Antiinflammatory Therapy with Canakinumab for Atherosclerotic Disease

Background: Experimental and clinical data suggest that reducing inflammation without affecting lipid levels may reduce the risk of cardiovascular disease. Yet, the inflammatory hypothesis of atherothrombosis has remained unproved. Methods: We conducted a randomized, double-blind trial of canakinumab, a therapeutic monoclonal antibody targeting interleukin-1β, involving 10,061 patients with previous myocardial infarction and a high-sensitivity C-reactive protein level of 2 mg or more per liter. The trial compared three doses of canakinumab (50 mg, 150 mg, and 300 mg, administered subcutaneously every 3 months) with placebo. The primary efficacy end point was nonfatal myocardial infarction, nonfatal stroke, or cardiovascular death. RESULTS: At 48 months, the median reduction from baseline in the high-sensitivity C-reactive protein level was 26 percentage points greater in the group that received the 50-mg dose of canakinumab, 37 percentage points greater in the 150-mg group, and 41 percentage points greater in the 300-mg group than in the placebo group. Canakinumab did not reduce lipid levels from baseline. At a median follow-up of 3.7 years, the incidence rate for the primary end point was 4.50 events per 100 person-years in the placebo group, 4.11 events per 100 person-years in the 50-mg group, 3.86 events per 100 person-years in the 150-mg group, and 3.90 events per 100 person-years in the 300-mg group. The hazard ratios as compared with placebo were as follows: in the 50-mg group, 0.93 (95% confidence interval [CI], 0.80 to 1.07; P = 0.30); in the 150-mg group, 0.85 (95% CI, 0.74 to 0.98; P = 0.021); and in the 300-mg group, 0.86 (95% CI, 0.75 to 0.99; P = 0.031). The 150-mg dose, but not the other doses, met the prespecified multiplicity-adjusted threshold for statistical significance for the primary end point and the secondary end point that additionally included hospitalization for unstable angina that led to urgent revascularization (hazard ratio vs. placebo, 0.83; 95% CI, 0.73 to 0.95; P = 0.005). Canakinumab was associated with a higher incidence of fatal infection than was placebo. There was no significant difference in all-cause mortality (hazard ratio for all canakinumab doses vs. placebo, 0.94; 95% CI, 0.83 to 1.06; P = 0.31). Conclusions: Antiinflammatory therapy targeting the interleukin-1β innate immunity pathway with canakinumab at a dose of 150 mg every 3 months led to a significantly lower rate of recurrent cardiovascular events than placebo, independent of lipid-level lowering. (Funded by Novartis; CANTOS ClinicalTrials.gov number, NCT01327846.

Effects of Once-Weekly Exenatide on Cardiovascular Outcomes in Type 2 Diabetes.

Abstract BACKGROUND: The cardiovascular effects of adding once-weekly treatment with exenatide to usual care in patients with type 2 diabetes are unknown. METHODS: We randomly assigned patients with type 2 diabetes, with or without previous cardiovascular disease, to receive subcutaneous injections of extended-release exenatide at a dose of 2 mg or matching placebo once weekly. The primary composite outcome was the first occurrence of death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke. The coprimary hypotheses were that exenatide, administered once weekly, would be noninferior to placebo with respect to safety and superior to placebo with respect to efficacy. RESULTS: In all, 14,752 patients (of whom 10,782 [73.1%] had previous cardiovascular disease) were followed for a median of 3.2 years (interquartile range, 2.2 to 4.4). A primary composite outcome event occurred in 839 of 7356 patients (11.4%; 3.7 events per 100 person-years) in the exenatide group and in 905 of 7396 patients (12.2%; 4.0 events per 100 person-years) in the placebo group (hazard ratio, 0.91; 95% confidence interval [CI], 0.83 to 1.00), with the intention-to-treat analysis indicating that exenatide, administered once weekly, was noninferior to placebo with respect to safety (P<0.001 for noninferiority) but was not superior to placebo with respect to efficacy (P=0.06 for superiority). The rates of death from cardiovascular causes, fatal or nonfatal myocardial infarction, fatal or nonfatal stroke, hospitalization for heart failure, and hospitalization for acute coronary syndrome, and the incidence of acute pancreatitis, pancreatic cancer, medullary thyroid carcinoma, and serious adverse events did not differ significantly between the two groups. CONCLUSIONS: Among patients with type 2 diabetes with or without previous cardiovascular disease, the incidence of major adverse cardiovascular events did not differ significantly between patients who received exenatide and those who received placebo. (Funded by Amylin Pharmaceuticals; EXSCEL ClinicalTrials.gov number, NCT01144338 .)

