The study, led by Benjamin J. Morasco of the VA Portland Health Care System and Oregon Health & Science University, drew its data from the Veterans’ Pain Care Organizational Improvement Comparative Effectiveness study, known as VOICE. That parent trial was a multisite, twelve-month randomized comparative effectiveness trial designed to test two real-world implementations of collaborative care for chronic pain, a model in which primary care teams work with specialized consultants to manage patients’ conditions systematically rather than leaving each clinician to improvise. Participants were randomized to one of two interventions that differed in resource intensity: an intensive interdisciplinary pain team, or a less resource-intensive pharmacist-led collaborative management approach. Both arms were grounded in the same collaborative care architecture, and both were delivered within the routine operations of the Veterans Health Administration, which is precisely what makes the trial pragmatic rather than a test of an idealized clinic that exists only in research settings.

For the secondary analysis, the research team collapsed the two treatment conditions and asked a different question than the original trial: did baseline substance use disorder status predict how patients fared? The answer required first establishing who carried that status. Of the 778 participants enrolled, 250, or 32.1 percent, met criteria for potential substance use disorder at baseline. That figure is striking in its own right, and it aligns with a broader literature documenting that roughly one in three patients on long-term opioid therapy for chronic pain has co-occurring substance use disorder. Epidemiological studies across health systems, including analyses of Norwegian health registries and large electronic health record datasets, have repeatedly found elevated rates of substance use diagnoses among chronic pain patients prescribed opioids, making this population impossible to ignore in any serious effort to improve opioid prescribing.

The demographic and clinical profile of the two groups differed in ways that matter for interpretation. Participants with potential substance use disorder were younger and more likely to have co-occurring mental health diagnoses than participants without it. Yet, critically, the groups showed no differences at baseline in pain interference, pain intensity, or prescription opioid dose. This baseline equivalence is methodologically important: it means that any divergence in outcomes during the trial could plausibly be attributed to substance use disorder status rather than to the groups starting from different levels of pain or different opioid exposures. The researchers measured pain using validated instruments, including the Brief Pain Inventory, which captures both the intensity of pain and the degree to which it interferes with daily functioning, a distinction that has become central to modern pain outcome assessment because interference often responds to treatment even when raw intensity does not fully remit.

The twelve-month results were unambiguous. Participants in both the potential substance use disorder group and the no-disorder group achieved statistically significant reductions in pain interference and pain intensity, alongside reductions in prescription opioid dose. In adjusted analyses that accounted for the demographic and clinical differences between groups, there was no difference between the groups in the magnitude of change on any of these outcomes. In other words, substance use disorder status did not blunt the response to collaborative care, did not prevent opioid dose reduction, and did not leave patients with more residual pain than their peers. For a population often excluded from trials or treated as a special case requiring separate pathways, this is a consequential null finding, in the best sense of the term.

The technical significance of this result becomes clearer when set against the prior evidence base. Earlier randomized trials had tested psychosocial pain interventions specifically tailored to patients in substance use disorder treatment, including work by Ilgen and colleagues and mindfulness-oriented recovery enhancement trials by Garland and colleagues, which showed that dedicated programs could help. But those studies evaluated interventions designed for the substance-using population, leaving open whether mainstream collaborative pain care, the kind most health systems could actually deploy, would work as well for these patients. A prior observational study by Morasco and colleagues had examined pain-related function over twelve months in primary care patients with musculoskeletal pain and found associations worth probing further. The new analysis closes that gap by embedding the substance use disorder question directly inside a rigorous randomized trial of standard collaborative care models, giving the finding a level of causal confidence that observational data cannot provide.

The opioid dose reduction component of the study carries particular weight given the national conversation about tapering. Systematic reviews, including one by Frank and colleagues, have documented that dose reduction and discontinuation of long-term opioid therapy can produce mixed patient outcomes, and observational studies from multiple health systems have linked rapid or forced tapering to overdose, mental health crisis, and other adverse events. The VOICE trial’s collaborative care approach, by contrast, paired dose reduction with active pain treatment, and the new analysis shows that patients with potential substance use disorder achieved dose reductions without differential harm to their pain outcomes. This suggests that the safest tapering is not simply a matter of lowering doses but of lowering them within a supportive treatment structure, and that patients with substance use disorder should not be steered away from such structures on the assumption that they will fail.

