The investigators are conducting the planned work through the HIV and Alcohol Research Center focused on Polypharmacy, or HARP, and aim to recruit 60 adults receiving care at the Atlanta Veterans Affairs Infectious Disease Clinic. Twenty participants are planned for each medication-specific pilot. Eligibility criteria include alcohol use disorder, a phosphatidylethanol, or PEth, concentration above 20 mg/nL, and polypharmacy, defined in the protocol as taking more than five medications. Each study medication would be prescribed for 12 weeks by an addiction physician. Participants would also meet with a clinical pharmacist for a motivational interviewing-based counseling session concerning their personal health risks associated with alcohol use in the context of polypharmacy.

Feasibility will be evaluated through recruitment, enrollment, retention, visit attendance and adherence to the study medication. The protocol identifies the proportion of patients offered participation who complete enrollment as the primary feasibility outcome. Acceptability will be examined through a participant satisfaction questionnaire and analysis of qualitative information from a subset of participants. The qualitative material is intended to capture participants’ views of the intervention’s different components and their perceived impact on alcohol consumption. These measures address whether the intervention can be delivered in the intended clinic and whether participants regard it favorably, rather than whether it produces a clinically proven reduction in drinking.

Safety and tolerability will be assessed by reviewing clinical and laboratory information and recording the frequency of adverse events. The investigators will also make descriptive comparisons before and after the 12-week intervention. Planned measures include readiness to change, self-reported and laboratory-based indicators of alcohol consumption, PEth concentration, polypharmacy, self-reported and laboratory-based measures of tobacco use, bothersome symptoms, and biomarkers of health related to HIV. The absence of a randomized comparison group and the open-label design mean that any before-and-after differences cannot establish that a medication caused a change in alcohol consumption. The protocol also does not provide evidence that any of the three medications is safe, tolerable or effective for adults with HIV and polypharmacy.

The researchers hypothesize that the three off-label medications, each combined with the pharmacist-delivered behavioral intervention, will be feasible, acceptable, safe and tolerable and will be associated with changes in alcohol consumption. Those statements are prospective expectations, not observed findings. The study’s limited scope—three separate pilots, 60 participants in total, 20 per medication, one Veterans Affairs clinic and a 12-week treatment period—means that it is intended to provide preliminary operational and descriptive information. The investigators state that future research will evaluate the most promising intervention package in randomized controlled trials. Until such trials produce comparative results, the protocol supports planning and feasibility assessment, not conclusions about the clinical benefit of spironolactone, varenicline or semaglutide for this population.

Subject of Research: Three planned open-label pilot studies of off-label medications for alcohol use disorder in adults with HIV and polypharmacy

Article Title: Feasibility, acceptability, safety, tolerability, and changes in alcohol consumption associated with off-label medications for alcohol use disorder among patients with HIV: protocol for an open-label pilot study

Article References: Haque, L. Y., Maisto, S. A., Weiss, J., Marconi, V. C., Hsieh, E., Garcia, A., Womack, J. A., Kidwai-Khan, F., Tang, Y., Dziura, J., Leggio, L., Bryant, K., Justice, A. C., Fiellin, D. A., & Edelman, E. J. (2026). Feasibility, acceptability, safety, tolerability, and changes in alcohol consumption associated with off-label medications for alcohol use disorder among patients with HIV: protocol for an open-label pilot study. Addiction Science & Clinical Practice. https://doi.org/10.1186/s13722-026-00728-5

Image Credits: AI Generated

DOI: 10.1186/s13722-026-00728-5

Keywords: HIV, alcohol use disorder, polypharmacy, spironolactone, varenicline, semaglutide, open-label pilot, clinical protocol, PEth, Veterans Affairs, Feasibility, acceptability

The study included nearly 2,400 women taking semaglutide and nearly 1,500 taking tirzepatide. Participants were over 45 years old and had a body mass index above 27 kg/m², and they were receiving treatment for overweight or obesity. Investigators compared weight-loss responses between hormone-therapy users and nonusers. The release described the research as the first known large real-world cohort of midlife women treated with these GLP-1-based obesity medications.

The result was consistent with earlier, smaller retrospective studies in postmenopausal women, which had suggested an association between hormone therapy and greater weight-loss responses to semaglutide and tirzepatide. The new analysis was presented as a larger, independent cohort. Its stronger finding for semaglutide may point to an interaction specific to GLP-1 signaling, the researchers said, while emphasizing that the difference between the two drugs deserves further investigation.

Dr. Regina Castaneda of Mayo Clinic Florida, the lead study author, said the consistent signal should not be overlooked. She also said it was too early to draw firm conclusions and that the findings need confirmation in adequately designed prospective trials. Castaneda noted that the association was biologically plausible in light of preclinical data suggesting a potential synergistic effect between estrogen and GLP-1 signaling. Because the study was observational, its findings should not be interpreted as establishing a causal treatment effect or as grounds for prescribing hormone therapy to improve weight loss. Weight loss is not an indication for menopause hormone therapy, the release emphasized.

The results were scheduled for discussion at The Menopause Society’s 2026 Annual Meeting in San Diego in a presentation titled “Menopause Hormone Therapy and Weight Loss Response to GLP-1-Based Therapies in Midlife Women: A Retrospective Cohort Study.” Around 20% of women aged 50 to 64 report current or past use of a GLP-1-based obesity medication, according to the release. The practical scope of the findings therefore remains limited to the population and medicines studied: an association was observed between hormone-therapy use and greater, sustained weight loss with semaglutide, whereas the final difference for tirzepatide was not statistically significant.

Subject of Research: Menopause hormone therapy and weight-loss response to GLP-1-based obesity medications in midlife women

Article Title: Hormone therapy may increase weight loss effectiveness of GLP-1s

Article References: Hormone therapy may increase weight loss effectiveness of GLP-1s. Original publication (Bibliographic details unavailable.)

Image Credits: AI Generated

DOI: Not provided

Keywords: semaglutide, tirzepatide, menopause, hormone therapy, weight loss, midlife women, GLP-1 medications, observational cohort, treatment response, Hormone, therapy, increase

CagriSema represents a convergence of two hormonal pathways that have reshaped metabolic medicine over the past decade. Semaglutide, already established as a blockbuster therapy for both diabetes and obesity, mimics glucagon-like peptide-1 to enhance insulin secretion, suppress glucagon release, and slow gastric emptying. Cagrilintide, by contrast, is a long-acting analogue of amylin, a peptide co-secreted with insulin from pancreatic beta cells that contributes to satiety signaling and post-meal glucose regulation. By pairing these two mechanisms in a single weekly injection, CagriSema is designed to exploit complementary appetite and glycemic pathways simultaneously, an approach that has generated considerable excitement about whether combination therapy could outperform either component alone.

To quantify that promise rigorously, the investigators searched PubMed, Embase via Elsevier, the Cochrane Library, and ClinicalTrials.gov through June 2026, identifying randomized controlled trials that compared CagriSema against placebo, semaglutide, or cagrilintide. They applied random-effects meta-analytic models, calculating mean differences for continuous outcomes such as HbA1c and body weight, and risk ratios for dichotomous outcomes such as adverse events and treatment discontinuation, each with 95 percent confidence intervals. Methodological quality was evaluated using the Cochrane Risk of Bias 2 tool, and the certainty of evidence was graded with the GRADE framework, yielding assessments that ranged from low to high across the reported outcomes. That spectrum of certainty is itself informative, signaling where the evidence base is robust and where longer-term data remain necessary.

The glycemic results were striking at both doses tested. At the 2.4 mg dose, CagriSema reduced HbA1c by a mean difference of 1.01 percentage points compared with controls, with a confidence interval spanning from 1.44 down to 0.57 percentage points, and lowered fasting plasma glucose by 1.41 mmol/L. The 1 mg dose, though slightly less potent on average, still delivered a clinically meaningful HbA1c reduction of 0.99 percentage points and a fasting plasma glucose decline of 1.04 mmol/L. For context, a reduction approaching one percentage point in HbA1c is comparable to or exceeds the effect seen with many established glucose-lowering agents, and achieving it with a single weekly injection would represent a significant therapeutic advance for patients whose glycemic targets remain out of reach on current regimens.

