JoAnn Sandra Koslowsky, RPh. 11/16/10 Journal Club1). The introduction is appropriate in length. It is not too short or too long. It containsrelevant information to the study and what is described in the article itself.2). The study objectives and hypothesis are clearly stated. They tell you that thecomparison of thiazolidinediones with other oral glucose-lowering agents is not known.These are meaningful and important, as they state in the introduction, in diabetics to helpprevent complications of type 2 diabetes.3). The study was experimental in design, as it was a randomized, double-blind controlledtrial. This design is appropriate for the question being investigated.4). The strengths of an experimental study are that there is a minimal chance of outsidefactors being responsible for the outcomes. Accurate comparisons and conclusions can bemade because investigators can control the exposure of treatment and interventions. Theweaknesses of an experimental study are that the study can be expensive and patientenrollment and long term follow-up can be difficult.5). The study population was well defined and included patients who had not previouslyreceived medication for their recently diagnosed (within 3 years) type 2 diabetes. Theywere predominately white, middle-aged males and females who were obese.6). The inclusion data was patient age between 30-75, fasting glucose levels between126-180 mg/dl, with their only treatment being lifestyle management. The exclusion dataincluded significant hepatic disease, renal impairment, CHF, uncontrolled hypertension,history of lactic acidosis and unstable or severe angina. Both inclusion and exclusion dataare clear and appropriate.7). The patients were selected based on age, fasting plasma glucose levels and currenttreatment of the type 2 diabetes.8). Patients were classified as newly diagnosed (within 3 years) type 2 diabetes.9). Selection bias is possible but was minimized by allowing everyone to have an equalchance in being placed in any of the three groups. There are no differences between thethree groups, except what intervention they were given.10). The patients were centrally randomized, which was concealed and stratifiedaccording to the sex of the patients, in blocks of six. This process was clearly explainedand is appropriate.
11). Patient disease and risk factors were considered during the randomization process.Patients were excluded based on hepatic disease, renal impairment, history of lacticacidosis, CHF and unstable or severe angina. I do agree that these patients should havebeen excluded from the study.12). The initial intervention was either 4mg of rosiglitazone, 500mg of metformin or2.5mg of glyburide, all given once daily. Each drug was increased, per protocol, to themaximum effective dose of 4mg rosiglitazone twice daily, 1000mg metformin twice dailyand 7.5mg glyburide twice daily. The drug, dose and route are all mentioned and they areappropriate drugs and doses.13). There were two active control groups which were drugs (metformin and glyburide)that had established efficacy and the results of these two groups were compared to thestudy group (rosiglitazone).14). Compliance is assessed and noted that 9 patients were excluded who did not receivethe drug and 224 patients who withdrew before the first scheduled evaluation of efficacy.15). It was a double-blind study so both the patients and investigators were unaware ofwhich patients received what treatment. Preparation was done at a central location and alldrugs were prepared in identical capsules, so no one could tell them apart.16). The primary outcome was the time to monotherapy failure on the basis of glucoselevels of greater than 180 mg/dl, after an overnight fast. I do believe that all importantoutcomes were considered. Secondary outcomes were fasting glucose levels, glycatedhemoglobin levels, weight, insulin sensitivity and beta-cell function.17). The measures used to evaluate the outcomes were adequately described. The primaryoutcome measurement was fasting plasma glucose levels. The secondary measurementswere glycated hemoglobin, beta-cell function, weight, waist circumference, hipcircumference and waist-to-hip ratio.18). The patients were followed every two months in the first year and every threemonths thereafter. The blood draws were in person. I believe the frequency wasappropriate. If the blood draws were more often, patients may have dropped out due toinconvenience.19). The length of the study was a median period of four years, which was an appropriateamount of time to answer the study’s question.20). The measures are appropriate. The measurements used are the standard of care forpatients with type 2 diabetes. The data used to measure the outcomes was objective andnot subjective. I believe the measures are reproducible.
