, Delhi, India 4Diabetes Care Clinic, New Panvel, Maharashtra, India 5EXCEL Endocrine Centre, Diabetes Corner, Kolhapur, Maharashtra, India 6Apollo Clinic, Kolkata, India Real-world experience of treatment individualization based on a fixed-dose combination of gliclazide extended release+ metformin extended-release in type 2 diabetes mellitus Abstract history of diabetes and 161 patients had hyperten- Background. To evaluate the efficacy of gliclazide sion. Target FPG was achieved with 1 tablet each of extended-release (XR) 60 mg + metformin XR 500 gliclazide XR 60 mg + metformin XR 500 mg FDC and mg fixed-dose combination (FDC) with metformin as metformin by 73.09%, 74.26%, and 60.66% patients an add-on (as needed) in real-world clinical practice. in groups M, GM, and U, respectively. Only 29.23% of Methods. This prospective observational study was patients required up-titration to 1 tablet of FDC + 2 performed in patients with type 2 diabetes mellitus tablets each of metformin and FDC at days 60 and 90. uncontrolled on metformin (group M) or on con- Mean FPG, PPG and HbA1c significantly reduced at ventional gliclazide XR 60 mg + metformin XR 500 day-90 (P < 0.001). mg (group GM), and newly diagnosed or untreated Conclusions. It can be concluded from this real-world patients with HbA1c >9% (group U) at 6 out-patient primary-care practice study that the use of gliclazide diabetes care units. Patients received gliclazide XR XR 60 mg + metformin XR 500 mg FDC and metformin 60 mg + metformin XR 500 mg FDC and metformin (as needed) was effective and well-tolerated, and >3 (as needed) at baseline for 30 days. Up-titration with out of 5 patients achieved target glycaemic control gliclazide capped at 120 mg and metformin every 30 within 30 days in all groups. (Clin Diabetol 2021; 10; days till day-90. The proportion of patients achieving 4: 337–341) target FPG was the primary endpoint. Results. Of 455 patients (mean age: 51.9 ± 11.3 years; Key words: gliclazide, diabetes mellitus, metformin, mean BMI 26.7 ± 6.2 kg/m2), 261 patients had a family glycaemic control, fixed-dose combination Address for correspondence: Introduction Diabetes has become a major healthcare issue Sanjay Kalra imposing a huge economic burden, with about 77 Bharti Hospital, Karnal, Haryana, India million cases reported in India [1]. Evidence shows that most patients receive oral hypoglycaemic agents, e-mail: [email protected], [email protected] but their poor adherence poses a major challenge in achieving glycaemic control. In Indian primary care Clinical Diabetology 2021, 10; 2: 337–341 DOI: 10.5603/DK.a2021.0042 Received: 30.09.2020 Accepted: 28.12.2020 337

Clinical Diabetology 2021, Vol. 10, No 4 settings, most patients are diagnosed and treated by Table 1. Demographic characteristics general physicians and increasing the effectiveness of diabetes treatment at these centres has remained a Demographic characteristics of patients, n = 455 priority. Most diabetes management guidelines rec- ommend metformin-based dual drug combination Age, years 51.9 (11.3) to achieve target glycaemic control [2, 3]. Despite Male 244 (53.6) the availability of newer classes of antihyperglycemic BMI, kg/m2 26.7 (6.2) agents, sulfonylureas (particularly gliclazide) have been Systolic Blood Pressure, mm Hg 132.5 (15.7) commonly used in combination with metformin ow- Diastolic Blood Pressure, mm Hg 81.3 (8.1) ing to its proven safety, efficacy, familiarity, guideline Risk factors recommendations, cost and coverage [4]. A fixed-dose 47 (10.3) combination (FDC) of gliclazide extended-release (XR) Smoking 137 (30.1) 60 mg plus (+) metformin XR 500 mg is available in Obesity India as a scored and breakable tablet making its up- Clinical history 20 (4.4) titration easier for better glycaemic control. 1 (0.2) Previous myocardial infarction 4 (0.9) The present study aimed to assess glycaemic con- Previous congestive heart failure 261 (57.4) trol in patients with type-2 diabetes mellitus (T2DM) Previous stroke 45 (9.9) receiving gliclazide XR 60 mg + metformin XR 500 Family history of diabetes 161 (35.4) mg FDC and metformin separately in addition, when History of other CVD 103 (22.6) required, in daily clinical practice. Hypertension Dyslipidaemia Material and methods This was a multi-centre, prospective observational Data are shown as mean (SD) or n (%); BMI: Body mass index; CVD: cardiovascular disease study conducted between November 2017 and March 2018. The study was approved by a central ethics baseline demographic and clinical characteristics. FPG committee and all patients provided written informed and postprandial plasma glucose (PPG) levels were consent. Patients with T2DM who received treatment taken at baseline and days 30, 60 and 90, and HbA1c per the clinical discretion of investigators as a part at baseline and at the end of study (day-90).  of routine clinical care with gliclazide XR 60 mg + metformin XR 500 mg FDC and add-on metformin XR Statistical analyses 500 mg (as per patient profile) were selected. These The primary endpoint was the number of patients patients were categorized into three groups: newly diagnosed or untreated patients with HbA1c > 9% achieving glycaemic control (FPG 90-130 mg/dL) on (Group U), those uncontrolled on metformin 500 mg an intention to treat basis at follow-up visits in each (Group M) and patients uncontrolled on conventional group. Other endpoints were changes in FPG, PPG gliclazide XR 60 mg + metformin XR 500 mg (Group and HbA1c from baseline at day 90. Categorical data GM). Individuals who were pregnant or breastfeeding were presented as percentages with their 95% CI, and exhibited hypersensitive reaction to sulfonylureas, changes in FPG along with their 95% CI. Statistical displayed severe hepatic or renal failure (creatinine analyses were conducted using SAS version 9.1. clearance < 30 mL/min), demonstrated contraindication to gliclazide, presented with uncontrolled and clinically Results significant disease(s) or known malignancy or had a This study enrolled a total of 455 patients (group high probability of lost-to-follow-up, were excluded. M: 197, group GM: 136 and group U: 122) at 6 centres All patients were prescribed 1 tablet containing across India. Patients had a mean age of 51.9 ± 11.3 gliclazide XR 60 mg + metformin XR 500 mg FDC years and a mean BMI of 26.7 ± 6.2 kg/m2 (Table 1). plus metformin 500 mg (as per need) for 30 days at More than half (n = 261) the patient population had baseline. Treatments were up-titrated at the discretion a family history of diabetes,35.4% (n = 161) patients of the investigators, based on fasting plasma glucose had hypertension, 30.1% (n = 137) had obesity, 22.6% (FPG) levels measured at days 30, 60 and 90. Dosing (n = 103) had dyslipidaemia and 9.9% (n = 45) had was capped at 120 mg for gliclazide and 1500 mg for history of cardiovascular diseases. metformin daily. Of 197 patients in group M, target FPG was Data were collected from the patient’s medical achieved by 73.09% (n = 144) with 1 tablet of gliclazide records maintained by the investigators. This included XR 60 mg + metformin XR 500 mg FDC plus 1 tablet 338

