Central sleep apnea is a fundamentally different beast from the far better-known obstructive form. In obstructive sleep apnea, the airway physically collapses even though the brain keeps issuing breathing commands; in the central form, the brain itself fails to send stable signals to the respiratory muscles, so the diaphragm simply stops contracting for stretches of ten, twenty, sometimes thirty seconds. The condition is especially common in patients with systolic heart failure, where unstable blood gases and heightened chemosensitivity make the respiratory control system oscillate like a poorly damped pendulum. Each apnea drains oxygen from the blood, jolts the sympathetic nervous system, and fragments sleep, and in heart failure populations this nocturnal burden is associated with worse outcomes.

Transvenous phrenic nerve stimulation, embodied commercially by the remedē System, was developed as an alternative to positive airway pressure therapy, which many central sleep apnea patients tolerate poorly or cannot use at all. The device is implanted much like a cardiac pacemaker: a lead is threaded into a vein and positioned adjacent to the phrenic nerve, and a pulse generator sewn beneath the skin in the upper chest delivers electrical bursts synchronized to inspiration. By recruiting the diaphragm directly, the stimulator stabilizes ventilation during sleep without requiring a mask, hose, or machine at the bedside. The pivotal randomized controlled trial published in The Lancet in 2016 by Costanzo, Ponikowski, Javaheri, and colleagues demonstrated significant reductions in the apnea-hypopnea index compared with a control group, and subsequent reports have extended safety and efficacy observations to five years.

The critique that provoked the reply, however, zeroes in on a subtle but important methodological point: the difference between how often patients use a therapy and whether the therapy actually changes the outcomes that matter. In drug research this distinction is familiar, since a prescription filled is not a prescription taken, and a pill taken is not necessarily a life prolonged. The commentators applied the same logic to neurostimulation, suggesting that high nightly usage figures, while impressive as measures of tolerability and adherence, do not by themselves establish that the device improves survival, cardiac function, or quality of life. Usage, in their framing, is a necessary but insufficient condition for efficacy, and conflating the two risks overstating what the evidence shows.

The reply authors counter that usage data in their studies were never offered as a substitute for efficacy endpoints but as a complement to them, and they point to the broader evidentiary record assembled over nearly a decade. That record includes the original randomized trial, long-term follow-up published in the journal Sleep by Fox, Oldenburg, Javaheri, and colleagues, the five-year safety and efficacy analysis in Nature and Science of Sleep, and, most recently, a win ratio analysis published in ESC Heart Failure by Abraham, Oldenburg, Lainscak, and colleagues that evaluated transvenous phrenic nerve stimulation against a composite hierarchy of clinical outcomes in heart failure patients. The win ratio method, increasingly popular in cardiology, ranks patients by a cascade of endpoints from death through worsening heart failure to symptom change, allowing a trial to detect clinically meaningful benefit even when individual components are individually underpowered.

The stakes of this statistical and conceptual argument are amplified by the checkered history of central sleep apnea treatment. Adaptive servo-ventilation, a sophisticated bilevel pressure machine that was once the dominant therapy for central apnea in heart failure, was dealt a devastating blow by the SERVE-HF trial published in the New England Journal of Medicine in 2015, in which Cowie, Woehrle, Wegscheider, and colleagues found that the therapy was associated with increased mortality in patients with predominant central apnea and systolic heart failure. That result transformed the field overnight: a device that measurably reduced apneas on paper turned out to harm the very patients it was meant to help. Ever since, the sleep medicine community has been rightly skeptical of surrogate endpoints, and any argument that leans on apnea index reductions or adherence statistics rather than hard clinical outcomes invites intense scrutiny.

It is against that backdrop that the American Academy of Sleep Medicine convened a clinical practice guideline, published in 2025 with Badr, Khayat, Allam, and colleagues as authors, to formalize recommendations for treating central sleep apnea in adults. Guideline panels must weigh exactly the tension at issue in this journal exchange: how much weight to give device usage and physiological endpoints, how much to randomized outcome data, and how to handle therapies whose evidence base is still maturing. The reply’s authors, several of whom participated in that guideline process, argue that the totality of evidence, including high nightly usage rates documented in their automatic activation study published earlier in 2026, supports a favorable risk-benefit profile for appropriately selected patients.

The automatic activation study itself deserves attention because it speaks directly to the usage question. Published in the Journal of Clinical Sleep Medicine with Khayat as first author, it examined a feature that allows the stimulator to activate itself when the patient falls asleep, removing the burden of remembering to turn the device on each night. The result was high nightly usage, which the investigators interpreted as evidence that the therapy integrates smoothly into patients’ lives, a prerequisite for any chronic implanted therapy to deliver benefit. Critics respond that usage, however high, remains an intermediate variable; defenders respond that no therapy, however efficacious in principle, can work if it is not actually running during the hours when central apneas occur.