Several design features strengthen the study’s real-world relevance. The pragmatic trial design meant that interventions were delivered in ordinary VA primary care settings rather than in specialized research clinics, and the enrollment of 778 patients across multiple sites provided the statistical power to detect meaningful differences if they existed. The identification of potential substance use disorder relied on validated screening approaches, including instruments such as the AUDIT-C for alcohol and the TAPS tool for unhealthy substance use, supplemented by diagnostic codes whose validity in administrative data has been verified through chart review in prior work. The trial was registered at ClinicalTrials.gov as NCT03026790, funded by the Patient-Centered Outcomes Research Institute, and supported by the Department of Veterans Affairs, with the funder having no role in the design, analysis, or decision to publish.

The study’s limitations deserve honest acknowledgment. The population consisted of veterans, most of whom receive integrated care within a single health system, so generalization to civilian populations with fragmented insurance and care remains an empirical question. The substance use disorder classification was based on screening and potential criteria rather than structured clinical interviews, and the analysis examined outcomes at twelve months rather than over longer horizons. The parent trial compared two collaborative care variants and collapsed them for this analysis, so the results speak to collaborative care as a class rather than distinguishing which model works better for which subgroup. Nonetheless, the consistency of the findings across pain interference, pain intensity, and opioid dose outcomes lends credibility to the central conclusion.

The clinical implications are straightforward and potentially practice-changing. Roughly a third of patients on long-term opioid therapy carry a substance use disorder diagnosis, and clinicians have long faced a dilemma: treat the pain aggressively and risk worsening the addiction, or prioritize addiction treatment and leave the pain undertreated. These results suggest that the dilemma is partly false. Collaborative care interventions for chronic pain improved pain outcomes and reduced opioid doses in patients with and without potential substance use disorder alike, indicating that substance use disorder status should not gate access to structured pain treatment. As health systems continue to grapple with the twin burdens of chronic pain and the opioid crisis, the message from this trial is that integrated, team-based care can serve both populations, and that excluding patients with substance use disorder from such care is neither necessary nor supported by the evidence.

Subject of Research: Collaborative care treatment outcomes for chronic pain and opioid dose reduction in patients with and without substance use disorder

Article Title: Pain and Opioid Dose Reduction Based on Substance Use Disorder Status: Secondary Analysis from a Pragmatic Effectiveness Trial

Article References: Morasco, B. J., Hammett, P. J., Krebs, E. E., Seal, K. H., DeRonne, B. M., Lovejoy, T. I., Bohnert, A. S. B., Frank, J. W., Makris, U. E., Naylor, J. C., Painter, J. T., Borsari, B., Hagedorn, H. J., & Becker, W. C. (2026). Pain and Opioid Dose Reduction Based on Substance Use Disorder Status: Secondary Analysis from a Pragmatic Effectiveness Trial. Journal of General Internal Medicine. https://doi.org/10.1007/s11606-026-10816-6

Image Credits: AI Generated

DOI: 10.1007/s11606-026-10816-6

Keywords: substance use disorder, chronic pain, long-term opioid therapy, opioid dose reduction, collaborative care, pragmatic trial, veterans health, pain interference, pain intensity, primary care, comparative effectiveness, opioid prescribing

The research team, drawing on Optum’s de-identified Clinformatics Data Mart Database covering January 2016 through June 2023, assembled one of the largest cohorts ever used to study this question. Adults with confirmed type 2 diabetes and evidence of chronic kidney disease were divided into two analytical samples. The first included patients who were ineligible for SGLT2 inhibitors—because of kidney failure, dialysis, or repeatedly low filtration rates—or who had shown a suboptimal response to them, a group the investigators describe as having substantial unmet clinical need. The second sample enrolled patients who met criteria mirroring the landmark FLOW trial, excluding anyone with a filtration rate below 25 mL/min/1.73 m² in the preceding six months or evidence of dialysis, transplantation, or kidney failure at baseline.

In the first sample, 16,646 patients initiated once-weekly subcutaneous semaglutide while 33,197 began a sulfonylurea, a dipeptidyl peptidase-4 inhibitor, or a thiazolidinedione—the three oral classes most commonly prescribed when SGLT2 inhibitors are not an option but which current American Diabetes Association guidelines do not prefer. Insulin was deliberately excluded as a comparator because its use typically signals more advanced disease, which would have muddied the statistical waters through confounding by indication. The researchers then tracked four clinical outcomes over time: glycated hemoglobin, estimated glomerular filtration rate, body weight, and systolic blood pressure, using linear mixed-effects models with spline terms for time to capture how benefits evolved across uneven follow-up periods.

