European Society of Cardiology 2018
Abstract
Martin J. Kurian, Peter J. Rentzepis, Ann M. Carracher, 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 Kurian, Rentzepis, Carracher, and Close review the latest developments relevant to researchers and clinicians.
The European Society of Cardiology 2018 Congress convened in Munich, Germany, from 25 to 29 August. There, Dr Peter Ueda (Karolinska Institutet, Solna, Sweden) presented an observational cohort study of 34 426 patients newly started on a sodium-glucose cotransporter 2 (SGLT2) inhibitor or a glucagon-like peptide-1 (GLP-1) receptor agonist. This analysis identified an approximately doubled risk of lower limb amputations (hazard ratio [HR] 2.23, 95% confidence interval [CI] 1.37-3.91) among patients taking SGLT2 inhibitors compared with GLP-1 agonists. The SGLT2 inhibitor cohort experienced 40 total events, compared with 22 total events in the GLP-1 receptor agonist cohort (2.7 vs 1.1 events per 1000 patient years). According to Dr Ueda, this effect was driven by the patient subgroup with a history of peripheral arterial disease (PAD) or lower limb amputations (HR 2.13, 95% CI 1.05-4.32; 30.2 vs 13.2 events per 1000 patient years). Furthermore, the absolute risk difference per 1000 patient-years was 1.5 in the total cohort (95% CI 0.4-3.3), compared with 14.9 in the high-risk cohort (95% CI 0.7-43.8). Dr Ueda highlighted that this study was mainly comprised of patients on empagliflozin (38%; n = 6506) and dapagliflozin (61%; n = 10 454), whereas 1% of SGLT2 inhibitor patients were initiated on canagliflozin (n = 254). Ultimately, however, Dr Ueda underscored that these observational results in no way confirm that amputations are a class effect of SGLT2 inhibitors.
In addition, a post hoc analysis of the Trial to Evaluate Cardiovascular and Other Long-term Outcomes with Semaglutide in Subjects with Type 2 Diabetes (SUSTAIN 6)1 found that the GLP-1 receptor agonist semaglutide consistently reduced risk for three-point major adverse cardiac events (MACE) across all levels of baseline cardiovascular (CV) risk. Two separate comparisons were presented, evaluating groups based on: (a) prior occurrence of myocardial infarction (MI) or stroke; and (b) established CV disease vs the presence of CV risk factors. In the MI/stroke analysis, patients who had a previous event (n = 1367; 41% of participants) saw a non-significant 24% relative risk reduction with semaglutide treatment (HR 0.76, 95% CI 0.55-1.05, P = 0.0921 vs placebo), whereas those with no prior MI or stroke (n = 1930) saw a non-significant 30% relative risk reduction (HR 0.70, 95% CI 0.47-1.04, P = 0.0791). In the second analysis, patients with established CVD at baseline (n = 2533; 77% of participants) experienced a non-significant 22% risk reduction with semaglutide vs placebo (HR 0.78, 95% CI 0.60-1.01, P = 0.633), whereas those with CV risk factors only (n = 764) experienced a significant 52% risk reduction with semaglutide vs placebo (HR 0.48, 95% CI 0.23-0.99, P = 0.0473). Overall, SUSTAIN 6 found that semaglutide treatment led to a 26% relative risk reduction on three-point MACE (HR 0.74, 95% CI 0.58-0.95, P < 0.001).
American Association of Diabetes Educators 2018
The American Association of Diabetes Educators 2018 meeting took place in Baltimore, (MD, USA) from 17 to 20 August. There, Dr James Gavin (Emory University School of Medicine, Atlanta, GA, USA) discussed considerations for selecting therapy after metformin usage. He predicted increased use of SGLT2 inhibitors as second-line therapy, broader use of GLP-1 agonists, and suggested a future “core therapy” of metformin/SGLT2 inhibitor/GLP-1 agonist combinations, with the option of low-dose pioglitazone. Dr Gavin also urged for greater thought to be given to individual patient pathophysiology, and discussed optimal sequencing of treatment, particularly criticizing an overreliance on metformin for too long. That is, metformin use as a first-line therapy is not in and of itself problematic, but keeping patients on metformin monotherapy despite not meeting glycemic targets does contribute to poorer patient outcomes.
