American Heart Association Scientific Sessions 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.
American Heart Association Scientific Sessions 2018
The American Heart Association Scientific Sessions 2018 took place in Chicago, Illinois, from November 10 to 12. There, Dr Stephen Wiviott (Brigham and Women's Hospital, Boston, Massachusetts) presented full results from the Multicenter Trial to Evaluate the Effect of Dapagliflozin on the Incidence of Cardiovascular Events (DECLARE-TIMI58) trial.1 AstraZeneca's (Cambridge, UK) sodium-glucose cotransporter 2 (SGLT2) inhibitor Farxiga (dapagliflozin) reduced risk for the coprimary endpoint of hospitalization for heart failure/cardiovascular (CV) death by 17% vs placebo (hazard ratio [HR] 0.83; 95% confidence interval [CI] 0.73-0.95; P = 0.005 for superiority), making it the first SGLT2 inhibitor to demonstrate a significant risk reduction on heart failure. Dapagliflozin was non-inferior to placebo on three-point major adverse cardiac events (MACE [the other coprimary endpoint]; CV death, non-fatal myocardial infarction (MI), non-fatal stroke), although results trended in favor of the SGLT2 inhibitor (HR 0.93; 95% CI 0.84-1.03; P < 0.001 for non-inferiority, P = 0.17 for superiority). DECLARE is unlike any other SGLT2 inhibitor CV outcomes trial to date and carries significant implications for the class and for patients, because it enrolled a majority of participants without baseline CV disease and included hospitalization for heart failure in a primary endpoint. Benefit on hospitalization for heart failure and CV death was virtually identical in the primary and secondary prevention cohorts: the HRs for the composite were nearly the same in the primary (HR 0.83; 95% CI 0.71-0.98) and secondary (HR 0.84; 95% CI 0.67-1.04) prevention groups (the latter narrowly crossed unity, although these analyses were not powered for superiority).
In commenting on DECLARE, Dr Javed Butler (Stony Brook University, Stony Brook, New York) asserted that SGLT2 inhibitors should be used in people with type 2 diabetes (T2D) to reduce heart failure risk, regardless of their effect on the classic three-point MACE. Supporting this claim was compelling data from a recent Swedish cohort study.2 Controlling HbA1c, smoking, low-density lipoprotein cholesterol (LDL-C), blood pressure, and albuminuria attenuated risk for MI (HR 0.84; 95% CI 0.75-0.93) and, non-significantly, stroke (HR 0.95; 95% CI 0.84-1.07) relative to matched controls without diabetes. However, the HR for heart failure hospitalizations remained elevated (HR 1.45; 95% CI 1.34-1.57), even after managing these other risk factors, suggesting that T2D confers heart failure risk independent of HbA1c, smoking, LDL-C, blood pressure, and albuminuria. Moreover, once patients with T2D develop heart failure, their mortality risk skyrockets and fewer than 10% survive after 5 years, compared with approximately 80% of those with T2D without heart failure.2 With this in mind, Dr Butler stated that any therapy indicated for improving heart failure outcomes should be a welcome addition to the diabetes care armamentarium.
Dr Subodh Verma (University of Toronto, Toronto, Canada) presented primary results from the EMPA-HEART CardioLink-6 Trial demonstrating that SGLT2 inhibitor Jardiance (empagliflozin) significantly reduced left ventricular mass (LVM) in patients (n = 97) with T2D and established coronary artery disease. Dr Verma explained that results from EMPA-HEART indicate that empagliflozin treatment may promote reverse remodeling of the heart, contributing to observed CV benefits. In the trial, 97 patients between 40 and 80 years of age with a history of T2D and established, well-treated coronary artery disease (CAD) were randomized to either once-daily 10 mg empagliflozin or placebo and tracked for 6 months. For the primary outcome of LVM, patients were assessed by cardiac magnetic resonance imaging (MRI), which is considered the “gold standard” for this endpoint; further, LVM is thought to be a strong predictor of CV outcomes. On this primary endpoint, empagliflozin treatment was associated with a significant reduction in LVM from baseline, reducing LVM by 2.6 g/m2, compared with a reduction of 0.01 g/m2 with placebo. The adjusted mean difference between groups was −3.35 g/m2 (95% CI −5.9, −0.81; P = 0.01). This result remained statistically significant even after conducting sensitivity regression analyses over height and weight.