The results were striking. By twelve months, patients on semaglutide had achieved model-estimated reductions of 1.18 percentage points in HbA1c, 6.24 kilograms in body weight, and 3.29 mmHg in systolic blood pressure, alongside a 2.75 mL/min/1.73 m² improvement in kidney filtration. The comparator drugs produced smaller gains in HbA1c and filtration rate and essentially no benefit on weight or blood pressure. More alarming for the control group, their modest eGFR improvement reversed entirely at around eighteen months, with kidney function declining below baseline and continuing to fall thereafter. When the two cohorts were compared directly, semaglutide’s advantages at twelve months translated into an additional 0.54 percentage point HbA1c reduction, 6.69 kilograms of extra weight loss, 3.63 mmHg greater blood pressure lowering, and 2.06 mL/min/1.73 m² more improvement in filtration rate, with all differences statistically significant and most benefits persisting beyond two years.

The second analysis addressed the question that matters most to nephrologists: does semaglutide actually keep kidneys from failing? Among 5,873 semaglutide users and 23,649 controls followed for a median of roughly a year, the composite renal outcome—initiation of dialysis, kidney transplantation, two filtration readings below 15 mL/min/1.73 m² at least 28 days apart, or death from any cause—occurred in 1.5 percent of semaglutide patients versus 3.5 percent of controls. Cumulative incidence curves diverged steadily, with rates of 1.1 percent versus 1.9 percent at one year widening to 2.7 percent versus 5.2 percent by four years. After adjusting for demographics, kidney disease stage, baseline filtration rate, comorbidities, and treatment intensity, semaglutide was associated with a 22 percent lower risk of the composite outcome, with a hazard ratio of 0.78 and a confidence interval that just cleared statistical significance.

These findings land with particular force because they replicate, in the messiness of routine care, what the randomized FLOW trial demonstrated under ideal conditions. That phase 3 study, published in 2024, showed a 24 percent reduction in major kidney disease events with once-weekly semaglutide versus placebo, prompting the U.S. Food and Drug Administration to approve the drug for reducing the risk of kidney disease worsening, kidney failure, and cardiovascular death in adults with type 2 diabetes and chronic kidney disease—the only GLP-1 receptor agonist to carry that indication. The new study’s 22 percent risk reduction sits squarely within the 21 to 28 percent range reported in prior comparative analyses of GLP-1 receptor agonists against dipeptidyl peptidase-4 inhibitors and sulfonylureas, suggesting the trial results translate faithfully to the clinic.

The magnitude of the renal protection observed has led researchers to suspect mechanisms beyond the drug’s obvious effects on glucose and weight. Semaglutide mimics the incretin hormone GLP-1, enhancing insulin secretion in a glucose-dependent manner, suppressing glucagon, slowing gastric emptying, and acting on appetite centers in the brain. But its kidney benefits appear to outstrip what improved metabolic control alone would predict, hinting at direct anti-inflammatory and hemodynamic effects within renal tissue—possibly reduced glomerular hyperfiltration, attenuated oxidative stress, and protection of the renal microvasculature. The FLOW trial added another layer of intrigue by showing that semaglutide also reduced heart failure outcomes, underscoring that cardiorenal protection and metabolic control travel together in this drug class.

The study is not without caveats, and the authors are candid about them. As a claims-based analysis, it relied on administrative codes and laboratory values rather than detailed clinical records, so the reasons patients avoided SGLT2 inhibitors—cost, formulary restrictions, clinician preference—could not be fully captured. Residual confounding is an inherent hazard of observational research, and differences in how often the two cohorts had laboratory tests drawn may have biased outcome comparisons. The database covered only commercially insured and Medicare Advantage populations, limiting generalizability to Medicaid beneficiaries and the uninsured. Laboratory data were available for just 30 to 40 percent of individuals, and sicker patients were likely overrepresented because they undergo more frequent monitoring. The on-treatment design also meant follow-up was relatively short for some analyses, with fewer patients contributing data at later time points, which reduces precision around the durability estimates.

Even with those limitations, the clinical implications are considerable. Roughly a quarter of American adults with type 2 diabetes carry a chronic kidney disease diagnosis, and that combination dramatically amplifies cardiovascular risk and mortality. For the substantial minority who cannot take or do not respond to SGLT2 inhibitors, treatment options have historically narrowed to drugs with hypoglycemia risk, weight gain, or limited renal data. The new evidence positions once-weekly semaglutide as a first-line alternative for exactly this population, offering simultaneous improvements in glycemia, weight, blood pressure, and kidney trajectory without increasing hypoglycemia risk. The sustained nature of the benefits—stable HbA1c and weight reductions and preserved filtration advantage through at least two years of follow-up—addresses a persistent worry about whether injectable therapies hold their value in real-world adherence conditions.

