Aleniglipron is an oral, small-molecule glucagon-like peptide-1 receptor agonist (GLP1-RA) in development for obesity treatment. The ACCESS phase 2b placebo-controlled, double-blind study randomized 230 adults (mean BMI 39.5 kg m-2, 54% female) with obesity or overweight to examine the effects of once-daily aleniglipron escalated every 4 weeks to 45, 90 or 120 mg. At week 36, the trial met its primary endpoint with a placebo-adjusted LS mean (95% confidence interval) body-weight change from baseline of -8.2% (-11.1 to -5.3%), -9.8% (-12.5 to -7.2%) and -11.3% (-13.9 to -8.6%) for the aleniglipron 45-, 90- and 120-mg arms, respectively (P < 0.0001, all doses versus placebo), with no apparent weight-loss plateau at the end of the double-blind period. Continued weight loss was observed at the interim analysis (median treatment duration of 20 weeks) of the ongoing open-label extension. Gastrointestinal events were generally mild to moderate and decreased in frequency over time, with little to no recurrence of vomiting after reintroduction following permitted dose interruptions. Treatment-related discontinuations were 10.4% across aleniglipron arms, with no events of drug-induced liver injury. Clinically relevant weight reductions of up to 11.3% with a tolerability profile consistent with the GLP-1RA class support further development of aleniglipron for obesity treatment. ClinicalTrials.gov registration: NCT06693843 .

Introduction: GSBR-1290 is a novel, oral, non-peptide GLP-1RA and a potential alternative to injectable or oral peptides used for the treatment of T2DM and obesity. These studies were designed to evaluate the safety, tolerability, and efficacy of GSBR-1290. Methods: Phase 1b: The safety and tolerability of multiple ascending doses of GSBR-1290 (5-90mg) and its effects on body weight (BW) were investigated in 24 HOV over 4 weeks. Phase 2a: The effects of GSBR-1290 on safety, tolerability, HbA1c, glucose, and BW were investigated in 54 participants with T2DM (45 and 90mg) over 12 weeks and in an interim 8-week analysis of 40 HOV (120mg). Results: Phase 1b: There were no study discontinuations (d/c) due to adverse events (AEs). Most AEs were mild and GI-related, consistent with GLP-1RAs. BW was significantly reduced (up to 4.9% placebo-adjusted, p=0.013) over 4 weeks. Phase 2a T2DM: Two participants d/c from the study due to an AE (1 attributed to study drug: 2.8% d/c rate). Placebo-adjusted HbA1c (45 mg: -1.01%, p=0.008; 90 mg: -1.02%, p=0.001), BW (45 mg: -3.51%, p=0.0019; 90 mg: -3.26%, p=0.0013), and plasma glucose (45 mg: -2.70, p=0.01; 90 mg: -2.50, p=0.0008) were significantly reduced at day 84. Phase 2a Obesity: There were no study d/c due to AEs. Placebo-adjusted BW decreased though day 56 (120 mg: -4.74%; p<0.0001). Complete 12-week results from the cohort of 24 additional participants will be available at presentation. For all phase 2a, AEs were mild-moderate and GI-related, with no SAEs related to GSBR-1290. Conclusions: GSBR-1290 demonstrated favorable safety and tolerability in this Phase 1b/2a study in participants with T2DM and in HOV. GSBR-1290 demonstrated clinical benefits in lowering BW, blood glucose, and HbA1c. These data provide clinical proof-of-concept of GSBR-1290 and support further clinical development in T2DM and obesity. Disclosure B. Coll: Employee; Structure Therapeutics, Inc. J. Zhang: Employee; Structure Therapeutics, Inc. L. Chen: Employee; Structure Therapeutics, Inc. L. Ibarra: Employee; Structure Therapeutics, Inc. H. Yue: Employee; Structure Therapeutics, Inc. A. Barth: Employee; Structure Therapeutics, Inc. M.A. Bach: Employee; Structure Therapeutics, Inc. Funding Structure Therapeutics, Inc

