Efficacy and Safety of Enlicitide, an Oral PCSK9 Inhibitor, in Participants with and without Diabetes Mellitus in a Pooled Analysis of Two Phase 3 Trials

Authors: Norman Lepor, et al.

This analysis evaluated the efficacy of enlicitide, an oral proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitor, in participants with and without diabetes mellitus (DM), and assessed its effect on the risk of new-onset or worsening diabetes. Data were pooled from two Phase 3 randomized, placebo-controlled trials: CORALreef Lipids and CORALreef Heterozygous Familial Hypercholesterolemia (HeFH). The integrated analysis included 3,212 participants, of whom 40% were women, 55% had a history of a major atherosclerotic cardiovascular disease (ASCVD) event, 97% were receiving statin therapy (57% on high-intensity statins), and 30% were receiving cholesterol absorption inhibitors. Participants were randomized in a 2:1 ratio to receive enlicitide 20 mg once daily or placebo for 52 weeks. At baseline, 1,490 participants had DM and 1,722 did not. Enlicitide produced substantial reductions in low-density lipoprotein cholesterol (LDL-C) in both groups. At Week 24, the mean LDL-C reduction was 65% in participants with DM and 61% in those without DM, demonstrating consistent efficacy regardless of diabetes status. The incidence of new-onset or worsening DM was similar between treatment groups. Overall, these events occurred in 5.8% of participants receiving enlicitide and 5.5% of those receiving placebo, with a relative difference of 0.2% (95% confidence interval [CI]: -1.5 to 1.9). Among participants without DM at baseline, new-onset diabetes occurred in 2.7% of the enlicitide group and 2.6% of the placebo group. Among those with pre-existing DM, worsening diabetes was reported in 9.3% and 8.8% of participants receiving enlicitide and placebo, respectively. No meaningful differences in hemoglobin A1c levels were observed over time between treatment groups.

Overall, enlicitide achieved marked LDL-C reductions in participants both with and without DM, without increasing the risk of new-onset or worsening diabetes compared with placebo. Oral inhibition of PCSK9 with enlicitide provides an effective approach to lowering LDL-C without adverse effects on glycemia.

Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of Orforglipron: A Multiple Dose Titration Study in Chinese Participants with Obesity or Overweight with Weight-Related Comorbidities

Authors: Shobha Bhattachar, et al.

This Phase 1 randomized, placebo-controlled study evaluated the safety, tolerability, pharmacokinetics, and pharmacodynamics of orforglipron, an oral non-peptide glucagon-like peptide-1 receptor agonist (GLP-1RA), in Chinese adults with obesity or overweight and weight-related comorbidities. A total of 24 participants with stable body weight were enrolled and received escalating doses of orforglipron for up to 16 weeks (maximum 12 mg) or 24 weeks (maximum 36 mg). Participants had a mean (range) age of 30.1 (19-48) years, mean body mass index (BMI) of 32.0 (29.1-34.9) kg/m², and 50% were female. No serious adverse events or deaths were reported in the orforglipron group. One participant discontinued treatment because of mild diarrhea. Most treatment-emergent adverse events were mild, with no severe adverse events reported. Decreased appetite was the most frequently reported adverse event, and gastrointestinal disorders were the most commonly reported adverse event category. The pharmacokinetic profile of orforglipron in Chinese participants was consistent with that observed in global studies. Within the 1–36 mg dose range, both AUC₀–₂₄ (42.7–2620 ng·h/mL) and Cmax (3.1–159 ng/mL) showed an approximately proportional increase with increasing dose. Treatment with orforglipron was associated with reductions from baseline in body weight (−10.21 kg), BMI (−3.48 kg/m²), waist circumference (−11.66 cm), fasting glucose (−0.52 mmol/L), and glycated hemoglobin (HbA1c) (−0.36%).

Overall, orforglipron demonstrated a favorable safety and tolerability profile, pharmacokinetic characteristics consistent with those observed globally, and was associated with meaningful reductions in weight and metabolic parameters in Chinese participants with obesity or overweight and weight-related comorbidities.

