NEJM Highlights November 2015: systems biology, RSV progress, a first in diabetes, hypertension goals, the case of Maryland


Systems biology finally gets real: an unexpected use for a diabetes drug

Chronic Myelogenous Leukemia (CML) has been the poster child first for a disease with a precise genetic cause (the Philadelphia chromosome), and then for targeted drug design (with imatinib – Gleevec). Unfortunately, few patients achieve a complete response to therapy which means that they have to stay on drug indefinitely. This commentary highlights recent research which shows that pioglitazone (Actos), an approved diabetes drug that activates a specific cellular pathway (STAT5) can synergistically enhance treatment with Gleevec to achieve a potential cure.  While this particular work affects only a relatively small number of patients, it is an example of an approach that will grow over time. We now have hundreds of approved drugs with selective biological targets. As our understanding of the way various biomolecular pathways fit together develops, there will be increasing opportunities to pick in the pharmacological toolbox and combine drugs from different disease areas to create new therapies. What the corresponding business model will be remains an open question though. Targeting Stem Cells in Chronic Myeloid Leukemia with a PPAR-γ Agonist (subscriber access)


A drug to treat RSV

On any winter night in the US, it is not unusual to find half the beds of a pediatric ward occupied by children with a respiratory syncytial virus (RSV) infection. Unfortunately, the search for a vaccine has been elusive and therapy is largely supportive. In a promising early study of a novel nucleoside analogue (ALS-008176, Alios Biopharma, now a subsidiary of J&J) in healthy adults deliberately infected with RSV, those subjects who subsequently received the study drug had lower viral loads and less symptoms than those who received placebo. If confirmed to also be effective in children (who bear most of the burden of RSV) under real-life conditions, this will be a block-buster.  Activity of Oral ALS-008176 in a Respiratory Syncytial Virus Challenge Study (subscriber access)


A first in diabetes

It is generally observed that diabetes leads to cardiovascular morbidity, but prospective studies showing that improved blood sugar control would lead to decrease major cardiovascular events have been noticeably lacking. In a first, a 3-year study of empagliflozin (Jardiance, BI/Eli Lilly, a relatively new agent to lower blood sugar by enabling its excretion in the urine) involving ~7000 patients at high cardiovascular risk, treatment lowered the yearly rate of major cardiovascular events from ~4%/yr in the placebo arm to ~3.5%/yr in the active arm. Given that this kind of result has not been observed with other diabetes drugs, one wonders if there isn’t another cause beyond the sugar lowering effect.  Finally, we note that the cardiovascular benefit for empagliflozin appears to be about half that of the new PCSK9 inhibitors (absolute risk reduction of ~1%/yr), whereas the price of Jardiance (~$4000/yr) is about 30% of the PCSK9 (~$14,000/yr) – a bargain? Empagliflozin, Cardiovascular Outcomes, and Mortality in Type 2 Diabetes; Cardiovascular Risk and Sodium–Glucose Cotransporter 2 Inhibition in Type 2 Diabetes (subscriber access)


Lowering the blood pressure goals

High blood pressure is clearly a source of cardiovascular risk, but how low should one go? In this massive NIH funded study with 9000+ non-diabetic hypertensive subjects, a target systolic blood pressure (SBP) of 140 mmHg was compared to 120 mmHg. The study was stopped early due to a lower incidence of major cardiovascular events in the lower SBP group – the absolute difference was ~0.5% less events per person year. Considering that most antihypertensive drugs are now generic, the cost of that benefit is certainly less than $1000/yr – a bargain. A Randomized Trial of Intensive versus Standard Blood-Pressure Control; Redefining Blood-Pressure Targets — SPRINT Starts the Marathon; Time to Reassess Blood-Pressure Goals (open access)


The Maryland experiment

Maryland had a unique model that disallowed variations between payers (including CMS) in the schedule of fees charged by hospitals.  With passage of the ACA, the state is now switching to an all-payer global payment system which essentially capitates individual hospitals across the population they serve with a modifier for quality measures. In this perspective, early results are presented showing a decrease in cost, and an improvement in most quality metrics. However, here the Journal fails us, in that this should never have been published as a perspective but rather have come out as a fully peer-reviewed paper complete with detailed methods. The importance of this experiment is too great, and without the customary supplementary materials on methodology that accompany such papers, it is hard to get to a conclusion with confidence. Maryland’s Global Hospital Budgets — Preliminary Results from an All-Payer Model (subscriber access)


The New England Journal of Medicine is a premier weekly medical journal covering many topics of interest to the health sector. In this monthly series we offer a brief overview of highlights that might be of interest to our clients and others.