This week in Endocrinology

This AudioScholar briefing is generated by artificial intelligence for healthcare professionals and trainees. It is not medical advice.

This week: a lower blood pressure target fails to cut cardiovascular events in type 2 diabetes, a glucagon dual agonist meets its cardiovascular safety bar, and resistance training protects muscle and strength during tirzepatide weight loss.

Welcome to This Week in Endocrinology. We're covering 10 papers this week: 3 in depth, 4 in brief, 3 quick signals.

The New England Journal of Medicine published OPTIMAL-DIABETES, a trial led by Santo [1]. This was a multicentre, open-label, randomised trial in Brazil that enrolled 9476 ethnically diverse patients with type 2 diabetes, elevated blood pressure and high cardiovascular risk. Patients were assigned to a systolic target below 120 or below 140 millimetres of mercury. The separation was real: mean systolic pressure during follow-up was about 122 in the intensive group and about 135 in the standard group. Over a median of four years, the primary composite of cardiovascular death, nonfatal heart attack, nonfatal stroke, or hospitalisation for unstable angina or heart failure occurred in 6.0 percent of the intensive group and 6.7 percent of the standard group. That difference was not statistically significant. Serious adverse events were similar, at about 15 percent in each arm. The main limitation is the open-label design in a single country, and the abstract does not report kidney outcomes or results by subgroup. The trial adds a large, contemporary randomised result in which a systolic target below 120 did not reduce major cardiovascular events in people with type 2 diabetes, compared with a target below 140.

The Lancet published SYNCHRONIZE-CVOT, led by Bozkurt [2]. This phase 3, double-blind, placebo-controlled cardiovascular safety trial ran at 524 sites in 34 countries and treated 5507 adults with a body mass index of 27 or more plus established cardiovascular disease or at least two obesity complications or risk factors. Participants received weekly survodutide, a glucagon and GLP-1 receptor dual agonist, at 3.6 or 6.0 milligrams, or placebo, for a median of about 22 months. The primary composite of cardiovascular death, stroke, heart attack, ischaemia-driven revascularisation or heart failure event occurred in 3.7 percent on survodutide and 4.1 percent on placebo. That met the prespecified noninferiority margin, while the estimate did not show a statistically significant reduction. Tolerability was the cost: nausea affected close to half of participants on survodutide against about one in eight on placebo, and gastrointestinal effects led about one in five survodutide users to stop treatment. The abstract does not report weight or glycaemic results. The trial was powered for safety over a relatively short follow-up, so it establishes cardiovascular safety for this new class without showing cardiovascular benefit.

Nature Medicine published a randomised trial led by Green that asked whether resistance exercise protects muscle during tirzepatide therapy [3]. The trial, registered in the Australian New Zealand Clinical Trials Registry, enrolled 120 adults with overweight or obesity, all on tirzepatide, who were randomised to supervised resistance training three times a week or usual activities for 40 weeks. Adherence to the exercise programme was 91 percent, and most participants reached the 15 milligram dose. Weight loss was the same in both groups, at about 22 kilograms, and fat loss did not differ. Lean soft tissue loss was about one kilogram smaller with exercise, roughly three and a half kilograms against four and a half. The larger difference was in strength: bench press, lat pulldown and knee extension strength all fell with tirzepatide alone and all rose with added training. The limitations are the modest sample, the 40-week horizon, and the use of body composition and strength rather than falls, fractures or disability as outcomes. It adds randomised evidence that a structured exercise programme can preserve muscle function during large incretin-driven weight loss.

Now, four in brief.

The Lancet also published COURAGE, a phase 2 trial led by Mosenzon that took a drug-based approach to the same muscle question [4]. Across 60 sites in the United States, 975 adults with obesity on semaglutide were randomised to placebo or trevogrumab, an antibody against myostatin, with or without garetosmab, which blocks activin A. Semaglutide alone cut lean mass by about seven percent. Adding trevogrumab reduced that loss by roughly three percentage points, and the combination by about four and a half points, with the combination also adding substantial extra fat loss. In the 52-week part, the 75 milligram dose preserved lean mass while the 25 milligram dose did not reach significance. This is phase 2 evidence on a surrogate, and unlike the exercise trial, the abstract reports no strength outcome.

