Lisa Kerr

Effects of Prandial Versus Fasting Glycemia on Cardiovascular Outcomes in Type 2 Diabetes: The HEART2D trial

OBJECTIVE—Hyperglycemia and Its Effect After Acute Myocardial Infarction on Cardiovascular Outcomes in Patients With Type 2 Diabetes Mellitus (HEART2D) is a multinational, randomized, controlled trial designed to compare the effects of prandial versus fasting glycemic control on risk for cardiovascular outcomes in patients with type 2 diabetes after acute myocardial infarction (AMI). RESEARCH DESIGN AND METHODS—Patients (type 2 diabetes, aged 30–75 years) were randomly assigned within 21 days after AMI to the 1) prandial strategy (PRANDIAL) (three premeal doses of insulin lispro targeting 2-h postprandial blood glucose <7.5 mmol/l) or the 2) basal strategy (BASAL) (NPH twice daily or insulin glargine once daily targeting fasting/premeal blood glucose <6.7 mmol/l). RESULTS—A total of 1,115 patients were randomly assigned (PRANDIAL n = 557; BASAL n = 558), and the mean patient participation after randomization was 963 days (range 1–1,687 days). The trial was stopped for lack of efficacy. Risks of first combined adjudicated primary cardiovascular events in the PRANDIAL (n = 174, 31.2%) and BASAL (n = 181, 32.4%) groups were similar (hazard ratio 0.98 [95% CI 0.8–1.21]). Mean A1C did not differ between the PRANDIAL and BASAL groups (7.7 ± 0.1 vs. 7.8 ± 0.1%; P = 0.4) during the study. The PRANDIAL group showed a lower daily mean postprandial blood glucose (7.8 vs. 8.6 mmol/l; P < 0.01) and 2-h postprandial blood glucose excursion (0.1 vs. 1.3 mmol/l; P < 0.001) versus the BASAL group. The BASAL group showed lower mean fasting blood glucose (7.0 vs. 8.1 mmol/l; P < 0.001) and similar daily fasting/premeal blood glucose (7.7 vs. 7.3 mmol/l; P = 0.233) versus the PRANDIAL group. CONCLUSIONS—Treating diabetic survivors of AMI with prandial versus basal strategies achieved differences in fasting blood glucose, less-than-expected differences in postprandial blood glucose, similar levels of A1C, and no difference in risk for future cardiovascular event rates.

A decrease in glucose variability does not reduce cardiovascular event rates in type 2 diabetic patients after acute myocardial infarction: a reanalysis of the HEART2D study

OBJECTIVE To assess the effect of intraday glucose variability (GV) on cardiovascular outcomes in a reanalysis of Hyperglycemia and Its Effect After Acute Myocardial Infarction on Cardiovascular Outcomes in Patients With Type 2 Diabetes Mellitus (HEART2D) study data. RESEARCH DESIGN AND METHODS Type 2 diabetic patients after acute myocardial infarction were randomized to an insulin treatment strategy targeting postprandial (PRANDIAL; n = 557) or fasting/interprandial (BASAL; n = 558) hyperglycemia. GV was calculated as mean amplitude of glycemic excursions (MAGE), mean absolute glucose (MAG) change, and SD. RESULTS The PRANDIAL strategy resulted in an 18% lower MAG than BASAL (mean [SEM] difference 0.09 [0.04] mmol/L/h, P = 0.02). In addition, MAGE and SD were lower in the PRANDIAL group, however, not significantly. HbA1c levels and cardiovascular event rates were comparable between groups. CONCLUSIONS A PRANDIAL strategy demonstrated lower intraday GV vs. a BASAL strategy with similar overall glycemic control but did not result in a reduction in cardiovascular outcomes. This does not support the hypothesis that targeting GV would be beneficial in reducing subsequent secondary cardiovascular events.