Sanjay Kalra et al., A real-world study of gliclazide and metformin combination of metformin at day-30 (Fig. 1A). About 15.29% and A 100 5.90 N = 197 15.38% of patients received up-titration to 1 tablet 80 15.29 6.41 of gliclazide XR 60 mg + metformin XR 500 mg FDC plus 2 tablets of metformin to achieve glycaemic con- 15.38 trol at day-60 and day-90, respectively. Only 5.90% and 6.41% of patients required 2 tablets of gliclazide Patients [%] 60 100.00 78.82 78.20 XR 60 mg + metformin XR 500 mg FDC to achieve glycaemic control at day-60 and day-90, respectively 40 (Figure 1A). Approximately 74.26% (n = 101) patients in group GM achieved glycaemic control with gliclazide 20 N = 144 N = 170 N = 156 XR 60 mg + metformin XR 500 mg FDC plus 1 tablet Day-30 of metformin at day-30; and approximately 12–15% 0 Day-60 Day-90 required up-titration to 1 tablet of gliclazide XR 60 Patient ow (n) 170 156 mg + metformin XR 500 mg FDC plus 2 tablets of 2 1 metformin at third and fourth follow-up visits. Only Controlled 144 25 40 0.87% patients required 2 tablets of gliclazide XR 60 mg + metformin XR 500 mg FDC at day-60. None of Uncontrolled 53 the patients required 2 tablets of gliclazide XR 60 mg + metformin XR 500 mg FDC at day-90 (Fig. 1B). The Lost to follow-up – proportion of patients who were newly diagnosed or untreated with HbA1c > 9% (group U) and achieved FDC of gliclazide + metformin (1 tab) + metformin (1 tab) target FPG with 1 tablet of gliclazide XR 60 mg + FDC of gliclazide + metformin (1 tab) + metformin (2 tabs) metformin XR 500 mg FDC plus 1 tablet of metformin FDC of gliclazide + metformin (2 tabs) at day-30 was 60.66% (n = 74). Around 12–14% of patients received up-titration to 1 tablet of gliclazide B 100 0.87 N = 136 XR 60 mg + metformin XR 500 mg FDC plus 2 tablets 80 12.17 14.78 of metformin at day-60 and day-90. About 12-19% of patients required 2 tablets of gliclazide XR 60 mg + Patients [%] 60 100.00 78.82 85.22 metformin XR 500 mg FDC to achieve glycaemic control at days 60 and 90 (Fig. 1C). Collectively, the majority of 40 patients achieved target FPG with 1 tablet of gliclazide XR 60 mg + metformin XR 500 mg FDC with 1 tablet 20 N = 101 N = 115 N = 115 of metformin at day-30 and only 29.23% (133/455) Day-30 required the up-titration of treatment. Moreover, only 0 Day-60 Day-90 a few patients remained uncontrolled at the end of the Patient ow (n) 115 115 study across three groups (Fig. 1). 7 1 Controlled 101 14 20 In patients uncontrolled on conventional gliclazide XR 60 mg + metformin XR 500 mg (group GM), mean Uncontrolled 35 FPG reduced from 159.85 ± 39.12 mg/dL at baseline to 105.38 ± 20.24 mg/dL at day-90 (P < 0.001; Figure 2A). Lost to follow-up – Similarly, PPG decreased from 231.43 ± 52.35 mg/dL to 162.19 ± 26.4 mg/dL (P < 0.001; Fig. 2B), and HbA1c FDC of gliclazide + metformin (1 tab) + metformin (1 tab) from 8.01 ± 0.69 % to 7.21 ± 0.57 % (P < 0.001; Fig. FDC of gliclazide + metformin (1 tab) + metformin (2 tabs) 2C). In patients uncontrolled on metformin (group M), FDC of gliclazide + metformin (2 tabs) mean FPG was reduced from 168.12 ± 37.21 mg/dL at baseline to 107.69 ± 21.22 mg/dL at day-90 (P < Patients [%]C 100 100.00 11.63 N = 122 0.001; Figure 2A). Similarly, PPG decreased from 246.52 80 13.95 19.48 ± 63.27 mg/dL to 155.53 ± 28.7 mg/dL (P < 0.001; 60 11.69 Figure 2B), and HbA1c from 8.29 ± 1.01% to 7.21 ± 40 74.42 0.61 mg/dL (P < 0.001; Figure 2C). In the last group 68.83 of patients who are newly diagnosed or untreated with HbA1c >9% (group U), mean FPG was reduced 20 N = 74 N = 86 N = 77 from 182.35 ± 48.32 mg/dL at baseline to 109.45 ± Day-30 0 Day-60 Day-90 Patient ow (n) 86 77 3 1 Controlled 74 33 43 Uncontrolled 48 Lost to follow-up – FDC of gliclazide + metformin (1 tab) + metformin (1 tab) FDC of gliclazide + metformin (1 tab) + metformin (2 tabs) FDC of gliclazide + metformin (2 tabs) Figure 1. Glycaemic control rate and pattern of FDC use. The bar graph shows the pattern of FDC use in patients who achieved glycaemic control and the table represents the overall glycaemic control rate; A. Group M, patients uncontrolled on metformin 500 mg (n = 197); B. Group GM, patients uncon- trolled on conventional gliclazide + metformin (n = 136); C. Group U, newly diagnosed or untreated patients with HbA1c > 9% (n = 122) 18.79 mg/dL at day-90 (P < 0.001; Fig. 2A). Similarly, PPG decreased from 267.2 ± 67.32 mg/dL to 169.14 ± 25.62 mg/dL (P < 0.001; Fig. 2B), and HbA1c from 89.53 ± 1.87 % to 7.44 ± 0.87 % (P < 0.001; Fig. 2C). 339

Clinical Diabetology 2021, Vol. 10, No 4 A 200 Baseline N = 455 groups. For patients who were uncontrolled on met- 160 Day-60 formin alone or with conventional gliclazide XR 60 mg 120 Day-90 + metformin XR 500 mg, approximately more than 80 FPG [mg/dL] 50% of patients achieved target FPG within 30 days 40 159.85 at the first visit. Moreover, about 37% of patients who 0 108.33 were newly diagnosed or untreated, with HbA1c > 9%, 105.38 achieved target FPG by 30 days. B 300 168.12 250 109.62 A line of evidence indicates that gliclazide reduces 200 107.69 HbA1c better than other insulinotropic agents [5]. Gli- 150 182.35 clazide is also cardio safe and has lower hypoglycaemia 100 121.13 risk [5, 6]. In the GUIDE (GlUcose control in type 2 50 109.45 diabetes: Diamicron MR vs glimEpiride) randomized, 0 head-to-head trial, its hypoglycaemic risk was found Patients Patients Newly to be lower compared to that of glimepiride [7]. A C 10 uncontrolled uncontrolled on diagnosed/ systematic review and meta-analysis of 18 studies 8 on metformin untreated including 1,67,327 patients with diabetes reported 6 conventional patients with superior cardiovascular (CV) safety of gliclazide [6]. 4 gliclazide + HbA1c > 9% Danish registry of 1,07,806 patients with diabetes with 2 metformin or without myocardial infarction who initiated single- 0 agent treatment with insulin secretagogues or met- Baseline N = 455 formin, also showed lower CV and all-cause mortality Day-60 risk with gliclazide at 9-year follow-up [8]. Similarly, in Day-90 the Steno-2 randomized trial conducted in 160 patients PPG [mg/dL] with diabetes, microalbuminuria, an intensive gliclazide 231.43 therapy showed a median 7.9 years of life gain with + 168.25 8.1 years free from-CV-events at 21.2 years of median 162.19 follow-up [9]. Unlike other SUs, greater selectivity of 246.52 gliclazide for pancreas rather than myocardial sulfony- 161.6 lureas receptors, along with its fibrinolytic properties 155.53 (which are independent of its glucose-lowering action) 267.2 could be attributed to better CV safety [10]. 183.13 169.14 Reductions in glycaemic parameters were in line with previously reported studies. Moreover, the results Patients Patients Newly showing the feasibility and effectiveness of gliclazide uncontrolled uncontrolled on diagnosed/ XR 60 mg + metformin XR 500 mg FDC are in line with on metformin untreated other studies conducted in India [11, 12]. conventional patients with gliclazide + HbA1c > 9% Clinical practice guidelines including the latest metformin WHO guidelines for diabetes management prefers gli- N = 455 clazide among other SUs, to be used with metformin Baseline as a combination therapy [2, 3]. However, compliance Day-90 to therapy remains a challenge. Treatment with FDC improves compliance and increases the probability of HbA1c [%] achieving target glycaemic control [13]. In this study, 8.01 > 70% of patients achieved target FPG in a short dura- 7.21 tion and could explain the ease of up-titration using 8.29 gliclazide XR 60 mg + metformin XR 500 mg FDC with 7.21 metformin (when required). This could help all patient 9.53 groups to achieve glycaemic control, faster. 7.44 A major limitation of this study is that patients Patients Patients Newly did not receive randomized treatment. The medication uncontrolled uncontrolled on diagnosed/ regimen was at the discretion of prescribing physicians. on metformin untreated However, these results represented the real-world conventional patients with primary-care practice data for efficient up-titration of gliclazide + HbA1c > 9% metformin Figure 2. Glycaemic control in patients receiving the gliclazide XR 60 mg + metformin XR 500 mg and metformin XR 500 mg based up-titration; A: Mean FPG at baseline and follow-up visits; B: Mean PPG at baseline and follow-up visits; C: Mean HbA1c at baseline and follow-up visits. FPG, PPG, and HbA1c were significantly reduced (P < 0.001) at Day-60 and Day-90 compared to respective baseline values; FPG: fasting plasma glucose; PPG: postprandial glucose Overall, as expected, the decrease in glycaemic param- eters were greater in Group U compared to Group M and Group GM. Altogether, the gliclazide XR 60 mg and metformin XR 500 mg-based combination treatment, up-titrated at the discretion of physician for 3 months, significantly reduced FPG, PPG and HbA1c from baseline in all 3 patient categories. Discussion In this study, treatment of type 2 diabetes with gliclazide XR 60 mg + metformin XR 500 mg FDC and metformin-improved glycaemic control in all three 340

