Efficacy and Safety of Mirikizumab in a Randomized Phase 2 Study of Patients With Crohn's Disease.

BACKGROUND: Mirikizumab is a humanized monoclonal antibody targeting interleukin 23p19 with demonstrated efficacy in psoriasis and ulcerative colitis. We investigated the safety and efficacy of mirikizumab in patients with moderate-to-severe Crohn's disease (CD). METHODS: Patients (N = 191) were randomized (2:1:1:2) to receive placebo (PBO), 200, 600, or 1000 mg mirikizumab, administered intravenously (IV) every 4 weeks. Patients who received mirikizumab and achieved ≥1 point improvement in Simple Endoscopic Score-CD at Week 12 (rerandomized maintenance cohort) were rerandomized to continue their induction IV treatment (combined IV groups [IV-C]) or receive 300 mg mirikizumab subcutaneously (SC) every 4 weeks. Nonrandomized maintenance cohort included endoscopic nonimprovers (1000 mg) and PBO patients (PBO/1000 mg) who received 1000 mg mirikizumab IV from Week 12. The primary objective was to evaluate superiority of mirikizumab to PBO in inducing endoscopic response (50% reduction from baseline in Simple Endoscopic Score-CD) at Week 12. RESULTS: At Week 12, endoscopic response was significantly higher by the predefined 2-sided significance level of 0.1 for all mirikizumab groups compared with PBO (200 mg: 25.8%, 8/31, 95% confidence interval [CI], 10.4-41.2, P = .079; 600 mg: 37.5%, 12/32, 95% CI, 20.7-54.3, P = .003; 1000 mg: 43.8%, 28/64, 95% CI, 31.6-55.9, P < .001; PBO: 10.9 %, 7/64, 95% CI, 3.3-18.6). Endoscopic response at Week 52 was 58.5% (24/41) and 58.7% (27/46) in the IV-C and SC groups, respectively. Frequencies of adverse events (AE) in the mirikizumab groups were similar to PBO. Through Week 52, frequencies of treatment-emergent AEs were similar across all groups. Frequencies of serious AE and discontinuations due to AE were higher in the nonrandomized maintenance cohort. CONCLUSION: Mirikizumab effectively induced endoscopic response after 12 weeks in patients with moderate-to-severe CD and demonstrated durable efficacy to Week 52. A detailed summary can be found in the Video Abstract. ClinicalTrials.gov, Number: NCT02891226.

Gastrin analogue administration adds no significant glycaemic benefit to a glucagon-like peptide-1 receptor agonist acutely or after washout of both analogues.

AIM: To determine if a 4-week course of 14 mg weekly GLP-1 agonist LY2428757 combined with 3 mg or 2 mg daily gastrin analogue TT223 (LY+TT223) results in long-term glycaemic changes. MATERIALS AND METHODS: Patients with in adequately-controlled type 2 diabetes mellitus ±metformin (N=151) were randomized to a 4-week course of LY+TT223 (3 mg), LY+TT223 (2 mg), LY+TT223 placebo (LY-only) or LY placebo+TT223 placebo (placebo). The primary objective was change in HbA1c from baseline to 5 month safter completion of therapy (i.e. at 6 months) and safety and tolerability with LY+TT223 versus LY-only. RESULTS: LY groups showed HbA1c reductions during the active treatment phase. These did not persist during follow-up phase. Combining TT223 with LY did not result in additional glycaemic effects during treatment or follow-up. At 6 months, LSM ± SE for change in HbA1c from baseline was: LY+TT223 (3 mg): -0.1 ± 0.2%; LY+TT223 (2 mg): 0.1 ± 0.2%; LY-only: -0.2 ± 0.2%; placebo: 0.04 ± 0.2%. Secondary analyses were consistent with primary results. LY+TT223 was not superior to LY for other time points or end points, including insulin secretory response to mixed meal tolerance tests. The most common adverse events (nausea and vomiting) were more frequent with LY+TT223 versus LY-only. The safety profile was consistent with previous findings. CONCLUSION: GLP-1+gastrin combination therapy did not improve glycaemic control versus GLP-1 alone.

Impact of Bowel Urgency on Quality of Life and Clinical Outcomes in Patients With Ulcerative Colitis.