Post Hoc Subgroup Analysis of the HEART2D Trial Demonstrates Lower Cardiovascular Risk in Older Patients Targeting Postprandial Versus Fasting/Premeal Glycemia

OBJECTIVE To identify the Hyperglycemia and Its Effect After Acute Myocardial Infarction on Cardiovascular Outcomes in Patients With Type 2 Diabetes Mellitus (HEART2D) trial subgroups with treatment difference. RESEARCH DESIGN AND METHODS In 1,115 type 2 diabetic patients who had suffered from an acute myocardial infarction (AMI), the HEART2D trial compared two insulin strategies targeting postprandial or fasting/premeal glycemia on time until first cardiovascular event (cardiovascular death, nonfatal MI, nonfatal stroke, coronary revascularization, or hospitalization for acute coronary syndrome). The HEART2D trial ended prematurely for futility. We used the classification and regression tree (CART) to identify baseline subgroups with potential treatment differences. RESULTS CART estimated the age of >65.7 years to best predict the difference in time to first event. In the subgroup aged >65.7 years (prandial, n = 189; basal, n = 210), prandial patients had a significantly longer time to first event and a lower proportion experienced a first event (n = 56 [29.6%] vs. n = 85 [40.5%]; hazard ratio 0.69 [95% CI 0.49–0.96]; P = 0.029), despite similar A1C levels. CONCLUSIONS Older type 2 diabetic AMI survivors may have a lower risk for a subsequent cardiovascular event with insulin targeting postprandial versus fasting/premeal glycemia.

Ixekizumab for the treatment of patients with active psoriatic arthritis and an inadequate response to tumour necrosis factor inhibitors: results from the 24-week randomised, double-blind, placebo-controlled period of the SPIRIT-P2 phase 3 trial

BACKGROUND Patients who have had inadequate response to tumour necrosis factor inhibitors have fewer treatment options and are generally more treatment refractory to subsequent therapeutic interventions than previously untreated patients. We report the efficacy and safety of ixekizumab, a monoclonal antibody that selectively targets interleukin-17A, in patients with active psoriatic arthritis and previous inadequate response to tumour necrosis factor inhibitors. METHODS In this double-blind, multicentre, randomised, placebo-controlled, phase 3 study (SPIRIT-P2), patients were recruited from 109 centres across ten countries in Asia, Australia, Europe, and North America. Patients were aged 18 years or older, had a confirmed diagnosis of psoriatic arthritis for at least 6 months, and had a previous inadequate response, distinguished by being refractory to therapy or had loss of efficacy, or were intolerant to tumour necrosis factor inhibitors. Patients were randomly assigned (1:1:1) by a computer-generated random sequence to receive a subcutaneous injection of 80 mg ixekizumab every 4 weeks or every 2 weeks after a 160 mg starting dose or placebo. The primary endpoint was the proportion of patients who attained at least 20% improvement in the American College of Rheumatology response criteria (ACR-20) at week 24. This study is registered with ClinicalTrials.gov, number NCT02349295. FINDINGS Between March 3, 2015, to March 22, 2016, 363 patients were randomly assigned to placebo (n=118), ixekizumab every 4 weeks (n=122), or ixekizumab every 2 weeks (n=123). At week 24, a higher proportion of patients attained ACR-20 with ixekizumab every 4 weeks (65 [53%] patients; effect size vs placebo 33·8% [95% CI 22·4-45·2]; p<0·0001) and ixekizumab every 2 weeks (59 [48%] patients; 28.5% [17·1-39.8]; p<0·0001) than did patients with placebo (23 [20%] patients). Up to week 24, serious adverse events were reported in three (3%) patients with ixekizumab every 4 weeks, eight (7%) with ixekizumab every 2 weeks, and four (3%) with placebo; no deaths were reported. Infections were reported in 47 (39%) patients with ixekizumab every 4 weeks, 47 (38%) with ixekizumab every 2 weeks, and 35 (30%) with placebo. Three (2%) serious infections, all in patients in the ixekizumab every 2 weeks group, were reported. INTERPRETATION Both the 2-week and 4-week ixekizumab dosing regimens improved the signs and symptoms of patients with active psoriatic arthritis and who had previously inadequate response to tumour necrosis factor inhibitors, with a safety profile consistent with previous studies investigating ixekizumab. FUNDING Eli Lilly and Company.