American Diabetes Association Summit on Therapeutic Inertia
In summarizing the discussions of the day, Dr Bill Polonsky (Behavioral Diabetes Institute, San Diego, California) pinpointed three broad areas of action: better support for physicians, better support for patients, and the need to dramatically fix the healthcare system.For years we have been going to more individualized approaches. What we've heard today is that we need to be more prescriptive. I find this challenging. I think that to address therapeutic inertia, you might be right. We might need to be more forceful, especially after years of doing the opposite of being more individualized.
American Diabetes Association Symposium: Use of Real-World Data to Improve the Prevention and Care of Diabetes-Related Outcomes
The ADA hosted a symposium on the use of real-world data to improve the prevention and care of diabetes-related outcomes in Washington, DC, from November 16 to 18. There, Dr Peter Stein (Deputy Director of the Food and Drug Administration's Center for Drug Evaluation and Research, Office of New Drugs, Washington, DC) provided a reserved perspective on the use of real-world data (RWD) and real-world evidence (RWE) in the drug regulatory landscape. Dr Stein emphasized that studies collecting RWD and RWE ask fundamentally different questions than randomized control trials (RCTs): namely, effectiveness vs efficacy. He cited several benefits to RWD, including: (a) analysis over a much broader and more diverse patient experience, (b) massive sample sizes that may reveal infrequent events and drug-drug interactions, and (c) lower resource intensity. In fact, Dr Stein believes RWD elements can be incorporated over the entire spectrum of drug development, from informing site selection and trial feasibility in RCTs to supplementing pragmatic RCTs with claims and electronic health record data.
Dr Kasia Lipska (Yale University, New Haven, Connecticut) highlighted a major challenge in hypoglycemia surveillance, which is that the reliance on healthcare utilization records makes systems miss approximately 95% of severe hypoglycemia events that are treated outside the medical system. A recent study (n = 13 359) on this topic found that although 11.7% of participants self-reported a severe hypoglycemia episode, only 0.8% of those individuals visited an emergency department or hospital.3 Interestingly, 20% of the participants who made it to the emergency department or hospital for hypoglycemia did not self-report an event, which suggests that patient or caregiver reporting of hypoglycemia requiring assistance is not completely reliable. In Dr Lipska's estimate, only approximately 5% of severe hypoglycemia requiring assistance shows up in an emergency department. Between 27% and 87% of people with diabetes who call emergency medical services for hypoglycemia are transported to a hospital emergency department. Dr Lipska attributed the wide variability to different state and county protocols for how emergency medical technicians should respond to hypoglycemia in the field.