Evolocumab Reduces CV Events in Patients with High-Risk Diabetes: Results from the VESALIUS-CV Trial

Authors: Lawrence Leiter, et al.

This prespecified analysis of the Very Effective Strategy of LDL-C Assessment and Intervention Using Subcutaneous Evolocumab in Cardiovascular Risk Reduction (VESALIUS-CV) trial evaluated the effect of evolocumab on cardiovascular outcomes in patients with high-risk diabetes mellitus (HR-DM: microvascular disease, insulin use, or duration ≥10 years) who had no prior myocardial infarction or stroke for prevention of first CV events. The trial randomized patients with low-density lipoprotein cholesterol (LDL-C) levels >90 mg/dL and either atherosclerosis or HR-DM to receive evolocumab 140 mg every 2 weeks or placebo. The dual primary endpoints were coronary heart disease death, MI or ischemic stroke (3-P MACE) and 3-P MACE in addition to ischemia-driven arterial revascularization (4-P MACE).  Among the 12,257 participants enrolled, 6,002 (49%) had HR-DM. The median age was 66 years, 50% were female, 66% were receiving high-intensity statins, 24% were using sodium-glucose cotransporter 2 inhibitors (SGLT2is) or glucagon-like peptide-1 receptor agonists (GLP-1RAs), and 67% had no qualifying atherosclerosis. After a median follow-up of 4.6 years, evolocumab reduced the risk of 3-point major adverse cardiovascular events (MACE; coronary heart disease death, myocardial infarction, or ischemic stroke) by 29% compared with placebo in patients with HR-DM. In participants without HR-DM, the reduction was 21% (interaction p=0.47). Evolocumab also reduced the risk of 4-point MACE (3-point MACE plus ischemia-driven arterial revascularization) by 21% in the HR-DM group and by 18% in those without HR-DM (interaction p=0.73). The risk of myocardial infarction was reduced by 35–36% in both groups (interaction p=0.97). A numerically lower mortality rate was also observed with evolocumab in both subgroups. Among patients with HR-DM, the benefits of evolocumab were consistent regardless of the presence of atherosclerosis, baseline LDL-C levels, statin intensity, or use of SGLT2is or GLP-1RAs (all interaction p>0.05).

Overall, evolocumab reduced cardiovascular events in patients with HR-DM, including those without established atherosclerosis and those already receiving other cardioprotective therapies.

The Efficacy of Cofrogliptin for Glycemic Control in Relapsed Type 2 Diabetes: A 12-Week Single-Center, Single-Arm, Exploratory Study

Authors: Shiying Shao et al..

This exploratory single-arm study is the first study that evaluated the efficacy and safety of cofrogliptin, a biweekly dipeptidyl peptidase-4 inhibitor (DPP-4i), in patients with relapsed type 2 diabetes (T2D) following a period of glycemic remission (HbA1c,6.5% without glucose lowering medications for ≥3 months). The biweekly administration of cofrogliptin offers clinical advantages such as low hypoglycemic risk, dosing unaffected by renal function, and minimal drug interaction. Twenty patients with a mean baseline glycated hemoglobin (HbA1c) of 6.91% received oral cofrogliptin 10 mg every two weeks for 12 weeks. After treatment, 40% of patients achieved an HbA1c level below 6.5%, compared with none at baseline (P<0.001). Additionally, 60% achieved an HbA1c level below 7.0%, compared with 30% before treatment (P<0.001). The treatment was well tolerated, and no severe hypoglycemic events were reported during the study period.

Overall, 12 weeks of cofrogliptin treatment improved glycemic target attainment in patients with relapsed T2D after remission and demonstrated a favorable safety profile, supporting its potential as a convenient and viable therapeutic option for this specific clinical scenario.

Long-Term Safety and Efficacy of HTD1801 in Patients with Type 2 Diabetes: Two Phase 3 Open-Label Extensions

Authors: Yingying Luo, et al.