Sustained response with ixekizumab treatment of moderate-to-severe psoriasis with scalp involvement: results from three phase 3 trials (UNCOVER-1, UNCOVER-2, UNCOVER-3)

Abstract Background: Scalp is a frequently affected and difficult-to-treat area in psoriasis patients. Objective: We assessed the efficacy of ixekizumab in the treatment of patients with scalp psoriasis over 60 weeks using the Psoriasis Scalp Severity Index (PSSI). Methods: In three Phase 3, multicenter, double-blind, placebo-controlled trials, patients with moderate-to-severe psoriasis in UNCOVER-1 (N = 1296), UNCOVER-2 (N = 1224) and UNCOVER-3 (N = 1346) were randomized to subcutaneous 80 mg ixekizumab every two weeks (Q2W) or every four weeks (Q4W) after a 160 mg starting dose, or placebo through Week 12. Additional UNCOVER-2 and UNCOVER-3 cohorts were randomized to 50 mg bi-weekly etanercept through Week 12. Patients entering the open-label long-term extension (LTE) (UNCOVER-3) received ixekizumab Q4W; UNCOVER-1 and UNCOVER-2 included a blinded maintenance period in which static physician global assessment (sPGA) 0/1 responders were re-randomized to placebo, ixekizumab Q4W, or 80 mg ixekizumab every 12 weeks (Q12W) through Week 60. Results: In patients with moderate-to-severe psoriasis with baseline scalp involvement, PSSI 90 and 100 were achieved at Week 12 in higher percentages of patients treated with ixekizumab Q2W (81.7% and 74.6%) or ixekizumab Q4W (75.6% and 68.9%) compared with patients treated with placebo (7.6% and 6.7%; p < .001 each ixekizumab arm versus placebo) or etanercept (55.5% and 48.1%; p < .001 each ixekizumab arm versus etanercept). These outcomes were maintained through Week 60 of the maintenance (UNCOVER-1 and UNCOVER-2) and LTE (UNCOVER-3) period in patients who continued on ixekizumab Q4W. Conclusion: Ixekizumab was efficacious in treating scalp psoriasis in patients with moderate-to-severe psoriasis, with most patients achieving complete or near-complete resolution of scalp psoriasis and maintaining this response over 60 weeks.

Safety and efficacy of ixekizumab in patients with PsA and previous inadequate response to TNF inhibitors: week 52 results from SPIRIT-P2

Abstract Objectives To assess the long-term safety and efficacy of ixekizumab, an IL-17A antagonist, in patients with active PsA. Methods In SPIRIT-P2 (NCT02349295), patients (n = 363) with previous inadequate response to TNF inhibitors entered the double-blind period (weeks 0–24) and received placebo or ixekizumab 80 mg every 4 weeks (IXEQ4W) or every 2 weeks (IXEQ2W) following a 160-mg starting dose at week 0. During the extension period (weeks 24–156), patients maintained their original ixekizumab dose, and placebo patients received IXEQ4W or IXEQ2W (1:1). We present the accumulated safety findings (week 24 up to 156) at the time of this analysis for patients who entered the extension period (n = 310). Exposure-adjusted incidence rates (IRs) per 100 patient years are presented. ACR responses are presented on an intent-to-treat basis using non-responder imputation up to week 52. Results From week 24 up to 156 (with 228 patient years of ixekizumab exposure), 140 [61.3 IR] and 15 (6.6 IR) patients reported infections and serious adverse events, respectively. Serious adverse events included one death and four serious infections. In all patients initially treated with IXEQ4W and IXEQ2W at week 0 (non-responder imputation), ACR20 (61 and 51%), ACR50 (42 and 33%) and ACR70 (26 and 18%) responses persisted out to week 52. Placebo patients re-randomized to ixekizumab demonstrated efficacy as measured by ACR responses at week 52. Conclusion During the extension period, the overall safety profile of ixekizumab remained consistent with that observed with the double-blind period, and clinical improvements persisted up to 1 year.

The Effect of Psoriatic Arthritis on Ixekizumab Clinical Outcomes in Moderate-to-Severe Psoriasis Patients: A Post Hoc Analysis

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THU0313 Ixekizumab improves nail and skin lesions through 52 weeks in patients with active psoriatic arthritis and inadequate response to tumour necrosis factor inhibitors

