Use Of A Combination Glimepiride & Atorvastatin Tablet On Diabetes Patients

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JOURNAL CLUB BACKGROUND AND OVERVIEW Article title/citation Study objectives/purpose Brief background Funding sources METHODS Study design and methodology Patient selection & enrollment Outcome measures/endpoints RESULTS Summary of study results DISCUSSION Brief summary of authors’ main discussion points Study strengths Study limitations Applicability & impact CONCLUSIONS Authors’ conclusions Evaluator’s conclusions Take home points Open-label randomized non-inferiority trial of a fixeddose combination of glimepiride and atorvastatin for the treatment of people whose Type 2 diabetes is uncontrolled on metformin Claire Colgrove 3/29/19 Publication Ambery P, Stylianou A, Atkinson G, et al. Glimepiride/Atorvastatin Investigational Team. 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. Diabetic Med. 2016. 33(8):1084-93. Funding source GlaxoSmithKline sponsored and provided the funding, development and publishing of the study. Background  People with type 2 diabetes have an increased risk of cardiovascular disease and are at increased risk for hypertension.  Treatment guidelines recommend anti-hypertensives and lipid-lowering therapy for most people with type 2 diabetes.  Nearly half the people surveyed in a national surveillance program in the US didn’t meet their recommended goals for glycemic control, blood pressure and lipids due to issues with compliance.  A previous study in healthy individuals, the glimepiride-atorvastatin formulation was shown to be bioequivalent to separately administered glimepiride and atorvastatin tablets, in terms of rate and extent of exposure. Objective The goal of the study was to demonstrate if the use of a combination Glimepiride/Atorvastatin tablet was just as efficacious as taking both drugs as separate tablets in improving glucose control and lipid profiles in Type 2 diabetes. Methods  Open-label, randomized, two-arm, parallel group study  Conducted between December 2011 – September 2013  20 week study  Conducted at 33 different centers in six different countries including Malaysia, Mexico, Philippines, Russia, South Korea and Thailand Inclusion Criteria Men and women aged 18 years or older with type 2 diabetes Must be on a stable dose of metformin for 3 months or longer Must have an HbA1c between 7.0 – 9.5 Must have an average blood glucose greater than 7.0 mmol/L, taken on 4 days out of the week Must not have used a statin within 2 months prior to screening and be eligible for statin therapy Exclusion Criteria Patients who were on other lipid–lowering or anti-diabetic agents other than metformin Type 1 diabetics or those who are in need of insulin therapy Patients who have concurrent myalgia Patients who have symptomatic hyperglycemia requiring therapy Patients who have hypertriglyceridemia Exclusion Criteria Continued Patients who have clinically significant cardiovascular disease Patients that have end stage renal disease Patients who have had cancer within the past 3 years Patients who show signs of abnormality on physical examination or laboratory tests Patients who are receiving drug therapy for liver disease Exclusion Criteria Continued  Patients that are receiving anti-viral/immunosuppressive therapy  Patients who have hemoglobinopathy that could interfere with the assessment of HbA1c  Patients who have hereditary lactose intolerance, a lactase deficiency or glucose-galactose malabsorption. Procedure  Patients were assigned (1:1) using an interactive web response system to receive either the fixed dose combination of glimepirideatorvastatin or the co-administration of glimepiride and atorvastatin once daily for 20 weeks.  Manufacture of the combination tablets was Dr. Reddy’s (1/10 mg, 2/10 mg, 3/10 mg, 4/10 mg, 1/20 mg, 2/20 mg, 3/20 mg and 4/20 mg)  Glimepiride (1, 2, 3 and 4 mg) and atorvastatin (10 and 20 mg) tablets were sourced from suppliers such as Sanofi and Pfizer Procedure Continued  All participants started on 10 mg atorvastatin and 1 mg glimepiride, either as combination or separate tablets  Participants were told to take the medication before or during breakfast or before their most substantial meal of the day  Glimepiride was up-titrated at weeks 2, 4, 6 and 10 if average fasting blood glucose was greater than 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 depending on if their LDL cholesterol was greater than 2.6 mmol/L.  Participants who required down-titration of their dose had to be withdrawn from the study, since the goal was to assess titration at higher doses. Assessments Co-primary efficacy endpoint  Baseline to week 20 change in HbA1c  Baseline to week 20 percent change in LDL cholesterol Secondary efficacy endpoint Baseline to week 12 change for HbA1c Baseline to 4 & 10 weeks percent change for LDL cholesterol Safety assessments Monitoring liver functions, hypoglycaemia and adverse events (AEs) Results were collected, analyzed and reported appropriately drug compliance was determined by counting returned tablets Statistical Methods  A 95% CI (two sided) for the co-primary endpoint differences was the basis of non-inferiority assessment.  < 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  Size of evaluable participants-191  Group power for HbA1c baseline comparison - 90%  LDL cholesterol baseline comparison power- 83%  Significance level of one sided test- 2.5% Statistical methods Results Study population  Total randomized participants- 427  Rate of study completion – 92 %  Pre-protocol inclusion HbA1c analysis - more than 90% of participants Reasons for Pre-protocol population exclusion  Incorrect titration of dose  Insufficient treatment compliance  Drug compliance Compliance with drug was 98% for each group  Use of non-inferiority hypothesis proved there was no advantage for taking separate agents as opposed to the two Participants Number of total patients: 427 Fixed dose combination of glimepiride-atorvastatin patients: 215 Co-administration of glimepiride and atorvastatin: 212 Selection Criteria Study Population Characteristic of study population in the two groups Matching baselines Matching demographic Average age of 57-58  59 & 64 % women predominance Efficacy secondary endpoint  Baseline to week 20 decreases for HbA1c and LDL cholesterol were recorded  At week 20, a combination of non-inferior to co-administered glimepiride with atorvastatin for the two co-primary endpoints  An LS mean change of 7.4 (95% CI 8.7, 6.2) mmol/mol [0.68 (95% CI 0.80, 0.57) %] in the population per-protocol was observed for HbA1c baseline to week 20  For referece and combination group, 7.5 (95% CI 8.7, 6.2) mmol/mol [0.69 (95 % CI 0.80, 0.57)%] LS mean change was observed The two-sided CI of 95% was less than Safety Secondary  Participants in Both groups experienced treatment emergent AEs( 64 and 61% for combination and reference group)  Drug related AEs as assessed were 9% & 11%  Only 1% of participants in combination group experienced non-fatal serious effects (SAEs)  3% of the participants in reference group had the (SAEs)  One participant succumbed to pancreatic carcinoma (from the reference group)  No (SAEs) could be directly linked to the drug study  Liver functions abnormalities were most common AEs Author’s Conclusion  The administration of the combined tablets is non-inferior to separate administration  There was consistency in safety levels in drug under tests and glimepiride, atorvastatin known profiles  The high levels of hyperglaecaemia on the combination cannot be explained  However, the observation can be attributed to reporting bias influence and collection of glucose in non-systematic manner Limitations  Use of Open-label design- investigators and participants had knowledge of treatment allocation  Data collection did not cover people with severe hyperglycemia  Study conducted in shorter time compared to other studies of same magnitude  Design of study could not support collection of long-term data to study outcomes of cardiovascular condition Discussion  The results obtained demonstrated administration of the combined agents is non-inferior to separate doses in decreasing LDL and HbA1c cholesterol levels by week 20  The study met the criteria of predefined for intention-to-treat and perprotocol population variables  Glycaemic and LDL cholesterol control improvement concurs with glimepiride and atorvastatin effects reported in other studies  The treatment time of 20 weeks was adequate for period of stable maintenance Study Strengths  The study met the objective of demonstrating that administration of the combined agents is non-inferior to separate doses in decreasing LDL and HbA1c cholesterol levels by week 20  The study met the criteria of predefined for intention-to-treat and per-protocol population variables  The Glycaemic and LDL cholesterol control improvement concurs with glimepiride and atorvastatin effects reported in other studies Study Weaknesses  Reported fatality in the course of study  There are conflicting interests in some of the researchers involved in the study  They didn’t use the same manufacturer between treatment groups  Unexplained high levels of hyperglaecaemia Conclusion/Clinical Applicability  The combined administration of the two medicine is clinically viable for several reasons:  The combination was found to be non-inferior to separate administration  Safety levels for the combined administration of the drugs is within acceptable limits  Improvement recoded in reduction of both Glycaemic and LDL cholesterol is in agreement with atorvastatin and glimepiride effects ...
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Journal Club
Article Title/Citation

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
Study/objectives/purpose The goal of the study was to demonstrate if the use of a combination
Glimepiride/Atorvastatin tablet was just as efficacious as taking both
drugs as separate tablets in improving glucose control and lipid profiles
in Type 2 diabetes.
Brief background
 People with type 2 diabetes have an increased risk of
cardiovascular disease and are at increased risk for
hypertension.
 Treatment guidelines recommend anti-hypertensives and lipidlowering therapy for most people with type 2 diabetes.
 Nearly half the people surveyed in a national surveillance
program in the US didn’t meet their recommended goals for
glycemic control, blood pressure and lipids due to issues with
compliance.
 A previous study in healthy individuals, the glimepirideatorvastatin formulation was shown to be bioequivalent to
separately administered glimepiride and atorvastatin tablets,
in terms of rate and extent of exposure.
Funding sources

 GlaxoSmith...

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Review

Anonymous
Thanks, good work

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