Both positions contain legitimate technical truth, and the exchange illustrates a broader dilemma in device medicine that drug regulation solved decades ago with adherence-adjusted analyses and per-protocol versus intention-to-treat frameworks. An implanted stimulator is unusual among therapies in that usage can be logged objectively, second by second, by the device itself, producing adherence data of a fidelity that pill counts and self-report can never match. That transparency is a scientific asset, but it also creates a temptation, conscious or not, to foreground the numbers that look best. The commentators’ warning is essentially a caution against letting beautiful adherence dashboards substitute for the harder question of whether the therapy changes the trajectory of heart failure and survival.

The reply, received in April 2026 and published on 28 July 2026 as volume 22, article 126 of the journal, does not resolve the debate, and it was not designed to. What it does is clarify where the disagreement actually lies: not over the raw data, which both sides acknowledge, but over the inferential weight each category of evidence should carry. Readers should also note the declared interests shaping the discussion, since the remedē System Pivotal Trial was sponsored by ZOLL Respicardia, two of the reply’s authors are company employees, and two others serve as consultants, while Costanzo and Khan report no conflicts. For patients with central sleep apnea and failing hearts, the practical takeaway is that phrenic nerve stimulation remains a real option with a growing evidence base, but that the scientific community is still actively negotiating what its evidence means, and that negotiation, conducted in letters and replies like this one, is precisely how the field earns the right to call a therapy effective rather than merely used.

Subject of Research: Debate over usage versus efficacy evidence for transvenous phrenic nerve stimulation in central sleep apnea

Article Title: Reply to “Usage is not efficacy in transvenous phrenic nerve stimulation for central sleep apnea”

Article References: Khayat, R. N., Khan, M., Morgenthaler, T. I., McKane, S., Germany, R., & Costanzo, M. R. (2026). Reply to “Usage is not efficacy in transvenous phrenic nerve stimulation for central sleep apnea”. Journal of Clinical Sleep Medicine, 22(1), Article 126. https://doi.org/10.1007/s44470-026-00099-3

Image Credits: AI Generated

DOI: 10.1007/s44470-026-00099-3

Keywords: central sleep apnea, phrenic nerve stimulation, neurostimulation, heart failure, sleep medicine, remedē System, adaptive servo-ventilation, clinical trial evidence, device adherence, Journal of Clinical Sleep Medicine, win ratio analysis, AASM guideline

CKM syndrome is a framework developed to describe the biological links among obesity, diabetes, high blood pressure, cardiovascular disease and chronic kidney disease. Rather than treating these conditions as isolated problems, the framework views them as interconnected consequences of metabolic stress, vascular damage, inflammation and declining organ function. In the operational classification used by the researchers, stages 2–3 encompass people with metabolic risk factors, kidney abnormalities or subclinical cardiovascular disease, while stage 4 represents established cardiovascular disease, kidney disease or both in the presence of metabolic risk. This distinction matters because patients with advanced CKM syndrome often have a high risk of hospitalization, progressive loss of kidney function and death, while also being more difficult to include in conventional trials. By mapping existing trial populations onto CKM stages, the investigators sought to test whether the benefits of SGLT2 inhibition extended across this clinically connected spectrum.

SGLT2 inhibitors were first developed as glucose-lowering medicines for type 2 diabetes, but their effects extend beyond blood sugar control. The drugs block the SGLT2 protein in the proximal tubule of the kidney, where much of the glucose and sodium filtered from the blood is normally reclaimed. Inhibition increases urinary glucose excretion and causes a modest increase in sodium loss. That change alters signaling between the kidney’s filtration apparatus and the renin–angiotensin system, helping to reduce pressure inside the glomeruli, the microscopic structures that filter blood. The medicines also produce a mild diuretic and natriuretic effect, reducing fluid congestion that can strain the heart. Researchers believe these mechanisms, together with changes in renal oxygen demand, vascular function and cardiac metabolism, help explain why the drugs can benefit patients with or without diabetes.

Sun, Guo and their colleagues searched PubMed/MEDLINE, Web of Science, Embase and the Cochrane Central Register of Controlled Trials for randomized controlled trials available through 25 February 2026. They included trials comparing an SGLT2 inhibitor with placebo or usual care and grouped trial populations, or mutually exclusive subgroups reported within trials, according to the CKM stage framework. Nineteen reports derived from 11 parent randomized trials met the criteria. A total of 18,547 participants were assigned to the CKM stages 2–3 group, while 54,673 were classified as stage 4. The researchers pooled six time-to-event outcomes using restricted maximum likelihood random-effects models. This statistical approach allows for the possibility that the true treatment effect differs somewhat among studies rather than assuming that all trials are estimating one identical effect.

