Cardiovascular safety trials: Be careful what you wish for (心血管安全性研究：当心你许的愿)

All clinicians want medications used for diabetes to be safe. We are dismayed by the not-infrequent occurrence of severe hypoglycemia with the very treatments that we are using to control the disease. Insulin and oral hypoglycemic agents (mainly sulfonylureas) are responsible for more than one-quarter of adverse drug reaction hospitalizations in the US. All the more important, then, that glucose-lowering agents not promote cardiovascular (CV) disease (CVD), explaining the great furor over the supposed increase in CV events with rosiglitazone described by Nissen and Wolski in 2007. Although we and others questioned that meta-analysis, it led to the 2008 US Food and Drug Administration (FDA) requirement that all glucose-lowering agents for which Phase 3 trials cannot exclude a chance of 5% or more that there may be a 1.8-fold increase in CV event rates should undergo a large CV safety trial to exclude a chance of 5% or more that there may be even a 1.3-fold increase in event rates. A short-term study performed in a population with relatively low event rates may not exclude this 1.8-fold increase. Indeed, we have observed that a drug given for 1 year to 2000 patients and 2000 controls, with a 1% event rate in both groups, would have an odds ratio for events of 1.0, but with a 95% confidence interval of 0.5397–1.8528, the upper limit then automatically triggering a CV safety trial. To make trial sizes manageable, CV safety studies typically recruit individuals whose annual CV risk is far greater than 1%. With greater numbers of events, the confidence limits go down rapidly. This brings us to two recently reported trials of the dipeptidyl peptidase (DPP)-4 inhibitors saxagliptin and alogliptin. In the Saxagliptin Assessment of Vascular Outcomes Recorded in Patients with Diabetes Mellitus (SAVOR) trial, 8280 type 2 diabetic patients were randomized to saxagliptin and 8212 to placebo. Of the study population as a whole, 79% had evidence of atherosclerotic disease, 82% had hypertension, 71% had dyslipidemia, 38% had prior myocardial infarction, 13% had prior heart failure, and 43% had prior coronary revascularization. The mean age of the study group was 65 years, mean body mass index was 31 kg/m, and the subjects had had diabetes for 10 years. In that study, 70% of subjects were treated with metformin, 40% with a sulfonylurea, and 41% with insulin. The primary endpoint of CV death, non-fatal myocardial infarction, or non-fatal stroke occurred at annual rates of 3.7% in both groups, whereas an endpoint expanded to include unstable angina hospitalization, coronary revascularization, and heart failure occurred at annual rates of 6.6% and 6.5% in those randomized to saxagliptin and placebo, respectively, demonstrating no significant difference, although 3.5% of those receiving saxagliptin and 2.8% of those receiving placebo were hospitalized for heart failure during the median 2.1-year period of observation. There was an improvement in glycemia, with HbA1c decreasing from 8% to 7.7% at the end of treatment with saxagliptin and to 7.9% with placebo, but hypoglycemia occurred more often with saxagliptin (in 15% vs 13% of subjects), although not with a significant increase in hospitalizations for this. Renal abnormality (not defined explicitly in the report) occurred significantly more often with saxagliptin, although the patients receiving saxagliptin also had a significantly greater likelihood of improvement in the level of albuminuria. In the Examination of Cardiovascular Outcomes with Alogliptin versus Standard of Care (EXAMINE) study, an even higher risk group was recruited, namely 5380 patients with diabetes who had had recent acute coronary syndrome. The mean age of this study group was 61 years, they had had diabetes for 7 years, 88% had had myocardial infarction, and 28% had congestive heart failure, with 63% and 13% having undergone percutaneous coronary intervention and coronary artery bypass grafting, respectively. Of those receiving alogliptin and placebo, 11.3% and 11.8%, respectively, exhibited the primary endpoint of CV death, non-fatal myocardial infarction, and non-fatal stroke. Baseline treatment included insulin for 30%, metformin for 66%, and a sulfonylurea for 46% of patients, and their baseline HbA1c was also 8%, decreasing by 0.3% with alogliptin but not changing with placebo, with a median 1.5-year period of observation. Hypoglycemia occurred less frequently in that trial, affecting 7% of patients, and at no greater frequency with alogliptin. In subgroup analysis, there was a suggestion that those with diabetes of <5 years duration, those not using insulin, those using metformin, and those with normal renal function or mild impairment may have greater benefit, with diabetes duration of 10 years or more, insulin use, lack of metformin, and moderate or severe renal bs_bs_banner