The scale of the discrepancy is easiest to see with the glucagon-like peptide-1 receptor agonists, the class of drugs behind the global weight-loss revolution. A recent synthesis of real-world evidence found that between 20 and 50 percent of patients discontinue GLP-1 receptor agonists within the first year. Many who stay on treatment use substantially lower doses than those studied in trials, and the weight loss observed in clinical practice is consistently lower than in randomized controlled trials. Crucially, among highly adherent patients, outcomes approach the trial results, which suggests the drugs themselves are not the problem. The drivers of early discontinuation are familiar ones: gastrointestinal side effects, cost, insurance barriers, and supply shortages that have repeatedly left pharmacies without stock.

The consequences of stopping, however, are not uniform, and this is where the stakes become far higher than a number on a bathroom scale. For patients prescribed GLP-1 receptor agonists solely for weight management, discontinuation primarily results in weight regain. But the same drugs also reduce the risk of cardiovascular events and clinically important kidney disease outcomes compared with placebo. Because these protective benefits depend on continued exposure to the drug rather than conferring durable protection after withdrawal, a patient who stops treatment forfeits not only the weight loss but also reductions in morbidity and mortality. The prescription, in other words, is a subscription to benefit, and cancellation carries a clinical price.

A similar shortfall appears with anticoagulants, medications whose value is about as unambiguous as it gets. A systematic review and meta-analysis of nearly 595,000 patients with atrial fibrillation found that only two-thirds maintained good adherence to direct oral anticoagulants, the modern stroke-preventing drugs that require far less monitoring than their predecessor warfarin. Among those who did not adhere, the risk of stroke increased by 39 percent. That finding quantifies the distance between prescribed therapy and delivered benefit even for medications with straightforward dosing, and it reframes nonadherence from a vague behavioral concern into a measurable contributor to preventable strokes and deaths.

A different kind of adherence failure is unfolding with the recombinant zoster vaccine, which protects against shingles and requires only two doses separated by two to six months. A nationwide study of more than 726,000 US adults found that adherence to the recommended schedule was just 72 percent, with completion rates markedly lower among racial and ethnic minorities, younger adults, and people with lower household income. What makes this particularly consequential is emerging evidence about what the vaccine might do beyond preventing a painful rash. A large-scale longitudinal analysis of US health records found that herpes zoster vaccination was associated with a reduced risk of dementia, with stronger protection in people who received both doses of the recombinant vaccine compared with a single dose. A target trial emulation among nearly 510,000 skilled-nursing facility residents similarly found the vaccine was associated with reduced dementia risk. If these findings are confirmed by ongoing trials, every person who fails to complete the two-dose series may be forgoing not only protection against shingles but a potential modification of dementia risk.

The underlying problem itself has barely changed in fifty years of research, and that is precisely the point. Marcum’s argument centers on the opportunity cost of nonadherence, the benefit forgone when effective therapy goes untaken. The logic is straightforward: when adherence rates stay static while treatment effects grow, the benefit lost through nonadherence grows with them. The numbers illustrate the leap in therapeutic power. In a network meta-analysis, semaglutide reduced body weight by 11.4 percent from baseline compared with 3.1 percent for the older drug orlistat. Direct oral anticoagulants reduce stroke or systemic embolism by 19 percent compared with warfarin. The recombinant zoster vaccine cuts shingles risk by 92 percent, versus 51 percent for its live attenuated predecessor. But these benefits are realized only under the conditions of trial participation, where drugs are free and adherence is monitored. In practice, where patients bear cost-sharing and juggle competing demands, the attenuation of benefit is substantial.

The economics of the problem are genuinely awkward. With therapies costing tens of thousands of dollars per year, improving adherence increases short-term expenditures, a tension that makes payers uneasy even though the downstream costs of preventable hospitalizations and disease progression are far greater. Nonadherence itself is also heterogeneous, ranging from cost-related gaps in treatment to unintentional lapses in complex regimens, and effective solutions must account for that variation. Nor is every discontinuation a failure. Stopping a therapy after an informed discussion of adverse effects with a healthcare provider is shared decision-making, and conflating it with nonadherence distorts both research and policy.