The clearest signals involved heart failure and kidney disease. For the composite heart-failure outcome, the hazard ratio was 0.80 in CKM stages 2–3, with a 95 percent confidence interval of 0.68 to 0.93, and 0.77 in stage 4, with a confidence interval of 0.73 to 0.81. A hazard ratio below 1 indicates fewer events in the SGLT2 inhibitor group; these estimates correspond roughly to relative reductions of 20 percent and 23 percent, respectively. For hospitalization for heart failure, the hazard ratio was 0.61 in stages 2–3 and 0.71 in stage 4, equivalent to approximate relative reductions of 39 percent and 29 percent. Kidney outcomes also favored treatment, with hazard ratios of 0.61 and 0.64 in the two groups. These findings are consistent with the drugs’ established ability to slow clinically important kidney deterioration and reduce heart-failure events in several different patient populations.

The statistical comparisons did not show that the apparent differences between groups were significant. The P value for the comparison of composite heart-failure outcomes between CKM stages 2–3 and stage 4 was 0.65. For heart-failure hospitalization it was 0.24, and for kidney outcomes it was 0.64. In practical terms, the available data did not demonstrate that one CKM group gained more or less benefit than the other. But a non-significant difference is not the same as proof of identical effects. The stages 2–3 analysis was based on only four estimates, creating wider confidence intervals and greater uncertainty. Stage 4 estimates were generally more precise because the group included more participants and more events. The researchers therefore describe the results as evidence of benefit in both groups, not as definitive evidence that the magnitude of benefit is equivalent.

The analysis also examined major adverse cardiovascular events, commonly known as MACE, and all-cause mortality. Estimates for MACE and mortality in CKM stage 4 were more precise, reflecting the larger evidence base in that category, but the source material does not report a single statistically significant stage-based difference for these outcomes. The researchers registered five main outcomes rather than designating one primary endpoint, while all-cause mortality was registered as a secondary outcome. That distinction is important because a study evaluating several outcomes can produce a complex pattern of results, and individual findings may vary in certainty. An exploratory Egger test for all-cause mortality produced a P value of 0.025, raising the possibility of small-study effects or publication bias. Such tests are difficult to interpret when the number of contributing estimates is limited, so the result is a warning signal rather than evidence that the overall mortality conclusion is invalid.

To test whether the findings depended on particular analytical decisions, the investigators performed prespecified sensitivity analyses. They examined alternative statistical models, removed the SOLOIST-WHF trial because a selected efficacy result was judged to have a high risk of bias, tested different definitions of kidney endpoints and assessed whether any single study disproportionately influenced the results. They also investigated possible small-study effects. The principal heart-failure and kidney findings remained stable across these checks, strengthening confidence that the observed pattern was not created by one trial or one endpoint definition. Nevertheless, meta-analysis inherits limitations from the studies it combines. Trial participants may differ in baseline kidney function, diabetes status, heart-failure phenotype, medication use and follow-up duration, while operationally assigning populations to CKM stages cannot fully reproduce the complexity of individual patients.

The findings arrive as SGLT2 inhibitors are increasingly used across cardiology, nephrology and endocrinology, including in patients with heart failure with reduced, mildly reduced or preserved ejection fraction and in people with chronic kidney disease. Their apparent benefits across these specialties have helped shift the drugs from narrowly targeted diabetes treatments to therapies with broader cardiorenal applications. The new review reinforces that cross-disciplinary picture: patients at different points along the CKM pathway experienced fewer heart-failure and kidney events when receiving an SGLT2 inhibitor than when receiving placebo or usual care. Still, treatment decisions must account for kidney function, volume status, genital and urinary infections, ketoacidosis risk and other individual factors. The authors’ central conclusion is appropriately cautious: SGLT2 inhibitors favored heart-failure and kidney outcomes in both CKM stage groups, but more evidence—especially in earlier-stage CKM disease—is needed to determine how treatment effects compare across the full continuum.

Subject of Research: Cardiorenal effects of SGLT2 inhibitors across cardiovascular-kidney-metabolic syndrome stages 2–3 and stage 4

Article Title: SGLT2 inhibitors and cardiorenal outcomes across operationally mapped cardiovascular-kidney-metabolic syndrome stages 2–3 and stage 4: a systematic review and meta-analysis

Article References: Sun, S., Guo, Y., Wu, H. et al. SGLT2 inhibitors and cardiorenal outcomes across operationally mapped cardiovascular-kidney-metabolic syndrome stages 2–3 and stage 4: a systematic review and meta-analysis. BMC Endocrine Disorders (2026). Original research article

Image Credits: AI Generated

DOI: 10.1186/s12902-026-02478-6

Keywords: SGLT2 inhibitors, cardiovascular-kidney-metabolic syndrome, heart failure, chronic kidney disease, cardiorenal outcomes, randomized controlled trials, systematic review, meta-analysis