Referenes
| Company updates | |
|---|---|
| 19 November 2018: | vTv Therapeutics (High Point, North Carolina) announced that interim results for its Phase 1/2 SimpliciT-1 study (n = 126) for hepatoselective glucokinase activator TTP399 as add-on to insulin are projected to be released in early 2019. |
| 19 November 2018: | Ligand Pharmaceuticals (San Diego, California) announced that partner Roivant (New York City, New York) plans to initiate proof-of-concept studies for glucagon receptor antagonist RVT-1502 in type 1 diabetes (T1D) before the end of the year. |
| 19 November 2018: | AstraZeneca presented at the American Society of Nephrology 2018 meeting a post-hoc analysis of pooled, 52-week data from Dapagliflozin Evaluation in Patients With Inadequately Controlled Type 1 Diabetes (DEPICT-1 and DEPICT-2) for SGLT2 inhibitor Farxiga (dapagliflozin) in T1D, demonstrating a dose-dependent reduction in urinary albumin: creatinine ratio (UACR) in patients with albuminuria at baseline (n = 251; defined as UACR ≥30 mg/g). At Week 52, the difference in UACR with dapagliflozin 10 mg vs placebo was −31.1% (95% CI −49.9%, −5.2%), whereas the difference with dapagliflozin 5 mg was −13.3% (95% CI −37.2%, 19.8%). The difference in UACR between dapagliflozin 10 mg and placebo was significant from Week 18 to Week 52. |
| 20 November 2018: | Mylan (Canonsburg, Pennsylvania) and Biocon (Bangalore, India) announced the launch of biosimilar insulin glargine Semglee in the UK, marking the first European launch of the product. Semglee is the second biosimilar glargine to reach the market in the UK, after Eli Lilly (Indianapolis, Indiana) and Boehringer Ingelheim's (Ingelheim am Rhein, Germany) Basaglar. |
| 23 November 2018: | Novo Nordisk (Bagsværd, Denmark) announced topline results from the Trial Investigating the Cardiovascular Safety of Oral Semaglutide in Subjects with Type 2 Diabetes (PIONEER 6; n = 3183) for Phase 3 oral semaglutide, demonstrating non-inferiority to placebo on three-point MACE and establishing CV safety for oral semaglutide. A non-significant 21% relative risk reduction (HR 0.79) was achieved on three-point MACE; however, no 95% CI or P-value was given. Novo Nordisk did provide individual MACE results, revealing that this trend was driven by a 51% risk reduction on CV death (HR 0.49; P = 0.03). However, non-fatal MI trended towards placebo (HR 1.18; NS), whereas non-fatal stroke trended towards oral semaglutide (HR 0.74; NS). Oral semaglutide was associated with a significant but statistically exploratory 49% reduction on all-cause mortality (HR 0.51; P = 0.008). |
| 23 November 2018: | Novo Nordisk announced results from the Dose-response, Safety and Efficacy of Oral Semaglutide vs Placebo and vs Liraglutide, All as Monotherapy in Japanese Subjects with Type 2 Diabetes (PIONEER 9) trial, examining oral semaglutide vs liraglutide in Japanese patients. PIONEER 9 randomized 243 people with T2D equally to 3, 7, or 14 mg oral semaglutide, liraglutide 0.9 mg, or placebo. On the primary endpoint of change in HbA1c at Week 26, all three doses achieved significant reductions from a baseline of 8.2%: HbA1c fell by 1.1%, 1.5%, and 1.7% with 3, 7, and 14 mg semaglutide, respectively, compared with a 0.1% fall with placebo. The 14-mg dose was also superior to liraglutide, which resulted in a 1.4% drop in HbA1c. These improvements were largely sustained at 52 weeks, when HbA1c reductions were 0.9%, 1.3%, and 1.5% from placebo for 3, 7, and 14 mg semaglutide, respectively, compared with a 0.5% increase with placebo and a 1.1% reduction with liraglutide. |
| 27 November 2018: | Zafgen (Boston, Massachusetts) announced that the US Food and Drug Administration (FDA) has placed a clinical hold on the company's Investigational New Drug (IND) application for injectable methionine aminopeptidase 2 (METAP2) inhibitor ZGN-1060 for T2D. The FDA cited potential CV risk based on Zafgen's prior METAP2 inhibitor beloranib, which was discontinued in 2016 due to two thrombosis-related deaths in a Phase 3 trial. |
| 30 November 2018: | ViaCyte (San Diego, California) announced securement of a US$80 million round of Series D financing led by Bain Capital Life Sciences (New York City, New York). ViaCyte has now raised US$105 million in the second half of 2018 to advance its pipeline of stem cell-based β-cell replacement therapies for insulin-requiring diabetes. |
| 30 November 2018: | Lexicon Pharmaceuticals (The Woodlands, Texas) announced that the FDA will convene an Advisory Committee on January 17, 2019, to review the Sanofi-partnered SGLT1/2 dual inhibitor sotagliflozin for adults with T1D. The New Drug Application for sotagliflozin was first submitted to the FDA by Sanofi (Paris, France) in March 2018 and was accepted for review in May 2018. The FDA's target decision date remains 22 March 2019. |