Introduction: Type 2 Diabetes Mellitus (T2DM) and obesity incidences are rising globally. The risk:benefit ratio of peptide GLP-1 receptor agonists (RAs) has been established; however, new therapeutic options are still needed. We report the results of a single ascending dose (SAD) study with GSBR-1290, a highly potent, orally bioavailable, fully biased small molecule GLP-1 RA. Methods: The study enrolled 48 healthy volunteers in 6 Cohorts, randomized 3:1 to receive GSBR-1290 (1, 10, 15, 30, 60, and 90 mg) or placebo, under fasting conditions. The safety, tolerability, and pharmacokinetics (PK) of a single dose of GSBR-1290 were investigated. The food effect on PK was also assessed in the 15 mg cohort. Results: Participants were well-balanced across the treatment groups: female (60%), white (66%), mean age (SD) 30 (8) years, and BMI (SD) 24.5 (3.0). All randomized subjects completed the study and there were no deaths or serious adverse events. Treatment-emergent adverse events (TEAEs) were reported for 32/36 participants (89%) following fasted administration of GSBR-1290 and for 7/12 participants (58%) following administration of placebo. The majority (94%) were mild or moderate in severity. As expected, the most common TEAEs were gastrointestinal-related and included nausea, vomiting, decreased appetite and diarrhea, consistent with other drugs in this class. No clinically significant changes in laboratory safety parameters were reported. PK (Cmax and AUC) of GSBR-1290 increased with dose, and a high fat meal was associated with a 20% decrease in the geometric mean AUC and a 36% decrease in Cmax. Conclusion: GSBR-1290 is a promising orally available GLP-1 RA and was well-tolerated in this SAD study in healthy volunteers. These data support further clinical development in a multiple ascending dose study in individuals with T2DM and obesity. Disclosure B.Coll: Employee; Amgen Inc., ShouTi Pharma Inc. J.J.Zhang: Employee; Structure Therapeutics Inc. S.J.Jacober: Consultant; Structure Therapeutics, Inc., Adocia, Employee; Sanofi-Aventis U.S., Applied Therapeutics Inc., Other Relationship; Eli Lilly and Company. C.Argent: None. L.Ibarra: Employee; Structure Therapeutics. M.Snyder: None. M.A.Bach: Employee; Structure Therapeutics, Stock/Shareholder; Johnson & Johnson. Funding Structure Therapeutics Inc.

Despite statin therapy, many patients with atherosclerotic cardiovascular disease (ASCVD) still suffer from ASCVD events. Predictors of residual ASCVD risk are not well-delineated. We aimed to develop an ASCVD risk prediction model for patients with previous ASCVD on statin use. We utilized statin-treated patients with ASCVD from the AIM-HIGH trial cohort. A 5-year risk score for subsequent ASCVD events with known ASCVD was developed using Cox regression, including potential risk factors with age, sex, and race forced in the model. Internal discrimination and calibration were evaluated. We included 3,271 patients with ASCVD (85.4% male, mean age 63.6 years, 65% on moder ateand 24% on high-intensity statin) with complete risk factor data and mean follow-up of 4.18 years. Overall, the estimated 5-year ASCVD risk was 21.1%: 10.2% of patients had a 5-year risk of >30%, and 38.8% had risk of between 20% and 30%. In the model, male sex, hemoglobin A1c, alcohol use (inversely), family history of cardiovascular disease, homocysteine, history of carotid artery disease, and lipoprotein(a) best predicted residual ASCVD risk. Niacin treatment status did not enter the model. A C-statistic of 0.59 was obtained, with the Greenwood-Nam-D'Agostino test showing excellent calibration. We developed a risk prediction risk model for predicting 5-year residual ASCVD risk in statin-treated patients with known ASCVD that may help in identifying such persons at the highest risk of recurrent events. Validation in larger samples with patients on high-intensity statin is needed. (c) 2020 Elsevier Inc. All rights reserved.

