Metformin, Asian ethnicity and risk of prostate cancer in type 2 diabetes: a systematic review and meta-analysis.

BACKGROUND: Metformin is associated with a reduced risk of some cancers but its effect on prostate cancer is unclear. Some studies suggest only Asians derive this benefit. Therefore, we undertook a systematic review with particular attention to ethnicity. METHODS: Medline, Embase, Scopus, Web of Science, and EBM Reviews were searched from inception to 2015. Two reviewers identified and abstracted articles. Studies were pooled using random effects model and stratified by Western- vs Asian-based populations. RESULTS: We identified 482 studies; 26 underwent full review. Of Western-based studies (n = 23), two were randomized trials and 21 were observational studies. All Asian-based studies (n = 3) were observational. There were 1,572,307 patients, 1,171,643 Western vs 400,664 Asian. Across all studies there was no association between metformin and prostate cancer (RR: 1.01, 95%CI: 0.86-1.18, I2: 97%), with similar findings in Western-based trials (RR: 1.38, 95%CI: 0.72-2.64 I2: 15%) and observational studies (RR: 1.03 95%CI: 0.94-1.13, I2: 88%). Asian-based studies suggested a non-significant reduction (RR: 0.75, 95%CI: 0.42-1.34, I2: 90%), although these results were highly influenced by one study of almost 400,000 patients (propensity-adjusted RR: 0.47 95%CI 0.45-0.49). Removing this influential study yielded an estimate more congruent with Western-based studies (RR: 0.98 95%CI:0.71-1.36, I2: 0%). CONCLUSION: There is likely no association between metformin and risk of prostate cancer, in either Western-based or Asian-based populations after removing a highly influential Asian-based study.

Safety of Concomitant Metformin and Proton Pump Inhibitor Use: A Population Retrospective Cohort Study.

PURPOSE: The purpose of this study was to investigate the effect of concomitant use on important clinical outcomes. METHODS: In this retrospective cohort study, a cohort of new metformin users was identified between 2004 and 2010 and followed up until termination of insurance coverage, December 31, 2010, or the outcomes were reached. The primary outcome was a composite of time to all-cause mortality or hospitalization; our secondary outcome was time to cardiovascular hospitalization. Exposures to metformin, a proton pump inhibitor (PPI), and/or a histamine2 receptor antagonist (H2RA) were compared with a Cox proportional hazards model after adjustment. FINDINGS: Relative to metformin-only users, metformin and PPI users were at increased risk of the primary outcome (adjusted hazard ratio [HR] = 1.55; 95% CI, 1.46-1.64); metformin and H2RA users also had an elevated risk (adjusted HR = 1.29; 95% CI, 0.97-1.70). Similar patterns were seen with cardiovascular-specific hospitalization. Compared with no drug use, metformin users had an increased risk of the primary outcome, but risk was substantially elevated when patients were taking PPIs or H2RAs, alone or in combination with metformin. IMPLICATIONS: Concomitant use of metformin and a PPI or metformin and an H2RA were associated with an increased risk of death or hospitalization. This finding suggests that the harm observed may not be due to a specific drug interaction but uncontrolled confounding secondary to an increased risk in those patients using a PPI or H2RA.

Mixed messages: The Blueprint for Pharmacy and a communication gap.

BACKGROUND: More than 5 years ago, the Blueprint for Pharmacy developed a plan for transitioning pharmacy practice toward more patient-centred care. Much of the strategy for change involves communicating the new vision. OBJECTIVE: To evaluate the communication of the Vision for Pharmacy by the organizations and corporations that signed the Blueprint for Pharmacy's Commitment to Act. METHODS: The list of 88 signatories of the Commitment to Act was obtained from the Blueprint for Pharmacy document. The website of each of these signatories was searched for all references to the Blueprint for Pharmacy or Vision for Pharmacy. Each of the identified references was then analyzed using summative content analysis. RESULTS: A total of 934 references were identified from the webpages of the 88 signatories. Of these references, 549 were merely links to the Blueprint for Pharmacy's website, 350 of the references provided some detailed information about the Blueprint for Pharmacy and only 35 references provided any specific plans to transition pharmacy practice. CONCLUSION: Widespread proliferation of the Vision for Pharmacy has not been achieved. One possible explanation for this is that communication of the vision by the signatories has been incomplete. To ensure the success of future communications, change leaders must develop strategies that consider how individual pharmacists and pharmacies understand the message.

Prevention of angiotensin II-mediated renal oxidative stress, inflammation, and fibrosis by angiotensin-converting enzyme 2.

Angiotensin-converting enzyme 2 (ACE2) is a monocarboxypeptidase capable of metabolizing angiotensin (Ang) II into Ang 1 to 7. We hypothesized that ACE2 is a negative regulator of Ang II signaling and its adverse effects on the kidneys. Ang II infusion (1.5 mg/kg⁻¹/d⁻¹) for 4 days resulted in higher renal Ang II levels and increased nicotinamide adenine dinucleotide phosphate oxidase activity in ACE2 knockout (Ace2(-/y)) mice compared to wild-type mice. Expression of proinflammatory cytokines, interleukin-1ß and chemokine (C-C motif) ligand 5, were increased in association with greater activation of extracellular-regulated kinase 1/2 and increase of protein kinase C-α levels. These changes were associated with increased expression of fibrosis-associated genes (α-smooth muscle actin, transforming growth factor-ß, procollagen type Iα1) and increased protein levels of collagen I with histological evidence of increased tubulointerstitial fibrosis. Ang II-infused wild-type mice were then treated with recombinant human ACE2 (2 mg/kg⁻¹/d⁻¹, intraperitoneal). Daily treatment with recombinant human ACE2 reduced Ang II-induced pressor response and normalized renal Ang II levels and oxidative stress. These changes were associated with a suppression of Ang II-mediated activation of extracellular-regulated kinase 1/2 and protein kinase C pathway and Ang II-mediated renal fibrosis and T-lymphocyte-mediated inflammation. We conclude that loss of ACE2 enhances renal Ang II levels and Ang II-induced renal oxidative stress, resulting in greater renal injury, whereas recombinant human ACE2 prevents Ang II-induced hypertension, renal oxidative stress, and tubulointerstitial fibrosis. ACE2 is an important negative regulator of Ang II-induced renal disease and enhancing ACE2 action may have therapeutic potential for patients with kidney disease.