21). There were steps taken in the study to reduce observer bias. Using objective data tomeasure the outcomes is one example. Another was the use of an independentadjudication committee, whose members were unaware of treatment assignments, todetermine if the primary outcome was reached. They used prespecified criteria todetermine this.22). There is no information bias in this study.23). Recall bias is not an issue in this study because the patients were not used as sourcesor information.24). There are sources of confounding bias. The study took measures to minimize thesesuch as having exclusion criteria, having patients be equal at baseline, by double-blindingand by randomization that was concealed and stratified.25). The statistical test, ANOVA, was described adequately and the appropriate data,which was continuous, was used in this study.26). The sample size, power and level of significance have been described. The initialenrollment of 3600 patients was amended and increased to 4182 patients, to compensatefor a higher anticipated rate of withdrawal. This number of 4182 patients was needed toachieve power. Risk reduction, cumulative index and P values were reported for all threegroups and they were all appropriate.27). The data was analyzed on an intent-to-treat basis. The analysis was strong because itaccounted for the question of why patients dropped out of the study. There were not anynegatives associated with this analysis because the investigators increased the patientenrollment due to the initial high drop out rate.28). All the patients enrolled in the study have been accounted for. The number ofdropouts, which was 224, was accounted for by the investigators for a primary reason ofadverse events.29). The study evaluated 4351 patients which is an adequate number of patients studied.30). The patient demographics represented in this study were middle-aged, obese andpredominately white males and females. There demographics are representative of thosepatients who would have type 2 diabetes. The groups did not have any significantdifferences in baseline variables.31). The primary outcome of the study showed that the number of patients who failedmonotherapy at five years was least with rosiglitazone. All outcomes are discussed suchas monotherapy failure, risk (incidence) reduction, treatment effect among older patientsand those with larger waist circumference, rate of progression to a confirmed fastingglucose level greater than 140 mg/dl and glycemic measures.
32). The results are presented appropriately. The authors used four tables and one graphto represent baseline characteristics, primary outcomes, secondary outcomes and adverseevents.33). The safety of the intervention was discussed. The authors mentioned CHF events,edema, GI effects, alanine aminotransferase levels, hematocrit levels and LDL levels.34). The authors do discuss limitations of the study, such as the high rate of withdrawalof patients. They do a good job of discussing this limitation and its implications. I do notsee any other limitations of the study.35). The author’s conclusions are consistent with the results. They concluded thatrosiglitazone delayed monotherapy failure better than metformin and gluburide. Theresults of patients who failed monotherapy support this conclusion.36). I do feel that the abstract does support the article, although there was no mention ofthe safety concerns of the thiazolidinedione, as was mentioned in the discussion part ofthe article.37). This article was published in the New England Journal of Medicine, which is areputable and peer-reviewed journal.38). The study was funded by grants from GlaxoSmithKline (GSK). The role of GSK inthis study was discussed. Two of the seven members of the study oversight steeringcommittee were from GSK. The sponsor, GSK, imposed no restrictions in the decision topublish the article, which did minimize their role.39). The study does have internal validity. The results given in the primary outcomesection of the article support the authors conclusion in the discussion that rosiglitazoneslowed progression to monotherapy failure better than metformin and glyburide.40). The study does have external validity. I believe there are many patient’s in thegeneral population, with type 2 diabetes, who have similar baseline characteristics topatients in this study. Therefore, there are numerous people who can benefit from using athiazolidinedione as first line choice monotherapy in the treatment of type 2 diabetes.41). The results are meaningful and important. The study shows that the use ofrosiglitazone can delay loss of glycemic control better than metformin or glyburide. Thiswould change my practice when consulted about monotherapy for patients with type 2diabetes, who fell into the same category as patients in this study. I would recommend athiazolidinedione as a first choice of therapy.
I believe this study was strong and well designed. The investigators posed and researchedan intervention that can be considered critical in the care of patients with type 2 diabetes.They adequately assessed the information revealed in the study for relevance, validityand importance. They used and experimental design which is considered the “Cadillac”of studies, although difficult and costly. I feel that the number of years the patients werefollowed was certainly a long enough period of time. The investigators used a largenumber of patients in their study and the selection and allocation process was perfectlyfine. Randomization and double-blinding is something we like to see in a study and wasused here. There was limited bias throughout the study and although it was sponsored byGlaxoSmithKline, the drug company had limited input into the publication of the study. Ibelieve the investigators did an excellent job in following through on a well-planned andthough out study. Overall, I think the study was very good and reflective of anintervention that can be very helpful to the current population, for which type 2 diabetesis very common.