Literature Review Regarding Cardiovascular Risk Associated With Rosiglitazone Biology Essay

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Rosiglitazone belongs to a class of drugs referred to as thiazolidinesdiones which are antidiabetic drugs. They enhance the response of tissues to insulin (Rang, Dale & Ritter, 1999).This drug is used to treat type two diabetes mellitus and it is currently being marketed by GlaxoSmithKline. Rosiglitazone is an agonist (drugs that activate receptors by producing a conformational change to the receptors) which acts on peroxisome proliferator activated receptor γ (PPAR-γ). The function of this receptor includes gene expression modulation, blood glucose reduction as a result of increased sensitivity for insulin in the peripheral tissues (Vamecq& Latruffe, 1999 and Campbell, 2005).

Type 2 diabetes is increasing in prevalence. Mortality from cardiovascular disease ranges from two fold to eight fold higher in people with diabetes compared to those without diabetes (Lago, Singh &Nesto, 2007). There have been controversial articles written about the increased risk of myocardial infarction associated with rosigligtazone. These article will be looking at evidence provided from key randomised clinical trials and observational studies with regards to the cardiovascular safety of rosiglitazone.

Clinical Trial Data

Three key studies were identified during literature screening. These studies included ADOPT, RECORD and DREAM trials which are discussed below:

ADOPT [A Diabetes Outcome Progression Trial] (Viberti et al., 2002)

This study was a prospective randomised controlled trial that was developed to compare the efficacy of rosiglitazone, gylburide and metformin, three antidiabetic agents that are currently available as first line treatment of type 2 diabetes with regards to their glucose control, β- cell function and cardiovascular risk. The study population was aged between 30-75 years diagnosed with type 2 diabetes within 3 years of study screening. The study design comprises of a pre-screening phase, screening phase, a run in period which was four weeks and a treatment period of 4 years. This study showed that the rate of congestive heart failure associated with rosiglitazone as compared to metformin was similar (at 95% confidence interval 0.66, 1.38, the hazard ratio was 0.96) and the rate of congestive heart failure associated with rosiglitazone as compared to gylburide was higher (statistically significant) at 95% Confidence interval 0.78, 1.73, the hazard ratio was 1.16 (Kahn et al., 2006).

Study Limitation:

Kahn et al (2006) did state that the "study was not designed to evaluate cardiovascular disease outcomes as the protocol excluded patients with known history of congestive heart failure" (p2440). At the end of this trial, heart failure was the only outcome that was reviewed and also the study was limited by the withdrawal rate.

RECORD [The Rosiglitazone Evaluated for Cardiac Outcomes and Regulation of Glycaemia in Diabetes] (Home et al., 2007)

This study was conducted in response to a recent meta analysis by Nissen & Wolski (2007) who raised concern about the increased risk of myocardial infarction and death from cardiovascular causes linked to rosiglitazone use in the treatment of type 2 diabetes. This study was a randomised, multicenter open label noninferiority trial in which patients with type 2 diabetes with inadequate glucose control with metformin or sulfonylurea alone where randomly allocated rosiglitazone or combination of metformin or sulfonylurea. The primary outcome of this study was hospitalisation or death from a cardiovascular cause. The study population included patients with age ranging from 40 to 75 years involving patients with type 2 diabetes. This revealed that rosiglitazone was linked to a small non significant increase in the risk of the primary outcome. The hazard ratio was 1.08 (95% confidence interval, 0.89 to 1.31). Home et al (2007)states that "there was no statistically significant difference between the rosiglitazone group and the control group for the secondary end points for acute myocardial infarction, fatal cardiovascular death and stroke" (p28). The hazard ratio for fatal cardiovascular causes was 0.80 (95% CI, 0.52 to 1.24). These results were essential in answering the Nissen & Wolski safety analysis concern (Home et al, 2007).

Study Limitations

The fact that the trial was open label was a limitation. The study drug randomisation was not concealed. In addition, the primary outcome compositing all hospitalisations and deaths from a cardiovascular cause was a weak choice for the study design.