The authors call for longer-term studies of hard cardiovascular endpoints and for analyses of how the drug’s comparative effectiveness varies across patient subgroups. But the headline finding is already hard to ignore: in the largest U.S. real-world study of its kind, a drug famous for reshaping the treatment of obesity and diabetes has now shown, outside the trial setting, that it can meaningfully slow the slide toward dialysis, transplantation, and death in one of medicine’s most vulnerable populations. For patients whose kidneys are failing and whose pharmaceutical options have been shrinking, that is not incremental progress—it is a genuine widening of the door.

Subject of Research: Comparative effectiveness of once-weekly semaglutide versus oral glucose-lowering drugs in patients with type 2 diabetes and chronic kidney disease

Article Title: Comparative Effectiveness of Once-Weekly Semaglutide Versus Sulfonylureas, DPP4 Inhibitors, and Thiazolidinediones in Patients with Type 2 Diabetes and Chronic Kidney Disease

Article References: Amamoo, J., Wang, Y., Liu, H., Sundar, M., Song, Y., Xie, L., Mehanna, S., Noone, J., Swift, C., & Weir, M. R. (2026). Comparative Effectiveness of Once-Weekly Semaglutide Versus Sulfonylureas, DPP4 Inhibitors, and Thiazolidinediones in Patients with Type 2 Diabetes and Chronic Kidney Disease. Advances in Therapy. https://doi.org/10.1007/s12325-026-03744-8

Image Credits: AI Generated

DOI: 10.1007/s12325-026-03744-8

Keywords: semaglutide, type 2 diabetes, chronic kidney disease, GLP-1 receptor agonists, SGLT2 inhibitors, comparative effectiveness, nephrology, kidney outcomes, HbA1c, FLOW trial, real-world evidence, cardiorenal outcomes

The study drew on administrative claims data from Optum’s deidentified Clinformatics Data Mart Database, which captures health records from large commercial and Medicare Advantage plans spanning all 50 US states. Researchers identified adults with confirmed diagnoses of both type 2 diabetes and established atherosclerotic cardiovascular disease who initiated oral semaglutide or another noninsulin glucose-lowering therapy between October 2019 and April 2024. After propensity score matching to balance baseline characteristics, the analysis compared 10,878 new users of oral semaglutide against 28,639 users of other noninsulin therapies, and conducted additional matched comparisons against specific drug classes, including dipeptidyl peptidase 4 inhibitors and sodium-glucose cotransporter 2 inhibitors. An as-treated approach was the primary analysis, with intention-to-treat sensitivity analyses confirming robustness.

The investigators assessed a battery of cardiovascular endpoints, ranging from the classic 3-point definition of major adverse cardiovascular events—ischemic stroke, myocardial infarction, and cardiovascular-related death—to broader composites that add hospitalization for unstable angina and heart failure, as well as modified versions that substitute all-cause death. Death was categorized as cardiovascular-related when claims showed a cardiovascular primary diagnosis within 30 days before death, while other events required an inpatient claim with a qualifying ICD-10-CM diagnosis code in the primary position. This multi-layered endpoint strategy matters because composite measures aggregate more events than their individual components, providing greater statistical power to detect treatment differences in a real-world population where follow-up periods are often short.

The headline finding was striking. Compared with users of other noninsulin glucose-lowering therapies, new users of oral semaglutide had a 17 percent lower risk of 3-point major adverse cardiovascular events and a 21 percent lower risk of the modified 3-point version. The benefits extended across the endpoint spectrum: oral semaglutide initiation was associated with a 26 percent lower risk of 5-point major adverse cardiovascular events, a 27 percent lower risk of the modified 5-point measure, and a 16 percent lower risk of 2-point events. Individually, oral semaglutide users experienced 23 percent lower risk of ischemic stroke and 29 percent lower risk of all-cause death, though the differences in myocardial infarction and cardiovascular-related death did not reach statistical significance in this dataset.