| Company Updates | |
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| August 12, 2018: | GI Dynamics (Lexington, MA, USA) announced that the US Food and Drug Administration (FDA) has approved a pivotal trial for EndoBarrier for use in patients with type 2 diabetes mellitus (T2DM) and obesity. The primary endpoint will be HbA1c reduction at 1 year, and the first stage of the trial will enroll up to 67 participants with T2DM and obesity. Of those, 50 will receive EndoBarrier and 17 will form a control group, and an additional year of follow-up after implant removal is planned. Data will also be gathered on insulin sensitivity and insulin use, CV risk factors, and non-alcoholic fatty liver disease. Following FDA review of an interim 6-month safety report, enrollment could expand to 240 participants in total. GI Dynamics will have to formally apply for this expansion and, if approved, an additional 130 participants would receive the endoscopically delivered device and another 43 would serve as controls. Enrollment of the trial's first stage is expected to complete during the first half of 2019 but is subject to GI Dynamics securing additional financing in 2018. The original US pivotal trial for EndoBarrier, Safety and Efficacy of EndoBarrier in Subjects With Type 2 Diabetes Who Are Obese (ENDO),2 failed to meet its primary efficacy and safety endpoints, after ENDO was terminated early due to a high incidence of hepatic abscesses. In this new trial, GI Dynamics and the FDA have agreed on four specific safety events that, if reported, will cause enrollment to be stopped and trigger a review of safety data among FDA, GI Dynamics, and the Data Safety and Monitoring Board. |
| August 16, 2018: | The FDA accepted a New Drug Application (NDA) for Evoke Pharma's (Solana Beach, CA, USA) Gimoti (nasal metoclopramide), a novel nasal spray for acute and recurrent diabetic gastroparesis symptoms in women. The NDA was submitted on June 1, 2018, and an FDA decision is expected by April 1, 2019. Gimoti would be the first non-oral treatment for diabetic gastroparesis approved in four decades. |
| August 16, 2018: | Zealand (Glostrup, Denmark) announced that a pediatric study for HypoPal (dasiglucagon hypoglycemia rescue pen) will begin in September 2018, with topline results expected in the first half of 2019. An NDA submission for HypoPal is still scheduled for the second half of 2019; a pediatric study for dasiglucagon is a requirement for regulatory submission. Zealand also stated that following FDA clarification of the regulatory pathway for Beta Bionics' (Boston, MA, USA) dual-hormone artificial pancreas system and an investigational device exemption received by the company in May 2018, dasiglucagon will enter a Phase 2b trial in the dual-hormone system in 2018. |
| August 17, 2018: | Novo Nordisk (Bagsværd, Denmark) announced the acquisition of Ziylo (Bristol, UK), a University of Bristol spin-off focused on developing synthetic glucose-binding molecules for therapeutic and diagnostic applications. Novo Nordisk plans to pair Ziylo's molecules with its insulin platform to develop a glucose-responsive insulin. Ziylo received an undisclosed upfront payment from Novo Nordisk, and could potentially receive upwards of US$800 million in development, regulatory, and sales milestones. Prior to its acquisition, all Ziylo employees were transferred to a new company, Carbometrics (Bristol, UK), which now holds the rights to develop non-therapeutic applications of Ziylo's glucose-binding molecules and has a focus on continuous glucose monitoring. According to Novo Nordisk's Senior Vice President of Global Drug Discovery Dr Marcus Schindler, this divide is reflected in the acquisition's structure and milestone payments, which are centered on glucose-responsive insulin development and commercialization. |
| August 20, 2018: | Novo Nordisk announced positive topline results from the Phase 3 Efficacy and Safety of Oral Semaglutide vs Placebo in Subjects With Type 2 Diabetes and Moderate Renal Impairment (PIONEER 5) trial for oral semaglutide. This is the sixth of 10 trials in the Phase 3 PIONEER program to read out. PIONEER 5 (n = 324) compared semaglutide to placebo in patients with T2DM and moderate renal impairment (estimated glomerular filtration rate [eGFR] 30-59 mL/min per 1.73 m2, or Stage 3 chronic kidney disease). Only the 14-mg dose of semaglutide was tested, which is the highest dose under investigation in PIONEER. At Week 26, oral semaglutide gave a significant benefit vs placebo on both HbA1c and body weight, in an intention-to-treat analysis. In an on-treatment analysis, oral semaglutide gave a 1.1% reduction in HbA1c at 26 weeks from a baseline of 8.0%, compared with a 0.1% reduction with placebo. Body weight reduction with oral semaglutide was 3.7 kg, compared with 1.1 kg with placebo. With oral semaglutide, 64% of participants achieved an HbA1c <7.0%, significantly higher than the 21% of participants on placebo. P-values were not disclosed nor were any other comparisons given. Among those with renal impairment on oral semaglutide, 19% experienced nausea, compared with 8% of those on placebo. The discontinuation rate was 15% in the oral semaglutide group vs 6% in the placebo group, the highest of any PIONEER trial so far. |
