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PHAR 9942 / PSCI 6602 JOURNAL CLUB ACTIVITY GRADING EVALUATION Presenter:_______________________________________________ Date:_____________ Reviewer:_______________________________________________ STYLE / PRESENTATION 2 points Presentation Exhibited professional appearance and demeanor, and spoke clearly throughout the presentation Mannerisms Eye Contact Slides Handout TOTAL Comments Adapted from Am J Pharm Educ. 2007;71(4):Article 63. 1 point SOMEWHAT exhibited professional appearance and demeanor, was difficult to hear or understand SOME things spoken Few (or no) distracting mannerisms (e.g., um) Maintained eye contact throughout the presentation Slides were organized, easy to read, and aesthetically pleasing Handout was organized, easy to read, and aesthetically pleasing 0 points Did NOT exhibit professional appearance and demeanor, was difficult to hear or understand MOST things spoken Score /2 Had distracting mannerisms /1 Did NOT maintain eye contact /1 Slides were NOT organized and difficult to read Handout was NOT organized and difficult to read /1 /1 /6 PHAR 9942 / PSCI 6602 JOURNAL CLUB ACTIVITY GRADING EVALUATION CONTENT / CRITICAL EVALUATION Study Overview Introduction - Authors’ affiliations/study support - Study objective(s) & rationale Methods – Design - Case-control, cohort, controlled experiment, etc. - Type of design (cross-over, parallel, etc.) - Type of assignment used - Blinding Methods – Patients/Subjects - How enrolled/from where? - Inclusion/exclusion criteria - # enrolled per group Methods – Treatment Regimen - Treatments used - Dosages/administration - Therapy duration Methods – Outcome Measures - Primary measures - Secondary measures Methods – Data Handling - Intention to treat, per protocol, etc. - # lost to follow-up - Reasons for dropouts Methods – Statistics - Tests used - Power of study Results - Results for each outcome measure - Confidence intervals - P-values - Compliance - Adverse effects Conclusion – Authors’ conclusion Adapted from Am J Pharm Educ. 2007;71(4):Article 63. 2 points 1 point 0 points Score Accurately and completely reported ALL relevant introduction, study design, and patients/subject components Accurately and completely reported MOST of the relevant introduction, study design, and patients/subject components Did NOT accurately and completely report most of the relevant introduction, study design, and patients/subject components /2 Accurately and completely reported ALL relevant treatment regimens, outcome measures, and data handling components Accurately and completely reported MOST of the relevant treatment regimens, outcome measures, and data handling components Did NOT accurately and completely most of the relevant treatment regimens, outcome measures, and data handling components /2 Accurately and completely reported ALL relevant statistics, results, and authors’ conclusion components Accurately and completely reported MOST of the relevant statistics, results, and authors’ conclusion components Did NOT accurately and completely most of the relevant statistics, results, and authors’ conclusion components /2 PHAR 9942 / PSCI 6602 JOURNAL CLUB ACTIVITY GRADING EVALUATION STUDY OVERVIEW TOTAL /6 Comments Analysis Analyzed all parts of study 4 points ALL parts appropriately critiqued with ALL relevant questions accurately addressed with strengths, weaknesses and their impact described 3 points Missed only ONE or TWO considerations or relevant questions in critique, with the rest appropriately addressed with strengths, weaknesses, and their impact described TOTAL Comments Adapted from Am J Pharm Educ. 2007;71(4):Article 63. 2 points 1 point 0 points MOST parts appropriately critiqued, some relevant questions with strengths, weaknesses, and their impact overlooked or inaccurate Only SOME parts appropriately critiqued, most relevant questions with strengths, weaknesses, and their impact overlooked or inaccurate Failed to appropriately critique any part, all relevant questions with strengths, weaknesses, and their impact overlooked or inaccurate Score /4 PHAR 9942 / PSCI 6602 JOURNAL CLUB ACTIVITY GRADING EVALUATION Conclusion Clear, concise conclusion stated 1 point Summarized accurately & completely: key points to be taken from study (which reflected limitations), drug’s role in therapy or clinical practice implications, and need for any further research in area 0 points Did NOT summarize accurately & completely a conclusion OR conclusion completely inaccurate TOTAL Comments Preparedness Response to questions TOTAL Comments Score /1 /1 1 point Correctly answered questions in a confident manner STYLE / PRESENTATION TOTAL POINTS: Score /1 /1 ______/6 CONTENT / CRITICAL EVALUATION TOTAL POINTS: ______/12 Adapted from Am J Pharm Educ. 2007;71(4):Article 63. 0 points Did NOT correctly answer questions OR handled questions unprofessionally DIABETICMedicine DOI: 10.1111/dme.13003 Research: Treatment Open-label randomized non-inferiority trial of a fixed-dose combination of glimepiride and atorvastatin for the treatment of people whose Type 2 diabetes is uncontrolled on metformin P. Ambery1, A. Stylianou2, G. Atkinson3, C. Dott3, L. Baylor Curtis3, N. Haque3, K. LaCroix4 and K. W. Min5 on behalf of the Glimepiride/Atorvastatin Investigational Team 1 Department of Medicine, Addenbrooke’s Hospital, Cambridge, 2Clinical Statistics, GlaxoSmithKline, Stevenage, 3Alternative Discovery and Development, GlaxoSmithKline, Brentford, UK, 4Global Clinical Safety and Pharmacovigilance, GlaxoSmithKline, Research Triangle Park, NC, USA and 5Diabetes Centre, Eulji Hospital, Eulji University School of Medicine, Seoul, Republic of Korea Accepted 15 October 2015 Abstract Aims To evaluate, in a randomized, open-label study, the non-inferiority of a bioequivalent fixed-dose combination of glimepiride and atorvastatin vs. separately co-administered tablets in people with Type 2 diabetes mellitus. Methods Participants with HbA1c ≥ 53 to < 80 mmol/mol (≥ 7.0 to < 9.5%), average fasting blood glucose > 7.0 mmol/l, who were on metformin for ≥ 3 months, were randomized to combination (n = 215) or co-administered glimepiride and atorvastatin (n = 212) once daily for 20 weeks. Up-titration of glimepiride (1–4 mg) and atorvastatin (10–20 mg) were based on average fasting blood glucose and LDL cholesterol, respectively. Co-primary endpoints were change from baseline to week 20 in HbA1c and LDL cholesterol. Non-inferiority was demonstrated for both co-primary endpoints: the upper limits of 95% CIs for differences (combination-reference) were less than the prespecified margins of 3.3 mmol/mol (0.3%) for change from baseline in HbA1c [difference 0.1 mmol/mol (95% CI 1.6, 1.9); 0.01% (95% CI 0.15, 0.17)] and 6% for percentage change from baseline in LDL cholesterol [difference 0.87% (95% CI 2.47, 4.21)]. Similar proportions of participants on combination and reference had treatment-emergent adverse events (64 vs. 61%). More participants on combination had hypoglycaemia (21 vs. 13%); most events were considered by the treating physician to be unrelated to study drug. Results Conclusions The combination was non-inferior to separately co-administered tablets and the safety profile was consistent with the known profiles of glimepiride and atorvastatin. The observed increase in hypoglycaemia on the combination cannot be explained, but may be attributable to non-systematic collectiof glucose readings and may have been influenced by reporting bias in this open-label trial. Diabet. Med. 33, 1084–1093 (2016) Introduction Type 2 diabetes mellitus is a chronic illness that requires continuing medical care, self-management and support. A stepwise approach to management is recommended, starting with advice concerning diet, exercise and weight reduction [1]. If glucose targets are not met by lifestyle interventions, treatment with metformin is recommended [1]. Other glucose-lowering therapies, such as a sulphonylurea, may then be added if glycaemic control is not achieved [1]. As Correspondence to: Anastasia Stylianou. E-mail: anastasia.2.stylianou@gsk.com 1084 people with Type 2 diabetes have an increased risk of cardiovascular disease [2], predominantly driven by risk factors such as dyslipidaemia and hypertension [3], multifactorial risk reduction strategies beyond glycaemic control are required; therefore, consensus treatment guidelines now recommend antihypertensives and lipid-lowering therapy for most people with Type 2 diabetes [1,4,5]. Persistence and adherence to therapy are critical in improving outcomes in Type 2 diabetes, but many people do not meet their personalized targets; for example, almost half of the surveyed adults with diagnosed diabetes participating in a national surveillance programme in the USA did not meet the ª 2015 Diabetes UK Research article What’s new? • We evaluated a bioequivalent fixed-dose combination of glimepiride plus atorvastatin versus separately coadministered tablets in people with Type 2 diabetes mellitus on metformin. • The combination was non-inferior to separately coadministered tablets with respect to reductions in HbA1c and LDL cholesterol after 20 weeks. • The safety profile of the combination was consistent with the known profiles of glimepiride and atorvastatin. • More participants on the combination reported hypoglycaemia. This cannot be explained but may be attributable to non-systematic collection of glucose readings and may have been influenced by reporting bias in this open-label trial. recommended goals for glycaemic control, blood pressure and lipids [6]. Simplification of dosage regimens, by combining medications in a single dosage form, is likely to improve compliance [7–9], thereby improving clinical outcomes. The aim of the present study was to demonstrate the noninferiority of a fixed-dose combination of glimepiride plus atorvastatin, compared with both agents taken concomitantly as separate tablets, in improving glucose control and lipid profiles in Type 2 diabetes. Glimepiride and atorvastatin are well-established medicines, with substantial clinical trials and post-marketing experience [10–12]. In a previous trial in healthy people, the glimepiride-atorvastatin formulation was shown to be bioequivalent to separately administered glimepiride and atorvastatin tablets, in terms of rate and extent of exposure (data on file). Participants and methods Study design and ethics This was an open-label, randomized, two-arm, parallel group study conducted at 33 centres in six countries (Malaysia, Mexico, Philippines, Russia, South Korea and Thailand) between December 2011 and September 2013. The study protocol (ATG115317) was approved by the relevant independent ethics committee for each centre and written informed consent was obtained from each participant. The procedures followed were in accordance with guidelines for good clinical practice and the Declaration of Helsinki. The trial was registered with ClinicalTrials.gov (NCT01495013). Participants Men and women aged ≥ 18 years with Type 2 diabetes on a stable dose of metformin for ≥ 3 months, with HbA1c ≥ 53 ª 2015 Diabetes UK DIABETICMedicine to < 80 mmol/mol (≥ 7.0 to < 9.5%) and average fasting blood glucose > 7.0 mmol/l, taken on 4 days in the week before enrolment, were eligible. Participants had to be statinna€ıve or have no statin use for 2 months before screening and be eligible for statin therapy (history of cardiovascular disease; ≥ 40 years with a cardiovascular risk factor; < 40 years with LDL cholesterol > 100 mg/dl). Exclusions were: other lipid-lowering or antidiabetic agents; Type 1 diabetes or current need for insulin therapy; concurrent myalgia; symptomatic hyperglycaemia requiring therapy; hypertriglyceridaemia; clinically significant cardiovascular disease; end-stage renal disease; cancer in the past 3 years; a clinically significant abnormality on physical examination or laboratory tests; receiving drug therapy to treat liver disease; antiviral or immunosuppressive therapy; haemoglobinopathy that could interfere with the assessment of HbA1c; and hereditary lactose intolerance, lactase deficiency or glucose-galactose malabsorption. Interventions Participants were randomly assigned (1:1) using an interactive web response system to receive glimepiride-atorvastatin fixed-dose combination or co-administration of glimepiride and atorvastatin (reference) once daily for 20 weeks. Block randomization was used and the randomization list was computer-generated using statistical software. The combination tablets (1/10, 2/10, 3/10, 4/10, 1/20, 2/20, 3/20 and 4/20 mg of glimepiride/atorvastatin, respectively) were manufactured by Dr Reddy’s Laboratories (Hyderabad, India). Glimepiride (1, 2, 3 and 4 mg) and atorvastatin (10 and 20 mg) tablets were sourced from commercial supplies (Amaryl; Sanofi Aventis, Anagni, Italy; Lipitor; Pfizer, Berlin, Germany). All participants started on 10 mg atorvastatin and 1 mg glimepiride, either as combination or separate tablets. Participants were advised to take study drug(s) shortly before or during a substantial breakfast or the first main meal. Glimepiride was up-titrated at weeks 2, 4, 6 and 10 if average fasting blood glucose was > 7 mmol/l in the preceding week and no individual value was < 4.5 mmol/l. Atorvastatin was up-titrated at weeks 6 or 12 if LDL cholesterol at the preceding visit was > 2.6 mmol/l. The study was designed to achieve rapid titration to enable participants to have exposure at the higher doses; thus, participants who required down-titration were to be withdrawn. Assessments The co-primary efficacy endpoints were change from baseline to week 20 in HbA1c and percent change from baseline to week 20 in LDL cholesterol. Secondary efficacy endpoints were change from baseline to week 12 in HbA1c and percent change from baseline to weeks 4 and 10 in LDL cholesterol. 