The class-specific comparisons sharpened the picture. Against matched users of dipeptidyl peptidase 4 inhibitors, each group comprising 7,218 patients, oral semaglutide users had a 22 percent lower risk of 3-point major adverse cardiovascular events, a 24 percent lower risk of the modified version, a 39 percent lower risk of ischemic stroke, and a 36 percent lower risk of all-cause death. Against sodium-glucose cotransporter 2 inhibitor users, the comparison was somewhat narrower, with 7,491 oral semaglutide users matched against 21,572 SGLT2 inhibitor users, yet oral semaglutide still delivered a 21 percent lower risk of 3-point events, a 22 percent lower risk of modified 3-point events, and significant reductions across the broader 5-point and 2-point composites. These are notable gains considering SGLT2 inhibitors themselves carry established cardiovascular benefits, meaning oral semaglutide outperformed an already cardioprotective comparator.

The economic implications were also meaningful. Oral semaglutide users accumulated fewer hospitalizations and lower overall medical costs than their counterparts on other therapies. Specifically, they had 19 percent fewer all-cause inpatient visits, 19 percent lower all-cause inpatient costs, and roughly $2,927 lower all-cause medical costs per patient per year compared with users of other noninsulin therapies. Against dipeptidyl peptidase 4 inhibitors, the savings were larger: 31 percent fewer all-cause inpatient visits and nearly $4,972 lower annual all-cause medical costs. Emergency room visits and costs were the notable exception, showing no significant differences in most comparisons, suggesting the cost advantages concentrate in inpatient and outpatient care rather than acute unscheduled visits.

The findings dovetail with the SOUL randomized clinical trial, which demonstrated that oral semaglutide was superior to placebo in reducing cardiovascular events among people with type 2 diabetes and established cardiovascular disease or chronic kidney disease, showing a 14 percent reduction in 3-point major adverse cardiovascular events. The real-world cohort had a slightly older average age than the trial population, a higher proportion of women, and broader representation of race, ethnicity, and geography, making it a useful complement to the trial’s controlled conditions. The US Food and Drug Administration has since approved oral semaglutide for cardiovascular risk reduction in adults with type 2 diabetes at high risk, including those without prior cardiovascular events, expanding its potential reach.

What makes oral semaglutide scientifically interesting is the chemistry behind the pill. Peptides like semaglutide are normally destroyed by digestive enzymes and cannot cross the intestinal wall, which is why GLP-1 receptor agonists have historically required injection. Oral semaglutide overcomes this by co-formulation with sodium N-(8-[2-hydroxybenzoyl]amino)caprylate, known as SNAC, an absorption enhancer that enables localized uptake of the peptide through the stomach lining without disrupting absorption of other molecules. This technological achievement matters clinically because injection aversion remains a real barrier for many patients, and an oral option with comparable cardiovascular protection could help combat therapeutic inertia in diabetes management.

The authors caution that the observational design cannot fully establish causation, and that claims data lack clinical granularity on kidney function, blood pressure, lipids, smoking, and lifestyle factors that may influence cardiovascular risk. Negative-control analyses examining outcomes theoretically unrelated to the drugs, such as breast or prostate cancer and arm or shoulder fractures, found no differences between groups, providing some reassurance against unmeasured confounding. Follow-up was relatively short, averaging roughly nine to ten months, and the study population was limited to the US health care setting. Still, the consistency of the results with the SOUL trial, combined with prior real-world evidence showing cardiovascular benefits of once-weekly injectable semaglutide, builds a coherent case that this class of drugs genuinely protects the heart in high-risk patients, whether delivered by needle or by pill.

Subject of Research: Real-world cardiovascular outcomes of oral semaglutide in adults with type 2 diabetes and atherosclerotic cardiovascular disease.

Article Title: Comparing Cardiovascular Outcomes in New Users of Oral Semaglutide Versus Other Noninsulin Glucose-Lowering Therapies Among Adults with Type 2 Diabetes and Atherosclerotic Cardiovascular Disease

Article References: Tan, X., Liang, Y., Zhong, C., Xie, L., Guevarra, M., Swift, C., & de Havenon, A. (2026). Comparing Cardiovascular Outcomes in New Users of Oral Semaglutide Versus Other Noninsulin Glucose-Lowering Therapies Among Adults with Type 2 Diabetes and Atherosclerotic Cardiovascular Disease. Diabetes Therapy. https://doi.org/10.1007/s13300-026-01919-8

Image Credits: AI Generated

DOI: 10.1007/s13300-026-01919-8

Keywords: oral semaglutide, type 2 diabetes, cardiovascular outcomes, major adverse cardiovascular events, GLP-1 receptor agonist, DPP4 inhibitors, SGLT2 inhibitors, ischemic stroke, real-world evidence, SNAC absorption, Diabetes Therapy, comparative effectiveness