European Society of Cardiology 2017
Abstract
Ann M. Carracher, Payal H. Marathe, and Kelly L. Close are of Close Concerns (http://www.closeconcerns.com), a healthcare information company focused exclusively on diabetes and obesity care. Close Concerns publishes Closer Look, a periodical that brings together news and insights in these areas. Each month, the Journal of Diabetes includes this News feature, in which Carracher, Marathe, and Close review the latest developments relevant to researchers and clinicians.
More than 31 000 attendees from around the world gathered in Barcelona, Spain, for the 2017 European Society of Cardiology conference. In presenting a post hoc analysis of the Liraglutide and Cardiovascular Outcomes in Type 2 Diabetes (LEADER)1 trial, Dr Neil Poulter (Imperial College London, UK) showed that results are still positive, indicating cardioprotection, after adjusting for baseline history of stroke or myocardial infarction (MI), which had no mediating effect on the significant association between Novo Nordisk's (Copenhagen, Denmark) glucagon-like peptide-1 (GLP-1) agonist Victoza (liraglutide) and cardiovascular risk reduction. Across the entire trial (n = 9340), liraglutide reduced risk for the primary outcome of three-point major adverse cardiac events (MACE; non-fatal MI, non-fatal stroke, and cardiovascular death) by 13% compared with placebo (P = 0.01 for superiority). Among 3692 patients with a prior history of stroke or MI, the hazard ratio (HR) for three-point MACE was 0.84 in favor of the GLP-1 agonist (95% confidence interval [CI] 0.72–0.97). Among the 5648 patients without prior stroke or MI, the HR for this primary endpoint was 0.89 (95% CI 0.76–1.05), with a trend in the right direction (numerically fewer MACE events on liraglutide vs placebo), although this was not statistically significant. Importantly, the P-value for treatment interaction was a non-significant 0.56, meaning history of stroke or MI did not significantly affect the overall results. Previous analyses of LEADER have adjusted for the occurrence of severe hypoglycemia, concomitant medication use, and recurrent cardiovascular events, none of which show a significant mediating effect on the association between liraglutide therapy and reduced risk for adverse cardiovascular events.
Similarly, Dr Javed Butler (Stony Brook University, Stony Brook, NY, USA) presented a late-breaking post hoc analysis of the Empagliflozin, Cardiovascular Outcomes, and Mortality in Type 2 Diabetes (EMPA-REG OUTCOME)2 study. He reported consistent benefits of Lilly (Indianapolis, IN, USA) and Boehringer Ingelheim's (Ingelheim, Germany) sodium–glucose cotransporter 2 (SGLT2) inhibitor Jardiance (empagliflozin) on lowering risk for heart failure and cardiovascular death across all subgroups stratified by 5-year heart failure risk. The 6314 participants in Lilly and Boehringer Ingelheim's large cardiovascular outcomes trial without a prior history of heart failure were stratified into low- to average-, high- or very high-risk groups for 5-year likelihood of heart failure according to the Health ABC HF Risk Score. People in the lowest risk category experienced a 29% relative risk reduction with empagliflozin versus placebo for the composite endpoint of heart failure hospitalization or cardiovascular death (HR = 0.71, 95% CI 0.52–0.96). Among those at low-to-average risk, the incidence of heart failure was 1.68/100 patient-years in the placebo group compared with 1.20/100 patient-years in the treatment group. This absolute risk increased for those categorized as high risk for heart failure, with events occurring at an incident rate of 4.03/100 patient-years in the placebo arm compared with 2.07/100 patient-years in the empagliflozin arm. Still, empagliflozin conferred a significant cardiovascular benefit in the form of a 48% relative risk reduction for the heart failure/cardiovascular death composite (HR = 0.52, 95% CI 0.36–0.75). Moving up the scale to the very high risk category, Dr Butler reported heightened incidence of heart failure at 7.0/100 patient-years among placebo-treated participants compared with 3.8/100 patient-years among empagliflozin-treated participants. In this third category, Jardiance was associated with a 45% relative risk reduction for the heart failure/cardiovascular death composite (HR = 0.55, 95% CI 0.30–1.00). Due to fewer events in each subgroup compared with the overall EMPA-REG OUTCOME trial, it is more challenging for any of these subgroup HRs to meet criteria for statistical significance, given wider CIs. There was no significant interaction between baseline heart failure risk and Jardiance's cardiovascular benefits (P = 0.428).