1085 DIABETICMedicine Fixed-dose combination of glimepiride and atorvastatin for type 2 diabetes  P. Ambery et al. Safety assessments included monitoring of adverse events (AEs), hypoglycaemia and liver function tests. Blood samples were taken at screening, baseline and during the treatment period for measurement of HbA1c (weeks 12 and 20), lipids (weeks 4, 10 and 20) and liver function tests (weeks 2, 6, 16 and 20). HbA1c and lipids were measured at a central laboratory. Liver function tests were measured at each centre’s laboratory. Participants were assigned a glucometer to measure blood glucose. They were trained to identify symptoms of hypoglycaemia and to document these in a diary card, together with the accompanying blood glucose reading. Participants also recorded their fasting blood glucose for at least 4 days in the week preceding a potential up-titration visit. Glucometer readings were examined by investigators and categorized using American Diabetes Association working group criteria for hypoglycaemia [13]. All values ≤ 3.9 mmol/l were recorded as hypoglycaemia, regardless of symptoms. The AE information was collected from the start of treatment until the last follow-up contact. Drug compliance was determined by counting returned tablets. Change from baseline in HbA1c and percentage change from baseline in LDL cholesterol were separately analysed for the observed case dataset using a mixed model for repeated measures with restricted maximum likelihood estimation. The baseline values for HbA1c and LDL cholesterol were included as covariates in the respective models. In case of drop-out, HbA1c and LDL cholesterol values at the early withdrawal visit were included in the analysis. Analyses were performed using SAS v. 9.2 or later. HbA1c results were reported as percentages and converted to mmol/mol as follows: HbA1c (mmol/mol)=[HbA1c (%) 2.15]910.93. Standard deviation and change from baseline values in mmol/mol were calculated by multiplying the percentage value by 10.93. Safety variables were summarized descriptively. Compliance was defined as: 100 9 total number of tablets consumed/(days of study drug exposure)*(number of tablets prescribed per day). Results Study population Statistical methods A non-inferiority hypothesis was used to show that participants taking the combination were not disadvantaged compared with participants taking the separate agents. Assessment of non-inferiority was based on the two-sided 95% CI for the difference between groups for each coprimary endpoint. If the upper limit of the 95% CI for the difference in change from baseline to week 20 for HbA1c was < 3.3 mmol/mol (< 0.3%), and percentage change from baseline to week 20 in LDL cholesterol was < 6%, then non-inferiority was to be concluded. Non-inferiority margins were selected based on regulatory guidance for diabetes [14] and previous lipid studies [15]. A sample size of 191 evaluable participants in each group provided 90% power for the comparison between groups for change from baseline in HbA1c (based on a non-inferiority margin of 0.3% assuming standard deviation of 0.9%) and 83% power for the comparison between groups for percentage change from baseline in LDL cholesterol (based on a non-inferiority margin of 6% assuming standard deviation of 20%) and a one-sided test with 2.5% significance level. Assuming up to 10% of participants would be nonevaluable, 424 participants were to be randomized (212 per group). The primary non-inferiority analysis was conducted on the per-protocol population (all participants without major protocol deviations). Analysis of the intention-to-treat population (all randomized participants with at least one postbaseline HbA1c or LDL cholesterol value) was conducted as a sensitivity analysis. The safety population comprised all participants who took at least one dose of study drug. 1086 A total of 427 participants were randomized (215 and 212 in combination and reference groups, respectively) and 393 (92%) participants completed the study (Fig. 1). Over 90% of participants were included in the per-protocol populations for the analysis of HbA1c (391/427, 92%) and LDL cholesterol (393/427, 92%). The most common reasons for exclusion from per-protocol populations were incorrect dose titration (six and seven participants in the combination and reference groups, respectively) and inadequate treatment compliance (four and six participants, respectively; Fig. 1). The two groups were well matched with regard to demographic and baseline characteristics (Table 1). In both groups, mean age was 57–58 years and there was a predominance of women (59 and 64%, respectively). Exposure and treatment compliance At the end of the 20-week treatment period or at premature discontinuation, 19 and 20% of participants in the combination and reference groups, respectively, remained on the lowest combination of glimepiride/atorvastatin 1/10 mg and 10% of participants in each group were on the highest combination of 4/20 mg (Table S1). Glimepiride 4 mg, irrespective of atorvastatin dose, was received by 42 and 44% of participants, respectively, with 34 and 35% of participants titrated to this dose at week 6. Atorvastatin 20 mg was received by 19 and 21% of participants, respectively, with 10 and 14% of participants titrated to this dose at week 6. Compliance with study drug was 98% in each group. ª 2015 Diabetes UK 768 assessed for eligibility 427 randomised Analysis Follow-up Enrollment DIABETICMedicine Allocation Research article 341 excluded • 327 did not meet eligibility criteria • 11 withdrew consent • 3 other reasons 215 allocated to combination group • 215 received allocated intervention 212 allocated to reference group • 212 received allocated intervention 199 completed the study to Week 20 16 discontinued prematurely: • 1 down-titration of study drug • 1 change in treatment for underlying disease • 2 sponsor discretion due to unacceptable visit window deviations • 4 withdrew consent • 1 lost to follow-up • 2 non-serious adverse events • 5 protocol violations 194 completed the study to Week 20 18 discontinued prematurely: • 5 withdrew consent • 2 non-serious adverse events • 3 serious adverse events • 8 protocol violations 213 in ITT population 2 excluded (did