The study, led by Chia Siang Kow and colleagues, took a fresh statistical look at the six clinical studies and ten intervention arms that tracked semaglutide or tirzepatide after treatment discontinuation, drawing on data covering 1776 participants. Rather than relying on simple pooled averages, the researchers reconstructed the arm-level data and applied a Bayesian hierarchical longitudinal model, a statistical framework that jointly models repeated measurements over time while explicitly accounting for variability between study arms. This approach allowed the team to go beyond asking how many kilograms are regained each month and instead translate the trajectory into clinically meaningful milestones, complete with full probability distributions that quantify uncertainty.

The headline finding is that people who stop taking these medications regain an estimated 1.04 kilograms per month on average, with a 95 percent credible interval of 0.80 to 1.29 kilograms per month. The modelled average participant had lost 15.35 kilograms by the time treatment ended. Under the linear model assumed by the researchers, half of that hard-won loss was projected to return within about 7.5 months, and participants were projected to be back at their baseline weight by roughly 15 months after stopping. In practical terms, the clock on the treatment’s benefits starts ticking almost the moment the final injection wears off.

The month-by-month trajectory is particularly striking. Within the follow-up window actually observed in the trials, which extended to 52 weeks, the modelled average weight change was still below baseline at six months, at minus 9.12 kilograms, but by then approximately 41 percent of the initial weight loss had already been regained. At nine months the average was minus 6.01 kilograms, corresponding to 62 percent regained, and by twelve months the average stood at minus 2.90 kilograms, meaning roughly 83 percent of the lost weight had returned. The posterior probability that the average trajectory had regained at least half of the initial weight loss climbed from just 12.5 percent at six months to 86.7 percent at nine months and a near-certain 99.5 percent at one year.

It is important to understand the mathematical machinery behind these numbers. The researchers assumed a constant linear regain slope rather than a curving trajectory, a choice justified because follow-up data were sparse and a prior systematic review had found that adding a nonlinear term did not improve model fit. Each study arm was treated as a repeated-measures trajectory with its own random effects for both the weight loss present at discontinuation and the subsequent regain rate. The Bayesian estimation relied on full Markov chain Monte Carlo sampling, with convergence confirmed by R-hat statistics hovering at approximately 1.00 and large effective sample sizes for the key slope parameters. Estimates extending beyond the maximum observed follow-up of 52 weeks, including the projected return to baseline at 15 months, are explicitly flagged as extrapolations of the average trajectory rather than directly observed outcomes.

One of the most provocative aspects of the analysis is its comparison of the two drugs. Tirzepatide arms showed a numerically faster unadjusted regain rate of 1.10 kilograms per month compared with 0.89 kilograms per month for semaglutide, and projected return to baseline was correspondingly sooner, at roughly 14.5 months versus 17.3 months. But when the researchers adjusted for the magnitude of initial weight loss and post-discontinuation support in a Bayesian meta-regression, the drug difference essentially vanished. The adjusted effect of tirzepatide versus semaglutide was a negligible minus 0.04 kilograms per month, with a posterior probability of only 40.2 percent that tirzepatide regains faster. In other words, the apparent difference in rebound between the two drugs likely reflects differences in how much weight was lost in the first place, not any inherent difference in the physiology of regain.

That observation points to one of the study’s most interesting exploratory findings: greater initial weight loss was itself the strongest directional predictor of faster absolute regain. Each additional 5 kilograms of weight lost during treatment was associated with a 0.20 kilograms per month faster regain slope, a result carrying a 92.1 percent posterior probability, though the credible interval included zero. The authors caution that this association may partly reflect mathematical coupling, since a larger initial loss simply creates more opportunity for absolute regain. Meanwhile, behavioural or lifestyle support after discontinuation showed a directional association with slower regain, an estimated effect of minus 0.19 kilograms per month with an 87.2 percent probability of benefit, but the imprecise estimate means the finding remains inconclusive. With only ten intervention arms available, all meta-regression results are explicitly exploratory and hypothesis-generating rather than definitive.

Sensitivity analyses reinforced the robustness of the core conclusion. A contrast analysis using the randomised differences between intervention and control arms showed a similar direction of effect, though with less precision. A post hoc analysis excluded the three SURPASS-1 arms, which came from a trial of adults with Type 2 diabetes receiving tirzepatide as glucose-lowering monotherapy rather than for weight management. Excluding those arms left the monthly regain slope essentially unchanged at 0.95 kilograms per month, though the projected time to 50 percent regain lengthened to 9.42 months because the average initial weight loss among the remaining arms was greater. The qualitative message of rapid regain survived every stress test the researchers applied.