| August 20, 2018: | Adocia (Lyon, France) was awarded US$11.6 million in damages from Eli Lilly (Indianapolis, IN, USA) for a disputed contractual milestone payment related to a terminated licensing agreement between the two companies for BioChaperone Lispro. The conflict dates back to Eli Lilly's January 2017 decision to terminate its licensing agreement for the ultra rapid-acting insulin, in order to prioritize its own internally developed next-generation mealtime insulin candidate (LY900014, now in Phase 3). Adocia has claimed additional damages of over US$1.8 billion against Eli Lilly for misappropriation and misuse of Adocia's confidential information. Another hearing is set for December 2018, for which a decision is expected in 2019. Adocia plans to submit further claims for interest, litigation fees, and costs accrued. On August 30, 2018, Adocia announced that Eli Lilly has filed counterclaims against Adocia seeking approximately US$188 million. A decision on that case is also expected in December 2018. |
| August 22, 2018: | Evotec (Hamburg, Germany) announced the formation of a strategic alliance with Novo Nordisk to discover and develop an early stage pipeline of small molecule therapies for the treatment of diabetes, obesity, non-alcoholic steatohepatitis, CV disease, and diabetic kidney disease. No financial specifics were disclosed. Evotec will first leverage its drug discovery platform, particularly in ligand-based design, to build a preclinical pipeline of small molecules. Novo Nordisk will then use Evotec's INDiGO platform to accelerate preclinical studies and investigational new drug (IND) application submission for suitable candidates. According to Evotec, the INDiGO platform can accelerate early drug candidates from nomination to IND submission in 52 weeks, and even less under certain circumstances, through in-house integration of preclinical processes. |
| August 29, 2018: | The FDA announced that it will require a new safety warning for necrotizing fasciitis of the perineum (Fournier's gangrene) to be added to the labels of all approved SGLT2 inhibitors and combination therapies containing SGLT2 inhibitors. Fournier's gangrene is an extremely rare but life-threating bacterial infection of the genitals and area around the genitals. The warning is based on 12 identified cases of the infection among those taking an SGLT2 inhibitor between March 2013 (when the first member of the class was approved) and May 2018. According to the announcement, all 12 cases developed within several months of the patients starting an SGLT2 inhibitor and required hospitalization and surgery. Several patients developed complications from surgery, and one patient died. Notably, diabetes is the most common comorbidity of and a known risk factor for Fournier's gangrene; diabetes is reportedly present in an estimated 20%-70% of patients with the infection. Approximately one in every 62 500 adult males is affected each year by Fournier's gangrene, and studies suggest a mortality rate of approximately 7.5%.3 |
| August 30, 2018: | AstraZeneca (Cambridge, UK) announced that the Bydureon BCise autoinjector (exenatide once weekly) has been approved in Europe, following submission to the European Medicines Agency in the second half of 2017. |
| September 4, 2018: | Novo Nordisk announced a research partnership with Ossianix (Hertfordshire, UK) with the aim of delivering therapeutic molecules for the treatment of diabetes and other metabolic diseases across the blood-brain barrier. According to the terms of the agreement, Ossianix will receive undisclosed upfront, preclinical, clinical, and commercial payments from Novo Nordisk, along with research and development funding and potential product royalties. Novo Nordisk will hold buy-out options and commercialization responsibilities for any therapeutics emerging from the collaboration. To this agreement, Ossianix brings its patented single domain variable new antigen receptor (VNAR) antibody, which is able to transport attached molecules across the blood-brain barrier. |