What can be done? Established interventions such as patient education, simpler dosing schedules, and improved communication remain necessary but demonstrably insufficient. A Cochrane review of 182 randomized trials found that even the most effective adherence interventions, typically bundles of education, counseling, and ongoing support from health system professionals, produced only modest improvements in adherence or clinical outcomes. At the bedside, clinicians can treat adherence as a clinical decision point: counseling patients on the cardiorenal benefits at risk when a GLP-1 receptor agonist is stopped, checking persistence at every anticoagulant renewal, and stressing the importance of completing the vaccine series. But individual effort has limits, and the evidence says those limits arrive quickly.

That is why Marcum calls for a system-level reconceptualization of adherence as a determinant of therapeutic value, meaning interventions that change the environment in which prescriptions are written, filled, and consumed. For GLP-1 receptor agonists, that means addressing the structural barriers of cost, insurance coverage, and supply that drive discontinuation. For chronic medications, it means expanding pharmacists’ authority to manage therapy through collaborative practice agreements and transition-of-care programs, and aligning cost-sharing with therapeutic value through value-based insurance design. For multi-dose vaccines, it means integrating completion tracking into electronic health records. The proof that such approaches can work already exists: a randomized trial of nearly 6,000 patients after myocardial infarction eliminated copayments for cardiovascular medications, improving adherence by 4 to 6 percent and reducing rates of first major vascular events without increasing total health spending.

Compounding everything is the fact that nonadherence is hard to detect in routine practice. Clinicians consistently underestimate it, and the available measures, including pharmacy refill records, self-report, and electronic health record documentation, each capture only a partial picture. Artificial intelligence may eventually help close this detection gap, though rigorous evidence that such tools improve clinically meaningful endpoints remains limited. The bottom line, Marcum argues, is that the limiting factor in realizing the full value of modern therapeutics is no longer only pharmacology; it is human behavior, reinforced by systems that make adherence difficult. Until the same rigor applied to drug discovery is applied to coverage design, pharmacist-led programs, health information technology, and implementation research, medicine will keep paying for the promise of transformative therapies while realizing only a fraction of their benefit.

Subject of Research: Medication nonadherence and the widening gap between clinical trial efficacy and real-world effectiveness

Article Title: The widening medication adherence gap

Article References: Marcum, Z. A. (2026). The widening medication adherence gap. PLOS Medicine, 23(9), e1005237. https://doi.org/10.1371/journal.pmed.1005237

Image Credits: AI Generated

DOI: 10.1371/journal.pmed.1005237

Keywords: medication adherence, GLP-1 receptor agonists, anticoagulants, herpes zoster vaccine, dementia risk, obesity treatment, stroke prevention, health systems, value-based insurance design, pharmacist-led programs, PLOS Medicine, real-world evidence

The study, published on 2 October 2026, tackles a problem that has limited previous work in the field. Although H. manillensis has recently emerged as a key genomic reference among medicinal leeches, researchers had not systematically combined whole-genome read mapping with RNA sequencing data at the level of individual samples. The new workflow does exactly that, layering together genome alignment, transcriptome alignment and counting, DNA barcoding to confirm species identity, phylogenetic placement, reference-guided cataloging of known antithrombotic genes, transcript-supported discovery of new candidates, and targeted sequence comparison of selected loci. By integrating these strands of evidence, the authors could distinguish genes that are genuinely present and expressed from those that merely appear in a reference annotation, a distinction that matters enormously when the goal is to prioritize candidates for drug development.

A crucial early step was making sure the samples really were what the researchers thought they were. Species misidentification is a surprisingly common hazard in leech research, where closely related species can look nearly identical. The team used the mitochondrial cytochrome c oxidase subunit I gene, the standard DNA barcode for animals, to verify all four samples. BLAST searches against reference databases returned a top hit of MN882684 with 99.842 percent identity across 1,266 base pairs for every sample, and phylogenetic analysis placed each one squarely within the H. manillensis reference clade. That confirmation matters because any downstream claim about antithrombotic gene content would be undermined if the animals had been mislabeled, and it gives future users of the dataset confidence that the gene catalog truly describes this species.