Sanjay Kalra et al., A real-world study of gliclazide and metformin combination the therapy using gliclazide XR 60 mg + metformin XR 3. Garber AJ, Abrahamson MJ, Barzilay JI, et al. Consensus state- 500 mg FDC with metformin (as per patient profile). ment by the American Association of Clinical Endocrinologists and American College of Endocrinology on the comprehensive Above all, the presented findings suggest that type 2 diabetes management algorithm–2018 executive summary. a gliclazide-metformin-based combination treatment, Endocr Pract. 2018; 24(1): 91–120, doi: 10.4158/CS-2017-0153, up-titrated at the discretion of physician for 3 months, indexed in Pubmed: 29368965. significantly reduced FPG, PPG and HbA1c levels from baseline in patients either uncontrolled on metformin 4. Kalra S, Aamir AH, Raza A, et al. Place of sulfonylureas in the man- alone or conventional gliclazide XR 60 mg + met- agement of type 2 diabetes mellitus in South Asia: A consensus formin XR 500 mg, and in newly diagnosed patients statement. Indian J Endocrinol Metab. 2015; 19(5): 577–596, or untreated patients with HbA1c > 9%. Overall, the doi: 10.4103/2230-8210.163171, indexed in Pubmed: 26425465. treatment was well tolerated by the patients. 5. Chan SP, Colagiuri S. Systematic review and meta-analysis of the Conclusion efficacy and hypoglycemic safety of gliclazide versus other insuli- It can be concluded from this real-world primary- notropic agents. Diabetes Res Clin Pract. 2015; 110(1): 75–81, doi: 10.1016/j.diabres.2015.07.002, indexed in Pubmed: 26361859. care practice study that efficient up-titration of therapy using gliclazide XR 60 mg + metformin XR 500 mg FDC 6. Simpson S, Lee J, Choi S, et al. Mortality risk among sulfonylu- plus metformin (as per individual patient need), can be reas: a systematic review and network meta-analysis. The Lancet an effective option to achieve optimal glycaemic control Diabetes & Endocrinology. 2015; 3(1): 43–51, doi: 10.1016/ in daily clinical practice. s2213-8587(14)70213-x. Acknowledgements 7. Schernthaner G, Grimaldi A, Di Mario U, et al. GUIDE study: The authors would like to thank CBCC Global Re- double-blind comparison of once-daily gliclazide MR and glime- piride in type 2 diabetic patients. Eur J Clin Invest. 2004; 34(8): search for providing scientific writing assistance in the 535–542, doi: 10.1111/j.1365-2362.2004.01381.x, indexed in development of this manuscript. Pubmed: 15305887. Funding 8. Schramm TK, Gislason GH, Vaag A, et al. Mortality and car- Serdia Pharmaceuticals (India) Pvt. Ltd. supported diovascular risk associated with different insulin secretagogues compared with metformin in type 2 diabetes, with or without a the conceptualization of the study and funded the previous myocardial infarction: a nationwide study. Eur Heart J. scientific writing assistance for the development of 2011; 32(15): 1900–1908, doi: 10.1093/eurheartj/ehr077, indexed this manuscript. in Pubmed: 21471135. Conflict of interest 9. Gæde P, Oellgaard J, Carstensen B, et al. Years of life gained by The authors declare no conflict of interest. multifactorial intervention in patients with type 2 diabetes mel- litus and microalbuminuria: 21 years follow-up on the Steno-2 REFERENCES randomised trial. Diabetologia. 2016; 59(11): 2298–2307, doi: 1. International Diabetes Federation. IDF Diabetes Atlas 9th Edition. 10.1007/s00125-016-4065-6, indexed in Pubmed: 27531506. Brussels, Belgium: International Diabetes Federation 2019. http:// www.diabetesatlas.org. 10. De Fa. Evidence-based benefits of a selective secretagogue: Di- 2. International Diabetes Federation. Recommendations For amicron MR 60 mg. Medicographia. 2016; 38: 77–87. Managing Type 2 Diabetes In Primary Care, 2017. www.idf.org/ managing-type2-diabetes. 11. Kalra S, Das AK. Epidemiologic Surveillance of Glycemic Response to a Scored, Breakable, Extended Release, Fixed Dose Combination of Gliclazide and Metformin in Persons with Type 2 Diabetes. J Assoc Physicians India. 2017; 65(6): 38–41, indexed in Pubmed: 28782312. 12. Mohan V, Chopra V, Sanyal D, et al. Treatment of Type 2 Diabetes with a Breakable Extended Release Gliclazide Formulation in Primary Care: The Xrise Study. J Assoc Physicians India. 2015; 63(12): 26–29, indexed in Pubmed: 27666900. 13. Lavernia F, Adkins SE, Shubrook JH. Use of oral combination therapy for type 2 diabetes in primary care: Meeting indi- vidualized patient goals. Postgrad Med. 2015; 127(8): 808–817, doi: 10.1080/00325481.2015.1085293, indexed in Pubmed: 26439384. 341