DREAM TRIAL [Diabetes Reduction Assessment with ramipril and rosiglitazone medications] (Dagenais, 2008)

This study looked at the effect of ramipril and rosiglitazone on the cardiovascular and renal outcomes in people with hampered glucose tolerance or hampered fasting glucose. Both impaired glucose tolerance and impaired fasting glucose are risks factors for cardiovascular disease and kidney disease. The study population included patients age greater than or less than 30 years of age with stated risk factors above but do not have cardiovascular disease or renal disease. These patients were randomised to receive either ramipril versus placebo and or rosiglitazone versus placebo. This study revealed that rosiglitazone did not reduce the overall risk of cardiovascular disease but significantly increased the risk of heart failure. The hazard ratio was 7.04 [95% Confidence interval 1.60 to31.0. This increase in risk is not statistically significant (Dagenais, 2008).

Observational Studies Data

A number of observational studies ranging from cohorts to meta analysis were identified during literature screening pertaining to rosiglitazone and increased risk of cardiovascular events and rosiglitazone providing a protective effect with longer use. A few of the findings of these articles will be discussed below starting with the Nissen and Wolski article which started the controversy.

Effect of Rosiglitazone on the risk of myocardial infarction and death from cardiovascular outcome (Nissen & Wolski, 2007)

These authors perform a meta analysis of 42 clinical trials undertaken by marketing authorisation holders. The authors searched published literature, Food and Drug Administration web site and clinical trial registry looked after by GlaxoSmithKline. Inclusion criteria in the analysis included studies with more than 24 weeks duration and use randomised control groups not receiving rosiglitazone and outcome date for both myocardial infarction and death from cardiovascular causes. The mean age of patients was 56 years. Overall, there were 86 myocardial infarctions in the rosiglitazone group and 72 myocardial infarctions in the control group. 39 deaths from cardiovascular causes in the rosiglitazone and 22 in the control group were reported. This study revealed that rosiglitazone group compared to the control group had an odd ratio for myocardial infarction as 1.43 (95% confidence interval, 1.03 to 1.98). The odd ratio for death from cardiovascular causes was 1.64 (95% confidence interval 0.98 to 2.74). These results showed that rosiglitazone has a statistically significant increase in risk of myocardial infarction and also an increased for death from cardiovascular causes (Nissen & Wolski, 2007).

Study Limitations:

Information from all studies available was not included in this study. Studies which did not report myocardial infarction were not included in the Nissen study which did not form part of the follow activities. Inclusion of the studies reporting myocardial infarction will diminish the magnitude of increased association between rosiglitazone and myocardial infarction reported. This study most importantly did not have access to the source data for 42 studies analysed hence analysis was made on table level data made available by the company (Margolis, Hofstad &Strom, 2008).

Long term risk of cardiovascular events with rosiglitazone- a meta-analysis (Singh, Loke & Furberg, 2007)

The authors of this article performed a systematic review of long term cardiovascular risk of rosiglitazone including myocardial infarction, heart failure and cardiovascular death. They searched MEDLINE, clinical trial register, FDA web site, GSK clinical trials register. Inclusion criteria included studies involving randomised trial where rosiglitazone is used for prevention or treatment of type 2 diabetes with at least 12 months of follow up. The result of this study showed that rosiglitazone statistically significantly increased the risk of myocardial infarction. The relative risk was 1.42 (95% confidence interval, 1.06 to1.91). There was a statistically significant increase for heart failure with rosiglitazone. The relative risk was 2.09 (95% confidence interval, 1.52 to 2.88). There was no significant increase in the risk of cardiovascular death. The relative risk was 0.90 (95% confidence interval, 0.63 to 1.26). This study showed that rosiglitazone use for a period of 12 months is associated with a significant risk if myocardial infarction and heart failure without a significant increase risk of cardiovascular death (Singh, Loke & Furberg, 2007).