The sequencing data itself was of high quality. Whole-genome mapping rates ranged from 72.17 percent to 92.75 percent across the four samples, with mean sequencing depths between 108.0-fold and 134.4-fold, deep enough to support confident read mapping and variant calling. The RNA-seq alignment rates ranged from 67.62 percent to 70.49 percent, providing a solid transcriptomic backbone for expression analysis. With these datasets in hand, the researchers turned to the central question: how many antithrombotic genes does the Asian buffalo leech carry, and which of them are actually switched on?

The reference-guided analysis recovered 72 known antithrombotic genes, matching the published annotation framework for the species and confirming that the pipeline was reproducing established results. The more exciting outcome came from the transcript-supported discovery stage, which added 38 new candidate transcripts. Of these, 30 represent novel isoforms of already-known gene loci, flagged by the annotation tool gffcompare with class code “j”, meaning they are splice variants or alternative transcripts of characterized genes. The remaining 8 are overlap-type candidates with class codes “o” and “x”, indicating transcripts that overlap known loci in ways that suggest either alternative structures or potentially distinct genes sharing genomic space. Notably, after filtering, no high-confidence class code “u” candidates, which would represent entirely unknown intergenic transcripts, survived, suggesting that the antithrombotic repertoire of this leech is largely built from elaborations of known gene families rather than from wholly novel loci hiding between annotated genes.

Among the gene families, one stood out for its sheer size. The H. manillensis elastase inhibitor family, abbreviated HMEI, was the largest supported family in the catalog, followed by hirustasin-related genes. Elastase inhibitors are of particular interest because elastase plays roles in inflammation and tissue remodeling as well as in clot-related processes, so a leech family that has expanded this class of inhibitors may be modulating more than just coagulation. Hirustasin, meanwhile, is a known serine protease inhibitor first characterized from the medicinal leech, and its relatives in H. manillensis reinforce the picture of a leech that deploys multiple independent inhibitory strategies against its host’s hemostatic system. The expansion of these families points to strong evolutionary pressure on blood-feeding animals to maintain a diverse and redundant toolkit for keeping blood liquid.

Expression data revealed a strikingly uneven picture across the four samples. The most abundant antithrombotic transcript overall was lefaxin_Hman2, a member of a family of anticoagulant proteins, yet expression of other loci varied dramatically from animal to animal, with clear sample-specific patterns among the HMEI genes in particular. This heterogeneity suggests that individual leeches may deploy somewhat different pharmacological cocktails when they feed, whether due to feeding status, physiological condition, or individual genetic variation. For drug discovery, that variability is a double-edged sword: it complicates any attempt to harvest a uniform product from leeches, but it also means that different individuals may naturally emphasize different bioactive molecules, broadening the pool of candidates accessible from this species.

Genetic variation added another layer of insight. The researchers assessed the variant burden across the antithrombotic genes and found it was highest for hyaluronidase_Hman2 and progranulin_Hman, two loci involved in tissue penetration and inflammation-related processes respectively. Intriguingly, the most highly expressed genes were not always the most variable, decoupling expression level from sequence diversity in a way that hints at different evolutionary constraints acting on different parts of the arsenal. Genes that interact directly with host immune and clotting proteins may be under pressure to diversify, while core anticoagulants may be conserved because their function cannot be tinkered with without cost. Selected-gene alignments confirmed localized substitutions and indel-rich regions in informative loci, providing concrete sequence differences that future functional studies can test.

