In this study, patients with type 2 diabetes who were newly treated with sulfonylureas were at higher risk of mortality and cardiovascular mortality than those who were newly treated with metformin, although there was no increased risk of cardiovascular hospital admission. The adjusted risk ratios were 1.43 (95% CI 1.15–1.17) and 1.70 (95% CI 1.18–2.45) for mortality and cardiovascular mortality, respectively. Our study is consistent with earlier studies that found patients treated with metformin were at lower cardiovascular risk but were unable to adjust for cardiovascular risk at baseline . For example, the risk ratio for overall mortality for patients treated with metformin compared with sulfonylureas was 0.60 (95% CI 0.48–0.74) in the Canadian study .
The key issue is whether this increased risk is the result of drug therapy, or whether patients prescribed sulfonylureas have a higher baseline cardiovascular risk than those in the monotherapy cohort. Severity of diabetes will clearly influence initial drug choice. This was indeed suggested by increased mean age and duration of diabetes in the sulfonylureas monotherapy cohort, and a higher proportion of males, patients with a previous cardiovascular hospital admission and aspirin users. As expected, patients in the sulfonylureas cohort had a lower BMI than those in the metformin cohort. However, the study suggests that sulfonylureas cannot always be used as recommended given that the mean BMI in this cohort was above 25 kg/m2.
Adjustment for all potential confounding variables (including BMI) resulted in reduced risk estimates, but patients in the sulfonylureas monotherapy cohort were still at higher risk of mortality and cardiovascular mortality than those in the metformin cohort. These increased risks were observed for all patients, regardless of location of care.
Patients in the combination cohorts had even higher risks of mortality and cardiovascular mortality compared with those in the metformin cohort, even after adjusting for underlying differences between groups. Combination cohort patients also had an increased risk of cardiovascular hospital admission. These results conflict with those from a previous study that, using the UK General Practice Research Database , found no increased risk of mortality in combination cohorts compared with patients prescribed drugs singly. However, it is important to recognise that these cohorts represent a heterogeneous mix of patients, with widely varying levels of exposure to sulfonylureas and metformin. It is also possible that prescribing practice may have changed over time, with patients now more likely to be prescribed metformin or combination therapy at an earlier stage of disease than previously, therefore over-estimating the risk associated with sulfonylureas in the later years of the study. However, we did not find evidence of such changing practice in our data, with mean duration of diabetes remaining similar for each cohort throughout the years of the study.
The most important question is whether we have adequately adjusted for differences in underlying cardiovascular risk between cohorts. Adjustment for a wide range of potential confounding variables was made, including age, sex, BMI, blood pressure, cholesterol, duration of diabetes, smoking, HbA1c and, very importantly, previous cardiovascular admission. As expected, current smoking, previous cardiovascular admission, increasing age and increasing cholesterol levels were all significant predictors of mortality and cardiovascular mortality, thereby providing evidence for the validity of our study. Patients for whom smoking status and cholesterol were unknown were also at increased risk. This is plausible if such patients were not regularly attending clinics and clinical data were therefore incomplete. The inconsistent results for blood pressure are more difficult to explain, although there is some evidence of increased risk among patients with the highest diastolic blood pressure. Patients taking statins were at reduced risk.
The risk factors for cardiovascular hospital admission were different from those for the other outcomes. For example, use of any of the drug types was associated with increased hospital admission; perhaps reflecting a lower threshold for admission in patients already taking cardiovascular medication. Patients with a higher BMI or HbA1c were also more likely to be admitted. An important caveat is that cardiovascular hospital admission is probably the least reliable of the three outcomes, with many selective factors likely to determine whether patients are admitted to hospital and whether they are assigned a primary cardiovascular diagnosis code. In contrast, mortality was ascertained from a validated national database.
It has been argued  that the results of the Canadian study  might support a cardioprotective effect of metformin rather than an increased cardiovascular risk among users of sulfonylureas, possibly derived from unrecognised differences between therapy groups (there was very little clinical information available for patients ). It is therefore important to note that the risks associated with sulfonylureas in our study are in line with what would be expected in a diabetic population, despite being higher than those for the metformin cohort. All-cause mortality of 28% and cardiovascular mortality of 12% over a seven-year follow-up are comparable with 24% and 11% over 5 years in the Canadian study, and 3% per year among middle-aged Finnish men . This is consistent with the theory that it may be metformin that is cardioprotective  (rather than sulfonylureas being cardiotoxic). The absolute risk of mortality is surprisingly low in the metformin cohort (8% over 7 years), and the proportion of cardiovascular deaths is less; thus, our study does provide some supporting evidence for this theory.
We carried out this study using well-validated data sources. Identification of study cohorts relied upon records of prescriptions dispensed, and identification of study outcomes relied upon national datasets. We are confident in the accuracy of the data, whilst acknowledging the difficulties of ascertaining (and adjusting for) cardiovascular risk using routine data sources. We also acknowledge the limitation of observational research, in that there can be no control for underlying differences between study cohorts. However, while it is possible that increased risks in the sulfonylureas monotherapy cohort and combination cohort are due to residual confounding or other unknown differences at baseline, the consistently higher risks that we have identified, with results that are similar to previous studies , suggest that this issue does warrant further investigation. But, as Sasali and Leahy argue , we are not yet in a position to advocate cautious prescribing of sulfonylureas to patients at high cardiovascular risk until further corroborating evidence is available.