| Company Updates | |
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| August 8, 2017 | XOMA (Berkeley, CA, USA) announced that all regulatory and local ethics authorities have approved protocol for a multidose Phase 2 clinical trial of XOMA 358, an insulin receptor antibody, in children over 2 years of age with congenital hyperinsulinemia in the UK and Germany. The company stated that first dosing may be initiated by a potential licensee, although no partner exists at this time. |
| August 16, 2017 | Novo Nordisk announced topline results from SUSTAIN 7, a head-to-head comparison of GLP-1 agonists semaglutide and Lilly's dulaglutide (branded Trulicity). For 40 weeks, study participants (n = 1201) with type 2 diabetes (T2D) on a background of metformin therapy were randomized to one of four treatment arms: (i) 0.5 mg semaglutide injection once weekly; (ii) 0.75 mg dulaglutide injection once weekly; (iii) 1.0 mg semaglutide once weekly; or (iv) 1.5 mg dulaglutide once weekly. Both low- and high-dose semaglutide demonstrated superior HbA1c-lowering efficacy than corresponding doses of dulaglutide. Mean HbA1c reduction was 1.5% in the 0.5 mg semaglutide group versus 1.1% in the 0.75 mg dulaglutide group (mean baseline HbA1c was 8.2%). Among patients on 1.0 mg semaglutide, HbA1c dropped by an average of 1.8%, compared with a decrease of 1.4% among people on 1.5 mg dulaglutide. The HbA1c treatment difference for both comparisons was approximately 0.4%, which reached statistical significance in favor of both 0.5 and 1.0 mg semaglutide, although no P-values were reported in the topline release. In addition, 69% of people on 0.5 mg semaglutide achieved HbA1c ≤7% after 40 weeks, compared with 52% of people on 0.75 mg dulaglutide. These values were 79% and 68% for 1.0 mg semaglutide and 1.5 mg dulaglutide, respectively. Moreover, 51% of people on lower-dose semaglutide achieved HbA1c ≤6.5% after 40 weeks, compared with 36% of people on lower-dose dulaglutide. These values were 68% and 49% for higher-dose semaglutide and dulaglutide, respectively. There was no imbalance in retinopathy as an adverse event between the semaglutide and dulaglutide groups in SUSTAIN 7, with four events across two semaglutide arms and five events across two dulaglutide arms. From an average baseline body weight of 95 kg, people on 0.5 mg semaglutide lost a mean 4.5 kg over 40 weeks, compared with 2.3 kg for people on 0.75 mg dulaglutide. Participants randomized to 1.0 mg semaglutide lost a mean of 6.4 kg, compared with 3.2 kg for people on 1.5 mg dulaglutide. The approximate doubling of weight loss benefit for semaglutide compared with dulaglutide was statistically significant for both comparisons (low dose and high dose). |
| August 18, 2017 | The US Food and Drug Administration (FDA) issued a label update for Merck's (Kenilworth, NJ, USA) dipeptidyl peptidase 4 (DPP-4) inhibitor sitagliptin products, including standalone Januvia (sitagliptin), Janumet (fixed-dose combination of sitagliptin with metformin), and Janumet XR (sitagliptin and metformin extended release). The new label reflects a heightened risk for heart failure, a warning that is also on the label for AstraZeneca's (Cambridge, UK) Onglyza (saxagliptin), Lilly and Boehringer Ingelheim's Tradjenta (linagliptin), and Takeda's (Osaka, Japan) Nesina (alogliptin). The concern over DPP-4 inhibitor products and heart failure stems primarily from the Saxagliptin and Cardiovascular Outcomes in Patients with Type 2 Diabetes Mellitus (SAVOR-TIMI 53) trial,3 which found a 27% increase in hospitalizations for heart failure among people on Onglyza compared with people on placebo (P = 0.007). Previously, Merck had petitioned the FDA for inclusion of Effect of Sitagliptin on Cardiovascular Outcomes in Type 2 Diabetes (TECOS)4 trial data on the Januvia label, which showed a neutral HR of 1.00 for sitagliptin and heart failure hospitalizations. The company received a Complete Response Letter from the FDA, which now cautions against the prescription of any DPP-4 inhibitor therapy to patients at risk for heart failure. |
| August 18, 2017 | Lexicon (The Woodlands, TX, USA) announced positive topline data from a trial extension of inTandem2 (n = 782 people with type 1 diabetes [T1D]) out to 52 weeks, demonstrating sustained HbA1c benefit with both 200- and 400-mg doses of the SGLT1/2 dual inhibitor sotagliflozin (n = 261 and 263, respectively) versus placebo (n = 258). Previously, 24-week data showed a 0.37% and 0.35% greater HbA1c-lowering benefit compared with placebo (P < 0.001 for both) for the 200- and 400-mg doses, respectively. New 52-week data show that sotagliflozin achieved all six secondary endpoints in the trial extension: body weight, bolus insulin use, fasting plasma glucose, net benefit (proportion of patients with HbA1c <7% with no episodes of diabetic ketoacidosis [DKA] or severe hypoglycemia), Diabetes Treatment Satisfaction Questionnaire status score, and two-item Diabetes Distress Screening Scale score. The 400-mg dose also significantly reduced systolic blood pressure in those with baseline hypertension. Zero patients randomized to placebo experienced a DKA event over the course of 1 year, compared with six patients on 200 mg sotagliflozin (2%) and nine patients on 400 mg sotagliflozin (3%). Severe hypoglycemia rates over 52 weeks were 5% in the placebo group (13 patients), 5% in the 200 mg sotagliflozin group (13 patients), and 2% in the 400 mg sotagliflozin group (six patients). |