Where CagriSema truly distinguished itself was in body weight and cardiometabolic parameters. The 2.4 mg dose produced a mean body weight reduction of 8.31 percent, with confidence intervals indicating the true effect could range from 10.58 down to 6.04 percent, alongside a 7.32 cm reduction in waist circumference and a 4.30 mmHg drop in systolic blood pressure. Remarkably, the 1 mg dose showed a comparable weight effect of 8.76 percent, with wider uncertainty reflecting fewer pooled participants at that dose level, plus reductions of 5.66 cm in waist circumference and 4.73 mmHg in systolic blood pressure. The near-parity in weight loss between the two doses raises intriguing pharmacological questions about whether the amylin component drives much of the weight effect and whether dose escalation primarily refines glycemic control rather than amplifying weight reduction.

Safety findings added important nuance to the efficacy story. Serious adverse events did not differ significantly between CagriSema and comparators at either dose, a reassuring signal that the combination does not appear to elevate major safety risks in the trial populations studied. However, gastrointestinal adverse events and treatment discontinuation were both more frequent with the 2.4 mg dose, consistent with the dose-dependent tolerability profile seen across the incretin-based drug class. The 1 mg dose produced a smaller increase in gastrointestinal side effects and, notably, did not significantly increase discontinuation rates compared with control groups. This dose-response asymmetry suggests that a substantial fraction of patients could capture most of the metabolic benefit at the lower dose while avoiding the tolerability ceiling that often forces dose interruption.

The GRADE certainty ratings, spanning low to high across outcomes, underscore both the strength and the limitations of the current evidence. High-certainty findings provide confidence in the core glycemic and weight effects, while lower-certainty outcomes reflect the inherent constraints of pooling a limited number of trials with heterogeneous designs, durations, and comparator arms. The authors themselves emphasize that long-term randomized studies are needed to confirm the safety and durability of CagriSema’s effects, a caveat that matters enormously for a therapy intended to be used chronically in a condition that requires lifelong management.

The clinical implications of this dose-specific analysis are considerable. For patients with type 2 diabetes whose primary challenge is glycemic control, the 1 mg dose appears to offer nearly the full HbA1c benefit with a more favorable tolerability profile. For those whose treatment goals prioritize substantial weight reduction and cardiovascular risk factor improvement, the 2.4 mg dose delivers greater effects on waist circumference and comparable blood pressure benefits, at the cost of more gastrointestinal events and higher discontinuation. This kind of dose-stratified evidence is precisely what prescribers need as incretin-based combination therapies move from trial protocols into routine endocrinology practice, where individualized titration decisions carry real consequences for adherence and outcomes.

Looking ahead, the CagriSema story sits at the frontier of a broader shift in metabolic medicine, where multi-agonist molecules are being engineered to replicate the coordinated hormonal responses that follow bariatric surgery. The meta-analysis confirms that combining amylin and GLP-1 signaling produces additive benefits on glucose and weight without a proportional increase in serious adverse events, validating the dual-pathway hypothesis in a large pooled population. As longer-duration trials mature and head-to-head comparisons against established therapies accumulate, the field will gain clarity on where CagriSema fits within the therapeutic arsenal. For now, this analysis provides the most comprehensive dose-specific evidence synthesis to date, and it suggests that for millions of people with type 2 diabetes, a single weekly injection targeting two hormonal systems simultaneously may soon offer a level of glycemic and weight control previously achievable only through surgical intervention.

Subject of Research: Dose-specific efficacy and safety of the cagrilintide-semaglutide combination CagriSema in type 2 diabetes

Article Title: Dose-specific efficacy and safety of cagrisema in type 2 diabetes mellitus: a systematic review and meta-analysis of randomized controlled trials

Article References: Khan, B. W., Khattak, M. H., Yahya, M., Khan, M. M., Qazi, T. I., Yar, S., Khan, M. M., Amjad, M. M., Bibi, H., Muneeb, M., Khan, S., Muiz, A., Fayyaz, M. M. N., Malik, A. A., Arify, J., Khan, U. Z., & Batool, A. (2026). Dose-specific efficacy and safety of cagrisema in type 2 diabetes mellitus: a systematic review and meta-analysis of randomized controlled trials. BMC Endocrine Disorders. https://doi.org/10.1186/s12902-026-02657-5

Image Credits: AI Generated

DOI: 10.1186/s12902-026-02657-5

Keywords: CagriSema, cagrilintide, semaglutide, type 2 diabetes, meta-analysis, randomized controlled trials, HbA1c, weight loss, GLP-1 receptor agonist, amylin analogue, cardiometabolic risk, drug safety

Glucagon-like peptide-1 receptor agonists, or GLP-1RAs, mimic the action of GLP-1, an incretin hormone synthesized primarily by intestinal L cells and brainstem neurons. Released when undigested nutrients enter the small intestine, GLP-1 signaling through the vagus nerve and central nervous system delays gastric emptying, improves satiety, and promotes glucose-dependent insulin release—the so-called ileal brake. Exenatide, modeled on exendin-4, a peptide isolated from Gila monster venom that resists degradation by the enzyme DPP-4, became the first FDA-approved GLP-1RA in 2005. That synthetic success inspired a generation of more potent, long-acting, CNS-penetrant agonists, including semaglutide, liraglutide, dulaglutide, lixisenatide, and the dual GLP-1/GIP agonist tirzepatide. Their popularity has been explosive: an estimated one in eight Americans has now tried a GLP-1RA.

Why would neurologists care? Because obesity and MS are deeply entangled. In the multi-center MS PATHS cohort, 42 percent of newly diagnosed people with MS in the United States were obese, and in a separate prospective cohort of 130 patients with at least moderate disability, 56 percent had a waist circumference consistent with abdominal obesity. A population-based case-control study of 3,249 people in the Swedish MS registry found that obesity at baseline is associated with faster disease progression—measured by time to an Expanded Disability Status Scale score of 3 or 4—more frequent T2 hyperintense demyelinating lesions on MRI, worse quality of life, and higher risk of cognitive worsening. The German National MS registry corroborated many of these findings, and Norwegian anthropometric data showed that high body mass index between ages 14 and 24 consistently increased MS susceptibility later in life in both sexes. Proposed mechanisms range from adipose tissue dysregulation and decreased vitamin D bioavailability to altered estrogen signaling, amplified Epstein–Barr virus immune responses, and gut microbiota dysbiosis.

Beyond weight loss, GLP-1RAs now carry FDA approvals for a remarkable list of comorbidities common in MS. Type 2 diabetes affects about 5 percent of people with MS, and poor glycemic control exacerbates the cognitive impairment that typically presents later in life. Tirzepatide became the first FDA-approved medication for obstructive sleep apnea in 2024, a condition that shares fatigue and cognitive deficits with MS; a Phase III trial showed it reduced apnea frequency, hypoxic burden, blood pressure, and fatigue. Semaglutide was approved in 2024 to reduce life-threatening cardiovascular events in adults with obesity or overweight—even without diabetes—and in 2025 for metabolic-associated steatohepatitis with moderate-to-advanced fibrosis, after a Phase III trial demonstrated improved resolution of steatohepatitis and reduced liver fibrosis. Semaglutide also reduced major kidney disease events in an international randomized trial in type 2 diabetes, relevant because people with MS face kidney complications from neurogenic bladder and, rarely, from treatments such as alemtuzumab. Emerging indications include alcohol use disorder, where semaglutide reduced heavy drinking days in patients with comorbid obesity, and knee osteoarthritis, where the STEP 9 trial of 407 participants found significant reductions in both body weight and pain.

The first MS-specific data come from small retrospective cohorts, and they are cautiously encouraging. In one single-center study of 49 adults with MS taking semaglutide or tirzepatide for an average of 24.2 months, average weight loss was 0.47 kilograms per month—roughly half the rate documented in the original Phase III semaglutide obesity trial, likely reflecting confounding factors such as steroid use. Still, the drugs worked. Twenty-nine percent of patients reported gastrointestinal side effects, but only 6 percent discontinued due to intolerability. MS disease activity fell within an expected range: one clinical relapse and four patients with new subclinical MRI lesions, in a cohort where 24 percent were not taking a disease-modifying therapy. A second retrospective study of 60 people with MS added a metabolic twist: after GLP-1RA initiation, average body mass index decreased while serum 25-hydroxy-vitamin D levels rose, without progression in EDSS scores or timed 25-foot walk duration. Lower vitamin D has been linked to increased relapse risk and new T2 lesions, so the increase in bioavailability is potentially meaningful.

