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Pegozafermin is a long-acting glycopegylated (pegylated with the use of site-specific glycosyltransferases) fibroblast growth factor 21 (FGF21) analogue in development for the treatment of nonalcoholic steatohepatitis (NASH) and severe hypertriglyceridemia. The efficacy and safety of pegozafermin in patients with biopsy-proven noncirrhotic NASH are not well established. In this phase 2b, multicenter, double-blind, 24-week, randomized, placebo-controlled trial, we randomly assigned patients with biopsy-confirmed NASH and stage F2 or F3 (moderate or severe) fibrosis to receive subcutaneous pegozafermin at a dose of 15 mg or 30 mg weekly or 44 mg once every 2 weeks or placebo weekly or every 2 weeks. The two primary end points were an improvement in fibrosis (defined as reduction by ≥1 stage, on a scale from 0 to 4, with higher stages indicating greater severity), with no worsening of NASH, at 24 weeks and NASH resolution without worsening of fibrosis at 24 weeks. Safety was also assessed. Among the 222 patients who underwent randomization, 219 received pegozafermin or placebo. The percentage of patients who met the criteria for fibrosis improvement was 7% in the pooled placebo group, 22% in the 15-mg pegozafermin group (difference vs. placebo, 14 percentage points; 95% confidence interval [CI], -9 to 38), 26% in the 30-mg pegozafermin group (difference, 19 percentage points; 95% CI, 5 to 32; P = 0.009), and 27% in the 44-mg pegozafermin group (difference, 20 percentage points; 95% CI, 5 to 35; P = 0.008). The percentage of patients who met the criteria for NASH resolution was 2% in the placebo group, 37% in the 15-mg pegozafermin group (difference vs. placebo, 35 percentage points; 95% CI, 10 to 59), 23% in the 30-mg pegozafermin group (difference, 21 percentage points; 95% CI, 9 to 33), and 26% in the 44-mg pegozafermin group (difference, 24 percentage points; 95% CI, 10 to 37). The most common adverse events associated with pegozafermin therapy were nausea and diarrhea. In this phase 2b trial, treatment with pegozafermin led to improvements in fibrosis. These results support the advancement of pegozafermin into phase 3 development. (Funded by 89bio; ENLIVEN ClinicalTrials.gov number, NCT04929483.).

Pegozafermin, a long-acting glycopegylated analog of human fibroblast growth factor 21, is in development for the treatment of severe hypertriglyceridemia (SHTG) and nonalcoholic steatohepatitis. Here we report the results of a phase 2, double-blind, randomized, five-arm trial testing pegozafermin at four different doses ( n  = 67; 52 male) versus placebo ( n  = 18; 12 male) for 8 weeks in patients with SHTG (triglycerides (TGs), ≥500 mg dl −1 and ≤2,000 mg dl −1 ). Treated patients showed a significant reduction in median TGs for the pooled pegozafermin group versus placebo (57.3% versus 11.9%, difference versus placebo −43.7%, 95% confidence interval (CI): −57.1%, −30.3%; P  < 0.001), meeting the primary endpoint of the trial. Reductions in median TGs ranged from 36.4% to 63.4% across all treatment arms and were consistent regardless of background lipid-lowering therapy. Results for secondary endpoints included significant decreases in mean apolipoprotein B and non-high-density lipoprotein cholesterol concentrations (−10.5% and −18.3% for pooled doses compared to 1.1% and −0.6% for placebo (95% CI: −21.5%, −2.0%; P  = 0.019 and 95% CI: −30.7%, −5.1%; P  = 0.007, respectively), as well as a significant decrease in liver fat fraction for pooled treatment ( n  = 17) versus placebo ( n  = 6; −42.2% pooled pegozafermin, −8.3% placebo; 95% CI: −60.9%, −8.7%; P  = 0.012), as assessed in a magnetic resonance imaging sub-study. No serious adverse events were observed to be related to the study drug. If these results are confirmed in a phase 3 trial, pegozafermin could be a promising treatment for SHTG (ClinicalTrials.gov registration: NCT0441186). In a phase 2, randomized clinical trial in patients with severe hypertriglyceridemia, pegozafermin, a long-acting analog of human fibroblast growth factor 21, was safe and met the primary endpoint of the trial for reducing serum triglyceride levels.

