Denosumab and risk of hypocalcaemia
Many people with osteoporosis are unable to tolerate oral bisphosphonates—many others would prefer a six monthly denosumab injection to a once weekly pill that comes with orders to stay upright and not eat or drink for 30 minutes after taking it. However, denosumab carries a risk of hypocalcaemia, explored in a cohort study of women in the US with chronic kidney disease. The risk of needing emergency treatment for hypocalcaemia increased with stage of chronic kidney disease: 3% of dialysis-dependent patients and 0.57% of non-dialysis-dependent patients with chronic kidney disease stages 4 and 5 had a hospital admission or emergency department visit for hypocalcaemia within 12 weeks of starting denosumab, compared with 0.00% and 0.03% respectively in those starting oral bisphosphonates.
Ann Intern Med doi:10.7326/M24-00
Tirzepatide for heart failure with preserved ejection fraction
GLP-1 studies seem so 2023: why study a glucagon-like peptide-1 (GLP-1) agonist when you can study a GLP-1 and glucose-dependent insulinotropic polypeptide agonist such as tirzepatide? The latest study recruited 731 patients with heart failure and an ejection fraction of at least 50% and a body mass index of 30 or more. Participants were randomised to receive either tirzepatide (up to 15 mg a week) or placebo and were followed up for 52 weeks. Of those in the tirzepatide group, 9.9% reached the composite primary outcome of death from cardiovascular causes or a worsening heart failure event, compared with 15.3% in the placebo group (hazard ratio 0.62 (95% CI 0.41 to 0.95)). This difference was driven by fewer heart failure events—there were actually three more cardiovascular deaths in the tirzepatide group, although this difference wasn’t statistically significant. Improvements in quality of life, as measured by the Kansas City Cardiomyopathy Questionnaire clinical summary score, were also greater in the tirzepatide arm of the trial.
N Engl J Med doi:10.1056/NEJMoa2410027
The mechanics of tirzepatide
Nature Medicine published a secondary analysis of the same study, exploring the possible mechanisms for these clinical benefits. Chronic systemic inflammation and enlarged blood volume are hallmarks of obesity-related heart failure with preserved ejection fraction, both of which seem to be modified by tirzepatide, according to this study. Blood volume was reduced from 12 weeks onwards compared with the placebo group, while systolic blood pressure, but not diastolic blood pressure, was reduced from four weeks of treatment. Inflammation, as measured by high sensitivity C reactive protein, was reduced by 24 weeks, and those taking tirzepatide even saw a small improvement in estimated glomerular filtration rate at 52 weeks (2.9 mL/min/1.73 m2 (95% CI 0.9 to 4.9)) and a 25% reduction in albumin-creatinine ratio (95% CI 12.7% to 35.5%).
Nat Med doi:10.1038/s41591-024-03374-z
Cheese and onion
Although known as the “cheese and onion” owing to its yellow, red, and green cover, I’m yet to find a pack of crisps that looks anything like the Oxford Handbook of Clinical Medicine. Back in the old days (2000s) before smartphones, one of the most useful things a house officer could do was carry a cheese and onion around with them. A page that often had the fancy red ribbon bookmark in it was the one on hyponatraemia, complete with warnings on the need to slowly reverse severe hyponatraemia to avoid osmotic demyelination syndrome.
A systematic review and meta-analysis of studies involving over 10 000 patients has found no statistically significant increase in the risk of osmotic demyelination syndrome with rapid correction of severe hyponatraemia (≥8-10 mmol/L per 24 hours) compared with slow correction (<8 or 6-10 mmol/L per 24 hours) or very slow correction (<4-6 mmol/L per 24 hours). Furthermore, the researchers found moderate certainty evidence that rapid correction was associated with fewer in-hospital deaths (32 and 221 fewer per 1000 treated patients compared with slow and very slow correction respectively).
JAMA Intern Med doi:10.1001/jamainternmed.2024.5981
Ablation for chronic subdural haematoma
With our ageing population—increasing numbers of whom take antiplatelets and anticoagulants—chronic subdural haematoma is estimated to become the most common cranial neurosurgical disease by 2030. For those requiring surgery, the rate of recurrence leading to repeat surgery is around 15%. Three randomised control trials of middle meningeal artery ablation in addition to surgery have just been published in the New England Journal of Medicine, aiming to find out whether artery ablation can reduce the risk of recurrence and progression in people with symptomatic non-acute subdural haematoma. Unfortunately, the answer is still unclear: it “appears to have added benefit over standard treatment” concludes an editorial, but further data are needed to determine which group of patients stand to benefit the most, and by how much.
N Engl J Med doi:10.1056/NEJMoa2313472, doi:10.1056/NEJMoa2401201, doi:10.1056/NEJMoa2409845, doi:10.1056/NEJMe2410915