Prescribing considerations are far from trivial. Cost is a major barrier: the 2024 KFF Health Tracking Poll found that more than half of adults who have taken GLP-1RAs say the cost was difficult to afford, and a NARCOMS survey of 4,181 people with MS found that although 40 percent had an indication, only 14.6 percent had ever taken a GLP-1RA. Sarcopenia is an emerging concern, since skeletal muscle possesses GLP-1 receptors and one-fifth of people with MS already have sarcopenia, associated with severe fatigue and inability to exercise. The lean-mass fraction of weight loss varies dramatically by drug: 45.2 percent in the STEP-1 semaglutide trial versus 25.7 percent in the SURMOUNT-1 tirzepatide study. Perhaps the most eye-catching safety signal is nonarteritic anterior ischemic optic neuropathy, or NAION. A retrospective study from the Massachusetts Eye and Ear Infirmary of 16,827 overweight or obese patients found NAION incidence of 6.7 percent in the semaglutide-treated group versus 0.8 percent in the non-treated group, though subsequent studies found a far more modest increase, with one meta-analysis reporting an absolute NAION risk of 0.09 percent. Causality is unconfirmed, but people with MS share vascular risk factors for NAION—diabetes, cardiovascular disease, sleep apnea—and are already vulnerable to visual loss from optic neuritis, making any ophthalmic complication especially problematic.

The deeper biological question is whether GLP-1RAs could be neuroprotective in MS itself. GLP-1 receptors are present in the central nervous system, particularly in brain areas essential for cognition, and GLP-1RA administration reduces inflammatory markers such as C-reactive protein, tumor necrosis factor alpha, and various interleukins, commonly through the NF-kB signaling pathway. In experimental autoimmune encephalomyelitis, the mouse model of relapsing-remitting MS, the results are striking. EAE markedly downregulates GLP-1 and GLP-1R, but GLP-1RA administration rescues GLP-1R signaling, improving clinical symptoms, maintaining CNS organ weight, reducing spinal cord damage, and attenuating myelin staining loss. Exendin-4 reduced pro-inflammatory cytokine expression in EAE-activated microglia via NF-kB; liraglutide delayed EAE onset and reduced severity by upregulating Nrf2 and the mitochondrial antioxidant MnSOD while reducing the neurodegenerative marker amyloid precursor protein; semaglutide increased CREB/BDNF/MBP markers of myelination while reducing NF-kB and TNF-alpha, acting through PI3K/Akt pathways.

Yet the myelin story is contradictory. A cuprizone-induced mouse model of acute demyelination suggested liraglutide restored myelinated nerve staining, improved behavior and brain weight, elevated p-AMPK/SIRT1 levels and Olig2 protein expression, and decreased microgliosis. But a subsequent study challenged these findings by identifying that the anorexigenic effect of GLP-1RAs confounds the amount of cuprizone the mice actually ingest. By controlling for cuprizone and adding a myelin-specific immune response, that study found the experimental brain-penetrant agonist NLY01 had no effect on demyelination or remyelination in the setting of inflammatory barriers specific to MS. The Parkinson’s disease experience offers a sobering parallel: NLY01 prevented microglial-mediated conversion of astrocytes to a neurotoxic phenotype in mouse models, and lixisenatide slowed motor disability progression in a Phase II trial, but a clinical trial of NLY01 at 2.5 and 5.0 milligrams showed no improvement in Parkinson’s motor or non-motor features. Whether GLP-1RAs truly cross the blood-brain barrier at clinically meaningful levels remains an unresolved research gap.

Two ongoing trials may settle the question for MS. At Northwestern University in Chicago, an actively enrolling study is investigating long-term outcomes of people with MS co-treated with ocrelizumab and a GLP-1RA, following patients for 72 weeks with patient-reported outcome measures, clinical assessments, and disease biomarkers. At Johns Hopkins University in Baltimore, a nearly two-year study will administer NLY01—the novel brain-penetrant agonist that showed promise in Parkinson’s trials—and measure change in normalized brain parenchymal volume on MRI to evaluate possible neuroprotection directly. The review’s authors also speculate that GLP-1RAs could complement statins, which reduced whole-brain atrophy by 43 percent annually in a randomized trial of 140 people with secondary progressive MS but could not modulate inflammatory markers—precisely where GLP-1RAs excel.

For now, the verdict is measured. Early observational data are reassuring on safety and tolerability, and effective treatment of comorbidities may itself carry disease-modifying potential in MS, given that at least 15 percent of people are clinically obese at diagnosis and weight loss improves outcomes. By pharmacologically inducing weight loss that dietary and exercise interventions struggle to achieve in patients burdened by fatigue, imbalance, and motor weakness, GLP-1RAs may help people with MS return to regular aerobic activity, with secondary benefits for mood and energy. But available evidence does not yet establish disease-modifying efficacy, and prospective randomized controlled trials are needed before the class can claim a role in the MS treatment regimen itself. As the multi-billion-dollar GLP-1 industry continues its expansion, the MS community is watching closely—because the next chapter of the Ozempic story may be written in the brain.

Subject of Research: Neurology

Article Title: Glucagon‐Like Peptide‐1 Receptor Agonists in Multiple Sclerosis: A Topical Narrative Review

Article References: Chang, A. Y., & Mateen, F. J. (2026). Glucagon‐Like Peptide‐1 Receptor Agonists in Multiple Sclerosis: A Topical Narrative Review. Annals of Clinical and Translational Neurology, Article acn3.70547. https://doi.org/10.1002/acn3.70547

Image Credits: AI Generated

DOI: 10.1002/acn3.70547

Keywords: GLP-1 receptor agonists, multiple sclerosis, semaglutide, tirzepatide, obesity, neuroprotection, experimental autoimmune encephalomyelitis, optic neuropathy, comorbidities, clinical trials, inflammation, disease-modifying therapy

The biological foundation for these effects lies in the incretin hormones themselves. GLP-1 is secreted by enteroendocrine L cells in the distal small intestine and colon, rising rapidly after meals rich in carbohydrates and fats. It enhances glucose-dependent insulin secretion, suppresses glucagon under hyperglycemic conditions, delays gastric emptying, and promotes satiety. GIP, its counterpart, is released by K cells in the duodenum and proximal jejunum and similarly boosts insulin secretion in a glucose-dependent manner. Both hormones are rapidly degraded by the enzyme dipeptidyl peptidase-4, which is why pharmaceutical versions have been engineered to resist degradation and act for days or weeks. Crucially, GLP-1 receptors are found not only in the pancreas but also in the gastrointestinal tract, the central nervous system, the heart, blood vessels, and the kidneys, providing a mechanistic basis for effects that extend well beyond blood sugar control.

The review details how GLP-1 receptor agonism may protect the cardiovascular system through several converging routes. Central receptor activation enhances satiety and reduces energy intake, and the resulting weight loss improves blood pressure, glycemic control, and lipid metabolism. Experimental and clinical evidence also points to direct anti-inflammatory, antioxidative, and vascular effects that improve endothelial function and attenuate fibrosis and cellular injury. In the kidneys, receptor activation promotes natriuresis, partly through modulation of sodium transport in the proximal tubule, and may influence kidney hemodynamics and glomerular hyperfiltration. However, the authors caution that GLP-1 receptor expression in the human kidney appears more restricted than previously assumed, meaning kidney protection likely arises from a combination of direct and indirect mechanisms, including improvements in glycemia, body weight, blood pressure, vascular function, and inflammation.

Tirzepatide occupies a distinct pharmacological position as a single peptide that activates both GIP and GLP-1 receptors. Pharmacological studies have shown an imbalanced signaling profile, with greater engagement of the GIP receptor than the GLP-1 receptor and distinct signaling properties at the latter. GIP receptors are expressed in pancreatic beta cells, adipose tissue, and brain regions involved in appetite regulation, and simultaneous activation of both receptors produces complementary effects on glucose regulation, energy intake, and body weight. This dual mechanism underpins the pronounced metabolic efficacy seen across the SURPASS and SURMOUNT trial programs, and it has fueled interest in whether such metabolic gains translate into cardiovascular and kidney protection.

The cardiovascular evidence for single GLP-1 receptor agonists is now firmly established. In the LEADER trial, liraglutide reduced the primary composite of cardiovascular death, non-fatal myocardial infarction, and non-fatal stroke with a hazard ratio of 0.87. REWIND showed a similar benefit for dulaglutide with a hazard ratio of 0.88, HARMONY Outcomes demonstrated a hazard ratio of 0.78 for albiglutide, and AMPLITUDE-O reported a hazard ratio of 0.73 for efpeglenatide. Semaglutide produced a hazard ratio of 0.74 in SUSTAIN-6, and the SELECT trial extended this benefit to people with overweight or obesity and established cardiovascular disease but without diabetes, with a hazard ratio of 0.80. The absence of diabetes in SELECT is particularly significant, demonstrating that glucose lowering is not required for cardiovascular benefit, although the trial does not establish independence from weight loss or other metabolic changes.

