European Association for the Study of Diabetes 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.
European Association for the Study of Diabetes 2017
More than 15 000 attendees from more than 130 countries gathered in Lisbon, Portugal, for the 2017 European Association for the Study of Diabetes (EASD) annual meeting. Dr Adrian Hernandez (Duke University, Durham, NC, USA) presented outcomes data from AstraZeneca's (Cambridge, UK) cardiovascular outcomes trial of the glucagon-like peptide-1 (GLP-1) agonist Bydureon (exenatide once weekly), the Exenatide Study of Cardiovascular Event Lowering Trial (EXSCEL).1 This 14 752-person trial compared Bydureon with placebo. The hazard ratio (HR) for three-point major adverse cardiac events (MACE; i.e. non-fatal stroke, non-fatal myocardial infarction [MI], or cardiovascular death) was 0.91 (95% confidence interval [CI] 0.83–1.00; P < 0.001 for non-inferiority, P = 0.06 for superiority), trending in favor of exenatide but missing statistical significance for superiority. The trial did not reach superiority for any individual component of the three-point MACE composite, but all these secondary outcomes trended in favor of exenatide, with HRs of 0.86 for non-fatal stroke (95% CI 0.70–1.07), 0.95 for non-fatal MI (95% CI 0.84–1.09), and 0.88 for cardiovascular death (95% CI 0.73–1.05). Dr Hernandez presented several subgroup analyses that probed for possible heterogeneity of effect among different patient populations. There was a significant interaction for age (P = 0.005 for interaction), whereby Bydureon was associated with statistically significant cardiovascular risk reduction in people older than 65 years (HR = 0.80; 95% CI 0.71–0.91). Dr Hernandez also reported an HR for all-cause mortality of 0.86 (95% CI 0.77–0.97; nominal P = 0.016) favoring exenatide versus placebo. By the trial's prespecified hierarchical testing structure, this can only be considered exploratory because exenatide did not meet superiority for its primary endpoint.
Also presented were data from two trials of sodium–glucose cotransporter (SGLT) inhibitors in patients with type 1 diabetes (T1D), namely the inTandem3 trial2 of Lexicon's (The Woodlands, TX, USA) Sanofi-partnered (Paris, France) SGLT-1/2 inhibitor sotagliflozin and the Dapagliflozin Evaluation in Patient with Inadequately Controlled Type 1 Diabetes (DEPICT1) trial3 of AstraZeneca's dapagliflozin. Professor Melanie Davies presented full inTandem3 results: the global, 24-week trial (n = 1402) investigated 400 mg sotagliflozin versus placebo on a primary endpoint of the proportion of patients achieving target HbA1c <7% with no severe hypoglycemia or diabetic ketoacidosis (DKA), with no run-in period of insulin optimization. The primary endpoint was met by 29% of people in the sotagliflozin arm versus 15% in the placebo arm (P < 0.001). Mean HbA1c reduction was 0.8% with sotagliflozin versus 0.3% with placebo, culminating in a treatment difference of 0.5% (P < 0.001). Sotagliflozin was associated with a treatment difference of −2.98 kg weight loss versus placebo (P < 0.001). In patients with systolic blood pressure ≥ 130 mmHg at baseline, sotagliflozin gave a treatment difference of 3.5 mmHg (P < 0.002) at 16 weeks. There were four DKA events (0.6%) in the placebo group, compared with 21 (3%) in the 400 mg sotagliflozin group, leading to 11 treatment discontinuations in the latter arm. In the sotagliflozin group, DKA was adjudicated in 4% of pump users and 2% of patients on multiple daily injections.
Dr Paresh Dandona (State University of New York, Buffalo, NY, USA) presented the safety and efficacy data from DEPICT1. Both doses of dapagliflozin met the primary endpoint of change in HbA1c over 24 weeks: the 5 mg dose gave a 0.4% drop versus placebo, whereas the 10 mg dose gave a 0.5% drop versus placebo (both P < 0.0001). Total daily insulin dose fell 9% versus placebo for the 5 mg dose of dapagliflozin and 13% versus placebo for the 10 mg dose (both P < 0.0001). The percentage change in body weight versus placebo was −3% for the 5 mg dose and −4% for the 10 mg dose (both P < 0.0001). Moreover, weight loss was continuous and there was very little flattening of the curve over 6 months, suggesting that more weight loss could be expected long term. Hypoglycemia was well balanced across all treatment arms, with 8% (5 mg), 6% (10 mg), and 7% (placebo) rates of severe hypoglycemia, and the proportion of patients with an HbA1c reduction of ≥0.5% without severe hypoglycemia was >50% for both doses, compared with approximately 25% for placebo. Continuous glucose monitor (CGM) readings showed 52% (12.5 h), 55% (13.2 h), and 44% (10.6 h) time-in-range for 5 mg dapagliflozin, 10 mg dapagliflozin, and placebo, respectively, translating to an extra 2.2 h in-range for low-dose dapagliflozin patients and an extra 2.6 h in-range for high-dose dapagliflozin patients versus placebo. There was a DKA event rate of 1% in the 5 mg group (four patients; two due to insulin pump failure, one to missed insulin dose, and one unexplained), 2% in the 10 mg group (five patients; one attributed to pump failure, three to missed insulin dose, and one to alcohol), and 1% in the placebo group (three patients; one due to pump failure, one to missed insulin dose, and one to stress). The DEPICT study protocol recommended that total insulin could be reduced by up to but no more than 20% to mitigate DKA risk.
