Faculty Bibliography

TERN-101 is a nonsteroidal farnesoid X-receptor agonist being developed for the treatment of nonalcoholic steatohepatitis (NASH). We assessed the safety, pharmacokinetics (PK), and pharmacodynamics (PD) of TERN-101 capsule and tablet formulations in healthy volunteers. In a randomized, double-blind, placebo-controlled study, 38 participants were enrolled and randomized to receive placebo or 25-, 75-, or 150-mg TERN-101 capsules orally once daily for 7 days. In a separate open-label PK and formulation-bridging study, 16 participants received single doses of TERN-101 tablets (5 and 25 mg) or capsules (25 mg). TERN-101 was overall well-tolerated in this healthy volunteer population; no pruritus was reported. TERN-101 capsule administration over 7 days resulted in decreases in serum 7α-hydroxy-4-cholesten-3-one that were sustained for 24 hours after the last dose (maximum suppression 91% from baseline), indicating target engagement in the liver. TERN-101 capsules exhibited less than dose-proportional PK. Relative to capsules, TERN-101 tablets showed increased bioavailability, with 24-hour plasma exposure of the 5-mg tablet similar to that of the 25-mg capsule. There was no significant effect of food on exposure. The overall safety, PK, and PD profiles of TERN-101 support its further evaluation for the treatment of NASH.

BACKGROUND:Inflammation is associated with coronary artery disease (CAD) and myocardial infarction (MI). Patients with gout are at increased risk of MI, and colchicine is associated with a reduced risk of MI. The objective of this study was to determine whether colchicine prevents incident development of CAD in patients with gout. METHODS:This retrospective study followed a cohort of male gout patients without known CAD at the time of gout diagnosis in the VA New York Harbor Healthcare System. The association between colchicine use and development of incident CAD, defined as evidence of ischemia or obstructive CAD on stress test or angiography, was determined using an inverse probability weighted (IPW) cox proportional hazard model. RESULTS:Among 178,877 patients, 1,638 met gout criteria, of whom 722 patients without known CAD at baseline (446 colchicine users and 276 non-users) were followed for a median of 96 months [57-117]. A trend toward association between colchicine use and reduced incident CAD was observed but not statistically significant (IPW HR 0.49 [0.23-1.05]). In patients without chronic kidney disease, colchicine use was associated with a lower rate of incident CAD (interaction p=0.005, IPW HR 0.31 [0.14-0.70]). Colchicine was also associated with a lower rate of the composite of incident CAD and MI (IPW HR 0.37 [0.16-0.83]). CONCLUSIONS:In male patients with gout and no known CAD, a trend of reduced incident CAD was observed with colchicine use that was not statistically significant. Larger, prospective studies will be required to definitively assess the primary prevention benefit of colchicine.

To assess the impact of allopurinol on diabetes in a retrospective cohort of Veterans' Affairs patients with gout.The New York Harbor VA computerized patient record system was searched to identify patients with an ICD-9 code for gout meeting at least 4 modified 1977 American Rheumatology Association gout diagnostic criteria. Patients were divided into subgroups based on >30 continuous days of allopurinol, versus no allopurinol. New diagnoses of diabetes, defined according to American Diabetes Association diagnostic criteria or clinical documentation explicitly stating a new diagnosis of diabetes, were identified during an observation period from January 1, 2000 through December 31, 2015.Six hundred six gout patients used allopurinol >30 continuous days, and 478 patients never used allopurinol. Over an average 7.9 ± 4.8 years of follow-up, there was no significant difference in diabetes incidence between the allopurinol and non-allopurinol groups (11.7/1000 person-years vs 10.0/1000 person-years, P = .27). A lower diabetes incidence in the longest versus shortest quartiles of allopurinol use (6.3 per 1000 person-years vs 19.4 per 1000 person-years, P<.0001) was attributable to longer duration of medical follow-up.In this study, allopurinol use was not associated with decreased diabetes incidence. Prospective studies may further elucidate the relationship between hyperuricemia, gout, xanthine oxidase activity, and diabetes, and the potential impact of gout treatments on diabetes incidence.