The kidney story has evolved more gradually and with important caveats. Early kidney findings from cardiovascular outcome trials were largely prespecified secondary or exploratory composites dominated by albuminuria, a frequent but relatively early marker of kidney damage. In LEADER, the kidney benefit was driven primarily by a reduction in new-onset persistent macroalbuminuria, while doubling of serum creatinine and end-stage kidney disease were not significantly reduced. REWIND showed a similar pattern, with the strongest effect on new macroalbuminuria and no individual significance for sustained eGFR decline or chronic kidney replacement therapy. The review emphasizes that improvement in albuminuria should not be considered equivalent to prevention of progressive loss of kidney function, a distinction that separates the earlier evidence from the dedicated kidney outcome trial FLOW.

FLOW changed the landscape by making chronic kidney disease progression the primary focus. In patients with type 2 diabetes and chronic kidney disease, semaglutide reduced the composite of kidney failure, sustained 50 percent or greater reduction in eGFR, or death from kidney-related or cardiovascular causes by 24 percent, with a hazard ratio of 0.76. Cardiovascular mortality fell with a hazard ratio of 0.71, all-cause mortality with 0.80, and the mean annual decline in eGFR was 1.16 milliliters per minute per 1.73 square meters per year less steep than with placebo. A subsequent prespecified participant-level pooled analysis of SELECT, FLOW, and SOUL, encompassing 30,787 participants across different formulations, doses, and diabetes statuses, found a 16 percent reduction in a harmonized kidney composite, with the association persisting even when cardiovascular death was excluded from the endpoint.

For tirzepatide, the cardiovascular evidence is expanding but remains qualitatively different. The SURPASS-CVOT trial directly compared tirzepatide with dulaglutide in patients with type 2 diabetes and established atherosclerotic cardiovascular disease, finding non-inferiority but not statistical superiority for major adverse cardiovascular events despite greater reductions in body weight and HbA1c. This finding illustrates a central theme of the review: greater metabolic efficacy does not necessarily translate proportionally into greater reduction in hard cardiovascular outcomes. In contrast, the SUMMIT trial produced particularly encouraging results in obesity-related heart failure with preserved ejection fraction, reducing the composite risk of cardiovascular death or worsening heart failure, an effect driven primarily by fewer worsening heart failure events rather than a standalone reduction in cardiovascular mortality.

The kidney evidence for tirzepatide remains the least mature component of its profile. Post-hoc analyses of SURPASS-4 suggest slower eGFR decline, reduced albuminuria, and a lower risk of composite kidney endpoints compared with insulin glargine, and a separate analysis using cystatin C-based estimates supported slower kidney function decline. However, these findings derive from trials not designed or powered to evaluate chronic kidney disease progression, and the review stresses that they should be interpreted as supportive and hypothesis-generating rather than definitive. No dedicated kidney outcome trial exists for tirzepatide, in stark contrast to the FLOW evidence for semaglutide.

The review also addresses combination therapy, safety, and future directions. Contemporary guidelines, including the 2026 AHA/ACC/ADA/ASN guideline, support the use of SGLT2 inhibitors, GLP-1-based therapies, or both in appropriate patients, and meta-analytic evidence suggests GLP-1 receptor agonist benefits are preserved during background SGLT2 inhibitor treatment, although the precise magnitude of incremental benefit from combination therapy remains uncertain. Gastrointestinal adverse events remain the most frequent tolerability limitation, concentrated during dose escalation, while meta-analyses have identified increased risks of gallbladder and biliary disease with both drug classes. Acute pancreatitis has not shown a statistically significant increase in trial meta-analyses, and the excess diabetic retinopathy complications seen with semaglutide in SUSTAIN-6 appear concentrated among patients with pre-existing retinopathy and rapid glycemic improvement. Looking ahead, the triple agonist retatrutide, targeting GLP-1, GIP, and glucagon receptors, is being evaluated in the ongoing TRIUMPH-Outcomes trial, and the authors argue that treatment selection should ultimately follow a phenotype-oriented framework in which the choice of incretin-based therapy reflects the clinical outcome most important to modify, the maturity of evidence supporting that outcome, and patient-specific characteristics rather than metabolic potency alone.

Subject of Research: Cardiovascular and kidney effects of GLP-1 receptor agonists and tirzepatide in cardiovascular-kidney-metabolic syndrome

Article Title: Beyond glycemic control: cardiovascular and kidney benefits of GLP-1 receptor agonists and the dual GIP/GLP-1 receptor agonist tirzepatide: a narrative review

Article References: Kierzkowski, F., Skrzypek, W., Bryl, W., Paczkowska, A., & Hoffmann, K. (2026). Beyond glycemic control: cardiovascular and kidney benefits of GLP-1 receptor agonists and the dual GIP/GLP-1 receptor agonist tirzepatide: a narrative review. Frontiers in Endocrinology, 17, Article 1977433. https://doi.org/10.3389/fendo.2026.1977433

Image Credits: AI Generated

DOI: 10.3389/fendo.2026.1977433

Keywords: GLP-1 receptor agonists, tirzepatide, semaglutide, cardiovascular-kidney-metabolic syndrome, chronic kidney disease, obesity, type 2 diabetes, heart failure with preserved ejection fraction, FLOW trial, SELECT trial, SURPASS-CVOT, incretin therapies

The connection between metabolic disease and mental illness is well established. In consultative work within endocrinology departments, physicians frequently observe psychotic symptoms or cognitive changes in patients with poorly controlled glycemia, sometimes progressing to delirium. A German study found that the prevalence of affective disorders in patients with type 2 diabetes is twice as high as in those without the disease. Depression, with its attendant risk of suicidality, sits at the endpoint of this metabolic spectrum. The overlap is not coincidental: atypical antipsychotics, which spare dopamine but trigger metabolic syndrome, hyperlipidemia and diabetes, illustrate how tightly the two domains are coupled, and the shared neurotransmission substrates revealed by drugs such as the GABA analog pregabalin—approved first for diabetic neuropathic pain and later tested for generalized anxiety disorder—underscore the point.

Inflammation is increasingly recognized as a therapeutic target in neuropsychiatric disorders, and type 2 diabetes is associated with acute and chronic stress and a systemic proinflammatory state. These mechanisms activate the hypothalamic-pituitary-adrenal axis, drive hepatic glycogenolysis, hyperglycemia, hyperlipidemia and insulin resistance, and contribute to core depressive features such as anhedonia, emotional dysregulation and cognitive slowing. Animal models have identified interaction pathways between the brain and adipose tissue, and between the brain and the microbiota, indicating that peripheral events strongly influence central nervous system activity and behavior. The focus, the authors argue, should not be solely on glycemic regulation but on immunometabolism as a route to depression onset.

The etiopathogenesis of type 2 diabetes is complex, encompassing insulin resistance in liver, muscle and adipose tissue, impaired insulin secretion, beta-cell dysfunction, immune dysregulation and meta-inflammation, hyperglucagonemia, disrupted gut microbiota, increased gastric glucose absorption, renal adaptation with enhanced glucose reabsorption and gluconeogenesis, decreased dopamine and heightened sympathetic tone in the brain. The new generation of drugs acts on the reduced secretion or effectiveness of glucagon-like peptide-1, a gastrointestinal hormone that regulates pancreatic islet function, enhances insulin production, reduces glucagon output and modulates satiety and gastric motility. GLP-1 receptors are found throughout the body and in the brain: activation produces hypophagic effects in the ventral hippocampus, and the agonists suppress appetite via cells of the circumventricular organs around the third and fourth brain ventricles, which transmit signals to deeper brain structures. Crucially, these compounds reduce central neuroinflammation by lowering interleukin-1 beta, interleukin-6 and tumor necrosis factor-alpha, and by limiting oxidative stress.

This biology intersects with a growing movement in precision psychiatry to classify subpopulations of patients with inflammatory depression, characterized by elevated inflammatory markers, increased glucose and lipid levels, neurovegetative symptoms, anxiety or irritability, and suicidal ideation. For this subtype, therapeutic strategies should target inflammation, immunometabolism and neurotransmitter metabolism, which makes the use of GLP-1 receptor agonists in these patients seem justified. Dual strategies that address metabolic disorders and depression simultaneously, the authors suggest, appear reasonable.