References
| Company Updates | |
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| September 5, 2017 | Ligand (San Diego, CA, USA) announced topline results from a Phase 2 study of the oral glucagon receptor antagonist LGD-6972 in type 2 diabetes (T2D). The 12-week trial (n = 166) found statistically significant HbA1c reductions for three doses of LGD-6972 versus placebo: the mean HbA1c drop was 0.9% for participants randomized to a 5-mg tablet once daily, 0.92% for those on 10 mg once daily, and 1.2% for those on 15 mg once daily, compared with 0.15% for patients on placebo (P < 0.0001 for all comparisons). The change in primary endpoint (HbA1c) was dose dependent, and the agent was well tolerated at all doses. No treatment-related serious adverse events occurred during the course of the trial, nor did investigators observe any dose-dependent changes in lipids, body weight, or blood pressure. |
| September 6, 2017 | With support from the Juvenile Diabetes Research Foundation (JDRF; Wellesley, MA, USA), Biocon (Bangalore, India) announced that it will initiate a two-part clinical trial of oral insulin candidate Insulin Tregopil in adults with T1D. The open-label study (estimated enrollment 70, across several centers in Europe) will assess multiple ascending doses of Insulin Tregopil to determine an optimal dose, and will then compare pharmacokinetic, pharmacodynamic, and safety and tolerability profiles for the agent versus Novo Nordisk's (Copenhagen, Denmark) NovoRapid (insulin aspart). The collaboration is part of JDRF's Industry Discovery and Development Partnership program, through which the organization provides financial support to accelerate breakthrough T1D research, although no details have yet been shared on specific funding amount allocated to Biocon. Previously, Bioncon has released positive Phase 1 data on Insulin Tregopil, which demonstrated more rapid onset and more rapid offset versus NovoRapid. |
| September 20, 2017 | Lilly's (Indianapolis, IN, USA) Humalog (insulin lispro) Junior KwikPen, approved by the US Food and Drug Administration (FDA) in June 2017, began shipping to distributors to become available in US pharmacies in early October. The Junior KwikPen contains 3 mL meal-time insulin lispro and allows for half-unit dosing, which can be useful for pediatric patients who may require lower insulin doses, or for any patients with higher insulin sensitivity. The new pen can dose up to 30 units per injection. In addition to finer dose adjustments, the Junior KwikPen is lighter and smaller than other half-unit insulin pens, including Novo Nordisk's NovoPen Junior for rapid-acting insulin aspart, launched in January 2003. Lilly's Junior KwikPen will be available in five-count cartons, and Becton Dickinson (Franklin Lakes, NJ, USA) pen needles are recommended. The new pen has also been filed with the European Medicines Agency (EMA), and awaits a regulatory decision for the European market. |
| September 25, 2017 | Boehringer Ingelheim (BI; Ingelheim, Germany) announced a collaboration with Geisinger Health (Danville, PA, USA) to develop a risk-prediction model for cardiovascular death, kidney failure, and hospitalization for heart failure in people with T2D. The project is part of BI's diabetes alliance with Lilly, and will use Geisinger's database of de-identified electronic health records (encompassing demographics, vital signs, medical history, current medications, and laboratory test results) to identify patients in the highest-risk tier for these diabetes complications. The companies aim to create a provider-facing tool that predicts an individual's risk of developing these adverse outcomes and helps guide more precise treatment decisions. The model is expected to be ready in the fourth quarter of 2017, with presentations at scientific meetings in early 2018 and a subsequent manuscript. |
| September 25, 2017 | Daiichi Sankyo (Tokyo, Japan) initiated a Phase 3 study of esaxerenone in patients with diabetic nephropathy in Japan. The study, ESAX-DN, will compare the oral mineralocorticoid (aldosterone) receptor antagonist versus placebo, with a primary endpoint of rate of remission to normoalbuminuria after 52 weeks. The company plans to enroll 400 patients with T2D and microalbuminuria who are taking an angiotensin II receptor blocker (ARB) or an angiotensin-converting enzyme (ACE) inhibitor, across 130 sites. The trial is expected to complete in March 2021. Secondary endpoints include change rate in urinary albumin:creatinine ratio (UACR) and estimated glomerular filtration rate (eGFR). Currently, there are no targeted therapies available beyond standard blood pressure medications (ARB and ACE inhibitors). Esaxerenone works by blocking aldosterone agonism, which typically promotes sodium retention in the kidneys, increasing water retention, blood volume, and blood pressure. As such, its dysfunction can lead to cardiovascular and renal disease, and it is considered a mediator of organ damage. |