Endocrine Reviews carried a narrative review by Braunstein and Braunstein on GLP-1 receptor agonists and thyroid cancer [5]. The authors argue that rodent C-cell findings do not translate to humans, citing primate studies, clinical trials, and meta-analyses of trials and cohort studies that mostly show no clear association. They attribute positive pharmacovigilance signals to reporting bias, and note that medullary carcinoma's share of thyroid cancer has fallen since these drugs arrived. They conclude that the boxed warning is no longer necessary. This is an expert narrative review, and the regulatory warning remains in place.

Diabetes Care published clinical guidance led by Simmons on disease-modifying immunotherapy in new-onset stage 3 type 1 diabetes [6]. The trigger is the United States approval of teplizumab for children and adolescents aged 8 to 17 with recently diagnosed stage 3 disease. The guidance covers who should lead care, eligibility and timing, assessment of beta-cell reserve and infection risk, how to sequence treatment with recovery from ketoacidosis and early education, and safety monitoring. It is consensus guidance, with teplizumab-specific recommendations flagged and broader principles framed for adaptation across health systems.

The Journal of Clinical Endocrinology and Metabolism published a series led by Doerfler of 585 resected RAS-positive thyroid nodules from a single institution [7]. About half of the nodules were cancer, a quarter were noninvasive follicular neoplasms, and a quarter were benign. Isolated KRAS mutations carried a much lower rate of cancer or noninvasive neoplasm, about a third, than NRAS or HRAS, at around three quarters or more. Persistent or recurrent disease occurred in half of cancers with additional high-risk mutations and in under one percent of isolated RAS cancers. Follow-up was short and the design retrospective, so the authors' suggestion of lobectomy or surveillance in select cases rests on early data.

Three quick signals.

The Journal of Clinical Endocrinology and Metabolism reported a single-centre retrospective cohort led by Hajikarimloo of 186 adults given Gamma Knife radiosurgery for Cushing disease after failed surgery [8]. Durable medication-free cortisol control reached about two thirds at ten years, while new pituitary hormone deficits reached about 42 percent. Retrospective data spanning decades limit how firm this is.

Also in that journal, Park and colleagues profiled serum steroids in 216 patients with primary aldosteronism who had adrenal venous sampling [9]. A three-steroid model matched a clinical model for identifying lateralised disease, and combining both performed better. Steroids did not predict surgical outcome. The models lack external validation.

Clinical Endocrinology published an Irish single-centre study led by O'Connell of 73 children tested for growth hormone deficiency [10]. Roughly one in four children with a subthreshold first stimulation test was not ultimately diagnosed, with discordance clustering around puberty, and IGF-I performed poorly. The sample is small and retrospective.

Stepping back across this week's papers, much of the obesity evidence still rests on body composition and strength measures, with no trial yet linking muscle preservation to falls, frailty or survival. The one large cardiovascular outcome trial in an obesity drug class was designed to exclude harm, so it cannot speak to benefit. Elsewhere, single-centre retrospective cohorts and expert opinion carry much of the weight in thyroid, adrenal, pituitary and paediatric questions, leaving those conclusions provisional.

If you only have time for one paper this week, make it OPTIMAL-DIABETES [1]. It is a large randomised outcome trial that reopens the question of whether pushing systolic pressure below 120 adds cardiovascular protection in type 2 diabetes.

That's your roundup for This Week in Endocrinology. The full transcript and references are available on the episode page. See you next week.

If this weekly briefing is useful, follow the show in your podcast app so new episodes arrive automatically. And a quick rating on Apple Podcasts or Spotify helps other physicians discover the show.

This is an automated summary generated by artificial intelligence, which can make mistakes. Always review the original source materials.