Endocrinology Research Analysis
June’s endocrinology literature was led by long-acting anti-obesity and diabetes therapeutics, including a monthly GLP-1/GIP-pathway agent with double-digit weight loss and large phase 3 trials validating once-weekly basal insulin and dual-incretin combinations. Mechanistic and preclinical advances introduced a creatine-dependent thermogenic drug (SANA) and an epigenetic β-cell identity axis (BRD4–ATF5) as emerging targets. Complementary work across the month reinforced biomarker-guided stratifi
Summary
June’s endocrinology literature was led by long-acting anti-obesity and diabetes therapeutics, including a monthly GLP-1/GIP-pathway agent with double-digit weight loss and large phase 3 trials validating once-weekly basal insulin and dual-incretin combinations. Mechanistic and preclinical advances introduced a creatine-dependent thermogenic drug (SANA) and an epigenetic β-cell identity axis (BRD4–ATF5) as emerging targets. Complementary work across the month reinforced biomarker-guided stratification (miRNA-based T1D risk scores) and refined combination reno-metabolic strategies (finerenone + SGLT2 inhibitor). Overall, the field is moving toward less frequent dosing, combination strategies, and molecularly guided care pathways.
Selected Articles
1. Once-Monthly Maridebart Cafraglutide for the Treatment of Obesity - A Phase 2 Trial.
A 52-week, double-blind, randomized, placebo-controlled phase 2 trial (n=592) showed once-monthly maridebart cafraglutide achieved 12.3–16.2% mean weight loss in obesity and 8.4–12.3% in obesity with type 2 diabetes, with meaningful HbA1c reductions in the diabetes subgroup; gastrointestinal events were common but manageable and mitigated by dose escalation.
Impact: First rigorous evidence that monthly incretin-pathway biologic dosing delivers durable, double-digit weight loss with glycemic benefit, redefining dosing frequency expectations in obesity pharmacotherapy.
Clinical Implications: Pending phase 3 results, monthly agents could expand options for patients seeking potent weight loss with lower injection burden; clinicians should proactively manage GI tolerability and compare against weekly regimens as data mature.
Key Findings
- Mean 52-week weight loss −12.3% to −16.2% in obesity; −8.4% to −12.3% with T2D.
- HbA1c decreased by ~1.2–1.6 percentage points in the diabetes subgroup.
- GI adverse events frequent but manageable; dose escalation improved tolerability without new safety signals.
2. Weekly Fixed-Dose Insulin Efsitora in Type 2 Diabetes without Previous Insulin Therapy.
In a 52-week, randomized, treat-to-target phase 3 trial (n=795), once-weekly fixed-dose efsitora was noninferior to daily glargine for HbA1c reduction, with fewer clinically significant/severe hypoglycemic events, fewer dose adjustments, and lower weekly insulin burden.
Impact: Validates a simpler, less hypoglycemia-prone basal insulin initiation strategy with weekly dosing, potentially changing first-step insulin paradigms.
Clinical Implications: For suitable insulin-naïve adults, weekly fixed-dose basal insulin can simplify titration and reduce hypoglycemia risk; careful fasting glucose monitoring within fixed escalation schemes is recommended.
Key Findings
- Noninferior HbA1c reduction at 52 weeks versus daily glargine.
- Lower rate of clinically significant/severe hypoglycemia (rate ratio ~0.57).
- Fewer dose adjustments (median 2 vs 8) and lower weekly insulin dose.
3. Cagrilintide-Semaglutide in Adults with Overweight or Obesity and Type 2 Diabetes.
A 68-week, double-blind, phase 3 trial (n=1206) showed once-weekly cagrilintide–semaglutide achieved −13.7% mean weight change vs −3.4% with placebo and markedly higher rates of HbA1c ≤6.5%; gastrointestinal adverse events were common but largely mild–moderate and transient.
Impact: Provides definitive, multicountry RCT evidence that dual incretin combination delivers large, clinically meaningful weight loss and glycemic control in T2D with obesity.
Clinical Implications: CagriSema may be a powerful weekly option for substantial weight loss and tight glycemic targets in T2D; anticipate and manage GI tolerability and provide counseling on expected efficacy and side effects.
Key Findings
- Mean weight change −13.7% vs −3.4% placebo at 68 weeks (P<0.001).
- HbA1c ≤6.5% achieved in 73.5% vs 15.9% with placebo.
- GI adverse events in ~72.5%, mostly mild–moderate and transient.
4. A nitroalkene derivative of salicylate, SANA, induces creatine-dependent thermogenesis and promotes weight loss.
SANA activates creatine-dependent thermogenesis and improves mitochondrial respiration, reducing hepatic steatosis and insulin resistance in preclinical models; a randomized phase 1A/B study showed favorable safety/tolerability and early body weight and glucose signals.
Impact: Introduces a first-in-class, non-UCP1/AMPK thermogenic pathway targeting creatine cycling, potentially complementing incretin-based anti-obesity therapy.
Clinical Implications: If efficacy is confirmed in phase 2/3, SANA could be combined with incretins to augment weight loss and metabolic health; long-term cardiometabolic safety and durability must be established.
Key Findings
- Activates creatine-dependent thermogenesis and increases mitochondrial respiration in adipose tissue.
- Improves hepatic steatosis and insulin resistance in diet-induced obesity models.
- Phase 1A/B randomized study shows favorable safety and early signals on weight and glucose.
5. BRD4 Signaling Maintains the Differentiated State of β Cells.
Across mouse models and human islet organoids, BRD4 maintains β-cell differentiation and insulin synthesis; BRD4 loss causes dedifferentiation and reduced insulin production, with ATF5 identified as a direct downstream target and a patient variant (p.R749C) perturbing signaling.
Impact: Provides convergent mechanistic and human genetic evidence for an epigenetic regulator (BRD4–ATF5) that preserves β-cell identity, nominating a new class of targets for diabetes.
Clinical Implications: Though preclinical, selective BRD4/BET pathway modulators could help preserve β-cell function; translational work must define selectivity, dosing, and human safety.
Key Findings
- BRD4 expression is reduced in human diabetic β cells and rises with calorie restriction in mice.
- Brd4 knockout impairs β-cell differentiation; BRD4 knockdown reduces insulin synthesis in human organoids.
- ATF5 is a direct BRD4 target; a patient BRD4 variant (p.R749C) perturbs signaling.