This study provides comparative data on the relationship between myocardial infarction and treatment with glitazones and sulfonylureas in patients who switched to or added those drugs to first-line treatment with metformin. Adding rosiglitazone treatment did not significantly increase risk of AMI compared to adding pioglitazone or a sulfonylurea. Patients in our study were drawn from the broadest population of glitazone patients studied to date. Our results are generalizable to patients with Type 2 diabetes who received metformin as first-line drug treatment. From our data, and for the 10-year period ending in March 2007, we estimated that metformin was used as first-line drug treatment in 77% of patients with Type 2 diabetes.
There is evidence from trials like ACCORD 
and UGDP 
that more intensive hypoglycemic therapy increases cardiovascular risk. The purpose of the analysis in was to estimate temporal associations within each drug to see if increased risk was generally associated with more treatment with OADs, an effect that could have been masked in the analysis of drug-to-drug comparisons in . In , an increased risk of AMI was not observed with pioglitazone, which is consistent with the null result for pioglitazone and MI reported in a meta-analysis of randomized trials of pioglitazone 
. However, our power to detect an association was lower because the use of pioglitazone in the source population was half that of rosiglitazone. Also in , addition of sulfonylurea therapy was associated with a significant 25% increase in risk that appeared to be independent of duration of use. The increase associated with the addition of rosiglitazone or a sulfonylurea could be clinically significant and suggests that either worsening glycemic control (which leads to treatment intensification) increases cardiovascular risk, or, alternatively, that increased risk is a result of more intensive therapy as shown for CV death but not AMI in the ACCORD trial 
. It is tempting to assume that former explanation is correct, but defending that assumption requires selective use of evidence or at least a clear refutation of evidence from clinical trials, meta-analyses and observational studies that lend merit to the latter explanation. In our opinion, increased risk of cardiovascular events as a consequence of treatment with any OAD is a credible hypothesis that requires more research.
The Nissen meta-analysis reported an overall 43% increase (95% CI, 3%–98%) in AMI events in patients treated with rosiglitazone compared to controls on various treatments including placebo 
. A direct comparison of our analysis with that overall result is not simple because only 35% of patients in the meta-analysis received metformin compared to 80% of patients in our study in the previous year. However, a subgroup comparison in the Nissen meta-analysis of trials that used metformin as a control showed an odds ratio of 1.14 (95% CI, 0.70–1.86). The odds ratio we observed (1.14 from ) was within the 95% confidence interval of the Nissen meta-analysis and was also not statistically significant. An interim analysis of the Rosiglitazone Evaluated for Cardiovascular Outcome (RECORD) trial also reported a similar hazard ratio to ours for AMI of 1.16 (95% CI, 0.75–1.81) for rosiglitazone (plus metformin or plus sulfonylurea) compared to treatment with metformin plus sulfonylurea 
Our results for rosiglitazone are close to the estimates reported in an observational analysis by McAfee. 
. Their study reported hazard ratios for MI outcomes of 1.19 for rosiglitazone compared to metformin, and a hazard ratio of 0.79 for rosiglitazone compared to sulfonylurea over three years of follow-up. We estimated odds ratios of 1.14 and 0.90, respectively.
In another recent Canadian study of cardiovascular outcomes among patients older than 65 years in Ontario, current treatment with a glitazone (rosiglitazone or pioglitazone) was associated with an odds ratio of 1.40 (95% CI, 1.05–1.86) for AMI compared to patients receiving other OAD medications 
. The effect size may have been greater than in other studies because, as the authors stated, “our TZD treated population may represent an older and more select population of patients with more advanced diabetes because under Ontario Drug Benefit reimbursement criteria, most of these patients will have failed or had a contraindication to other drugs.”
As with most population-based outcomes studies of prescription drugs, our study was susceptible to channeling bias, which is a type of confounding by indication where marketing leads to sicker patients being more likely to be early users of new drugs. The expected direction of such a bias is to increase the association between glitazones and AMI. We cannot say if our study was more influenced by such forces than other epidemiologic studies of the glitazones, but the 6-month odds ratios for the glitazones () increased after multivariable adjustment, which suggests that we likely underestimated the true effect. However, it is still possible that patients with deteriorating health led their physicians to add OADs, and our results could have been biased upwards if such deteriorations were not captured in our claims data but affected AMI risk. Specifically, among patients with diabetes who fluctuate between periods of good and poor control of their blood sugar, glitazones would be initiated in poor periods when risk of AMI might be transiently higher. Therefore, the transient elevation in AMI risk after initiation of rosiglitazone may, at least in part, be due to confounding by indication. Direct comparison of glitazone starters and sulfonylurea starters would be less biased because both classes of drugs would tend to be initiated in periods of poor control. We expect that our within-drug analysis of adding/switching treatment versus not adding/switching treatment () would be more vulnerable to this kind of bias than our analysis using comparator drugs ().
Exposure definitions (current or past use) could not be measured with certainty since dispensing records were used rather than a direct measure of consumption. Some patients dispensed medications may not have taken their drug, causing them to mistakenly be classified as exposed instead of unexposed. So long as the sensitivity and specificity of the exposure definitions were the same in cases and controls, any plausible error rate in classifying exposed patients as unexposed would have biased our estimates towards the null.
Although Nissen's meta-analysis is persuasive, the generalizability of clinical trial results to the general population is often questionable. Most studies have commonly found a non-significant increase in risk of AMI on the order of 15% to 20% for rosiglitazone compared to metformin. Our findings were similar in patients who added or switched treatment from metformin, a meaningful real- world contrast since intolerance or failure on metformin would be the most common pathway to starting a glitazone. A risk increase of 15% to 20% is clinically significant. The RECORD trial, designed to evaluate the cardiovascular safety of rosiglitazone, likely did not enroll enough patients to detect a 15% risk increase in AMI or cardiovascular death.
In our cohort of prior metformin users, adding rosiglitazone was not associated with an increased risk of AMI compared to adding a sulfonylurea, or compared to adding pioglitazone. For each of rosiglitazone and sulfonylureas separately, adding treatment with those agents was accompanied by significantly increased AMI risk after their initiation. It is unknown if the risk was increased due to worsening glycemic control which led to treatment, or if the risk was increased by more intensive treatment itself. Both hypotheses are credible and more research is needed since they have very different implications for treatment.
The study received ethics approval from the University of British Columbia (UBC CREB Number H02-70020). The BC Ministry of Health approved data access.