The practical significance of the work lies in its framework as much as its findings. By combining species confirmation, deep genome mapping, transcriptome evidence, and rigorous annotation-based filtering, the study provides a reproducible pipeline for prioritizing antithrombotic candidates not just in H. manillensis but potentially in other blood-feeding species. The 38 transcript-supported candidates, particularly the 30 novel isoforms of known loci, represent a concrete shortlist for laboratory follow-up: expressing these variants recombinantly and testing their activity against thrombin, factor Xa, elastase, and platelet pathways would be the logical next step. The authors are affiliated with the Yunnan International Joint Laboratory with South and Southeast Asia for the Integrated Development of Animal-Derived Anti-Thrombosis Chinese Medicine at Qujing Normal University, and the work was funded under grant number 202503AP140025, reflecting a broader national effort to translate leech-derived molecules into modern antithrombotic therapies.

For a field that began with the discovery of hirudin in medicinal leech saliva more than a century ago, this study marks a shift from serendipity to systematic genomics. Cardiovascular disease remains the leading cause of death worldwide, and existing anticoagulants carry well-known risks of bleeding complications, so the demand for molecules with refined, targeted activity continues to grow. The Asian buffalo leech, now genomically characterized at the sample level with a verified catalog of 72 known genes and 38 new transcript-supported candidates, offers researchers a richer starting point than ever before. What remains is the functional work: confirming what these newly identified isoforms actually do, and whether any of them can be developed into the next generation of clot-preventing drugs. The leech, it turns out, still has plenty to teach modern medicine.

Subject of Research: Whole-genome and transcriptome profiling of antithrombotic genes in the Asian buffalo leech Hirudinaria manillensis

Article Title: Integrated whole-genome and transcriptome profiling of antithrombotic genes in Asian buffalo leech (Hirudinaria manillensis)

Article References: Farooq, T., Naeem, M., Bashir, N. H., Liu, Z., Chen, Y., & Chen, H. (2026). Integrated whole-genome and transcriptome profiling of antithrombotic genes in Asian buffalo leech (Hirudinaria manillensis). BMC Genomics. https://doi.org/10.1186/s12864-026-13354-x

Image Credits: AI Generated

DOI: 10.1186/s12864-026-13354-x

Keywords: Hirudinaria manillensis, antithrombotic genes, leech genomics, whole-genome sequencing, RNA-seq, COI barcoding, hirudin, medicinal leech, transcriptomics, drug discovery, anticoagulants, BMC Genomics

The study, published in BMC Geriatrics by a team of hospital pharmacists and pharmacoepidemiologists affiliated with Assistance Publique–Hôpitaux de Paris and Paris-Saclay University, set out to measure how often DOAC prescriptions in hospitalized older adults deviated from European Society of Cardiology (ESC) guidelines, and whether the situation had improved since a comparable assessment in 2018. The answer, in short, is that it had not.

Between November 2022 and May 2023, the researchers consecutively enrolled older adults who were already taking a DOAC before admission and who stayed in one of three French university hospitals for more than 24 hours. The participating departments spanned cardiology, internal medicine, post-emergency care, and acute geriatrics, giving a broad picture of real-world prescribing across the acute care pathway. In total, 536 patients were eligible, with a mean age of 84.1 years and a slight majority of women; 421 patients formed the primary analysis cohort.

The pharmacological profile of the cohort reflected current practice. Apixaban dominated, accounting for 70.1 percent of prescriptions, and atrial fibrillation was the indication in 83.6 percent of cases. This matters because apixaban, like all DOACs, has a narrow therapeutic window whose appropriateness hinges on patient-specific factors: renal function, age, body weight, and the indication being treated. Unlike warfarin, which is monitored with routine blood tests, DOAC dosing is fixed at prescription time, so an error at the moment of prescribing persists silently until harm occurs.

Using ESC guidelines as the benchmark, the team classified prescriptions as appropriate or inappropriate at two critical moments: hospital admission and hospital discharge. On admission, 32.0 percent of prescriptions were judged inappropriate. By discharge, the figure had fallen to 24.9 percent, a statistically significant improvement (p = 0.004), suggesting that the hospital stay does correct some errors, but leaves a substantial fraction of patients heading home with potentially unsafe anticoagulation.