Background: Bowel urgency is commonly experienced by patients with ulcerative colitis (UC) and is associated with reduced health-related quality of life (QoL). Mirikizumab, a humanized monoclonal antibody directed against the p19 subunit of IL-23, significantly reduced bowel urgency in a double-blind, randomized, placebo-controlled Phase 2 clinical trial in patients with moderate-to-severe UC (NCT02589665). Methods: All patients (N = 249) reported symptoms including absence or presence of bowel urgency. Absence of urgency was defined as no urgency for the 3 consecutive days prior to each scheduled visit. Missing urgency data were imputed as present. After 12 weeks of induction treatment, patients who achieved clinical response continued maintenance mirikizumab treatment through Week 52. We assessed the relationship of urgency with QoL, clinical outcomes, and inflammatory biomarkers at Weeks 12 and 52. Results: Patients with absence of urgency demonstrated significantly greater improvement in Inflammatory Bowel Disease Questionnaire (IBDQ) scores even after adjusting for rectal bleeding (RB) and stool frequency (SF), significantly higher rates of all clinical outcomes at Weeks 12 and 52, and a greater decrease in inflammatory biomarkers C-reactive protein and fecal calprotectin compared to those with presence of urgency. Absence of urgency at Week 12 was associated with improved IBDQ scores at Week 52, while Week 12 RB or SF status was not. Conclusions: Absence of urgency is strongly associated with improvement in QoL as well as clinical measures of UC disease activity. These findings suggest urgency may be a useful surrogate marker of disease activity and an important treatment target for UC.

Serum TSH and total T4 in the United States population and their association with participant characteristics: National Health and Nutrition Examination Survey (NHANES 1999-2002).

OBJECTIVE: Describe thyrotropin (TSH) and thyroxine (T4) levels in the U.S. population and their association with selected participant characteristics. DESIGN: Secondary analysis of data from the National Health and Nutrition Examination Survey (NHANES) collected from 4392 participants, reflecting 222 million individuals, during 1999-2002. RESULTS: Hypothyroidism prevalence (TSH > 4.5 mIU/L) in the general population was 3.7%, and hyperthyroidism prevalence (TSH < 0.1 mIU/L) was 0.5%. Among women of reproductive age (12-49 years), hypothyroidism prevalence was 3.1%. Individuals aged 80 years and older had five times greater odds for hypothyroidism compared to 12- to 49-year-olds (adjusted odds ratio [OR] = 5.0, p = 0.0002). ORs were adjusted for sex, race, annual income, pregnancy status, and usage of thyroid-related medications (levothyroxine/thyroid, estrogen, androgen, lithium, and amiodarone). Compared to non-Hispanic whites, non-Hispanic blacks had a lower risk for hypothyroidism (OR = 0.46, p = 0.04) and a higher risk for hyperthyroidism (OR = 3.18, p = 0.0005), while Mexican Americans had the same risk as non-Hispanic whites for hypothyroidism, but a higher risk for hyperthyroidism (OR = 1.98, p = 0.04). Among those taking levothyroxine or desiccated thyroid, the adjusted risk for either hypothyroidism (OR = 4.0, p = 0.0001) or hyperthyroidism (OR = 11.4, p = 4 x 10(-9)) was elevated. CONCLUSIONS: Associations with known factors such as age, race, and sex were confirmed using this data set. Understanding the prevalence of abnormal thyroid tests among reproductive-aged women informs decisions about screening in this population. The finding that individuals on thyroid hormone replacement medication often remain hypothyroid or become hyperthyroid underscores the importance of monitoring.

A safe and cost-effective short hospital stay protocol to identify patients at low risk for the development of significant hypocalcemia after total thyroidectomy.