This analysis evaluated the long-term efficacy and safety of HTD1801, an anti-inflammatory metabolic modulator that activates adenosine monophosphate-activated protein kinase (AMPK) and inhibits the NLRP3 inflammasome, in patients with type 2 diabetes (T2D). Data were obtained from the 52-week open-label extension phases of the Phase 3 SYMPHONY-1 (monotherapy) and SYMPHONY-2 (add-on to metformin) studies. A total of 817 patients entered the extension studies, including 383 from SYMPHONY-1 and 498 from SYMPHONY-2. Patients initially assigned to HTD1801 continued treatment, while those receiving placebo switched to HTD1801. The glycated hemoglobin (HbA1c) reductions achieved during the initial 24-week double-blind phase were maintained through Week 52 in patients who continued HTD1801, with mean reductions of 1.2% in SYMPHONY-1 and 1.1% in SYMPHONY-2. Patients who switched from placebo to HTD1801 achieved similar HbA1c reductions of 1.3% and 1.2%, respectively. Improvements in low-density lipoprotein cholesterol (LDL-C), high-sensitivity C-reactive protein (hs-CRP), and estimated glomerular filtration rate (eGFR) were also sustained over 52 weeks. The safety profile of HTD1801 remained consistent throughout the study and was similar to that observed during the double-blind phase.

Overall, HTD1801 provided durable glycemic control and maintained improvements in cardiovascular, kidney, and inflammatory markers through 52 weeks, with a consistent safety profile. These findings support its potential as a well-tolerated, effective therapy for patients with T2DM.

Development of Preliminary Predictive Models for Dorzagliatin Treatment Response and Diabetes Remission in Type 2 Diabetes: A Focus on Personalized Medicine

Authors: Yue Tang, et al.

This study developed predictive models to help identify patients with type 2 diabetes (T2D) who are most likely to achieve glycemic control or diabetes remission with dorzagliatin, a first-in-class glucokinase activator launched in 2022. The models were based on data from the Phase III SEED and DAWN trials and the DREAM observational study that reported 52 -week drug-free remission after treatment with dorzagliptin. A logistic regression model was developed to predict glycated hemoglobin (HbA1c) response, while a Cox proportional hazards model was used to predict the probability of diabetes remission. The HbA1c response model included age, sex, body mass index (BMI), diabetes duration, metformin use, baseline HbA1c, Homeostatic Model Assessment of β-cell function (HOMA-β), and Homeostatic Model Assessment of Insulin Resistance (HOMA-IR). The diabetes remission model included age at diabetes diagnosis, BMI, diabetes duration, pre-treatment HbA1c, and changes in HOMA2-β after treatment. Both models incorporated measures of β-cell function, reflecting the effects of dorzagliatin observed in previous studies. The predictive performance of both models was good, with an area under the receiver operating characteristic (ROC) curve greater than 0.7.

Based on these models, web-based visual prediction tools were developed to support individualized treatment decisions and help clinicians identify patients with a higher likelihood of achieving glycemic control or diabetes remission with dorzagliatin.

Ertugliflozin Mitigates Blood Pressure Increments during a High-Sodium Diet in People with Type 2 Diabetes

Authors: Britt Wever, et al.

This randomized, placebo-controlled crossover study evaluated whether ertugliflozin, a sodium-glucose cotransporter-2 inhibitor (SGLT2i), could reduce the blood pressure increase associated with a high-sodium diet in people with type 2 diabetes (T2D) described as sodium-sensitive hypertension. A total of 34 participants followed high-sodium and moderate-sodium diets with compliance verified by 24-h urinary sodium excretion after 7-10 days and received either ertugliflozin 15 mg daily or placebo for 10 days. At baseline, participants had a mean systolic blood pressure (SBP) of 131 mmHg and diastolic blood pressure (DBP) of 80 mmHg. Urinary sodium excretion during the high-sodium diet was similar between the ertugliflozin and placebo groups, indicating comparable sodium intake. During placebo treatment, the high-sodium diet significantly increased SBP by 7.2 mmHg (P=0.0002) and DBP by 3.5 mmHg (P=0.0015) compared with baseline. In contrast, during ertugliflozin treatment, increases in SBP (+2.1 mmHg; P=0.240) and DBP (+1.5 mmHg; P=0.175) were not significantly different from baseline. Ertugliflozin significantly reduced the high-sodium diet–induced increase in SBP compared with placebo (P=0.007), while the reduction in DBP showed a similar trend (P=0.057).