Comparative studies evaluating traditional versus newer antianginal (AA) medications in chronic stable angina pectoris (CSA) on cardiovascular (CV) outcomes and utilization are limited, particularly in patients with diabetes mellitus (DM). Claims data (2008 to 2012) were analyzed using a commercial database. Patients with CSA receiving a β blocker (BB), calcium channel blocker (CCB), long-acting nitrate (LAN), or ranolazine were identified and followed for 12 months after a change in AA therapy. Patients on traditional AA medications were required to have concurrent sublingual nitroglycerin. Therapy change was defined as adding or switching to another traditional AA medication or ranolazine to identify patients whose angina was inadequately controlled with previous therapy. Four groups were identified (BB, CCB, LAN, or ranolazine users) and matched on relevant characteristics. A DM subset was identified. Logistic regression compared revascularization at 30, 60, 90, 180, and 360 days. Negative binomial regression compared all-cause, CV-, and DM-related (in the DM cohort) health care utilization. A total of 8,008 patients were identified with 2,002 patients in each matched group. Majority were men (mean age 66 years). A subset of 3,724 patients with DM (BB, n = 933; CCB, n = 940; LAN, n = 937; and ranolazine, n = 914) resulted from this cohort. Compared to ranolazine in the overall cohort, traditional AA medication exhibited greater odds for revascularization and higher rates in all-cause outpatient, emergency room visits, inpatient length of stay, and CV-related emergency room visits. In the DM cohort, ranolazine demonstrated similar benefits over traditional AA medication. In conclusion, ranolazine use in patients with inadequately controlled chronic angina is associated with less revascularization and all-cause and CV-related health care utilization compared to traditional AA medication.

OBJECTIVE:--The prevalence of gestational diabetes mellitus (GDM) varies in direct proportion with the prevalence of type 2 diabetes in a given population or ethnic group. Given that the number of people with diabetes worldwide is expected to increase at record levels through 2030, we examined temporal trends in GDM among diverse ethnic groups. RESEARCH DESIGN AND METHODS--Kaiser Permanente of Colorado (KPCO) has used a standard protocol to universally screen for GDM since 1994. This report is based on 36,403 KPCO singleton pregnancies occurring between 1994 and 2002 and examines trends in GDM prevalence among women with diverse ethnic backgrounds. RESULTS:--The prevalence of GDM among KPCO members doubled from 1994 to 2002 (2.1-4.1%, P < 0.001), with significant increases in all racial/ethnic groups. In logistic regression, year of diagnosis (odds ratio [OR] and 95% CI per 1 year = 1.12 [1.09-1.14]), mother's age (OR per 5 years = 1.7 [1.6-1.8]) and ethnicity other than non-Hispanic white (OR = 2.1 [1.9-2.4]) were all significantly associated with GDM. Birth year remained significant (OR = 1.06, P = 0.006), even after adjusting for prior GDM history. CONCLUSIONS:--This study shows that the prevalence of GDM is increasing in a universally screened multiethnic population. The increasing GDM prevalence suggests that the vicious cycle of diabetes in pregnancy initially described among Pima Indians may also be occurring among other U.S. ethnic groups.

To assess the usefulness of health plan administrative data for identifying patients with irritable bowel syndrome (IBS). In this retrospective study of 442 medical records of patients in nine U.S. health plans, five sets of criteria that used administrative data were used to identify potential IBS patients. Physician reviewers provided an assessment of the likelihood of the diagnosis of IBS being present. IBS was considered to be present if the physician reviewer categorized the case as definite, probable, or possible based on medical record review. Analyses were also performed with cases categorized as possible placed in an “IBS not present” category. The positive predictive value (PPV) for the five sets of criteria ranged from 63% to 83% with the highest PPV found with one of the most restrictive criteria. When cases characterized as possible were included in the “IBS not present” category, the PPV for each of the five sets of criteria decreased substantially, ranging from 33% to 63%. The PPV of different criteria used to identify patients with IBS from administrative data varies substantially based on the criteria that are used. Use of criteria with a higher PPV may come at the expense of generalizability.