| September 27, 2017 | Intarcia (Boston, MA, USA) announced that the FDA has issued a Complete Response Letter (CRL) for ITCA 650, its implantable exenatide minipump providing continuous subcutaneous release of the glucagon-like peptide-1 (GLP-1) agonist. The company submitted a New Drug Application (NDA) in November 2016, and the NDA was accepted for active review in February 2017. According to Intarcia's announcement, management hopes to meet with the FDA soon to discuss next steps, but the content of the CRL suggests that no new pivotal trials or long-term activities will be necessary; however, the contents of the CRL are confidential and it is not known what part of the submission it pertains to. The submission covered not only the pharmaceutical agent itself, but also the novel delivery device (Intarcia's Medici platform technology, including the implantable minipump, components that confer high temperature stability, and placement and removal kits for the implantable). |
| September 29, 2017 | Novo Nordisk announced FDA approval of the next-generation meal-time insulin Fiasp (faster-acting insulin aspart). This regulatory decision comes following a Class II resubmission in March 2017. The FDA issued a CRL for the company's initial NDA last October, citing concerns with the immunogenicity and pharmacology assay for faster-acting insulin aspart. The US launch is scheduled for late December 2017 or the first quarter of 2018. Novo Nordisk plans to price Fiasp on par with NovoLog in the US. In the Phase 3 Onset program,4 Fiasp demonstrated superior HbA1c-lowering and improvements in postprandial glucose excursions than Novo Nordisk's NovoLog (insulin aspart) without increasing risk for hypoglycemia. Fiasp was approved by the EMA in January 2017, and has also launched in Canada with parity pricing to NovoLog. |
| October 2, 2017 | The FDA approved a label update for Mannkind's (Westlake Village, CA, USA) inhaled meal-time insulin Afrezza, reflecting the faster onset and faster offset of the product. The revised Afrezza label includes clinical trial data to show onset of insulin action within 12 min, peak effects within 35–45 min, and a return to baseline approximately 1.5 h after dosing with a 4-unit cartridge or approximately 3 h after dosing with a 12-unit cartridge. This reinforces the product's ultrarapid-acting nature. Faster onset reduces unpredictability around meals for people with diabetes, whereas faster offset lowers the hypoglycemia risk stemming from residual insulin in the bloodstream. |
| October 2, 2017 | Johnson & Johnson (New Brunswick, NJ, USA) announced that a Supplemental New Drug Application (sNDA) has been filed with the FDA, requesting a new cardiovascular indication for the SGLT-2 inhibitor Invokana (canagliflozin) and for fixed-dose combinations Invokamet (canagliflozin/metformin) and Invokamet XR (canagliflozin/metformin extended-release). This application was based on data from the Canagliflozin and Cardiovascular and Renal Events in Type 2 Diabetes (CANVAS) trial,5 which demonstrated a 14% risk reduction for three-point MACE (non-fatal MI, non-fatal stroke, or cardiovascular death) associated with canagliflozin versus placebo (P = 0.0158 for superiority). The company is seeking an indication for the reduced risk of major adverse cardiovascular events. Assuming a standard 10- to 12-month review period, a decision from the FDA is expected in the late third quarter or early fourth quarter of 2018. |
| October 4, 2017 | Novo Nordisk's next-generation basal insulin Tresiba (insulin degludec) has launched in Canada, following late-August approval by Health Canada. The product is the first insulin to be added to Canada's National Register of Innovative Drugs. As seen in the SWITCH6, 7 and DEVOTE8 trials, Tresiba produces a very flat pharmacokinetic and pharmacodynamic profile, allows for flexible dosing, and has lower hypoglycemia risk versus standard-of-care Lantus (Sanofi's [Paris France] insulin glargine). |