not have post-baseline HbA1c and LDL cholesterol value) 211 in ITT population 1 excluded (did not have post-baseline HbA1c and LDL cholesterol value) 200 in PP population 13 excluded from ITT due to major protocol deviation: • 6 incorrect titration • 4 inadequate study drug compliance • 2 violation of inclusion/exclusion criteria • 1 prohibited medication 193 in PP population 18 excluded from ITT due to major protocol deviation: • 7 incorrect titration • 6 inadequate study drug compliance • 2 violation of inclusion/exclusion criteria • 2 prohibited medication • 1 metformin dose change 1 additional patient excluded from PP analysis of HbA1c as did not have a post-baseline HbA1c value 1 additional patient excluded from PP analysis of HbA1c as did not have a post-baseline HbA1c value FIGURE 1 Enrolment, randomization and follow-up of study participants. Combination, fixed-dose combination of glimepiride-atorvastatin; ITT, intention-to-treat; PP, per-protocol; Reference: co-administered glimepiride and atorvastatin tablets. Efficacy Decreases in HbA1c and LDL cholesterol from baseline to week 20 were observed in both groups (Fig. 2).The combination was non-inferior to co-administered glimepiride and atorvastatin for both co-primary endpoints at week 20. In the per-protocol population, the least squares (LS) mean change from baseline to week 20 in HbA1c was 7.4 (95% CI 8.7, 6.2) mmol/mol [ 0.68 (95% CI 0.80, 0.57) %] vs. ª 2015 Diabetes UK 7.5 (95% CI 8.7, 6.2) mmol/mol [ 0.69 (95% CI 0.80, 0.57)%] for the combination and reference group, respectively. The upper limit of the two-sided 95% CI for the between-group difference was less than the prespecified noninferiority margin of 3.3 mmol/mol (0.3%) [difference 0.1 mmol/mol (95% CI 1.6, 1.9); 0.01% (95% CI 0.15, 0.17)]. The LS mean percentage change in LDL cholesterol from baseline to week 20 was 38.38% (95% CI 40.72, 36.03) vs. 39.25% (95% CI 41.62, 36.88) for 1087 DIABETICMedicine Fixed-dose combination of glimepiride and atorvastatin for type 2 diabetes  P. Ambery et al. Table 1 Demographic and baseline characteristics Combination N = 215 Mean (SD) age, years 57.3 (8.8) Gender, n (%) Men 89 (41.4) Women 126 (58.6) Geographic ancestry, n (%) East Asian 50 (23.3) South-East Asian 65 (30.2) White/Caucasian/European 24 (11.2) Hispanic-Latino 76 (35.3) Mean (SD) vital statistics Weight, kg 71.9 (17.5) Hip circumference, cm 100.9 (12.4) Hip–waist ratio 1.1 (0.1) Family history of cardiovascular disease, n (%) Premature coronary artery 22 (10.2) disease Peripheral artery disease or 13 (6.0) stroke Smoking history, n (%) Current smoker 36 (16.7) Past smoker 33 (15.3) Mean (SD) blood pressure, mmHg Systolic blood pressure 129.9 (14.6) Diastolic blood pressure 78.5 (8.3) Mean (SD) HbA1c, mmol/mol 63 (7.8) Mean (SD) HbA1c, % 7.9 (0.71) Mean (SD) LDL cholesterol, 3.12 (0.91) mmol/l Reference N = 212 57.9 (10.7) 77 (36.3) 135 (63.7) 48 66 24 74 (22.6) (31.1) (11.3) (34.9) 71.4 (15.4) 101.2 (12.7) 1.1 (0.1) 17 (8.0) 16 (7.5) 30 (14.2) 30 (14.2) 129.2 77.2 63 7.9 3.28 (13.9) (8.6) (7.2) (0.66) (0.90) Combination: fixed-dose combination of glimepiride-atorvastatin; Reference; co-administered glimepiride and atorvastatin tablets. combination and reference. The upper limit of the two-sided 95% CI for the between-group difference was less than the prespecified non-inferiority margin of 6% [difference 0.87% (95% CI 2.47 to 4.21)]. Intention-to-treat analyses supported the primary perprotocol analyses. In the intention-to-treat population, LS mean differences between groups were 0.2 (95% CI 1.4, 1.7) mmol/mol [0.02 (95% CI 0.13, 0.16)%] for change from baseline in HbA1c at week 20 and 1.29% (95% CI 1.98, 4.57)] for percentage change in LDL cholesterol at week 20. Changes in HbA1c and LDL cholesterol at other time points for the per-protocol population were similar to those observed at week 20 (Fig. 2). LS mean differences between groups were 0.1 (95% CI 1.4, 1.6) mmol/mol [0.01 (95% CI 0.13, 0.15)%] for change from baseline in HbA1c at week 12, and 0.85% (95% CI 3.98, 2.28) and 0.92% (95% CI 4.20, 2.36) for percent change in LDL cholesterol at weeks 4 and 10, respectively. Safety Similar proportions of participants in the combination and reference groups had treatment-emergent AEs [64% (138/ 1088 215) vs. 61% (130/212)], AEs assessed as drug-related [9% (20/215) vs. 11% (24/212)] and non-serious AEs leading to discontinuation [1% (2/215) vs. 1% (2/212)]. Non-fatal serious adverse events (SAEs) were experienced by 1% (3/215) and 3% (7/212) of participants in the combination and reference groups, respectively. One additional participant in the reference group died from pancreatic carcinoma. None of the SAEs was assessed by the investigator as related to study drug. The most common AEs were abnormalities in liver function tests (Fig. 3). Investigators were instructed to report all out of range transaminase and bilirubin levels as AEs, regardless of clinical significance. At least one liver function test AE was reported for 39% (83/215) and 29% (61/212) of participants in combination and reference groups, respectively. All of the liver function test AEs were of mild intensity, except for one moderate liver function test AE in the reference group. None of the liver function test AEs was assessed as serious or severe, or led to discontinuation. There were no events of possible drug-induced liver injury with hyperbilirubinaemia. A review of maximum normalized liver function test values, and maximum relative change from baseline in liver function test values, showed no differences between the groups (Fig. 4). Hypoglycaemia was reported more frequently in the combination group [88 events for 45/215 (21%) participants] than the reference group [54 events for 27/212 (13%) participants]. Most events (> 95%) were classified as mild and none led to discontinuation of study drug (Table 2). All events resolved within a day without medical intervention. Similar numbers of participants in the combination and reference groups had glucometer readings considered to be potentially severe (< 2.8 mmol/l; four and three participants, respectively). The majority of participants who experienced hypoglycaemia had a single occurrence; few participants had ≥ 5 events (five and three participants, respectively) and none had > 9 events over the 20-week study. Most hypoglycaemic events were considered by the investigators to be unrelated to study drug [64/88 (73%) and 37/54 (69%) events]. Discusssion This is, to our knowledge, the first trial of a fixed-dose combination of glimepiride-atorvastatin. We showed that the combination was non-inferior to the two agents taken concomitantly in lowering HbA1c and LDL cholesterol