European Heart Journal (2011) 32, 1900–1908 CLINICAL RESEARCH doi:10.1093/eurheartj/ehr077 Prevention Mortality and cardiovascular risk associated Downloaded from https://academic.oup.com/eurheartj/article/32/15/1900/565965 by guest on 08 January 2022 with different insulin secretagogues compared with metformin in type 2 diabetes, with or without a previous myocardial infarction: a nationwide study Tina Ken Schramm 1*, Gunnar Hilmar Gislason 2, Allan Vaag 3, Jeppe Nørgaard Rasmussen 4, Fredrik Folke5, Morten Lock Hansen 2, Emil Loldrup Fosbøl 2, Lars Køber 1, Mette Lykke Norgaard 2, Mette Madsen 6, Peter Riis Hansen 2, and Christian Torp-Pedersen 2 1Department of Cardiology B, section 2141, Rigshospitalet, The Heart Center, Copenhagen University Hospital, Blegdamsvej 9, 2100 Copenhagen, Denmark; 2Department of Cardiology, Gentofte University Hospital, Hellerup, Denmark; 3Department of Endocrinology, Rigshospitalet, Copenhagen, Denmark; 4Statens Serum Institute, Copenhagen, Denmark; 5Department of Cardiology, Herlev University Hospital, Herlev, Denmark; and 6Institute of Public Health, University of Copenhagen, Copenhagen, Denmark Received 17 July 2010; revised 23 January 2011; accepted 25 February 2011; online publish-ahead-of-print 6 April 2011 See page 1832 for the editorial comment on this article (doi:10.1093/eurheartj/ehr019) Aims The impact of insulin secretagogues (ISs) on long-term major clinical outcomes in type 2 diabetes remains unclear. We examined mortality and cardiovascular risk associated with all available ISs compared with metformin in a nation- wide study. ..................................................................................................................................................................................... Methods All Danish residents .20 years, initiating single-agent ISs or metformin between 1997 and 2006 were followed for up and results to 9 years (median 3.3 years) by individual-level linkage of nationwide registers. All-cause mortality, cardiovascular mortality, and the composite of myocardial infarction (MI), stroke, and cardiovascular mortality associated with indi- vidual ISs were investigated in patients with or without previous MI by multivariable Cox proportional-hazard ana- lyses including propensity analyses. A total of 107 806 subjects were included, of whom 9607 had previous MI. Compared with metformin, glimepiride (hazard ratios and 95% confidence intervals): 1.32 (1.24–1.40), glibenclamide: 1.19 (1.11–1.28), glipizide: 1.27 (1.17–1.38), and tolbutamide: 1.28 (1.17–1.39) were associated with increased all- cause mortality in patients without previous MI. The corresponding results for patients with previous MI were as follows: glimepiride: 1.30 (1.11– 1.44), glibenclamide: 1.47 (1.22–1.76), glipizide: 1.53 (1.23–1.89), and tolbutamide: 1.47 (1.17–1.84). Results for gliclazide [1.05 (0.94– 1.16) and 0.90 (0.68–1.20)] and repaglinide and [0.97 (0.81–1.15) and 1.29 (0.86–1.94)] were not statistically different from metformin in both patients without and with previous MI, respectively. Results were similar for cardiovascular mortality and for the composite endpoint. ..................................................................................................................................................................................... Conclusion Monotherapy with the most used ISs, including glimepiride, glibenclamide, glipizide, and tolbutamide, seems to be associated with increased mortality and cardiovascular risk compared with metformin. Gliclazide and repaglinide appear to be associated with a lower risk than other ISs. ----------------------------------------------------------------------------------------------------------------------------------------------------------- Keywords Diabetes type 2 † Insulin secretagogues † Metformin † Mortality † Cardiovascular disease † Population * Corresponding author. Tel: +45 26 15 54 75, Fax: +45 70 20 12 81, Email: [email protected] Published on behalf of the European Society of Cardiology. All rights reserved. & The Author 2011. For permissions please email: [email protected].

Insulin secretagogues and cardiovascular risk 1901 Introduction diagnoses according to the International Classification of Diseases Downloaded from https://academic.oup.com/eurheartj/article/32/15/1900/565965 by guest on 08 January 2022 (ICD)—the 8th revision (ICD-8) before 1994, and the 10th revision Despite the lack of definitive evidence concerning their long-term (ICD-10) from 1994 onwards. Information about causes of death is cardiovascular safety and efficacy, insulin secretagogues (ISs) are recorded in the National Causes of Death Register. widely used in type 2 diabetes. In addition to lifestyle intervention, monotherapy with oral glucose-lowering agents is generally the Study population initial treatment strategy in type 2 diabetes. In the context of the suggested legacy effect of glucose-lowering agents in the 10-year The study population comprised all individuals aged 20 years and follow-up of the UK Prospective Diabetes Study (UKPDS), the above who initiated single-agent treatment with an IS or metformin impact of the initial treatment in type 2 diabetes may be crucial between 1997 and 2006. in terms of long-term risk.1 Primarily on the basis of the results of the UKPDS metformin substudy, metformin is the primary Glucose-lowering therapy drug of choice in type 2 diabetes.2 Nevertheless, the long-term cardiovascular safety and efficacy of metformin compared with Claimed prescriptions of monotherapy with glimepiride, gliclazide, glib- different ISs remains unclear. Despite the extensive use of ISs, enclamide, glipizide, tolbutamide, repaglinide, or metformin were regis- few randomized studies have assessed long-term mortality tered within consecutive 3-month intervals. If no prescriptions were outcomes related to monotherapy with individual ISs.3,4 In The registered for a particular interval, we estimated the available medi- University Group Diabetes Program (UGDP), tolbutamide was cation from that available in up to three previous 3-month periods associated with increased total and cardiovascular mortality, to take account of potential stockpiling of pills. Patients receiving causing the premature discontinuation of the tolbutamide arm in insulin monotherapy (n ¼ 8783) and combination therapy (n ¼ 3434) the study.4 On the contrary, the initial UKPDS study found no only were excluded. effect of other older sulphonylureas (SUs), i.e. chlorpropamide and glibenclamide on macrovascular disease complications or mor- Prior myocardial infarction tality .3 Nevertheless, the results of the UGDP led to a change of product labelling in the USA, including a warning about the potential Prior MI was identified as a hospitalization with MI as the primary or for increased cardiovascular mortality that persists for all SUs mar- secondary diagnosis (ICD-10 codes I21– I22 and ICD-8 code 410) keted in the USA. Few observational studies focused on long-term up to 19 years before the study inclusion. mortality associated with subsets of individual ISs, of which none included metformin as a comparator.5–7 In particular, glibenclamide Co-morbidity has been reported to increase overall and cardiovascular mortality when compared with other ISs such as gliclazide and glimepiride,5,6 Co-morbidity was assessed by registration of hospital admissions whereas glibenclamide was not associated with an increased mortality 1 year before the inclusion date. Diagnoses listed in Table 1 and the risk in a recent large observational study when compared with glime- Charlson co-morbidity index, based on ICD-10 codes, were used.9 piride.7 Most studies of individual ISs as monotherapy focused on populations with a broad range of cardiovascular risk profiles Concomitant medical treatment only,4–6 or included patients receiving combination therapy.6 (Anatomical Therapeutic Chemical) To date, there are no reports comparing outcomes between all Medical treatment with aspirin (ATC code: MB01AC06), statins available ISs and metformin and with the enormous costs of ade- (C10AA), beta-blockers (C07), angiotensin-converting enzyme inhibi- quately powered large randomized clinical trials, it is unlikely that tors/angiotensin receptor blockers (RASi) (C09), nitrates (C01D), such trials will ever be conducted. We therefore performed a calcium channel blockers (C08), and other antihypertensive drugs nationwide study to compare the mortality and cardiovascular (C02) drugs were registered as prescription claims up to 6 months risk related to monotherapy with available ISs compared with met- before the inclusion date and during follow-up. formin in patients with high and low cardiovascular risk as defined by previous myocardial infarction (MI). Outcome measures Methods Outcome measures were: all-cause mortality, cardiovascular death (I00 –I99), and the composite of MI (I21– I22), stroke (I61– I64), or car- Data sources diovascular death. All residents in Denmark are assigned a unique, permanent civil regis- Statistical analysis tration number enabling individual-level cross-linkage of nationwide administrative registries. The Danish Registry of Medicinal Product Time-dependent, multivariable Cox proportional-hazard regression Statistics (National Prescription Registry) keeps information about all models were constructed for the full population of patients receiving dispensed drug prescriptions from pharmacies since 1995, registered monotherapy with ISs or metformin to estimate differences among according to the international Anatomical Therapeutic Chemical risk groups with patient age as the underlying time variable. All Cox (ATC) system. All hospitalizations since 1978 are registered in the models were censored for deaths from causes unrelated to the end- National Patient Registry8 At discharge, each hospitalization is regis- point of interest. Due to the time-dependent analysis, patients were tered with one primary diagnosis and, if appropriate, secondary not considered at risk in a given treatment group before initiating the treatment and they left the treatment group if the treatment was modified or terminated. With this approach, any patient could belong to any treatment group but only during exposure to treatment. All models were adjusted for age, sex, calendar year of initiation of glucose-lowering pharmacotherapy, gross income, co-morbidity, and time-dependent adjustment for cardiovascular medical treatment during follow-up. In addition, matched samples of the individual ISs and metformin were constructed based on the propensity to receive metformin, quantified by