Advancing age, female sex, recent prior fracture and falls, and specific comorbidities and medications contribute to imminent (within 1-2 years) risk of fracture in Medicare enrollees. Clinician awareness of these risk factors and their dynamic nature may lead to improved osteoporosis care for elderly patients.

In the Active-Controlled Fracture Study in Postmenopausal Women With Osteoporosis at High Risk (ARCH) clinical trial (NCT01631214), 1 year of romosozumab followed by alendronate reduced the risk of vertebral and nonvertebral fractures compared to alendronate alone in women with prevalent fracture. We performed post hoc analyses of data from patients in ARCH (romosozumab, n = 1739; alendronate, n = 1726) who had a baseline BMD measurement and received at least one open-label alendronate dose. We evaluated 1-year mean BMD and corresponding T-score changes; proportions of patients achieving T-scores > -2.5 at the total hip (TH), femoral neck (FN), and lumbar spine (LS); and group differences in fracture rates after 12 months, while all participants were on alendronate. Subsequently, we investigated the relationship between T-scores achieved at the TH, FN, and LS at 12 months and subsequent fracture incidence. At 1 year, mean change from baseline in TH BMD was 6.3% (T-score change 0.31) with romosozumab versus 2.9% (T-score change 0.15) with alendronate (p < .001). The proportion of patients with TH T-score > -2.5 increased from 34% at baseline to 55% after 1 year of romosozumab and from 32% at baseline to 44% after 1 year of alendronate. Compared with patients receiving alendronate in year 1, those receiving romosozumab had a 75% reduction in new or worsening vertebral fracture (p < .001) in year 2, and a 19% reduction in nonvertebral fracture (p = .120) and 40% reduction in hip fracture (p = .041) during the open-label period. TH and FN T-scores achieved at month 12 were associated with subsequent nonvertebral and vertebral fracture rates and the relationships were independent of treatment received. LS T-score at 12 months was associated with vertebral but not nonvertebral fracture risk. We conclude that 1 year of romosozumab leads to larger BMD gains versus alendronate, and that the T-score achieved with either therapy is related to subsequent fracture risk. These data support the use of T-score as a therapeutic target for patients with osteoporosis. © 2020 The Authors. Journal of Bone and Mineral Research published by American Society for Bone and Mineral Research.

Antiresorptive therapies reduce fracture risk; however, long-term bone turnover inhibition may raise concerns about rare, but serious, skeletal adverse events-atypical femoral fracture (AFF) and osteonecrosis of the jaw (ONJ). Denosumab, a fully human monoclonal antibody against RANKL, has demonstrated sustained low vertebral and nonvertebral fracture rates with low skeletal adverse event rates in the 3-year FREEDOM trial and its 7-year Extension (in which all subjects received open-label denosumab). In this analysis, we aimed to estimate fractures prevented relative to skeletal adverse events observed with 10 years of denosumab therapy. We modeled a hypothetical placebo group using the virtual-twin method, thereby allowing calculation of fractures prevented with denosumab treatment (relative to the virtual-placebo group) in the context of AFF or ONJ events observed in the long-term denosumab group. Estimated virtual-placebo and observed long-term denosumab exposure-adjusted fracture rates per 100,000 subject-years were calculated for fractures classified as clinical (3180 and 1777, respectively), major osteoporotic (2699 and 1525), vertebral (1879 and 901), and nonvertebral (2924 and 1528), and compared with observed AFF and ONJ in the long-term denosumab group (5 and 35 per 100,000 subject-years, respectively). The skeletal benefit/risk ratio (fractures prevented per adverse event observed) for clinical fractures was 281 (AFF) and 40 (ONJ). Based on this model, denosumab treatment for up to 10 years has a favorable skeletal benefit/risk profile when comparing fractures prevented per skeletal adverse event observed. Clinical trial registration: NCT00089791.