The apolipoprotein A1 (apoA1) remnant ratio has been identified as an independent cardiovascular (CV) risk factor. Higher apoA1 remnant ratios may predict lower CV risk in some patients. This analysis aimed to evaluate the effects of evolocumab on the change from baseline in the apoA1 remnant ratio compared with placebo. This pooled post hoc analysis included 2464 patients with mixed dyslipidemia treated with evolocumab 140 mg every 2 weeks (Q2W) or 420 mg once monthly (QM) in three phase 3 evolocumab trials. The apoA1 remnant ratio was calculated by dividing apoA1 by the difference between non-high-density lipoprotein cholesterol (non-HDL-C) and low-density lipoprotein cholesterol (LDL-C). ApoA1 remnant ratio strata were generated using previously published tertile (< 4.7, 4.7–6.8, and > 6.8) and partitioning categories (< 3.6, 3.6–6.0, and > 6.0). The baseline apoA1 remnant ratio in evolocumab and placebo treatment arms was 7.1 and 7.3, respectively. At week 12, evolocumab 140 mg Q2W and 420 mg QM increased the apoA1 remnant ratio by 25.0% and 33.6%, respectively, versus placebo (p < 0.0001 for both groups). When patients were categorized by week 12 apoA1 remnant ratio thresholds (< 3.6 vs. > 3.6, and < 4.7 vs. > 4.7), those with higher week 12 apoA1 remnant ratios were significantly more likely to have also achieved a target non-HDL-C level of < 100 mg/dl. In the subset of women > 50 years of age, the proportion of patients at apoA1 remnant ratio thresholds < 3.6, 3.6–6.0, and > 6.0 at baseline shifted toward or remained at higher thresholds at week 12. This post hoc analysis suggests that evolocumab increases the apoA1 remnant ratio. Amgen Inc. Plain language summary available for this article.

Background Elevated lipoprotein(a) (Lp(a)), a low‐density lipoprotein‐like particle bound to the polymorphic apolipoprotein(a) (apo(a)), may be causal for cardiovascular disease. However, the metabolism of Lp(a) in humans is poorly understood. Methods and Results We investigated the kinetics of Lp(a)‐apo(a) and low‐density lipoprotein‐apoB‐100 in 63 normolipidemic men. The fractional catabolic rate (FCR) and production rate PR) were studied. Plasma apo(a) concentration was significantly and inversely associated with apo(a) isoform size (r=−0.536, P<0.001) and apo(a) FCR (r=−0.363, P<0.01), and positively with apo(a) PR (r=0.877, P<0.001). There were no significant associations between the FCRs of apo(a) and low‐density lipoprotein‐apoB‐100. Subjects with smaller apo(a) isoform sizes (≤22 kringle IV repeats) had significantly higher apo(a) PR (P<0.05) and lower apo(a) FCR (P<0.01) than those with larger sizes. Plasma apo(a) concentration was significantly associated with apo(a) PR (r=0.930, P<0.001), but not with FCR (r=−0.012, P>0.05) in subjects with smaller apo(a) isoform size. In contrast, both apo(a) PR and FCR were significantly associated with plasma apo(a) concentrations (r=0.744 and −0.389, respectively, P<0.05) in subjects with larger isoforms. In multiple regression analysis, apo(a) PR and apo(a) isoform size were significant predictors of plasma apo(a) concentration independent of low‐density lipoprotein‐apoB‐100 FCR and background therapy with atorvastatin and evolocumab. Conclusions In normolipidemic men, the plasma Lp(a) concentration is predominantly determined by the rate of production of Lp(a) particles, irrespective of apo(a) isoform size and background therapy with a statin and a proprotein convertase subtilisin‐kexin type 9 inhibitor. Our findings underscore the importance of therapeutic targeting of the hepatic synthesis and secretion of Lp(a) particles. Lp(a) particle catabolism may only play a modest role in determining Lp(a) concentration in subjects with larger apo(a) isoform size. Clinical Trial Registration URL: http://www.clinicaltrials.gov. Unique identifier: NCT02189837.

Background The 2013 American College of Cardiology/American Heart Association cholesterol guidelines recognize cardiovascular disease and diabetes mellitus but not chronic kidney disease ( CKD ) as high‐risk conditions warranting statin therapy. Statin use may be lower for adults with CKD compared with adults with conditions that have guideline indications for statin use. Methods and Results We analyzed data from the National Health and Nutrition Examination Surveys from 1999–2002 through 2011–2014 to determine trends in the percentage of US adults ≥20 years of age with and without CKD taking statins. CKD was defined by an estimated glomerular filtration rate <60 mL/min per 1.73m 2 or albumin‐to‐creatinine ratio ≥30 mg/g. Statin use was identified through a medication inventory. Between 1999–2002 and 2011–2014, the percentage of adults taking statins increased from 17.6% to 35.7% among those with CKD and from 6.8% to 14.7% among those without CKD . After multivariable adjustment, adults with CKD were not more likely to be taking statins compared with those without CKD (prevalence ratio, 1.01; 95% CI] 0.96–1.08). Among adults without a history of cardiovascular disease, those with CKD but not diabetes mellitus were less likely to be taking statins compared with those with diabetes mellitus but not CKD (prevalence ratio, 0.54; 95% CI , 0.44–0.66). Among adults with a history of cardiovascular disease, there was no difference in statin use between those with CKD but not diabetes mellitus versus those with diabetes mellitus but not CKD (prevalence ratio, 0.95; 95% CI , 0.79–1.15). Conclusions CKD does not appear to be a major stimulus for statin use among US adults.