Table 1 Baseline characteristics Metformin Glimepiride Gliclazide ........................................................................................................................ No previous myocardial infarction (n ¼ 98 199) Frequency (%)a 43 340 (54.3) 36 313 (37.0) 5926 (6.0) 1997 – 99 (n ¼ 30 764)b 4561 (14.8) 8310 (27.0) 1568 (5.1) 2000 – 02 (n ¼ 36 512)b 13 624 (37.3) 13 748 (37.7) 1912 (5.2) 2003 – 05 (n ¼ 46 153)b 25 155 (50.1) 14 255 (30.9) 2446 (5.3) ........................................................................................................................ Age (years)c 52.5 + 14.0 60.9 + 13.3 60.0 + 13.2 Men, frequency (%) 22 067 (50.9) 20 071 (55.3) 3345 (56.5) Person (years) 75 957 75 742 11 730 ........................................................................................................................ Treatment duration (years)c 1.76 + 1.58 2.11 + 1.75 2.10 + 1.75 Co-morbidityd Congestive heart failure 478 (1.1) 894 (2.5) 96 (1.6) Cardiac dysrhythmia 715 (1.6) 1176 (3.2) 125 (2.1) Peripheral vascular disease 128 (0.3) 228 (0.6) 31 (0.5) Cerebrovascular disease 692 (1.6) 1013 (2.8) 81 (1.4) Chronic pulmonary disease 659 (1.5) 959 (2.6) 92 (1.6) Peptic ulcer disease 161 (0.3) 291 (0.8) 31 (0.5) No previous myocardial infarction Liver disease 114 (0.3) 229 (0.6) 27 (0.5) Chronic renal failure 22 (0.1) 80 (0.2) 3 (0.1) Acute renal failure 24 (0.1) 62 (0.2) 8 (0.1) Shock 84 (0.2) 175 (0.5) 14 (0.2) Malignancy 432 (1.0) 907 (2.5) 112 (1.9) Charlson index 0.06 + 0.3 0.14 + 0.5 0.09 + 0.4 Concomitant cardiovascular medication, frequency (%)d Aspirin 12 122 (28.0) 11 321 (31.2) 1770 (29.9) Statins 11 296 (26.1) 8348 (23.0) 1280 (21.6) RASi 21 943 (50.6) 17 346 (47.8) 2754 (46.5) Beta-blockers 12 090 (27.9) 10 692 (29.4) 1713 (28.9) Nitrates 4491 (10.4) 5372 (14.8) 800 (13.5) Calcium blockers 11 849 (27.3) 10 666 (29.4) 1714 (28.9) Other antihypertensives 1699 (3.9) 1460 (4.0) 289 (4.9) ........................................................................................................................

Glibenclamide Glipizide Tolbutamide Repaglinide P-value Downloaded from https://academic.oup.com/eurheartj/article/32/15/1900/565965 by guest on 08 January 2022 ...................................................................................................................... 1902 T.K. Schramm et al. 12 495 (12.7) 6965 (7.1) 5335 (5.4) 2513 (2.6) , 0.001 7796 (25.3) 4128 (13.7) 3257 (10.6) 747 (2.4) , 0.001 3014 (8.2) 1594 (4.3) 1302 (3.6) 1233 (3.4) , 0.001 1685 (3.7) 1243 (2.6) 776 (1.7) 533 (1.2) , 0.001 ...................................................................................................................... 63.2 + 13.7 63.0 + 13.5 64.4 + 13.5 57.9 + 12.6 , 0.001 6798 (54.4) 3771 (54.1) 2872 (53.8) 1407 (56.0) , 0.001 29 038 16 130 12 337 4925 , 0.001 ...................................................................................................................... 2.35 + 2.08 2.35 + 2.08 2.36 + 2.13 1.97 + 1.76 , 0.001 299 (2.4) 168 (2.4) 140 (2.6) 18 (0.7) , 0.001 379 (3.0) 226 (3.2) 152 (2.8) 38 (1.5) , 0.001 14 (0.6) , 0.001 87 (0.7) 63 (0.9) 47 (0.9) 30 (1.2) , 0.001 348 (2.9) 197 (2.8) 177 (3.3) 29 (1.2) , 0.001 304 (2.4) 197 (2.8) 141 (2.6) 14 (0.6) , 0.001 93 (0.7) 81 (1.1) 57 (1.1) 66 (0.5) 45 (0.6) 59 (1.1) 7 (0.3) , 0.001 25 (0.2) 20 (0.3) 13 (0.2) 3 (0.1) , 0.001 15 (0.1) 12 (0.2) 10 (0.2) 2 (0.1) , 0.001 39 (0.3) 25 (0.4) 21 (0.4) 3 (0.1) , 0.001 315 (2.5) 170 (2.4) 136 (2.5) 46 (1.8) , 0.001 0.13 + 0.5 0.14 + 0.5 0.14 + 0.5 0.08 + 0.4 , 0.001 3210 (25.7) 1827 (26.2) 1403 (26.3) 665 (26.5) , 0.001 1735 (13.9) 1145 (16.4) 743 (14.0) 617 (24.6) , 0.001 4743 (54.0) 2767 (39.7) 1885 (35.3) 1113 (44.3) , 0.001 3007 (24.1) 1729 (24.8) 1192 (22.3) 623 (24.8) , 0.001 2469 (19.8) 1043 (15.0) 721 (13.5) 290 (11.4) , 0.001 3213 (25.7) 1903 (29.3) 1432 (26.8) 672 (26.7) , 0.001 362 (2.9) 218 (3.1) 165 (3.1) 97 (3.9) , 0.001 ......................................................................................................................

Previous myocardial infarction (n ¼ 9607) Frequency (%)a 2906 (30.2) 3894 (43.3) 517 (6.9) 1997 – 99 (n ¼ 2614)b 279 (10.7) 754 (28.8) 133 (5.1) 2000 – 02 (n ¼ 3221)b 921 (28.6) 1448 (45.0) 163 (5.1) 2003 – 05 (n ¼ 4041)b 1706 (42.2) 1692 (41.9) 221 (5.5) ........................................................................................................................ Age (years)c 65.8 + 10.7 70.9 + 11.0 70.5 + 10.9 Men, frequency (%) 2125 (73.1) 2738 (70.3) 358 (69.3) Person (years) 5189 8261 1080 ........................................................................................................................ Treatment duration (years)c 1.67 + 1.48 1.98 + 1.60 1.96 + 1.78 Co-morbidity, frequency (%)d Congestive heart failure 141 (4.9) 430 (11.0) 44 (8.5) Cardiac dysrhythmia 138 (4.8) 340 (8.7) 27 (5.2) Peripheral vascular disease 21 (0.7) 63 (1.6) 6 (1.2) Cerebrovascular disease 69 (2.4) 170 (4.4) 17 (3.2) Chronic pulmonary disease 93 (3.2) 209 (5.4) 27 (5.2) Peptic ulcer disease 24 (0.8) 48 (1.2) 7 (1.4) Liver disease 4 (0.1) 8 (0.2) 0 Previous myocardial infarction Chronic renal failure 3 (0.1) 33 (0.9) 0 Acute renal failure 5 (0.2) 20 (0.5) 2 (0.4) Shock 7 (0.2) 34 (0.9) 2 (0.4) Malignancy 29 (1.0) 73 (1.9) 6 (1.2) Charlson index 0.23 + 0.6 0.40 + 0.8 0.28 + 0.6 Concomitant cardiovascular medication, frequency (%) Aspirin 2120 (73.0) 2682 (68.9) 353 (68.3) Statins 1909 (65.7) 2054 (52.8) 279 (54.0) RASi 2085 (71.8) 2699 (69.3) 342 (66.2) Beta-blockers 2171 (74.7) 2826 (72.6) 362 (70.0) Nitrates 1850 (63.7) 2615 (67.2) 357 (69.1) Calcium blockers 1545 (53.2) 2095 (53.8) 286 (55.3) Other antihypertensives 138 (4.9) 176 (4.5) 23 (4.5) aPercentages of the total population. bPercentages of all patients in the respective time period. cMean + standard deviation. dPercentages of all patients in the respective treatment group.

