Risk of Death and Cardiovascular Outcomes with Thiazolidinediones: A Study with the General Practice Research Database and Secondary Care Data

Abstract

ObjectiveTo describe the likely extent of confounding in evaluating the risks of cardiovascular (CV) events and mortality in patients using diabetes medication.MethodsThe General Practice Research Database was used to identify inception cohorts of insulin and different oral antidiabetics. An analysis of bias and incidence of mortality, acute coronary syndrome, stroke and heart failure were analysed in GPRD, Hospital Episode Statistics and death certificates.Results206,940 patients were identified. The bias analysis showed that past thiazolidinedione users had a lower mortality risk compared to past metformin users. There were no differences between past users of rosiglitazone and pioglitazone (adjusted RR of 1.04; 95% CI 0.93–1.18). Current rosiglitazone users had an increased risk of death (adjusted RR 1.20; 95% CI 1.08–1.34) and of hospitalisation for heart failure (adjusted RR of 1.73; 95% CI 1.19–2.51) compared to current pioglitazone users. Risk of mortality was increased two-fold shortly after starting rosiglitazone. Excess risk of death over 3 years with rosiglitazone was 0.3 per 100 in those aged 50–64 years, 2.0 aged 65–74, 3.0 aged 75–84, and 7.0 aged 85+. The cause of death with rosiglitazone was more likely to be due to a disease of the circulatory system.ConclusionsHigher risks for death (overall and due to cardiovascular disease) and heart failure were found for rosiglitazone compared to pioglitazone. These excess risks were largest in patients aged 65 years or older. The European regulatory decision to suspend rosiglitazone is supported by this study.

Antihyperglycemic Medication Use Among Medicare Beneficiaries With Heart Failure, Diabetes Mellitus, and Chronic Kidney Disease

“…Thiazolidinediones have been shown to increase risk of heart failure in case reports from as early as 2002, which has been supported by clinical trial and observational data and led to an FDA issued black box warning in 2007 against their use in heart failure patients. 5, 21-24 Observational studies suggest that insulin and sulfonylureas may be associated with higher risks for fluid retention and heart failure respectively, and the initial results of the FIGHT trial suggest that liraglutide provides no cardiovascular outcome benefit to heart failure patients. 25-27 Recently, heart failure risk with DPP4 inhibitors has been rigorously studied, with one study showing no increased risk of heart failure (TECOS – Trial Evaluating Cardiovascular Outcomes with Sitagliptin) and two showing neutral to higher risk (EXAMINE – Examination of cArdiovascular outcoMes with alogliptIN vs standard of carE in patients with type 2 diabetes and acute coronary syndrome and SAVOR-TIMI 53 – Saxagliptin Assesment of Vascular Outcomes Recorded in Patients with Diabetes Mellitus).…”

The peroxisome-proliferator activated receptor-γ agonist pioglitazone modulates aberrant T cell responses in systemic lupus erythematosus

“…Given the significantly increased cardiovascular risk that has been well described in SLE[42, 43], identifying a therapy with potential dual roles in the control of aberrant adaptive immune responses and cardiovascular damage is very attractive in this disease. However, moving forward with the possibility of exploring the role of TZDs in lupus activity, it will be important to be cautious, given the potential risk that these agents may pose with regards to heart failure, bladder cancer and disruptions in bone biology, as described in other patient groups[44-46]. Indeed, newer compounds are being explored and may prove particularly effective and safer in the future.…”

Pattern of risks of systemic lupus erythematosus among statin users: a population-based cohort study

“…Each prescription length was calculated by dividing the number of prescribed tablets by the prescribed daily dose. Since statin therapy compliance declines substantially over time,17 the time of follow-up was divided into periods of current, recent and past exposure to statins, with patients moving between these three exposure categories over time 18. Current exposure was defined as the time from the date of a prescription until 3 months after its expected duration of use.…”