An opinionated take on NEJM highlights for the third quarter of 2023

How the US taxpayer saved 25M+ people

A short piece celebrating the 20th anniversary of PEPFAR, a program that few outside of the field of Global Health are aware of. The world is not always nasty and brutish – it’s a shame it’s not said a bit more often. PEPFAR at 20 — A Game-Changing Impact on HIV in Africa


A hypertension trend?

A second study of an investigational antihypertensive drug in the Journal this year; are we back in the 80s or something?  Joking aside, cardiac and vascular disease remains the number one cause of mortality and disability, and despite a plethora of therapeutic agents, hypertension remains an important driver, mostly because of compliance and access. Zilebesiran (Alnylam) is an RNAi that reduces angiotensinogen synthesis, a pathway precursor to the targets of many traditional antihypertensive agents. In a phase 1b trial it was shown that: (1) it achieved reduction of blood pressure ~20 mmHg (SBP), a magnitude that is highly clinically significant; (2) response to a single subcutaneous injection was sustained at 24 weeks; (3) there was no renal impact, something that may be a differentiating factor; (4) it was well tolerated (though I would have really liked to see some PRO data, given that some antihypertensive agents have significant impact on QOL). It’s early days, but the potential is real. Combined with inclisiran for lipids (despite lower-than-expected uptake so far), one could imagine a new paradigm where management of cardiovascular risk is a matter of a couple of shots twice a year, rather than being tethered to a pillbox for the rest of one’s life. Zilebesiran, an RNA Interference Therapeutic Agent for Hypertension


Lilly is on a roll

As if tirzepatide (Mounjaro) was not enough, Lilly comes out with two mid-stage compounds with impressive efficacy. One is retatrutide, an injectable (subcutaneous) peptide that targets the glucagon receptor in addition to the GLP-1 and GIP receptors (already targeted by tirzepatide), and the results are spectacular with weight loss at a year of more than 25% for non-diabetic individuals with BMI > 35, and normalization of many markers of cardiovascular risk. We are now getting to bariatric surgery territory. The other is orforglipron, an oral small molecule that is a partial agonist of the GLP-1 receptor (same as semaglutide) which achieved a weight loss of 15% at week 36 (for reference Rybelsus (Novo) achieved the same level of weight loss but after 68 weeks). My gripe is that (as for the zilbesiran study above) no PROs are reported about how patients actually feel about their quality of life.  Triple–Hormone-Receptor Agonist Retatrutide for Obesity — A Phase 2 Trial; Daily Oral GLP-1 Receptor Agonist Orforglipron for Adults with Obesity


Rumbles of change in ESRD

Hemodiafiltration is an alternative to hemodialysis where a much larger fraction of the uremic plasma is allowed to diffuse through a high flux membrane. To replace that outflow, a large volume (20+ liters per session) of sterile crystalloid solution is infused as the final step of the loop. Until now, it has not been clear what approach is more favorable in ESRD, but a robust, large European trial involving 1360 randomized subjects followed for a median of 2.5 years is providing the beginning of answer: patients in the hemodiafiltration group were 25% less likely to die than those in the hemodialysis group (17% vs. 22% dying). The applicability of these results to the US population (which is substantially different) is not automatic, but, curiously, I am unable to find a single US study looking at this. Effect of Hemodiafiltration or Hemodialysis on Mortality in Kidney Failure


A new option for sickle cell

As we wait for the FDA decision on Bluebird’s LentiGlobin ex-vivo gene therapy for sickle cell disease (PDUFA in December), a CRISPR-based alternative is emerging from Novartis. Instead of introducing a normal version of hemoglobin in hematopoietic stem cells as with LentiGlobin, the idea is to maintain transcription of fetal hemoglobin (which is non-sickling) by editing the promoter(s) (functionally, the repressors) using the CRISPR platform and a judiciously chosen guide RNA with which to edit stem cells (also ex-vivo). Results with the first three patients have been promising – all three have maintained a high level of fetal hemoglobin and experienced a much reduced burden of disease over a 6 to 18 months duration. Bigger and longer studies will be needed to see how this compares with Bluebird’s approach, but a couple sentences in the discussion caught my attention:

“Previous studies of autologous HSCT for sickle cell disease used freshly collected cells to manufacture the cellular drug product. In contrast, in the current study, we used a cryopreserved apheresis product to facilitate future access to OTQ923 therapy for the majority of patients with sickle cell disease who reside in low-resource settings.”

Significant given that most individuals with sickle cell disease live in Western Africa. CRISPR-Cas9 Editing of the HBG1 and HBG2 Promoters to Treat Sickle Cell Disease


Offered without comment:

“To reduce unnecessary EMS transport referrals to hospital emergency departments for mild traumatic brain injury, Munich EMS authorities placed a mobile computed tomographic (CT) scanner on the festival grounds in 2022.” Mobile Computed Tomography at Munich Oktoberfest


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

We use cookies
This website collects cookies to deliver better user experience and to analyze our website traffic and performance; we never collect any personal data or target you with ads.