Background Ixekizumab (IXE) is a high-affinity monoclonal antibody selectively targeting interleukin-17A. Compared to placebo (PBO), IXE resulted in significantly greater reduction and clearance of fingernail and skin lesions at Wk 24 in patients (pts) with active psoriatic arthritis (PsA) and inadequate response (IR) to tumour necrosis factor inhibitors (TNF-i).1 Objectives This analysis examined the persistence of effect at 1 year. Methods In this Phase 3, double-blind trial (SPIRIT-P2; NCT02349295), pts with active PSA who were TNF-i-IR were randomised to PBO or 80 mg IXE SC every 2 or 4 Wks (IXEQ2W, IXEQ4W), after a 160 mg starting dose.2 At Wk 16, pts with IR to treatment (ERB supplement defined) received rescue therapy and pts on PBO were re-randomised to IXEQ2W or IXEQ4W. The primary objective was ACR20 at Wk 24, and an extension from Wks 24 to 156 is on-going. In this analysis, efficacy was assessed at Wk 52 for the intent-to-treat (ITT) population of pts randomised to IXE at Wk 0 by Nail Psoriasis Severity Index (NAPSI) scores in pts with baseline fingernail psoriasis (IXEQ4W, n=89; IXEQ2W, n=74), PASI 75/90/100 response rates in pts with baseline BSA ≥3 (IXEQ4W, n=68; IXEQ2W, n=68), and the rate of Static Physician Global Assessment (sPGA) of psoriasis scores of 0 or 1 (0=cleared, 1=minimal) in pts with baseline sPGA ≥3 (IXEQ4W, n=60, IXEQ2W, n=62). For categorical variables, nonresponder imputation was used for missing data. Percent change from baseline was calculated using modified baseline observation carried forward. Results At Wk 52, NAPSI total score (observed cases; mean (SD)) was 5.0 (12.7), 4.4 (7.6), IXEQ4W, IXEQ2W, respectively, with a mean percent change from baseline of −15.2 (19.7),–14.4 (19.0), IXEQ4W, IXEQ2W, respectively. The percentage of pts achieving a NAPSI score of 0 (0=cleared) was 46.1% (n=41), 32.4% (n=24), IXEQ4W, IXEQ2W, respectively. The percentage of pts achieving PASI responses was 60.3% (n=41), 54.4% (n=37) for PASI 75; 50.0% (n=34), 39.7% (n=27) for PASI 90; and 39.7% (n=27), 35.3% (n=24) for PASI 100, IXEQ4W, IXEQ2W, respectively. The percentage of pts achieving sPGA 0 or 1 was 61.7% (n=37), 66.1% (n=41), IXEQ4W, IXEQ2W, respectively. Safety was consistent with the larger study population. Conclusions In patients with active PsA, an inadequate response to TNF-inhibitors, and baseline fingernail or skin lesions, treatment with ixekizumab resulted in persistent1 reduction and clearance of nail and skin lesions after 1 year. References [1] Kristensen L, et al. Ann Rheum Dis2017;76(Suppl 2):927. [2] Nash P, et al. Lancet2017;389:2317–27. Disclosure of Interest J. F. Merola Consultant for: Merck Research Laboratories, AbbVie, Eli Lilly and Company, Novartis, Janssen, UCB, Sumumed, Celgene, Sanofi Regeneron, and GSK, Speakers bureau: AbbVie, P. Rich Grant/research support from: AbbVie, Allergan, Anacor Pharmaceuticals, Boehringer Ingelheim, Cassiopea SpA, Dermira, Eli Lilly and Company, Galderma Laboratories, Janssen-Ortho, Kadmon Corporation, Leo Pharma, Merck, Moberg Derma, Novartis, Pfizer, Ranbaxy Laboratories Limited, Sandoz, Viamet, Cellceutix, Cutanea, J. P. Dutz Grant/research support from: AbbVie, Novartis, Amgen, Consultant for: Cipher, Eli Lilly and Company, Speakers bureau: Janssen, AbbVie, Novartis, Amgen, Leo Pharma, Celgene, D. Adams Shareholder of: Eli Lilly and Company, Employee of: Eli Lilly and Company, L. Kerr Shareholder of: Eli Lilly and Company, Employee of: Eli Lilly and Company, L. E. Kristensen Grant/research support from: UCB, Biogen, Janssen Pharmaceuticals, Novartis, Speakers bureau: Pfizer, AbbVie, Amgen, UCB, Bristol-Myers Squibb, Biogen, MSD, Novartis, Eli Lilly and Company, Janssen Pharmaceuticals.