What does the safety record actually show? The picture is genuinely mixed. The U.S. Food and Drug Administration issued a warning in 2024 about suicidal thoughts or actions in patients taking these medicines, then in 2026 requested removal of the suicidal behavior and ideation warning from GLP-1 receptor agonist labels. The European Medicines Agency stated in 2024 that it found no evidence of an association. World Health Organization pharmacovigilance data show variable associations with depression and suicidality depending on the agent used, and meta-analyses have found no differences compared with other diabetes drugs, though a higher risk was noted with liraglutide, while semaglutide appears less frequently linked to suicidality than liraglutide. Meanwhile, retrospective cohort studies of obese or diabetic patients have reported no link—or even improvement—with reduced risk of sudden or recurrent suicidal thoughts, and a large cohort study of type 2 diabetes patients using active comparators found no difference. Genetic proxy activation of GLP-1 receptors showed reduced risk for anxiety, depression or emotional lability, and a French nationwide case-time-control study of completed suicides and attempts found no specific risk related to prior psychiatric history or obesity during GLP-1 receptor agonist use.

No clear causal mechanism linking the drugs to suicidality has been established, and the authors propose inflammation as the missing link that could explain both beneficial and unwanted effects. A simplified account is that inflammation is ameliorated by these drugs—but, they caution, we do not fully know what happens when a longstanding pathological balance is abruptly disturbed across cascades of chronic stress and the reward system, involving leptin and ghrelin, GABA and dopamine, together with smoldering inflammation. The mechanistic detail is intricate: GLP-1 administration enhances satiety, indirectly prolongs fasting periods, reduces meal frequency and decreases meal-initiation pleasure via dopamine pathways. It also reduces meta-inflammation and inhibits leptin resistance. The resulting satiety, provided by leptin, blocks ghrelin and reduces the indirect pleasure of food intake. Ghrelin normally acts on reward pathways by stimulating dopamine neurons in the ventral tegmental area and promoting dopamine turnover in the nucleus accumbens, and it suppresses orexigenic neurons through GABA-dependent signaling. Reduced orexigenic activity is associated with improved sleep—which is essential for alleviating depression and decreasing suicidality—while insomnia may itself contribute to depression and suicidality by increasing inflammation, implying that the anti-inflammatory properties of GLP-1 receptor agonists could be doubly beneficial.

Recent preclinical work adds a striking twist. The GLP-1 receptor system appears to have evolved, at least in part, to regulate feeding-related motivation. As Gao and colleagues recently described, when energy balance is positive, GLP-1 receptor signaling dampens activity in the brain’s reward circuitry and reduces effort-based food seeking, a phenomenon also observed in other motivated behaviors. The signaling seems to influence affective behavior depending on energy levels: in the short term it could shift from exploration to conservation, redirecting external exploration toward internal regulation. Conversely, long-term treatment promotes anxiolytic and antidepressant effects rather than a fleeting interoceptive response. This timing matters clinically, because the beneficial effects of these medications are rooted in endocrine physiology rather than willpower, and guidelines indicate they show their effects only after extended periods of consistent dosing without complete discontinuation. Following intensive therapy with tirzepatide, treatment must continue to promote long-term weight maintenance, especially with comorbid type 2 diabetes—suggesting that prolonged dosing could benefit non-responders by ameliorating depressive symptoms and suicidality.

Clinical trials are now directly testing these questions. An eight-week Phase II trial will evaluate depressive symptoms with tirzepatide in patients with obesity and alcohol use disorder, and a Phase IV study will assess whether semaglutide improves depressive symptoms over 26 weeks in patients with major depressive disorder who also have overweight or obesity. The authors note it will be particularly insightful to study the drugs’ impact on affective symptoms during the maintenance phase or after discontinuation. In the meantime, they propose a prescribing triad: the response profile depends on the properties of the specific drug; the patient’s primary somatic diagnosis—diabetes, obesity, or both, with additional comorbidities—must be considered crucial; and mental disturbances or a formal psychiatric diagnosis must be taken into account. Patients can be divided at the start of treatment into those with depression and those without, with particular attention to mood disorders and suicidality risk, and schizophrenia may also be a context for these immunometabolic strategies.

One further warning deserves emphasis: rapid and substantial weight loss can itself produce significant mental disturbances, and in bariatric surgery an association between depression and peripheral inflammation has been observed regardless of obesity, with intensified baseline inflammation predicting poorer weight loss six months after surgery. The authors conclude that only an integrative approach is justified: endocrinologists should include basic psychological exploration and refer to a psychiatrist if psychopathology appears, at the start of treatment and longitudinally, while all desired and unwanted effects are presented to patients and unrealistic aims are discussed to avoid frustration. The effects of these drugs beyond the desired outcomes, they write, should not be minimized—they are far more potent than the marketing concept of GLP-1 care suggests.

Subject of Research: The potential link between GLP-1 receptor agonist use, inflammation, depression and suicidality

Article Title: Suicidality as a potential risk and therapeutic target during widespread GLP-1 receptor agonists use: implications of inflammation

Article References: Borovcanin, M. M., & Petrovic, I. (2026). Suicidality as a potential risk and therapeutic target during widespread GLP-1 receptor agonists use: implications of inflammation. Frontiers in Synaptic Neuroscience, 18, Article 1869086. https://doi.org/10.3389/fnsyn.2026.1869086

Image Credits: AI Generated

DOI: 10.3389/fnsyn.2026.1869086

Keywords: GLP-1 receptor agonists, semaglutide, tirzepatide, suicidality, inflammation, type 2 diabetes, obesity, depression, leptin, ghrelin, dopamine, immunometabolism

The argument rests on a simple clinical reality. Stroke predominantly affects older adults, and the comprehensive work-up that follows an acute event frequently uncovers previously undiagnosed cardiovascular comorbidities. Approximately one in five individuals presenting with acute stroke has type 2 diabetes, whether pre-existing or newly identified, and impaired kidney function and heart failure are also common among stroke survivors. Each of these conditions now has guideline-supported indications for the newer drug classes, which means a large share of patients treated in stroke units could benefit from therapies that stroke guidelines have yet to embrace.

The story of these agents begins with a regulatory mandate. Because some older antidiabetic drugs were linked to adverse cardiovascular outcomes, the U.S. Food and Drug Administration required in 2008 that all new glucose-lowering agents demonstrate cardiovascular safety in dedicated outcomes trials. That requirement produced an unexpected discovery: certain drugs not only met the safety bar but actively reduced cardiovascular events, with additional benefits for heart failure and chronic kidney disease. The therapeutic paradigm shifted, positioning these molecules as cardiometabolic agents with disease-modifying effects that extend far beyond glycemic control.

SGLT2 inhibitors work by blocking the sodium–glucose cotransporter 2 in the proximal renal tubules, increasing urinary excretion of glucose and water. The result is modest reductions in blood glucose, blood pressure and body weight, and the drugs are generally well tolerated, though they are not recommended when the glomerular filtration rate falls below 20 mL/min/1.73 m² and they carry an increased risk of ketoacidosis and genital infections. Despite only limited reductions in HbA1c, the class significantly reduces cardiovascular events and improves survival in patients with type 2 diabetes at high cardiovascular risk, with benefits consistent across multiple agents, supporting a class-wide effect.

The cardiovascular benefit of SGLT2 inhibitors is driven mainly by reductions in cardiovascular mortality and heart failure hospitalizations, with a more modest effect on atherosclerotic cardiac events. Subsequent trials showed that the drugs reduce heart failure-related hospitalizations regardless of whether ejection fraction is reduced or preserved, and in chronic kidney disease they slow progression and preserve kidney function even in the absence of diabetes. Heart failure and nephrology guidelines now recommend SGLT2 inhibitors as first-line medical treatment for chronic kidney disease with albuminuria or heart failure, irrespective of diabetes status. The recently updated NICE guidelines in the United Kingdom go further, recommending the class as first-line therapy alongside metformin in type 2 diabetes.

Importantly, current evidence does not support a clear reduction in recurrent stroke with SGLT2 inhibitor therapy. That gap separates the class from incretin-based therapies, which have shown a more direct effect on cerebrovascular risk. A meta-analysis of GLP-1 receptor agonists confirmed a reduction in stroke risk in people with type 2 diabetes, with a hazard ratio of 0.83, and a smaller effect on myocardial infarction. In patients with type 2 diabetes, the cardiovascular benefit is reflected in an approximately 14 percent reduction in the composite major adverse cardiovascular event endpoint of myocardial infarction, stroke and cardiovascular death, corresponding to a number needed to treat of 65 to avoid one event over 2.1 years.