1168 (12.2) 660 (7.3) 501 (5.6) 186 (2.1) , 0.001 Downloaded from https://academic.oup.com/eurheartj/article/32/15/1900/565965 by guest on 08 January 2022 691 (26.4) 376 (14.4) 306 (11.7) 50 (1.9) , 0.001 Insulin secretagogues and cardiovascular risk 303 (9.4) 162 (5.0) 121 (3.8) 95 (2.9) , 0.001 174 (4.3) 122 (3.0) 74 (1.8) 41 (1.0) , 0.001 ...................................................................................................................... 70.9 + 11.0 70.5 + 10.4 71.2 + 114 68.2 + 10.3 , 0.001 817 (70.0) 460 (69.7) 325 (64.9) 131 (70.4) , 0.001 2917 1523 1150 1412 , 0.001 ...................................................................................................................... 2.28 + 1.96 2.19 + 1.90 2.12 + 1.98 2.04 + 1.76 , 0.001 139 (11.9) 67 (10.2) 66 (13.2) 15 (8.1) , 0.001 101 (7.4) 50 (7.6) 44 (8.9) 13 (7.0) , 0.001 12 (1.8) 12 (2.4) , 0.001 24 (1.7) 28 (4.2) 24 (4.8) 0 , 0.001 42 (3.6) 34 (5.2) 29 (5.8) 6 (3.2) , 0.001 67 (5.7) 13 (2.6) 7 (3.8) , 0.001 25 (2.1) 8 (1.2) 1 (0.5) , 0.001 4 (0.6) 0 1 (0.5) 6 (0.5) 13 (1.1) 5 (0.7) 5 (1.0) 1 (0.5) , 0.001 3 (0.3) 2 (0.3) 4 (0.8) 1 (0.5) , 0.001 5 (0.4) 4 (0.6) 6 (1.2) 1 (0.5) , 0.001 12 (1.8) 16 (3.2) 3 (1.6) , 0.001 28 (2.4) 0.35 + 0.7 0.42 + 0.8 0.28 + 0.6 , 0.001 0.41 + 0.7 699 (59.9) 413 (62.6) 290 (57.9) 131 (70.4) , 0.001 457 (39.1) 256 (38.8) 188 (37.5) 105 (56.5) , 0.001 673 (57.6) 408 (61.8) 281 (56.1) 121 (65.1) , 0.001 713 (61.0) 416 (63.0) 278 (55.5) 123 (66.1) , 0.001 754 (64.6) 408 (61.8) 326 (65.1) 125 (67.2) , 0.001 570 (48.8) 313 (47.4) 255 (50.9) , 0.001 115(61.8) , 0.001 49 (4.2) 27 (4.1) 15 (3.0) 11 (5.9) 1903

1904 T.K. Schramm et al. logistic regression using the greedy match algorithm conditional on base- Since patients were able to shift to monotherapy during follow-up, Downloaded from https://academic.oup.com/eurheartj/article/32/15/1900/565965 by guest on 08 January 2022 the sum of individuals in the different monotherapy groups adds line variables [gmatch macro for SAS, & Mayo Clinic College of Medicine up to more than the total study population. A total of 75 354 patients without previous MI and 6448 with previous MI entered the propen- http://ndc.mayo.edu/mayo/research/biostat/upload/gmatch.sas (access sity analysis (Supplementary material online, Table S1). Event rates ed 15 October 2009]. C-statistics ranged from 0.71 to 0.87 indicating are accessible in Supplementary material online, Table S2. A total good discriminative power. of 76 473 (70.9%) patients received ISs, with glimepiride [n ¼ 40 207(52.6%)] being the most used agent (Table 1). On average, Cumulative mortality was estimated by adjusted Kaplan– Meyer lower age and co-morbidities were found in patients treated with plots for the first (baseline) monotherapy treatment only. For all ana- metformin and repaglinide, while those treated with gliclazide had lyses, a two-sided P-value of ,0.05 was considered significant. lower co-morbidity. Owing to interactions with previous MI (P , 0.01), results were presented for patients with and without previous All statistical calculations were performed using the SAS statistical MI separately. Since interactions between individual ISs varied across software package version 9.1 (SAS Institute Inc., Cary, NC, USA). different endpoints and risk groups, subgrouping of ISs was not feasible. Results All-cause death On 1 January 1997, there were 4 107 126 inhabitants in Denmark aged .20 years without previous use of glucose-lowering medi- Multivariable and propensity-matched analyses revealed a consist- cations; of these 107 806(2.6%) initiated monotherapy with ISs ent increase in all-cause deaths associated with glimepiride, gliben- or metformin [9607 (8.9%) with previous MI] and were included. clamide, glipizide, and tolbutamide compared with metformin in During the observation period, most patients (77%) received patients with and without previous MI (Figures 1 and 2, Tables 2 only one IS or metformin as monotherapy. In 22 and 23% of and 3, and Supplementary material online, Table S2). Results for patients without and with previous MI, respectively, the treatment regimen changed during follow-up. Baseline characteristics are summarized in Table 1 and in Supplementary material online, Table S1 for propensity analyses. Figure 1 Hazard ratios (95% CI) for different endpoints in relation to monotherapies with different glucose-lowering agents according to previous myocardial infarction.

Insulin secretagogues and cardiovascular risk 1905 Figure 2 Multivariable adjusted Kaplan–Meier plots demonstrating the cumulative mortality for the first glucose-lowering treatment course Downloaded from https://academic.oup.com/eurheartj/article/32/15/1900/565965 by guest on 08 January 2022 only according to previous myocardial infarction. gliclazide and repaglinide were not statistically different from met- studies where monotherapy was ensured for at least 3 months formin. Gliclazide was associated with a significantly lower risk than prior to an event. other SUs (P , 0.001 for all comparisons), whereas the risk with this agent was not statistically different from that of repaglinide Discussion (P ¼ 0.4– 0.5) in patients with and without previous MI, respectively. This nationwide study showed that compared with metformin, increased mortality and cardiovascular risk was associated with Cardiovascular death most first- and second-generation SUs (glimepiride, glibenclamide, glipizide, and tolbutamide). This study is the first, to our knowl- Similar results to those observed for all-cause death were obtained edge, to analyse major cardiovascular endpoints with all currently for cardiovascular death in all analyses (Figures 1 and 2, Tables 2 approved ISs monotherapies in a nationwide setting. and 3, and Supplementary material online, Table S2 and Figures 1 and 2). In accordance with the UGDP,4 we demonstrated an increased risk with tolbutamide in patients with and without previous MI. Myocardial infarction, stroke, or Other retrospective cohort studies supported our results by indi- cardiovascular death cating increased total5,6 and cardiovascular mortality5 associated with glibenclamide compared with glimepiride,5 and gliclazide.5,6 Results for the combined endpoint were similar to those for car- In contrast, no differences in all-cause mortality were observed diovascular death in most analyses (Figures 1 and 2, Tables 2 and for glibenclamide, glipizide, and glimepiride in a recent large obser- 3, and Supplementary material online, Table S2). In the propensity vational study, although a non-significant trend towards increased analyses of patients without previous MI, gliclazide showed a small, mortality was found for glibenclamide and glipizide compared but significant increase in risk for the combined endpoint com- with glimepiride in patients with documented coronary artery pared with metformin monotherapy (Table 3). disease (CAD).7 Supporting our results was the demonstration of a dose-dependent increase in all-cause mortality with first- Additional analyses generation SUs and glibenclamide in contrast to metformin.10 Fur- thermore, in the DIGAMI study, diabetes patients with acute MI Similar results as those presented were obtained in sub-studies of were allocated to glucose-insulin infusion followed by patients who did not change therapy during follow-up, in studies of the initial (baseline) monotherapy treatment course alone, and in

