Metformin: Have we Been Overcautious in CKD?

SOURCE: Inzucchi SE, et al. JAMA 2014;312:2668-2675.

Boundaries devised by regulatory agencies around the world for safe use of metformin differ from FDA labelling in the United States. Many other nations allow more liberal use of metformin, indicating it as safe at lower levels of renal function than the boundaries physicians are used to: creatinine ≥ 1.5 md/dL for men, ≥ 1.4 mg/dL for women, or an eGFR < 60 mL/min/1.73 m2. The observation that metformin has been used in patients with chronic kidney disease (CKD) beyond these boundaries safely, and the relative rarity of lactic acidosis related to metformin in the United States, has stimulated a reappraisal of the recommendations for patients with CKD. Metformin is cleared by the kidneys, but the original dosing and safety recommendations put into place more than 20 years ago are reportedly based on potential administration of metformin at doses up to 3g/d, which, of course, is substantially above the usual maximum dose actually used in the United States (2000-2550 mg/d).

Inzucchi et al reviewed the literature in reference to studies that evaluated metformin, kidney disease, and lactic acidosis. Several trials even included plasma metformin measured at eGFR levels as low as < 30 mL/min. The authors opine that — contingent on regular monitoring — metformin might be safely used in diabetics with CKD down to an eGFR as low as 30 mL/min.


Reduction in Prostate Cancer Mortality with Screening

SOURCE: Schroder FH, et al. Lancet 2014;384:2027-2035.

The pendulum swing in enthusiasm for prostate cancer screening from strong endorsement to disenchantment resulted from a huge clinical trial database of two mega trials that enrolled more than 250,000 men. One trial, the European Randomised Study of Screening for Prostate Cancer (n = 182,160), demonstrated a reduction in prostate cancer-related mortality at 9-years follow-up, but no reduction in total mortality. Since all-cause mortality was not reduced, policy makers rightly questioned the propriety of advising large-scale screening if the overall rate of death was not altered.

The European Randomized Study of Screening for Prostate Cancer now has data on up to 13 years of follow-up, which remain concordant with their findings at 9 and 11 years: a reduction in prostate cancer mortality (rate ratio 0.79, or a 21% reduction), but again no reduction in all-cause mortality.

Although a 21% relative reduction in prostate cancer mortality might seem impressive, the absolute risk reduction is much less so: avoidance of one prostate cancer death/781 men screened. Based on the recommendations of the United States Preventive Services Task Force, most primary care clinicians have minimized screening of average-risk adult men for prostate cancer. These results confirm the rationale for that clinical posture. n


Doing the Right Thing for Acute Bronchitis in Healthy Adults: Antibiotics

SOURCE: Smith S. JAMA 2014;312:2678-2679.

The scenario is commonplace, evokes sympathy, and might even make you feel a little uncomfortable: Your third patient of the morning comes in with an apparently viral bronchitis, with the chief complaint of “I need some antibiotics.” While an antibiotic prescription might seem to be the path of least resistance, the literature does not provide support that it is the wisest path.

Most cases of acute bronchitis in healthy individuals are viral. A review of seven randomized trials found that antibiotic treatment provided a short-term benefit of .5 day shorter duration of cough than placebo. This modest benefit needs to be weighed in comparison to the many adverse effects associated with antibiotic administration. Concordant with these observations, the National Institute for Care Excellence (United Kingdom) guidelines have suggested that antibiotics not be used for healthy persons in the absence of pneumonia.

While some patients will be disappointed if antibiotics are not dispensed, an explanation of the risk:benefit ratio will often assuage them. Despite increasing awareness of the limited benefits of antibiotics, over-prescribing remains commonplace. n