at 20 weeks. The predefined non-inferiority criteria were met for both variables for the per-protocol population (primary analysis) and intention-to-treat population. The observed improvements in glycaemic control and LDL cholesterol are consistent with the effects of glimepiride [9–13 mmol/mol (0.8–1.2%) reduction] and atorvastatin (37–39% reduction) reported in other studies [16–20]. The study duration of 20 weeks was considered adequate to assess change from baseline in efficacy variables [16–18]; ª 2015 Diabetes UK Research article DIABETICMedicine Change in HbA1c (mmol/mol) from baseline Week 20 22 2 0 0 -22 -2 -44 -4 Combination Week 4 Percentage change in LDL cholesterol from baseline (b) Reference Combination Week 10 Change in HbA1c (%) from baseline Week 12 (a) Reference Week 20 50 0 -50 -100 Combination Reference Combination Reference Combination Reference FIGURE 2 Box plots of (a) change from baseline in HbA1c and (b) percentage change from baseline in LDL cholesterol by visit for the per-protocol population. For each plot, the bottom and top of each box are the lower and upper quartiles, respectively; the band inside the box is the median; the open diamond is the mean; the whiskers represent the non-outlier minimum and maximum values (Q1-1.5*IQR and Q3 + 1.5*IQR, where IQR is interquartile range); open circles are outliers. Combination: fixed-dose combination of glimepiride-atorvastatin; Reference: co-administered glimepiride and atorvastatin tablets. however, to allow a stable maintenance period before the final evaluation, the titration schedule for glimepiride was more rapid than typically seen in clinical practice. Incremental increases of glimepiride dose were permitted at 2-weekly intervals up to week 10 if clinically indicated, based on average fasting blood glucose values recorded in the week before the up-titration visit. Approximately 40% of participants in each group were titrated to the highest glimepiride dose of 4 mg, with most receiving this dose from week 6 onwards. Atorvastatin was up-titrated in line with the labelling instructions, with increases at weeks 6 and 12 based on LDL cholesterol levels. ª 2015 Diabetes UK The overall safety profile was generally similar across groups, except that hypoglycaemia was reported more frequently for the combination than for the reference group. Blood glucose was not monitored and recorded systematically in this study. Instead, hypoglycaemic events were selfreported by participants who were trained to perform home blood glucose monitoring and educated to recognize and record the symptoms of such events, or were recorded by investigators when reviewing glucometer readings. Nonetheless, the overall incidence of hypoglycaemia was generally consistent with findings from other recent studies with glimepiride (8–17%) [18,21]. 1089 DIABETICMedicine Fixed-dose combination of glimepiride and atorvastatin for type 2 diabetes  P. Ambery et al. ▲● Hypertension Hypoglycaemia Alanine aminotransferase increased Blood bilirubin increased Aspartate aminotransferase increased Headache Myalgia Bilirubin conjugated increased Upper respiratory tract infection Diarrhoea Nasopharyngitis Pharyngitis ● ▲ ● ▲ ▲ ● ▲ ● ▲● ▲ ● ▲ ● ●▲ ●▲ ●▲ ● 0 ▲ 5 10 15 20 25 Percentage of participants ● Combination (n=215) ■ ■ ■ ■ ■ ■ ■ ■ ■ ■ ■ ■ .25 1 2 4 8 32 Relative risk with 95% CI ▲ Reference (n=212) FIGURE 3 Percentage of participants with the most frequent treatment-emergent adverse events (≥ 3% total incidence) sorted by relative risk for fixed-dose combination vs. reference. Combination: fixed-dose combination of glimepiride-atorvastatin; Reference: coadministered glimepiride and atorvastatin tablets. A relative risk > 1 means that the adverse event occurred more frequently in the combination group and relative risk < 1 means that the adverse event occurred more frequently in the reference group (post hoc analysis). There is no reason to believe that the pharmacokinetics of glimepiride may have influenced the differential rates of hypoglycaemia between the two groups, since the fixed-dose combination has been shown to be bioequivalent to coadministered glimepiride and atorvastatin tablets. Preclinical studies suggest that atorvastatin may increase the bioavailability of glimepiride [22], but if such an interaction occurs in humans it would be expected to affect both groups similarly. Most of the participants with hypoglycaemia had single episodes that were classified as mild, required no pharmacological intervention or change in dosing, and were assessed as unrelated to study drug. Only a small number of participants (four and three in combination and reference groups, respectively) had a blood glucose reading considered to be of potential clinical concern (≤ 2.8 mmol/l). Hypoglycaemic events might be expected after up-titration of glimepiride as a result of increased endogenous insulin production; however, there was no evidence of a dose-related increase in incidence in either group. The observed pattern of single events, or intermittent events days or weeks apart, is more likely to reflect the timing of food intake relative to the glucoselowering effect of glimepiride. Given equivalence on objective measures of glucose and LDL cholesterol control for the combination versus separate tablets, reporting bias with respect to hypoglycaemia is a possibility. Patients instructed to take the combination tablet in this open-label study may well have perceived increased risk of hypoglycaemia, affecting both symptoms of low blood glucose and frequency of monitoring. Unfortunately, frequency of monitoring (use of home blood glucose testing strips) was not recorded. In retrospect, such measurements could have provided important data on the objectivity of home 1090 glucose monitoring. The frequency of monitoring is already well recognized to be a confounder in blood pressure studies, and in cardiac rhythm monitoring in phase I/II clinical trials [23]. Without these data, the assumption of reporting bias (excess recording of hypoglycaemia symptoms, and excess home blood glucose monitoring) cannot be confirmed. The known safety profile of atorvastatin includes skeletal muscle-related effects and liver injury [24,25]. Myalgia was reported with similar incidence in the two groups, and no serious skeletal muscle AEs were reported. Increases in liver transaminases are also reported with statin use. To monitor the effect of atorvastatin, all out of range liver function tests were reported as AEs during the study, irrespective of their clinical significance. Although a higher incidence of liver function test AEs was reported in the combination group than the reference group, a review of the change in