Angiotensin-receptor blockade versus converting-enzyme inhibition in type 2 diabetes and nephropathy.

BACKGROUND: Few studies have directly compared the renoprotective effects of angiotensin II-receptor blockers and angiotensin-converting-enzyme (ACE) inhibitors in persons with type 2 diabetes. METHODS: In this prospective, multicenter, double-blind, five-year study, we randomly assigned 250 subjects with type 2 diabetes and early nephropathy to receive either the angiotensin II-receptor blocker telmisartan (80 mg daily, in 120 subjects) or the ACE inhibitor enalapril (20 mg daily, in 130 subjects). The primary end point was the change in the glomerular filtration rate (determined by measuring the plasma clearance of iohexol) between the baseline value and the last available value during the five-year treatment period. Secondary end points included the annual changes in the glomerular filtration rate, serum creatinine level, urinary albumin excretion, and blood pressure; the rates of end-stage renal disease and cardiovascular events; and the rate of death from all causes. RESULTS: After five years, the change in the glomerular filtration rate was -17.5 ml per minute per 1.73 m2 (where the minus sign denotes a decrement) in the telmisartan-treated subjects, as compared with -15.0 ml per minute per 1.73 m2 in the enalapril-treated subjects; the treatment difference was thus -2.6 ml per minute per 1.73 m2 (95 percent confidence interval, -7.1 to 2.0 ml per minute per 1.73 m2)[corrected] The lower boundary of the confidence interval, in favor of enalapril, was greater than the predefined margin of -10.0 ml per minute per 1.73 m2, indicating that telmisartan was not inferior to enalapril. The effects of the two agents on the secondary end points were not significantly different after five years. CONCLUSIONS: Telmisartan is not inferior to enalapril in providing long-term renoprotection in persons with type 2 diabetes. These findings do not necessarily apply to persons with more advanced nephropathy, but they support the clinical equivalence of angiotensin II-receptor blockers and ACE inhibitors in persons with conditions that place them at high risk for cardiovascular events.

Azithromycin inhibits interleukin-6 but not fibrinogen production in hepatocytes infected with cytomegalovirus and chlamydia pneumoniae.

Chlamydia pneumoniae and cytomegalovirus (CMV) have been associated with the development of atherosclerosis. Inflammatory stimuli initiate the biosynthesis of fibrinogen, interleukin (IL)-6 and plasminogen activator inhibitor (PAI)-1 in the liver. Chronic infection may perpetuate the inflammatory status. We hypothesized that infection of human hepatocytes with the intracellular pathogens C pneumoniae and CMV accelerates biosynthesis of fibrinogen, IL-6, and PAI-1 but that this biosynthesis can be reduced with the use of azithromycin. HepG2 human hepatocytes were infected with C pneumoniae and CMV in vitro in the presence of 0, 0.016, 0.125, or 1 microg/mL azithromycin. We measured IL-6, PAI-1, and fibrinogen after 24, 48, 72, and 96 hours. C pneumoniae-infected hepatocytes produce IL-6 (2667 +/- 309 pg/mL vs 137 +/- 120 pg/mL in uninfected cells after 96 hours. Incubation with 0.016 microg/mL azithromycin decreased IL-6 levels to a mean of 1516 +/- 402 pg/mL, and incubation with 0.125 and 1 microg/mL azithromycin decreased IL-6 to 871 +/- 364 and 752 +/- 403 pg/mL, respectively. C pneumoniae-induced IL-6 production was time- and dose-dependent. The interaction of C pneumoniae with azithromycin treatment was significant, indicating an inhibitory effect of azithromycin on C pneumoniae-induced IL-6 production. CMV infection did not lead to IL-6 production by hepatocytes. C pneumoniae and CMV infection did not induce any changes in PAI-1 production. Fibrinogen production was increased by CMV infection after 72 hours (838 +/- 88 ng/mL; P <.01) and after 96 hours by infection with both C pneumoniae and CMV (765 +/- 100 and 846 +/- 123 ng/mL, respectively; P <.05). Azithromycin did not suppress CMV- or C pneumoniae-induced fibrinogen production. Moreover, we could not confirm an antiinflammatory effect of azithromycin in experiments with cross-titrations of azithromycin against either IL-1 or IL-6 (P >.05). Azithromycin reduces C pneumoniae-induced IL-6 production, but not fibrinogen production, by human hepatocytes. This is a result of the antimicrobial properties of azithromycin and not a direct antiinflammatory effect.