The clinical implications are considerable. Because discontinuation is common in routine practice, driven by cost, tolerability problems, access restrictions, treatment fatigue and genuine uncertainty about how long therapy should last, the findings suggest that clinicians should plan proactive monitoring within the first several months after stopping treatment, when early regain can be identified and maintenance strategies reassessed. The authors are careful to note that their data do not determine whether dose tapering, lower-dose maintenance, drug switching, intermittent treatment or any specific behavioural programme can prevent regain; those questions require dedicated trials. They also stress that the analysis captured body-weight trajectories only, so any statements about cardiometabolic benefits, cost-effectiveness or the consequences of fixed-duration treatment policies remain hypotheses informed by the weight pattern rather than direct findings.

What the study ultimately delivers is a statistically rigorous quantification of something patients and clinicians have long suspected: incretin-based anti-obesity medications suppress appetite and enable weight loss while they are active, and withdrawing that physiological support removes the very mechanism holding the weight down. Between-study heterogeneity was real but moderate, with a between-arm standard deviation of 6.78 kilograms for initial weight loss and 0.26 kilograms per month for the regain slope, suggesting that while individual experiences vary, the average trajectory is consistently steep. As these drugs reshape obesity medicine and public expectations, the analysis argues that their long-term value must be judged not only by the dramatic losses achieved during treatment but by an honest accounting of what follows when the treatment ends, and by research that extends follow-up beyond one year, reports regain in both absolute and percentage terms, and directly tests the maintenance strategies that patients will increasingly demand.

Subject of Research: Weight regain after discontinuation of the incretin-based anti-obesity medications semaglutide and tirzepatide

Article Title: Weight Regain Trajectories After Discontinuation of Semaglutide or Tirzepatide: A Reconstructed Aggregate‐Data Bayesian Longitudinal Meta‐Analysis

Article References: Kow, C. S., Thiruchelvam, K., Ramachandram, D. S., & Zaihan, A. F. (2026). Weight Regain Trajectories After Discontinuation of Semaglutide or Tirzepatide: A Reconstructed Aggregate‐Data Bayesian Longitudinal Meta‐Analysis. Endocrinology, Diabetes & Metabolism, 9(5), Article e70325. https://doi.org/10.1002/edm2.70325

Image Credits: AI Generated

DOI: 10.1002/edm2.70325

Keywords: semaglutide, tirzepatide, weight regain, obesity, incretin therapies, GLP-1 receptor agonists, Bayesian meta-analysis, treatment discontinuation, weight loss maintenance, anti-obesity pharmacotherapy, Weight, Regain

The research team, led by Jesper N. Bech of the University Clinic in Nephrology and Hypertension at Gødstrup Hospital and Aarhus University in Denmark, together with colleagues from the United Kingdom, the United States, Germany, Spain, Israel, and Denmark, extracted data from de-identified electronic medical records, insurance claims, and national health registries covering the years 2018 through 2023, and through 2024 for Denmark. Their study population comprised 64,501 adults with diagnosed hypertension who had been maintained on a stable two-drug regimen and then initiated a third antihypertensive medication, a step that clinicians interpret as treatment intensification in patients whose blood pressure remains above goal. The third medication fell into one of six commonly prescribed classes: angiotensin-converting enzyme inhibitors, angiotensin II receptor blockers, calcium channel blockers, beta-blockers, diuretics, or mineralocorticoid receptor antagonists.

The headline result is stark. Across countries and drug classes, between 54 percent and 100 percent of patients had discontinued their third medication within 12 months of starting it, and between 67 percent and 100 percent had done so within 24 months. In most countries, the median time to discontinuation was remarkably short, ranging from just 0.1 to 0.5 years, meaning that half of patients in many cohorts had abandoned the new drug within roughly two to six months. Denmark stood out as the exception, with discontinuation rates of 54 to 67 percent at one year and median persistence of 0.5 to 0.8 years, a difference the investigators suggest may partly reflect differences in how Danish physicians prescribe and dispense medications, with prescriptions commonly issued for 100 days or more.

Adherence told a similarly sobering story. The researchers measured adherence using the proportion of days covered, a pharmacoepidemiological standard that tracks how much of a follow-up period a patient actually has medication available based on prescription fills and dispensations. Median adherence to the third drug declined steadily over time, and the proportion of patients achieving the conventional threshold of more than 80 percent adherence at six months was 66 to 79 percent in Denmark but only 8 to 52 percent elsewhere. By 24 months, the picture in most countries had deteriorated further. Notably, adherence and persistence patterns were broadly similar across the six drug classes within each country, suggesting that the problem is less about which particular medication is chosen and more about systemic factors governing how patients engage with complex multidrug regimens.