FRI0502 Ixekizumab reduces disease activity in active psoriatic arthritis patients who had previous inadequate response to tumour necrosis factor-inhibitors

Background Psoriatic arthritis (PsA) is a chronic immune-mediated inflammatory disease associated with psoriasis, peripheral arthritis, enthesitis, dactylitis, and spondylitis. Ixekizumab (IXE), a monoclonal high affinity antibody that selectively targets interleukin-17A, has improved disease activity and physical function in bDMARD-naïve patients with active PsA.1 Herein, results are presented from a phase 3 trial (SPIRIT-P2; NCT02349295) with IXE in patients with active PsA and previous inadequate response to tumour necrosis factor-inhibitors (TNF-i). Objectives To explore the impact of IXE, as assessed by composite endpoints that incorporate multiple disease domains including peripheral arthritis, skin disease, enthesitis, dactylitis, spinal disease, functioning, and global disease assessment, up to 24 weeks (wks). Methods In this phase 3, multicentre, double-blind study, 363 adult patients with active PsA and a history of inadequate response to TNF-i were randomly assigned at a 1:1:1 ratio to subcutaneous administration of 80-mg IXE either every 4 wks (Q4W; N=122) or every 2 wks (Q2W; N=123) following a 160-mg starting dose at Wk 0 or placebo (PBO; N=118). TNF-i inadequate response was defined as lack of efficacy to one or two TNF-i or intolerance to TNF-i. Response to treatment and disease activity were measured at Wks 12 and 24 by the following composite endpoints: minimal disease activity with skin component measured with the Psoriasis Area and Severity Index (MDA) or the static Physician Global Assessment of psoriasis (mMDA) and Composite Psoriatic Disease Activity Index (CPDAI) as well as traditional measures by Psoriatic Arthritis Response Criteria (PsARC). Treatment comparisons were made by a logistic regression model for categorical data with missing values imputed by nonresponder imputation (NRI); a mixed model for repeated measures analysis was used for continuous data. Results At Wks 12 and 24, significantly more patients receiving IXEQ4W or IXEQ2W achieved MDA, mMDA, and PsARC compared with patients receiving PBO (Table). Results for MDA were similar to mMDA results within each treatment group at each time point. CPDAI total scores for patients receiving IXEQ4W or IXEQ2W were significantly improved compared with results for patients receiving PBO. Conclusions Treatment with either IXEQ2W or IXEQ4W provides improvement in disease activity across multiple symptom domains, as measured by various composite endpoints, in patients with active PsA and who had a previous inadequate response to TNF-i. References Mease P et al. 2017 ARD 76(1):79. Disclosure of Interest L. Coates Grant/research support from: Abbvie, Janssen, Consultant for: Abbvie, Celgene, Janssen, Sun Pharma, Pfizer, UCB, MSD, Novartis, Eli Lilly and Company, P. Mease Grant/research support from: Abbvie, Amgen, Bristol Myers Squibb, Celgene, Crescendo, Genentech, Janssen, Eli Lilly and Company, Merck, Novartis, Phizer, UCB Pharma, Sun, Consultant for: Abbvie, Amgen, Bristol Myers Squibb, Celgene, Crescendo, Genentech, Janssen, Eli Lilly and Company, Merck, Novartis, Pfizer, UCB Pharma, Sun, Speakers bureau: Abbvie, Amgen, Bristol Myers Squibb, Celgene, Crescendo, Genentech, Janssen, Pfizer, UCB Pharma, M. Husni Consultant for: Eli Lilly and Company, Novartis, Abbvie, Celgene, Bristol Myers Squibb, Amgen, Janssen, and UCB phrama, E. Lespessailles Grant/research support from: Amgen and Eli Lilly and Company, Speakers bureau: Expancience, Novartis and Servier, D. Adams Shareholder of: Eli Lilly and Company, Employee of: Eli Lilly and Company, O. Benichou Shareholder of: Eli Lilly and Company, Employee of: Eli Lilly and Company, L. Kerr Shareholder of: Eli Lilly and Company, Employee of: Eli Lilly and Company, P. Helliwell Grant/research support from: AbbVie, Amgen, Bristol-Myers Squibb, Celgene, Eli Lilly and Company, Janssen, Merck, Novartis, and UCB