Combination Of Glimepiride And Atorvastatin For The Treatment Of Diabetes

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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 ...
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