Author + information
- Payal Kohli, MD,
- David D. Waters, MD∗ (, )
- Rita Nemr, MD,
- Benoit J. Arsenault, PhD,
- Michael Messig, PhD,
- David A. DeMicco, DPharm,
- Rachel Laskey, PhD and
- John J.P. Kastelein, MD, PhD
- ↵∗San Francisco General Hospital, Division of Cardiology, 1001 Potrero Avenue, Room 5G1, San Francisco, California 94114
Statins reduce coronary and cerebrovascular events in primary and secondary prevention. More intensive statin therapy compared with moderate-intensity statin therapy decreases risk even further (1). Therefore, the 2013 American College of Cardiology/American Heart Association (ACC/AHA) guidelines recommend high-intensity statin therapy in high-risk patients. This recommendation is partly on the basis of the documented safety of higher doses. However, meta-analyses have reported a slight increase in the risk of new-onset diabetes (NOD) with statin therapy over placebo; this risk increases by an additional 12% with high-intensity therapy (2).
Fasting blood glucose (FBG) >100 mg/dl is a strong predictor of NOD; however, the incidence of NOD during statin therapy in patients with pre-diabetes (PD), which is defined as a FBG of 100 to 126 mg/dl, compared with those with normal glucose levels, has not been previously reported. We describe the incidence of NOD in patients with and without PD at baseline from the TNT (Treating to New Targets) and IDEAL (Incremental Decrease in Clinical Endpoints Through Aggressive Lipid Lowering) randomized clinical trials.
We pooled patients without diabetes at baseline from both the TNT and IDEAL trials (3,4). The TNT study randomized 10,001 patients with documented coronary heart disease to atorvastatin 10 or 80 mg/day and followed them for a median of 4.9 years (3). The IDEAL study randomized 8,888 patients with a previous myocardial infarction (MI) to simvastatin 20 to 40 mg/day or atorvastatin 80 mg/day with a median follow-up of 4.8 years (4).
The primary endpoint of our analysis was the composite of coronary heart disease death, nonfatal MI, resuscitated cardiac arrest, and stroke. NOD was defined prospectively as at least 2 post-baseline FBG measurements ≥126 mg/dl or at least 1 post-baseline FBG ≥36 mg/dl above baseline (5). FBG was measured at each 12-month visit in TNT and at randomization and at the end of study in IDEAL. We also included patients who had NOD identified through adverse event reporting or patients who received new concomitant diabetic medication.
Of the total 15,056 patients from both trials without diabetes at baseline, 5,924 (39%) had PD, and 9,132 (71%) patients did not. PD and non-PD patients were evenly balanced across the statin treatment arms. Compared with those without PD, PD patients were more likely to be older, to be men, to have metabolic syndrome, to have higher baseline blood pressure, and to have a history of hypertension. PD patients also had, on average, a higher body mass index, higher FBG, higher triglyceride levels, and lower levels of high-density lipoprotein cholesterol.
During the mean 5-year follow-up, 14.2% of PD patients developed NOD compared with 2.9% of patients without PD (hazard ratio [HR]: 5.29, 95% confidence interval [CI]: 4.6 to 6.1; p <0.001). As shown in Figure 1, the incidence of NOD was not time-dependent, and occurred at the same rate throughout the trial. In patients with PD, the risk of NOD was higher in the high-intensity statin group (HR: 1.20, 95% CI: 1.04 to 1.37; p = 0.010). In patients without PD, the difference between the high- and moderate-intensity treatment groups was not statistically significant (HR: 1.08, 95% CI: 0.85 to 1.38; p = 0.527).
The primary composite endpoint was greater for the PD group compared with the non-PD group (10.5% and 9.6%, respectively; HR: 1.11, 95% CI: 1.00 to 1.23, p = 0.05). High-intensity statin treatment compared with moderate-intensity statin treatment reduced cardiovascular events in patients with PD (9.5% vs. 11.5%; HR: 0.82, 95% CI: 0.70 to 0.96; p = 0.014) and without PD (8.9% vs. 10.2%; HR: 0.87, 95% CI: 0.76 to 0.99; p = 0.038).
In summary, in this analysis of 2 large cohorts of patients without diabetes who were taking statins, PD was a very strong predictor of the development of NOD during the 5-year follow-up, with high-intensity statin therapy, compared with moderate-intensity statin therapy, significantly increasing the risk of NOD in the PD group, but not in the non-PD group. In contrast, the risk of cardiovascular events was only marginally greater in the PD group compared with the non-PD group, and high-intensity statin therapy compared with moderate-intensity statin therapy significantly reduced cardiovascular events in both groups.
Please note: The TNT and IDEAL clinical trials were funded by Pfizer, Inc. Dr. Kohli is a member of the advisory board for Amgen; and has received travel reimbursement fees from Pfizer, Inc. Dr. Waters has received honoraria for participating in the Steering Committee for the TNT Trial with Aastrom, Cerenis, CSL, Pfizer, Inc., and Sanofi-Aventis; has received honoraria for lectures from Pfizer, Inc., and Zydus Medica; and has received consulting fees from Novo Nordisk, and Pfizer, Inc. Dr. Arsenault has received consultancy fees (modest) from Pfizer, Inc. Drs. Messig, DeMicco, and Laskey are employees of Pfizer, Inc., and report owning stock in the company. Dr. Kastelein has received consulting fees from Pfizer, Inc. Dr. Nemur reports that she has no relationships relevant to the contents of this paper to disclose. This paper was presented in part at the American College of Cardiology Annual Scientific Sessions, Washington, DC, March 2014.
- 2015 American College of Cardiology Foundation