The individual trial data are striking. Semaglutide reduced nonfatal stroke with a hazard ratio of 0.61 and showed a trend toward reduction in nonfatal myocardial infarction, though it had no effect on cardiovascular death. A recent small randomized study of patients with type 2 diabetes following minor stroke or high-risk transient ischemic attack observed a reduction in 90-day recurrent stroke with liraglutide. Beyond glycemic effects, incretin-based therapies produce substantial weight loss that appears to be a class effect, with greater reductions from injectable than oral formulations, and recent American Gastroenterological Association guidelines recommend incretins alongside lifestyle intervention for adults with obesity regardless of diabetes status.

The mechanisms underlying the stroke risk reduction remain unclear, but potential pathways include effects on platelet aggregation, endothelial function and overall cardiometabolic health. The interplay among obesity, type 2 diabetes, chronic kidney disease, heart failure and cardiovascular disease has also prompted the emergence of the concept of cardiovascular–kidney–metabolic syndrome, with a new 2026 guideline from American heart, kidney and diabetes organizations providing Class 1 recommendations for both drug classes in patients with type 2 diabetes and atherosclerotic cardiovascular disease. Combination therapy with SGLT2 inhibitors and GLP-1 receptor agonists has not been evaluated in dedicated randomized trials, but a meta-analysis of current evidence suggests it is safe and effective, though use remains limited, likely due to high costs.

On practical grounds, the commentary authors note that both drug classes can usually be initiated during the hospital stay for acute stroke once the patient is clinically stable. SGLT2 inhibitors should be started after assessment of renal function and volume status, with counseling on the risk of genital infections, dehydration and sick-day management, while GLP-1 receptor agonists should be initiated at a low dose and titrated slowly to improve gastrointestinal tolerability. Early outpatient follow-up is recommended to assess adherence and tolerability and to adjust concomitant medications as needed.

The authors conclude that the diagnostic work-up following an acute stroke should include screening for potentially modifiable risk factors, including type 2 diabetes, chronic kidney disease, heart failure and obesity, and that patients identified with these conditions should be managed in accordance with current evidence-based guidelines, including consideration of SGLT2 inhibitors and incretin-based therapies when appropriate. Clinicians should carefully weigh competing risks, particularly the substantial risk of all-cause mortality following stroke, alongside patient preferences, and clear pathways are needed for responsibility, titration and follow-up. Additional studies are required to assess whether these agents reduce stroke incidence, recurrence or severity, and to identify the specific patient subgroups and care settings in which they confer benefit, but the message is clear: stroke practice may need to evolve ahead of guideline updates to optimize care and improve long-term outcomes.

Subject of Research: Cardiometabolic drugs after stroke

Article Title: Cardiometabolic drugs after stroke: time to embrace SGLT2 inhibitors and incretin-based therapies?

Article References: Ihle-Hansen, H., Ihle-Hansen, H., Blauenfeldt, R. A., Dawson, J., Diederichsen, S. Z., & Hagberg, G. (2026). Cardiometabolic drugs after stroke: time to embrace SGLT2 inhibitors and incretin-based therapies?. Frontiers in Stroke, 5, Article 1918465. https://doi.org/10.3389/fstro.2026.1918465

Image Credits: AI Generated

DOI: 10.3389/fstro.2026.1918465

Keywords: stroke, SGLT2 inhibitors, GLP-1 receptor agonists, secondary prevention, type 2 diabetes, heart failure, chronic kidney disease, obesity, cardiovascular-kidney-metabolic syndrome, semaglutide, stroke guidelines, clinical practice

The technical distinction at the heart of the argument is deceptively simple. Relative risk reduction describes the proportional decrease in event risk between two groups, calculated as one minus the risk ratio, expressed as a percentage. Absolute risk reduction, by contrast, is the raw difference in cumulative event rates between the control and treatment groups at a specified time point. The number needed to treat is simply the inverse of that absolute reduction: it tells you how many patients must be treated, over that same period, to prevent one additional event. For time-to-event outcomes, the authors stress that these absolute measures should be estimated from cumulative event probabilities using appropriate survival methods, not by crudely subtracting annualized incidence rates. A hazard ratio of 0.79, for example, indicates an estimated 21 percent lower hazard assuming the proportional hazards interpretation holds, and is emphatically not the same thing as a 21 percent reduction in cumulative risk.

The consequences of conflating these measures are vividly illustrated by the PIONEER-6 trial of oral semaglutide. A physician reviewing the study sees a hazard ratio of 0.79 for major adverse cardiovascular events and may reasonably conclude that semaglutide offers a substantial cardiovascular benefit. Yet the trial actually reported such events in 3.8 percent of patients on the drug versus 4.8 percent on placebo over a median follow-up of 15.9 months, an absolute difference of roughly one percentage point and a number needed to treat of approximately 100 over that period. The distinction is not a statistical nicety. It directly shapes how clinicians, patients, guideline committees, and policymakers weigh therapeutic benefit, and it can mean the difference between an enthusiastic endorsement and a measured one.

The problem extends far beyond cardiology. In oncology, the CLEOPATRA trial showed that adding pertuzumab to trastuzumab and docetaxel improved overall survival in HER2-positive metastatic breast cancer with a hazard ratio of 0.68; in an eight-year landmark analysis, overall survival was 37 percent versus 23 percent, an absolute gap of roughly 14 percentage points. In neurology, the AFFIRM trial of natalizumab in relapsing multiple sclerosis reported a 68 percent reduction in annualized relapse rate, while the proportion of patients remaining relapse-free at two years was 67 percent versus 41 percent, an absolute difference of 26 percentage points. Across therapeutic areas, relative and absolute measures tell complementary but strikingly different stories, and the discrepancy is pervasive.

The authors assembled a comparison of seven major cardiorenal outcome trials to show how widely absolute benefit varies even when relative effects look similar. In CREDENCE, canagliflozin produced a hazard ratio of 0.80 for major adverse cardiovascular events, with events in 9.9 percent of treated patients versus 12.2 percent on placebo over a mean follow-up of 2.62 years, a crude absolute difference of 2.3 percentage points; the trial’s own survival-based estimate at 2.5 years was an absolute risk reduction of 2.5 percentage points, corresponding to a number needed to treat of 40. In HARMONY Outcomes, albiglutide yielded a hazard ratio of 0.78, with events in 7.1 percent versus 9.0 percent over 1.6 years, an absolute difference of 1.9 percentage points and a number needed to treat of roughly 53. Viewed through hazard ratios alone, these agents appear broadly comparable; the absolute measures reveal differences in benefit that are strongly driven by baseline event risk and follow-up duration rather than by any intrinsic superiority of one molecule over another.

The kidney field illustrates a further layer of complexity. Canagliflozin in CREDENCE and empagliflozin in EMPA-KIDNEY showed broadly similar relative effects on renal outcomes, with hazard ratios of 0.70 and 0.72 respectively, yet the composite endpoints differed importantly between the trials. CREDENCE used a composite of doubling of serum creatinine, end-stage kidney disease, and renal or cardiovascular death, whereas EMPA-KIDNEY included kidney disease progression defined by a sustained 40 percent or greater decline in estimated glomerular filtration rate, end-stage kidney disease, sustained filtration below 10 milliliters per minute per 1.73 square meters, or renal death, together with cardiovascular death. DAPA-CKD used yet another composite built around a 50 percent or greater sustained decline in filtration rate. These differing definitions, eligibility criteria, baseline risk profiles, and follow-up durations all influence absolute event rates, and EMPA-KIDNEY enrolled a broader and overall lower-risk population. Apparent differences in absolute benefit across these trials therefore cannot be read as evidence of differential drug efficacy.

The stakes are rising because the volume of cardiovascular and kidney outcome trials involving GLP-1 receptor agonists and SGLT2 inhibitors has expanded rapidly, and these therapies are increasingly prescribed across cardiology, nephrology, endocrinology, and primary care. As treatment indications broaden, clinicians need measures that communicate not merely whether a therapy works but how much benefit an individual patient can realistically expect. Absolute measures are often already partially available in journals that report event rates alongside hazard ratios, from which attentive readers can estimate absolute effects themselves, but explicit reporting would make the calculations immediately accessible and reduce the risk of misinterpretation. Methodological evidence indicates that numbers needed to treat derived from differences in incidence rates can be biased, whereas estimates built on cumulative event probabilities from survival analysis are more appropriate.