| August 25, 2017 | The FDA approved a new cardiovascular indication for Novo Nordisk's GLP-1 agonist Victoza (liraglutide), adding to the product label that Victoza reduces risk for MACE in T2D patients with established cardiovascular disease. Victoza is the first diabetes drug with an indication to prevent heart attacks, stroke, and cardiovascular death in patients with established cardiovascular disease (Lilly and Boehringer Ingelheim's SGLT2 inhibitor Jardiance is indicated for the reduction of cardiovascular death specifically). In June 2017, an FDA Advisory Committee voted 17–2 in favor of this label change. The update was approved based on LEADER1 trial data, which reported a 13% risk reduction for three-point MACE (non-fatal MI, non-fatal stroke, and cardiovascular death) with liraglutide versus placebo (P = 0.01 for superiority). The European Medicines Agency (EMA) approved a similar indication for Victoza's EU label in July 2017, following a Committee for Medicinal Products for Human Use (CHMP) endorsement in June, with cardiovascular risk reduction extending to T2D patients facing high cardiovascular risk. |
| August 28, 2017 | Health Canada approved Novo Nordisk's next-generation basal insulin Tresiba (insulin degludec) for adults with T1D and T2D. The product has also been added to Canada's national Register of Innovative Drugs, which confers clinical data protection. The product is scheduled for launch in October 2017. Insulin degludec has been associated with significantly reduced risk for hypoglycemia compared with Sanofi's (Paris, France) Lantus (insulin glargine) in the SWITCH 1 and SWITCH 2 trials,5, 6 as well as the Efficacy and Safety of Degludec versus Glargine in Type 2 Diabetes (DEVOTE) cardiovascular outcomes trial,7 which found a 40% risk reduction for severe hypoglycemia versus Lantus and a 53% risk reduction for severe hypoglycemia overnight. The FDA is evaluating SWITCH 1 and SWITCH 2 alongside DEVOTE in considering a Tresiba label claim for hypoglycemia risk reduction. |
| August 31, 2017 | The New England Journal of Medicine (NEJM) published renal outcomes results from Novo Nordisk's LEADER1 trial of GLP-1 agonist Victoza (liraglutide), presenting more granular renal data than the original LEADER paper (also in Marso et al.1). Liraglutide was associated with 22% reduced risk for the composite renal endpoint (new-onset persistent macroalbuminuria, persistent doubling of serum creatinine, end-stage renal disease, death due to renal causes) versus placebo, corresponding to an HR of 0.78 (P = 0.003). This benefit was driven by new-onset persistent macroalbuminuria: liraglutide reduced risk for this component endpoint by 26% (HR = 0.74, P = 0.004). |
| August 31, 2017 | Daiichi Sankyo (Tokyo, Japan) announced positive topline results from the REDUCER trial (RandomizEd, Double-blind, placebo-controlled 14-week stUdy of mirogabalin in patients with diabetiC pEripheral neuRopathic pain), a Phase 3 multicenter study (n = 750) conducted in Asia and followed by a 52-week open-label extension. The primary endpoint of the study was change in weekly average daily pain score (ADPS) from baseline to Week 14; mirogabalin showed statistically significant reductions in ADPS compared with placebo for both the 10- and 15-mg doses of mirogabalin twice daily, with no safety signals indicated in analyses thus far. Mirogabalin, an oral therapy that selectively binds the α2δ-2 subunit of calcium channels widely found in the nervous system in areas that mediate pain transmission, pointing to the potential use of mirogabalin in specific pain syndromes. Secondary endpoints in the REDUCER trial include change in ADPS from baseline to Week 14 in patients receiving 15 mg once daily versus placebo and comparison of the proportion of patients by treatment group with ≥30- and ≥50-point reductions in ADPS from baseline to Week 14. Further REDUCER results will be disclosed in upcoming scientific forums. According to the developer, up to 50% of people with diabetes have peripheral neuropathy, and between 11% and 26% of people with diabetes experience peripheral neuropathic pain. Currently, mirogabalin is being developed for marketing in Asia. |
| September 1, 2017 | Sanofi announced that the FDA has granted tentative approval to the company's biosimilar insulin lispro (Lilly's rapid-acting insulin Humalog) under brand name Admelog. Although Admelog has met all regulatory requirements for commercial approval, its US distribution cannot begin until patent infringement disputes with Lilly are settled. No details have been disclosed to date regarding when these patent issues may be resolved. Sanofi's biosimilar was approved by the EMA in July 2017 under the European Union brand name Insulin lispro Sanofi. The product is the first biosimilar mealtime insulin to reach the commercial market. |