Vitrectomy for center-involved diabetic macular edema

David J Browning,1 Chong Lee,1 Michael W Stewart,2 Maurice B Landers III3 1Charlotte Eye, Ear, Nose and Throat Associates, Charlotte, NC, 2Mayo Clinic, Jacksonville, FL, 3Kittner Eye Center, University of North Carolina, Chapel Hill, NC, USA Purpose: To determine the effect of vitrectomy for center-involved diabetic macular edema (CI-DME). Methods: This was a retrospective study of 53 eyes of 45 patients who had vitrectomy for CI-DME and were followed up for at least 12&nbsp;months. Charts were reviewed for visual acuity (VA), central subfield mean thickness measured by optical coherence tomography, presurgical and postsurgical interventions for CI-DME, and number of office visits in the first 12&nbsp;months after surgery. Preoperative spectral domain optical coherence tomography was performed on 38 patients, and they were graded for ellipsoid zone (EZ) intactness by three independent graders with assessment of agreement between graders using intraclass correlation coefficients and Bland&ndash;Altman analysis. Results: The median VA improved from 20/100 (interquartile range [IQR], 20/63&ndash;20/200) at baseline to 20/63 (IQR, 20/32&ndash;20/125) at 12&nbsp;months. The median central subfield mean thickness improved from 505&nbsp;&micro;m (IQR, 389&ndash;597&nbsp;&micro;m) at baseline to 279&nbsp;&micro;m (IQR, 246&ndash;339&nbsp;&micro;m) at 12&nbsp;months. Intergrader agreement for EZ intactness was moderate (intraclass correlation coefficients 0.4294&ndash;0.6356). There was no relationship between preoperative intactness of the EZ and the 12-month change in VA. Conclusion: Vitrectomy consistently thins the macula in CI-DME and, on average, leads to clinically significant improvement in VA comparable in size to that reported with serial intravitreal anti-vascular endothelial growth factor injections. A large, comparative, prospective, randomized clinical trial of these two treatments is needed to determine which is more effective and cost-effective. Keywords: center-involved diabetic macular edema, diabetic macular edema, vitrectomy, spectral domain OC

Long-term visual and retinopathy outcomes in a predominately type 2 diabetic patient population undergoing early vitrectomy and endolaser for severe vitreous haemorrhage

PURPOSE: To evaluate the long-term visual outcome of type 2 diabetic patients receiving early vitrectomy and endolaser for severe vitreous haemorrhage (VH). MATERIALS AND METHODS: Retrospective case note review of 88 eyes (69 type 2 diabetics and 19 type 1 diabetics) of 80 patients who underwent vitrectomy and endolaser within 6 months of VH. Post-operative and most recent VA, in addition to long-term retinopathy grading, were analysed. A subset of patients fulfilling the criteria for the Diabetic Retinopathy Vitrectomy Study was compared with this study. RESULTS: Mean pre-operative visual acuity (VA) in the type 2 group was 0.64 logMAR, with 1 eye showing perception light (PL), 10 eyes detecting hand movements (HMs), and 7 eyes counting fingers (CFs). At the 2-week post-operative visit, the mean VA had improved to 0.46 logMAR, with two eyes showing PL, two eyes detecting HM, and one eye CF (P=0.0002); at the last review, mean VA score was 0.36 logMAR, with three eyes showing PL and four eyes detecting HM (P=0.0008). Mean pre-operative VA in the type 1 group was 0.47 logMAR, with one eye showing PL, one eye detecting HM, and two eyes CF. At the 2-week post-operative visit, the mean VA had improved to 0.37 logMAR, with one eye showing PL (P=0.002), and at the latest review, the mean VA was 0.20 logMAR (P=0.027). CONCLUSION: Our study shows that type 2 DM patients can observe improvement in VA and stabilisation of their proliferative retinopathy after early vitrectomy and endolaser for vitreous haemorrahage, which is maintained after long-term follow-up