Study Limitations

There were limited data from randomised control trials of rosiglitazone hence the risk ratios were imprecise. The confidence intervals were wide due to the small numbers. There was unavailable information on the time to event data for myocardial infarction and heart failure which could affect the calculation of the hazard ratio. In this study it was difficult to determine if the harmful effects were immediate or a lag time to harm was involved (Singh, Loke &Furberg, 2007).

Coronary heart disease outcomes in patients receiving antidiabetic agents- (McAfee et al, 2007)

This cohort study compared the risk of myocardial infarction and coronary revascularisation in type two diabetic patients treated with rosiglitazone, metformin or sulfonylurea. Data from a large US insurer was used. Hospitalisation for myocardial infarction or coronary revascularisation was identified. The source population was derived from ingenix research database. The study groups were divided into 3. The monotherapy study group which involves patient on rosiglitazone, metformin or sulfonylurea in whom neither the study drug nor insulin had been given in the preceding six months and none of the 3 drugs named above or insulin have been dispensed within 30 days following the initial drug dispense. The dual therapy study group involves patient on rosiglitazone and metformin or rosiglitazone and sulfonylurea or metformin plus sulfonylurea in whom the same drug pair or insulin had not been used in the six months preceding the first dispense of the second drug administered in the pair. Lastly in the third group, combination with insulin study group, patients on rosiglitazone and insulin or other oral antidiabetic agents in whom the same drug combination had not been used in six months preceding the first dispensing of the second drug. The results showed that there was no difference between the risks of composite outcome with rosiglitazone monotherapy compared to metformin monotherapy. The hazard ratio was 1.07, 95% confidence interval was 0.85 to 1.34. In addition, there was no difference between the risks of the composite outcome with rosiglitazone monotherapy compared with sulfonylurea. The hazard ratio was 0.82, 95% confidence interval was 0.67 to 1.02. (McAfee et al., 2007).

Study Limitations

The statistical power of the study was limited by the rarity of the outcomes particularly in combination with insulin cohorts. In addition, there were few elderly patients in this study population which may affect the ability to generalise the results to the elderly (McAfee et al., 2007).


In reviewing the data from the randomised clinical trial studies above (ADOPT, DREAM and RECORD), the data for ADOPT suggested that there was no statistically significance difference with regards to congestive heart failure between rosiglitazone and metformin but significance increase was associated with rosiglitazone when compared to gylburide. As stated previously, this study was not design to measure cardiovascular events and the only focus was on heart failure. In terms of heart failure, this drug is associated with a slight risk of heart failure which is shown across all studies. The DREAM trial showed that rosiglitazone did not reduce the overall risk of cardiovascular event as stated previously but an increase risk of heart failure was identified. Type 2 diabetes is a confounding factor for cardiovascular disease hence this patients are predispose to cardiovascular events.

The RECORD trial as documented by Home et al (2007) showed that rosiglitazone was linked to a "small non significant increase" with regards to its primary outcome (hospitalisation for cardiovascular events) and there was no statistically significant increase between rosiglitazone and the control group for the secondary end points (myocardial infarction and cardiovascular deaths) as opposed to meta analysis of 42 clinical trials reported by Nissen and Wolski(2007) and Singh et al.,(2007) who both commented on the significant increase of myocardial infarction and heart failure associated with rosiglitazone. Nissen and Wolski (2007) and Singh et al., (2007) both differ with regards to cardiovascular mortality. Nissen and Wolski reported an increase in risk while Singh et al reported a non significant increase risk in cardiovascular mortality. McAfee et al., (2007) results shows that there was no significant increase in risk and suggested a protective action for rosiglitazone.

All this studies had various limitations as stated previously, in my view, rosiglitazone is likely associated with increased heart failures but not enough evidence has been provided with regards to cardiovascular mortality as the reports are conflicting hence each patient's safety profile should be assessed before administering rosiglitazone and drug withdrawal is not supported.