One domain where absolute effects prove especially valuable is in weighing efficacy against safety. Relative risks alone are insufficient for balancing events caused by treatment against events prevented. The ASCEND trial, which tested aspirin against placebo in patients with type 2 diabetes, is an instructive example: the absolute reduction in serious vascular events was 1.1 percentage points, while the absolute increase in major bleeding was 0.9 percentage points. Placed side by side, those figures make the delicate balance between benefit and harm immediately apparent in a way that any pair of relative percentages never could. The recently published SOUL trial of oral semaglutide reinforces the point about method as well: over a median follow-up of 49.5 months, major adverse cardiovascular events occurred in 12.0 percent of treated patients versus 13.8 percent on placebo, a crude absolute difference of 1.8 percentage points, while the prespecified survival-based estimate at three years was an absolute risk reduction of 2.0 percentage points and a number needed to treat of 50. The corresponding annualized incidence rates, 3.1 and 3.7 events per 100 person-years, form an incidence rate difference that should never be converted directly into a conventional number needed to treat by taking its reciprocal.

The authors are careful to acknowledge that their argument cuts both ways. Relative measures have genuine and distinct advantages: where there is no strong evidence of effect modification, relative risk reductions are generally more generalizable beyond the trial population, because absolute event rates vary substantially with baseline risk, secular trends, geography, and selection criteria. For an individual patient, the most appropriate estimate of absolute benefit comes from applying an applicable relative treatment effect to that patient’s own baseline risk over a specified time horizon, rather than simply importing the trial’s figure. Moderate to large relative reductions in the 20 to 39 percent range represent substantial treatment effects even in lower-risk populations and can have major consequences for population-level disease burden. The proposal, then, is not that absolute measures should supplant relative ones, but that they should travel together.

There are also inherent limits to the number needed to treat itself. It is inherently time-specific, so a figure calculated over one year is not equivalent to one calculated over five, because treatment effects and baseline event rates change over time. Cardiorenal trials typically run for two to five years, yet in practice these therapies are used far longer, and longer treatment may yield greater cumulative benefit, though this cannot be assumed to accrue linearly given changing hazards, competing risks, adherence, and discontinuation. Trial populations are highly selected and may differ substantially from routine clinical practice. The proposed solution is straightforward: journals should routinely require absolute risk reduction, number needed to treat, and baseline event rates alongside relative measures, with the time horizon and estimation method clearly stated, ideally at standardized time points such as one, three, and five years. Guidelines and regulators should follow suit. Transparent communication of treatment effects, the authors conclude, is essential if clinicians and patients are to make genuinely informed decisions.

Subject of Research: Reporting of absolute risk reduction and number needed to treat in cardiorenal outcome trials

Article Title: Relative risk reduction is not enough: why cardiorenal trials should routinely report absolute risk reduction and number needed to treat

Article References: Zaitoon, H., Abdul-Ghani, M., & DeFronzo, R. A. (2026). Relative risk reduction is not enough: why cardiorenal trials should routinely report absolute risk reduction and number needed to treat. eClinicalMedicine, 101, Article 104258. https://doi.org/10.1016/j.eclinm.2026.104258

Image Credits: AI Generated

DOI: 10.1016/j.eclinm.2026.104258

Keywords: absolute risk reduction, number needed to treat, hazard ratio, cardiorenal outcome trials, SGLT2 inhibitors, GLP-1 receptor agonists, semaglutide, chronic kidney disease, major adverse cardiovascular events, clinical trial reporting, eClinicalMedicine, evidence-based medicine

The design of the study is deliberately straightforward. Half of the participants, all of whom will have alcohol use disorder, opioid use disorder, or both, will be randomly assigned to receive once-weekly semaglutide injections for 52 weeks. Crucially, the medication will be offered as an additional support layered on top of existing care, not as a replacement for traditional addiction treatment. Participants will remain eligible for all other behavioral health supports throughout the study period. Recruitment will focus on individuals who are clinically appropriate for GLP-1 medications and who face an elevated risk of criminal-justice involvement, a targeting strategy that reflects the county’s interest in directing new interventions toward those with the greatest needs and its broader commitment to reintegration and community safety.

The scientific rationale rests on a growing but still preliminary body of evidence. Phase 2 trials conducted internationally have indicated that GLP-1 receptor agonists can decrease heavy drinking among people with alcohol use disorder and reduce opioid craving among people with opioid use disorder. Prior research published in The Lancet and JAMA Psychiatry, along with earlier work on the related drug liraglutide, has suggested that these medications, originally developed to mimic gut hormones that regulate appetite and blood sugar, may also modulate reward circuitry in the brain. Researchers involved in the trial describe the effect in practical terms: rather than feeling dominated by cravings, whether for sugar, alcohol, or drugs, many patients report that GLP-1 medications help quiet that internal noise, restoring a sense of personal agency that addiction erodes.

What sets this trial apart from most addiction medication studies is the breadth of its outcome measures. Where typical trials primarily track substance use, this study will exploit Allegheny County’s nationally recognized linked administrative data infrastructure to examine whether treatment improves real-world outcomes across entire systems. Researchers will follow participants’ employment, housing stability, health care utilization and costs, mental health, self-control and impulsivity, weight, and involvement with the criminal justice system, including rearrest, reconviction, and reincarceration. The team will also calculate total fiscal and social costs, allowing the study to answer not only a clinical question but a policy one: whether any clinical benefit is large enough to justify sustained public investment.

The partnership behind the trial grew out of an unlikely collaboration between a research organization and a county government. Alex Jutca, Director of the Allegheny County Department of Human Services, described reaching out to CASPR executive director and co-founder Nicholas Reville two years ago after reading his addiction medicine blog. The two began talking regularly about GLP-1 medications, addiction, recidivism, and the challenges the county was facing, and the trial concept emerged from those conversations. The collaboration combines clinical treatment expertise, the county’s integrated data systems and social service partnerships, economic analysis, and addiction-policy expertise within a single randomized study, a structure its architects say is extremely unusual for county government.

Clinical leadership will come from UPMC Western Psychiatric Hospital’s Addiction Medicine Services, which will serve as the lead clinical site alongside other addiction treatment partners in Allegheny County. Antoine Douaihy, MD, Professor of Psychiatry and Medicine at the University of Pittsburgh School of Medicine and Senior Academic Director of Addiction Medicine Services at Western Psychiatric Hospital, said the trial examines the effectiveness and safety of GLP-1 receptor agonists and their impact on outcomes including employment, housing, health, and recidivism, noting that drug use disorders are major drivers of criminal justice involvement and intersect with systemic inequities and disparities. He expressed enthusiasm that the trial holds promise to change the landscape of addiction treatment and expand the recovery toolbox.

The research team itself is multidisciplinary by design, bringing together economists, addiction psychiatry specialists, and policy researchers from MIT, the University of Pittsburgh, the University of California San Diego, and UPMC Western Psychiatric Hospital. Named investigators include Diana Martínez Heredia of the Allegheny County Department of Human Services, Frank Schilbach and Dhruv Gaur of MIT, J. Travis Donahoe of the University of Pittsburgh, Gordon Dahl of the University of California San Diego, and Antoine Douaihy of UPMC. This composition allows the trial to be studied from clinical, economic, and behavioral angles simultaneously, an approach intended to produce evidence that can guide decisions well beyond Pittsburgh.

Indeed, scalability is a central theme of the trial’s design. Reville emphasized that because the intervention is a medication rather than a complex service program, a positive result in Pittsburgh should translate almost everywhere, making the trial easy for other cities to adopt. Jutca added that if results are positive, the county will consider the approach on an ongoing basis for individuals with substance use disorders and will work with other cities and counties across the country to disseminate findings, consistent with the broader goals of the Allegheny Recovery Partnership, which aims to build a coordinated system of care that keeps people engaged in treatment over time. Both leaders stressed that new medications become most valuable when integrated into systems that consistently support recovery.

The trial also builds on CASPR’s earlier pilot work, including a program with OpenDoors in Rhode Island that provides semaglutide to women in a post-incarceration sober housing program. Reville reported remarkable outcomes from that pilot, with women describing the disappearance of drug dreams and reporting that they felt better than they had ever felt, allowing them to rebuild careers and family relationships once cravings quieted. That program has drawn national media attention, including coverage in The New York Times and The Washington Post. Reville argued that GLP-1 medications may prove especially impactful because many patients are already familiar with the drug class and eager to take it, a level of patient enthusiasm he suggested could make a sustainable population-level impact possible and mark the most significant advancement in addiction medicine in decades.