Kidney Disease Improving Global Outcomes (KDIGO) guidelines provide recommendations for statins among adults with chronic kidney disease (CKD) while the American College of Cardiology/American Heart Association (ACC/AHA) provides statin recommendations for the general population. These guidelines

Background Fluid retention is a common adverse event in patients who receive endothelin (ET) receptor antagonist therapy, including the highly selective ETA receptor antagonist, atrasentan. Objective We performed longitudinal assessments of thoracic bioimpedance in patients with type 2 diabetes mellitus and nephropathy to determine whether a decrease in bioimpedance accurately reflected fluid retention during treatment with atrasentan. Study Design We conducted a randomized, double-blind, placebo-controlled study in 48 patients with type 2 diabetes mellitus and nephropathy who were receiving stable doses of renin angiotensin system inhibitors and diuretics. Methods Patients were randomized 1:1:1 to placebo, atrasentan 0.5 mg, or atrasentan 1.25 mg once daily for 8 weeks. Thoracic bioimpedance, vital signs, clinical exams, and serologies were taken at weeks 1, 2, 4, 6, and 8, with the exception of serum hemoglobin, which was not taken at week 1, and serum brain natriuretic peptide, which was only taken at baseline, week 4, and week 8. Results Alterations in bioimpedance were more often present in those who received atrasentan than in those who received placebo, though overall differences were not statistically significant. Transient declines in thoracic bioimpedance during the first 2 weeks of atrasentan exposure occurred before or during peak increases in body weight and hemodilution (decreased serum hemoglobin). Conclusions We conclude that thoracic bioimpedance did not reflect changes in weight gain or edema with atrasentan treatment in this study. However, the sample size was small, and it may be of interest to explore the use of thoracic bioimpedance in a larger population to understand its potential clinical use in monitoring fluid retention in patients with chronic kidney disease who receive ET receptor antagonists.

AimsThe selective endothelin (ET) A receptor antagonist atrasentan has been shown to lower albuminuria in North American and Asian patients with type 2 diabetes and nephropathy. As drug responses to many drugs may differ between North American and Asian populations, we assessed the influence of geographical region on the albuminuria and fluid retention response to atrasentan.Materials and methodsTwo 12‐week double‐blind randomised controlled trials were performed with atrasentan 0.75 or 1.25 mg/d vs placebo in patients with type 2 diabetes and nephropathy. The efficacy endpoint was the percentage change in albuminuria. Bodyweight change, a proxy of fluid retention, was used as a safety endpoint. Pharmacodynamics were determined in Asians (N = 77) and North Americans (N = 134). Atrasentan plasma concentration was measured in 161 atrasentan‐treated patients.ResultsMean albuminuria reduction in Asian, compared to North American, patients was, respectively, −34.4% vs −26.3% for 0.75 mg/d ( P = .44) and −48.0% vs −28.9% for 1.25 mg/d ( P = .035). Bodyweight gain did not differ between North American and Asian populations. Atrasentan plasma concentrations were higher in Asians compared to North Americans and correlated with albuminuria response (7.2% albuminuria reduction per doubling atrasentan concentration; P = .024). Body surface area (β = −1.09 per m2; P < .001) and bilirubin, as a marker of hepatic organic anion transporter activity, (β = 0.69 per mg/dL increment; P = .010) were independent determinants of atrasentan plasma concentration; correction by body surface area and bilirubin left no significant difference in plasma concentration between Asian and North American populations.ConclusionThe higher exposure and albuminuria reduction of atrasentan in Asian patients is not associated with more fluid retention, suggesting that Asian patients are less sensitive to atrasentan‐induced sodium retention.