liver function tests from baseline showed no difference between groups with respect to clinically significant measurements during the study. A limitation of the study is the open-label design, such that both participants and investigators were aware of the treatment allocation. Whilst this was unlikely to influence the primary efficacy variables, which were objective laboratory assessments, it may have biased subjective assessments such as AE reporting or glucose monitoring by participants [26]. Other limitations are that data are restricted to people with HbA1c of < 80 mmol/mol (< 9.5%); therefore, no inferences can be made for those with severe hyperglycaemia. Additionally, the study was of relatively short duration and not designed to provide long-term data regarding cardiovascular outcomes. Treatment regimens for Type 2 diabetes are becoming more complex with respect to multiple therapies targeting glucose, lipids and blood pressure [1]. Many people with ª 2015 Diabetes UK Research article DIABETICMedicine Maximum normalised value LFTs excluding baseline (a) Combination Reference 4 3 2 1 0 ALT (b) AST Total bilirubin ALT Combination AST Total bilirubin Reference LFTs maximum relative change from baseline 6 5 4 3 2 1 ALT AST Total bilirubin ALT AST Total bilirubin FIGURE 4 Box plots of (a) maximum normalized values for liver function tests, excluding baseline values, by treatment and (b) maximum relative change in liver function tests by treatment. The normalized value is the ratio of the observed value to the upper limit of the normal reference range for that particular local laboratory (e.g. a normalized value of 2 represents an observed value that was twice the upper limit of the normal range). The relative change from baseline was calculated as the ratio of the normalized value at a particular visit/normalized value at baseline. For each plot, the bottom and top of each box are the lower and upper quartiles, respectively; the band inside the box is the median; the open diamond is the mean; the whiskers represent the non-outlier minimum and maximum values (Q1-1.5*IQR and Q3 + 1.5*IQR, where IQR is interquartile range); open circles are outliers. ALT, alanine aminotransferase; AST, aspartate aminotransferase; LFT, liver function test. Combination: fixed-dose combination of glimepiride-atorvastatin; Reference: co-administered glimepiride and atorvastatin tablets. Type 2 diabetes miss their treatment targets [6] and combination therapies offer the potential to improve outcomes by simplifying dosing regimens. Traditionally, cross-indication combination therapies, such as glucose- and lipid-lowering agents, have not featured in regimens for treatment simplification. More studies investigating cross-indication combination products should be encouraged, but where possible they should be blinded. ª 2015 Diabetes UK Funding sources GlaxoSmithKline sponsored the study and provided the funding for the study, development and publishing of the present manuscript. All authors of the study were involved in all stages of study conduct, analysis and interpretation, approved the final version of the manuscript and all agreed to publish the findings of this study. 1091 Fixed-dose combination of glimepiride and atorvastatin for type 2 diabetes  P. Ambery et al. DIABETICMedicine Table 2 Summary of hypoglycaemic events A. Number of participants Combination N = 215 Reference N = 212 Participants reporting at least one 45 (20.9) 27 hypoglycaemic event Serious event 0 0 Drug-related event 12 (5.6) 9 Event with glucometer reading 4 (1.9) 3 ≤ 2.8 mmol/l* Participants with the specified number of events* 1 26 (12.1) 17 2-4 14 (6.5) 7 5-9 5 (2.3) 3 † Participants with at least one event in specified period Within first 4 weeks of 15 (7.0) 14 treatment 4-8 weeks of treatment 10 (4.7) 7 8-12 weeks of treatment 13 (6.0) 8 ≥ 12 weeks of treatment 20 (9.3) 8 B. Number of hypoglycaemic events n = 88 Maximum intensity Mild 84 (95.5) Moderate 4 (4.5) Severe 0 Causality Related 24 (27.3) Not related 64 (72.7) American Diabetes Association Workgroup category Documented symptomatic 37 (42.0) hypoglycaemia Asymptomatic hypoglycaemia 30 (34.1) Probable symptomatic 9 (10.2) hypoglycaemia Relative hypoglycaemia 12 (13.6) Action taken with regard to study drug Study drug withdrawn 0 Dose reduced‡ 0 Dose not changed 88 (100) Dose interrupted 0 (12.7) (4.2) (1.4) (8.0) (3.3) (1.4) (6.6) (3.3) (3.8) (3.8) n = 54 52 (96.3) 2 (3.7) 0 17 (31.5) 37 (68.5) 18 (33.3) 20 (37.0) 4 (7.4) 12 (22.2) 0 5 (9.3) 48 (88.9) 1 (1.9) Data in part A of the table are number and percentage of participants with the event (denominator is total number of participants in each group). Data in part B of the table are number and percentage of events in given category (denominator is total number of hypoglycaemic events in each group). Combination: fixed-dose combination of glimepiride-atorvastatin; Reference: coadministered glimepiride and atorvastatin tablets. *Post hoc analysis. † Subjects are counted in each period within which they had at least one event; if a subject had more than one hypoglycaemic event in a specified period then the subject is counted only once within that period. ‡ One participant in the reference group had five episodes of hypoglycaemia with action of ‘dose reduced’. Dose reductions were not allowed and this participant was excluded from the per protocol population. Competing interests G.A., C.D., L.B.C., A.S., N.H. and K.L. are employees and hold stock/stock options in GlaxoSmithKline. At the time this study was conducted, P.A. was an employee of GlaxoSmithKline; he is now an employee of MedImmune 1092 Ltd and has an honorary contract with Cambridge University Hospitals Trust. K.W.M. has no conflict of interest to disclose. Acknowledgements We thank and acknowledge the participants, investigators and other site personnel who participated in this clinical trial. We thank colleagues at GlaxoSmithKline and Dr Reddy’s Laboratories who supported the development of the glimepiride-atorvastatin fixed-dose combination and DiagnoSearch Life Sciences Pvt. Ltd, Mumbai, India for project management, clinical data management, statistical analysis and writing the clinical study report. Writing assistance for this manuscript was provided by Julie Taylor of Peak Biomedical Ltd, paid for and on behalf of GlaxoSmithKline. References 1 Inzucchi SE, Bergenstal RM, Buse JB, Diamant M, Ferrannini E, Nauck M et al. Management of hyperglycaemia in type 2 diabetes: a patient-centered approach. Position statement of the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD). Diabetologia 2012; 55: 1577–1596. 