The blood pressure outcomes raise equally difficult questions. Among the subset of patients with recorded blood pressure measurements at 12 months, only 23 to 50 percent in the United States, 35 to 66 percent in the United Kingdom, 42 to 55 percent in Germany, 57 to 70 percent in Spain, 63 to 89 percent in Israel, and 35 to 71 percent in Denmark had blood pressure below their country-specific target, which was 130/80 mmHg in the United States and 140/90 mmHg everywhere else. Median reductions in systolic blood pressure over the first year were modest, ranging from essentially zero for some drug classes in some countries to around 14 mmHg for calcium channel blockers at best. At 24 months, many patients showed no meaningful improvement, and some experienced worsening systolic pressures relative to baseline.

Perhaps most striking was what the medication data revealed about dosing behavior. When the investigators plotted daily dose categories and discontinuation across the first 365 days after the index prescription, they found that up-titration to higher doses was uncommon. Patients overwhelmingly started on low or usual doses and stayed there, even as a substantial proportion remained above their blood pressure targets. In some cases, prescriptions fell below licensed doses altogether: at least half of patients receiving the mineralocorticoid receptor antagonist spironolactone in the UK, USA, and Spain were dispensed 25 mg or less, below the 50 mg threshold generally considered the licensed starting dose for hypertension, and a similar pattern appeared for eplerenone. The authors interpret this combination of low starting doses, minimal up-titration, and high discontinuation as a signature of therapeutic inertia, the well-documented clinical phenomenon in which providers fail to intensify treatment despite evidence that a patient’s condition remains uncontrolled.

The clinical stakes of this gap are considerable. Hypertension is the leading modifiable risk factor for cardiovascular and renal disease worldwide, and meta-analyses indicate that every 10 mmHg reduction in systolic blood pressure lowers the risk of major cardiovascular events by roughly 20 percent. Yet globally, only about one in five people with hypertension achieves guideline-recommended blood pressure control. Patients who require multiple medications and still fail to reach target face elevated risks of stroke, ischemic heart disease, heart failure, chronic kidney disease, diabetes, and death. The EnligHTN analysis also showed that many of these patients carried substantial comorbid disease at baseline: the prevalence of heart failure ranged from 2 to 56 percent across cohorts, chronic kidney disease from 14 to 84 percent, and type 2 diabetes from 8 to 38 percent, conditions that complicate blood pressure management both biologically and pharmacologically.

The authors are careful to note important limitations. Discontinuation was inferred from prescribing and dispensing records rather than direct measurement of medication intake, so the estimates reflect loss of observed treatment continuity rather than definitive proof that patients stopped taking their pills; gaps may also reflect clinician-directed strategy changes or incomplete data capture. Blood pressure measurements were missing for a majority of patients at follow-up, ranging from 50 to 90 percent at the 12- and 24-month time points, so control rates describe only those patients with documented monitoring and may not generalize to the full cohort. The setting in which readings were taken could not always be determined, leaving open the possibility of white-coat or pseudo-resistant effects, and some prescribed doses may have been intended for indications other than hypertension.

Even with those caveats, the scale and consistency of the findings across six distinct healthcare systems carry a clear message. High discontinuation, suboptimal adherence, and therapeutic inertia converge to leave many patients with harder-to-control hypertension undertreated and unprotected. The study’s authors argue that the field needs two parallel advances: adherence-focused strategies that reduce pill burden and support patients in staying on therapy, and new classes of antihypertensive agents that are better tolerated and more effective at targeting the underlying pathophysiology in patients who do not respond adequately to existing drugs. With newer pharmacological options entering the hypertension landscape, the real-world treatment patterns documented by EnligHTN provide a crucial benchmark against which any genuine improvement in persistence, adherence, and blood pressure control will have to be measured.

Subject of Research: Real-world antihypertensive medication adherence, discontinuation, and blood pressure control in patients with harder-to-control hypertension

Article Title: Antihypertensive Medication Patterns in Patients with Hypertension that is Harder to Control: Insights from the EnligHTN Study

Article References: Bech, J. N., McCormack, T., Bhalla, V., Ben Dor, N. R., Segura, J., Hougaard Christiansen, S., Andersen, I. T., Erhard, C., Rhodes, K. M., Norris, T., Coto, E., & Weil, J. (2026). Antihypertensive Medication Patterns in Patients with Hypertension that is Harder to Control: Insights from the EnligHTN Study. Advances in Therapy. https://doi.org/10.1007/s12325-026-03771-5

Image Credits: AI Generated

DOI: 10.1007/s12325-026-03771-5

Keywords: hypertension, antihypertensive medications, medication adherence, blood pressure control, treatment discontinuation, therapeutic inertia, EnligHTN study, real-world evidence, observational cohort study, treatment persistence, cardiovascular risk, polypharmacy