PrimeCuts-This Week in the Journals

May 26, 2009

disruptionMichael Chen MD

Faculty Peer Reviewed

We’ve all seen the now almost omni-present ads on TV, in newspapers and magazines, and especially on the MTA subways: the image of a woman or man holding up missing digits or limbs talking about the multiple amputations brought about by their smoking or diabetes. The image of a person with amputated limbs evokes a strong emotional response that can linger with us for some time and can provide a powerful message to those needing to control their diabetes or to quit smoking.

This week many of the larger online news publications, including Reuters and CNN, picked up on a story that can be summarized in the Associated Press headline: “Diabetes Drug Lowers Amputation Risk.” Those of us in the medical community likely prefer to refer to the article, from this week’s Lancet, as the FIELD study and will recognize the “diabetes drug” in question as the fibrate Tricor. Rajami et. al.’s study was a large randomized control trial that compared the effectiveness of the lipid lowering drug fenofibrate vs. placebo in reducing the number of lower-limb amputation events in Type 2 diabetics. The study showed a significant decrease in the number of first minor amputations, especially those without known large vessel disease, and in overall first amputations in the fenofibrate group. This effect appeared to emerge after 1.5 years of fenofibrate use. Proposed mechanisms for fenofibrate’s vascular effects  include potential anti-inflammatory, anti-angiogenic and endothelial-mediated properties that may improve wound-healing.

Lancet also published an article by Ray and colleagues examining the effects of intensive vs. standard glycemic control on cardiovascular events and death in type 2 diabetics. This meta-analysis of five randomized control trials demonstrated that a reduction in A1C by 0.9% resulted in a significant 17% reduction in non fatal MI, 15% reduction in events of CAD, and a non-significant effect on all-cause mortality. Although these results may appear obvious, prior studies have provided evidence to show tight glycemic control improves mortality and microvascular benefits, but had failed to consistently show benefits on cardiovascular events. This has lead to Class IIB recommendations for the benefit of glycemic control on cardiovascular events by the AHA and ACP in the most recent guidelines. These guidelines may evolve as more direct evidence linking tight blood sugar control and CHD events emerges.

Tight blood pressure control in diabetics has long been a dogma in the fight to prevent both the microvascular and macrovascular events in diabetics but our pathophysiologic understanding of blood pressure regulation itself and the role of salt intake is still somewhat limited. An article in Nature Medicine this week proposes an updated model of salt regulation in the interstitial and vascular compartments that implicates the lymphatic system and macrophages as important regulators of the salt environment in the body. The study, published by Machnik et. al, demonstrated that a high-salt diet (HSD) activated signaling in the mononuclear phagocyte system (MPS) leading to increased VEGF-C secretion, lymph capillary network hyperplasia and increased endothelial nitric oxide synthase expression. Inhibition of these processes led to increased blood pressure in rats. This implies that there may be a three-compartment model of salt-fluid regulation involving the lymphatic system and that within this system, the macrophage/dendritic cell system may be crucial in the buffering of the salt balance of the body. This model may provide a better understanding of salt regulation in the body, control of hypertension, and potential therapeutic targets.

From diabetes to hypertension and now from hypertension to the front-lines of primary care, the BMJ recently highlighted an article that seeks to upend some of the standards of care for blood pressure monitoring in the outpatient setting. Using data from the treatment arm of the perindopril against recurrent stroke study, Keenan and colleagues analyzed blood pressure readings for patients on the ACE-inhibitor perindopril from three months of treatment and every three months thereof until 3 years of treatment had been achieved. They demonstrated that changes in recorded blood pressure at the early follow-up intervals, i.e. six months after treatment, were much more likely to reflect measurement error than a true increase in blood pressure. Based on their study the probability that an increase in blood pressure was true as opposed to falsely positive was barely greater than 50% if the first monitoring interval was at 2 years. This is not to suggest that doctors start checking blood pressures every few years, but rather that we improve our shorter-term blood pressure monitoring accuracy with improved baseline blood pressures, more frequent follow ups for abnormal blood pressures, and better machines.

Often times we find that the major news outlets tend to exaggerate when it comes to “breaking news” long known by the medical community, the MRSA outbreak being one that comes to mind. But in this case providing a little sensationalization to diabetes and amputations may be of benefit. Coupled with some potential advances in hypertension highlighted in this week’s journals there is some certainly more progress being made to fight these chronic diseases. This is good news for both the patients in those ads and for those of us who no longer wish to see such graphic representations on our commutes home.

Dr. Chen is a second year resident in internal medicine at NYU Medical Center.

Peer reviewed by Barbara Porter, MD MPH,  Clinical Assistant Professor of Medicine, NYU Medical Center


Keenan K, Hayen A, Neal BC et. al. Long term monitoring in patients receiving treatment to lower blood pressure: analysis of data from placebo controlled randomised controlled trial. BMJ. 2009;338:b1492

Machnik A, Neuhofer W, Jantsch J et. al. Macrophages regulate salt-dependent volume and blood pressure by a vascular endothelial growth factor-C-dependent buffering mechanism. Nature Medicine. 2009;15:545-552

Ray K, Seshasai S, Wijesuriya S et. al. Effect of intensive control of glucose on cardiovascular outcomes and death in patients with diabetes mellitus: a meta-analysis of randomised controlled trials. The Lancet. 2009; 373(9677):1765-1772

Rajamani K, Colman PC, Li LP et. al. Effect of fenofibrate on amputation events in people with type 2 diabetes mellitus (FIELD study): a prespecified analysis of a randomised controlled trial. The Lancet. 2009; 373(9677):1780-1788

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