2 Mazzone T. Intensive glucose lowering and cardiovascular disease prevention in diabetes: reconciling the recent clinical trial data. Circulation 2010; 122: 2201–2211. 3 Mooradian AD. Dyslipidemia in type 2 diabetes mellitus. Nat Clin Pract Endocrinol Metab 2009; 5: 150–159. 4 Stone NJ, Robinson JG, Lichtenstein AH, Bairey Merz CN, Blum CB, Eckel RH et al. 2013 ACC/AHA guideline on the treatment of blood cholesterol to reduce atherosclerotic cardiovascular risk in adults: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines. Circulation 2014; 129: S1–S45. 5 National Institute for Health and Care Excellence. Lipid modification: cardiovascular risk assessment and the modification of blood lipids for the primary and secondary prevention of cardiovascular disease [Guideline CG181]. July 2014. Available at https://www.nice.org. uk/guidance/cg181/resources/guidance-lipid-modification-cardiovas cular-risk-assessment-and-the-modification-of-blood-lipids-for-theprimary-and-secondary-prevention-of-cardiovascular-disease-pdf Last accessed 17 November 2014. 6 Ali MK, Bullard KM, Saaddine JB, Cowie CC, Imperatore G, Gregg EW. Achievement of goals in U.S. diabetes care, 1999-2010. N Engl J Med 2013; 368: 1613–1624. 7 Pan F, Chernew ME, Fendrick AM. Impact of fixed-dose combination drugs on adherence to prescription medications. J Gen Intern Med 2008; 23: 611–614. 8 Cheong C, Barner JC, Lawson KA, Johnsrud MT. Patient adherence and reimbursement amount for antidiabetic fixed-dose combination products compared with dual therapy among Texas Medicaid recipients. Clin Ther 2008; 30: 1893–1907. 9 Thayer S, Arondekar B, Harley C, Darkow TE. Adherence to a fixed dose combination of rosiglitazone glimepiride in subjects switching from monotherapy or dual therapy with a thiazolidinedione and or a sulfonylurea. Ann Pharmacother 2010; 44: 791– 799. 10 Langtry HD, Balfour JA. Glimepiride. A review of its use in the management of type 2 diabetes mellitus. Drugs 1998; 55: 563–584. 11 Colhoun HM, Betteridge DJ, Durrington PN, Hitman GA, Neil HA, Livingstone SJ et al. Primary prevention of cardiovascular ª 2015 Diabetes UK Research article 12 13 14 15 16 17 18 19 disease with atorvastatin in type 2 diabetes in the Collaborative Atorvastatin Diabetes Study (CARDS): multicentre randomised placebo-controlled trial. Lancet 2004; 364: 685–696. Sever PS, Dahl€ of B, Poulter NR, Wedel H, Beevers G, Caulfield M et al. Prevention of coronary and stroke events with atorvastatin in hypertensive patients who have average or lower-than-average cholesterol concentrations, in the Anglo-Scandinavian Cardiac Outcomes Trial-Lipid Lowering Arm (ASCOT-LLA): a multicentre randomised controlled trial. Lancet 2003; 361: 1149–1158. Diabetes Association Workgroup on Hypoglycemia. Defining and reporting hypoglycemia in diabetes: a report from the American Workgroup on Hypoglycemia, American Diabetes Association. Diabetes Care 2005; 28: 1245–1249. Food and Drug Administration. Draft Guidance for Industry: Diabetes Mellitus: developing drugs and therapeutic biologics for treatment and prevention. Centre for Drug Evaluation and Research (CDER), USA; 2008. Available at http://www.fda.gov/downloads/Drugs/Guidances/ucm071624.pdf. Last accessed 17 November 2014. Ahmad H, Cheng-Lai A. Pitavastatin a new HMG CoA reductase inhibitor for the treatment of hypercholesterolemia. Cardiol Rev 2010; 18: 264–267. McKenney J, Ballantyne CM, Feldman TA, Brady WE, Shah A, Davies MJ et al. LDL-C goal attainment with ezetimibe plus simvastatin coadministration vs atorvastatin or simvastatin monotherapy in patients at high risk of CHD. Med Gen Med 2005; 7: 3. Park JS, Kim YJ, Choi JY, Kim YN, Hong TJ, Kim DS et al. Comparative study of low doses of rosuvastatin and atorvastatin on lipid and glycemic control in patients with metabolic syndrome and hypercholesterolemia. Korean J Intern Med 2010; 25: 27–35. Srivastava S, Saxena GN, Keshwani P, Gupta R. Comparing the efficacy and safety profile of sitagliptin versus glimepiride in patients of type 2 diabetes mellitus inadequately controlled with metformin alone. J Assoc Physicians India 2012; 60: 27–30. Charpentier G, Fleury F, Kabir M, Vaur L, Halimi S. Improved glycaemic control by addition of glimepiride to metformin ª 2015 Diabetes UK DIABETICMedicine 20 21 22 23 24 25 26 monotherapy in Type 2 diabetic patients. Diabet Med 2001; 18: 828–834. Cefalu WT, Leiter LA, Yoon K, Arias P, Niskanen L, Xie J et al. Efficacy and safety of canagliflozin versus glimepiride in patients with type 2 diabetes inadequately controlled with metformin (CANATA-SU): 52 week results from a randomised, double blind, phase 3 non- inferiority trial. Lancet 2013; 382: 941–950. Nauck M, Frid A, Hermansen K, Shah NS, Tankova T, Mitha IH et al. Efficacy and safety comparison of liraglutide, glimepiride, and placebo, all in combination with metformin, in type 2 diabetes: the LEAD (liraglutide effect and action in diabetes)-2 study. Diabetes Care 2009; 32: 84–90. Galani V, Vyas M. In vivo and in vitro drug interactions study of glimepride with atorvastatin and rosuvastatin. J Young Pharm 2010; 2: 196–200. Myers MG, Stergiou GS. Reporting bias: Achilles’ heel of home blood pressure monitoring. J Am Soc Hypertens 2014; 8: 350–357. Bruckert E, Hayem G, Dejager S, Yau C, Begaud B. Mild to moderate muscular symptoms with high-dosage statin therapy in hyperlipidemic patients–the PRIMO study. Cardiovasc Drugs Ther 2005; 19: 403–414. Clarke AT, Mills PR. Atorvastatin associated liver disease. Dig Liver Dis 2006; 38: 772–777. Wood L, Egger M, Gluud LL, Schulz KF, J€ uni P, Altman DG et al. Empirical evidence of bias in treatment effect estimates in controlled trials with different interventions and outcomes: metaepidemiological study. BMJ 2008; 336: 601–605. Supporting Information Additional Supporting Information may be found in the online version of this article: Table S1. Dose at the end of the 20-week treatment period or the time of premature discontinuation. 1093 introduction Study objective Authors affiliation/study support Method/study design Methods – Patients/Subjects -How enrolled/from where? -Inclusion/exclusion criteria -# enrolled per group -Inclusion/exclusion criteria -# enrolled per group Methods – Treatment Regimen -Treatments used Dosages/administration -Therapy duration Methods – Outcome Measures -Primary measures -Secondary measures Methods – Data Handling -Intention to treat, per protocol, etc. -# lost to follow-up -Reasons for dropouts Methods – Statistics -Tests used -Power of study • Confidence interval measures • What is needed to be seen to be considered non inferior • Can be considered non inferior because 1.9 is less than 3.3 • Based analysis on the people that obeyed the rules of the study • Sensitivity analysis to look at are the reults still the same • Intent to treat also done Results -Results for each outcome measure Confidence intervals -P-values -Compliance Adverse effects Conclusion – Authors’ conclusion Study strengths Study weaknesses My conclusion is this study a good study? Clinical applicability PHAR 9942 / PSCI 6602 JOURNAL CLUB ACTIVITY GRADING EVALUATION Presenter:_______________________________________________ Date:_____________ Reviewer:_______________________________________________ STYLE / PRESENTATION 2 points Presentation Exhibited professional appearance and demeanor, and spoke clearly throughout the presentation Mannerisms Eye Contact Slides Handout TOTAL Comments Adapted from Am J Pharm Educ. 2007;71(4):Article 63. 