Background/Purpose : Several studies implicate gout and/or xanthine oxidase activity as risk factors for type 2 diabetes. However, no studies have directly evaluated the effect of the xanthine oxidase inhibition on type 2 diabetes development. We therefore assessed the impact of allopurinol use on diabetes incidence in a retrospective cohort study of Veterans' Affairs patients with gout. Methods : The New York Harbor VA Computerized Patient Record System was searched to identify patients with an ICD-9 code for gout also meeting at least 4 1977 American Rheumatology Association gout diagnostic criteria. Pharmacy records were reviewed, and subjects divided into subgroups based on >30 continuous days of allopurinol prescription, versus no allopurinol. Incident diagnoses of diabetes, defined as first hemoglobin A1c <= 6.5% or physician documentation, were identified during an observation period from January 1, 2000 through December 31, 2015. Categorical variables, including the primary endpoint, were analyzed utilizing Fisher's exact test. Continuous variables were analyzed using binomial regression and the Student's T test. Results : 1032 subjects were allopurinol users, and 485 subjects were allopurinol never-users. The average duration of allopurinol use was 48.4 months. There were significantly more Black subjects in the allopurinol group, whereas there were significantly more Asian subjects and subjects with chronic kidney disease in the non-allopurinol group. Over a mean 94.3 months of follow-up, there was no significant difference in diabetes incidence between the allopurinol and non-allopurinol groups (8.0/1000 person-years versus 11.3/1000 person-years, p=0.64). There was also no significant difference in diabetes incidence when subjects were analyzed by baseline serum urate level, colchicine use, allopurinol dose, extent of urate lowering with allopurinol or achieving target urate level. When stratified into quartiles by duration of allopurinol use, a significant difference was observed between diabetes incidence in the longest and shortest quartiles among subjects in the allopurinol cohort (7.3 per 1000 person-years versus 21.3 per 1000 person-years, p=0.007). Conclusion : In this study, allopurinol use was overall not associated with reduced diabetes incidence, but longer durations of allopurinol use may have been associated with decreased diabetes. Prospective studies may further elucidate the relationship between hyperuricemia, gout, xanthine oxidase activity and diabetes, and the potential impact of gout treatments on diabetes incidence. (Figure Presented )

Romosozumab, which binds sclerostin, rebuilds the skeletal foundation before transitioning to antiresorptive treatment. This subgroup analysis of an international, randomized, double-blind study in postmenopausal women with osteoporosis showed efficacy and safety outcomes for romosozumab followed by denosumab in Japanese women were generally consistent with those for the overall population.

OBJECTIVES/OBJECTIVE:Gout patients with chronic kidney disease (CKD) accumulate the active allopurinol metabolite oxypurinol, suggesting that allopurinol may promote greater serum urate (sU) lowering in CKD patients. METHODS:We identified all patientswith gout diagnoses on either 100 mg or 300 mg of allopurinol daily, with available pre- and on-treatment sU levels, in our system in a 1-year period. Mean sU decrement by dosing per CKD groups was determined by CKD stage. RESULTS:Of 1,288 subjects with gout, 180 met entry criteria, with 83 subjects receiving 100 mg and 97 receiving 300 mg allopurinol. Subjects with CKD stage 1 experienced less sU lowering with 100 mg than 300 mg of allopurinol. Subjects with stage 4 and 5 CKD had equivalent sU decreases across the 100 mg and 300 mg allopurinol groups. However, the 100 mg group started at a higher pre-treatment sU and ended at a higher final sU than the 300 mg group. CONCLUSIONS:The strategy of titrating allopurinol to sU in patients with kidney impairment may result in greater sU lowering at lower doses than in patients without CKD but may also pose a treatment challenge from a possible drug ceiling effect.