1906 T.K. Schramm et al. Table 2 Frequencies of events subcutaneous insulin treatment or conventional therapy for 12 months.11 Interestingly, a more favourable effect was evident in Events no (%) patients with an MI and not previously treated with insulin, who by virtue of study assignment to insulin treatment theoretically .......................................................... avoided any possible toxicity of SUs.11 Conversely, the UKPDS,3 and A Diabetes Outcome Progression Trial (ADOPT),12 did not MI, stroke, or find glibenclamide to be associated with increased risk, although neither of these studies was designed or powered for cardiovascu- All-cause Cardiovascular cardiovascular lar events. The UKPDS is the only randomized trial focusing on patients at low risk,3 and mortality studies with individual ISs in death death death patients at increased cardiovascular risk are sparce.4,7,13 In a ................................................................................ recent Danish regional registry study of MI patients, however, glib- enclamide, glipizide, and tolbutamide were associated with No previous myocardial infarction increased mortality within 1 year, whereas glimepiride and glicla- zide showed lower risk.13 Metformin 1548 (3.6) 827 (1.9) 1646 (3.8) SUs and, in particular, glibenclamide have been linked to inter- Glimepiride 4081 (11.2) 2251 (6.2) 3517 (9.7) ference with the protective effect of ischaemic pre-conditioning of the heart, by binding to cardiac sulphonylurea 2A receptors.14 Gliclazide 442 (7.5) 256 (4.3) 440 (7.4) Indeed, in patients with established ischaemic heart disease, gliben- clamide but not glimepiride and gliclazide may diminish myocardial Glibenclamide 1546 (12.4) 876 (7.0) 1376 (11.0) pre-conditioning.15,16 Our findings of increased risk with most ISs, including glimepiride, may therefore suggest the contribution of Glipizide 947 (13.6) 559 (8.0) 820 (11.8) mechanisms other than interference with ischaemic Downloaded from https://academic.oup.com/eurheartj/article/32/15/1900/565965 by guest on 08 January 2022 pre-conditioning. A protective effect of metformin and possibly Tolbutamide 794 (14.8) 457 (8.6) 687 (12.8) of gliclazide and repaglinide (rather than a detrimental effect of other ISs) could be hypothesized, but the precise relationships Repaglinide 147 (5.9) 69 (2.8) 138 (5.5) and mechanisms underlying these effects await further studies. Since the UKPDS in 1998, evidence has definitely evolved Total 9505 (9.7) 5295 (5.4) 8624 (8.8) ................................................................................ Previous myocardial infarction Metformin 213 (7.3) 169 (5.8) 245 (8.4) Glimepiride 737 (18.9) 591 (15.2) 751 (19.3) Gliclazide 63 (12.2) 48 (9.3) 63 (12.2) Glibenclamide 265 (22.2) 207 (17.7) 267 (22.9) Glipizide 141 (21.4) 115 (17.4) 154 (23.3) Tolbutamide 120 (24.0) 94 (18.8) 114 (22.8) Repaglinide 26 (14.0) 21 (11.3) 28 (15.1) Total 1565 (16.3) 1245 (13.0) 1622 (16.9) Table 3 Propensity analyses demonstrating hazard ratios (95% confidence intervals) for different endpoints in relation to monotherapies with different glucose-lowering agents according to previous myocardial infraction All-cause death Cardiovascular death MI, stroke, or cardiovascular ...................................... ...................................... death ...................................... HR (95% CI) P-value HR (95% CI) P-value HR (95% CI) P-value ............................................................................................................................................................................... No previous myocardial infarction Metformina 1 1 1 Glimepiride (n ¼ 22 340) 1.27 (1.18– 1.36) ,0.001 1.26 (1.14– 1.39) 0.001 1.29 (1.20–1.39) ,0.001 Gliclazide (n ¼ 4739) 1.05 (0.91– 1.21) 0.50 1.15 (0.95– 1.39) 0.15 1.18 (1.02–1.36) 0.03 Glibenclamide (n ¼ 7412) 1.13 (1.02– 1.25) 0.03 1.13 (0.98– 1.31) 0.10 1.16 (1.04–1.29) 0.009 Glipizide (n ¼ 4981) 1.16 (1.03– 1.30) 0.02 1.24 (1.06– 1.46) 0.009 1.24 (1.09–1.40) 0.001 Tolbutamide (n ¼ 3879) 1.12 (0.99– 1.26) 0.08 1.16 (0.98– 1.36) 0.02 1.17 (1.03–1.33) ,0.001 Repaglinide (n ¼ 1931) 1.00 (0.78– 1.29) 0.98 1.03 (0.37– 2.83) 0.96 0.87 (0.49–1.54) 0.87 ............................................................................................................................................................................... Previous myocardial infarction Metformina 1 1 1 Glimepiride (n ¼ 1952) 1.30 (1.08– 1.57) 0.007 1.29 (1.04– 1.60) 0.02 1.22 (1.30–1.46) 0.03 Gliclazide (n ¼ 447) 0.85 (0.61– 1.17) 0.32 0.75 (0.52– 1.08) 0.87 0.71 (0.52–1.99) 0.04 Glibenclamide (n ¼ 594) 1.34 (1.03– 1.75) 0.031 1.40 (1.04– 1.88) 0.03 1.10 (0.85–1.41) 0.50 Glipizide (n ¼ 515) 1.58 (1.19– 2.09) 0.002 1.53 (1.06– 2.21) 0.02 1.54 (1.12–2.10) 0.008 Tolbutamide (n ¼ 329) 1.46 (1.06– 2.01) 0.02 1.85 (1.67– 2.92) 0.009 1.44 (1.01–2.05) 0.04 Repaglinide (n ¼ 163) 1.15 (0.68– 1.98) 0.91 1.10 (0.61– 2.00) 0.75 1.10 (0.67–1.82) 0.69 aPatients in each group of ISs were matched on an equal number of patents receiving metformin.