OBJECTIVE: Determine the impact of fracture, coronary disease, and diabetes on changes in rates of discontinuation and initiation of estrogen therapy with (EPT) and without (ET) progestin, before (September 1, 1999 to June 30, 2002, baseline) versus 5 months after (follow-up) release of the Women's Health Initiative EPT trial results (WHI). DESIGN, SETTING, AND PARTICIPANTS: Observational cohort; 169,586 women 40 to 80 years old from 5 U.S. HMOs. METHODS: We used pharmacy data to identify ET and EPT users. A woman was a user any month she filled >=1 estrogen prescription and in subsequent months based upon the number of pills/patches dispensed. We used inpatient and outpatient claims to identify fracture January 1, 1999 to June 30, 2002 and pharmacy data to identify disease-based groups of medications for diabetes and cardiovascular disease. MEASURES: EPT/ET prevalence, initiation, and discontinuation rates. RESULTS: Baseline to follow-up EPT and ET prevalence declined 45% and 22%, respectively, with no difference by comorbidity. Follow-up EPT initiation was half the baseline rate irrespective of comorbidity. Compared to baseline, follow-up EPT discontinuation rates increased among women with diabetes (relative risk [RR], 6.9; 95% confidence interval [CI], 5.6 to 8.4), cardiovascular disease (RR, 5.5; 95% CI, 4.9 to 6.2), fracture (RR, 3.8; 95% CI, 2.4 to 5.7), and no comorbidity (RR, 4.4; 95% CI, 3.9 to 4.9). The RRs for follow-up versus baseline EPT discontinuation were higher among women with diabetes (P<.01) and cardiovascular disease (P<.01) versus women without these comorbidities. ET discontinuation rates among these same groups were elevated 2- to 2.8-fold. CONCLUSIONS: Diabetes and cardiovascular disease were associated with higher EPT discontinuation rates post-WHI compared to women without comorbidity; comorbidity had little impact on changes in prevalence or initiation of ET/EPT after release of the WHI. [PUBLICATION ABSTRACT]

Increasing Prevalence of Gestational Diabetes Mellitus (GDM) Over Time and by Birth Cohort Kaiser Permanente of Colorado GDM Screening Program Dana Dabelea , MD, PHD 1 , Janet K. Snell-Bergeon , MPH 1 , Cynthia L. Hartsfield , PHD 2 , Kimberly J. Bischoff , MSPH 2 , Richard F. Hamman , MD, PHD 1 and Robert S. McDuffie , MD 3 1 Department of Preventive Medicine and Biometrics, University of Colorado Health Sciences Center, Denver, Colorado 2 Kaiser Permanente of Colorado Clinical Research Unit, Denver, Colorado 3 Kaiser Permanente of Colorado Perinatology, Denver, Colorado Address correspondence and reprint requests to Dana Dabelea, MD, PhD, 4200 E. 9th Ave., Box C245, Denver, CO 80262. E-mail: dana.dabelea{at}uchsc.edu Abstract OBJECTIVE —The prevalence of gestational diabetes mellitus (GDM) varies in direct proportion with the prevalence of type 2 diabetes in a given population or ethnic group. Given that the number of people with diabetes worldwide is expected to increase at record levels through 2030, we examined temporal trends in GDM among diverse ethnic groups. RESEARCH DESIGN AND METHODS —Kaiser Permanente of Colorado (KPCO) has used a standard protocol to universally screen for GDM since 1994. This report is based on 36,403 KPCO singleton pregnancies occurring between 1994 and 2002 and examines trends in GDM prevalence among women with diverse ethnic backgrounds. RESULTS —The prevalence of GDM among KPCO members doubled from 1994 to 2002 (2.1–4.1%, P < 0.001), with significant increases in all racial/ethnic groups. In logistic regression, year of diagnosis (odds ratio [OR] and 95% CI per 1 year = 1.12 [1.09–1.14]), mother’s age (OR per 5 years = 1.7 [1.6–1.8]) and ethnicity other than non-Hispanic white (OR = 2.1 [1.9–2.4]) were all significantly associated with GDM. Birth year remained significant (OR = 1.06, P = 0.006), even after adjusting for prior GDM history. CONCLUSIONS —This study shows that the prevalence of GDM is increasing in a universally screened multiethnic population. The increasing GDM prevalence suggests that the vicious cycle of diabetes in pregnancy initially described among Pima Indians may also be occurring among other U.S. ethnic groups. GDM, gestational diabetes mellitus KPCO, Kaiser Permanente of Colorado NDDG, National Diabetes Data Group OGTT, oral glucose tolerance test Footnotes A table elsewhere in this issue shows conventional and Système International (SI) units and conversion factors for many substances. Accepted August 27, 2004. Received November 23, 2004. DIABETES CARE

