Of 17,802 JUPITER trial participants, 121 (0.7 percent) were missing data on at least one risk factor for diabetes and 78 (0.4 percent) were found at randomization to have fasting glucose ≥126 mg/dL or clinical diabetes. The remaining 17,603 trial participants (98.9 percent) had complete data and were included in the current analysis.
Compared to trial participants with no major diabetes risk factors (N=6095), those with one or more major diabetes risk factor (N=11508) were more likely to be female, have lower baseline levels of HDL cholesterol, and higher baseline levels of blood pressure, HbA1c, glucose, and triglycerides. By contrast, smoking was more prevalent among those with no major diabetes risk factor. In gender specific analyses, levels of hsCRP were higher among those with one or more major diabetes risk factor (). As anticipated, trial participants with one or more major diabetes risk factor had higher risk of developing diabetes during trial follow-up (incidence rate 1.88 vs 0.18 per 100 person years, HR = 10.5, 95%CI 6.98–15.8, P=0.001). Tabular data stratifying these groups by randomized treatment assignment are shown in the appendix
Baseline characteristics of participants in the JUPITER trial among those with none or at least one major risk factor for diabetes (metabolic syndrome, impaired fasting glucose, HbA1c > 6 percent, or body mass index ≥ 30 kg/m2).
Overall, incident diabetes occurred more frequently in the rosuvastatin group (270 reports of diabetes, vs. 216 in the placebo group, HR=1.25, 95%CI 1.05–1.49, P=0.01). The average time from randomization to diagnosis of diabetes was 84.3 weeks in the rosuvastatin group and 89.7 weeks in the placebo group, an acceleration of 5.4 weeks.
As shown in , virtually all of the excess risk of diabetes associated with rosuvastatin occurred among those with baseline evidence of impaired fasting glucose.
Figure 1 Incidence rates (per 100 person years) of physician diagnosed diabetes in the JUPITER trial according to baseline fasting glucose levels. Data are shown separately for those allocated to placebo (white bars) and those allocated to rosuvastatin (black (more ...)
presents incidence rates for cardiovascular events, total mortality, and diabetes among those with and without at least one major diabetes risk factor, according to statin or placebo allocation. For trial participants with at least one major diabetes risk factor, random allocation to rosuvastatin was associated with a 39 percent reduction in the primary endpoint (HR 0.61,95%CI 0.47–0.79, P=0.0001), a 36 percent reduction in venous thromboembolism (HR 0.64,95%CI 0.39–1.06, P=0.08), a 17 percent reduction in total mortality (HR 0.83,95%CI 0.64–1.07, P=0.15) and a 28 percent increase in diabetes (HR 1.28,95%CI 1.07–1.54, P=0.01). In absolute terms for those with diabetes risk factors, 134 total cardiovascular events or deaths were avoided for every 54 new cases of diabetes diagnosed. In analyses limited to first events only, the number of major cardiovascular events or deaths avoided among those with one or more diabetes risk factors was 93.
Table 2 Absolute number of events, incidence rates (per 100 person years), and hazard ratios (HR) for cardiovascular endpoints, death, and diabetes in the JUPITER trial among those with or without major diabetes risk factors, according to random allocation to (more ...)
For trial participants with no major diabetes risk factor, random allocation to rosuvastatin yielded a 52 percent reduction in the primary endpoint (HR 0.48,95%CI 0.33–0.68, P=0.0001), a 53 percent reduction in VTE (HR 0.47,95CI 0.21–1.03, P=0.05), a 22 percent reduction in total mortality (HR 0.78,95%CI 0.59–1.03, P=0.08) and no increase in diabetes (HR 0.99, 95%CI 0.45–2.21, P= 0.99). In absolute terms for those without a major diabetes risk factor, 86 total cardiovascular events or deaths were avoided with no excess new cases of diabetes diagnosed. In analyses limited to first events only, the number of major cardiovascular events or deaths avoided among those with no major diabetes risk factor was 65.
The cumulative incidence of cardiovascular events or death for those with and without major diabetes risk factors is shown in , while the cumulative incidence of diabetes for those with and without major diabetes risk factors is shown in . There were no significant violations of the proportional hazards assumptions for the data contained in these Figures. As anticipated with respect to the primary cardiovascular endpoint, the relative treatment benefits attributable to rosuvastatin were similar among those with and without diabetes risk factors (P- for interaction = 0.28).
Cumulative incidence of cardiovascular events and total mortality among those with and without major risk factors for diabetes.
Cumulative incidence of diabetes among those with and without major risk factors for diabetes.
Risks of diabetes associated with rosuvastatin allocation did not change substantially as the number of major diabetes risk factors increased. For those with 1, 2, 3, or 4 major risk factors for diabetes, the observed hazard ratios for physician diagnosed diabetes associated with rosuvastatin were 1.2, 1.2, 1.4, and 1.4, respectively; none of these hazard ratios differed significantly from that observed for the study as a whole.
As shown in , the relative benefits and risks of rosuvastatin were generally consistent for all components of the JUPITER primary and secondary endpoints and in all subgroups evaluated, including among those with or without metabolic syndrome, with or without impaired fasting glucose, with or without body mass index ≥ 30 kg/m2, or with or without HbA1c > 6 percent. In no instance were tests for interaction significantly different from that observed in the main analyses of those with none or at least one of these major diabetes risk factors.
Figure 4 Hazard ratios and 95% confidence intervals for specific vascular events, total mortality, and diabetes in subgroup analyses among those with or without metabolic syndrome; among those with fasting glucose ≥ or < 100 mg/dL; among those (more ...)
provides data concerning rates of adverse events (other than incident diabetes) and measured laboratory values in the JUPITER trial comparing rosuvastatin to placebo among those with and without one or more major diabetes risk factor. As shown, those with and without diabetes risk factors had similar non-diabetes adverse event rates attributable to rosuvastatin. As also shown, among those with and without diabetes risk factors, measured HbA1c at 24 months increased by 0.1 percent among those allocated to rosuvastatin (both p-values 0.001). Of interest, measured fasting glucose levels were not significantly different in the rosuvastatin and placebo groups; thus, as anticipated, had we relied on biochemical determination of diabetes rather than physician diagnosis, we could have systematically underestimated true effects.
Adverse events and measured laboratory values for fasting glucose and HbA1c during follow-up among those with and without major diabetes risk factors.
In an analysis limited to those who developed diabetes during the JUPITER trial (N = 270 on rosuvastatin, N = 216 on placebo), 18 primary cardiovascular endpoints occurred. Of these, 8 were on rosuvastatin (incidence rate 1.10 per 100 person years) and 10 were on placebo (incidence rate 1.73 per 100 person years). Thus, among the 486 JUPITER trial participants who developed diabetes during follow-up, the cardiovascular risk reduction associated with rosuvastatin (hazard ratio 0.63, 95% confidence interval 0.25–1.60) was consistent with that observed for the trial as a whole (0.56, 95% confidence interval 0.46–0.69).
In sensitivity analyses, we found no substantive change for any of these findings when alternative definitions of metabolic syndrome or alternative cut-points for body mass index or HbA1c were used.
In analyses stratified by age, the hazard ratio (95%CI) for incident diabetes associated with rosuvastatin as compared to control was 1.26 (1.02–1.56) for those aged 50 to 69 years and 1.25 (0.90–1.74) for those aged 70 and over8