Insulin secretagogues and cardiovascular risk 1907 indicating a safer cardiovascular profile for metformin than for co-morbidities were in general lower in patients treated with met- Downloaded from https://academic.oup.com/eurheartj/article/32/15/1900/565965 by guest on 08 January 2022 other oral glucose-lowering agents.17 Moreover, there have been formin, gliclazide, and repaglinide, i.e. leaving room for confounding surprisingly few reports on lactate acidosis, the potentially most by indication. By performing propensity analyses on matched popu- severe complication with metformin.18 Accordingly, in 2007, the lations with balanced covariates, however, we believe that this US product label was modified to remove the heart failure potential bias was reasonably dealt with (see Supplementary contraindication. material online, Table S1). Recent studies have reported reduced cardiac ventricular In conclusion, we demonstrated increased mortality and cardio- mass,19 and reduced cardiovascular and cancer mortality in vascular risk associated with the most used ISs in patients at rela- patients with type 2 diabetes treated with gliclazide when com- tively low and high cardiovascular risk, when compared with pared with glibenclamide.6 Repaglinide predominantly targets the metformin; the risk associated with gliclazide and repaglinide was post-prandial blood glucose rise, which is thought to be associated not statistically significantly different from metformin. The notion with increased cardiovascular risk.20 Furthermore, less progression that individual ISs can exhibit clinically important differences in of the carotid intima-media thickness was reported in patients their safety profile warrants further studies. receiving repaglinide compared with glimepiride.21 Overall, our study adds to these smaller studies by demonstrating that treat- Supplementary material ment with gliclazide and repaglinide may be associated with improved cardiovascular outcomes. Due to lower numbers of Supplementary material is available at European Heart Journal these ISs, however, we cannot exclude that the lack of statistical online. significance for gliclazide and repaglinide could be due to lack of study power. Interestingly, in the Action in Diabetes and Vascular Funding Disease (ADVANCE) study all patients were assigned to gliclazide in the intensive treatment arm,22 which could explain the lower This study was supported by an unrestricted research grant from the cardiovascular risk in these patients as opposed to the Action to Danish Pharmacist Foundation (Grant No. 31– 03) and a research Control Cardiovascular Risk in Diabetes (ACCORD) study, grant from the Danish Agency for Science Technology and Innovation where other glucose-lowering agents were predominantly used.23 (Grant No. 271-08-0944). The present study has several strengths. Owing to the nation- Conflict of interest: none declared. wide setting, we avoided selection bias related to sex, age, income, willingness to participate, participation in the labour References market, and links to physicians or health insurance plans. The con- firmation of our results in sensitivity analyses of patients not 1. Holman RR, Paul SK, Bethel MA, Matthews DR, Neil HA. 10-year follow-up switching therapy and analysis with inclusion of the first of intensive glucose control in type 2 diabetes. N Engl J Med 2008;359: single-agent treatment course only ruled out the possible con- 1577 –1589. founding effect of other previous treatment regimens. The diagno- sis of MI and stroke in the National Patient Registry has proved to 2. Effect of intensive blood-glucose control with metformin on complications in be valid with a positive predictive value of 93% for MI24 and 74 – overweight patients with type 2 diabetes (UKPDS 34). UK Prospective Diabetes 97% for stroke.25 The National Prescription Register is linked to Study (UKPDS) Group. Lancet 1998;352:854 – 865. the partial reimbursement policy for drug expenses by the national health security systems, and has been shown to be accurate.26 3. Intensive blood-glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes Some limitations should be acknowledged. The effect of unmea- (UKPDS 33). UK Prospective Diabetes Study (UKPDS) Group. Lancet 1998;352: sured confounders cannot be discounted. Well-known risk factors 837 –853. such as lipid disorders, hypertension, body mass index, smoking, physical activity, dietary factors, and blood glucose regulation 4. Meinert CL, Knatterud GL, Prout TE, Klimt CR. A study of the effects of hypogly- were not accessible, although this limitation was addressed by cemic agents on vascular complications in patients with adult-onset diabetes. II. using time-dependent adjustments for concomitant cardiovascular Mortality results. Diabetes 1970;19(suppl.):789 –830. medications, as proxies for other risk factors. There remains a theoretical possibility of metformin use in patients without overt 5. Khalangot M, Tronko M, Kravchenko V, Kovtun V. Glibenclamide-related excess diabetes such as in high-risk patients to prevent diabetes or in in total and cardiovascular mortality risks: data from large Ukrainian observational those with polycystic ovarian syndrome (PCO). However, it cohort study. Diabetes Res Clin Pract 2009;86:247 –253. seems unlikely that the more beneficial mortality outcome data for metformin may be due to metformin treatment in such 6. Monami M, Balzi D, Lamanna C, Barchielli A, Masotti G, Buiatti E, Marchionni N, patients. Finally, we did in fact not find any registered metformin Mannucci E. Are sulphonylureas all the same? A cohort study on cardiovascular use in patients diagnosed with PCO. A similar duration of diabetes and cancer-related mortality. Diabetes Metab Res Rev 2007;23:479 – 484. was ascertained by inclusion of patients initiating glucose-lowering medications during follow-up only. Confounding by indication is an 7. Pantalone KM, Kattan MW, Yu C, Wells BJ, Arrigain S, Jain A, Atreja A, important bias to be acknowledged in observational studies such as Zimmerman RS. The risk of overall mortality in patients with type 2 diabetes ours e.g. patients with renal failure and heart failure were likely to receiving glipizide, glyburide, or glimepiride monotherapy: a retrospective analysis. preferentially receive an IS rather than metformin. Furthermore, Diabetes Care 2010;33:1224 –1229. 8. Andersen TF, Madsen M, Jorgensen J, Mellemkjoer L, Olsen JH. The Danish National Hospital Register. A valuable source of data for modern health sciences. Dan Med Bull 1999;46:263 – 268. 9. Nuttall M, van der Meulen J, Emberton M. Charlson scores based on ICD-10 administrative data were valid in assessing comorbidity in patients undergoing urological cancer surgery. J Clin Epidemiol 2006;59:265 – 273. 10. Simpson SH, Majumdar SR, Tsuyuki RT, Eurich DT, Johnson JA. Dose-response relation between sulfonylurea drugs and mortality in type 2 diabetes mellitus: a population-based cohort study. CMAJ 2006;174:169–174. 11. Malmberg K, Ryden L, Efendic S, Herlitz J, Nicol P, Waldenstrom A, Wedel H, Welin L. Randomized trial of insulin-glucose infusion followed by subcutaneous insulin treatment in diabetic patients with acute myocardial infarction (DIGAMI study): effects on mortality at 1 year. J Am Coll Cardiol 1995;26:57 –65. 12. Kahn SE, Haffner SM, Heise MA, Herman WH, Holman RR, Jones NP, Kravitz BG, Lachin JM, O’Neill MC, Zinman B, Viberti G. Glycemic durability of rosiglitazone, metformin, or glyburide monotherapy. N Engl J Med 2006;355:2427 –2443.

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For the use of a Registered Medical Practitioner or a Hospital or a Laboratory only This package insert is continually updated: Please read carefully before using a new pack. Gliclazide and Metformin hydrochloride extended-release tablets DIAMICRON® XR MEX60/1000 1. GENERIC NAME Gliclazide (60 mg) and Metformin (1000mg) extended release tablet 2. QUALITATIVE AND QUANTITATIVE COMPOSITION DIAMICRON® XR MEX 60/1000 is an extended release preparation containing gliclazide 60 mg and metformin 1000 mg in a Fixed Dose Combination. Each uncoated bi-layered scored tablet contains gliclazide I.P. (as extended release)....60 mg and metformin hydrochloride I.P. (as extended release)…. 1000 mg List of excipients Lactose monohydrate I.P. Maltodextrin I.P. Polyvinyl pyrrolidone I.P. Hydroxy propyl methyl cellulose I.P. Silicon dioxide I.P. Magnesium stearate I,P, Lake Ponceau 4R 3. DOSAGE FORM AND STRENGTH Gliclazide 60 mg and Metformin 1000 mg in a fixed dose combination. It belongs to uncoated bi-layered scored extended release tablet dosage form 4. CLINICAL PARTICULARS 4.1 Therapeutic indication DIAMICRON® XR MEX 60/1000 is indicated for the treatment of noninsulin dependent diabetes (Type II) in adult patients where single drug therapy, diet and exercise do not result in adequate glycemic control . 4.2 Posology and method of administration Posology: The starting dose for DIAMICRON® XR MEX 60/1000 is 1 tablet daily and should be increased to a maximum dose of 2 tablets daily only on the consultation of the doctor. DIAMICRON® XR MEX 60/1000 is a scored tablet and can be broken for sequential increase or Page 1 of 16