OBJECTIVE: Determine the impact of fracture, coronary disease, and diabetes on changes in rates of discontinuation and initiation of estrogen therapy with (EPT) and without (ET) progestin, before (September 1, 1999 to June 30, 2002, baseline) versus 5 months after (follow‐up) release of the Women's Health Initiative EPT trial results (WHI). DESIGN, SETTING, AND PARTICIPANTS: Observational cohort; 169,586 women 40 to 80 years old from 5 U.S. HMOs. METHODS: We used pharmacy data to identify ET and EPT users. A woman was a user any month she filled ≥1 estrogen prescription and in subsequent months based upon the number of pills/patches dispensed. We used inpatient and outpatient claims to identify fracture January 1, 1999 to June 30, 2002 and pharmacy data to identify disease‐based groups of medications for diabetes and cardiovascular disease. MEASURES: EPT/ET prevalence, initiation, and discontinuation rates. RESULTS: Baseline to follow‐up EPT and ET prevalence declined 45% and 22%, respectively, with no difference by comorbidity. Follow‐up EPT initiation was half the baseline rate irrespective of comorbidity. Compared to baseline, follow‐up EPT discontinuation rates increased among women with diabetes (relative risk [RR], 6.9; 95% confidence interval [CI], 5.6 to 8.4), cardiovascular disease (RR, 5.5; 95% CI, 4.9 to 6.2), fracture (RR, 3.8; 95% CI, 2.4 to 5.7), and no comorbidity (RR, 4.4; 95% CI, 3.9 to 4.9). The RRs for follow‐up versus baseline EPT discontinuation were higher among women with diabetes (P<.01) and cardiovascular disease (P<.01) versus women without these comorbidities. ET discontinuation rates among these same groups were elevated 2‐ to 2.8‐fold. CONCLUSIONS: Diabetes and cardiovascular disease were associated with higher EPT discontinuation rates post‐WHI compared to women without comorbidity; comorbidity had little impact on changes in prevalence or initiation of ET/EPT after release of the WHI.

Determine the impact of fracture, coronary disease, and diabetes on changes in rates of discontinuation and initiation of estrogen therapy with (EPT) and without (ET) progestin, before (September 1, 1999 to June 30, 2002, baseline) versus 5 months after (follow-up) release of the Women's Health Initiative EPT trial results (WHI). Observational cohort; 169,586 women 40 to 80 years old from 5 U.S. HMOs. We used pharmacy data to identify ET and EPT users. A woman was a user any month she filled > or =1 estrogen prescription and in subsequent months based upon the number of pills/patches dispensed. We used inpatient and outpatient claims to identify fracture January 1, 1999 to June 30, 2002 and pharmacy data to identify disease-based groups of medications for diabetes and cardiovascular disease. EPT/ET prevalence, initiation, and discontinuation rates. Baseline to follow-up EPT and ET prevalence declined 45% and 22%, respectively, with no difference by comorbidity. Follow-up EPT initiation was half the baseline rate irrespective of comorbidity. Compared to baseline, follow-up EPT discontinuation rates increased among women with diabetes (relative risk [RR], 6.9; 95% confidence interval [CI], 5.6 to 8.4), cardiovascular disease (RR, 5.5; 95% CI, 4.9 to 6.2), fracture (RR, 3.8; 95% CI, 2.4 to 5.7), and no comorbidity (RR, 4.4; 95% CI, 3.9 to 4.9). The RRs for follow-up versus baseline EPT discontinuation were higher among women with diabetes (P<.01) and cardiovascular disease (P<.01) versus women without these comorbidities. ET discontinuation rates among these same groups were elevated 2- to 2.8-fold. Diabetes and cardiovascular disease were associated with higher EPT discontinuation rates post-WHI compared to women without comorbidity; comorbidity had little impact on changes in prevalence or initiation of ET/EPT after release of the WHI.