The consequences of such errors are not abstract. An excessive dose in a frail 85-year-old with declining kidney function increases the risk of major bleeding, including intracranial hemorrhage. An insufficient dose, conversely, can mean therapeutic failure, allowing a stroke or systemic embolism to occur despite the patient dutifully taking their medication. In older patients with polypharmacy, where DOACs interact with other drugs and renal clearance is often reduced, the margin for error shrinks further, which is why inappropriate prescribing is considered a major patient safety concern in geriatric care.

To understand who was most at risk, the researchers used logistic regression to identify predictive factors for inappropriate prescribing. Two variables stood out at admission: age over 80 years nearly doubled the odds of an inappropriate prescription (odds ratio 1.80, 95 percent confidence interval 1.20–2.72), and elevated serum creatinine above 133 µmol/L, a marker of impaired kidney function, similarly raised the odds (OR 1.84, 95 percent CI 1.13–2.98). At discharge, age over 80 remained a strong risk factor (OR 2.71, 95 percent CI 1.63–4.61), while a body weight below 60 kilograms was unexpectedly protective (OR 0.42, 95 percent CI 0.25–0.69), possibly because clinicians scrutinize low-weight patients more carefully when selecting doses.

The renal connection deserves particular emphasis. DOACs are cleared substantially by the kidneys, and estimates of glomerular filtration rate in older adults vary depending on the formula used, whether Cockcroft–Gault, MDRD, or CKD-EPI. The study’s authors assessed prescriptions against the Summary of Product Characteristics for each molecule, which specify dose reductions based on renal function, age, and weight. When kidney function is overestimated, or when a hospitalization changes a patient’s renal status without the prescription being adjusted, the fixed daily dose can quickly become dangerous. Advanced age and impaired renal function, the two risk factors identified here, are precisely the conditions that make this pharmacokinetic tightrope hardest to walk.

Perhaps the most sobering finding is the comparison with 2018. Using chi-squared tests, the team compared their results with data collected five years earlier and found no significant changes. Despite growing awareness of DOAC dosing pitfalls, updated guidelines, and the expansion of clinical pharmacy services in French hospitals, the rate of inappropriate prescribing in this vulnerable population has remained essentially flat. The authors conclude that further efforts to optimize DOAC prescribing are warranted, and they point toward concrete interventions: pharmacist-led medication reviews at admission and discharge, and integrated prescribing tools embedded in electronic medical records that would automatically flag doses inconsistent with renal function, age, and weight.

The study has the strengths and limits of its design. As a prospective observational study, it captures real prescribing behavior rather than idealized trial conditions, and its multicenter scope across four department types strengthens generalizability within the French hospital system. But it also reflects a single country’s practice in a single year, and appropriateness was defined by ESC guidelines rather than patient-specific outcomes, so the findings measure guideline concordance rather than directly measured harm. Even so, the message is clear and actionable: the transition points of hospital care, admission and discharge, remain moments where older patients on DOACs are at elevated risk of a prescribing error, and after years of stagnation, systematic medication reconciliation and decision support may be the tools that finally bend the curve.

Subject of Research: Appropriateness of direct oral anticoagulant prescribing in hospitalized older adults

Article Title: Appropriateness prescriptions of direct oral anticoagulants in hospital in 2023 in the older population: a prospective observational multicenter study

Article References: Rodier, T., Gibert, A., Lepors, A., Fernandez, C., Hindlet, P., Savoldelli, V., & Schwab, C. (2026). Appropriateness prescriptions of direct oral anticoagulants in hospital in 2023 in the older population: a prospective observational multicenter study. BMC Geriatrics. https://doi.org/10.1186/s12877-026-08330-9

Image Credits: AI Generated

DOI: 10.1186/s12877-026-08330-9

Keywords: DOACs, anticoagulants, older adults, prescribing appropriateness, medication safety, atrial fibrillation, apixaban, renal function, polypharmacy, hospital discharge, pharmacist-led medication review, geriatrics