Why the Best Drugs Fail: The Widening Medication Adherence Gap

Some of the most remarkable medicines in modern history are sitting in pharmacy drawers, uncollected or abandoned. Drugs that produce clinically meaningful weight loss, anticoagulants that prevent stroke with minimal monitoring, and vaccines that may even lower the risk of dementia have all arrived within the span of a few years. Yet across nearly every therapeutic area, a substantial proportion of patients discontinue, underuse, or never fill these prescriptions at all. Writing in PLOS Medicine, Zachary A. Marcum of the University of Washington argues that the gap between how well medications perform in clinical trials and how well they actually work in everyday practice is widening, and that the widening is driven less by pharmacology than by a stubborn, decades-old problem: medication nonadherence.

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