OBJECTIVE: The objective of this retrospective chart review was to determine if serial postoperative serum calcium levels early after total thyroidectomy can be used to develop an algorithm that identifies patients who are unlikely to develop significant hypocalcemia and can be safely discharged within 24 hours after surgery. METHODS: Records of 135 consecutive patients who underwent total/completion thyroidectomy and were operated on by the senior author from 2001 to 2005 have been reviewed. For the entire study group, reports of the early postoperative serum calcium levels (6 hours and 12 hours postoperatively), final thyroid pathology, preoperative examination, inpatient course, and postoperative follow up were reviewed. An endocrine medicine consultation was obtained for all patients while in the hospital after surgery. For patients who developed significant hypocalcemia, reports of their management and the need for readmission or permanent medications for hypoparathyroidism were reviewed. According to the change in serum calcium levels between 6 hours and 12 hours postoperatively, patients were divided into two groups: 1) positive slope (increasing) and 2) nonpositive (nonchanging/decreasing). RESULTS: All patients with a positive slope (50/50) did not develop significant hypocalcemia in contrast to only 59 of 85 patients (69.4%) with a nonpositive slope (P < .001, positive predictive value of positive slope in predicting freedom from significant hypocalcemia = 100%, 95% confidence interval = 92.9-100). In the nonpositive slope group, 61 patients had a serum calcium level > or =8 mg/dL at 12 hours postoperatively (< or =0.5 mg/dL below the low end of normal), and 53 (87%) of these patients remained free of significant hypocalcemia in contrast to only 6 (25%) of 24 patients with serum calcium level <8 mg/dL at 12 hours postoperatively (sensitivity = 90%, positive predictive value = 87%). In addition, of the eight patients who developed significant hypocalcemia in the nonpositive slope group with a serum calcium level > or =8 mg/dL at 12 hours postoperatively, 7 (88%) patients developed the signs and symptoms during the first 24 hours after total thyroidectomy. Readmission and permanent need for calcium supplementation happened in two patients, respectively, all with serum calcium levels <8 mg/dL at 12 hours after total thyroidectomy. The compressive and/or symptomatic large multinodular goiter as an indication for thyroidectomy was associated with developing significant hypocalcemia (P < .05). There was no statistically significant correlation between the development of significant hypocalcemia and gender, age, thyroid pathology other than goiter, or neck dissection. CONCLUSION: Patients with a positive serum calcium slope (t = 6 and 12 hours) after total thyroidectomy are safe to discharge within 24 hours after surgery with patient education with or without calcium supplementation. In addition, patients with a nonpositive slope and a serum calcium level > or =8 mg/dL at 12 hours postoperatively (< or =0.5 mg/dL below the low end of normal) are unlikely to develop significant hypocalcemia, especially beyond 24 hours postoperatively, and therefore can be safely discharged within 24 hours after total thyroidectomy with patient education and oral calcium supplementation. Our management algorithm identifies those patients at low risk of developing significant hypocalcemia early in the postoperative course after total thyroidectomy to allow for a short hospital stay and safe discharge.

The Discovery, Preclinical, and Early Clinical Development of Potent and Selective GPR40 Agonists for the Treatment of Type 2 Diabetes Mellitus (LY2881835, LY2922083, and LY2922470).

The G protein-coupled receptor 40 (GPR40) also known as free fatty acid receptor 1 (FFAR1) is highly expressed in pancreatic, islet ß-cells and responds to endogenous fatty acids, resulting in amplification of insulin secretion only in the presence of elevated glucose levels. Hypothesis driven structural modifications to endogenous FFAs, focused on breaking planarity and reducing lipophilicity, led to the identification of spiropiperidine and tetrahydroquinoline acid derivatives as GPR40 agonists with unique pharmacology, selectivity, and pharmacokinetic properties. Compounds 1 (LY2881835), 2 (LY2922083), and 3 (LY2922470) demonstrated potent, efficacious, and durable dose-dependent reductions in glucose levels along with significant increases in insulin and GLP-1 secretion during preclinical testing. A clinical study with 3 administered to subjects with T2DM provided proof of concept of 3 as a potential glucose-lowering therapy. This manuscript summarizes the scientific rationale, medicinal chemistry, preclinical, and early development data of this new class of GPR40 agonists.

Smoke exposure is associated with a lower prevalence of serum thyroid autoantibodies and thyrotropin concentration elevation and a higher prevalence of mild thyrotropin concentration suppression in the third National Health and Nutrition Examination Survey (NHANES III).

Few modifiable exposures influencing autoimmune thyroid disease have been identified. Studies evaluating cigarette smoke and thyroid disorders have yielded conflicting results. The relationship between smoking and thyroid abnormalities was evaluated in the 1988-1994 Third National Health and Nutrition Examination Survey (NHANES III), a cross-sectional study that used a complex, multistage, stratified, clustered sampling approach to reflect the entire noninstitutionalized United States population. Among 18,148 persons who underwent thyroid testing, data regarding age, gender, iodine status, smoke exposure, and thyroid tests were complete for 16,046 persons. After excluding those taking thyroid-altering medications, 15,592 remaining subjects were analyzed. Subjects with serum cotinine levels greater than 15 ng/ml were classified as smokers. Outcome measures included the presence of 1) antithyroperoxidase antibody levels of 0.5 IU/ml or more or antithyroglobulin antibody levels of 1.0 IU/ml or more, 2) TSH concentration greater than 4.5 mU/liter, 3) TSH concentration less than 0.1 mU/liter, and 4) TSH concentration of 0.1-0.4 mU/liter. Fewer smokers (11%, 95% confidence interval (CI) = [10-13%]) had thyroid autoantibodies compared with nonsmokers (18%, 95% CI = [17-19%]). Prevalence in smokers after adjustment for age, gender, race-ethnicity, and iodine status was 13%, 95% CI = [12-15%]. Fewer smokers (2.6%, 95% CI = [2.0-3.2%]) had elevated TSH compared with nonsmokers (5.5%, 95% CI = [4.7-6.3%]). The adjusted rate in smokers was 3.4%, 95% CI = [2.6-4.3%]). Among persons with thyroid autoantibodies, smokers had 40% lower odds of TSH elevation compared with nonsmokers (adjusted odds ratio [95% CI] = 0.6 [0.4-0.97]). Among persons without TSH elevation, smoke exposure was associated with 200% greater odds of low normal TSH 0.1-0.4 mU/liter (adjusted odds ratio [95% CI] = 2.0 [1.3-2.9]). Smoking appears to be negatively associated with serological evidence of thyroid autoimmunity and hypothyroidism and positively associated with mild TSH decreases. Eliminating smoke exposure may help prevent the low normal TSH measurements that are characteristic of mild hyperthyroidism. Understanding the underlying mechanism could help identify potential pathways for the prevention of autoimmune thyroid disease.