Organizers are also attentive to the ethical dimensions of the work. Jutca said the team is working closely with community leaders and partners to ensure that trial participants are treated with respect throughout the process, noting that while addiction is widespread, its costs are unequally distributed. The county wants to demonstrate that widening inclusion in medical research is both important and possible while upholding high clinical and safety standards. CASPR, which funds and publishes research with the VA, created the first-ever pilot programs giving GLP-1 receptor agonists to patients receiving addiction treatment, and advocates for policies enabling faster medication development, is funded by individuals and foundations and accepts no direct or indirect funding from pharmaceutical companies. If the trial succeeds, its architects believe the result will be a major advance: a way to give people a better chance to recover, stay healthy, find employment, maintain stable housing, and avoid returning to the justice system.

Subject of Research: A randomized clinical trial testing whether semaglutide reduces alcohol and opioid use and justice involvement among adults with substance use disorders.

Article Title: CASPR and Allegheny County announce major new randomized clinical trial: GLP-1RA recovery and stability trial

Article References: CASPR and Allegheny County announce major new randomized clinical trial: GLP-1RA recovery and stability trial. (n.d.). Original publication

Image Credits: AI Generated

DOI: Not provided

Keywords: semaglutide, GLP-1 receptor agonists, alcohol use disorder, opioid use disorder, randomized controlled trial, addiction medicine, recidivism, Allegheny County, CASPR, Arnold Ventures, criminal justice involvement, recovery

The implications reach well beyond the obesity clinic. Systolic blood pressure, the force blood exerts against artery walls when the heart contracts, is among the most powerful modifiable predictors of heart attack, stroke and premature death. For decades, clinicians have observed that losing weight lowers blood pressure, but the evidence base was built largely on lifestyle interventions that produced modest, hard-to-sustain reductions. The 2003 meta-analysis by Neter and colleagues, drawing on 25 trials and fewer than 5,000 participants, estimated that each kilogram lost yielded roughly 1 mmHg of systolic improvement. The new analysis updates that relationship for an era in which a single weekly injection can strip away 10 to 20 percent of body weight, approaching the results of bariatric surgery.

The researchers, led by Massimo Nardone and Marcel Muskiet, systematically searched MEDLINE, Embase and Cochrane databases through December 2025, screening more than 2,000 records to identify eligible trials. To qualify, studies had to be phase 3, randomized and placebo-controlled, enrolling adults with a body mass index of at least 30, or at least 27 with a weight-related comorbidity such as hypertension or sleep apnea. Crucially, the trials had to be designed for obesity treatment rather than glucose control, ensuring the analysis captured the drugs as they are actually deployed in weight management. The final dataset spanned liraglutide, semaglutide, tirzepatide, CagriSema, orforglipron, mazdutide and ecnoglutide, with median treatment duration of 68 weeks.

The pooled results were unambiguous. Across all trials, active treatment produced a placebo-adjusted weight loss of 10.1 percent and a systolic blood-pressure reduction of 4.9 mmHg. Heterogeneity between trials was substantial, but the meta-regression showed that most of it traced back to a single variable: how much weight participants actually lost. Trials in which patients shed less than 5 percent of body weight saw systolic pressure fall by only 3.1 mmHg, while those achieving 10 to 15 percent weight loss recorded drops of 5.4 mmHg. Most dramatic were trials exceeding 15 percent weight loss, where systolic pressure fell by an average of 8.1 mmHg, a figure that approaches the lower end of what standard antihypertensive monotherapy achieves.

That benchmark matters. A 2025 meta-analysis of more than 484 double-blind, placebo-controlled trials of conventional blood-pressure drugs, including ACE inhibitors, beta-blockers, calcium-channel blockers and diuretics, found an average systolic reduction of 8.7 mmHg. By that yardstick, the most powerful of the new obesity agents are delivering cardiovascular benefits of a comparable order of magnitude through weight loss alone. The authors calculated that matching the full effect of a standard antihypertensive drug would require roughly 23 percent weight loss, a target within sight of next-generation therapies such as retatrutide, which is currently in phase 3 testing.

Not every drug behaved identically, however. Tirzepatide, which engages both the GLP-1 and GIP receptors, produced the largest blood-pressure reduction at 7.1 mmHg alongside 14.9 percent weight loss, while mazdutide achieved 6.4 mmHg. CagriSema, the amylin-GLP-1 combination that produced nearly 14 percent weight loss, yielded a comparatively smaller 5.5 mmHg reduction, and phase 2 studies of cagrilintide alone showed meaningful weight loss without significant blood-pressure benefit. These discrepancies hint that receptor-specific biology, involving pathways such as GIP, glucagon and amylin signalling, may modulate the hemodynamic effects of these drugs in ways that are not yet understood, sometimes amplifying and sometimes potentially blunting the benefits of weight reduction.

Diabetes status also shaped the response. Trials enrolling participants without type 2 diabetes recorded greater weight loss, 11.1 percent versus 6.6 percent, and larger blood-pressure reductions, 5.4 versus 3.5 mmHg, than those enrolling people with diabetes. Yet the direction of effect was consistent in both groups, and baseline blood pressure itself did not materially modify the response, countering earlier suggestions of a floor effect at lower starting pressures. The authors note that patients with diabetes often take medications and have metabolic profiles that blunt weight loss, which likely explains much of the difference.

Intriguingly, the true cardiovascular impact of these drugs may be even larger than the headline numbers suggest. Several trials reported that participants on active treatment reduced or stopped their background antihypertensive medications during follow-up, which would narrow the measured gap between drug and placebo. A participant-level analysis of three STEP trials of semaglutide found twice the rate of antihypertensive de-escalation compared with controls, and mediation analyses suggested that nearly 89 percent of the observed systolic reduction was mediated by weight loss. In the REDEFINE-1 trial of CagriSema, roughly 40 percent of participants on blood-pressure medication either reduced or discontinued it. The measured 4.9 mmHg average may therefore understate the drugs’ intrinsic effect.

Mechanistically, the findings reinforce that shrinking adipose tissue is the dominant driver of blood-pressure improvement, acting through improved insulin sensitivity, reduced sympathetic nervous system activation, enhanced sodium excretion by the kidneys and favourable effects on vascular function. But they do not rule out weight-independent actions. GLP-1 receptors are expressed in the kidney and vasculature, and mechanistic studies have documented direct GLP-1-mediated natriuresis, improved endothelial function and reduced arterial stiffness. The example of albiglutide, which conferred cardiovascular benefit despite minimal weight loss and little blood-pressure reduction, is a reminder that the cardiovascular pharmacology of this class is not reducible to the bathroom scale alone.

The study has limitations the authors acknowledge. The analysis operated at the trial level rather than the individual level, leaving it vulnerable to ecological bias and unable to adjust for patient-specific confounders. Blood pressure was not a primary endpoint in any of the included trials, and measurements came predominantly from office visits rather than ambulatory monitoring. Thirty-six of the 37 trials were judged at low risk of bias, and sensitivity analyses excluding the one high-risk trial left the core relationship essentially unchanged. Even so, the authors caution that the association describes treatment effects across studies, not a causal chain within any individual patient. What the analysis does establish, with unusual precision, is that in the era of potent obesity pharmacotherapy, weight loss has re-emerged as a first-order lever for blood-pressure control, one that international guidelines now formally endorse and that clinicians treating the roughly half of hypertensive adults who also live with obesity can no longer afford to treat as an afterthought.

Subject of Research: The relationship between weight loss and blood pressure reduction with GLP-1 receptor agonists and multi-hormone receptor modulators in adults with overweight or obesity

Article Title: Weight loss and blood pressure lowering with GLP-1 receptor agonists and multi-hormone receptor modulators in overweight and obesity: a systematic review and meta-regression of phase 3 clinical trials

Article References: Nardone, M., Kugathasan, L., Daunt, L., Parikh, E. J., River Zhang, H.-Y., Pasricha, S. V., Orchanian-Cheff, A., Cherney, D. Z., Odutayo, A., & Muskiet, M. H. (2026). Weight loss and blood pressure lowering with GLP-1 receptor agonists and multi-hormone receptor modulators in overweight and obesity: a systematic review and meta-regression of phase 3 clinical trials. eClinicalMedicine, 101, Article 104251. https://doi.org/10.1016/j.eclinm.2026.104251

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DOI: 10.1016/j.eclinm.2026.104251

Keywords: obesity, hypertension, GLP-1 receptor agonists, multi-hormone receptor modulators, semaglutide, tirzepatide, weight loss, systolic blood pressure, meta-analysis, cardiovascular risk, pharmacotherapy, eClinicalMedicine