1 point SOMEWHAT exhibited professional appearance and demeanor, was difficult to hear or understand SOME things spoken Few (or no) distracting mannerisms (e.g., um) Maintained eye contact throughout the presentation Slides were organized, easy to read, and aesthetically pleasing Handout was organized, easy to read, and aesthetically pleasing 0 points Did NOT exhibit professional appearance and demeanor, was difficult to hear or understand MOST things spoken Score /2 Had distracting mannerisms /1 Did NOT maintain eye contact /1 Slides were NOT organized and difficult to read Handout was NOT organized and difficult to read /1 /1 /6 PHAR 9942 / PSCI 6602 JOURNAL CLUB ACTIVITY GRADING EVALUATION CONTENT / CRITICAL EVALUATION Study Overview Introduction - Authors’ affiliations/study support - Study objective(s) & rationale Methods – Design - Case-control, cohort, controlled experiment, etc. - Type of design (cross-over, parallel, etc.) - Type of assignment used - Blinding Methods – Patients/Subjects - How enrolled/from where? - Inclusion/exclusion criteria - # enrolled per group Methods – Treatment Regimen - Treatments used - Dosages/administration - Therapy duration Methods – Outcome Measures - Primary measures - Secondary measures Methods – Data Handling - Intention to treat, per protocol, etc. - # lost to follow-up - Reasons for dropouts Methods – Statistics - Tests used - Power of study Results - Results for each outcome measure - Confidence intervals - P-values - Compliance - Adverse effects Conclusion – Authors’ conclusion Adapted from Am J Pharm Educ. 2007;71(4):Article 63. 2 points 1 point 0 points Score Accurately and completely reported ALL relevant introduction, study design, and patients/subject components Accurately and completely reported MOST of the relevant introduction, study design, and patients/subject components Did NOT accurately and completely report most of the relevant introduction, study design, and patients/subject components /2 Accurately and completely reported ALL relevant treatment regimens, outcome measures, and data handling components Accurately and completely reported MOST of the relevant treatment regimens, outcome measures, and data handling components Did NOT accurately and completely most of the relevant treatment regimens, outcome measures, and data handling components /2 Accurately and completely reported ALL relevant statistics, results, and authors’ conclusion components Accurately and completely reported MOST of the relevant statistics, results, and authors’ conclusion components Did NOT accurately and completely most of the relevant statistics, results, and authors’ conclusion components /2 PHAR 9942 / PSCI 6602 JOURNAL CLUB ACTIVITY GRADING EVALUATION STUDY OVERVIEW TOTAL /6 Comments Analysis Analyzed all parts of study 4 points ALL parts appropriately critiqued with ALL relevant questions accurately addressed with strengths, weaknesses and their impact described 3 points Missed only ONE or TWO considerations or relevant questions in critique, with the rest appropriately addressed with strengths, weaknesses, and their impact described TOTAL Comments Adapted from Am J Pharm Educ. 2007;71(4):Article 63. 2 points 1 point 0 points MOST parts appropriately critiqued, some relevant questions with strengths, weaknesses, and their impact overlooked or inaccurate Only SOME parts appropriately critiqued, most relevant questions with strengths, weaknesses, and their impact overlooked or inaccurate Failed to appropriately critique any part, all relevant questions with strengths, weaknesses, and their impact overlooked or inaccurate Score /4 PHAR 9942 / PSCI 6602 JOURNAL CLUB ACTIVITY GRADING EVALUATION Conclusion Clear, concise conclusion stated 1 point Summarized accurately & completely: key points to be taken from study (which reflected limitations), drug’s role in therapy or clinical practice implications, and need for any further research in area 0 points Did NOT summarize accurately & completely a conclusion OR conclusion completely inaccurate TOTAL Comments Preparedness Response to questions TOTAL Comments Score /1 /1 1 point Correctly answered questions in a confident manner STYLE / PRESENTATION TOTAL POINTS: Score /1 /1 ______/6 CONTENT / CRITICAL EVALUATION TOTAL POINTS: ______/12 Adapted from Am J Pharm Educ. 2007;71(4):Article 63. 0 points Did NOT correctly answer questions OR handled questions unprofessionally
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introduction
Type 2 Diabetes is a type of illness that fundamentally requires a lot of management, care and support. It is
essentially advisable that step by step approach is entirely recommended and this should be able to start by
providing best piece of advice concerning diet intake, weight reduction and most importantly undertaking
exercises. It is also important to note that if the glucose interventions are not able to be met by the lifestyle
then it clearly means that the treatment of Metformin is highly recommended.

Study objective


The main objective is to essentially evaluate particularly in a randomized
manner when it comes to non-inferiority of bioequivalent dose that is fixed.
The dose combination should be that of atorvastatin and glimepiride verses
tablets that are separately co-administered in people with Type 2 diabetes
Mellitus

Authors affiliation/study support


GlaxoSmithKline were able to sponsor the study and they provided the
funding that was very important for the study, They also ensured the
development and the publication of the manuscript. All the authors of the
study were entirely involved in entirely all the stages of the study conduct,
interpretation, analysis, approving of the final manuscript and finally
publishing the finds of the same study.

Method/study design


It is important to note that this is a randomized, open-label, parallel group
and two arm study that was conducted in six diverse countries specifically ...


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