We assessed the effect of atrasentan therapy on a pre‐specified panel of 13 urinary metabolites known to reflect mitochondrial function in patients with diabetic kidney disease. This post‐hoc analysis was performed using urine samples collected during the RADAR study which was a randomized, double‐blind, placebo‐controlled trial that tested the effects of atrasentan on albuminuria reduction in patients with type 2 diabetes and nephropathy. At baseline, 4 of the 13 metabolites, quantified by gas‐chromatography mass spectrometry, were below detectable levels, and 6 were reduced in patients with eGFR < 60 mL/min/1.73 m2. After 12 weeks of atrasentan treatment in patients with eGFR < 60 mL/min/1.73 m2, a single‐value index of the metabolites changed by −0.31 (95%CI −0.60 to −0.02; P = .035), −0.08 (−12 to 0.29; P = .43) and 0.01 (−0.21 to 0.19; P = .913) in placebo, atrasentan 0.75 and 1.25 mg/d, respectively. The metabolite index difference compared to placebo was 0.13 (−0.17 to 0.43; P = .40) and 0.35 (0.05‐0.65; P = .02) for atrasentan 0.75 and 1.25 mg/d, respectively. These data corroborate previous findings of mitochondrial dysfunction in patients with type 2 diabetes, nephropathy and eGFR < 60 mL/min/1.73 m2, suggesting that atrasentan may prevent the progression of mitochondrial dysfunction common to this specific patient population. Future studies of longer treatment duration with atrasentan are indicated.

Background: Doubling of serum creatinine is often used as a marker for worsening kidney function in nephrology trials. Most people with chronic kidney disease die of other causes before reaching end-stage renal disease. We were interested in the association between doubling of serum creatinine and the risk of a first-time diagnosis of angina pectoris, congestive heart failure (CHF), myocardial infarction (MI), stroke, or transient ischemic attack in patients with chronic kidney disease and with diagnosed type 2 diabetes mellitus.Methods: We identified all adult patients registered in the "Clinical Practice Research Datalink" between 2002 and 2011 with incident chronic kidney disease and type 2 diabetes mellitus and did a cohort study with a Cox proportional hazard analysis.Results: We identified in total 27,811 patients, 693 developed angina pectoris, 1,069 CHF, 508 MI, 970 stroke, and 578 transient ischemic attacks. Patients whose serum creatinine doubled during follow-up had increased risks of CHF (hazard ratio [HR] 2.98, 95% confidence interval [CI] 2.27-3.89), MI (HR 2.53, 95% CI 1.62-3.96), and stroke (HR 1.93, 95% CI 1.38-2.69), as compared with patients whose serum creatinine did not double. The relative risks of angina pectoris (HR 1.18, 95% CI 0.66-2.10) or a transient ischemic attack (HR 1.32, 95% CI 0.78-2.22) were similar in both groups.Conclusion: Diabetic patients with a doubling of serum creatinine were at an increased risk of CHF, MI, or stroke, compared with diabetic patients whose serum creatinine did not double during follow-up.

Background and objectives Endothelin A receptor antagonists (ERAs) decrease residual albuminuria in patients with diabetic kidney disease; however, their clinical utility may be limited by fluid retention. Consequently, the primary objective of this study was to identify predictors for ERA-induced fluid retention among patients with type 2 diabetes and CKD. A secondary objective was to determine if the degree of fluid retention necessarily correlated with the magnitude of albuminuria reduction in those patients receiving ERAs.Design, setting, participants, & measurements A post hoc analysis was conducted of the phase IIb atrasentan trials assessing albuminuria reduction in 211 patientswith type 2 diabetes, urine albumin/creatinine ratios of 300-3500 mg/g, and eGFRs of 30-75 ml/min per 1.73 m(2) who were randomly assigned to receive placebo (n= 50) or atrasentan 0.75 mg/d (n= 78) or 1.25 mg/d (n= 83) for 12 weeks. Changes in body weight and hemoglobin (Hb) after 2 weeks of treatment were used as surrogate markers of fluid retention.Results Baseline predictors of weight gain after 2 weeks of atrasentan treatment were higher atrasentan dose, lower eGFR, higher glycated hemoglobin, higher systolic BP, and lower homeostatic metabolic assessment product. Higher atrasentan dose and lower eGFR also predicted decreases in Hb. There were no changes in B-type natriuretic peptide. There was no correlation between reduction in albuminuria after 2 weeks of atrasentan treatment and changes in body weight or Hb.Conclusions In the Reducing Residual Albuminuria in Subjects With Diabetes and Nephropathy With Atrasentan/JAPAN trials, atrasentan-associated fluid retention was more likely in patients with diabetes and nephropathy who had lower eGFR or received a higher dose of atrasentan. Finding that albuminuria reduction was not associated with changes in body weight and Hb suggests that the albuminuria-reducing efficacy of atrasentan is not impaired by fluid retention.