High-dose atorvastatin reduces periodontal inflammation: a novel pleiotropic effect of statins

Abstract

Objectives: The purpose of this study was to test whether high-dose statin treatment would result in a reduction in periodontal inflammation as assessed by (18)F-fluorodeoxyglucose positron emission tomography (FDG-PET)/computed tomography (CT).

Background: Periodontal disease (PD) is an independent risk factor for atherosclerosis.

Methods: Eighty-three adults with risk factors or with established atherosclerosis and who were not taking high-dose statins were randomized to atorvastatin 80 mg vs. 10 mg in a multicenter, double-blind trial to evaluate the impact of atorvastatin on arterial inflammation. Subjects were evaluated using FDG-PET/CT at baseline and at 4 and 12 weeks. Arterial and periodontal tracer activity was assessed while blinded to treatment allocation, clinical characteristics, and temporal sequence. Periodontal bone loss (an index of PD severity) was evaluated using contrast-enhanced CT images while blinded to clinical and imaging data.

Results: Seventy-one subjects completed the study, and 59 provided periodontal images for analysis. At baseline, areas of severe PD had higher target-to-background ratio (TBR) compared with areas without severe PD (mean TBR: 3.83 [95% confidence interval (CI): 3.36 to 4.30] vs. 3.18 [95% CI: 2.91 to 3.44], p = 0.004). After 12 weeks, there was a significant reduction in periodontal inflammation in patients randomized to atorvastatin 80 mg vs. 10 mg (ΔTBR 80 mg vs. 10 mg group: mean -0.43 [95% CI: -0.83 to -0.02], p = 0.04). Between-group differences were greater in patients with higher periodontal inflammation at baseline (mean -0.74 [95% CI: -1.29 to -0.19], p = 0.01) and in patients with severe bone loss at baseline (-0.61 [95% CI: -1.16 to -0.054], p = 0.03). Furthermore, the changes in periodontal inflammation correlated with changes in carotid inflammation (R = 0.61, p < 0.001).

Conclusions: High-dose atorvastatin reduces periodontal inflammation, suggesting a newly recognized effect of statins. Given the concomitant changes observed in periodontal and arterial inflammation, these data raise the possibility that a portion of that beneficial impact of statins on atherosclerosis relate to reductions in extra-arterial inflammation, for example, periodontitis. (Evaluate the Utility of 18FDG-PET as a Tool to Quantify Atherosclerotic Plaque; NCT00703261).

Keywords: (18)F-fluorodeoxyglucose; C-reactive protein; CRP; CT; FDG; HDL; LDL-C; PD; PET; ROI; SUV; TBR; atherosclerosis; computed tomography; high-density lipoprotein; imaging; inflammation; low-density lipoprotein cholesterol; nuclear medicine; periodontal disease; positron emission tomography; region of interest; standardized uptake value; statins; target-to-background ratio.

Figure 1:. Trial consort diagram

* Some subjects were excluded for more than 1 reason. Therefore, the sum of individual totals is >80.

Figure 2:. Measurement of periodontal FDG uptake on an axial mandibular section

Rectangular regions of interest (ROIs), shown as dotted yellow rectangles, drawn around the teeth from the premolar to the second molar in each quadrant. The maximum SUV value is then recorded for each ROI. Arrow indicates an area of a broken tooth. A) PET, B) CT and C) composite PET/CT image. Brighter red to yellow colors represent higher FDG PET activity. *=tongue FDG activity

Figure 3:. Lateral view of the mandible from an angulated sagittal plane for patients without (A) and with severe bone loss (B).

Dotted line indicates the estimated alveolar bone margin without bone loss. Bone loss on CT is dichotomized into severe and non-severe categories, and plotted against target to background ratio (TBR) (C). *= p <0.05, error bars represent SEM.

Figure 4:. Change in periodontal FDG uptake (TBR) at 4 and 12 weeks from the baseline in patients with active periodontitis (by PET).

Error bars represent 95% Confidence Interval, † p=0.003, ‡ p=0.022, * p= 0.045, § p= 0.01

Figure 5.. Prior to Randomization, Periodontal FDG uptake Correlated with Carotid Inflammation.

FDG uptake within periodontal tissues was compared with carotid FDG uptake (a measure of carotid inflammation) at baseline. A significant relationship was observed (r= 0.67, p<0.001). FDG=¹⁸F-fluorodeoxyglucose; TBR= target-to-background ratio

Figure 6.. In the Setting of Statin Therapy, Changes in Periodontal Activity Correlate with Changes in Carotid Inflammation.

After 12-weeks of statin treatment, a significant relationship was observed between changes in periodontal activity (FDG uptake measured as ΔTBR) and changes in carotid arterial inflammation (measured as ΔTBR). FDG=¹⁸F-fluorodeoxyglucose; TBR= target-to-background ratio

Figure 7.. Interrelationships between Arterial and Extra-arterial Inflammatory Processes.

Inflammatory processes in multiple distinct tissues may be inter-related. Within this paradigm, statins can have direct as well as in-direct benefits on arterial inflammation. Statins can impact arterial inflammation through direct actions on the atheromatous milieu. Additionally, statins reduce inflammation in extra-arterial locations (such as periodontal tissues). Theoretically, that reduction in extra-arterial inflammation may decrease chronic cytokine production by those sites hence decreasing pro-inflammatory stimulation of atheroscerlotic plaques.