Development and use of evidence-based clinical practice guidelines for thyroid disease.

Clinical practice guidelines offer recommendations for optimizing health care. Guideline panels can rely on several methods for gathering information about current practice and synthesizing evidence that addresses specific questions. Clinical practice guidelines, including many that address thyroid disease, often rely on conventional narrative literature reviews and expert opinion rather than systematic evaluation of the published literature as the basis for their recommendations. This undermines the authority of practice guidelines and potentially results in disparate, invalid, or misleading recommendations. In contrast, incorporation of rigorous systematic reviews of literature and guidance by groups with multidisciplinary expertise decreases bias in evidence selection and increases precision of treatment effect estimates. Improved reliability and accuracy of evidence assessment, in turn, strengthens ultimate guideline recommendations. Cost-effective analyses further contribute to useful clinical practice guidelines and may encourage the explicit acknowledgment of values and preferences. Valid recommendations, however, prove futile in the absence of implementation. Adherence to guidelines may be improved with integration of user-friendly computer applications into clinical practice. By overcoming barriers to implementation and addressing the limitations of current guidelines, endocrinologists can play an essential role in improving the quality, efficiency, and cost-effectiveness of clinical practice related to thyroid disorders.

Comparison of prandial AIR inhaled insulin alone to intensified insulin glargine alone and to AIR insulin plus intensified insulin glargine in patients with type 2 diabetes previously treated with once-daily insulin glargine.

BACKGROUND: Patients with type 2 diabetes often initiate insulin with once-daily basal insulin. Over time, many patients intensify their insulin regimens in an attempt to attain and sustain glycemic targets. This study compares three intensification approaches: changing insulin glargine to preprandial AIR inhaled insulin (developed by Alkermes, Inc. [Cambridge, MA] and Eli Lilly and Company [Indianapolis, IN]; AIR is a registered trademark of Alkermes, Inc.), intensifying glargine via validated titration algorithms (IG), or adding AIR insulin while intensifying glargine (AIR + IG). METHODS: Five hundred sixty patients with hemoglobin A(1c) (A1C) of 7.5-10.5%, on one or more antihyperglycemic medications, and on once-daily insulin glargine for > or =4 months were randomly allocated to one of the three treatments lasting 52 weeks. The primary objective assessed between-group differences in A1C mean change from baseline to 24 weeks using last-observation-carried-forward (LOCF) in the intent-to-treat population. RESULTS: At 24 weeks, A1C was reduced from a mean baseline of 8.5% to 7.7%, 7.9%, and 7.5% for the AIR, IG, and AIR + IG groups, respectively. AIR produced 0.20% greater A1C decrease than IG (least-squares mean difference = -0.20%; 95% confidence interval [CI], -0.39, -0.02). AIR + IG had a 0.35% greater A1C decrease versus IG (95% CI, -0.57, -0.13). The -0.15% difference between AIR + IG versus AIR was not significant (P < 0.198). More hypoglycemia categorized as severe occurred with AIR alone versus IG alone at LOCF end points. More nocturnal hypoglycemia occurred with IG alone versus AIR alone and AIR + IG. CONCLUSIONS: Preprandial inhaled insulin provides an alternative for patients not optimized on insulin glargine alone. Glycemic control, hypoglycemic risk, delivery preference, and regimen complexity must be considered when selecting insulin initiation and optimization regimens.