Overall, ertugliflozin prevented the blood pressure rise associated with high sodium intake in patients with T2D without affecting sodium excretion, suggesting a potential mechanism contributing to its cardiovascular and kidney benefits.

Novel GLP-1RA (GmFc) Greatly Reduces GI Adverse Effects while Exhibiting Glycemic Control and Satiety in Rodents

Authors: Yi Liu, et al.

This preclinical study compared Genetically Modified Fc fragment of an Immunoglobulin (GmFc), a novel glucagon-like peptide-1 receptor agonist (GLP-1 RA), with dulaglutide and semaglutide in rodent models to evaluate gastrointestinal tolerability, glycemic control, and effects on food intake and body weight. In a conditioned taste aversion model in mice, GmFc showed lower indicators of nausea-related behavior than dulaglutide. At equivalent doses, GmFc demonstrated a 3.9-fold lower relative aversion index (RAI) than dulaglutide, and at a 10-fold higher dose, the RAI remained 1.6-fold lower. In another mouse model assessing neuronal activation associated with nausea and emesis, GmFc produced significantly lower c-Fos activation in the nucleus tractus solitarius (NTS) region compared with semaglutide (108±49 vs 276±56 c-Fos-positive cells; P<0.001). In streptozotocin-induced diabetic rats, GmFc (4.5 mg/kg) reduced blood glucose by 16.2% more than dulaglutide (0.45 mg/kg) (P<0.01). GmFc also reduced 24-hour food intake by 20%. After one week of treatment, rats receiving GmFc weighed 4.5 g less than those receiving dulaglutide (P<0.01).

Overall, GmFc demonstrated glucose-lowering and appetite-suppressing effects comparable to or greater than currently available GLP-1 receptor agonists, while showing fewer indicators associated with gastrointestinal adverse effects in rodent models. These findings which may enable administration of higher therapeutic doses for enhanced glycemic control compared to current GLP-1 RAs on the market.

Icovamenib, a Menin Inhibitor, Improves Endogenous Insulin Secretion in Type 1 Diabetes: Results from the COVALENT-112 Study

Authors: Juan Pablo Frias, et al.

This Phase 2 study evaluated icovamenib, an oral menin inhibitor, in adults with type 1 diabetes (T1D) to assess its effects on endogenous insulin secretion. Participants were grouped according to disease duration and baseline C-peptide levels and received icovamenib 100 mg or 200 mg once daily for 12 weeks. A total of 37 participants were enrolled. In Cohort 1 (diagnosed ≤3 years with measurable C-peptide), participants receiving 100 mg showed a 7% reduction in C-peptide area under the curve (AUC) at Week 12 and a 31% reduction at Week 52. In contrast, those receiving 200 mg showed a 56% increase in C-peptide AUC at Week 12 and a 7% reduction from baseline at Week 52. In Cohort 2 (diagnosed >3 to ≤15 years with minimal C-peptide), C-peptide levels remained stable during treatment. At Week 52, participants receiving 100 mg showed a 29% reduction in C-peptide AUC, while those receiving 200 mg showed a 3% reduction. Icovamenib was generally well tolerated, with no serious treatment-emergent adverse events reported. Two participants receiving 200 mg in Cohort 2 discontinued treatment because of elevated liver enzyme levels. All other adverse events were mild to moderate in severity.

Overall, icovamenib appeared to slow the decline in endogenous insulin secretion in adults with T1D, with greater effects observed at the higher dose. These findings suggest a potential effect beyond the natural decline observed in T1D with a dose-response trend, although limited by small sample size. Additionally, suggesting that menin inhibition could improve residual beta-cell function.

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